Prevention of loss and restoration of bone mass by certain prostaglandin agonists

Preventing loss and restoring bone mass with prostaglandin agonists

Certain

Hello full description

Background of the invention

This application is a partial application of Application No. 97180721 filed in the office on 08/21/1418 AH corresponding to 12/21/1997 AD.

This invention relates to prostaglandin agonists, to drug compositions containing these agonists and to the use of these agonists to prevent bone loss or restore or increase bone mass, including the treatment of conditions that show low bone mass in mammals - humans.

Osteoporosis is a general skeletal disease, characterized by osteopenia and deterioration of bone tissue, with a concomitant increase in bone fragility and susceptibility to fractures. In the United States, the condition affects more than 25 million people and causes more than 1.3 million fractures each year, including 500,000 vertebral fractures.

250000 His thighs, 240,000 wrists each year. Femoral fractures are the most common fragility complication

Bones are dangerous, such that 5-02% of patients die within a year; More than 50% of those living are physically disabled. Older people are more susceptible to osteoporosis, so the problem is predicted to increase more strongly as people age. The global fracture incidence threatens to triple over the next 60 years, and one study indicated that there will be 4.5 million femoral fractures in 2050. Women are more susceptible to osteoporosis than men. Women experience a sharp acceleration of bone loss in the following five years after menopause. Other factors that increase the risk include smoking, alcoholism, and lifestyle. Static and lack of calcium intake.

There are two main types of drug therapy used to treat osteoporosis. The first is the use of anti-resorptive compounds to reduce bone tissue absorption.

Estrogen is an example of an antiresorptive agent. Estrogen is known to reduce fractures. In addition, Black et al have determined in EP 0605193A1 that estrogen, especially when administered orally, reduces plasma LDL levels and raises those of bound high-density lipoproteins (HDL's). However, estrogen fails to restore bone back to young adult levels in a fragile bone structure. In addition, estrogen therapy is long-term, however

However, it is involved in a variety of diseases, including an increased risk of uterine cancer, endometrial cancer and possibly breast cancer, which makes many women avoid this treatment. The significant undesirable effects associated with estrogen therapy support the need to find alternative treatments for osteoporosis that have the desired effect on plasma LDL but do not induce undesirable effects.

A second type of drug therapy to treat osteoporosis is the use of anabolic agents to induce bone formation and increase bone mass. This class of agents is expected to restore bone to the existing fragile bone structure.

US Patent No. 12,236 41 explains

interhenylene 8-aza-9-dioxohia-l,12-secoprostaglandins

In order to treat patients with kidney damage.

Certain prostaglandin antagonists are described in GB 1,478,281, GB 1,479,156 and US Patent Nos. 4,675,203, 4,055,596, 4,175,203, 3,987,096, and 3,996,106 so that they are useful, for example, as renal vasodilators. US Patent No. 4,033,996 explains

8-aza-9-oXo(and dioxo)-thia-11,12-secoprostaglandins

Certain drugs are useful as dilators of renal blood vessels, to prevent clot formation, to increase the release of growth hormone, and as regulators of the immune response.

French patent No. 897566 describes certain amino acid derivatives for the treatment of neurological, mental or cardiovascular disease. (1437;1961;26.Org. Chem J) explains

N-acetyl-N-benzyl-p-aminophenylmercaptoacetic acid

In addition to osteoporosis, approximately 20-25 million women and an increasing number of men suffer from visible vertebral fractures as a result of low bone mass, in addition to 250,000 femoral fractures recorded annually in America alone. The latter case is accompanied by a mortality rate of 2.1% within the first two years, and an average of 30% of patients require home exposure care after fracture. While this is indeed remarkable, the economic and downtime consequences of a slow or incomplete healing of these fractures are significant.

Bone bones are expected to increase, as a result of the increasing age of the general population. While there are several promising treatments (bis-phosphonates, etc.) in development to prevent bone loss with aging and thus reduce the possibility of disabling non-healing fractures, these treatments are not used to restore bone mass once a fracture has occurred. showed estrogens, see:

(Bolander et al., 1992, 38th Annual Meeting Orthopedic Research Society)

They improve the quality of healing of appendicular fractures. Therefore, estrogen replacement therapy appears to be an approach to treat fracture healing. However, patients undergoing estrogen therapy are relatively infrequent due to side effects, including return of menstruation, breast tenderness, increased risk of endometrial cancer, increased perceived risk of breast cancer, and concomitant use of progestins. In addition, men are more likely to use estrogen therapy. Clearly there is a need for treatment that benefits patients with disabling bone fractures or who have low bone mass and which will increase patient compliance.

Although there are various treatments for osteoporosis, there is still a constant need and ongoing research in this art for alternative osteoporosis treatments. In addition, there is a need for bone fracture healing treatments. General description of the invention

This invention relates to a compound of formula I:

<img file="SA2048B1_D0001.tif" />

or a pharmaceutically acceptable salt or prodrug, where either (1): B is N;

A is (C3-C7cycloalkylsulfonyl), (C1-C6)alkylsulfonyl

C3-C7) cycloalkyi(C1-C6)alkylsulfonyl), the aforementioned A parts are mono-substituted,

double or triple on the carbon individually with C1-C4 (alkyl, hydroxy) or halo; Q is:

-,-C2-C6)alkylene-W-(C1-C3)alkylene)

-C3-C8)alkylene)-, optionally replacing the aforementioned -C3-C8)alkylene) with up to four individually selected fluoro or C1-C4)alkyl substituents,

X-(C1-C5)alkylene--,

,-(C1-C5)alkylene-X-

,-(C1-C3)alkylene-X-(C1-C3)alkylene-

C3)alkylene--,-(C2-C4)alkylene-WX-(C0

-,-(C0-C4)alkylene-XW-(C1-C3)alkylene

-C2-C5)alkylene-WXW-(C1-C3)alkylene)-, since the two states of W are independent of each other,

C1-C4)alkylene-ethenylene-(C1-C4)alkylene-)-, C5)alkylene--C2)alkylene-X-(C0-,-(C1-C4)alkylene-ethenylene-(C0 C2)alkylene-XW -(C1-C3)alkylene-,-(C1-C4)alkylene-ehenylene-(C0 -,-(C1-C4)alkylene-ehynylene-(C1-C4)alkylene C3)alkylene-or-C1-C4)alkylene -ethylene-X-(C0)-; w is aminosulfonyl-,sulfonyl,sulfino,thio,oxy,,sulfonylamino,-mono-N-(C1-C4)alkyleneaminosulfonyl-,N-(C1-C4)alkylenecarboxamido,carboxamido,N-(C1-C4)alkylenesulfonylamino,carbamoyl ,N-(C1-C4)alkylenecarboxamidooxy -carboxamidooxy carbamoyloxy, -mono-N-(C1-C4)alkylenecarbamoyl, or mono-N-(C1-C4)alkylenecarbamoyloxy-, wherein said w alkyl groups on the carbon are optionally replaced with one to three fluorine atoms;

The The said ring is optionally single- or double-substituted separately with halo.

hydroxyl, difluoromethyloxy, trifluoromethyloxy, trifluoromethyl, (C1-C3)alkyl, C1-C4alkoxy), or carbamoyl;

z is,1,2,4-oxadiazolyl,tetrazolyl,C1-C6)alkoxycarbonyl,carboxyl C1-C4)alkylsulfonylcarbamoyl,5-oxo-l,2,4-oxadiazolyl) or phenylsulfonylcarbamoyl;

K is the C1-C8)alkylene bond; thio(C1-C4)alkylene or oxy(C1-C4)alkylene, the said being optionally monounsaturated and where K is optionally mono-, di- or tri-substituted separately with methyl, fluoro or chloro;

M is Ar1-S-Ar2,-Ar1-V-Ar2'-Ar- or Ar1-o-Ar2-, where Ar2 and Ar1 are each a partially saturated, fully saturated or completely unsaturated ring with optionally five to eight members. It has one to four individually selected heteroatoms of oxygen, sulfur and nitrogen, or, a bicyclic ring consisting of two joined rings of partially saturated, completely saturated or completely unsaturated nat five or six members, taken separately; Optionally they have one to four individually selected heteroatoms of nitrogen, sulfur and oxygen; The parts of Ar2 and Ar1 are Ar The above are optionally substituted, on one ring if the part is monocyclic, or one or both rings if the part is bicyclic, on a carbon with up to three

Separately selected substituents of r3, r2, r1 where r3, r2, r1 are nitro, hydroxy' C1-C6 alkoxy, halo, C1-C4)alkoxy(C1-C4)alkyl), C1-C4)alkoxycarbonyl),

)C3-C4)alkyl, (C3-C7)cycloalkyl(C1-C4)alkyl), C3-C7)cycloalkyl(C1-C4)alkanoyl), '(C1-C8)alkanoyl 'formyl' (C1-C4)alkanoylamino '(C1-C6)alkanoyl(C1-C6)alkyl C1-C4)alkoxycarbonylamino), sulfonamido, C1-C4)alkylsulfonamido), amino, mono-N- or di-N,N-(C1-C4)alkylamino, carbamoyl , cyano, mono-N- ordi-N,N-(Ci-C4)alkylcarbamoyl, thiol, alkylthio(C1-C6), C1-C4)alkylsulfonyl'(C1-C6)alkylsulfinyl) or mono-N- or di- N,N-(C1-C4)alkylaminosulfinyl;

(r3, r2, r1 are optionally mono-, di- or triple-substituted on each carbon individually with a halo or hydroxy; and

V is a C1-C3)alkylene bond or optionally mono- or di-substituted with a hydroxy or fluoro;

Provided that when K is M, (C2-C4)alkylene is Ar, and Ar is cyclohept-l-yl, cyclohex-l-yl, cyclopent-l-yl or cyclooct-l-yl then the C5-C8)cycloalkyl substituents are not substituted. At the one position with hydroxy;

Or (2):

B is N;

alkanoyl, (C1-C6)alkanoyl is A(C3-C7)cycloalkyl(C1-C6), the aforementioned A parts being optionally mono-, di- or tri-substituted on the carbon individually with a hydroxy or halo; Q is:

-,-(C2-C6)alkylene-W-(C1-C3)alkylene

C4-Cg)alkylene-)-, optionally replace the aforementioned -C4-Cg)alkylene)- with up to four individually selected fluoro or C1-C4)alkyl), alkylene-(5X-(C1-C-), , -(C1-C5)alkylene-X-,-(C1-C3)alkylene-X-(C1-C3)alkylene-C3)alkylene--,-(C2-C4)alkylene-WX-(C0 -C3)alkylene -C4)alkylene-XW-(C0-,-(C1

-alkylene-WXW-(C1-C3)alkylene(5C2-C)-, where the two W states are independent of

each other,

C1-C4)alkylene-ethenylene-(C1-C4)alkylene-)-, C2)alkylene-X-(C0-C5)alkylene--,-(C1-C4)alkylene-ehenylene-(C0 C2)alkylene-XW -(C1-C3)alkylene--,-(C1-C4)alkylene-ethylene-(C0 -,-(C1-C4)alkylene-ethynylene-(C1-C4)alkylene or -C3)alkylene-C1-C4) alkylene-ethynylene-X-(C0)-; w is aminosulfonyl-,sulfonyl,sulfino,thio,oxy,sulfonylamino,-mono-N-(C1-C4)alkyleneaminosulfonyl-

N-(C1-C4)alkylenecarboxamido, carboxamido, N-(C1-C4)alkylenesulfonylamino, carbamoyl, N-(C1-C4)alkylenecarboxamidooxy, carboxamidooxy

mono-N-(C1-C4)alkylenecarbamoyl-, carbamoloxy, or

mono-N-(C1-C4)alkylenecarbamoyloxy-, wherein said w alkyl groups on the carbon are optionally replaced with one to three fluorines; X is a five- or optionally six-membered aromatic ring having one or two individually selected heteroatoms of oxygens; Nitrogen, sulfur; Said ring is optionally mono- or di-substituted separately with trifluoromethyl, (C1-C3)alkyl, halo, C1-C4alkoxy, hydroxyl 'difluoromethyloxy' (trifluoromethyloxy)' or carbamoyl; Z is carboxyl, 1,2,4-oxadiazolyl, tetrazolyl, (C1-C6)alkoxycarbonyl. C1-C4)alkylsulfonylcarbamoyl,5-oxo-l,2,4-oxadiazolyl) or phenylsulfonylcarbamoyl;

thio(C1-C4)alkylene, (C1-C8)alkylene is K or oxy(C1-C4)alkylene, the aforementioned C1-C8)alkylene being optionally monounsaturated and where K is optionally mono-, di- or tri-substituted separately with methyl, fluoro or chloro;

M is V-Ar2, -Ar-Ar1-S-Ar2, -Ar1- or Ar1-O-Ar2-, where Ar2, Ar1, and Ar are each a partially saturated, fully saturated, or fully unsaturated ring with five to eight members. Optionally having one to four separately selected heteroatoms of oxygen, sulfur and nitrogen, or, a bicyclic ring consisting of two joined partially saturated, fully saturated or completely unsaturated rings with five or six members, taken separately, optionally having one to four heteroatoms. Separately selected nitrogen, sulfur and oxygen;

The said parts of Ar2, Ar1, and Ar are optionally substituted, on one ring if the part is monocyclic, or one or both rings if the part is bicyclic, on carbon with up to three individually selected substitutions of R1, R3, and R2, where R3 and R2 are, R1 are H'

C1-C6alkoxy, halo, nitro, hydroxy), (C1-C4) alkoxy(C1-C4)alkyl,

, (C3-C7)cycloalkyl, (C1-C7)alkyl, (C1-C4)alkoxycarbonyl

,formyl,(C3-C7)cycloalkyl(C1-C4)alkanoyl,(C3-C7)cycloalkyl(C1-C4)alkyl C1-C8)alkanoyl),(alkanoyl(C1-C6)alkyl(,(C1-C4) alkanoylamino, (C1-C6)alkylsulfonamido, (C1-C4)alkoxycarbonylamino

C4)alkylamino,amino,mono-N-or di-N,N-(C1,,thiol,cyano,mono-N-or di-N,N-(C1-C4)alkylcarbamoyl,carbamoyl C1-C6)alkylsulfinyl, (C1-C6)alkylthio), (C1-C4)alkylsulfonyl, or

mono-N- or di-N,N-(C1-C4)alkylaminosulfinyl;

R3, R2 and R1 are optionally single-, di- or triple-substituted on each carbon individually with a halo or hydroxy; And

V is a C1- C3)alkylene bond optionally mono- or di-substituted with a hydroxy or fluoro;

Provided that when K is and M is (C2-C4)alkylene (C2-C4)alkylene is Ar and Ar is cyclopent-1-yl,

cyclohept-l-yl, cyclohex-l-yl or cyclooct-l-yl then the (C5-C5) substituents do not replace the cycloalkyl at the one position with the hydroxy;

Provided that 6-[(3-phenyl-propyl)-(2-propyl-pentanoyl)-amino]-hexanoic acid and its ethyl ester are not included.

Or (3):

B is C(H);

A is C3-C7)cydoalkyl(C1-C6)alkanoyl, (C1-C6)alkanoyl), the parts of A mentioned are

Optionally mono-, di- or triple-substituted on the carbon individually with a hydroxy or halo; Q is:

-,-(C2-C6)alkylene-W-(C1-C3)alkylene

C4-C8)alkylene-), optionally replacing -C4-C8)alkylene- with up to four individually selected fluoro or C1-C4)alkyl substituents, X-(C1-C5)alkylene--,,_ (C1-C5)alkylene-X-,-(C1-C3)alkylene-X-(C1-C3)alkylene-C3)alkylene--,-(C2-C4)alkylene-WX-(C0 -C4)alkylene- XW-(C1-C3)alkylene-,-(C0

(C2-C5)alkylene WXW -(C1-C3)alkylene)-, where the two W states are independent of

each other,

C1-C4)alkylene-ehenylene-(C1-C4)alkylene-)-, C2)alkylene-X-(C0-C5)alkylene--,-(C1-C4)alkylene-ethenylene-(C0 C2)alkylene-XW -(C1-C3)alkylene--,-(C1-C4)alkylene-ethylene-(C0 -,-(C1-C4)alkylene-ethynylene-(C1-C4)alkylene or-C1-C4)alkylene-ethynylene- X-(C0-C3)alkylene-)-; w is aminosulfonyl-,sulfonyl,sulfino,thio,oxy,sulfonyIamino,-mono-N-(C1-C4)alkyleneaminosulfonyl-

N-(C1-C4)alkylenesulfonylamino,N-(C1-C4)alkylenecarboxamido,carboxamido,

,carbamoyl,N(C1-C4)alkylenecarboxamidooxy,carboxamidooxy carbamoyloxy,-mono-N-(C1-C4)alkylenecarbamoyl, or

-mono-N-(C1-C4)alkylenecarbamoyloxy, where the aforementioned W alkyl groups on the carbon are optionally replaced with one to three fluorines;

The Said ring is optionally mono- or di-substituted separately with trifluoromethyl, (C1-C3)alkyl, halo, C1-C4)alkoxy, hydroxyl, difluoromethyloxy, trifluoromethyloxy), or carbamoyl; Z is,1,2,4-oxadiazolyl,tetrazolyl,(Ci-C6)alkoxycarbonyl,carboxyl C1-C4)alkylsulfonylcabamoyl,5-oxo-l,2,4-oxadiazolyl) or phenylsulfonylcarbamoyl;

K is a bond, thio(C1-C4)alkylene, (C1-C8)alkylene C4-C7)cycloalkyl(C1-C6)alkylene) or oxy(C1-C4)alkylene, the aforementioned (C1-C8)alkylene is optionally not Mono-saturated and where K is optionally mono- or tri-substituted individually with methyl, fluoro or chloro;

M is V-Ar2, -Ar-Ar1-S-Ar2, -Ar1- or Ar1-O-Ar2-, where Ar2 and Ar1, Ar, are each a partially saturated, fully saturated, or completely unsaturated ring with five to eight members.

Optionally, it has one to four separately selected heteroatoms of oxygen, sulfur, and nitrogen, or, a bicyclic ring consisting of two joined rings that are partially saturated, completely saturated, or completely unsaturated, with five or six members, taken separately, and optionally have one to four heteroatoms. Separately selected nitrogen, sulfur and oxygen;

The said parts of Ar1, Ar and Ar2 are optionally substituted, on one ring if the part is monocyclic, or one or both rings if the part is bicyclic, on carbon with up to three separately selected substitutions of R3, R2, R1, where R3 and R2 are R1 are halo, nitro, hydroxy, H, alkoxy (C1-C4) alkyl, (C1-C6)alkoxy (C1-C4)

C1-C7) alkyl, (C1- C4)alkoxycarbonyl), (C3-C7)cycloalkyl),

(C3-C7)cycl0alkyl(C1-C4)alkan0yl,(C3-C7)cycl0alkyl(C1-C4)alkyl (C1-C4)alkanoyamion,(C1-C6)alkanoyl(C1-C6)alkyl,(C1-C8) )alkanoyl,forml)

(C1-C4)alkylsulfonamido,sulfonamido,(C1-C4)alkoxycarbonylamino,carbamoyl,mono-N-ordi-N,N-(C1-C4)alkylamino,amino thiol,cyano,mono-N-or di-N, N-(C1-C4)alkylcarbamoyl, )(C1-C6 alkylthio,

C1-C4)alkylsulfonyl, (C1-C6)alkylsulfinyl) or mono-N- or di-N,N-(C1-C4)alkylaminosulfinyl;

R2, R1 and 3R are optionally single-, di- or triple-substituted on each carbon individually with a halo or hydroxy; And

V is a C1- C3)alkylene bond optionally mono- or di-substituted with a hydroxy or fluoro;

Provided that when K is C2-C4 (M) and Ar is cyclopent-l-yl,

cyclohept-l-yl, cyclohex-l-yl or cyclooct-l-yl, then the C5-C8 (cycloalkyl) substituents at one position are not replaced with the hydroxy.

A preferred group of compounds, denoted group A, contains such compounds having the formula I as shown above where: B is N;

A is C3-C6)cycloalkylsulfonyl, (C1-C6)alkylsulfonyl) or

(C3-C6) cycloalkyl(C1-C6) alkylsulfonyl The parts of A mentioned in the information are mono-substituted,

doublet or triplet on carbon with fluoro;

X is Thienyl, Phenyl, or Thiazolyl, Thienyl, Phenyl or Thiazolyl mentioned news, replaced by unilateral or bilaterally replaced separately with -, Chloro, Fluoro Difluoromethoxy, Methoxy or Trifluoromethoxy; w is thio,oxy or sulfonyl; z is C1- C4)alkoxycarbonyl,carboxyl) or tetrazolyl;

K is methylene or ethylene;

Ar2, Ar1, Ar are each individually thienyl, phenyl, (C5-C7)cycloalkyl pyrazinyl, isoxazolyl, imidazolyl, furanyl, oxazolyl, pyrimidyl, pyridyl, thiazolyl or pyrazolyl;

1R is C6)alkoxy, halo-1CsOcycloalkyl, (C1-C7)alkyl, (C), or C3-C7)cycloalkyl(C,-C4)alkyl), which is C1-C7)alkyl, (C1-C6)alkoxy) , the aforementioned C3-C7)cydoalkyl or C4)alkyl-1C3-C7)cydoalkyl(C) mono-, di- or tri-substituted individually with a fluoro, hydroxy or chloro; And

R3 and R2 are difluoromethoxy, methoxy, methyl, fluoro, chloro, trifluoromethoxy or trifluoromethyl.

A group of preferred compounds from among the compounds of group A denotes group B. It contains these compounds, where:

A is C1-C3)alkylsulfonyl);

Q is:

_,-(C2-C6)alkylene-W-(C1-C3)alkylene

(C4-C8) alkylene-, optionally replace the aforementioned alkylene(C4-C8) with up to four substitutions

Individually selected fluoro or C1-C4 alkyl,

X-(C2-C5)alkylene--,

-,-C1-5alkylene-X)

-C1-C3)alkylene-X-(C1-C3)alkylene)-, -C3)alkylene-C2-C4)alkylene-WX-(C0)-, or C4)alkylene-XW-(C1-C3)alkylene- -C0)-;

M is V-Ar2-1Ar- or Ar1-O-Ar2- where Ar2 and Ar1 are individually phenyl pyridyl or thienyl;

V is a bond or C1-C2)alkylene);

1R is C1-C4)alkyl, fluoro, chloro) or C1-C4)alkoxy, which is C1-C4)alkyl.

- The aforementioned alkoxy and (C1-C4alkoxy) are optionally mono-, di- or tri-substituted separately with the hydroxy.

or fluoro; And

R3 and R2 are each individually chloro or fluoro.

Particularly favored compounds among group B compounds are: 7-[(2'-Hydroxymethyl-biphenyl-4-ylmethyl)-methanesulfonyl-amino]-heptanoic

acid;

7-{[4-(3-Hydroxymethyl-thiophen-2-yl)-benzyl]-methanesulfonyl-amino}-

heptanoic acid, and

7-[(2'-Chloro-biphenyl-4-ylmethyl)-methanesulfonyl-amino]-heptanoic acid Particularly favored compounds among group B compounds are compounds where:

(a) A is methylsulfonyl;

Q is n-hexylene;

Z is carboxyl;

K is methylene; And

M is 4-(2-hydroxymethylphenyl)phenyl;

(b) A is methylsulfonyl;

Q is n-hexylene;

Z is carboxyl;

K is methylene; And

M is 4-(2-hydroxymethylthien-2-yl)phenyl; And

(c) A is methylsulfonyl;

Q is n-hexylene; z is carboxyl;

K is methylene; The M is .4-(2-chlorophenyl)phenyl

A preferred group of compounds, denoted group C, contains such compounds having the formula I as shown above where: B is N;

A is, (C3-C6)cycloalkylsulfonyl, (C1- C6)alkylsulfonyl C3-C6)cycloalkyl(C1-C6)alkylsulfonyl);

X is thienyl, phenyl, or thiazolyl; w is thio,oxy or sulfonyl; z is C1-C4)alkoxycarbonyl,carboxyl) or tetrazolyl;

K is C1-C8)alkylene or oxy(C1-C4)alkylene, said C1-C8)alkylene being optionally monounsaturated and wherein K is optionally mono-, di- or tri-substituted individually with a fluoro, methyl or chloro;

M is Ar-, where said Ar- is,thiazolyl,pyridyl,thienyl,phenyl,benzo[b]thiophenyl,benzo[b]furanyl,naphthalenyl,isoxazolyl,oxazolyl,benzisoxazolyl,benzimidazolyl,benzo[l,3]dioxolyl, Furanyl, indanyl, pyrimidyl, pyrazolyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzo[l,4]dioxinyl, indolyl, benzothiazolyl, benzoxazolyl, isoquinolinyl, quinolinyl, imidazolyl cycloheptyl, cyclobutyl, cyclopentyl, cyclohexyl, 1,2 ,3 ,4-tetrahydronaphthalenyl or chromanyl;

R1 is C1-C7)alkanoyl, (C3-C7)cycloalkyl, (C1-C7)alkyl, (C1-C8)alkoxy, halo)

Or C3-C7)cycloalkyl(C1-C4)alkyl), it is (C1-C7)alkyl, (C1- C7)alkoxy.

) C3-C7)cycloalyl C3-C7)alkanoyl) or C3-C7)cycloalkyl(C1-C4)alkyl) mentioned

Optionally mono-, di- or tri-substituted individually with a fluoro, hydroxy or chloro; And R3 and R2, each of them separately, are C1-C7)alkyl, trifluoromethyl, halo, hydroxy), C5)alkanoyl-C3-C7)cycloalkyl, cyano' (C1),

trifluoromethoxy,difluoromethoxy,formyl,(C3-C7)cyloalyl(C1-C4)alkyl or

carbamoyl

It is particularly preferable for group C compounds that K should not optionally be mono-, di- or tri-substituted separately with a fluoro, methyl or chloro.

A group of compounds favored among the compounds of group C, denoted group D, contains such compounds where: K is methylene;

A is C1- C3)alkylsulfonyl);

M is Ar- and Ar- is furanyl, oxazolyl, thienyl, pyridyl, thiazolyl, phenyl, cyclopentyl or cyclohexyl where Ar- is replaced with at least 1R;

1R is C1-C7)alkyl or C1-C5)alkoxy, C1 is C7)alkyl or (C1-C5)alkoxy

The aforementioned are optionally mono-, di- or tri-substituted individually with a hydroxy or fluoro; And

R3 and R2, each of them separately, are difluoromethoxy, methyl, fluoro, and chloro; trifluoromethoxy or trifluoromethyl.

Particularly favorable compounds among Group D compounds are:

7-{[4-(l-Hydroxy-hexyl)-benzyl]-methanesulfonyl-amino]-heptanoic acid, 7-[(4-Butyl-benzyl)-methanesulfonyl-amino]-heptanoic acid, 7-{[5- (l-Hydroxy-hexyl)-thiophen-2-ylmethyl]-methanesulfonyl-amino}-heptanoic

acid, and

4-Butyl-benzyl)-methnesulfonyl-amino]-methyl}phenyl-acetic acid)];-3)

A group of compounds preferred among the compounds of group D, denoted by group E, contains these compounds where:

Q is -C2-C6)alkylene-W-(C1-C3)alkylene)-; And

w is oxy.

A group of compounds favored among the compounds of group D, denoted by group F, contains

On these vehicles where:

Q is -C3-C8)alkylene), optionally replace the mentioned -alkylene-(C3-C8) with one to

four .fluorines

Particularly favorable compounds among the compounds of group F are compounds where:

(a) A is methylsulfonyl;

Q is n-hexylene;

Z is caboxyl;

K is methylene; And

M is 4-(l-hydroxy-n-hexylene-l-yl)phenyl;

(b) A is methylsulfonyl;

Q is n-hexylene;

Z is carboxyl;

K is methylene; And M is 4-(n-butylene-l-yl)phenyl; and (c) A is methylsulfonyl;

Q is n-hexylene;

Z is carboxyl;

K is methylene; And

M is .5-(l-hydroxy-n-hexylene-1-yl)thien-2-yl

A group of compounds preferred among the compounds of group D, denoted by group G, contains these compounds where:

Q is -X-(C1-C5)alkylene_; And

X is thienyl or phenyl; The aforementioned thienyl phenyl may optionally be mono- or di-substituted individually with trifluoromethyl, chloro, fluoro or methoxy.

A group of compounds favored among the compounds of group D, denoted by group H, contains

On these vehicles where:

Q is -C1- C5)alkylene-X)-; And

X is thienyl or phenyl; The aforementioned thienyl and phenyl are optionally mono- or di-substituted individually with trifluoromethyl, chloro, fluoro or methoxy.

A group of preferred compounds among the compounds of group D, denoted by group I, contains these compounds where:

Q is -C1-C3)alkylene-X-(C1-C3)alkylene)-; And

X is thienyl or phenyl; The aforementioned thienyl and phenyl are optionally mono- or di-substituted individually with trifluoromethyl, chloro, fluoro or methoxy.

A particularly favored compound among the compounds of group I is the compound where:

A is methylsulfonyl;

Q is 3-methylenephenylmethyl;

Z is carboxyl;

K is methylene; The M is .4-(n-butylene-l-yl)phenyl

A group of preferred compounds among the compounds of group D, denoted group J, contains these compounds where:

Q is -C3)alkylene-C2-C4)alkylene-WX-(C0)-;

X is thienyl or phenyl; Said thienyl and phenyl are optionally mono- or di-substituted individually with trifluoromethyl, chloro, fluoro or methoxy; And W is oxy.

A group of preferred compounds among the compounds of group D, denoted group K, contains these compounds where:

Q is -C4)alkylene-XW-.(C1-C3)alkylene-C0)-;

X is thienyl or phenyl; Said thienyl and phenyl are optionally mono- or di-substituted individually with trifluoromethyl, chloro, fluoro or methoxy; And

w is oxy.

A group of compounds preferred among the compounds of group D, denoted by group L, contains

On these vehicles where:

Q is -C3)alkylene-C2-C4)alkylene-WXW-(C1)-;

W is oxy; And

X is thienyl or phenyl; The aforementioned thienyl and phenyl are optionally mono- or di-substituted individually with trifluoromethyl, chloro, fluoro or methoxy.

A group of preferred compounds among the compounds of group D, denoted group M, contains these compounds where:

Q is -C1-C4)alkylene-ethenylene-(C1-C4)alkylene)-;

M is Ar- and Ar- is pyridyl, thiazolyl, phenyl or thienyl. A preferred group of compounds among the compounds of group D, denoted by group N, contains these compounds where:

C3)alkylene-HoQ-C1-C4)alkylene-ethenylene-(Co-C2)alkylene-X-(C0)-;

X is thienyl or phenyl; The aforementioned thienyl and phenyl are optionally mono- or di-substituted individually with trifluoromethyl, chloro, fluoro or methoxy.

A group of compounds preferred among the compounds of group D, denoted by group O, contains these compounds where:

C2)alkylene-XW-(C1-C3)alkylene- is Q-C1-C3)alkylene-ethenylene-(C0)-;

W is oxy; And

X is thienyl or phenyl; The aforementioned phenyl and thienyl are optionally mono- or di-substituted individually with trifluoromethyl, chloro, fluoro or methoxy.

A group of preferred compounds among the compounds of group D, denoted group P, contains these compounds where:

Q is -C4)alkylene-C1-C4)alkylene-ethynylene-(C1)-.

A group of compounds that are preferred among the compounds of group D, denoted by group Q, contains these compounds where:

Q is -C3)alkylene-C1-C4)alkylene-ehynylene-X-(C0)-;

X is thienyl or phenyl; The aforementioned thienyl and phenyl are optionally mono- or di-substituted individually with trifluoromethyl, chloro, fluoro or mehoxy.

A group of preferred compounds among the compounds of group C, denoted as group R', contains these compounds, where:

A is C1-C3)alkylsulfonyl);

K is C1-C8)alkylene);

Ar- is benzo[l,3]dioxolyl,benzofuranyl,thienyl,pyridyl,thiazolyl,phenyl l,4]dioxine]2,3-dihydrobenzo;2,3-dihydrobenzofuranyl;,benzimidazolyl cyclopentyl,benzo[b]thiophenyl or cyclohexyl ; And

R2, R1 and R3 are each individually trifluoromethyl, halo, hydroxy trifluoromethoxy, difluoromethoxy, (C1-C4) alkoxy, or C1-C7) alkyl.

Favorite combinations among the R group are:

7{[3-(3-Chloro-phenyl)-propyl]-methanesulfonyl-amino}-heptanoicacid, 7{[3-(3,5-Dichloro-phenyl)-propyl]-methanesulfonyl-amino}-heptanoic acid, and

5-(3-{[3-(3- Chloro-phenyl)-propyl]-methanesulfonyl-amino}-propyl)-thiophene-2

,carboxylic acid

A group of preferred compounds among the compounds of group R, denoted as group S', contains these compounds, where:

Q is -C2-C6)alkylene-W-(C1-C3)alkylene)-; And

W is .oxy

A group of preferred compounds among the compounds of group R, denoted group T, contains these compounds where:

Q is -C3-C8)alkylene, optionally replacing the mentioned -C3-C8)alkylene with one to four fluorines.

Particularly favorable compounds among the T group are compounds where:

(a) A is methylsulfonyl;

Q is n-hexylene; z is carboxyl;

K is propylene; The M is 3-chlorophenyl; (b) A is methylsulfonyl;

Q is n-hexylene; z is carboxyl;

K is propylene; The M is 3,5-dichlorophenyl

A group of preferred compounds among the compounds of group R, denoted group U, contains these compounds where:

Q is X-(C1-C5)alkylene--; And

X is thienyl or phenyl; The aforementioned thienyl and phenyl are optionally mono- or di-substituted individually with trifluoromethyl, chloro, fluoro or methoxy.

A group of compounds that are preferred among the compounds of group R, denoted by group V, contains these compounds, where:

Q is -C1-C5)alkylene-X)-; And

X is thienyl or phenyl; The aforementioned thienyl and phenyl are optionally mono- or di-substituted individually with trifluoromethyl, chloro, fluoro or methoxy. A particularly favored compound among group V is a compound where:

A is methylsulfonyl;

ZQ is 3-(2-carboxylthien-5-yl)-n-propylene;

K is propylene; The M is .3-chlorophenyl

A group of preferred compounds among the compounds of group R, denoted group W, contains these compounds where:

Q is C1-C3)alkylene-X-(C1-C3)alkylene)-; And

X is thienyl or phenyl; The aforementioned thienyl and phenyl are optionally mono- or di-substituted individually with trifluoromethyl, chloro, fluoro or methoxy.

Groups of compounds preferred among the compounds of group R, denoted group X, contain such compounds as:

Q is -C3)alkylene-C2-C4)alkylene-WX-(C0)-;

X is thienyl or phenyl; Said thienyl and phenyl are optionally mono- or di-substituted individually with trifluoromethyl, chloro, fluoro or methoxy; And W is oxy.

A group of preferred compounds among the compounds of group R, denoted group Y, contains these compounds where:

Q is -C4)alkylene-XW-(C1-C3)alkylene-C0)-;

X is thienyl or phenyl; Said thienyl and phenyl are optionally mono- or di-substituted individually with trifluoromethyl, chloro, fluoro or methoxy; And W is oxy.

A group of preferred compounds among the compounds of group R, denoted group Z, contains these compounds where:

Q is -C2-C4)alkylene-WXW-(C1-C3)alkylene)-;

W is oxy;W

X is thienyl or phenyl; The aforementioned thienyl and phenyl are optionally mono- or di-substituted individually with trifluoromethyl, chloro, fluoro or methoxy.

A preferred group among the compounds of group R, denoted by the group Al, contains these compounds where:

Q is -C1-C4)alkylene-ethenylene-(C1-C4)alkylene)-;

M is Ar- and Ar- is pyridyl, thiazolyl, phenyl or thienyl. A preferred group of compounds among the compounds of group R, denoted group B1, contains these compounds where:

C3)alkylene-HoQ-C1-C4)alkylene-ethenylene-(Co-C2)alkylene-X-(C0)-;

X is thienyl or phenyl; The aforementioned phenyl and thienyl are optionally mono- or di-substituted individually with trifluoromethyl, chloro, fluoro or methoxy.

A group of preferred compounds among the compounds of group R, denoted group CI, contains these compounds where:

C1-C3)alkylene-ethenylene-(Co-C2)alkylene-XW-(C1-C3)alkylene-HoQ)-;

W is oxy;W

X is thienyl or phenyl; The aforementioned thienyl and phenyl are optionally mono- or di-substituted individually with trifluoromethyl, chloro, fluoro or methoxy.

A group of preferred compounds among the compounds of group R, denoted group DI, contains these compounds where:

Q is -C1-C4)alkylene-ethynylene-(C1-C4)alkylene)-.

A group of compounds favored among the compounds of group R, denoted group El, contains these compounds where:

Q is -C1-C4)alkylene-ethymylene-X-(C0-C3)alkylene)-;

X is thienyl or phenyl; The aforementioned thienyl and phenyl are optionally mono- or di-substituted individually with trifluoromethyl, chloro, fluoro or methoxy.

A group of compounds that is preferred among the compounds of group C is designated as group FI. It contains these compounds where:

A is C1-C3)alkylsulfonyl);

K is oxy(C1-C4)alkylene;

Ar- is phenyl; thienyl; thiazolyl; cyclopentyl, benzo[l,3]dioxolyl, pyridyl or cyclohexyl; And

R3, R2, and R1, each of them individually, are trifluoromethyl, halo, and hydroxy; trifluoromethoxy, difluoromethoxy (C1-C7) alkyl) or (C1-C4) alkoxy)

Particularly favorable compounds from the Fl group are:

,7-{[2-(3.5-Dichloro-phenoxy)-ethyl]-methanesulfonyl-amino}-heptanoic acid

5-(3[2-(3,5-Dichloro-phenoxy)-ethyl]-mehanesulfonyl-amino}-propyl)-

thiophene-2-carboxylic acid, and N-[2-(3,5-Dichloro-phenoxy)-ethyl]-N-[6-(lH-tetrazol-5-yl)-hexyl]-

methanesulfonamide

A group of preferred compounds among the compounds of the Fl group, denoted by the Gl group, contains these compounds where:

Q is C2-C6)alkylene-W-(C1-C3)alkylene)-; And

W is .oxy

A group of preferred compounds among the compounds of the Fl group, denoted by the Hl group, contains

On these vehicles where:

Q is -C3-C8)alkylene, optionally replace the mentioned -C3-C8)alkylene with one to

four .fluorines

A particularly favored compound among the compounds of the Hl group is the compound where:

mehylsulfonyl is A;

Q is n-hexylene;

Z is carboxyl;

K is oxyethylene; The M is 3,5-dichlorophenyl

A group of compounds favored among the group Fl, denoted group II, contains these

Vehicles where:

Q is X-(C1-C5)alkylene--; And

X is thienyl or phenyl; The aforementioned thienyl and phenyl are optionally mono- or di-substituted individually with trifluoromethyl 'Chloro' fluoro or methoxy.

A group of preferred compounds among the compounds of group Fl, denoted by group JI, contains

On these vehicles where:

Q is -C1-C5)alkylene-X)-; And

X is thienyl or phenyl; The hydrogens thienyl and phenyl are optionally mono- or di-substituted separately with chloro, fluoro; trifluoromethyl or .methoxy

A particularly favored compound among the compounds of group JI is the compound where:

A is methylsulfonyl;

ZQ is 3-(2-carboxylthien-5-yl)-n-propylene;

K is oxyethylene;

M is 3,5-dichlorophenyl

A group of preferred compounds among the FI group compounds, denoted by the Kl group, contains these compounds where:

Q is -C1-C3)alkylene-X-(C1-C3)alkylene)-; And

X is thienyl or phenyl; The aforementioned thienyl and phenyl are optionally mono- or di-substituted separately with chloro, fluoro; trifluoromethyl or .methoxy

A group of compounds is preferred among the FI group compounds; Denotes the group Ll, containing

On these vehicles where:

Q is -C2-C4)alkylene-WX-(C0-C3)alkylene)-;

X is thienyl or phenyl; The aforementioned phenyl and thienyl are optionally mono- or di-substituted individually with chloro, fluoro; trifluoromethyl or methoxy; And W is oxy.

A group of preferred compounds among the compounds of group FI denotes the group, Ml

It contains these compounds where:

Q is -C4)alkylene-XW-(C1-C3)alkylene-C0)-;

thienyl is X or phenyl; The aforementioned thienyl and phenyl are optionally mono- or di-substituted individually with a fluoro; chloro; trifluoromethyl or methoxy; And W is oxy.

A group of preferred compounds among the FI group compounds, denoted by the Nl group, contains these compounds where:

Q is -C2-C4)alkylene-WXW-(C1-C3)alkylene)-;

w is oxy; And

X is thienyl or phenyl; The aforementioned thienyl and phenyl are optionally mono- or di-substituted individually with trifluoromethyl, chloro, fluoro or methoxy.

A group of preferred compounds among the compounds of group Fl, denoted group O1, contains these compounds where:

Q is -C1-C4)alkylene-ethenylene-(C1-C4)alkylene)-;

M is Ar- and Ar- is pyridyl, thiazolyl, phenyl or thienyl.

A group of preferred compounds among the compounds of group Fl, denoted group PI, contains these compounds where:

C1-C4)alky1ene-ethenylene(C0-C2)akylene-X--(C0-C3)alkylene is Q)-;

X is thienyl or phenyl; The aforementioned thienyl phenyl may optionally be mono- or di-substituted individually with trifluoromethyl, chloro, fluoro or methoxy.

A group of preferred compounds among the compounds of group Fl, denoted group Ql, contains these compounds where:

C1-C3)alkylene- ethenylene-(C0-C2)alkylene-XW--(C1-C3)alkylene--HQ )-;

W is oxy; And

X is thienyl or phenyl; The aforementioned thienyl phenyl may be mono- or di-substituted individually with trifluoromethyl, chloro, fluoro or methoxy.

A group of preferred compounds among the compounds of group Fl, denoted group RI, contains these compounds where:

Q is -C1-C4)alkylene-ethynylene-(C1-C4)alkylene)-.

A group of preferred compounds among the compounds of group Fl, denoted group S1, contains these compounds where:

Q is -C1-C4)alkylene-ethynylene-X-(C0-C3)alkylene-)-;

X is thienyl or phenyl; The aforementioned phenyl and thienyl are optionally mono- or di-substituted individually with trifluoromethyl, chloro, fluoro or methoxy.

A group of preferred compounds among the compounds of group C1, denoted by group T1, contains

On these vehicles where:

A is C1-C3)alkylsulfonyl);

K is C3-C8)alkylene, the aforementioned C3-C8)alkylene is monounsaturated;

Ar- is phenyl, thienyl, thiazolyl, pyridyl, cyclopentyl or cyclohexyl, and R3, R1, R2 are each individually trifluoromethyl, halo, hydroxy, trifluoromethoxy, difluoromethoxy, C1-C4 alkoxy, or C1-C7 alkyl.

Particularly preferred compounds among the compounds of the Tl group are:

Trans-(4-{[3-(3,5-Dichloro-phenyl -allyl]- methanesulfony-amino}butoxy)-acetic)

acid,

Trans-N-[3-(3,5-Dichloro-phenyl)-allyl]-N-[6-(lH-tetrazolyl-5-yl)-hexyl]-

methanesulfonamide,

Trans-5-(3-{[3-(3,5-Dichloro-phenyl)-allyl]-methanesulfonyl-amino}-propyl)-

thiophene-2-carboxylic acid, and

Trans-[3-({[3-(3,5-Dichloro-phenyl)-allyl]-methanesulfonyl-amino}-methyl)-

phenyl]-acetic acid.

A group of preferred compounds among the compounds of group TI, denoted by group U, contains these compounds, where:

Q is -C2-C6)alkylene-W-(C1-C3)alkylene)_; And W is .oxy

A particularly favored compound from group Ul is the compound where:

A is methylsulfonyl;

Q is methyloxy-n-butylene;

Z is carboxyl;

K is trans-2-n-propenylene; The M is 3,5-dichlorophenyl

A group of compounds that is preferred among the group Tl denotes the group. VI, containing

These vehicles where:

Q is -C3-C8)alkylene, optionally replacing the mentioned -C3-C8)alkylene with one to four fluorines.

The preferred compound among the Group VI compounds is the compound where:

A is methylsulfonyl;

Q is n-hexylene;

Z is (5-(lH-tetrazolyl;

K is trans-2-n-propenylene; The M is 3,5-dichlorophenyl

A group of preferred compounds among the compounds of group Tl, denoted by group Wl, contains these compounds where: Q is --X-(C1-C5)alkylene; And

X is thienyl or phenyl; The aforementioned thienyl and phenyl are optionally mono- or di-substituted individually with chloro, fluoro, trifluoromethyl or methoxy.

A group of compounds favored among the compounds of group Tl, denoted group XI, contains these compounds where: Q is -C1-C5)alkylene-X)-; And

X is thienyl or phenyl; The aforementioned thienyl phenyl may optionally be mono- or di-substituted individually with trifluoromethyl chloro, fluoro or methoxy. A preferred compound within Group XI is the compound where:

A is methylsulfonyl;

ZQ is 3-(2-carboxylthien-5-yl)-n-propylene;

K is trans-2-n-propenylene; The M is 3,5-dichlorophenyl

A group of preferred compounds among the compounds of the Tl group, denoted by the Yl group, contains these compounds, where:

Q is -C1-C3)alkylene-X-(C1-C3)alkylene)-; And

X is thienyl or phenyl; Said phenyl and thienyl are optionally mono- or di-substituted individually with trifluoromethyl, chloro, fluoro or methoxy.

A group of preferred compounds among the compounds of group Tl, denoted group Zl, contains these compounds where:

Q is -C2-C4)alkylene-WX-(C0-C3)alkylene)-;

X is thienyl or phenyl; The diluted thienyl and phenyl are optionally mono- or di-substituted individually with trifluoromethyl, chloro, fluoro or methoxy; And W is oxy.

A group of preferred compounds from among the compounds of group Tl is referred to as group A2. It contains these compounds, where:

Q is C0-C4)alkylene-XW-(C1-C3)alkylene-)-;

X is thienyl or phenyl; Said thienyl and phenyl are optionally mono- or di-substituted individually with trifluoromethyl, chloro, fluoro or methoxy; And W is oxy.

A group of preferred compounds among the compounds of group Tl, denoted group B2, contains these compounds, where:

Q is -C2-C4)alkylene-WXW-(C1-C3)alkylene)-;

W is oxy;W

X is thienyl or phenyl; The aforementioned phenyl and thienyl are optionally mono- or di-substituted individually with trifluoromethyl, chloro, fluoro or methoxy.

A group of preferred compounds from group Tl, denoted group C2, contains these compounds where:

Q is -C1-C4)alkylene-ethenylene-(C1-C4)alkylene)-;

M is Ar-, and Ar- is pyridyl, thiazolyl, phenyl, or thienyl. A preferred group of compounds among the compounds of group Tl, denotes group D2, contains these compounds, where:

C1-C4)alkylene-ethenylene -(C0-C2)alkylene-X-(Co-C3)alkylene- is Q)-;

X is thienyl or phenyl; The aforementioned thienyl and phenyl are optionally mono- or di-substituted individually with trifluoromethyl, chloro, fluoro or methoxy.

A group of compounds preferred among the compounds of group TI, denoted group E2, contains these compounds where:

C1-C3)alkylene-ethenylene-(Co-C2)alkylene-XW-(C1-C3)alkylene-HoQ)-;

W is oxy;W

X is thienyl or phenyl; The aforementioned thienyl phenyls are optionally mono- or di-substituted individually with trifluoromethyl, chloro, fluoro or methoxy.

A group of preferred compounds among the compounds of group TI, denoted group F2, contains these compounds where:

Q is -C1-C4)alkylene-ethynylene-(C1-C4)alkylene)-.

A group of compounds preferred among the compounds of group TI, denoted group G2, contains these compounds where:

C1-C4)alkylene-ethynylene-X -(C0-C3)alkylene- isQ-;

X is thienyl or phenyl; The aforementioned thienyl phenyls are optionally mono- or di-substituted individually with trifluoromethyl, chloro, fluoro or methoxy.

A group of preferred compounds, denoted group H2, contains such compounds having the formula I as shown above where: B is N;

A is C1-C6)alkanoyl)' or C3-C7)cycloalkyl(C1-C6)alkanoyl), the parts of A being

The mentioned ones are optionally mono-, mono- or triple-substituted on the carbon individually with a hydroxy or

halo;

X is Thienyl 'Phenyl' or Thiazolyl, Thienyl, Phenyl or Thiazolyl mentioned optionally, two unilateral or bilateral replacement separately with 'Trifluoromethly' Chloro, Fluoro, Fluoro, Fluoro

difluoromethoxy'methoxy or trifluoromethoxy; w is thio,oxy or sulfonyl;

z is carboxyl, (C1-C4)alkoxycarbonyl or tetrazolyl;

C1-C8)alkylene is K or C1-C8)alkylene oxy, the aforementioned C1-C8)alkylene is

Optionally monounsaturated and where K is optionally mono- or triple-substituted separately with a methyl,

fluoro or chloro;

Ar is thiazolyl, pyridyl, thienyl, phenyl, (C5-C7)cydoalkyl, oxazolyl, naphthalenyl 'isoxazolyl, benzo[b]furanyl, furanyl, indanyl, benzo[b]thiophenyl, benzisoxazolyl, benzimidazolyl, benzo[l,3) dioxolyl

pyrimidyl, pyrazolyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzo [L, 4] Dioxinyl, benzox L, Cyclopentyl, Cyclohexyl, L, 2,3,4-tetrahydronaphthalenyl, indolel or chromanyl; 1Ar Ar2 each individually form C5-C7)cycloalkyl), phenyl, thienyl), thiazolyl,pyrimidyl 'pyridyl, oxazolyl, furanyl, pyrazinyl, isoxazolyl, imidazolyl or pyrazolyl;

1 R is C1-C7), alkanoyl, (C1-C7)alkanoyl (C1-C6) )alkanoyl, halo) or C3-C7)cydoalkyl(C1-C4)alkyl), which is C1-C7)alkoxy),C1-C6 (alkoxy),

C1-C7)alkanoyl'(C3-C7)cydoalkyl) or C3-C7)cycloalkyl(C1-C4)alkyl) mentioned

Optionally mono-, di- or tri-substituted individually with fluoro'hydroxy or chloro; R3 and R2, each of them separately, are difluoromethoxy, halo, and hydroxy; or carbamoyl.

It is particularly preferable for group H2 that K should not optionally be mono-, di- or tri-substituted separately with a fluoro, methyl or chloro.

A group of compounds that is preferred among the compounds of group H2, referred to as group I2, contains these compounds, where:

A is C1-C6)alkanoyl, said C1- C6)alkanoyl being optionally mono-, di- or triple-substituted on the carbon separately with the halo; Q is:

-C2-C6)alkylene-W-(C1-C3)alkylene)-,

alkylene-(C4-C8) Optionally replaces the aforementioned C4-C8)alkylene with up to four individually selected fluoro or C1-C4)alkylene substituents.

(C2-C4)alkylene- WX-(Co-C3)alkylene-C4)alkylene-XW-(C1-C3)alkylene--,-(C0 K is methylene or ethylene;

M is Ar1-V-Ar2- or Ar1-O-Ar2- where 1Ar and Ar2 are individually phenyl pyridyl or thienyl;

V is a bond or C1-C2)alkylene);

R1 is C1-C4)alkyl, fluoro, chloro or C1-C4)alkoxy, which is (C1-C4alkyl)

The above two are optionally mono-, di- or tri-substituted separately with the hydroxy

or fluoro; And

R3 and R2 are each individually chloro or fluoro.

A group of compounds favored among the compounds of group H2, referred to as group 2J, contains these compounds, where:

A is C1-C6)alkanoyl, said C1-C6)alkanoyl being optionally mono-, di- or triple-substituted on the carbon individually with a hydroxy or halo; K is methylene;

Q is:

,-(C2-C6)alkylene-W-(C1-C3)alkylene

C4-C8)alkylene-)-, optionally replacing the aforementioned C4-C8)alkylene-) with up to four substituents.

Individually selected fluoro or C1-C4 (alkylene)

X-(C2-C5)alkylene--,

-,-(C1- C5)alkylene-X

C-C3)alkylene-X-(C1-C3)alkylene-)-,

-)alkylene-(C2-C4)alkylene-WX-(C0-C3)-, or

-C0-C4)alkylene-XW-(C1-C3)alkylene-)-;

M is Ar- and the phenyl is -Ar, furanyl, oxazolyl 'thienyl, pyridyl, thiazolyl, cyclopentyl or cyclohexyl where Ar- is replaced with at least 1R;

1R is C1-C7)alkyl or C1-C5)alkyl, C1-C7)alkyl or C1-C5)alkyl.

The aforementioned are optionally mono-, di- or tri-substituted individually with a hydroxy or fluoro; R3 and R2, each individually, are methyl, fluoro, chloro, trifluoromethoxy, or trifluoromethyl.

A group of preferred compounds among the compounds of group H2 is referred to as group K2. It contains these compounds, where:

A is C1-C6)alkanoyl, said C1-C6)alkanoyl being optionally mono-, di- or triple-substituted on the carbon separately with the halo; K is C1-C8)alkylene);

Q is:

C2-C6)alkylene-W-(C1-C3)alkylene-)-,

C4-C8)alkylene-), optionally replacing the aforementioned C4-C8)alkylene with up to four individually selected fluoro or C1-C4)alkyl substituents.

X-(C2-C5)alkylene--,

-C1-C5)alkylene-X)-,

-C1-C3)alkylene-X-(C1-C3)alkylene)-,

-C2-C4)alkylene-WX-(C0-C3)alkylene-)-, or

C0-C4)alkylene-XW-(C1-C3)alkylene-)-;

M is Ar- and Ar- is benzo[1,3]dioxolyl,benzofuranyl,thienyl,phenyl,benzimidazolyl,2,3-dihydrobenzofuranyl,2,3-dihydrobenzo[l,4]dioxinyl cyclopentyl,benzo[b]thiophenyl or cyclohexyl; And

R2, R1 and R3 are each individually trifluoromethyl, halo, hydroxy, C1-C4)alkoxy, trifluoromethoxy, difluoromethoxy or (C1-C7)alkoxy.

A group of preferred compounds among the compounds of group 2H, denoted group L2, contains these compounds where:

A is C1-C6)alkoxy, the aforementioned C1-C4)alkoxy is optionally mono- or di-substituted.

or triplet on carbon separately with halo; K is oxy(C1-C4)alkoxy;

Q is:

-C2-C6)alkylene-W-(C1-C3)alkylene)-,

-C4-C8)alkoxy) -optionally replaces -C4-C8)alkoxy)- with up to four selected substituents each.

Separately from fluoro or C1-C4)alkoxy), -, -C2-C4)alkylene-WX-(C0-C3)alkylene)-, or -C0-C4)alkylene-XW-(C1-C3)alkylene)-;

M is Ar- and Ar- is cyclopentyl, benzo[l,3]dioxolyl, thienyl, phenyl or cyclohexyl; And

r1, r3 and r2, each of them individually, is trifluoromethyl, halo, hydroxy (C1-C4)alkoxy, trifluoromethoxy, difluoromethoxy) or (C1-C7)alkyl).

A group of preferred compounds among the compounds of group H2 is referred to as group M2. It contains these compounds, where:

A is C3-C6 alkanoyl. The aforementioned C3-C6 alkanoyl is mono- or di-substituted.

or triplet on carbon separately with halo;

K is C3-C8) alkanoyl, and the aforementioned C3-C8) alkanoyl is monounsaturated;

Q is:

-,-(C2-C6)alkylene-W-(C1-C3)alkylene

-C4_C8)alkylene)-, optionally replacing the aforementioned -C4-C8)alkanoyl) with up to four individually selected fluoro or C1-C4)alkanoyl substituents,

X-(C2-C5)alkylene--,

C1-C5)alkanoyl)-X-)-,

-C1-C3)alkylene-X-(C1-C3)alkylene)-,

-C2-C4)alkanoyl)WX-(C0-C3)alkylene-),or

-C0-C4)alkylene-XW-(C1-C3)alkylene)-;

Ar is M- and Ar- is cyclopentyl, thienyl, phenyl or cyclohexyl; And R3, R1, R2, each of them individually, to be trifluoromethyl, halo, hydroxy (C1-C4)alkoxy, trifluoromethoxy) or C1-C7)alkyl).

A group of preferred compounds, denoted group N2, contains such compounds having the formula I as shown above where: B is C(H);

C1-C6)alkanoyl) is A, or C3-C7)cycloalkyl(C1-C6)alkanoyl), said parts of A being optionally mono-, di- or tri-substituted on the carbon individually with a hydroxy or halo;

" w is thio,oxy or sulfonyl; z and carboxyl, (C1-C4)-alkoxycarbonyl or tetrazolyl;

K is C1-C8)alkylene or C1-C4)alkylene oxy, which is C1-C8)alkylene.

optionally monounsaturated and where K is optionally mono- or triple-substituted separately with methyl fluoro or chloro;

Ar is C5-C7)cycloalkyl, oxazolyl, thiazolyl, pyridyl, thienyl, phenyl) isoxazolyl, naphthalenyl, benzo[b]furanyl, indanyl, benzo[b]thiophenyl furanyl, benzisoxazolyl, benzimidazolyl, benzo[l,3] dioxolyl

l,4]dioxinyl]pyrimidyl,pyrazolyl,2,3-dihydrobenzofuranyl,2,3-dihydrobenzo,benzohiazolyl,benzoxazolyl,isoquinolinyl,quinolinyl,imidazolyl,pyrazinyl cyclopentyl,cyclohexyl,1,2,3,4-teü-ahydronaphthalenyl, indolyl or chromanyl;

1Ar and Ar2 are individually thiazolyl, thienyl, phenyl, (C5-C7)cycloalkyl pyridyl, pyrimidyl, pyrazinyl, isoxazolyl, imidazolyl, furanyl, oxazolyl or pyrazolyl;

1R is C1-C7)alkanoyl,(C3-C7)cycl0alkyl,(C1-C7)alkyl (C1-C6)alkoxy,halo)

Or C3-C7)lycloalkyl(C1-C4)alkyl), it is alkoxy(C1-C6) alkyl (C1-C7)

C1-C7)alkanoyl, (C3-C7)cycloalkyl) or alkyl(C1-C4)(C3-C7)cycloalkyl mentioned above.

Informationally mono-, di- or tri-substituted individually with a fluoro, hydroxy or chloro; And

R3 and R2 individually are difluoromethoxy, halo, hydroxy, trifluoromethyl, trifluoromethoxy, (C1-C5) alkanoyl, (C1-C4) alkoxy, C1-C7) alkyl.

cyano, C3-C7)cycloalkyl)4 formyl, (C3-C7)cycloalkyl(C1-C4)alkyl or carbamoyl.

It is particularly preferable for group N2 that K should not optionally be mono-, di- or tri-substituted separately with a fluoro, methyl or chloro.

A group of preferred compounds among the compounds of the N2 group, denoted by the O2 group, contains these compounds, where:

A is C1-C6)alkanoyl, the said A being optionally mono-, di- or triple-substituted on the carbon separately with the halo;

Q is:

-C2-C6)alkylene-W-(C1-C3)alkylene)-,

-C4-Cg)alkylene)-, optionally replacing the aforementioned -C4-C8)alkylene with up to four individually selected fluoro or C4-C8)alkylene substituents.

X-(C2-C5)alkylene--,

,-(C1-C5)alkylene-X-

,-(C1-C3)alkylene-X-(C1-C3)alkylene-

-C2-C4)alkyleneW-X-(C0-C3)alkylene-),or

-C0-C4)alkylene-XW-(C1-C3)alkylene-)-,

K is methylene or ethylene;

M is Ar1-V-Ar2- or Ar1-O-Ar2-, where Ar1 and Ar2 are individually, phenyl pyridyl or thienyl;

V is a bond or C1-C2)alkylene);

R1 is C1-C4)alkyl, fluor, chloro or C1-C4)alk0xy, which is C1-C4)alkyl.

The above two are optionally mono-, di- or tri-substituted separately with the hydroxy

or fluoro; And

R3 and R2 are each individually chloro or fluoro.

A group of preferred compounds among the compounds of group N2, denoted group P2, contains these compounds where:

A is a C1-C6)alkanoyl, the said A being optionally mono-, di- or triple-substituted on the carbon individually with a hydroxy or halo; K is methylene;

Q is:

-C2-C6)alkylene-W-(C1-C3)alkylene)-,

-C4-C8)alkylene-, optionally replaces the aforementioned C4-C8)alkylene with up to four substituents.

Individually selected fluoro or C1-C4)alkyl,

X-(C2-C5)alkylene--,

,-(C1-C5)alkylene-X-

,-(C1-C3)alkylene-X-(C1-C3)alkylene-

-C2-C4)alkylene-WX-(C0-C3)alkylene-)-, or

C0-C4)alkylene-XW-(C1-C3)alkylene-)-;

M is Ar- and Ar- is furanyl, oxazolyl, thienyl, pyridyl, thiazolyl, phenyl, cyclopentyl or cyclohexyl where Ar- is replaced with at least 1R;

1R is C1-C7)alkyl or C1-C6)alkoxy, the aforementioned C1-C7)alkyl or C1-C6)alkoxy being optionally mono-, faba- or tri-substituted individually with a hydroxy or fluoro; And

R3 and R2 are each individually difluoromethoxy, methyl, fluoro, chloro, trifluoromethoxy or trifluoromethyl.

A group of preferred compounds among the compounds of group N2, denoted group Q2, contains these compounds, where:

A is alkanoyl(C1-C6), the aforementioned A is optionally mono-, di- or tri-substituted on

carbon separately with halo; K is C1-C8)alkylene); Q is:

,-(C2-C6)alkylene-W-(C1-C3)alkylene-

Optionally replace the aforementioned alkylene-(C4-C8) with up to four individually selected substituents from

fluoro or C1-C4)alkyl),alkylene-(X-,(C2-C5,-(C1-C5)alkylene-X--,-(C1-C3)alkylene-X-(C1-C3)alkylene -C2 -C3)alkylene-WX-(C0-C3)alkylene)-, or -C0-C4)alkylene-XW-(C1-C3)alkylen-)-;

M is Ar- and Ar- is benzofuranyl, thienyl, phenyl, benzo[1,3] dioxolyl, benzimidazolyl,2,3-dihydrobenzofuranyl,2,3-dihydrobenzo[l,4]dioxinyl cyclopentyl, benzoblthiophenyl or cyclohexyl; And

R3, R2, and R1, each of them individually, are trifluoromethyl, halo, hydroxy, C1-C4)alkoxy, trifluoromethoxy, or C1-C7)alkyl.

A group of preferred compounds among the compounds of group N2 is referred to as group R2. It contains these compounds, where:

A is a C1-C6 alkanoyl. The aforementioned A is optionally mono-, di- or tri-substituted on

carbon separately with halo; K is oxy(C1-C4)alkylene;

Q is:

,-(C2-C6)alkylene-W-(C1-C3)alkylene-

- Optionally replace the aforementioned alkylene(C4-C8-alkylene-(C4-C8) with up to four substituents.

Individually selected fluoro or alkyl(C1-C4),

alkylene-X-(C2-C5(-,

-(C1-C5)alkylene-X)-,

,-(C1-C3)alkylene-X-(C1-C3)alkylene-

-C2-C4)alkylene-WX-(Co-C3)alkylene)-, or

C0-C4)alkylene-XW-(C1-C3)alkylene-)-;

M is Ar- and Ar- is l,3]dioxolyl,thienyl,phenyl]cyclopentyl,benzo] or cyclohexyl; And

R2, R1 and R3, individually, are trifluoromethyl, halo, hydroxy (C1-C4)alkoxy, trifluoromethoxy or C1-C7)alkyl).

A group of preferred compounds among the compounds of group N2, denoted group S2, contains these compounds where:

A is a C1-C6 alkanoyl. The aforementioned A is optionally mono-, di- or tri-substituted on

carbon separately with halo;

K is C3-C8)alkylene, the aforementioned C3-C8)alkylene is monounsaturated;

Q is:

_,-(C2-C6)alkylene-W-(C1-C3)alkylene

-C4-C8)alkylene), optionally replacing the aforementioned -C4-C8)alkylene with up to four individually selected fluoro or C1-C4)alkylene substituents.

X-(C2-C5)alkylene--,

,-(C1-C5)alkylene-X-

(C1-C3)alkylene-X-(C1-C3)alkylene)-,

-C2-C4)alkylene-WX-(C0-C3)alkylene--)-, or

-C0-C4)alkylene-XW-(C1-C3)alkylene-)-;

M is Ar- and Ar- is cyclopentyl, thienyl, phenyl or cyclohexyl; And

R3, R2, R1, each of them separately is halo, hydroxy, trifluoromethyl,

C1-C4)alkoxy, trifluoromethoxy) or (C1-C7)alkyl.

A particularly preferred compound of group J2 is the compound where:

A is propanoyl;

Q is n-hexylene;

Z is carboxyl;

K is methylene; And M is (nl-hydroxylhexyl)phenyl)-4

A particularly favored compound among the compounds of group HI is the compound where:

A is methylsulfonyl;

Q is n-hexylene;

Z is (5-(lH-tetrazolyl;

K is oxyethyl; The M is 3,5-dichlorophenyl

A particularly favored compound among the compounds of group Yl is the compound where:

A is methylsulfonyl;

Q is 3-methylenephenylmethyl;

Z is carboxyl;

K is trans-2-n-propenylene; The M is 3,5-dichlorophenyl

This invention also relates to a method for increasing and maintaining bone mass and preventing further bone loss in a mammal comprising administering to the mammal a therapeutically effective amount of the Formula I compound or a pharmaceutically acceptable salt or prodrug thereof.

This invention also relates to a method for treating a mammal with a condition characterized by low bone mass, which includes administering to a mammal with a condition characterized by low bone mass, a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt or prodrug thereof. It is preferable to treat postmenopausal women and men

Over the age of sixty. It also includes people of any age with very low bone mass, that is, ≥1.5 standard deviations below normal levels for a young person.

Another aspect of this invention relates to methods for treating osteoporosis, bone fractures, bone resection, bone loss associated with periodontitis, or internal growth of an artificial structure in a mammalian organism (including a human being), including administering to a subject suffering from osteoporosis, bone fracture, or resection. Bone, bone loss associated with periodontitis, or ingrowth of a prosthetic A quantity treated for osteoporosis, bone fracture, bone resection, bone loss associated with periodontitis of the Formula I compound or a pharmaceutically acceptable salt or prodrug thereof.

Another aspect of this invention relates to a method for treating osteoporosis in a mammal (including a human) comprising administering to an osteoporotic organism an osteoporosis-therapeutic amount of the Formula I compound or a pharmaceutically acceptable salt or prodrug thereof.

Another aspect of this invention relates to a method for treating bone loss resulting from osteotomy in a mammal (including a human) comprising administering to a mammal that has undergone osteotomy to repair bone integrity a therapeutically effective amount of the Formula I compound or a pharmaceutically acceptable salt or prodrug thereof. In one aspect, Formula I is used topically on the site of bone resection.

Another aspect of this invention relates to a method for treating alveolar bone loss in a mammalian organism (including a human), including administering to an organism suffering from alveolar bone loss an alveolar bone loss treatment amount of the formula I compound or a pharmaceutically acceptable salt or prodrug thereof.

Another aspect of this invention relates to a method for treating periodontitis-associated bone loss in an organism (including a human) comprising administering to an organism suffering from periodontitis-associated bone loss a treatment amount of the formula I compound, a salt, or a prodrug. Pharmacologically acceptable.

Another aspect of this invention relates to a method for treating childhood idiopathic bone loss in a mammal comprising administering to a child suffering from idiopathic bone loss a childhood idiopathic bone loss treatment amount of the Formula I compound or a pharmaceutically acceptable salt or prodrug thereof.

Another aspect of this invention relates to a method for treating "secondary osteoporosis", including glucocorticoid-induced osteoporosis, hyperthyroidism-induced osteoporosis, osteoporosis

Bone resulting from immobilization, osteoporosis resulting from hepain or osteoporosis resulting from immunosuppression in a mammal (including a human) by giving a mammal suffering from “secondary osteoporosis” a therapeutic amount of the “secondary osteoporosis” compound of the Formula I compound or a pharmaceutically acceptable salt or prodrug thereof. .

Another aspect of this invention relates to a method for treating glucocorticoid-induced osteoporosis in a mammal (including a human), including administering to a mammal suffering from glucocorticoid-induced osteoporosis a glucocorticoid-induced osteoporosis-treating amount of the Formula I compound or a pharmaceutically acceptable salt or prodrug thereof. .

Another aspect of this invention relates to a method for treating hyperthyroidism-induced osteoporosis in a living organism (including a human) comprising administering to a mammal suffering from hyperthyroidism-induced osteoporosis an amount of the formula compound to treat hyperthyroidism-induced osteoporosis. I or a pharmaceutically acceptable salt or prodrug thereof.

Another aspect of this invention relates to a method for treating sedentary osteoporosis in a mammal (including a human) comprising administering to a mammal suffering from sedentary osteoporosis a sedentary osteoporosis treatment amount of the Formula I compound, a salt, or a prodrug. Pharmacologically acceptable.

Another aspect of this invention relates to a method for treating heparin-induced osteoporosis in a mammal (including a human) comprising administering to a mammal suffering from heparin-induced osteoporosis an osteoporosis-treating amount of 0n heparin of the Formula I compound or a pharmaceutically acceptable salt or prodrug thereof. .

Another aspect of this invention relates to a method for treating immunosuppressive osteoporosis in a mammal (including a human) comprising administering to a mammal suffering from immunosuppressive osteoporosis an immunosuppressive osteoporosis treatment amount of the Formula I compound, a salt, or a prodrug. Pharmacologically acceptable.

Another aspect of this invention relates to a method for treating a bone fracture in a mammal (including a human) comprising administering to a mammal suffering from a bone fracture a bone fracture treatment amount of the Formula I compound or a pharmaceutically acceptable salt or prodrug thereof. In one aspect of this invention for the treatment of a bone fracture

The Formula I compound or a pharmaceutically acceptable carrier or prodrug is used topically at the site of the bone fracture. In another aspect of this invention, the compound of Formula I or a pharmaceutically acceptable salt or prodrug thereof is given generally.

Another aspect of this invention relates to a method for increasing bone healing after facial or maxillary orthognathic or mandibular orthognathic surgery in a mammal (including a human) comprising administering to a mammal that has had facial, maxillary or mandibular orthognathic surgery a bone-increasing amount of a compound. Formula I or a pharmaceutically acceptable salt or prodrug thereof. In one aspect of this method, the Formula I compound or a pharmaceutically acceptable salt or prodrug thereof is applied topically to the orthopedic site.

Another aspect of this invention relates to a method for causing endogenous growth of an artificial composition in a mammal (including a human being) by administering to the mammal a therapeutically effective amount of the Formula I compound or a pharmaceutically acceptable salt or prodrug thereof.

Another aspect of this invention relates to a method for inducing osteosynthesis in a mammal (including a human) comprising administering to a mammal subject to surgery for osteosynthesis a therapeutically effective amount of the Formula I compound or a pharmaceutically acceptable salt or prodrug thereof.

Another aspect of this invention relates to a method for increasing long bone correction in a mammal (including a human) comprising administering to a mammal suffering from insufficient long bone size an amount that increases the long bone of the Formula I compound or a pharmaceutically acceptable salt or prodrug thereof.

Another aspect of this invention relates to a method for use in place of a bone graft in a mammal (including a human) involving administering to the mammal a therapeutically effective amount of the Formula I compound or a pharmaceutically acceptable salt or prodrug thereof. In another aspect of this method, the Formula I compound or a pharmaceutically acceptable salt or prodrug thereof is applied topically to the site of the bone graft. Also, when a bone graft is needed, an amount of Formula I compound or a pharmaceutically acceptable salt or prodrug thereof may be applied to the bone graft site to restore bone.

The preferred dose is approximately 0.001 to 100 mg/kg/day of Formula I compound or a pharmaceutically acceptable salt or prodrug thereof. A particularly preferred dose is approximately 1.0 to 10 mg/kg/day of formula I compound or a pharmaceutically acceptable salt or prodrug thereof.

This invention also relates to pharmaceutical compositions comprising a therapeutically effective amount of the Formula I compound, a pharmaceutically acceptable salt or prodrug thereof, and a pharmaceutically acceptable carrier substance.

This invention also relates to pharmaceutical compositions for increasing bone mass including a bone mass-increasing amount of a formula I compound, a pharmaceutically acceptable salt or prodrug thereof, and a pharmaceutically acceptable carrier substance.

This invention also relates to medicinal compositions for the treatment of a condition of low bone mass in a mammal (including a human), comprising a treatment amount for a condition of low bone mass of the Formula I compound, a pharmaceutically acceptable salt or prodrug thereof, and a pharmaceutically acceptable carrier substance.

This invention also relates to medicinal compositions for the treatment of osteoporosis or bone fractures, bone resection, bone loss associated with periodontitis, bone graft replacement or internal growth of an artificial composition in a mammalian organism (including a human being) including a therapeutically effective amount of the Formula I compound or a salt. Or a pharmaceutically acceptable prodrug and a pharmaceutically acceptable carrier substance.

The invention also relates to drug compositions for the treatment of “secondary osteoporosis,” including glucocorticoid-induced osteoporosis, hyperthyroidism-induced osteoporosis, immobilized osteoporosis, heparin-induced osteoporosis, or immunosuppressive osteoporosis in a mammal. (Including human) We include a “secondary osteoporosis” treatment quantity of the Formula I compound, a pharmaceutically acceptable salt or prodrug thereof, and a pharmaceutically acceptable carrier substance.

This invention also relates to medicinal compositions for the treatment of osteoporosis in a mammalian organism (including humans) comprising an osteoporosis-treatment amount of the Formula I compound, a pharmaceutically acceptable salt or prodrug thereof, and a pharmaceutically acceptable carrier substance.

This invention also relates to medicinal compositions for increasing the healing of a bone fracture in a mammal (including a human being), including a bone fracture treatment quantity of the formula I compound, a pharmaceutically acceptable salt or prodrug thereof, and a pharmaceutically acceptable carrier substance.

This invention also relates to compositions medicinally for the treatment of bone loss from osteotomy in a mammal (including a human being). An amount for treating bone loss from osteotomy consists of a compound of Formula I, a pharmaceutically acceptable salt or prodrug thereof, and a pharmaceutically acceptable carrier.

This invention also relates to pharmaceutical compositions for the treatment of alveolar bone loss in a mammal (including a human), including an alveolar bone loss treatment amount of the Formula I compound, a pharmaceutically acceptable salt or prodrug thereof, and a pharmaceutically acceptable carrier.

This invention also relates to medicinal compositions for the treatment of childhood idiopathic bone loss in a child comprising a treatment-for-childhood idiopathic bone loss amount of the Formula I compound, a pharmaceutically acceptable salt or prodrug thereof, and a pharmaceutically acceptable carrier substance.

This invention also relates to medicinal compositions for increasing bone healing after facial or maxillary orthognathic or mandibular orthognathic surgery in a mammal (including a human) comprising a bone healing amount of a compound of Formula I, a pharmaceutically acceptable salt or prodrug thereof, and an acceptable carrier substance. Pharmacologically.

This invention also relates to medicinal compositions for the treatment of bone loss associated with periodontitis in a mammal (including a human), including a quantity to treat bone loss associated with periodontitis of the Formula I compound, a pharmaceutically acceptable salt or prodrug thereof, and a pharmaceutically acceptable carrier substance.

This invention also relates to medicinal compositions for treating the endogenous growth of a synthetic composition in a mammal (including a human), including an amount for treating the endogenous growth of a synthetic composition of the Formula I compound, a pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutically acceptable carrier.

This invention also relates to medicinal compositions for inducing vertebral bone adhesion in a mammal (including a human) comprising a therapeutically effective amount of the Formula I compound, a salt or prodrug of which the drug is urinated, and a pharmaceutically acceptable carrier substance.

This invention also relates to pharmaceutical compositions for increasing the straightening of a long bone in a mammal (including a human) comprising a bone mass-increasing treatment amount of a formula I compound, a pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutically acceptable carrier.

This invention also relates to pharmaceutical compositions for the treatment of glucocorticoid-induced osteoporosis in a living organism (including humans) including a glucocorticoid-related osteoporosis treatment amount of the Formula I compound, a pharmaceutically acceptable salt or prodrug thereof, and a pharmaceutically acceptable carrier.

This invention also relates to medicinal compositions for the treatment of osteoporosis resulting from increased activity of the thyroid gland in a living being (including humans), including an amount for treating osteoporosis resulting from increased activity of the thyroid gland.

The thyroid gland is made up of a Formula I compound, a pharmaceutically acceptable salt or prodrug thereof, and an acceptable carrier

Pharmacologically.

This invention also relates to medicinal compositions for the treatment of immobilized osteoporosis in a mammal (including a human), including an immobilized osteoporosis treatment amount of the Formula I compound, a pharmaceutically acceptable salt or prodrug thereof, and a pharmaceutically acceptable carrier substance.

This invention also relates to medicinal compositions for the treatment of heparin-induced osteoporosis in a mammalian organism (including humans) comprising a heparin-induced osteoporosis treatment amount of the Formula I compound, a pharmaceutically acceptable salt or prodrug thereof, and a pharmaceutically acceptable carrier.

This invention also relates to medicinal compositions for the treatment of immunosuppressive osteoporosis in a mammalian organism (including a human) in which a quantity for the treatment of immunosuppressive osteoporosis of the Formula I compound, a pharmaceutically acceptable salt or prodrug thereof, and a pharmaceutically acceptable carrier substance is made.

Another aspect of this invention relates to combinations of Formula I compounds, a pharmaceutically acceptable salt or prodrug thereof, and other compounds as described below.

Another aspect of this invention relates to drug compositions acting as a compound of Formula I, a salt or pharmaceutically acceptable prodrug thereof, and an antiresorptive agent and using such compositions to treat (e.g., prevent) conditions of low bone mass, including osteoporosis in mammals (e.g., humans, in particular women) or use these combinations for other bone mass-increasing uses.

The combinations of this invention include a therapeutically effective amount of a first compound; The first mentioned compound is a compound of Formula I or a pharmaceutically acceptable salt or prodrug thereof; A therapeutically effective amount of a second compound; The brown compound mentioned is an anti-absorption agent such as an anti-estrogen or bisphosphonate.

Preferred antiestrogens include raloxifene, droloxifene, tamoxifen, 4-hydroxy-tamoxifen, idoxifene, levormeloxifene, centroman, toremifene,

6-(4-hydroxy-phenyl)-5-[4-(2-piperidin-l-yl-ethoxy)-benzyl]-naphthalen-2-ol)

{4-[2-(2-Aza-bicyclo[2.2.1]hept-2-yl)-ethoxy]-phenyl}-[6-hydroxy-2-(4-hydroxy-

,phenyl)-benzo[b]thiophen-3-yl]-methanone

Cis-6-(4-fluoro-phenyl)-5-[4-(2-piperdin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro

naphthalene-2-ol;

(-)-Cis-6-phenyl-5-[4-(2-pyrrolidin-l-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-

naphthalene-2-ol;

Cis-6-phenyl-5-[4-(2-pyrrolidin-l-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-

naphthalene-2-ol;

Cis-l-[6'-pyrrolodinoethoxy-3'-pyridyl]-2-phenyl-6-hydroxy-l,2,3,4-

tetrahydronaphthalene;

l-(4'-Pyrrolidinoethoxyphenyl)-2-(4&amp;-fluorophenyl)-6-hydroxy-l,2,3,4-

terahydroisoquinoline;

Cis-6-(4-hydroxyphenyl)-5-[4-(2-piperidin-l-yl-ethoxy)-phenyl)-5,6,7,8-tetrahydro-naphthalene-2-ol; and

l-(4'-Pyrrolidinolethoxyphenyl)-2-phenyl-6-hydroxy-l,2,3,4-

tetrahydroisoquinoline;

Pharmacologically acceptable salts, including droloxifene, are particularly preferred, including estrogen antagonists Cis-6-(4-fhroro-phenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-pheny]-5, 6,7,8-tetrahedronaphthalene-2-ol;

(-)-Cis-6-phenyl-5-[4-(2-pyrrolidin-l-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-

naphthalene-2-ol;

Cis-6-phenyl-5-[4-(2-pyrrolidin-l-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-

naphthalene-2-ol;

Cis-l-[61-pyirolodinoethoxy-31-pyridyl]-2-phenyl-6-hydroxy-l,2,3,4-

tetrahydronaphthalene;

l-(4'-Pyrrohdinoethoxyphenyl)-2-(4&amp;-fluorophenyl)-6-hydroxy-l)2,3,4-

tetrahydroisoquinoline;

Cis-6-(4-hydroxyphenyl)-5-[4-(2-piperidin-1-yl-ethxy)-pheny

naphthalene-2-ol; and

l-(4'-Pyrrolidinolethoxyphenyl)-2-phenyl-6-hydroxy-l,2,3,4-

tetrahydroisoquinoline;

And the salts that are accepted medicinally.

The preferred bisphosphonates are alendronic acid, tiludronic acid, clodronic acid, etidronic acid, risedronic acid, ibandronic acid and pamidronic acid and their pharmaceutically acceptable salts.

Another aspect of this invention is a method for treating mammals suffering from low bone mass, including giving a mammal suffering from a condition represented by low bone mass:

a) a therapeutically effective quantity of a first compound, where said first compound is a compound of Formula I or a pharmaceutically acceptable salt or prodrug thereof; And

b) A therapeutically effective amount of a second compound, the second compound being an anti-resorptive agent such as an anti-estrogen or a bisphosphonate.

These formulations and methods may also be used for other bone mass-increasing uses.

Preferred eshogen antagonist(s) in this method include droloxifene, raloxifene,

levormeloxifene, centroman, toremifene, 4-hydroxy-tamoxifen, tamoxifen, idoxifene

6-(4-hydroxy-phenyl)-5-[4-(2-piperidin-l-yl-ethoxy)-benzyl]-naphthalen-2-ol,

{4-[2-(2-Aza-bicyclo[2.2.1]hept-2-yl)-ethoxy]-phenyl}-[6-hydroxy-2-(4-hydroxy-

phenyl)-benzo[b]thiophen-3-yl]-methanone,

Cis-6-(4-fluoro-phenyl)-5-[4-(2-piperidin-l-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-

naphthalene-2-ol;

(-)-Cis-6-phenyl-5-[4-(2-pyrrolidin-l-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-

naphthalene-2-ol;

Cis-6-phenyl-5-[4-(2-pyrrolidin-l-yl-ethoxy)-phenyl)-5,6,7,8-tetrahydro-

;naphthalene-2-ol

Cis-l-[6'-pyrrolodinoethoxy-3'-pyridyl]-2-phenyl-6-hydroxy-l,2,3,4-

tetrahydronaphthalene;

l-(4'-Pyrrolidinoethoxyphenyl)-2-(4&amp;-fluorophenyl)-6-hydroxy-l,2,3,4-

tetrahydroisoquinoline;

Cis-6-(4-hydroxyphenyl)-5-[4-(2-piperidin-l-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol; and

l-(4'-Pyrrolidinoleth5xyphenyl)-2-phenyl-6-hydroxy-l,2,3,4-

tetrahydroisoquinoline;

Pharmacologically acceptable salts, including droloxifene, are particularly preferred, including estrogen antagonists Cis-6-(4-fluoro-phenyl)-5-[4-(2-piperidin-l-yl-ethoxy)-phenyl]-5, 6,7,8-tetrahydro-naphthalene-2-ol;

(-)-Cis-6-phenyl-5-[4-(2-pyrrolidin-l-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-

naphthalene-2-ol;

Cis-6-phenyl-5-[4-(2-pyrrolidin-l-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-

naphthalene-2-ol;

Cis-l-[6'-pyrrolodinoethoxy-3'-pyridyl]-2-phenyl-6-hydroxy-l,2,3,4-

tetrahydronaphthalene;

l-(4'-Pyrrolidinoethoxyphenyl)-2-(4&amp;-fluorophenyl)-6-hydroxy-l,2,3,4-

tetrahydroisoquinoline;

Cis-6-(4-hydroxyphenyl)-5-[4-(2-piperidin-l-yl-ethoxy)-phenyl)-5,6,7,8-tetrahydro-naphthalene-2-ol; and

l-(4'-Pyrrolidinolethoxyphenyl)-2-phenyl-6-hydroxy-l,2,3,4-

tetrahydroisoquinoline;

And the salts that are accepted medicinally.

Preferred bisphosphonates include alendronicacid, tiludronic acid, pamidronic acid, clodronic acid, etidronic acid, risedronicacid, and ibandronicacid.

And its salts are accepted medicinally.

A favorable aspect of this method is one in which the condition of low bone mass is osteoporosis.

Another favorable aspect of this method is one in which the first compound and the second compound are given at essentially the same time.

Another favorable aspect of this method is one in which the first compound is given for a period of from about a week to about three years.

Informationally, giving the first compound is followed by giving the second compound, so that the second compound is an antagonist/anti-estrogen for a period of time from about three months to about three years, without giving the first compound during the second period from about three months to about three years.

Alternatively, administration of the first compound is followed by administration of the second compound such that the second compound is an estrogen antagonist for a period of more than about three years without administration of the first compound during a period of more than about three years.

Another aspect of this invention is a set including:

a) A therapeutically effective quantity of the Formula I compound, a pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutically acceptable carrier substance in the form of a first unit dose;

b) A therapeutically effective quantity of an anti-resorptive agent such as an anti-estrogen or bisphosphonate and a pharmaceutically acceptable carrier in the form of a second dosage unit; and b) Container means to contain the first and second dosage forms mentioned.

Preferred antiestrogens in this group include droloxifene, centchroman, toremifene, 4-hydroxy-tamoxifen, tamoxifen, raloxifene, idoxifene, and levormeloxifene.

6-(4-hydroxy-phenyl)-5-[4-(2-piperidin-l-yl-ethoxy)-benzyl]-naphthalen-2-ol,

2-(2-Aza-bicyclo[2.2.1]hept-2-yl)-ethoxy]-phenyl}-[6-hydroxy-2-(4-hydroxy--4}

,phenyl)-benzo[b]thiophen-3-yl]-methanone

Cis-6-(4-fluoro-phenyl)-5-[4-(2-piperidin-l-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-

naphthalene-2-ol;

(-)-Cis-6-phenyl-5-[4-(2-pyrrolidin-l-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-

naphthalene-2-ol;

Cis-6-phenyl-5-[4-(2-pyrrolidin-l-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-

naphthalene-2-ol;

Cis-l-[6'-pyrrolodinoethoxy-3'-pyridyl]-2-phenyl-6-hydroxy-l,2,3,4-

tetrahydronaphthalene;

l-(4'-Pyrrolidinoethoxyphenyl)-2-(4&amp;-fluorophenyl)-6-hydroxy-l,2,3,4-

tetrahydroisoquinoline;

Cis-6-(4-hydroxyphenyl)-5-[4-(2-piperidin-l-yl-ethoxy)-phenyl]-5,6,78-tetrahydro-naphthalene-2-ol; and

l-(4'-Pyrrolidmolethoxyphenyl)-2-phenyl-6-hydroxy-l,2,3,4-

tetrahydroisoquinoline;

Pharmacologically accepted ones include droloxifene salts and salts; particularly preferable include estrogen antagonists Cis-6-(4-fluoro-phenyl)-5-[4-(2-piperidin-l-yl-ethoxy)-phenyl]-5. ,6,7,8-tetrahydro-naphthalene-2-ol;

(-)-Cis-6-phenyl-5-[4-(2-pyrrolidin-l-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-

naphthalene-2-ol;

Cis-6-phenyl-5-[4-(2-pyrrolidin-l-yl-ethoxy)-phenyl]-5,6,7,8-tetraydro-

naphthalene-2-ol;

Cis-l-[6'-pyn0olodinoethoxy-3'-pyridyl]-2-phenyl-6-hydroxy-l,2,3,4-

tetrahydronaphthalene;

l-(4'-Pyrrolidinoethoxyphenyl)-2-(4''-fluorophenyl)-6-hydroxy-l,2,3,4-

tetrahydroisoquinoline;

Cis-6-(4-hydroxyphenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-5,

naphthalene-2-ol; and

l-(4'-Pyrrolidmolethoxyphenyl)-2-phenyl-6-hydroxy-l,2,3,4-

tetrahydroisoquinoline;

And the salts that are accepted medicinally.

Includes preferred bisphosphonates, tiludronic acid, alendronic acid,

ibandronic acid, risedronic acid, clodronic acid, etidronic acid and pamidronic acid and their pharmaceutically acceptable salts.

Another aspect of this invention relates to a medicinal composition comprising a compound of Formula I, a pharmaceutically acceptable salt or primer thereof, and another bone-building agent (although the other bone-building agent may be a different compound of Formula I) and for the use of such compositions to treat conditions represented by bone mass. A few, including osteoporosis in mammals (e.g., humans, especially women) or the use of these formulations for other bone mass-increasing uses.

The combination includes a therapeutically effective amount of the first component; The first compound mentioned is a compound of Formula I or a pharmaceutically acceptable salt or prodrug thereof; A therapeutically effective amount of a second compound, the said second compound being another bone-building factor.

Preferred osteogenic factors - IGF-1 optionally with IGF-1-binding protein 3, prostaglandin, sodium fluoride antagonist, prostaglandin, parathyroid hormone (PTH), active parts of parathyroid hormone, parathyroid hormone-related peptides and active agents and analogues. Of peptides related to parathyroid hormone, growth hormone or stimulants of growth hormone secretion and their pharmaceutically acceptable salts.

Another aspect of this invention is a method for treating neurotic mammals with low bone mass comprising administering to a mammal with a condition characterized by low bone mass:

a) A therapeutically effective amount of the first compound; The first compound mentioned is a compound of Formula I or a pharmaceutically acceptable salt or prodrug thereof; And

b) A therapeutically effective amount of a second compound. The aforementioned second compound is a bone-building factor other than the Formula I compound.

These formulations and methods may be used for other bone mass-increasing uses

Preferred osteogenic factors include IGF-1 optionally with IGF-1-binding protein 3, prostaglandin, prostaglandin antagonist, sodium fluoride, parathyroid hormone (PTH), active parts of parathyroid hormone, parathyroid hormone-related peptides, active parts, and analogues. Of peptides related to the parathyroid hormone' growth hormone or stimulants of growth hormone secretion and their pharmaceutically acceptable salts.

A favorable aspect of this method is one in which the condition of low bone mass is osteoporosis.

Another favorable aspect of this method is one in which compound one and compound two are given at essentially the same time.

Another aspect of this invention is a set including:

a) A therapeutically effective quantity of the Formula I compound or a pharmaceutically acceptable salt or prodrug thereof and a pharmaceutically acceptable carrier in the form of a first unit dose;

b) A therapeutically effective amount of a second compound, where said second compound is a bone-building factor other than the Formula I compound; And

c) Container means for containing the first and second dosage forms.

The preferred anabolic agents include IGF-1 optionally with IGF-1-binding protein 3; prostaglandin, antagonist/antagonist sodium fluoride 'prostaglandin, parathyroid hormone (PTH), active parts of the parathyroid hormone, peptides related to the parathyroid hormone and active parts and homologs of peptides related to the parathyroid hormone' growth hormone or stimulants of growth hormone secretion and pharmaceutically acceptable salts thereof.

A preferred group of compounds, such as group T2, contains such compounds of formula I as shown above where:

B is N;

A is C1-C3)alkylsulfonyl);

Q is:

C3-C5)alkylene-O-(C1-C3)alkylene)-,

(C5-C7)alkylene Optionally replaces the aforementioned C5-C7)alkylene with up to four individually selected fluoro substituents or C1-C4)alkyl)' -C2-C4)alkylene-X)-'

(CH2)-meta-phenylene-O-(CH2)- is optionally mono- or di-substituted separately with

chloro'trifluoromethoxy,difluoromethoxy,trifluoromethyl,methoxy or fluoro or _(CH2)-meta-phenylene-(CH2)- optionally mono- or di-substituted separately with chloro'trifluoromethoxy'difluoromethoxy,trifluoromethyl or fluoro; M is V-Ar2-1Ar- or Ar1-O-Ar2-;

V is a bond or -CH2-;

z is C1-C4)alkoxycarbonyl' Carboxyl) or tetrazolyl;

X is thiazolyl, thienyl, or furanyl;

K is methylene;

Ar1 is thiazolyl, thienyl, furanyl, (C5-C7)cycloalkyl, phenyl, or pyridyl;

Ar2 is pyridyl,thiazolyl,thienyl,phenyl,(C5-C7)cycloalkylk'pyrimidyl pyrazinyl'isoxazolyl,imidazolyl'furanyl,oxazolyl,triazolyl or pyrazolyl; R1 is C1-C4)alkyl, fluoro, chloro or C1-C4)alkoxy)' is C1-C4)alkyl.

The above two are optionally mono-, di- or tri-substituted separately with hydroxy

or fluoro; And

R3 and R2 are each individually difluoromethoxy, trifluoromethyl, methoxy, chloro'trifluoromethoxy or fluoro.

A group of preferred compounds among the compounds of group T2' is referred to as group U2. It contains these compounds, where:

Q is

-(CH2)-meta-phenylene-(CH2)-;

M is Ar1-Ar2-;

'Ar is phenyl;

Ar2 is (C5-C7) cycloalkyl pyrimidyl, pyridyl, thiazolyl, thienyl, phenyl,

oxazolyl, imidazolyl 'furanyl, pyrazinyl' isoxazolyl or pyrazolyl, said Ar2 being optionally mono- or di-substituted separately with R1 or R2;

1R is trifluoromethyl, methoxy, methyl, fluoro, chloro, difluoromethoxy or trifluoromethoxy; And

R2 is chloro,methoxy or fluoro.

A set of preferred compounds among the compounds of group T2, denoted by group V2, contains these compounds where: Q is:

-(CH2)-meta-phenylene-O-(CH2)-;

M is Ar2-1Ar-;

Ar1 is phenyl;

Ar2 is, pyrimidyl, pyridyl, thiazolyl, thienyl, phenyl, (C5-C7)cycloalkyl pyrazinyl, isoxazolyl, imidazolyl, furanyl, oxazolyl or pyrazolyl, said Ar2 being optionally mono- or di-substituted separately with R1 or R2;

R1 is difluoromethoxy' trifluoromethyl, methoxy, methyl, fluoro, chloro or trifluoromethoxy; And

R2 is chloro,methoxy or fluoro.

A particularly favored compound of group U2 is the compound where:

A is methylsulfonyl;

Z is carboxyl; The M is .4-(cyclohexyl)phenyl

A particularly favored compound of group U2 is the compound where:

A is methylsulfonyl;

Z is carboxyl; The M is .4-(thiazol-2-yl)phenyl

A particularly favored compound of group U2 is the compound where:

A is methylsulfonyl; z is carboxyl; And M is 4-(prazin-2-yl)phenyl. Particularly favorable compounds among group U2 are:

a)(3-{[(4-Cyclohexyl-benzyl)-methanesulfonyl-amino]-methyl}-phenyl)-acetic)

;acid

b) (3-{[Methanesulfonyl-(4-thiazol-2-yl-benzyl)-amino]-methyl}-phenyl)-acetic)

acid; or

c) (3-{[Methanesulfonyl-(4-pyrazin-2-yl-benzyl)-aminol-methyl}-phenyl)-acetic)

acid

A group of preferred compounds, denoted group W2, contains such compounds having the formula I as shown above where: B is N;

A is C1-C3)alkylsulfonyl);

Q is _C2-C4)alkylene-X)-;

X is thiazolyl or furanyl; Said thiazolyl or furanyl may optionally be mono- or di-substituted individually with trifluoromethyl, chloro, fluoro, mehoxy, mehyl difluoromethoxy or trifluoromethoxy;

K is oxy-ethylene or propylene, the aforementioned propylene being optionally monounsaturated;

M is Ar-, said Ar- being oxazolyl, thiazolyl, pyridyl, thienyl, phenyl cyclobutyl, cyclopentyl, cyclohexyl, imidazolyl, pyrimidyl, isoxazolyl, or cycloheptyl;

R1 is (C1-C7)alkanoyl, (C3-C7)cycloalkyl, (C1-C7)alkyl, (C1-C6)alkoxy, halo) or C3-C7)cycloalkyl(C1-C4)alkyl), it is, (C1) -C7)alkyl, (C1-C6)alkoxy) C1-C7)alkanoyl, (C3-C7)cycloalkyl) or C3-C7)cycloalkyl (C1-C4)alkyl) are optionally mono-, di- or tri-substituted individually with fluoro, hydroxy or chloro; And

R3 and R2 are each individually difluoromethoxy, trifluoromethyl, methoxy, chloro, trifluoromethoxy or fluoro.

A group of preferred compounds among the compounds of group W2, denoted by group X2, contains these compounds where: A is methylsulfonyl;

Z is carboxyl, or C1-C4)alkoxycarbonyl);

Q is -propylene-x-;

X is hiazolyl;

K is oxy-ethylene or propylene;

M is an optional phenyl mono- or di-substituted separately with methoxy, chloro, fluoro-trifluoromethoxy, methyl, difluoromethoxy or trifluoromethyl. A particularly favored compound of group X2 is a compound where:

Z is carboxyl;

K is propylene; The M is .3-(chloro)phenyl

A particularly favored compound of group X2 is a compound where:

Z is carboxyl;

K is oxy-ethylene; And M is 3,5-dichlorophenyl. Particularly favorable compounds among group X2 are:

a) 2-(3-{[2-(3,5-Dichloro-phenoxy)-ethyl]-methanesulfonyl-amino}-propyl)-)

thiazole-4-carboxylic acid; and (b) 2-(3-{[3-(3-Chloro-phenyl)-propyl)-methanesulfonyl-amino}-propyl)-thiazole-

4-carboxylic acid.

Another aspect of this invention relates to a compound of the formula:lA

<img file="SA2048B1_D0002.tif" />

Or a pharmaceutically acceptable salt or prodrug thereof, where either (1): B is N;

A is C3-C7)cycloalkylsulfonyl, (C1-C6)alkylsulfonyl, C3-C7)cycloalkyl(C1-C6)alkylsulfonyl, the aforementioned parts of A are optionally mono-, di- or triple-substituted on the carbon individually with C1-C4). alkyl, hydroxy) or halo; Q is:

_C2-C6)alkylene-W-(C1-C3)alkylene)-;

_C3-C8)alkylene)-, optionally replacing the aforementioned -C3-C8)alkylene) with up to four individually selected fluoro or C1-C4)alkyl substituents,

alkylene-(x-(c1-c5-,,-(C1-C1)alkylene-X-,-(C1-C3)alkylene-X-(C1-C3)alkylene-C0-C3)alkylene--,-( C2-C4)alkylene-WX) C0-C4)alkylene-XW-(C1-C3)alkylene-,-

-C3)alkylene-C2-C5)alkylene-WXW-(C1)-, since the two states of w are independent of each other,

C1_C4)alkylene-ethenylene-(C1-C4)alkylene-)-, C2)alkylene-X-(C0-C5)alkylene--,-(C1-C4)alkylene-ethenylene-(C0 C2)alkylene-XW-( C1-C3)alkylene--,-(C1-C4)alkylene-ethenylene-(C0-,-(C1-C4)alkylene-ethynylene-(C1-C4)alkylene C3)alkylene-or-C1-C4)alkylene- ethynylene-X-(C0)-; w is aminosulfonyl-,sulfonyl,sulfino,thio,oxy,sulfonylamino,-mono-N-(C1-C4)alkyleneaminosulfonyl-,N-(C1-C4)alkylenecarboxamido,carboxamido,N-(C1-C4)alkylenesulfonylamino,carbamoyl ,N-(C1-C4)alkylenecarboxamidooxy -carboxamidooxy carbamoyloxy, -mono-N-(1C-C4)lkylenecarbamoyl, or

mono-N-(alkylenecarbamoyloxy(C-C4 -),) where the w alkyl groups are informatively replaced

Mentioned on a carbon with one to three fluorines;

X is a five- or six-membered aromatic ring having one or two individually selected heteroatoms of oxygen, nitrogen, sulfur, and Said ring is optionally mono- or di-substituted separately with trifluoromethyl, (C1-C3)alkyl, halo, C1-C4)alkoxy, hydroxyl, difluoromethyloxy, trifluoromethyloxy), or carbamoyl; Z is,1,2,4-oxadiazolyl,tetrazolyl,(C1-C6)alkoxycarbonyl,carboxyl C1-C4)alkylsulfonylcarbamoyl,5-oxo-l,2,4-oxadiazolyl) or phenylsulfonylcarbamoyl;

K is a bond, thio(C1-C4)alkylene, (C1-C8)alkylene or oxy(C1-C4)alkylene, the aforementioned being optionally mono-unsaturated and where K is optionally mono-substituted,

Binary or triple bonded with methyl, fluoro or chloro;

M is Ar1-(C1-C3)-S-(C1-C3)-Ar2 or -Ar1-(C1-C3)-S-Ar2-,-Ar1-S-(C1-C3)-Ar2-,-Ar1 -O-Ar2, -Ar1-S-Ar2, -Ar1-V-Ar2, -Ar, where Ar2 and Ar1 are each individually a partially saturated, fully saturated or completely unsaturated ring with five to eight members and optionally one to Four heteroatoms selected separately from oxygen, sulfur, and nitrogen, or a circular double ring consisting of two joined rings that are partially saturated, completely saturated, or completely unsaturated, with five or six members, taken separately, indicating that they have one to four heteroatoms selected each. Separately from nitrogen, sulfur and oxygen;

The said parts of Ar2, 1Ar, Ar are optionally substituted, on one ring if the part is monocyclic, or one or both rings if the part is bicyclic, on carbon, nitrogen or sulfur with up to three separately selected substitutions of R3, R2, R1. Where R3 and R2, R1 are (C1-C4)alkoxy(C1-C4)alkyl, (C1-C6)alkoxy, halo, nitro, hydroxy, oxy, (C3-C7)cycloalkyl, (C1-C7)alkyl. (C1-C4)alkoxycarbonyl,formyl,(C3-C7)cycloalkyl(C1-C4)alkan0yl,(C3-C7)cycloalkyl(C1-C4)alkyl,(C1-C4)alkanoylamino (C1-C6)alkanoyl(C1-C6)alkyl,(C1-C8)alkanoyl,amino,(C1-C4)alkylsulfonamido,sulfonamido,(C1-C4)alkoxycarbonylamino

mono-N- or di-N,N-(C1-C4)alkylamino, cyano,mono-N- or di-N,N-(C1-C4)alkylcarbamoyl,carbamoyl,alkylsulfinyl,(C1-C6)alkylthio,thiol (C1-C6)alkylsulfonyl, (C1-C6) or mono-N- or di-N,N-(C1-C4)alkylaminosulfinyl;

R2, R1 and 3R are optionally single-, di- or triple-substituted on their respective carbons with a halo or hydroxy; And

V is a bond or C1-C3 (alkylene) optionally monounsaturated and optionally mono-substituted or

Secondly separately with hydroxy or fluoro;

Provided that when K is C2-C4)alkylene and M is Ar and Ar is cyclohept-l-yl, cyclohex-l-yl, cyclopent-l-yl or cyclooct-l-yl then the C5-C8) cycloalkyl substituents are not At the one position with hydroxy;

Or (2):

B is N;

A is an alkanoyl, (C1-C6)alkanoyl(C5-C3-C7)cycloalkyl(C1-C6), the parts of said A being optionally mono-, fa- or triple-substituted on the carbon individually with a hydroxy or halo; Q is:

,-(C2-C6)alkylene-W-(C1-C3)alkylene

C4-C8)alkylene-), optionally replacing the aforementioned -C4-C8)alkylene) with up to four individually selected fluoro or (C1-C4)alkyl substituents.

X-(C1-C5)alkylene-_,

,-(C1-C5)Oalkylene-X-

C3)alkylene--,-(C1-C3)alkylene-X-(C1

C3)alkylene--,-(C2-C4)alkylene-WX-(C0

-C4)alkylene-XW-(C1-C3)alkylene-,-(C0

-C2-C5)alkylene-WXW-(C1-C3)alkylene)-, since the two states of w are independent of each other,

,-(C1-C4)alkylene-ethenylene-(C1-C4)alkylene-

C1-C4)alkylene-ehenylene-(C0-C2)alkylene-X-(C0-C5)alkylene-)-' '-(C1-C4)alkylene-ethenylene-(C0-C2)alkylene-XW-(C1- C3)aJkylene--C1-C4)alkylene-ethynylene-(C1-C4)alkylene)-, C1-C4)alkylene-ethynylene-X-(C0-C3)aIkylene-OR)-; w is aminosulfonyl- 'Sulfonyl' Sulfino,thio,oxy; mono-N-(C1-C4)alkyleneaminosulfonyl--;sulfonylamino; 'N-(C1-C4)alkylenecarboxamido, carboxamido, N-(C1-C4)alkylenesulfonylamino carboxamidooxy, carbamoyl 'N-(C1-C4)alkylenecarboxamidooxy, mono-N-(C1-C4)alkylenecarbamoyl-, carbamoyloxy, or mono-N-(C1-C4)alkylenecarbamoyloxy-' wherein the aforementioned W alkyl groups on the carbon are optionally replaced with one to three fluorines;

X is a five- or optionally six-membered aromatic ring having one or two individually selected heteroatoms of oxygen, nitrogen, sulfur, and The mentioned ring is optional

Mono- or di-substituted individually with (C1-C3)alkyl halo), trifluoromethyl' trifluoromethyloxy, C1-C4)alkoxy' hydroxyl' difluoromethyloxy), or carbamoyl, Z is carboxyl, tetrazolyl' (C1-C6)alkoxycarbonyl, 1,2 ,4-oxadiazolyl,

oxo 5- oxo -1,2,4-oxadiazolyl-, C1-C4)alkylsulfonylcarbamoyl) or

phenylsulfonylcarbamoyl;

K is thio(C1-C4)alkylene' (C1-C8alkylene or oxy(C1-C4)alkylene') said (C1-C8) alkylene is optionally monounsaturated and where K is optionally mono-substituted'

Binary or triple bonded with methyl, fluoro or chloro;

M is S-Ar2'-Ar1-V-Ar2,-Ar-O-Ar2'-Ar1-S-(C1-C3)-Ar2-'-Ar2-1Ar-'

Ar2 and Ar1, Ar where, -Ar2-(C1-C3)-S-(C1-C3)-Ar2 or -Ar1-(C1-C3)-S-Ar2- is a partially saturated ring unit, K-saturated or unsaturated. Fully saturated with five to eight members - optionally having one to four individually selected heteroatoms of oxygen, sulfur and nitrogen, or a bicyclic ring consisting of two joined rings - partially saturated, - fully saturated or

Totally unsaturated with five or six members, taken separately, having one to four separately selected heteroatoms of sulfur nitrogen and oxygen;

The aforementioned parts of rA2, Ar, and Ar are optionally substituted, on one ring if the part is monocyclic, or one or both rings if the part is bicyclic, on carbon, nitrogen, or sulfur, with up to three separately selected substitutions of R3, R2, and R1. Where R2, R1 and 3R are

C1-C4)alkoxy(C1-C4)alkyl, (C1-C6)alkoxy, halo, nitro, hydroxy, oxy), (C3-C7)cycloalkyl, (C1-C7)alkyl, (C1-C4)alkoxycarbonyl, formyl, (C3-C7)cycloalkyl(C1-C4)alkanoyl, (C3-C7)cycloalkyl(C1-C4)alkyl alkanoyl(C1-C6)alkyl, (C1-C8)alkanoyl(, (C1-C4)alkanoylamino, (C1-C6,amino,(C1-C4)alkylsulfonamido,sulfonamido,(C1-C4)alkoxycarbonylamino,carbamoyl,mono-N-or di-N,N-(C1-C4)alkylamino,(C1-C6)alkylthio, thiol,cyano,mono-N-or di-N,N-(C1-C4)alkylcarbamoyl C1-C4)alkylsulfonyl (C1-C6)alkylsulfinyl) or mono-N- or di-N,N-(C1-C4)alkylaminosulfinyl;

1R, R2, R3 are optionally mono-, di- or triple-substituted on their respective carbons with a halo or hydroxy; And

V is a bond or (C1-C3) alkylene, optionally monounsaturated and optionally mono-substituted or

Diode separately with hydroxy or fluoro;

Provided that when K is M, (C2-C4)alkylene is Ar, and Ar is cyclopent-l-yl, cyclohept-l-yl, cyclohex-l-yl or cyclooct-l-yl then the C5-C8)cycloalkyl substituents are not substituted. At the one position with hydroxy;

Provided that 6-[(3-phenyl-propyl)-(2-propyl-pentnoy1)-amino]-hexanoic acid ethyl ester thereof are not included.

Another aspect of this invention relates to drug compositions including:

A therapeutically effective quantity of a compound of Formula IA or a pharmaceutically acceptable salt or prodrug thereof, and a therapeutically effective quantity of

-2-(4-[methoxy-phenyl)-3-[4-(2-piperidm-l-ethoxy)--phenoxy]-benzo[b]thiophen

-6

or a pharmaceutically acceptable salt thereof or 3-[4-(l,2-diphenyl-but-l-enyl)-phenyl]-acrylic acid or a pharmaceutically acceptable salt thereof.

Another aspect of this invention relates to a method for treating a mammal with a condition of low bone mass which includes administering to said mammal:

A therapeutically effective quantity of a compound of Formula IA or a pharmaceutically acceptable salt or prodrug and a therapeutically effective quantity of

2-(4-methoxy-phenyl)-3-[4-(2-pipendin-l-yl-ethoxy)-phenoxy]-benzo[b]thiophen-

6-ol

or a pharmaceutically acceptable salt thereof or 3-[4-(l,2-diphenyi-but-l-enyl)-phenyl]-acrylic acid or a pharmaceutically acceptable salt thereof.

Another aspect of this invention relates to a group including:

A therapeutically effective quantity of a compound of Formula IA or a pharmaceutically acceptable salt or prodrug thereof and a pharmaceutically acceptable carrier in the form of a first unit dose; A therapeutically effective amount of

2-(4-mehoxy-phenyl)-3-[4-(2-piperidin-l-yl-ethoxy)-phenoxy]-benzo[b]thiophen-

6-

or a pharmaceutically acceptable salt thereof or 3-[4-(l,2-diphenyl-but-l-enyl)-phenyl]-acrylic acid or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier in the form of a second unit dosage; And container means to contain the first and second mentioned dosage forms. Another aspect of this invention relates to a method for treating a mammal in need of kidney reconstruction that includes administering to said mammal a therapeutically effective amount of a compound of Formula IA or a pharmaceutically acceptable salt or prodrug thereof.

Another aspect of this invention relates to a method for treating a mammal with a condition characterized by low bone mass, which includes administering to said mammal a therapeutically effective amount of a compound of the formula or a pharmaceutically acceptable salt or prodrug thereof.

Another aspect of this invention relates to a pharmaceutical composition that constitutes a therapeutically effective amount of a compound of Formula IA, a pharmaceutically acceptable salt or prodrug thereof, and a pharmaceutically acceptable carrier substance.

Another aspect of this invention relates to a method for reducing intraocular pressure in a mammal involving administering a pharmacologically effective amount of a compound of Formula IA or a pharmaceutically acceptable salt or prodrug thereof to a mammal in need thereof.

The phrase &amp;condition(s) which presents with low bone mass&amp; refers to a condition in which the level of bone mass is below the normal level for the particular age group as defined in the basics of:

The World Health Organization &amp;Assessment of Fracture Risk and its Application to Screening for Postmenopausal Osteoporosis (1994). Report of a World Health Organization Study Group. World Health Organization Technical Series 843&amp;.

Included in “condition(s) of low bone mass” are primary and secondary osteoporosis. Secondary osteoporosis includes glucocorticoid-induced osteoporosis, hyperthyroidism-induced osteoporosis, immobilization-induced osteoporosis, heparin-induced osteoporosis, and immunosuppression-induced osteoporosis. Also included are periodontal disease, alveolar bone loss, osteotomy, and idiopathic bone loss in childhood. 'Condition(s) of low bone mass' also includes long-term complications of osteoporosis such as curvature of the spine, loss of height and prosthetic surgery.

The phrase “condition of low bone mass” also refers to a mammal with a much higher than average chance of developing these diseases as described above including osteoporosis (eg, postmenopausal women, men over 60).

Other uses for increasing or enhancing bone mass include increasing the rate of bone fracture healing, enhancing the rate of successful bone grafts, bone healing after facial orthognathic or maxillary orthognathic or mandibular orthognathic surgery, in-growth of a prosthesis, vertebral osteosynthesis or long bone orthotics.

Those skilled in the art note that the term bone mass actually refers to the mass of bone over a unit area which sometimes (although not strictly speaking) refers to bone mineral density.

The term 'treating', 'treating' or 'treatment' as used here includes both preventive and mitigating treatment.

“Pharmaceutically acceptable” means that the carrier, diluent, excipients, and/or salt must be compatible with the other components of the formulation, and not be harmful to the user.

The phrase “prodrug” refers to compounds that are predrugs that, after administration, release the drug into the body through some chemical or physiological process (e.g., a prodrug that reaches a physiological pH or is converted by enzymatic action to the desired drug form). Representative prodrugs upon dissociation release the corresponding free acid, and those hydrolyzable ester-forming residues of formula I compounds include but are not limited to substituents where the Z portion individually is a carboxyl and the free hydrogen is replaced by a (C1-C4) alkyl, l-(alkanoyloxy)ethyl, (C1-C7)alkanoyloxymethyl has 4 to 9 carbon atoms, l-methyl-l-(alkanoyloxy)-ethyl has 5 to 1 carbon atoms, alkoxycarbonyloxymethyl has 3 to 6 carbon atoms, l-(alkoxycarbonyloxy)ethyl has 4 to 7 carbon atoms, l-methyl-l-(alkoxycarbonyloxy)ethyl has 5 to 8 carbon atoms, N-(alkoxycarbonyl)aminomethyl has 3 to 9 carbon atoms, l-(N). -(alkoxycarbonyl)amino)ethyl has 4 to 1 atoms

Carbon, gamma-butyrolacton-4-yl,4-crotonolactonyl,3-phthalidyl,

C2)alkylamino(C2-C3)alkyl-di-N,N-(C3 (as b-dimethylaminoethyl), N,N-di(C1-C2)alkylcarbamoyl-(C1-C2)alkyl,carbamoyl-(C1-C2) alkyl .piperidino-, pyrrolidino- or morpholino(C2-C3)alkyl

Representative five- to six-membered aromatic rings with one or two individually selected heteroatoms of oxygen, nitrogen and sulfur (i.e., pyrazinyl, pyrimidinyl, pyridazinyl, pyridinyl, isothiazolyl, isoxazolyl

Partially saturated, fully saturated or completely unsaturated rings with five to eight representative members optionally have one to four individually selected heteroatoms of oxygen, sulfur.

The nitrogens (i.e., Ar2, Ar1, Ar) are cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and phenyl. The five-membered NAT rings are also furyl, thienyl, -2H, and pyrrolyl

3H-pyrrolyl, pyrrolyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolidinyl, l,3-dioXolanyl oxazolyl, thiazolyl, imidazolyl, 2H-imidazolyl, 2-imidazolinyl, imidazolidinyl pyrazolyl, 2-pyrazolinyl, pyrazolidinyl, isothiazo lyl,isoxazolyl, 1,2-dhhiolyl 1,3-dthiolyl, 1,2,4-oxadiazolyl, 1,2,3-oxadiazolyl, 3H-l,2-oxathiolyl. . 1,2,3-triazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl

3H-1,2,3-dioxazolyl, 1,2,3,5-oxatriazolyl, 1,2,3,4-oxatriazoly, 1,3,4- thiadiazolyl

5H-1,2,5-oxathiazolyl,1,3,4-dioxazolyl,1,3,2-dioxazolyl,1,2,4-dioxazolyl

Representative six-membered rings are also 4H-pyranyl, 2H-pyranyl, pyridinyl, piperidinyl, 1,2-dioxinyl, 1,3-dioxinyl, morpholinyl, 1,4-dioxanyl, 1,4-dhhianyl, thiomorpholinyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazinyl, piperazinyl

2H-1,3-oxazinyl,4H-1,2-oxazinyl,1,3,5-trithianyl,1,2,3-triziny,1,2,4-triazinyl 2H-1,2-ohaziny,1,4 -oxazinyl,6H-1,2-oxaziny,6H-1,3-oxazinyl 4H-l,4-oxazinyl, 1,2,5-oxathiazinyl, p-isoxazinyl, o-isoxazinyl, 1,4-oxazinyl .1 3,5,2-oxadiazinyl and 1,2,5-oxathiazinyl, 1,2,6-oxathiazinyl, 1,2,6-oxadiazinyl.

Representative seven-membered rings are also oxepinyl, azepinyl, and thiepinyl

1.2.4- diazepinyl.

Representative eight-membered rings are also cyclooctyl and cyclooctenyl

cyclooctadienyl.

Representative bicyclic rings consisting of joined partially saturated, fully saturated or fully unsaturated five- or six-membered rings, taken individually, optionally having one to four individually selected heteroatoms of nitrogen, sulfur and oxygen are indolizinyl;

cyclopenta(b)pyridinyl,indolinyl,lH-isoindolyl,3H-indolyl,isoindolyl,indolyl,pyrano(3,4-b)pyrrolyl,benzofuryl,benzo(b)thienyl,isobenzofuryl

benzo(c)thienyl, lH-indazolyl, anthranilyl, benzoxazolyl, indoxazinyl, quinolinyl, 4H-quinolizinyl, purinyl, benzthiazolyl, benzimidazolyl, isoquinolinyl, cinnolinyl, quinoxalinyl, quinazolinyl, phhalazinyl naphthyl, isoindenyl, indenyl, pteridinyl, l,8- naphthyridinyl, tetralinyl,

pyrido(3,2-b)-pyridinyl, pyrido(3,4-b)-pyridinyl, 2H-1-benzopyranyl, decalinyl

,2H-1,4-benzoxazinyl,2H-1,3-benzoxazinyl,pyrido(4,3-b)-pyridinyl

4H-l,4-benzoxazinyl

For alkylene, it means a saturated hydrocarbon (straight or branched) in which a hydrogen atom is removed from each of the terminal carbon atoms. A representation of these groups (assuming the length listed includes the particular example) are methylene, ethylene, propylene, butylene,

pentylene, heptylene, hexylene).

For halo it means iodo, bromo, chloro, or .fluoro

For alkyl, it means straight-chain saturated hydrocarbon or branched-chain saturated hydrocarbon. Representative representations of these alkyl groups (assuming the length listed includes the particular example) are isopropyl, propyl, ethyl, methyl, butyl, sec-butyl, tertiary butyl, pentyl, isopentyl, neopentyl, tertiarypentyl, 2-methylbutyl, l-methylbutyl, 3-methylbutyl, heptyl, isohexyl, hexyl and octyl.

For alkoxy, it means a straight-chain saturated alkyl or a branched-chain saturated alkyl linked by an oxy. A representation of these alkoxy groups (assuming the length listed includes the particular example) are butoxy, isopropoxy, propoxy, ethoxy, methoxy, isobutoxy, tertiary pentoxy, neopentoxy, isopentoxy, pentoxy, tertiary butoxy, hexoxy, octoxy, and heptoxy, isohexoxy.

As used herein the term mono-N-or di-N,N-(C1-Cx) alkyl... refers to a portion

C1-Cx)alkyl) taken separately when di-N,N-(C1-Cx)alkyl... (X denotes integers).

Unless otherwise specified, the parts &amp;M&amp; specified above are optionally replaced (for example, the mere notation of a substitution such as 1R in a subfamily or dependency element does not mean that M is always replaced by part R1 unless it is stated that part M is replaced by 1R).

It must be understood that if the carbocyclic or heterocyclic part is linked or otherwise connected to a classified subject substance, through different ring atoms without indicating a special point of contact, then all possible points are designated, whatever it is through a carbon atom or; For example, a trivalent nitrogen atom. For example, the term &amp;pyridyl&amp; means 2-, 3-, or 4-pyridyl, the term &amp;thienyl&amp; means 2- or 3-thienyl, and so on.

The phrase “pharmaceutical-acceptable salt” refers to non-toxic anionic salts containing anions such as (but not limited to), bromide, sulfate, iodide, chloride

lactate, oxalate, fumarate, maleate, acetate, phosphate, bisulfate, tartrate, citrate, gluconate, 4-toluene-sulfonate, and methanesulfonate. The phrase also refers to non-toxic cationic salts such as (but not limited to): magnesium, calcium, potassium, sodium ammonium or protonated benzathine (choline, (N)N'-dibenzylethylenediamine, meglamine, ethylenediamine, diethanolamine, ethanolamine piperazine, (N-benzylphenethylamine). )benethamine, (N-methylglucamine) or (2-amino-2-hydroxymethyl-l,3-propanediol)tromethamine.

As used herein, the terms “reaction-inert solvent” and “inert solvent” refer to a solvent that does not react with starting materials, reagents, intermediates, or products in a way that adversely affects the yield of the desired product.

The negative or positive sign between parentheses used here in the nomenclature indicating plane polar light is rotated by a special stereoisomer.

A chemist of ordinary skill will note that certain compounds of this invention contain one or more atoms that may be in a particular stereochemical or geometric conformation, giving rise to stereoisomers and conformational isomers. all of these

Isomers and mixtures thereof are included in this invention. Also included are hydrates

Compounds of this invention.

A chemist of ordinary skill will note that certain combinations of heteroatom-containing substituents tabulated in this invention define compounds that are less stable under physiological conditions (e.g., those containing acetal or aminal linkages). Accordingly, these compounds are less preferred.

DTT means DMSO .dithiothreitol means EDTA .dimethyl sulfoxide means '.ethylenediamine tetraacetic acid

The methods and compounds of this invention lead to bone formation that reduces fracture rates. This invention makes an important contribution to this purpose by providing compounds and methods that increase bone formation leading to the prevention, delay, and/or reversal of osteoporosis and related bone diseases.

Other features and advantages become clear from the specification and claims describing the invention.

Detailed description of the invention

In the detailed description of the invention, the reference to “Formula I” must be interpreted as a reference to Formula I or Formula IA in order to include the present material added in this continuity part.

In general, the compounds of this invention may be manufactured by processes involving processes known in the chemical arts, particularly in light of the description contained herein. Certain processes for manufacturing the compounds of this invention are provided as additional features of the invention and are illustrated by the following reaction programs. may be

Other processes are described in the experimental part.

Some substituents (eg, carboxyl) may well be prepared by converting another functional group (examples for carboxyl are hydroxyl or carboxaldehyde) at a later point in the synthetic sequence.

In general, compounds of formula I where B is the nitrogen can be prepared by sequential alkylation of the sulfonamide or amide with two suitable alkyl halides or alkylsulfonates; Or reductive amination of an amine containing the necessary acidic function (suitably protected) by an aldehyde followed by reaction with an acylating agent or sulfonyl chloride followed by hydrolysis.

In general, compounds of formula I (where B is nitrogen) N, M, K, A and Q as described in the general description of the invention) may be prepared according to the methods described in Programs 1 and 2 below. In general, the sequences involve sequential alkylation of the appropriate sulfonamide or amide of formula I by two appropriate alkyl halides or alkylsulfonates. It is noted that programs 1 and 2 differ depending on the addition of the two alkylating agents. The alkylation method is typically chosen based on the reactivity of the electrophilic side chain. In order to minimize the amount of second alkylation that occurs in the first alkylation step, the less active electrophilic side chain typically enters first. One of the alkylating agents typically contains a carboxylic acid or acid isostere suitably masked by an appropriate protecting group. In programs 1 and 2, the precursor of the acid of formula 3 is a carboxylic ester where R represents either a straight-chain lower alkyl, preferably methyl or ethyl, or a tert-butyl or phenyl group. Other acid isosteres may be used with appropriate modification of these programs using methods known to those skilled in the art (see Program 6 which describes -tetrazole for example). Typical alkylating agents are benzylic or allylic, primary, secondary and preferably alkyl bromides or alkyl iodides.

Sulfonamide or amide formula 1 is converted into an anion by a strong base such as lithium bis(trimethylsilyl)amide, lithium diisopropylamide, sodium hydride,

potassium tert-butoxide, potassium bis(trimethylsilyl)amide, etc., in an organic solvent such as tetrahydrofuran, dimethylformamide (THF) or benzene/dimethylformamide at a temperature of about -78°C to about 10°C. The resulting anion is alkylated with a suitable alkyl halide or alkyl sulfonate of formula 2 or 3 (where 1 In some cases, varying amounts of a di-alkylated side product of the amide or sulfonamide are produced and can be removed using chromatographic techniques, preferably flash chromatography:

(W.C. Still, M. Kahn, A. Mitra, J. Orgh. Chem. 43,2923, 1978).

Compounds of formula 4 or 5 are converted back to the anion using a suitable base e.g

lithium diisopropylamide, lithium bis(trimethylsilyl)amide, sodium hydride

potassium tert-butoxide, potassium bis(trimethylsilyl)amide, or potassium carbonate in a protonated solvent such as benzene/dimethylformamide, THF, dimethylformamide, or acetone at a temperature from about -78°C to about 10.0°C. Alkylation (as described above) with a suitable alkyl halide or second alkyl sulfonate (formula compound 3 or 2) provides the corresponding formula 6 ester. The ester of formula 6 is hydrolyzed to the corresponding formula acid (in cases where R represents methyl or ethyl) by a dilute aqueous base solution (preferably sodium or potassium hydroxide in aqueous methanol or ethanol), lithium hydroxide in an aqueous alcoholic solvent, aqueous tetrahydrofuran at temperature From about 0°C to about 0.8°C, or using methods described in:

Organic Synthesis&amp;, Second Edition, T. W. Greene and Protecting Groups in&amp;

PGM Wuts, John Wiley and Sons, Inc., 1991

<img file="SA2048B1_D0003.tif" />

Compounds of formula I (for example, compounds of formula 31 or 41 where B is N and A, Z, Q, M, and K are as specified in the general description of the invention) may also be prepared from amines (see Programs 3-4 for example) . In general, suitable amine starting materials (compounds of formulas 9 and 10) may be commercially available or may be prepared using methods known to those skilled in the art (see:

&amp;The Chemistry of Amino, Nitroso and Nitro Compounds and their Derivatives&amp;,

Ed. s. Patai, J. Wiley, NewYork, 1982).

The starting nitriles formula may be prepared from an amine. For example, according to Programs 3 and 4, materials may either be available from commercial sources or may be prepared using the corresponding nitriles 7 or 8. that

Methods known to those skilled in the art (see:

Rappaport, &amp;The Chemistry of the Cyano Group&amp;, Interscience, New York, 1970 or Patai and Rappaport, &amp;The Chemistry of Functional Groups&amp;, pt. 2, Wiley, New

(1983, York

Formula 7 or 8 nitrile is reduced by a reducing agent such as borane-tetrahydrofuran complex, borane-methyl sulfide, lithium aluminum hydride complex, or by hydrogenation in the presence of a Raney nickel, platinum, or palladium catalyst in a protonated solvent such as methanol or ethanol at a temperature from about 0°C to about 0 5 Celsius. The resulting amine formula 9 or 0 1 is converted to either sulfonamide or amide formula 1 1 or 2 1 by treatment (acylation) with acid chloride or sulfonyl chloride in the presence of a weak base such as pyridine, triethylamine, or 4-methylmorpholine in a nonprotonated solvent such as methylene chloride or diethyl ether at a temperature from about 0-2°C to about 0-5°C. Alternatively, amines of formula 9 or 10 are conventionally coupled to carboxylic acids in an inert solvent such as dichloromethane or DMF (N,N-dimethylformamide) with a coupling reagent such as EDC (l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride) or DCC). l,3-dicyclohexylcarbodimide) in the presence of l-hydroxybenzotriazole hydrate (HOBT)) to generate compounds of formula 1 1 or 2 1. In the case where the amine is present in the form of the hydrochloride salt, it is preferable to add one equivalent of a suitable base such as triethylamine to the reaction mixture. Alternatively, coupling can be done with a coupling reagent agent such as

benzotriazol-l-yloxy-tris(dimethylamino)-phosphonium hexafluorophosphate (BOP) in an inert solvent such as methanol. These coupling reactions generally take place at a temperature from about 0.3°C to about 0.8°C, preferably 0°C to about 25°C. For a discussion of other cases used for conjugation of peptides see:

Houben-Weyl, Vol. XV, part II, E. Wunsch, Ed., George Theime Verlag, 1974, Stuttgart.

Alkylation and, if desired, deprotection, of compounds of formula 1 1 or 2 1 as described in Programs 1 and 2 yield the corresponding acid compounds of formulas 13 and 14.

Amines of formulas 9 and 10 may also be prepared by reduction of amides of formulas 1 and 16. Reduction can be achieved by using reagents such as borane-tetrahydrofuran complex, borane-methyl sulfide complex, or diisobutylaluminum hydride in a nonprotonated solvent such as tetrahydrofuran or diethyl ether at a temperature from about -78°C to about 60°C.

Amines of formula 9 and 01 can also be obtained from the corresponding nitro prefixes by reduction of the nitro group using reducing reagents such as HCl/zinc, hydrogenation in the presence of palladium, Raneynickel, or platinum catalysts, and other reagents as described by:

P. N. Rylander in 'Hydrogenation Methods', 1985, Academic Press, New York.

<img file="SA2048B1_D0004.tif" />

<img file="SA2048B1_D0005.tif" />

The description and preparation of other amines and alkylating agents useful for the above synthesis are described below in the section entitled Preparations.

An alternative to the alkyl chemistry described above for preparing compounds of formula I (wherein B is N and A, M, K and Q are as described in the general description of the invention) includes reductive amination of an amine containing the necessary acid functional (suitably protected) by an aldehyde namely Shown in Program 5. Alternatively, the aldehyde may have an acidic functional to pair with the amine.

Aminoselectivity is typically carried out by a reducing agent such as sodium cyanoborohydride or sodium triacetoxyborohydride, preferably at a pH between 6 and 8. The reaction occurs naturally in a protonated solvent such as methanol or ethanol at temperatures from about -78°C to about 4.0°C (for main reference see:

A. Abdel-Magid, C. Maryanoff, K. Carson, Tetrahedron Lett. 39, 31, 5595-5598, 1990).

Other use cases include: sodium cyanoborohydride and titanium isopropoxide

(2552-4, 55, 1990. R. J. Mattson et al, J. Org. Chem) Or the synthesis of imine under conditions of dehydration followed by reduction. The resulting amine, formulas 42 and 42a, is converted to the desired sulfonamide or amide in combination with acid chloride, sulfonyl chloride, or carboxylic acid as described in Programs 3 and 4. If desired, hydrolysis provides the corresponding acid.

<img file="SA2048B1_D0006.tif" />

The description and use of aldehydes useful in Program 5 above may be found in the Preparations section.

tetrazoles, i.e. I) Alternatively, another method for preparing certain compounds of the formula (they are as described above) is described in program 6. Q, M, A, K and N is B Formula 0 6 where alkyl halide or sulfonate Formula 4 The starter with amide or sulfonamide to perform the alkyl bromide process; 'Sulfonate or iodide is preferred, or sulfonate or halide is suitable (where X' is suitable).

To provide formula 59 compounds. nitrile primary' secondary, which contains allylic or 'benzylic'

Alkylation is achieved by treating the compound of formula 59 with a base such as 'potassium bis(trimethylsilyl)amide' lithium bis(trimethylsilyl)amide in a non-atonic solvent such as potassium carbonate, or potassium tert-butoxide. Alkylation occurs at acetone or 'benzene/dimethylformamide' dimethylformamide nitrile. The temperature is about -78°C to about 100°C. Preferred cases for converting dibutyltin oxide, formula 0 6, include treatment with the resulting tetrazole upon recondensation of steam: toluene in trimethylsilylazide, and

(S. J. Wittenberger and B. G. Donner, J. Org. Chem. 1993, 58, 4139-4141, 1993).

See tetrazoles for a review of alternative preparations for RN Butler, Tetrazoles, In Comprehensive Heterocyclic Chemistry; Potts, K. T. Ed.; Pergamon Press: Oxford, 1984, Vol. 5, pp. 791-838.

<img file="SA2048B1_D0007.tif" />

Alternatively, another method for preparing a certain compound of formula I (where B is N, Q'A and M as described in the general description of the invention) is described in Program 7. maybe

Prepare formula 46 esters using procedures described earlier (see Programs 1 and 2). Subsequent Heck coupling of this intermediate to an arylhalide (preferably aryl bromide, aryl triflate, aryl iodide, or ring system containing iodide, vinyl bromide, or triflate) is achieved by a palladium catalyst, such as palladium acetate or (0)tetrakis(triphenylphosphine)palladium In the presence of trialkylamine, such as triethylamine, in some cases, triarylphosphine may be added to the reaction. The reaction typically takes place in a nonprotonated solvent such as dimethylformamide or acetonitrile at a temperature of about 0°C.

to about 150% (see,

RF Heck in Comp. Org. Syn., Vol. 4, Ch. 4.3, p. 833 or Daves and Hallberg,

Chem. Rev. 1989, 89,1433).

If desired, compounds of Formula 47 can be hydrolyzed to the corresponding acid. Alternatively, compounds of Formula 47 can be hydrogenated and, if desired, further hydrolyzed to the corresponding acid of Formula 49. Suitable conditions for hydrogenation include the use of a palladium or platinum catalyst in an alcoholic solvent such as ethanol or methanol at a temperature from about 0°C to about 50°C. In cases where M represents a partially saturated ring system, hydrogenation generates a saturated ring system.

<img file="SA2048B1_D0008.tif" />

Alternatively, another method for preparing certain compounds of formula I is described in Program 8 (where B is M and A, Q, K and N are as described in the general description of the invention R and as described in Programs 1 and 2). Compounds of formula 51 may be prepared as described in Programs 1 and 2 by alkylation of compounds of formula 5 with an electrophile of formula 2 containing the appropriate function on the M ring, for subsequent conversion to an aldehyde. For example, the electrophilic substances of Formula 2 (Program 2) may contain a protected alcohol on the M ring, which can be deprotected after alkylation and oxidized to an aldehyde, using reagents known to those of skill in the art, to generate compounds of Formula 51. An alternative method is to alkylate with an electrophile of formula 2 where M contains a vinyl group. After alkylation, oxidative cleavage of the double bond provides the desired aldehyde of formula 51. Oxidative cleavage can be achieved by converting the double bond to 1,2-diol using osmium tetroxide N-methylmorpholine catalysts followed by oxidative cleavage to aldehyde using sodium periodate. Alternatively, oxidative cleavage via ozonolysis followed by reduction using reagents such as triphenylphosphine, methyl acetic acid/zinc sulfide, or thiourea, generates the desired aldehyde of formula 51. The addition of metal L where metal L represents any organometallic reagent ml organometallic or Grignard reagent in a nonprotonated solvent such as diethyl ether or tetrahydrofuran at a temperature from about -78°C to about 80°C, followed by hydrolysis of the ester as described above , the compound of formula 0 5 provides the required 0

<img file="SA2048B1_D0009.tif" />

Alternatively, another method for preparing certain compounds of formula I (where B is Q and A, K, and N are as described in the general description of the invention) is described in Program 9. The appropriate sulfonamide or amide (formula 5) is alkylated using the conditions described in my program.

1 and 2 by an electrophilic material containing aromatic bromide, iodide or a ring system containing Ar1) vinyl bromide or iodide to provide compounds of formula 53. Suzuki-type coupling of the compound of formula 53 with Ar2)aryl boronic acid provides compounds of formula 53a. For a review of the Suzuki reaction see:

1993, 47, 221. A. R. Martin and Y. Yang in Acta Chem. Scand The coupling reaction is achieved using about two equivalents of a base, such as sodium carbonate, thallium hydroxide, sodium hydroxide, potassium carbonate, potassium phosphate, or sodium methoxide, in the presence of a palladium catalyst, such as palladium (0)palladium, palladium acetate, tetrakis(triphenylphosphine)palladium tris(0). dibenzylideneacetone)dipalladium(0),chloride or (0)l,4-bis(diphenylphosphine)butane]palladium]. The reaction may be carried out in aqueous alcoholic solvents (methanol or tetrahydrofuran, aqueous ethanol, aqueous acetone, aqueous glycol dimethyl ether, or aqueous benzene at a temperature ranging from about 0°C to about 120°C. When A r1 represents a partially saturated ring, if desired At this point, the ring may be reduced to provide a saturated ring system. The conditions for achieving this transformation include hydrogenation in the presence of a catalyst such as palladium or platinum in an alcoholic solvent (ethanol or methanol) and/or ethyl acetate. Hydrolysis of ester compounds of formula 53a, if desired, provides the corresponding acid. The resulting acids with functional groups may contain one of two ring systems (1Ar or Ar2) which can be modified using methods known to those skilled in the art. Examples of such modifications are shown in Program 01.

<img file="SA2048B1_D0010.tif" />

Compounds of formula 54 containing an aldehyde functional group may be prepared using methods described in Programs 8 and 9. According to Program 10, treatment of the compound of formula 4 5 with a suitable organometallic reagent (metal L), mL of organometallic or high Grignard reagent, in a nonprotonated solvent such as diethyl ether or tetrahydrofuran at a temperature from about -78°C to about 80°C, followed by decomposition aqueous form of the ester, providing compounds of formula 56 (where B is K and Q, A and N are as described in the general description of the invention Ar2 and Ar1 are as described in Program 9). Alternatively, aldehyde reduction followed by hydrolysis provides compounds of formula 5 5 .

<img file="SA2048B1_D0011.tif" />

Alternatively, another method for preparing certain compounds of formula I (i.e., compounds of formula 57 where B is Q and A, K, and N are as described in the general description of the invention and R is as described in Programs 1 and 2) and thus acids are described in Program 1 1. Corresponding to the starter, alcohol Formula 58 can be prepared using methods described in Programs 1 and 2. Intermediate 58 is coupled to a variety of M-aryl alcohols representing an aromatic ring using Mitsonobu's conditions, for review see:

1,1981,. Mitsunobu, Synthesis O

Coupling is typically achieved by adding a coupling agent such as triphenylphosphine DEAD (diethyl azodicarboxylate) or diisopropyl azodicarboxylate into a carrier solvent such as methylene chloride or tetrahydrofuran at a temperature from about 0°C to about 80°C. If desired, subsequent hydrolysis gives the corresponding acid.

<img file="SA2048B1_D0012.tif" />

Alternatively, another method for preparing certain compounds of formula I (i.e., compounds of formula 106 where B is N and A, M and K are as described in the general description of the invention R) and as described in Programs 1 and 2 and accordingly, acids are described in Program 2 1. the interview). A compound of formula 102 is added to a compound of formula 105 (where If desired, the ester of formula 6 0 1 can be converted to the corresponding acid by hydrolysis or deprotection.

<img file="SA2048B1_D0013.tif" />

Alternatively, another method for preparing certain compounds of formula I (i.e., compounds of formula 107 or 180 where B is N and A, and Q are as described in the general description of the invention and, accordingly, the corresponding acids) is described in Program 13 in Program 13. Chloromethyl compounds process the formula

4 0 1 By a suitable substituted aromatic ring system, M, such as 4-ethoxybenzene or thiophene in the presence of a Lewis acid such as titanium tetrachloride or a mineral acid such as hydrochloric acid in a non-protonated solvent such as chloroform at a temperature of about 0°C to about 0.8°C to produce a compound. Formula 107 which may then be hydrolyzed or deprotected as described above to produce the corresponding acid. Alternatively, chloromethyl compounds of formula 4 0 1 can be treated with a Lewis acid such as vinyl silane and suitably substituted titanium tetrachloride in a nonprotonated solvent such as methylene chloride at a temperature from about -0 5 C to about 0 5 C to give compounds of formula 8 0 1 which may subsequently decompose. It is hydrolyzed or deprotected as described above to produce the corresponding acid. If desired, reduction of the double bond can be achieved using conditions described in Program 7.

<img file="SA2048B1_D0014.tif" />

Alternatively, another method for preparing certain compounds (i.e., compounds of formula 109, where B is N and A, R, Q are as described above and, therefore, the corresponding acids) is described in Program 4 1. Chloromethyl compounds of formula 4 0 1 are treated with a Lewis acid such as titanium tetrachloride and suitably substituted allyl silane in a nonprotonated solvent such as

chloroform at a temperature from about 0°C to about 0–8°C to give compounds Formula 109 which may subsequently be hydrolyzed or deprotected as described above.

<img file="SA2048B1_D0015.tif" />

Alternatively, another method for preparing certain compounds of formula I (i.e., compounds of formula 112, where B is R, Q, A, N and M are as described above and, therefore, the corresponding acids) is described in Program 5 1. Chloromethyl compounds of formula 4 0 1 are treated with sulfinic acid formula 1 1 1 in the presence of a base such as triethylamine in a nonprotonated solvent such as chloroform at a temperature from about -30°C to about 0.5°C to give compounds of formula 112 which may be hydrolyzed or deprotected after This is as described above to produce the corresponding acid.

<img file="SA2048B1_D0016.tif" />

Compounds of formula I (where B is K, M, Q, and C (H are as described in the general description of the invention, R is a small-chain alkyl group, and R1 represents alkyl groups on A as described in the general description of the invention) may be prepared according to program 6 1. The beta-ketoesters of formula 3 1 1 are alkylated successively with compounds of formula 4 1 1 followed by alkylation of the compounds of formula 1 1 .

Formula 6 1 1 to give the compounds of formula 7 1 1. (41-Med. Chem. 26, 1993, p335.J). Alkylation processes can be carried out in a suitable solvent such as ether, THF, DMF, or benzene using a suitable base such as LDA, sodium hydride, or potassium carbonate at a temperature from about -78°C to about 80°C. Di-substituted keto esters from the resulting formula 117 are hydrolyzed and decarboxylated to give the corresponding compound of formula 118 using an aqueous base such as sodium hydroxide for the ester to hydrolyze, followed by quenching with an acid such as aqueous hydrochloric acid for decarboxylation to take place.

<img file="SA2048B1_D0017.tif" />

Alternatively, compounds of formula I may be prepared (wherein B is K(, M, Q, and C(H are as described in the general description of the invention, 1R is as described above, and R1 is alkyl groups on A as described in the general description of the invention) According to Program 17, the sequential alkylation of the malonate derivative of formula 119 provides dialkylated species of formula 1 2 1. Deprotection of the ester group by treatment with a strong acid such as TFA or HCl in ethanol at a temperature of about 0 -2°C to about 50. Celsius leads to the decarboxylated product of formula 122. The conversion of an acid into acid chloride using thionyl chloride or oxalyl chloride in a solvent

Deprotonated at a temperature from about -78°C to about 50°C or to amide

Weinreb using methoxymethyl amine in the presence of a suitable coupling agent such as DCC or DEC in a nonprotonated solvent at a temperature from about -3°C to about 50°C provides compounds of formula 123. Formula 123 is a suitable substrate for the addition of various organometallic species (e.g., Grignard reagents, organocadmium reagents) that provide keto-acid compounds of Formula 118 after hydrolysis of the terminal ester.

Alternatively, compounds of formula 118 may be prepared using previously described methods (e.g., see Programs 7'8, 9, 10 and 11) employing post-linkage one or both side chains.

<img file="SA2048B1_D0018.tif" />

Cosmetics

Amines, Amides, and Sulfonamides

Certain amides or sulfonamides described in Formulas 21, 22, and 23 may be prepared (where w and Z are as described in the general description of the invention and X and M are aromatic ring systems, or

saturated) according to program 18. Alkynyl amides or sulfonamides Formulas 25, 26, and 27 are prepared by coupling alkynyl sulfonamide or amide Formula 4 2 with a vinyl halide or aromatic, preferably vinyl bromide or idoide or aromatic (where W and Z are as specified above and where M and X represent an aromatic ring or ring system Partially saturated). Coupling is typically achieved in the presence of copper iodide, a palladium catalyst, such as palladium chloride, such as bis(triphenylphosphine)palldium dichloride, or (0)amine, and tetrakis(triphenylphosphine)palladium, such as triethylamine diisopropylamine, or butylamine in a nonprotonated solvent such as acetonitrile at a temperature of About 0 Celsius to about 100 Celsius. The resulting alkynes of formulas 25, 26, and 27 can be converted to the corresponding alkanes of formulas 21, 22, or 23, by hydrogenation in the presence of a palladium or platinum catalyst and in solvents such as ethanol, methanol, and/or ethyl acetate at a temperature from about 0°C to about 50°C. . Alternatively, an alkyne can be converted to cis-alkene using the Lindlar catalyst Pd-CaCO3-PdO in the case where M represents the

Partially saturated ring, hydrogenation converts M into a fully saturated ring system. Alkylation and deprotection as described in Programs 1 and 2 provide the corresponding formula I compounds.

<img file="SA2048B1_D0019.tif" />

According to Program 9 1 compounds of formula 33 (where X and A are as described in the general description of the invention) may be prepared from the appropriate amine of formula 32 (e.g., methoxyarylalkylamine). Amines of Formula 32 are commercially available or may be prepared by methods known to those skilled in the art (for example, see Program 4) and converted to sulfonamides or amides of Formula 31 using methods, for example, described in Programs 3 and 4. The resulting aromatic methyl ether of Formula 31 is unprotected by reagent agents such as boron tribromide, acetic acid/hydrogen bromide, pyridinium hydrochloride, or other reagent agents as

It is described in:

Protecting Groups in Organic Synthesis, Second Edition, TW Greene and PGM Wuts, John Wiley and Sons, Inc., 1991.

In potassium carbonate using a mild base such as bromoalkylester it is alkylated by at a temperature of about acetone or dimethylformamide a non-protonated solvent such as the desired formula 33. Sulfonamide or amide 0 Celsius to about 0 0 1. Celsius generated

<img file="SA2048B1_D0020.tif" />

Alkylating agents There are several methods for synthesizing the required alkylating agents used in the above procedures and are known to those skilled in the art (see: &amp;The Chemistry of the Carbon-Halogen Bond', Ed. s. Patai, J. Wiley, New York, 1973 and &amp;The Chemistry of Halides, Pseudo-Halides, and Azides&amp;, Eds. s. Patai and z. Rappaport, J. Wiley, New York, 1983).

Some examples are shown in Programs 0 2-26. As shown in Program 02, the tolyl or allylic subject matter can be converted by halogenation to benzylic or allylic bromides (where Z, w, X, M are as described in the general description of the invention). This reaction is typically carried out by NBS (N-bromosuccinimide) in the presence of a radical initiator such as AIBN or peroxide, preferably benzoyl peroxide. Alternatively, the reaction can be initiated with light. The reaction takes place in an inert solvent such as carbon tetrachloride or chloroform at a temperature of about . 50 Celsius to about 100 Celsius.

<img file="SA2048B1_D0021.tif" />

Program 1 2 illustrates the synthesis of alkyl agents useful for the preparation of compounds of formula I where M represents a biaryl or aryl cyclic group. A Suzuki-type coupling of an yl iodide or bromide or a ring system containing Ar(vinyl bromide or iodide) with methylaryl boronic acid (Ar) using the conditions described in Program 9 provides compounds of formula 34. If vinyl bromide or iodide is used, the compounds of Formula 34 can be reduced to generate a fully saturated ring. Reduction is achieved by hydrogenation in the presence of palladium or platinum catalysts typically in protonated solvents (methanol, tetrahydrofuran, ethyl acetate, or ethyl acetate) using reagent agents and conditions as described in Program 02 that provide alkyl agents of formula 35.

<img file="SA2048B1_D0022.tif" />

Another common way to access alkyl halides is by halogenation of an alcohol or alcohol derivative. We obtain alcohols from commercial sources or can be prepared using methods known to those skilled in the art. For example, in Program 22, a carboxylic acid or ester is reduced to an alcohol using reagents such as lithium aluminum hydride, sodium borohydride, borane-tetrahydrofuran complex, borane-methyl sulfide complex, etc. The corresponding alkyl chlorides are typically prepared from alcohols by reagents such as hydrogen chloride, phosphorous oxychloride, phosphorous pentachloride, thionyl chloride, or carbon tetrachloride/triphenylphosphine. To prepare alkyl bromides, alcohol is usually treated with reagents such as phosphorous tribromide, hydrogenbromide, bromine/triphenylphosphine, or allylbromide/carbonyldiimidazole, see:

(38, 4189, 1983).lizuka, K. Chem. Pharm. Bull.(Kamijo, T., Harada, H.) To reach alkyl iodides, alcohol typically reacts with reagents such as imidazole/iodine/triphenylphosphine or hydrogen iodide. Alkyl chlorides are converted to the more reactive alkyl bromides or alkyl iodides by treatment with an inorganic salt such as sodium iodide, lithium bromide, sodium bromide, or potassium iodide in solvents such as acetone or methyl ethyl ketone. Alkyl sulfonates can also be used as electrophiles or may be converted to alkyl halides. . Sulfonates are prepared from alcohol using a mild base such as triethylamine or sulfonyl chloride and pyridine in an inert solvent such as methylene chloride or diethyl ether. Conversion to a halide is achieved by treatment with an inorganic halide (potassium iodide, sodium bromide, sodium iodide,

Or (etc., lithium bromide, lithium chloride, potassium bromide

Tetrabutylammonium halide

<img file="SA2048B1_D0023.tif" />

Cinnamic acids or esters are usually available from commercial sources and can be converted into alkylating agents of formula 37 or 38 as follows (see Program 23). Cinnamic acid or ester derivatives are reduced by hydrogenation in the presence of palladium or platinum catalysts typically in protonated solvents (e.g., methanol, tetrahydrofuran (ethanol, or ethyl acetate). Reduction and conversion to alkyl halide or sulfonate as described in Program 22 provides formula 38. Depending on suitability, cinnamic acids or esters are directly converted to alcohols (Formula 39) by treatment with reagents such as lithium aluminum hydride in inert solvents such as tetrahydrofuran diethyl ether. Alternatively, the cinnamic acid or ester can be reduced to allylic alcohol formula 40 using reagents such as aluminum chloride/lithium aluminum hydride, diisobutylaluminum hydride, or lithium borohydride. Conversion to allylic halide or sulfonate as described in Program 2 2 provides reagent agents of formula 37.

<img file="SA2048B1_D0024.tif" />

In Program 24, the preparation of alkylating agents of formula 1 4 (where W and M are as specified in the general description of the invention) is described. Compounds of formula 2-4 are alkylated with different bases, the choice of which depends on the nature of W and M. Some of the preferred bases are sodium hydroxide, lithium bis(trimethylsilyl)amide, lithium diisopropylamide, sodium hydride, potassium tert-butoxide, potassium bis(trimethylsilyl)amide, etc. Treatment of the resulting anion with various dialkylhalides generates alkylating agents of the desired formula 1 4 . In order to prepare compounds where W is attached to the oxygen M and is an aromatic ring, preferred conditions include formation of an alkoxide anion with sodium hydroxide followed by the addition of a dihaloalkane, e.g., dibromoalkane. The reaction occurs naturally in water at a temperature of approximately 57°C to approximately 25°C.

<img file="SA2048B1_D0025.tif" />

Aldehydes useful for the chemistry described in Program 5 are available from commercial sources or can be prepared from intermediates using methods known to those skilled in the art. Program 25 shows a representative method used to prepare hydroxy aldehydes of formula 43 (where M in Program 5 contains an alkyl group substituted with the hydroxy). Diadehyde treatment, where one of the aldehydes such as acetal of formula 44 (where the OR groups are conventional substituents used in protected acetal groups), is protected by an organometallic (metal L) reagent, preferably organolithium or a Grignard reagent, in an inert solvent such as tetrahydrofuran or diethyl ether, providing compounds of formula 5-4. The subsequent hydrolysis of acetal under mildly acidic conditions, e.g., dilute hydrogen chloride, Amberlyst-15 resin, silica gel, or agents

Other detector as described in:

&amp;Protecting Groups in Organic Synthesis&amp;, Second Edition, TW Greene and PGM Wuts, John Wiley and Sons, Inc., 1991 Formula 43 Required hydroxy aldehydes provides

<img file="SA2048B1_D0026.tif" />

Chloromethyl intermediates Chloromethyl intermediates may be prepared as described in Programs 26 and 27. In general, the appropriate sulfonamide or carboxamide of Formula 101 or 103 is treated with a formaldehyde equivalent such as paraformaldehyde in an inert organic solvent such as methylene chloride or chloroform with a suitable catalyst such as zinc chloride, HCl, or trimethylsilyl chloride when

The temperature ranges from about 0°C to about 60°C to give chloromethyl derivatives of the formula 2 0 1 and 0 4 1, respectively.

<img file="SA2048B1_D0027.tif" />

Those of the art note that anti-resorptive agents (eg, bisphosphonate(s), progestins polyphosphonates, anti-estrogens, estrogen, estriol, estrone combinations, Premarin, progestin/estrogen, or 17α- or 17ß-ethynyl estradiol) may be used in Combination with compounds of this invention.

Representative progestins are available from commercial sources and include: algestone acetophenide, chlormadinone acetate, anagestone acetate, amadinone acetate, altrenogest,

delmadinone acetate, clomegestone acetate, clogestone acetate, cingestol, ethynodiol diacetate, ethynerone, dydrogesterone, dimethisterone, desogestrel, gestonorone caproate, gestodene, gestaclone, flurogestone acetate, etonogestrel, levonorgestrel, hydroxyprogesterone caproate, haloprogesterone, gestrinone, melengestrol acetate, medroxyprogesterone acetate, medrogestone lynestrenol, norethynodrel, norethindrone acetate, norethindrone, methynodiol diacetate, progesterone, oxogestone phenpropionate, norgestrel, norgestomet, norgestimate, tigestol, quingestrone, quingestanol acetate

The preferred progestins are norethindrone, medroxyprogestrone and norethnoderl

Bone resorption inhibitor polyphosphonates include representative polyphosphonates of the type described in U.S. Pat. No. 6,683,080, registered August 8, 1972, the explanations of which are incorporated herein by reference. The preferred polyphosphonates are diphosphonates (also referred to as bis-phosphonates). Tiludronate disodium is a particularly preferred polyphosphonate. ibandronic acid is a particularly preferred polyphosphonate. Alendronate is a particularly preferred polyphosphonate. Another preferred polyphosphonate is 6-amino-l-hydroxy-hexylidene-bisphosphonic acid l-hydroxy-3(methylpentylamino)-propylidene-bisphosphonic acid. Polyphosphonates may be given in the acid form, a soluble alkali metal salt, or an alkaline earth metal salt. Esters of biodegradable polyphosphonates are similarly included. Specific examples include methane diphosphonicacid, l,l-diphosphonic acid, ethane-l-hydroxy, methane dichloro diphosphonic acid, pentane-l-hydroxy-l,l-diphosphonic acid, ethane-l-amino-l,l-diphosphonic acid. methane hydroxy diphosphonic acid, ethane-2-amino-1,1-diphosphonic acid, propane-3-amino-l-hydroxy-l,l-diphosphonic acid, propane-N,N-dimethyl-3-amino-l- hydroxy-l,l-diphosphonic acid,propane-3-3-dimethyl-3-amino-l-hydroxy-l,l-diphosphonicacid,amino methane diphosphonic acid

N,N-dimethylamino methane diphosphonic acid, N(2-hydroxyethyl) amino methane diphosphonic acid, butane4-amino-l-hydroxy-l,l-diphosphonicacid, pentane-5-amino-l-hydroxy-l,l-diphosphonic acid

hexane-6-amino-l-hydroxy-l,l-diphosphonic acid and esters and salts thereof are pharmaceutically acceptable.

In particular, the compounds of this invention may be combined with a mammalian estrogen. Any antiestrogen may be used as the second compound of this invention. The term anti-estrogen refers to compounds that bind to the estrogen receptor, inhibit bone deterioration and prevent bone loss. In particular, estrogen antagonists are defined as chemical compounds capable of binding to estrogen receptor sites in mammary tissue, mimicking the effects of estrogen in one or more tissues. Antiestrogens are defined here as chemical compounds capable of binding to estrogen receptor sites in mammary tissue and blocking the effects of estrogen in one or more tissues. These activities are measured by those skilled in the art according to standard tests including estrogen receptor binding testing methods, standard bone histological morphometry and densitometry,

(Eriksen EF et al., Bone Histomorphometry, Raven Press, New York, 1994, pages

1-74; Grier SJ et al., The Use of Dual-Energy X-Ray Absorptiometry In Animals, Inv. Radiol. 1996, 31(1):50-62; Wahner HW and Fogelman I., The Evaluation of Osteoporosis: Dual Energy X-Ray Absorptiometry in Clinical Practice., Martin Dunizz Ltd., London 1994, pages 1-296).

Many of these compounds are described and referenced below.

The preferred anti-estrogen is droloxifene:

(-(phenol, 3-[l-[4[2-(dimehylamino)ehoxy]phenyl]-2-phenyl-l-butenyl]-, (E)

and associated compounds described in U.S. Patent No. 5,047,431 (the explanation of which is incorporated herein).

By reference).

Tamoxifen: Another preferred estrogen antagonist is (ethanamine, 2-[-4-(l,2-diphenyl-l-butenyl)phenoxy]-N,N-dimethyl, (Z)-2-, 2-hydroxy- l,2,3-propanetricarboxylate(l:l))

and associated compounds described in US Patent No. 4,536,516 (the explanation of which is incorporated herein by reference).

Another related compound is 4-hydroxy tamoxifen described in US Patent No. 4,623,660 (the illustration of which is incorporated herein by reference). The preferred anti-estrogen is raloxifene:

methanone, [6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thien-3-yl][4)[2-(l-)

(piperidinyl)ethoxy]phenyl]-, hydrochloride

Described in US Patent No. 4,418,068 (the explanation of which is incorporated herein by reference).

Another preferred anti-estrogen is toremifene:

1-ethanamine, 2-[4-(4-chloro-l,2-diphenyl-l-butenyl)phenoxy]-N,N)dimethyl-,(Z)

((2-hydroxy-l,2,3-propanetricarboxylate(l:l

described in U.S. Patent No. 4,996,225 (the explanation of which is incorporated herein by reference). Another preferred anti-estrogen is centchroman:

dimethyl-3-phenyl-chroman4-yl)-phenoxy]-ethyl)-l-[2-[[4-(-methoxy-2,2)

,pyrrolidine

described in U.S. Patent No. 3,822,287 (the explanation of which is incorporated herein by reference). Thanks also to levormeloxifene.

Another preferred anti-estrogen is iodxifene:

[pyrrolidine, l-[-[4-[[l-(4-iod0phenyl)-2-phenyl-lbutenyllphen0xy]ethyl

Described in US Patent No. 155,4839 (the explanation of which is incorporated herein by reference). Another favorite is an anti-estrogen

6-[4-hydroxy-phenyl)-5-[4-(2-piperidin-l-yl-ethoxy)-benzyl)-naphthalen-2-ol

described in U.S. Patent No. 5,484,795 (the explanation of which is incorporated herein by reference). Another preferred anti-estrogen is

4-[2-(2-aza-bicyclo[2.2.1]hept-2-yl)-ethoxy]-phenyl}-[6-hydroxy-2-(4-hydroxy-}

phenyl)-benzo[b]thiophen-3-yl]-methanone

Explained, together with the methods in PCT Circular No. 95/10513 wo on behalf of the institution

Pfizer.

Another preferred antiestrogen is GW5638

;3-[4-(l,2-diphenyl-but-l-enyl)-phenyl]-acrylicacid

Look:

Wilson, T.M. and coworkers in Endrocrinology 1997,138, 9, 3901-3911.

Another preference includes compounds as described in U.S. estrogen patent No. 5,552,412, the description of which is hereby incorporated by reference. that

Particularly favorable compounds described here are:

Cis-6-(4-fluoro-phenyl)-5-[4-(2-piperidin-l-yl-ethoxy)-pheny]-5,6,7,8-tetrahydro-

naphthalene-2-ol;

(-)-Cis-6-phenyl-5-[4-(2-pyrrolidin-l-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-

naphthalene-2-ol;

Cis-6-phenyl-5-[4-(2-pyrrolidin-l-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-

naphthalene-2-ol;

Cis-l-[6'-pyrrolodinoethoxy-3'-pyridyl]-2-phenyl-6-hydroxy-l,2,3,4-

tetrahydronaphthalene;

l-(4'-Pynolidinoethoxyphenyl)-2-(4''-fluorophenyl)-6-hydroxy-l,2,3,4-

tetrahydroisoquinoline;

Cis-6-(4-hydroxyphenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-5,6,7, naphthalene-2-ol; and

l-(4'-Pyrrolidinolethoxyphenyl)-2-phenyl-6-hydroxy-l,2,3,4-

tetrahydroisoquinoline.

Another is described in U.S. Patent No. 4, 413,381, for an estogen (integrated antagonist/antigen (explained herein by reference).) US Patent No. 4,3381,41(d) discloses

2-phenyl-3-aroylbenzothiophene-l-oxide and 2-phenyl-3-aroyl-benzothiophene.

It is noted by those skilled in the art that other bone anabolic agents (agents that increase bone mass) may be used in combination with the compounds of this invention. A bone mass-increasing agent is a compound that increases bone mass to a level higher than the critical value for bone fracture (as detailed in:

The World Health Organization Study World Health Organization, &amp;Assessment of Fracture Risk and its Application to Screening for Postmenopausal Osteoporosis (1994). Report of a WHO Study Group. World Health Organization Technical

(&amp;843 Series

Any prostaglandin, or prostaglandin antagonist may be used as the second compound of this invention (this involves using two different compounds of formula I of this invention). Those skilled in the art note that IGF-1, with or without IGF-binding protein 3, sodium fluoride, parathyroid hormone (PTH), active parts of PTH, growth hormone or growth hormone secretagogues may also be used. The following sections describe representative second compounds of this invention in more detail.

Any prostaglandin may be used as the second compound of this invention. The term prostaglandin refers to compounds similar to PGE1, PGE2, PGD2, PGD1 and natural prostaglandin PGF2, which are useful in treating osteoporosis. These compounds bind to prostaglandin receptors. This association is measured by those skilled in the art according to standardized tests (e.g.,

An s. et al., Cloning and Expression of the EP2 Subtype of Human Receptors for Prostaglandin E2, 1993, Biochemical and Biophysical Research Communications

.(263-270:(1)197

Prostaglandins are alicyclic compounds related to the basic compound prostanoic acid. Sequence the primary prostaglandin carbon atoms from the carboxylic carbon atom through the cyclopentyl ring to the terminal carbon atom on the adjacent side chain. Naturally, the adjacent side chains are in the trans direction. The presence of an OXO group at C-9 of the cyclopentyl moiety indicates a class E prostaglandin while PGE2 contains a trans double bond at the C13-C14 position and a cis double bond at the C5-C6 position.

The assortment of prostaglandins is described and indicated below. However, those skilled in the art will know other prostaglandins. An analogy of prostaglandins is described in U.S. Patent Nos. 4,171,331 and 3,927,197 (incorporated herein by reference).

Look:

Norrdin et al., The Role of Prostaglandins in Bone In Vivo, (Prostaglandins Leukotriene Essential Fatty Acids 41,139-150, 1990)

Anabolic Actions of Prostaglandins in Bone. (Bone, 21:297-304)

Prostaglandins are a recent revision of the osteogenic action of the invention. As a second compound, in particular aspects of this prostaglandin may be used as an agonist/antagonist to the prostaglandin agonist/antagonist compounds of the invention. The term refers to an antagonist/antagonist

For example, prostaglandin binds to receptors

J. W. Regan et al., Cloning of a Novel Human Prostaglandin Receptor with Characteristics of the Pharmaceologically Defined EP2 Subtype, Molecular Pharmacology, 46:213-220, 1994).

Within the body (for example, stimulates bone formation and increases bone mass). Prostaglandin determines the effect and mimics

Those skilled in the art easily detect these effects with standard tests:

(Eriksen EF et al., Bone Histomorphometry, Raven Press, New York, 1994, pages 1-74; Grier SJ et al., The Use of Dual-Energy (1):50-62; Wahner HW and Fogelman I., The Evaluation of Osteoporosis: Dual Energy X-Ray Absorptiometry in Clinical Practice., Martin Dunitz Ltd., London 1994, pages 1-296).

An assortment of these compounds is described and referenced below. However, those skilled in the art will know of other prostaglandine antagonists. Representative prostaglandine agonists/antagonists are shown as follows.

US Patent No. 3,932,389 (incorporated) is disclosed herein

By reference) about

2-descarboxy-2-(tetrazol-5-yl)-ll-desoxy-15-substituted-omega-

pentanorprostaglandins

Useful for bone formation activity.

U.S. Patent No. 8892 1 0 4 (incorporated herein by reference) discloses 16-aryl-13,14-dihydro-PGE2 p-biphenyl esters useful for osteogenic activity.

U.S. Patent No. 4,219,483 (incorporated herein by reference) discloses 2,3,6-substituted-4-pyrones useful for osteogenic activity.

U.S. Patent No. 4,132,847 General Assignment (incorporated herein by reference) discloses 2,3,6-substituted-4-pyrones useful for osteogenic activity.

U.S. Patent No. 9 0 3 0 0 0 4 (incorporated herein by reference) discloses 16-aryl-13,14-dihydro-PGE2 p-biphenyl esters useful for osteogenic activity.

US Patent No. 6 1 0 3982 (incorporated herein by reference) discloses

The 16-aryl-13,14-dihydro-PGE2 p-biphenyl esters are beneficial for osteogenic activity.

US Patent No. 4,621,100 (incorporated herein by reference) discloses substituted cyclopentanes useful for osteogenic activity.

U.S. Patent No. 5,216,183 (incorporated herein by reference) discloses cyclopentanones useful for osteogenic activity.

Sodium fluoride may be used as a second compound in particular aspects of this invention. The term sodium fluoride refers to sodium fluoride in all its forms (eg, slow-release sodium fluoride, prolonged-release sodium fluoride). Sodium fluoride long-lasting release is described in U.S. Patent No. 4,904,478, incorporated herein by reference. The activity of sodium fluoride is easily determined by those skilled in the art of biological protocols (for example, see:

Eriksen EF et al., Bone Histomorphometry, Raven Press, New York, 1994, pages

1-74; Grier sJ et al.. The Use of Dual-Energy X-Ray Absorptiometry In Animals,

Inv. Radiol., 1996, 31(1):50-62; Wahner HW and Fogelman I., The Evaluation of Osteoporosis: Dual Energy X-Ray Absorptiometry in Clinical Practice., Martin Dunitz Ltd., London 1994, pages 1-296).

As a second compound in particular aspects of this invention (PTH), any parathyroid hormone may be used, including parts or parathyroid hormone. The term parathyroid hormone refers to metabolites thereof and structural methylations thereof that can stimulate bone formation and increase bone mass. Also included are peptides related to parathyroid hormone and active parts and homologs of related peptides. The primary functional activity of bone is easily determined by parathyroid hormone. See WO 94/01460.

By those skilled in the art of standardized testing (for example, see:

Eriksen EF et al., Bone Histomorphometry, Raven Press, New York, 1994, pages 1-74; Grier SJ et al., The Use of Dual-Energy X-Ray Absorptiometry In Animals, Inv. Radiol., 1996, 31(1):50-62; Wahner HW and Fogelman I., The Evaluation of Osteoporosis: Dual Energy X-Ray Absorptiometry in Clinical Practice., Martin Dunitz Ltd., London 1994, pages 1-296).

An assortment of these compounds is described and referenced below. However, those skilled in the art will know about other parathyroid hormones. Representative parathyroid hormones are described in the following references.

&amp;Human Parathyroid Peptide Treatment of Vertebral Osteoporosis&amp;, Osteoporosis Int., 3, (Supp 1):199-203.

&amp;PTH 1-34 Treatment of Osteoporosis with Added Hormone Replacement Therapy: Biochemical, Kinetic and Histological Responses” Osteoporosis Int. 1:162-170.

Any growth hormone or any substance that causes an influx of growth hormone secretion may be used as a second compound in special aspects of this invention. The term growth hormone surge substance refers to a compound that stimulates the release of growth hormone or mimics the effect of growth hormone (eg, increases bone formation leading to increased bone mass). These effects are easily determined by those skilled in the art according to standard tests. A variety of these compounds are described in published PCT patent applications Nos. 95/14666 WO; 95/13069 WO; 94/19367 WO; 94/13696 WO;

and 95/34311 WO. However, those skilled in the art will know about other growth hormones and other substances

Causing an influx of growth hormone secretion.

A substance that causes an influx of growth hormone secretion is particularly preferred:

N-[l(R)-[l,2-Dihydro-l-methanesulfonylspiro[3H-indole-3,4'-piperidin]-l'-yl)

cabonyl]-2-(phenylmethjfloxy)ethyl]-2-amino-2-methylpropanamide:MK-677.

Other favorable substances that cause a surge of growth hormone secretion include:

2-amino-N-(2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydropyrazolo-[4,3-c]pyridin-5 -yl)-l-(R)-benzyloxymehyl-2-oxo-ehyl)-isobutyramide or its L-tartaric acid salt;

2-amino-N-(l-(R)-benzyloxymethyl-2-(3a-(R)-(4-fluoro-benzyl)-2-methyl-3-oxo-

2,3,3a,4,6,7-hexahydro-pyrazolo-[4,3-c]pyridin-5-yl)-2-oxo-ethyl)-isobutyramide;

2-amino-N-(2-(3a-(R)-benzyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]

pyridin-5-yl)-l-(R)-benzyloxymethyl-2-oxo-ethyl)-isobutyramide;and

2-amino-N-(l-(2,4-difluoro-benzyloxymethyl)-2-oxo-2-(3-oxo-3a-pyridin-2-

ylmethyl-2-(2,2,2-trifluoro-ethyl)-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-

yl)-ethyl)-2-methyl-propionamide.

Some preparation methods useful for preparing the compounds described here may require protection for low functionality (e.g., primary amine, secondary amine, carboxyl in formula I precursors). The need for this protection will vary depending on the nature of the functional component and the conditions of the preparation method. The need for such protection is easily measured by one skilled in the art. Using these methods of protection/unprotection is also a skill in the art. For a general description of protection groups and their use, see:

TW Greene, Protective Groups in Organic Synthesis, John Wiley &amp; Sons, New York, 1991.

The starting materials and reagents for the compounds described above are also readily available or can be easily synthesized by those skilled in the art using conventional methods of organic synthesis. For example, many of the compounds used here are related to, or derived from, compounds found in...

Nature, which has great scientific interest and commercial need, and therefore many of these compounds are commercially available, described in the literature, or easily prepared from other commonly available materials by methods described in the literature. These compounds include, for example, prostaglandines.

Some of the compounds of this invention have asymmetric carbon atoms and are therefore enantiomers or diastereomers. Mixtures of stereoisomers can be separated into their individual stereoisomers on the basis of their physicochemical differences by self-identified methods, for example, by chromatography and/or fractional crystallization. Enantiomers can be separated by converting the enantiomer mixture into a stereodimer mixture by reacting with a suitable optically active compound (e.g., alcohol), separating the stereodimers and converting (e.g., hydrolysis) the individual stereodimers to the corresponding pure enantiomer. All such isomers, including stereodimers, enantiomers and mixtures thereof are part of this invention. Also, some of the compounds of this invention are regioisomers (e.g., substituted biaryls) and are considered as part of this invention.

Many of the compounds of this invention are acidic and form a salt with a pharmaceutically acceptable cation. Some of the compounds of this invention are basic and form a salt with a pharmaceutically acceptable anion. All of these salts are in the art of this invention and can be prepared by traditional methods. For example, they may be prepared simply by contacting the presence of acid and base, usually in a chemically balanced ratio, in either an aqueous, non-aqueous or partially aqueous medium, depending on suitability. Salts are transpired either by filtration, precipitation with a non-solvent followed by filtration, evaporation of the solvent, or, in the case of aqueous solutions, by freeze-drying, as appropriate.

In addition, when the compounds of this invention form hydrates or dissolved substances they are also in the art of the invention.

All of the compounds of this invention are intended for therapeutic use as agents that stimulate bone formation and increase bone mass in mammals, particularly humans. Because bone formation is closely related to the occurrence of osteoporosis and bone-related diseases, these compounds, by their effective action on bone, prevent, stop and/or reverse osteoporosis.

The use of the compounds of the present invention as medical agents in the treatment of conditions characterized by low bone mass (e.g., osteoporosis) in mammals (males, humans, especially women) is demonstrated by the activity of the compounds of this invention in

Conventional tests, including the in vivo test, receptor binding test, cyclic AMP test and fracture healing test (each described below). The in vivo test may be used (with appropriate modifications within the limits of skill in the art) to measure the activity of other anabolic agents in addition to the prostaglandin antagonists of this invention. An agonist/antiestrogen protocol may be used to measure the activity of agonists/antiestrogens in particular and also other antiresorptive agents (with appropriate modifications within the limits of skill in the art). The combination and sequential treatment system described below is useful for demonstrating the use of conjugates of anabolic agents (e.g., compounds of this invention) and antiresorptive agents (e.g., antagonists/antiestrogens) described herein. These tests also provide a means by which the activities of the compounds of this invention (or other anabolic agents and antiresorptive agents described herein) can be compared with each other and with the activities of other known compounds. The results of these comparisons are useful for calculating dose levels in mammals, including humans, for the treatment of these diseases.

Testing for an anabolic factor within the body

The activity of bone anabolic factors can be tested in signaling bone formation and increasing bone mass in a healthy male or female mouse, sex hormone deficiency in a male (orchiectomy) or female (ovariectomy) mouse.

Male or female mice of different ages (such as 3 months old) can be used in the study. whether

Mice are intact or castrated (ovariectomized or orchidectomized), and injected subcutaneously or gavage-fed with prostaglandin antagonists at various doses (eg, 1, 3, or 10 mg/kg/day) for 30 days. In castrated mice, treatment is started the day after surgery (in order to prevent bone loss) or at the time when bone loss has already occurred (in order to restore bone mass). During the study, all mice were allowed free access to water and a commercial pellet diet (Teklad Rodent Diet #8064, Harlan Teklad, Madison, Wis) containing 1.46% calcium, 0.99% phosphorus, and 4.96 IU/g of Vitamin D3. All mice were given subcutaneous injections of 10 mg/kg calcein on days 12 and 2 before slaughter. Slaughter mice. The following final points are calculated: Measurements

Femoral bone minerals:

The right femur of each rat was removed at necropsy and scanned using a dual-energy The examination field size is 5.08X1.902cm, the resolution is 0.0127X0.0254cm and the examiner speed is 7.25mm/s. Femoral scan images analyze bone area, bone mineral content (BMC), and bone mineral density (BMD) of each femur (WF), and measure the inferior femoral metaphysis (DFM), tibia (FS), and proximal femur (PF).

Histological morphometric analysis of the greater tibia:

The right great leg bone is removed at autopsy, dissected free of muscle, and cut into three pieces. The proximal portion and tibia of the greater tibia are fixed in 70% ethanol, dehydrated in graded concentrations of ethanol, defatted in acetone, and then immersed in methyl methacrylate (Eastman Organic Chemicals, Rochester, NY).

The anterior portions of the inferior metaphysis of the proximal tibia are cut at 4 and 10 μm in thickness using a Reichert-Jung Polycut S microcutter. 4-μm sections are stained with modified Masson's Trichrome while 10-μm sections remain unstained. One of the 4-µm sections and one of the 10-µm sections from each mouse were used for histological morphometry of the porous bone.

Transverse sections of the tibia greater than 10 μm thickness were cut using a Reichert-Jung Polycut S mini-cutter. These sections are used for histological morphometric analysis of the hypotenuse.

Porous bone histological morphometry: A two-column 2/OS histological morphometric system (R&amp;M biometrics, Inc., Nashville, Tenn.) is used for static and dynamic histological morphometric measurements of the secondary cancellous material of the inferior metaphysis of the upper aspect of the tibia between 2 , 1 and 3.6 millimeters in the lower part, the connection between the growth plate and the upper metaphysis. The first 1.2 millimeters of the inferior metaphyseal area of the greater tibia need to be deleted in order to determine measurements of the secondary spongy layer. 4 µm sections are used to calculate bone size indices.

Bone synthesis and bone resorption, while 0-1 µm sections are used to calculate indices related to bone formation and bone recession.

1) Measurements and calculations related to the size and structure of the septal bone: (1) Total metaphyseal area (TV, square mm): The metaphyseal area is between 1.2 and 3.6 mm away from the growth plate-epiphysis connection. (2) Alveolar bone area (BV, mm square): The total area of the alveoli within the TV. (3) Circumference of septal bone (BS, mm):

The total perimeter length of the septa. (4) Septal bone volume (%BV /TV, (1,199/2,000)BS/BV)x). (7) Alveolar bone separation (TBS, µm): (0 0 0 9/2 9 1, 1)BV-TV)x).

2) Measurements and calculations related to bone resorption: (1) Osteoclast cell number (OCN, number): The total number of osteoclast cells in the total metaphyseal space. (2) Osteoclast cell circumference (OCP, mm): The length of the pericyte covered by osteoclasts. (3) Number of osteoclast cells/mm (OCN/mm, number/mm): BS/OCN. (4)% of osteoclast cell circumference (% OCP,): OCP/

100XBS.

3) Measurements and calculations related to bone formation and recession: (1) Single calcein-marked circumference (SLS mm): The total length of the septal circumference marked with a single calcein marker. (2) Double calcein-labeled perimeter (DLS, mm): Total length of the perimeter marked with two calcein labels. (3) Width between markers (TT.W, µm): average distance between two calcein markers. (4) .7 for perimeter of mineralization (PMS%), . 100XBS/(DLS+SLS/2): (5) Mineral Addition Rate (MAR, µm/

Day): ILW/mark interval. (6) Bone formation rate/surface circumference (BS/BFR, µm per day/µm): (2/BS/MAR x (DLS+SLS). (7) Bone turnover rate (BTR, y/%): (2/) XBV/MAR x(DLS+SLS0 100.

Cortical bone histological morphometry: A dual-column 2/OS histological morphometric system (R&amp;M biometrics, Inc., Nashville, Tenn.) is used for static and kinematic histological morphometry of the cortical bone of the tibia of the greater tibia. The total tissue area, the area of the medullary aperture, the circumference of the periosseous membrane, the inner circumference of the cortex, the single-marked circumference, and the circumference are measured.

Marked bilaterally, the width between the marks on both the periosseous membrane surface and the inner cortical surface, measured as cortical bone area (total tissue area - marrow aperture area), percentage of cortical bone area (cortical area / total tissue area x 100), percentage of marrow area. (Area of marrow aperture/total tissue area x 100), the percentage of the marked circumference of the periosseous membrane and the inner cortex. [(unilaterally marked contour/2+ bilaterally marked contour)/total circumference x 100], mineral addition speed (width between marks/intervals), and bone formation rate [mineral addition rate x[(singly marked contour/2+ bilaterally marked contour)/ total circumference].

statistics

Statistics can be calculated using StatView 4.0 packages (Abacus Concepts, Inc., Berkeley, Calif). An analysis of variance (ANOVA) followed by Fisher's PLSD is used to compare differences between groups.

Calculation of the increase in CAMP in 293-S cell lines for redundant human EP2 EP4 receptors.

Expression stable

cDNAs representing complete open reading frames for the EP4 and EP2 receptors are generated by reverse transcriptase polymerase chain reaction using oligonucleotide primers based on imprinted sequences (1, 2) and RNA from primary human kidney cells (EP2) or primary human lung cells (EP4) and seal the cDNAs to Invitrogen multiple copy locus (pcDNA3) is used to accept the host carrying the human embryonic kidney cell 293-S gene by co-precipitation of calcium phosphate. Groups that resist G418 are expanded and tested for specific binding to 3-H[PGE2]. Host gene recipients that exhibit a high level of specific binding to 3-H[PGE2] are further characterized by Scatchard analysis to calculate Kds and Bmax for PGE2. The lines selected for screening the compound had approximately 0 0 338.4 receptor/cell Kd = 12 nM for EP2 (PGE2), and approximately 0 0 256.4 receptor/cell Kd = 2.9 nM for EP4 (PGE2). Conformational demonstration of both receptors in native 293-S cells is of no value. Cells were maintained in RPMI supplemented with fetal bovine serum (10% final) G418 (700 μg/ml final).

cAMP responses in lines EP4/293-S and EP2/293-S were measured by detaching cells from culture flasks in PBS minus calcium and magnesium ions by vigorously repeating the addition of serum-free PRMi to a final concentration of 1 x 0 1 6 cells/ml. Add 3-isobutyl-l-methylxanthine (IBMX) to a final concentration of 1 mM - Divide into complete aliquots - Immediately transfer 1 mL cell suspension to a 2 mL individual screw-cap microcentrifuge and incubate for 0-1 minutes, uncovered, at 37°C. , CO2 5%, and relative humidity 95%. The compound to be tested is then added to the cells in 1:100 dilutions so that the final concentration of DMSO or ethanol is 1%. Immediately after adding the compound, cover the tubes, mix by stirring twice.

Incubate at 37°C for 12 minutes. The samples are then analyzed by incubation at 100°C for 10 minutes and immediately cooled on ice for 5 minutes. The cell debris was transformed into micropellets by centrifugation at 1000 x g for 5 minutes, and the purified lysates were transferred to fresh tubes. cAMP concentrations are measured using a commercially available radioimmunoassay system for cAMP (NEN-DuPont, 033-NEK) after diluting the pure lysates 10:1 in test buffer.

cAMP RIA. Typically, cells are treated with 6-8 concentrations of the compound to be tested in 1 log increments. EC50 calculations are performed on a Hewlett Packard 32SII manual calculator using linear regression analysis on the linear portion of the dose-response curves.

the reviewer

1. Regan, JW Bailey, TJ Pepper, DJ Pierce, KL Bogardus, AM Donello, JE Fairbaim, CE Kedzie, KM Woodward, DF and Gil, DW 1994 Cloning of a Novel Human Prostaglandin Receptor with Characteristics of the Pharmacologically Defined EP2 Subtype. Mol. Pharmacology 46:213-220.

2. Bastien, L., Sawyer, N., Grygorczyk, R., Metters, K., and Adam, M. 1994 Cloning, Functional Expression, and Characterization of the Human Prostaglandin E2 Receptor EP2 Subtype, J. Biol. Chem. Vol. 269, 16:11873-11877.

E2 binding test with prostaglandin receptors

Membrane preparation: All processes are performed at 4°C. Prostaglandin E2 type 1 receptor (EPI)

Expressing cells that have received the host carrier of the gene, receptor type 2 (EP2), type 3 (EP3), or

Type 4 (EP4) were collected and suspended at 2 million cells per milliliter in pH control buffer A [50 mM Tris-HCl (pH 7.4), 10 mM MgCl,

1 mM EDTA, 1 mM Pefabloc peptide, 10 μM phosporamidon peptide, (Simga, St Louis, Mo.)

Simga, St. Louis, Mo.), 1 µM, Pepstatin A Peptide A

Simga, St. Louis, Mo.), 0 1 μM - peptide

Antipain peptide (Simga, St. Louis, Mo.), 100 μM. Louis, Mo.))]. These are analyzed by sound with a Branson Sonifier (Model #250, Branson Ultrasonics Corporation, Danbury, Conn.) in two bursts of 15 s. Residues and non-lysed cells were removed by centrifugation at 100 × g for 10 minutes. The membranes are then collected by centrifugation at 45,000 x m for 30 minutes. The formed films are resuspended in the form of pellets to 1-3 mg protein/ml, and the protein concentration is calculated according to Bradford, M., Anal. Biochem., 72, 248 (1976) [Bradford]. The repackaged films are then stored by freezer at -80°C until used. Binding test: Frozen films prepared as above are thawed and diluted to 1 mg protein/ml in pH control buffer A. Combine one volume of the film preparation with 0.05 volume of test compound or pH control solution and one volume of 3 nM 3H-prostaglandin TRK 431, Amersham, Arlington Heights, I11 (E2#) in pH control solution A. Incubate the mixture ( A total volume of 5 0 2 µl) for an hour at 5 2 C. The membranes are then obtained by filtration through GF/C #1205-401, Wallac, Gaithersburg, Md., glass-textile type filters using a Tomtec Model Mach II/96 collector, Tomtec, Orange, Conn. The bound 3H-prostaglandin E2 is trapped by the membranes, the pH adjusting solution and unbound 3H-prostaglandin E2 pass through the filter to waste. Each sample was then washed 3 times with 3 ml of (50 μM tris-HCl (pH 7.4), 10 mM MgCl, 1 mM EDTA). The filters were then dried by heating in a short-wave oven. In order to calculate the 3H- Membrane-bound prostaglandin, dried filters are placed in bags

Plastic flash fluid and prepared in a Beta plate reader (1205 Wallac, Gaithersburg, Md.) (LKB).

IC50 is measured by the concentrations of test compound required to displace '50% of 3H-prostaglandin.

E2 specifically bound.

Fracture healing tests

Testing the effects on fracture healing after general administration Fracture technique: 3-month-old Sprage-Dawley rats are anesthetized with Ketamine. We make a 1 cm cut on the anterolateral side of the upper part of the greater leg bone or thigh. The following describes the surgical technique for the greater tibia. The cut continues until we reach the bone, and an opening of 1 millimeter is created 4 millimeters above the lower side of the bony prominence of the greater tibia and 2 millimeters on the inner side of the anterior edge. The intramedullary nail is performed with a 0.8 mm stainless steel tube (maximum load 36.3 N, maximum stiffness 61.8 N/mm, tested under the same conditions as bone). The spinal canal foramen is not enlarged. We create a standard closed fracture 2 millimeters above the junction of the greater and lesser tibia with a 3-point bend using adjustable flat-jaw forceps. In order to minimize soft tissue injury, we take care not to displace the fracture. The skin is closed with a monofilament nylon sequin. The operation is performed under sterile conditions. Radiographs of all fractures are taken immediately after nailing, avoiding animals with fractures outside the designated tibial space or with displaced nails. We randomly divide the remaining animals into the following groups, with 10-12 animals/each subgroup, in order to test fracture healing. The first group is given a daily dose of a carrier fluid (water: 0 0 1% ethanol = H9:H) at 1 ml/mouse, while the others are given a daily dose of 0.01 to 100 mg/kg/day of the compound to be tested. (1 ml/mouse) for 10, 20, 4,0 and 8 days.

At 10, 20, 4 0 and 8 0 days, 10-12 mice from each group were anesthetized with Ketamine and lysed by exsanguination. Both leg bones are removed by dissection and all living tissue is stripped. Bones from 5-6 mice from each group were stored in 70% ethanol for histological analysis, and bones from another 5-6 mice from each group were stored in neutral Ringer's solution (+4 C, pH 7.4) for x-rays and biokinetic tests. It is performed.

Mosekilde Histological analysis: Published by Methods of histological analysis of fractured bone from

:Bak and

(The Effects of Growth Hormone on Fracture Healing in Rats: A Histological Description. Bone, 14:19-27, 1993).

Briefly, by spreading the fracture side of 8 ml on each side of the fracture line, the decalcified person is immersed in methylmethacrylate, and anterior sections are cut on a Reichert-Jung multi-cut mini resection at 8 μm thickness. Masson-Trichrome stained anterior medial sections (including both the greater and lesser tibia) are used in order to view the cellular and histological response to fracture healing with or without treatment. Sirius red-stained sections are used to demonstrate the structural properties of the bone healing material and to differentiate between woven bone and stratified bone at the fracture site. The following measurements are made: (1) fracture aperture - measured as the shortest distance between the ends of the cortical bone in the fracture, (2) torque length and diameter of the healing material, (3) total bone volume area of the healing material, (4) bone tissue over tissue area within the healing material area. The healing, (5) the connective tissue in the healing material, (6) the cartilage space in the healing material. Biokinetic Analysis: Published by Andreassen and Bak's Biokinetic Analysis Methods

(1989,45:292-297 The Effects of Aging on Fracture Healing in Rats. Calcif Tissue mnt).

Briefly, x-rays are taken for all fractures before biomechanical testing. Analysis of the kinematics of healed fractures by a 3- or 4-point curvature fracture procedure. It measures maximum load, stiffness, energy at maximum load, deflection at maximum load, and maximum stress.

Testing the effects on fracture healing after topical administration - female or male hunting dogs approximately two years old are used in the study. Transverse radial fractures occur with continuous slow loading in three-point bending as described by:

Nunamaker, D.M.; Wood, F.E.: ;.Lenehan et al. (Lenehan, TM; Balligand, M). (1985;3:499-507 Effects of EHDP on Fracture Healing in Dogs. J. Orthop Res

The wire is pulled through the fracture site to confirm complete anatomical disruption of the bone. Next, we administer prostaglandin antagonists locally to the fracture site by slow-release compound from slow-release globules or mini-pumps for 10, 15, or 20 weeks.

Histological analysis: Published by: Methods of histological analysis of fractured bone from:

Peter et al. (Peter, CP; Cook, WO; Nunamaker, DM; Provost, MT; Seedor,

JG; Rodan, GA Effects of alendronate on fracture healing and bone remodeling in dogs. J. Orthop. Res. 14:74-70, 1996) and Mosekilde and Bak (The Effects of Growth Hormone on Fracture Healing in Rats: A Histological Description. Bone, 14:19-27, 1993).

Briefly, the fracture side is spread 3 cm on each side of the fracture line, immersed undecalcified in methylmethacrylate, and cut on a small Reichert-Jung resection at 8 µm thickness for the anterior segments. Medial anterior sections stained with Masson-Trichrome (including both the greater and lesser tibia) are used in order to view the cellular and histological response to bone healing with and without treatment. Sections stained with Sirius Red are used to demonstrate the structural properties of the healing material and to differentiate between woven bone and stratified bone at the fracture site. The following measurements are made: (1) fracture aperture - measured as the shortest distance between the ends of the cortical bone in the fracture, (2) length and diameter of the healing material, (3) total bone volume area of the healing material, (4) bone tissue per tissue area within the area of the healing material , (5) Connective tissue in the healing material, (6) Cartilage space in the healing material.

Biokinetic Analysis: Published by Biokinetic Analysis Methods from:

Bak and Andreassen (The Effects of Aging on Fracture Healing in Rats. Calcif Tissue Int 45:292-297,1989) and Peter et al. (Peter, CP; Cook, WO; Nunamaker, DM; Provost, MT; Seedor, JG; Rodan, GA Effects of Alendronate on Fracture Healing And Bone Remodeling In Dogs. J. Orthop. Res. 14:74-70,1996) .

Briefly, x-rays are taken for all fractures before biomechanical testing. Kinematic properties of healed fractures are analyzed by 3- or 4-point fracture bending procedures. It measures maximum load, stiffness, energy at maximum load, deflection at maximum load, and maximum stress.

Anti-estrogen system

Antiestrogens are a type of compound that inhibit bone loss and prevent bone loss resulting from estrogen deficiency. The ovariectomized rat bone loss model is widely used as a model of bone loss

Bone after menopause. Using this model, the effectiveness of antigen/antagonist compounds can be tested

Estrogens help prevent bone loss and inhibit bone resorption.

This study uses female rats (Sprague-Dawley Charles River, Wilmington, Mass.) of different ages (such as 5 months). The rats live individually in cages measuring 20 cm And a commercial meal in the form of pellets

(Agway ProLab 3000, Agway County Food, Inc., Syracuse, NY) contains 97.0% calcium, 0.85% phosphorus, and 1.05 IU of vitamin D3.

A group of mice (8 to 10) are sham operated on and treated with a carrier fluid before the operation (10% ethanol and 90% saline solution, 1 ml/day), while the rest of the mice have their ovaries removed on both sides (OVX) and treated with any of the two carrier liquids (before the operation). 7 1beta-estradiol

E-8876 'Sigma (E2, 17β-estradiol, 30 mcg/kg, daily subcutaneous injection), or an anti-estrogen (such as droloxifene at 5, 10, or 20 mg/kg, daily before surgery)

For a specific period (such as 4 weeks) all mice are given by subcutaneous injection 1 mg/kg calcein (fluorochrome bone marker) 12 and 2 days before slaughter in order to examine motor changes in tissue. Bone. After 4 weeks of treatment, the mice were slaughtered and dissected. The following endpoints are measured: Bone weight gain: body weight at autopsy - body weight at surgery. Weight and histology of the uterus of each mouse during filtration; It is weighed immediately. Next, the uterus is prepared for histological parameters such as uterine cross-section tissue area, ground layer thickness, and cavity epithelial thickness.

Total blood cholesterol: We obtain the blood by puncturing the heart and clot it at 4°C. Then it is centrifuged at 2000 g for 10 minutes to analyze the serum samples for total serum cholesterol. Using the high-performance cholesterol calorimeter test:

(Boehringer Maimheim Biochemicals, Indianapolis, Ind.).

Femur mineral measurement: The right femur of each rat was removed at dual-energy , Waltham, Mass.) &amp;Regional High Resolution Scan&amp;

The scanning dimension is 1.902 Femoral scan images analyze bone area, bone mineral content (BMC), and bone mineral density (BMD) of each femur (WF), and measure the inferior femoral metaphysis (DFM), tibia (FS), and proximal femur (PF). Histological morphometric analysis of the reticular bone of the metaphysis of the greater tibia: The greater tibia is removed during dissection, dissected free of muscle, and cut into three parts. Place the top portion in 70% ethanol, dehydrate with graded concentrations of ethanol, defatted in acetone, and then immersed in methyl methacrylate (Eastman Organic Chemicals, Rochester, NY). Anterior sections of the proximal metaphysis of the greater tibia are cut at 4 to 10 µm in thickness using a Reichert-Jung S. multi-piece retractor. A 4 µm section and a 1 µm section are used.

from each mouse for histological morphometry of the retinacular bone. 4 µm sections were stained with dye

Masson Trichrome modified while 10µm sections remain unstained.

A two-column calcaneal histological 2/OS system (R&amp;M biometrics, Inc., Nashville, Tenn.) is used for static and kinematic morphometric measurements of the secondary cancellous tissue of the metaphysis of the greater tibia proximal between 1.2 and 3.6 mm below the growth plate connection. Bone metaphysis. The first 1.2 millimeters are removed from the metaphyseal area of the greater tibia in order to determine measurements in the secondary spongy tissue. The 4 µm fractions are used to measure parameters related to bone size, bone structure, and bone resorption, while the 10 µm fractions are used to measure parameters related to bone formation and bone recession. 1- Measurements and calculations related to the size and structure of the septal bone:

(1) Total metaphyseal area (TV, mm2): The area of the metaphysis between 1.2 and 3.6 mm below the growth plate-upper metaphysis connection.

(2) Septal bone area (BV, mm2): The total area of the septa within the TV. (3)Septal bone circumference (BS, millimeters): Length of the total circumference of the septa. (4) Septal bone volume (100XBV/TV), TV/BV%.

(5)Septal bone number (TBN, #/mm): BS/TV x2/1,199.

(6)Septal bone thickness (TBT' µm): (1,199/2000)BV/BS)x). (7) Septal bone separation (TBS, micrometers): (2000/1,199)TV-BV)x). 2- Measurements and calculations related to bone resorption:

(1) Osteoclast number (OCN, #): The total number of osteoclasts in the total metaphyseal area. (2) Osteoclast circumference (mm, OCP): The length of the perimeter of the septum covered by osteoclast. (3) Number of osteoclasts/mm (mm/OCN, #mm): OCN/BS. (4) Osteoclast circumference percentage (%ocp, %): XOCP/BS100. 3- Measurements and calculations related to bone formation and recession:

(1) Single calcein-marked circumference (SLS; millimeters): The total length of the septal circumference marked by a single calcein.

(2) Double calcin circumference (DLS, mm): The total length of the perimeter marked with two calcin markers.

(3) Intermarker width (ILW, µm): average distance between two calcein marks. (4) Percentage of mineralized perimeter (XBS / (DLS+SLS/2)): PMS100%. (e) Mineral addition rate (MAR, µm day): LW/mark period. (6) Bone formation rate/surface reflectance Surface (BFR/BS, square meter density/μm):

(BS/MAR

(7) Bone loss rate (y/%, BTR): (SLS/2+DLS xMARXBV

statistics

Statistics can be calculated using StatView 4.0 packages (Abacus Concepts, Inc., Berkeley, CA). Analysis of variance (ANOVA) followed by Fisher's PLSD is used to compare differences between groups.

Combined and sequential treatment system

The following systems may be varied by those skilled in the art. For example, an intact male or female mouse, a male deficient in sex hormones (testes removed) or a female rat (ovaries removed) may be used. In addition, males or females of different ages (such as 12 months of age) can be used in these studies. Mice may be either intact or infertile (ovariectomized or testicular removed), and given anabolic agents.

Such compounds of this invention are given in different doses (1 mL, 3 or 6 mg/kg/day) for a certain period (such as two weeks or two months), followed by the administration of an anti-resorption agent such as droloxifene in different doses (1 mL, 10 mg/kg/day) for a period Specific treatment (such as two weeks or two months), or combination treatment with both Al-Bani and Al-anti-resorptive drugs at different doses for a specific period (such as two weeks or two months). In castrated mice, treatment can be initiated the day after surgery (for the purpose of preventing bone loss) or at the time when bone loss has already occurred (for the purpose of restoring bone mass).

Mice are slaughtered under anesthesia with ketamine. The following endpoints are calculated: Femur mineral measurement: The right femur is removed from the mouse during necropsy and examined using a dual-energy , Mass.) &amp;Regional High Resolution Scan). The field size of the examiner is 5.08 x 1.902 cm, the resolution is 0.0254 x 0.0127 cm, and the speed of the examiner is 7.25 mm/s. Femoral scan images analyze and calculate bone area, bone mineral content (BMC), and bone mineral density (BMD) for the entire femur (WF), distal femoral metaphysis (DFM), femoral tibia (FS), and proximal femur (PF). Lumbar bone mineral measurements: A dual-energy Bone area, bone mineral content (BMC), and bone mineral density (BMD) were calculated for each lumbar protuberance and each of the six lumbar vertebrae (lumbar vertebrae 1–6) in anesthetized rats. Mice are anesthetized by injection (intraprotonally) with 1 ml/kg of a mixture of ketamine/Rombone (ratio 4 to 3), and then placed on the rat platform. The field size of the examiner is 1.9X6 cm, the resolution is 0.0127X0.0254 cm, and the speed of the examiner is 7.2 mm/s. We obtain images of all the lumbar protuberances and decomposition. Bone area (BA) 30, bone mineral content (BMC) are calculated; Bone mineral density (MBC divided by BA) is calculated for each lumbar protuberance and each of the six lumbar vertebrae (lumbar vertebrae 1-6).

Histological morphometric analysis of the reticular bone of the proximal metaphysis of the greater tibia: The right greater tibia is removed at dissection, dissected free of muscle, and cut into three parts.

The upper part of the tibia is placed in 70% ethanol, dehydrated with graded concentrations of ethanol, defatted in acetone, and then immersed in methyl methacrylate (Eastman Organic Chemicals, Rochester, NY). Anterior sections of the proximal metaphysis of the greater tibia are cut at a thickness of 4 and 10 micrometers using a mini-reichert Jung. A 4-μl section and a 10-μm section from each mouse were used for morphological histological measurement of retinal bone. 4-μm sections are stained with modified Masson Trichrome stain while 10-μm sections remain unstained.

A two-column 2/OS histological morphometric system (R&amp;M biometrics, Inc., Nashville, Tenn.) is used for static and kinematic histological morphometric measurements of the secondary cancellous tissue of the metaphysis of the greater tibia proximal between 1.2 and 3.6 mm below the growth plate connection. Bone metaphysis. The first 1.2 millimeters are removed from the metaphyseal area of the greater tibia in order to determine measurements in the secondary spongy tissue. The 4 µm fractions are used to measure parameters related to bone size, bone structure, and bone resorption, while the 10 µm fractions are used to measure parameters related to bone formation and bone recession. 1- Measurements and calculations related to the size and structure of the septal bone:

(1) Total metaphyseal area (TV, 2 mm): Metaphyseal area between 1.2 and 3.6 mm below the upper growth plate-metaphyseal junction.

(2) Septal bone area (BV, mm2): The total area of the septa within the TV. (3)Septal bone circumference (BS, millimeters): Length of the total circumference of the septa. (4)Septal bone volume (XBV/TV, TVVBVX 100). (e)Septal bone number (TBN, #/mm): BS/TV x2/1.199. (6)Septal bone thickness (TBT, micrometers): BV /BS)x(1,199/2000)). (7) Alveolar bone separation (TBS, µm): (1.199/2000 )TV-BV)x). 2- Measurements and calculations related to bone resorption:

(1) Osteoclast number (OCN, #): The total number of osteoclasts in the total metaphyseal area. (2) Osteoclast circumference (OCP, mm): The length of the periphery covered by osteoclast. (3) Number of osteoclasts per millimeter (OCN/mm, #/mm): OCN/BS.

(4) Osteoclast circumference percentage (%ocp, %): XOCP/BS1001. 3- Measurements and calculations related to bone formation and recession:

(1)Single calcein-marked circumference (SLS, millimeters): The total length of the septal perimeter marked with a single calcein.

(2) Double calcein-marked perimeter (DLS, mm): The total length of the perimeter marked with two calcein markers.

(3) Intermarker width (ILW, µm): average distance between two calcein marks. (4) Percentage of mining area (%, PMS): (DLS+SLS/2) / 0XBS 0 1.

(e) Mineral addition rate (MAR, µM/day): IEW/mark period. (6) Bone morphology rate/surface reflectance (BFR/BS, square µm/density/µm):

BSMAR

(7) Bone recession rate (y/%, BTR): (SLS/2+DLS) XMAR/BV X100.

statistics

Statistics can be calculated using StatView 4.0 packages (Abacus Concepts, Inc., Berkeley, CA). Pan test analysis (ANOVA) followed by Fisher's PLSD is used to compare differences between groups.

Use of the prostaglandin receptor antagonist in kidney regeneration The role of the prostaglandin receptor antagonist in kidney regeneration is investigated by the ability of PGE2 or the prostaglandin receptor antagonist to increase the expression of bone morphogenetic protein 7 (7-BMP) in wild type 293S cells and in 293S cells that host the EP2 receptor gene carrier. Methods: 293S and S EP2 cells are grown in Dulbecco Modified Egale Medium (.DMEM, Gibco, BRL; Gaithersburg, Md). One day before treatment with PGE2 or a prostaglandin antagonist, cells were placed in dishes at a density of 5 x 1,610 cells/10 cm dish. The next day, the cell monolayer was washed once with OptiMEM (Gibco, BRL), followed by the addition of 10 ml OptiMEM/dish in the presence and absence of carrier fluid (PGE2, DMSO (6-10 mol) or prostaglandin antibody (6-10 mol). Gram cells are collected and RNA is extracted for 8, 1, and 4 2 hours. Northern spot analysis is performed with a total of (0.2 mg/lane).

Blots by 7-BMP probe labeled by p32. Blots are normalized for RNA loading by hybridization with an 18s ribosomal RNA probe labeled with 32P. It is observed that both 2PGE and the prostaglandin antagonist, in a time-dependent manner, increase the expression of 7-BMP in EP2 293S cells but not in the original cell line. Given the known role of 7-BMP in kidney regeneration and the ability of the prostaglandin antagonist to increase the expression of 7-BMP in 293S kidney cells in a time- and receptor-specific manner indicates a role for the prostaglandin antagonist in kidney regeneration.

The compounds of this invention may be administered by any method that delivers the compound of this invention generally and/or locally (e.g., at the site of a bone fracture, osteotomy, or orthopedic surgery). These routes include oral, intraserum, intraduodenal, etc. Generally, the compounds of this invention are administered orally, but administration into the blood (e.g., intravenous, intramuscular, subcutaneous or intraspinal) may be used, for example, when oral administration is inappropriate for the purpose or when the patient is unable to swallow the drug .

The compounds are used to treat and promote healing of bone fractures and bone resections by topical application (e.g., to sites of bone fractures or bone resections) of the compounds of this invention or combinations thereof. The compounds of this invention are applied to sites of bone fractures or osteotomies, for example, either by injecting the compound in a suitable solvent (ml, oily solvent such as arachis oil) into the cartilage growth page or, in cases of open surgery, by topical application thereof of those compounds if appropriate. Such as bone wax, demineralized bone powder, polymeric bone cements, bone sealing materials, etc. Alternatively, topical application can be made by placing a solution or dispersion of the compound in a suitable state on a surface, or embedding it in solid or semi-rigid implants traditionally used in orthopedics, such as Gore-tex® mesh, dacron, gel-foam and Kiel bone, Or industrial formulations.

Compounds of this invention may also be applied topically to the site of a fracture or bone resection in a suitable carrier in combination with one or more of the anabolic or anti-bone resorptive agents described above.

The two compounds hidden from this invention may be administered in combination at the same time or sequentially in any manner, or a single drug composition may be administered comprising the Formula I compound as described above and a second compound as described above in a pharmaceutically acceptable carrier .

For example, an osteoblastic agent may be used alone in combination with an antiresorptive agent for 1 week to 3 years, followed by the antiresorptive agent alone for 3 months to 3 years, with an optional repeat of the full course of treatment. Alternatively, for example, an osteoblastic agent may be used alone or in combination with an antiresorptive agent for 3 months to 3 years, followed by the antiresorptive agent alone for the remainder of the patient's life. For example, in one preferred route of administration the formulation I compound as described above may be administered once daily and a second compound as described above (e.g., an antagonist/anti-estrogen) may be administered daily in a single or multiple doses. Alternatively, for example, another preferred route of administration is that the compounds may be given sequentially, giving the Formula I compound as described above once daily for a period of time sufficient to increase bone mass to a higher level.

Bone:

(World Health Organization Study &amp;Assessment of Fracture Risk and its Application to Screening for Postmenopausal Osteoporosis (1994). Report of a World Health Organization Study Group. World Health Organization Technical Series 843&amp;)

Followed by administration of a second compound, as described above (eg, antagonist/anti-estrogen), daily in single or multiple doses. Compound 1 should preferably be administered as described above once daily in a rapid-release form such as oral administration (eg, it is preferable to run out of the sustained-release form).

However, the amount and timing of the compounds administered depends, of course, on the person being treated and the judgment of the treating physician. Therefore, due to the variation from patient to patient, the doses given below are a guideline and the doctor may titrate the doses of the drug to achieve the treatment (such as increasing bone mass) that the doctor considers appropriate for the patient. To determine the required treatment dose, the physician must weigh various factors such as the starting level of bone mass, the patient's age, the presence of a pre-existing disease, as well as the presence of other diseases (eg, cardiovascular disease).

Generally, an amount of the compound of this invention is used that is sufficient to increase bone mass to a level that is above the critical value for bone fracture (as detailed in the World Health Organization study previously blogged here).

Generally, the effective dose of the anabolic agents described above is in the range of 0.001 to 0.01 mg/kg/day, preferably 0.01 to 50 mg/kg/day. The following paragraphs provide preferred dosages for various antiresorptive agents. The amount of antiresorptive agent used is measured by its activity as a bone loss inhibitor. This activity is measured by the individual pharmacokinetics of the compound and its minimum effective dose in inhibiting bone loss using a system such as the one described above (ie, an antagonist/anti-estrogen system).

Generally, the effective dose of an antiresorptive agent is approximately 0.001 mg/kg-ION

To about 0.2 mg/kg/day.

Generally, the effective dose of progestins is about 0.1 to 1.0 mg per day; The preferred dose is about 0.25 to 5 mg per day.

In general, the effective dose of polyphosphonates is measured by their potency as a bone resorption inhibitor according to standard tests.

Daily administration limits for some polyphosphonates are approximately 0.001 mg/kg/day

To about 0.2 mg/kg/day.

In general, an effective dose for the treatment in this invention e.g. bone resorption therapy in this invention, for antiestrogen/s in this invention is in the range from 0.01 to 200 mg/kg/day, preferably 0.5 to 100 mg/kg/day. today.

Specifically, an effective dose of droloxifene is in the range of 0.1 to 40 mg/kg/day, preferably 0.1 to 5 mg/kg/day.

Specifically, the effective dose of raloxifene is 1.0 to 0.1 mg/kg/day, preferably 1.0 to 1.0 mg/kg/day.

Specifically, an effective dose of tamoxifen is in the range of 0.1 to 100 mg/kg/day, preferably 0.1 to 5 mg/kg/day. Specifically, an effective dose of:

Cis-6-(4-fluoro-phenyl)-5-[4-(2-piperidin-l-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-

naphthalene-2-ol;

(-)-Cis-6-phenyl-5-[4-(2-pyrrolidin-l-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-

naphthalene-2-ol;

Cis-6-phenyl-5-[4-(2-pyrrolidin-l-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-

naphthalene-2-ol;

Cis-l-[6'-pyrrolodinoethoxy-3'-pyridyl]-2-phenyl-6-hydroxy-l,2,3,4-

tetrahydronaphthalene;

l-(4'-Pyrrolidinoethoxyphenyl)-2-(4&amp;-fluorophenyl)-6-hydroxy-l,2,3,4-

tetrahydroisoquinoline;

Cis-6-(4-hydroxyphenyl)-5-[4-(2-piperidin-l-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol; or

l-(4'-Pyrrolidinolethoxyph£nyl)-2-phenyl-6-hydroxy-l,2,3,4-

tetrahydroisoquinoline;

It is in the range of 0.0001 to 100 g/kg/day, preferably 0.001 to 1 mg/kg/day.

Specifically, the effective dose of 4-hydroxy tamoxifen is in the range of 0.001 to 100 mg/kg/day, preferably 1 0 0.0 to 1 0 mg/kg/day.

The compounds of the present invention are generally administered in the form of a pharmaceutical composition comprising at least one of the compounds of this invention together with a pharmaceutically acceptable vehicle or diluent. Therefore, the compounds of this invention may be administered individually or together in any oral, blood, rectal or transdermal dosage form.

For oral administration, the drug composition can be in the form of solutions, suspensions, tablets, pills, capsules, powders, and the like. Tablets are used containing different excipients such as sodium citrate, calcium carbonate and calcium phosphate along with various hydrolyzants such as starch, preferably potato or tapioca, and certain compound silicate, along with binding agents such as sucrose, polyvinylpyrrolidone, gelatin and acacia. In addition, sledging factors such as

5-(3-{[2-(3,5-Dichl0r0-phen0xy)-ethyl]-methanesulf0nvl-amin0}-pr0pyl)-furan-2-

carboxylic acid

Step A:

5-(3-{[2-(3,5-Dichl0r0-phen0xy)-ethvll-methanesulfbnyl-amin0l-pr0pyl)-furan-2-carboxylic acid methyl ester

Reaction time: 72 hours at room temperature;

MS 450 (M+1).

Step (B):

5-(3-{[2-(3,5-Dichloro-phenoXy)-ethyll-methanesulfonyl-amino}-propyl)-furan-2-carboxylic acid

1H NMR(400MHZ, CDCI3) δ6.8-7.7(m,5H), 6.19(d,lH,J=3.8),4.2(t,2H,J),3.8

(m,2H),3.25-3.4(m,4H) 2.95(S,3H), 2.65(m)2H), 1.8-2.0(m,2H); MS 435(Ml),

436 (M+1).

Example 127

Trans-5-(3-{[3-3,5-Dichloro-phenyl)-allyl]-methanesulfonyl-aminol-propyl)-furan-2-carboxylic acid

Step A:

Trans-5-(3-{[3-(3,5-Dichloro-phenyl)-allvn-methanesulfonvl-amino}-propyl)-furan-2-carboxvlic acid methyl ester

Reaction time: 72 hours at room temperature;

MS 446 (M+).

Step (B):

Trflns-5-(3-{[3-(3,5-Dichloro-phenyl)-allyll-methanesulfonyl-amino|-propyl)-furan-2-carboxvlic acid

1H NMR(400 MHZ, CDCI3) δ 7.0-7.5(m,2H), 6.0-6.6(m,3H), 4.0(d,2H,J=5), 3.2(m,

2H), 2.6-2.7(m,2H), 1.7-2.0(m,2H); MS 430 (Ml), 432 (M+1).

Example 128

3-(2-{[2-(3,5-Dichloro-phenoxv)-ethyll-methisulfonyl-aminol-ethyl)-benzoic

acid

Step A:

3-(2-{[2-3,5-Dichloro-phenoxy)-ethyl]-methanesulfonyl-amino}-ethy)-benzoic acid methyl ester

Reaction time: 2 hours at room temperature;

MS 446 (M+).

Step (B):

3-(2-{[2-(3,5-Dichloro-phenoxy)-ethyl]-methanesulfonyl-amino}-ethyl)-benzoic

acid

IH NMR(400MHz, CDCI3) δ 6.8-7.9(m,7H), 4.2(t,2H,J=6.7), 3.2-3.3(m,4H), 2.85(S,3H), 2.3(t,2H, J=6.8); MS 431 (Ml).

Example 129

[3-(3-{[3-(3-Chloro-phenyl-)propyl]-methanesulfonyl-aminol-propyl)-phenyl]-acetic acid

Step A:

[3-(3-{[3-(3-Chloro-phenyl)-propyl]-methanesulfony-amino}-propyl)-phenyl]-acetic acid methyl ester

Reaction time 2 hours at room temperature 1HNMR(400MHz, CDCI3) δ 7.03-7.29(m,8H), 3.68(S,3H), 3.59(S,2H), 3.15-3.2(m,4H), 2.8(S). ,3H), 2.58-2.64(m,4H), 1.84-1.94(m,4H).

Step (B):

[3-(3-{[3-(3-Chloro-phenyl)-propyl]-methanesulfonyl-aminol-propyl)phenyl]-acetic acid

IH NMR(400MHz, CDCI3) δ 7.02-7.29(m,8H), 3.61(S,2H), 3.14-3.19(m,4H), 2.78(s,3H), 2.57-2.8(m,4H), 1.82 -1.93(m,4H).

Example 130

6-(3-[3-Benzor[1.3]dioxol-5-yl-propyl)-methanesulfonyl-amino]-propyl{-

thiophene-2-carboxylic acid

Step A:

5-{3-[3-Benzor[1.3]dioXol-5-yl-propyl)-methanesulfonyl-amion]-propyl}-thiophene-2-carboxylic acid methyl ester

Reaction time is two hours at room temperature

1HNMR(400MHz, CDCI3) δ7.61(d,lH), 6.79(d,lH), 6.58-6.72(m,3H), 5.91(S,2H), 3.85(S,3H), 3.14-3.21(m ,4H), 2.87(t,2H), 2.8(S,3H), 2.55(t,2H), 1.82-1.99(m,4H).

Step (B):

5-(3-[(3-Benzo[l.3]dioxol-5-yl-propyyl)methanesulfonyl-amino]-propyl}-thiophene-2-carboxylic acid

1H NMR(400MHz, CDCI3) s 7.7(d,lH), 6.83(d,lH), 6.59-6.73(m,3H), 5.91(s,2H), 3.15-3.22(m,4H), 2.89(2.81 (t,2H),2.81(s,3H), 2.55(t,2H), 1.83-2.01(m,4H); MS 424 (Ml).

Example 131

(3-{[4-Isobutyl-benzyl)methanesulfonyl-amino]-methy}-phenyl)-acetic acid

Step A:

(3-{[(4-Isobutyl-benzyl)methanesulfonyl-amino]-methyl}-phenvl)-acetic acid methyl ester

Reaction time: 2 hours at room temperature. 1H NMR(400MHz, CDCI3) δ 7.2- 7.32(m,6H), 7.1 l(d)2H), 4.3(d,4H), 3.69(S,3H), 3.62(S). ,3H), 3.62(S,3H), 2.75(s, 3H), 2.46(S,2H), 1.81-1.88(m,lH), 0.88(d,6H); MS 404 (M+l), 426 (M+23).

Step (B):

(3-{[4-Isobutyl-benzy)-methanesulfonyl-amino]-methyl)-phenyl)-acetic acid 1HNMR(400MHz, CDCI3) δ7.18-7.31(m,6H), 7.1(d,2H), 4.29 (d,4H), 3.63(s, 2H), 2.73(S,3H), 2.45(d,2H), 1.8-1.87(m,lH), 0.88(d,6H).

Example 132

7-[(4-Isopropyl-benzyl)-methanesulfonyl-amino]-heptanoic acid

Step A:

7-[(4-Isopropyl-benzyl)-methanesulfonyl-amino]-heptanoic acid ethyl ester

Reaction time is 4-2 hours at room temperature.

1H NMR(400MHz, CDl3) δ 7.2-7.3(m,4H), 4.35(S,2H), 4.1(q,2H), 3.15(t,2H), 2.85-2.95(m,lH), 2.8(S ,3H), 2.25(t,2H), 1.48-1.62(m,4H), 1.18-1.32(m,13H); MS 384 (M+l).

:(Step (b

7-[(4-Isopropyl-benzyl)-methanesulfonyl-amino]-heptanoic acid MS 356 (M+l).

Example 133

7-{(2-(3,5-Difluoro-phenoxy)-ethyl]-methanesulfonyl-amino}-heptanoic acid

Step A:

7-{[2-(3,5-Diflu0r0-phen0xy)-ethyl]-methanesulf0nyl-amin0}-heptan0ic acid methyl ester

Reaction time: 4-2 hours at 50°C.

1H NMR(400MHz, CDCI3) δ 6.39-6.45(m,3H), 4.08(t,2H), 3.65(S,2H), 3.58(t,2H), 3.23-3.27(m,2H), 2.88(S ,3H), 2.3(t,2H), 1.57-1.65(m,5H), 1.33-1.35(m,4H); MS 394 (M+l).

Step (B):

7-{[2-(3,5-Difluoro-phenoxy)-ethyl]-methanesulfonyl-amino}-heptanoic acid 1H NMR(400MHz, CDCI3) δ 6.39-6.45(m,3H), 4.08(t,2H), 3.58(t,2H), 3.25(t,2H), 2.35(t,2H), 1.64(m,5H), 1.24-1.37(m,4H); MS 380 (Ml).

Example 134

7-{[2-(3,5-Dimethyl-phenoxy)-ethyl]-methanesulfonyl-amino}-heptanoic acid

Step A:

7-{[2-(3,5-Dimethyl-phenoxy)-ethyl]-methanesulfonyl-amino}-heptanoic acid methyl ester

Reaction time: 4-2 hours at 50°C

1H NMR(400 MHZ, CDC13) δ 6.61(s,lH), 6.49(s,2H), 4.06-4.14(m,2H), 3.65(S,3H),

3.61(t,2H), 3.26(t,2H), 2.9(S,3H), 2.27-2.32(m,8H), 1.55-1.63(m,4H), 1.25(bs,4H); MS 385 (M+l).

Step (B):

7-{[2-(3.5-Dimethvl-phenoxy)-ethyl]-methanesulfonyl-amino}-heptanoic acid 1H NMR(4000 MHZ, CDCI3) δ 6.61(s,lH), 6.49(s,2H), 4.06-4.07 (m,2H), 3.59-3.61

(m,2H), 3.27(t,2H), 2.91(S,3H), 2.34(t,2H), 2.27(S,6H), 1.63-1.65(m,4H), 1.36(bs,4H); MS 370 (Ml).

Like 135

(2-(3-l(4-Butvl-benzyl)-mthanesulfonyl-amino]-propyl}-phenyl)-acetic acid

Step A:

(2-{3[(4-Butyl-benzyl)-methanesulfonyl-amino]-propyl}-pheny)-acetic acid methyl ester

1H NMR(400MHz, CDCI3) δ 7.11-7.23(m)7H), 6.99-7.01(m,lH), 4.31(S,2H), 6.63(S,3H), 3.54(S,2H), 3.19(t ,2H), 2.78(S)3H), 2.49-2.59(M,4H), 1.72-1.8(m,2H), 1.54-1.59(m,2H), 1.27-1.36(m,2H), 0.89(t) ,3H); MS 432 (M+l).

step b

(2-{3-[(4-Butyl-benzyl)-methanesulfonyl-amino]-propyl}-phenyl)-acetic acid 1H NMR(400 MHZ, CDCI3) δ 7.13-7.27(m,7H), 7.02(d, lH), 4.32(S,2H), 3.59(s,2H),

3.21(t,2H), 2.79(S,3H), 2.5-2.61(m,4H), 1.73-1.81(m,2H), 1.54-1.62(m,2H), 1.29-1.38(m,2H), 0.92(t,3H); MS 416 (Ml).

Example 136

5-(3-{[2-(Benzo[1.3]dioxol-5-yloxy)-ethyl]-methanesulfonyl-amino}-propyl)-thiophene-2-carboxvlic acid

Step A:

5-(3-{[2-(Benzo[1,31dioxol-5-yloxy)ethyl]-methanesulfonyl-amino}-propyl)-thiophene-2-carboxylic acid methyl ester

Reaction time: 4-2 hours at room temperature

1H NMR(400 MHZ, CDCl3)δ 7.61(d,1H),6.8(d,lH), 6.67-6.7(m,lH), 6.41(d,lH),

6.24-6.27(m,1H),5.91(s,2H),4.03(t,2H), 3.85(s,3H), 3.59(t,2H), 3.33(t,2H), 2.89

(S,3H), 2.88-2.92(m,2H), 2.01-2.08(m,2H); MS 442 (M+l).

Step (B):

5-(3-{[2-(Benzo[1,3]dioxol-5-yloxy)-ethyl]-methanesulfonyl-amino}-propyl)-thiophene-2-carboxvlic acid

1H NMR(400 MHZ, CDCl3) δ 7.69(d,lH), 6.84(d,lH), 6.68(d,lH), 6.4(s,lH), 6.24-6.27(m,lH), 5.91(S, 2H), 4.03(t,2H), 3.6 (t,2H), 3.34(t)2H), 2.9(S,3H), 2.9-2.94 (m,2H), 2.02-2.l(m, 2H); MS 426 (Ml).

Example 137

[3-({2-(3-Chloro-phenoxy)thyl]-methanesulfonyl-amino]-methyl)-phenyl]-

acetic acid

Step (A):

[3-({[2-(3-Chloro-phenoxy)-ethyl}-methanesulfonyl-amino}-methyl)-phenyl]-acetic

acid methyl ester

1H NMR(400MHz, CDCI3) δ 7.15-7.33(m,5H), 6.93-6.95(m, lH), 6.8-6.81(m,lH), 6.69-6.71(m,1H),4.49(s,2H) , 3.96-4.02(m,2H), 3.67(S,2H), 3.54-3.67(m,4H), 2.94

(S,3H).

Step (B):

[3-({[2-(3-Chloro-phenoxy-phenoxy)-ethyl]-methanesulfony-amino}-methyl)-phenyl]-acetic

acid

1H NMR(400MHZ, CDCl3) δ 7.13-7.33(m,5H), 6.91(d,lH), 6.78(S,2H), 6.66-6.69

(m,lH), 4.48(S,2H), 3.98(t,2H), 3.62(S,2H), 3.56(t,2H), 2.92(s,3H).

Example 138

[3-(2-{[3-(3-Chloro-phenyl)-propyl]-methanesulfonyl-amino}-ethyl)P-phenyl]acetic

acid

Alkylation Step A: Alkylation

[3-(2-{[3-3(Chloro-phenyl)-propyl]-methanesulfonyl-amino}-ethyl)-phenyl]-acetic acid tert-butyl ester

Step (a) is performed with appropriate starting materials in a manner similar to step (a) of Example 1 with a reaction time of 24 hours at room temperature;

MS 466 (M+).

Ester for Hydrolysis Step B: Hydrolysis of [3-(2-{[3-(3-Chloro-phenyl)-propyl)-methanesulfonyl-amino}-ethyl)-phenyl]-acetic acid

Stir for 48 hours at room temperature solution of

3-(2-{[3-(3-chloro-phenyl)-propyl]-methanesulfonyl-amino}-ethyl)-phenyl]-acetic]

acid tert-butyl ester

(170 mg, 0.36 mmol) in dioxane/HCl (5 ml). The reaction is concentrated and the residue is placed in dilute aqueous NaOH (10 ml, pH = 9.3). The aqueous solution was washed with EtOAc (10 ml) and the layers were separated. The aqueous layer was acidified after extraction with EtOAc by diluted aqueous HCl to pH 2.5. After extracting the acidic aqueous layer with EtOAc (10 mL), the organic solution was dried over MgSO4, filtered, and concentrated to provide the title compound as oil (20 mg).

1H NMR(400MHz, CDCI3) δ 6.9-7.5(m,8H), 3.0-3.3(m,4H), 2.95(S,3H), 2.45-2.85(m,4H), 1.8(m,2H); MS 408 (Ml).

Al-Ha'alin 139-140

Examples 139-140 are prepared in a similar manner to Example 138 by starting with appropriate alkylating agents, sulfonamides, in the alkylation step (a), followed by hydrolysis of the ester in step (b), with variations in the temperature and time of the reaction in step (a), as noted.

Example 139

[3-(2-([2-(3,5-Dichloro-phenoxy)-ethyl]-methanesulfonyl-amino}-ethyl)-phenyl]-acetic acid

Step A:

[3-(2-{[2-(3,5-Dichloro-phenoxy)-ethyl]-methanesulfonyl-amino}-ethyl)-phenyl]-acetic acid tert-butyl ester

Reaction time is 4 hours at room temperature. Step (B):

[3-(2-{[2-(3,5-Dichloro-phenoxy)-ethyl]-methanesulfonyl-amino}-ethyl)-phenyl]-acetic acid

1HNMR(400MHz, CDCl3) δ6.7-7.5(m,7H), 4.2(m,2H), 3.25(m,4H), 2.95(S,3H),

2.35-2.65(m,2H); MS 445 (Ml).

Example 140

5-(3-{[3-(3-Chloro-phenyl)-propvl]-trifluoroacetyl-amino}-propyl)-thiophene-2-carboxylic acid

Step A:

5-(3-{[3-(3-Chloro-phenyl)-proPyl]-trifluoroacetyI-amino}-propyl)-thiophene-2-carboxylic acid tert-butyl ester

Reaction time: 24 hours at room temperature;

MS 508 (M+18).

Step (B):

5-(3-{[3-(3-Chloro-phenyl)-propyl]-trifluoroacetyl-amino}-propyl(thiophene-2-carboxylic acid)

1H NMR(400MHz, CDCl3) δ 6.6-7.8(m,6H), 3.22(m,4H), 2.8(m,2H),

1.6-2.02(m,4H); MS 433 (Ml).

Example 141

3-[(2,3-Dihydro-benzo[l,4]dioxin-5-ylmethyl)-methanesulfonyl-amino]-)

methyl}-phenyl)-acetic acid

Step (A): Reductive Amination

(3-2,3-Dihydro-benzo[1-4]dioxin-5-ylmethyl-amino]-methyl]}-phenyl)-aceticacid

ethyl ester

Triethylamine (65 mg, 0.646 mmol) is added to a solution of...

1,4-cenzodioxan-6-carbaldehyde (100 mg, 0.606 mmol)

3 hydrochloride and -aminomethyl-phenyl)-acetic acid ethyl ester (48 1 mg, 0.645

mmol) in MeOH (2.5 mL). The reaction was stirred for 3 hours, cooled to 0°C, and NaBH4 (37 mg, 0.975 mmol) was added. After stirring at room temperature for 10 minutes, add a 1:1 mixture of saturated aqueous NaHCO3:water. The product was extracted in CH2CI2, the organic solution was dried over MgSO4, filtered and concentrated to produce the title compound.

(202 mg).

1H NMR(400MHz, CDCI3) δ 7.14-7.27(m,4H), 6.84(s,lH), 6.78(S,2H), 4.22(S,4H), 4.12(q,2H), 3.75(S,2H ), 3.67(S,2H), 3.57(S,2H); MS 343 (M+l).

Sulfonamide Step (B): Formation of (3-{[(2,3-Dihydro-benzo[ 1,4]dioxin-5-ylmethyl)-methanesulfonyl-amino]-methyl }-phenyl)acetic acid ethyl ester

0.05 ml, 0.643 mmol (mol) to methanesulfonyl chloride solution is added

from

3-{[2,3-Dihydro-benzo[l,4]dioxin-5-ylmethyl-amino]-methyl}-phenyl)-acetic acid)

ethyl ester

(200 mg, 585.0 mmol) triethylamine (71 mg, 0.702 mmol) in CH2CI2 (0.1 mmol). The reaction was stirred for 16 hours and diluted with CH2CI2. The organic solution is washed with water, then with salt solution, dried on MgS04, filtered and dried. The product was purified by flash chromatography (20% EtOAc in hexanes to 40% EtOAc in hexanes) to provide the title compound (210 mg).

4.24(1H NMR (400MHZ,CDCI3) δ 7.2-7.31(m,4H), 6.75- 6.82(m,3H), 4.3(s,2H H 4.13(q,2H), 3.59(S,2H), 2.74 (S,3H), 1.24(t,3H); MS 420 (M+),(4.2(S,2H (S,4H))

(17+437 (M

Step C: Hydrolysis of the Ester

3-2,3-Dihydro-benzori[1,4]dioxin-5-ylmethyl)methanesulfony)-amino[-]})

methyl}-pheny)-acetic acid

Aqueous NaOH (2 m, 0.5 ml) is added to a solution of 3-{[(2,3-Dihydro-benzo[l,4]dioxin-5-ylmethyl)-methanesulfonyl-amino]-methyl}-)

phenyl)-acetic acid ethyl ester (210 mg, 0.5 mmol) in MeOH (3 mL) at 0°C. The reaction was stirred at room temperature for 1 hour and diluted with 1 N HCl. The resulting product is extracted in CH2CI2 and the organic solution is washed with water and then with saline solution. The organic solution is dried on

MgSO4, filtered, and concentrated to provide the title compound (165 mg).

4.22 1(4.29(S,2H) ,(6.73-6.81(m,3H) 1H NMR(400MHz, CDCI3) δ7.19-7.32(m,4H

(2H), 2.75(S,3H S,4H), 4.18(S,2H), 3.63(s,)

Examples 14-162

Examples 142-162 are prepared in a manner similar to Example 141 by starting with the appropriate aldehyde amine reagents in step (a), followed by formation of the desired sulfonamide in step (b) and hydrolysis of the ester in step (c).

Example 142

3-{[(5-Ethyl-thiophene-2-ylmethyl)-methanesulfonyl-aminol-methyl}-phenyl)-acetic acid

Step A:

(3-( {[(5-Ethyl-thiophene-2-ylmethyl)-aminol-methyl}-phenyl}acetic acid ethyl ester 1HNMR(400MHz, CDCl3)δ7.15-7.29(m,4H), 6.7(d, lH), 6.59(d,lH), 4.11-4.15(m,2H), 3.9(s,2H)1 3.8(S,2H)1 3.58(S,2H), 2.76-2.82(m,2H), 1.84 (bs,lH), 1.2-1.29 (m,6H); MS318(M++l).

Step (B):

(3-{[-Ethvl-thiophen-2-ylmethyl)-methanesulfony-amino]-methyl}-phenyl)-acetic acid ethyl ester

1HNMR(400MHz, CDCl3) δ7.23-7.35(m,4H), 6.77(d,lH), 6.63-6.64(m,lH), 4.4(s,2H), 4.38(S,2H), 4.15(q ,2H), 3.62(S,2H), 2.82(q,2H), 2.77(S,3H), 1.23-1.31(m,

6H); MS413(M++18).

:Step (c)

3- {[(5-Ethyl-thiophene-2-ylmethyl)-methanesulfonyl-amino1-methyl}-phenyl)-acetic acid

1H NMR(400MHz, CDCl3) δ 7.23-7.33(m,4H), 6.74(s,lH), 6.61(s, lH), 4.38(S,2H), 4:36(S,2H), 3.66(S ,2H), 2.8(q,2H), 2.75(S,3H), 1.25-1.3(m,3H); MS 366 (M+-l).

Example 143

(3-{[Methanesulfonyl-(5-phenyl-furan-2-ylmethyl)-amino]-methyl}-phenyl)-acetic

acid

Step (A):

(3-{[(5-Phenyl-furan-2-ylmethyl)-amino]-methyl)-phenyl)-acetic acid methyl ester 1HNMR(400MHz, CDCI3) δ7.62(d,2H), 7.34(t,2H ), 7.14-7.29(m,5H), 6.55(d,lH), 6.24(d,lH), 3.81(d,4H), 3.66(S,3H), 3.59(S,2H), 1.73(bs, lH).

Step (B):

(3-{[Methanesulfonyl-(5-phenyl-furan-2-yImethyl)-amino1-methyl}-phenyl)-acetic acid methyl ester

1HNMR(400MHz, CDCI3) δ7.62(d,2H), 7.38-7.42(m,2H), 7.23- 7.38(m,5H), 6.6-6.61(m,lH), 6.34(d,lH), 4.37 (d,4H), 3.69(S,3H), 3.63(S,2H), 2.89(s,3H); MS 436 (M++23).

Step (c):

(3-{[Methanesulfonyl-(5-phenyl-furan-2-ylmethyl)-amino]-methyl}-phenyl)-acetic

acid

1H NMR(400MHz, CDCI3) 7.6 δ(d,2H), 7.37(t,2H), 7.22-7.33(m, 5H), 6.57(d,lH), 6.31(d,lH), 4.36(s,2H ), 4.33(s,2H), 3.64(s,2H), 2.87(s,3H); MS 398 (M+-l).

Example 144

(3-{[(3-Hvdroxy-4-propoxy-benzyl)-methanesulfonyl-amino]-methy}-phenyl)-acetic acid

Step A:

{3-[(3-Hydroxy-4-propoxy-benzylamino)-methyl]-pheyl}-acetic acid methyl ester IH NMR(400MHZ, CDCl3) δ 7.24-7.3(m,3H), 7.16(d,lH), 6.91(s, 1H), 6.79(s,2H),

3.98(t,2H),3.77(s,2H), 3.7(S,2H), 3.68(S,3H), 3.61(S,2H), 1.82(q,2H), 1.03(t,3H); MS 365 (M++22).

Step (B):

(3-{[Methanesulfonyl-(3-methanesulfonyloxy-4-propoxy-benzyl)-aminol-methyl)-pheny)-acetic acid methyl ester

IH NMR(400MHZ, CDCl3) δ 7.31-7.17(m,6H), 6.93(d)lH), 4.28(s,2H), 4.23(s,2H),

3.97(t,2H), 3.68(S,3H), 3.61(s,2H), 3.16(S,3H), 2.78(s,3H), 1.82(m,2H), l.03(t,3H) . 3-{[(3-Hydroxy-4-propoxy-benzyl)-methanesulfonyl-amino]-methyl }-phenyl)-acetic acid

1HNMR(400MHZ, CDCl3) δ 7.34-7.2(m,4H), 6.84-6.78(m,3H), 4.31(s,2H), 4.2(s,

2H), 3.98(t,2H), 3.65(S,2H), 2.76(s,3H), 1.83(m,2H), l.04(t,3H).

Example 145

[3-({[2-(4-Chloro-phenylsulfanyl)-ethyl]-methanesulfonyl-amino}-methyl)-phenyl]-acetic acid MS 414 (M+).

Example 146

(3-{[Methanesulfanyl-(4-phenethylsulfanyl-benzyI)-amino1-methyl}phenyl)-acetic

acid

Step A:

(3-{[(4-Phenethylsulfanyl-benzyl)-aminol-methyl}-phenyl)-acetic acid methyl ester 1H NMR(400MHz, CDCl3) δ 7.16-7.33(m,13H), 3.78(d,4H), 3.68 (s,3H), 3.61(s,2H), 3.12-3.16(m,2H), 2.89-2.93(m,2H); MS 406 (M+l).

Step (B):

(3-{[Methanesulfonyl-(4-phenethvlsulfanyl-benzyl)-amino]-methyl}pheny)-acetic acid methyl ester

1HNMR(400MHz, CDCl3) δ7.18-7.31(m,13H), 4.3(d,4H), 3.69(s, 3H), 3.61(s,2H), 3.13-3.19(m,2H), 2.84-2.94 (m,2H), 2.78(s,3H); MS 505 (M+22).

Step (c):

(3-{[Methanesulfonyl-(4-phenethylsulfanyl-benzyl)-amino]-methylbheny)-acetic

acid

1HNMR(400MHz, CDCl3) δ7.13-7.29(m,13H), 4.27(d,4H), 3.61(s,2H), 3.12-3.16(m,2H), 2.88-2.92(m,2H), 2.76 (S,3H); MS 468 (Ml).

Example 147

[3-({[3-3,5-Dichloro-phenoxy)-benzyl]-methanesulfonyl-amino}-methyl)-phenyl]-acetic acid

Step A:

[3-({[3-(3-(3,5-Dichloro-phenoxy)-benzyl]-amino)-methyl)-phenyl]-acetic acid methyl ester

1H NMR(400MHz, CDCl3) δ 7.21-7.33(m,4H), 7.15(d,2H), 7.03-7.04(m,2H),6.88-

6.9(m,lH), 6.84(s,2H), 3.78(d,4H), 3.66(s,3H), 3.59(S,2H), 1.82(bs,lH).

Step (B):

[3-({[3-(3,5-Dichloro-phenoxy)-benzyl]-methanesulfonyl-amino}-methyl)-phenyl]-acetic acid methyl ester

1HNMR(400MHz, CDCl3)δ6.81-7.17(m,llH), 4.31(d,4H),3.65(s,3H), 3.58(s,2H), 2.8(s,3H).

Step (c):

[3-({[3-3,5-Dichloro-phenoxy)-benzyl]-methanesulfonyl-amino}-methyl)-phenyI]-acetic acid

1H NMR(400MHz, CDCl3) δ 7.07-7.35(m,8H), 6.92-6.93(m,2H), 6.82(s,lH), 4.32(d,4H), 3.62(s,2H), 2.81(s ,3H).

Example 148

(3-{[Methanesulfonyl-(4-pyrimidin-2-yl-benzyl)-amino1-methyl}-phenyl)-acetic

acid

Step A:

(3-{ [(4-Pyrimidin-2-yl-benzyl)-aminol-methyl } -phenyl)-acetic acid methyl ester 1H NMR(400MHz, CDCl3) δ 8.77(d,2H), 8.37(d,2H) , 7.44(d) 2H), 7.23- 7.29(m, 3H), 7.14-7.16(m,2H), 3.86(s,2H), 3.79(s,2H), 3.66(s,2H), 3.6(s ,2H); MS 348 (M+l).

Step (B):

(3-{[Methanesulfonyl-(4-pvrimidin-2-yl-benzyl)-amino]-methyl}-phenyl)-acetic acid methyl ester

1HNMR(400MHz, CDCl3) δ 8.83(s,2H), 8.43(s,2H), 7.44-7.49(m,2H), 7.23-7.33(m,5H), 4.37-4.41(m,4H), 3.71( s,3H), 3.61-3.68(m,2H), 2.82(s,3H); MS 426 (M+l).

Step (c):

(3-{[Methanesulfonyl-(4-pyrimidin-2-yl-benzyl)-amino]-methyl}-phenyl)-acetic

acid

1H NMR(400MHz, CDCI3) δ 8.82(d,2H), 8.15(d,2H), 7.3(d,2H), 7.24-7.27(m,3H), 7.15-7.17(m,lH), 7.03(s ,lH), 4.42(s,2H), 4.37(s,2H), 3.52(s,2H), 2.9(s,3H).

Example 149

(3{[Methanesulfonyl-(4-thiazol-2-yl-benzyl)-amino]-methyl)-phenyl)-acetic acid

Step A:

(3-{[(4-Thiazol-2-yl-benzyl)-amino]-methyl}-phenyl)-acetic acid methyl ester

1H NMR(400 MHZ, CDCl3) δ 7.82-7.91(m,3H), 7.38-7.4(m,2H), 7.22-7.29(m,4H),

7.14-7.16(m,1H), 3.82(s,2H), 3.78(s,2H), 3.66(s,3H), 3.59(s,2H); MS 353 (M+l).

Step (B):

(3{[Methanesulfonyl-(4-thiazol-2-yl-benzyl)-aminol-methyl}-phenyl)-acetic acid methyl ester

1H NMR (400MHZ, CDCl3) δ 7.92(d,2H), 7.84(d,lH), 7.17-7.37(m,7H), 4.33(d)

4H), 3.67(s,3H), 3.59(s,2H), 2.8(s,3H); MS 431 (M+l).

Step (c):

3{[Methanesulfonvl-(4-thiazol-2-yl-benzyl)-amino]-methyl } -phenyl)-acetic acid 1H NMR(400MHz, CDCl3) 7.85-6.98 δ(m,10H)) 4.3-4.4(d ,4H), 3.45(s,2H), 2.82(s,3H); MS 415 (Ml).

Example 150

(3-{[(4-Benzyl-3-hydroxy-benzyl)methanesulfonyl-amino]-methyl}-phenyl)-acetic acid

Step A:

(3-{[4-Benzyl-3-hydroxy-benzyl)-amino]-methyl-phenyl)-acetic acid methyl ester 1H NMR(400MHz, CDCl3) δ 7.24-7.43(m,11H), 7.16(d,lH) ), 6.93(d)2H), 3.78(s,2H), 3.74(s,2H), 3.68(s,3H), 3.61(s,2H); MS 376 (M+l).

Step (B):

(3-{[(4-Benzyl-3-hydroxy-benzyl)-methanesulfonyl-amino]-methyl}-phenyl)-acetic acid methyl ester

1H NMR(400MHZ, CDCl3) 7.43-7.2δ(m,12H), 6.94(d,2H), 4.3(s)2H), 4.26(s,2H),

3.69(S,3H), 3.62(s,2H), 2.75(s,3H); MS 475 (M+22).

Step (c):

(3-{[(4-Benzyl-3-hydroxy-benzyl)-methanesulfonyl-amino]-methyl}-phenyl)-acetic

acid

1H NMR(400MHZ, CDCl3) δ 7.2-7.43(m,12H), 6.93(d,2H), 4.29(s, 2H), 4.25(S,2H),

3.64(s,2H), 2.74(S,3H); MS 438 (Ml).

Example 151

3-{[Methanesulfonyl-(4-pyrazin-2-yl-benzyl)-amino]-methyl}-phenyl)-acetic acid

Step A:

(-3-{[4-Pyrazin-2-yl-benzyl)-amino]-methyl}-pheny)-acetic acid methyl ester 1H NMR(400MHz, CDCI3) δ 9.0(s,lH), 8.6(s,lH ), 7.96-7.98(m,2H), 7.46-7.48(m,2H),7.11-7.3(m,4H) 3.77-3.88(m,4H), 3.58-3.69(m,5H); MS 348 (M+l).

:(Step (b

3-{[Methanesulfonyl-(4-pyrazin-2-yl-benzyl)-amino]-methyl}-phenyl)-aceticacid methyl ester

1H NMR(400MHZ, CDCl3) δ 9.03(s,lH), 8.63-8.64(m,lH), 8.52(d,lH)) 8.0(d)2H),

7.46(d,2H), 7.21-7.34(m,4H), 4.41(s,2H), 4.36(s,2H), 3.7(s, 3H), 3.62(s,2H),

2.83(s,3H); MS 426 (M+l).

Step (c)

3-{[Methanesulfonyl-(4-pyrazin-2-yl-benzyl)-amino]-methyl}-phenyl)-aceticacid 1H NMR(400MHZ, CDCl3) δ 8.96(s,lH), 8.61-8.62(m,lH) ), 8.56- 8.57(m,lH), 7.78

(d,2H), 7.34(d,2H), 7.16-7.3(m,3H), 7.05(s,lH), 4.42(s,2H), 4.38 (s,2H), 3.52 (s,2H), 2.91(s,3H); MS 410 (Ml).

Example 152

(3-{[Methanesulfonyl-(4-phenoxy-benzyiy amino]-methyl}-phenyl)-acetic acid

Step A:

(3-{[Phenoxy-benzyl)-amino]-methyl}-pheny)-acetic acid methyl ester 1H NMR(4000 MHZ, CDCl3) δ 7.2-7.34(m,7H), 7.17-7.19(m,2H), 7.06-7.11(m,2H),

6.96-7.0(m,4H) 3.97(d,4H), 3.69(s,3H), 3.63(s,2H); MS 362 (M+l).

:(Step (b

(3-{[Methanesulfonyl-(4-phenoxy-benzyl)-amino]-methyl}-phenyl)-acetic acid, methyl ester

1H NMR(400MHz, CDCl3) δ 7.2-7.37(m,9H), 7.12(t,lH), 6.95-7.01(m,3H), 4.32(d,4H), 3.69(s,3H), 3.62(s ,2H), 2.79(s,3H); MS 457 (M+18).

Step (c):

(3-{[Methanesulfonyl-(4-phenoxy-benzyl)-amino]-methyl}-phenyl)-acetic acid 1H NMR(400MHz, CDCl3) δ 7.22-7.36(m,9H), 7.12(t,lH), 6.94-7.01(m,3H), 4.32(d,4H), 3.65(s,2H), 2.97(S,3H); MS 424 (Ml).

Example 153

[3-({Methanesulfonyl-[4-(4-methyl-[l,2,31triazol-l-yl)-benzyl)-amino}-methyl)-phenyl]-acetic acid

Step A:

[3-({[4-(4-Methyl-[ 1.2.3 ]triazol-1 -yl)-benzyl]-amino }-methyl)phenyl]-acetic acid methyl ester

IH NMR(400MHZ, CDCl3) δ 7.55(d,2H), 7.33(d,2H), 7.16- 7.3(m,4H), 3.84(t,2H),

3.77(s,4H), 3.68(s,3H), 3.61(s,2H), 2.59(t,2H), 2.31(bs, IH), 2.14(t,2H); MS 353 (MH+).

Step (B):

[3-({Methanesulfonyl-[4-(4-methyl-[l,2,3]triazol-l-yl)-benzyl]-amino}-methyl)-phenyl]-acetic acid methyl ester

IH NMR(400MHZ, CDCI3)δ 7.61(d,2H), 7.2- 7.33(m,6H), 4.3(S,4H), 3.86(t,2H),

3.69(s,3H), 3.62(s,2H), 2.77(s,3H), 2.61(t,2H), 2.17(t,2H). [3-({Methanesulfonyl-[4-(4-methyl-[1,2,3]triazol-l-yl)-benzyl]-amino}-methyl)-phenyl]-acetic acid

1H NMR(400 MHZ, CDCI3) 7.43 δ(d,2H), 7.14-7.31(m, 5H), 7.05(s,lH), 4.28(d)

4H), 3.82(t,2H), 3.5(S,2H), 2.82(s,3H), 2.6(t,2H), 2.13(t,2H).

Example 154

[3-({Methanesulfonyl-[4(2-oxo-pyrrolidin-l-yl)-benzyl]-amino}-methyl)-phenyl]-acetic acid

Step A:

[3-({[4-(2-Oxo-pyrrolidin-l-yl)-benzyl]-amino}-methy)-phenyl]-acetic acid methyl ester

1HNMR(400MHz, CDCl3)δ7.63-7.68(m,lH), 7.52-7.58(m,2H),7.41-7.47(m,2H),

7.17-7.36(m,4H), 3.9(S,2H), 3.83(s,2H), 3.69(s,3H), 3.63(s,2H), 2.34(s,3H); MS 351 (MH+).

Step (B):

[3-({Methanesulfonyl[4-(2-oxo-pyrrolidin-l-yl)-benzyl]-amino}-methyl)-phenyl]-acetic acid methyl ester

1HNMR(400MHz, CDCl3) δ7.57(s,lH), 7.41-7.48(m,4H), 7.25-7.3(m,lH), 7.17-7.2(m,3H), 4.36(s,2H), 4.14 (s,2H), 3.68(s,3H), 3.61(s,2H), 2.86(s,3H), 2.33(s,3H).

Step (C-):

[3-({Methanesulfonyl-[4-(2-oxo-pyrrolidin-l-yl)-benzyl]-amino}-methyl)-phenyl]-acetic acid

1H NMR(400MHz, CDCI3) δ 7.58(s,lH), 7.13-7.39(m,8H), 4.4(s,2H), 4.37(s,2H), 3.56(s,2H), 2.91(s,3H ), 2.29(s,3H).

Example 155

5-{3[(2,3-Dihydro-benzo[l.41dioxin-6-ylmethyl)-methanesulfonyl-amino]-propyl }-thiophene-2-carboxylic acid

Step A:

Dihydro-benzo[l,4]dioxin-6-ylmethyl)-amino]-propyl}-thiophene5-{3-[(2,3)

carboxylic acid methyl ester

In step (a), triethylamine is replaced by N,N-diisopropylethylamine

MS 348 (M+l.)

Step (B):

5-{3-[(2,3-Dihydro-benzo[l.4]dioxin-6-ylmethyl)-methanesulfonyl-amino]-propyl}-thiophene-2-carboxylic acid methyl ester MS 443 (M+18).

Step (c):

5-(3-[(2,3-Dihydro-benzo[l,4]1dioxin-6-ylmethyl)-methanesulfonyl-amino1-propyl)-thiophene-2-carboxylic acid

1HNMR(400MHz, CDCl3) δ7.7(d,lH6.8-6.5 ,(3.8=J ,(m,4H), 4.4(s,2H), 3.23(m,2H), 2.8(m,2H), 1.7(m,2H); MS 400(M+1), 398(Ml).

Example 156

(3-{[(4-Ethoxy-benzyl)-methanesulfonyl-amino]-methyl }-phenyl)-acetic acid 1HNMR(400MHz, CDCl3) δ 7.16-7.31(m,6H), 6.83(d,2H), 4.27 (s,2H), 4.22(s,2H), 3.99(q,2H), 3.62(s,2H), 2.71(s,3H), 1.38(t,3H); MS 376 (Ml).

Example 157

(3-{[(4-Dimethylamino-benzyl)-methanesulfonyl-amino]-methyl}-phenyl)-acetic

acid

1H NMR(400MHz, CDCl3)δ 7.14-7.37(m,6H), 6.66(d,2H), 4.27(s,2H), 4.19(s,2H), 3.61(s,2H), 2.91(s,6H ), 2.69(s,3H); 375 (Ml).

Example 158

(3-{[(4-Cyclohexyl-benzyl)-methanesulfonyl-amino]-methyl}-phenyl)-aceticacid 1H NMR(400MHz, CDC3l) δ 7.32-7.16(m,8H), 4.31(s,2H), 4.28 (s,2H), 3.64(s,2H), 2.75(s,3H), 2.48(m,lH), 1.83(m,5H), 1.38(m,5H).

Example 159

5-{3-[((4-Dimethylamino-benzyl)-methanesulfonyl-amino]-propyl}-thiophene-2-carboxylic acid

Step A:

5-[3-(4-Dimethylamino-benzylamino)-propyl]-thiophene-2-carboxylic acid methyl

ester

The compound of the title of step (a) is prepared by following the procedure described in step (a) of Example 141 except that the triethylamine is replaced by N,N-diisopropylethylamine. Step (B):

5-{3-[(4-Dimethylamino-benzyl)-methanesulfonyl-amino]-propyl}-thiophene-2-

carboxylic acid methyl ester MS411(M+1).

Step (c):

5-{3-[(4-Dimethylamino-benzyl)-methisulfonyl-amino]-propvl}-thiophene-2-carboxylic acid

1H NMR(400MHz, CDCI3) δ 7.7(d,lH), 7.15(d)2H), 6.72(m,3H), 4.43(s,2H), 3.22(m,2H), 2.95(S,6H), 2.85(m,2H), 2.8(s,3H), 1.82(m)2H); MS 395 (Ml).

Example 160

(3-{[Methanesulfonyl-(4-pentyl-benzyl)-amino]-methyl}-phenyl)-acetic acid

Step A:

{3-[(4-Pentyl-benzylamino)-methyll-phenyl}-acetic acid methyl ester 1H NMR (400MHz, CDCl3) δ 7.29-7.12(m,8H), 3.78(s,2H), 3.76(s,2H ), 3.68(s,3H), 3.61(s,2H), 2.57(t,2H), 1.59(t,2H), 1.59(t,2H), 1.31(m,4H) 0.88(t,3H); MS 340

(M+l).

Step (B):

(3-{[Methanesulfonyl-(4-pentyl-benzyl)-aminol-methy}-phenyl)-acetic acid methyl ester

1HNMR(400MHz, CDCl3)δ 7.32-7.14(m,8H 4.31(s,2H), 2.29(s,2H), 3.69(s,3H),

3.62(s,2H), 2.75(s,3H), 2.59(t,2H), 1.59(m,2H), 1.31(m,4H), 0.88(t,3H).

Step (c):

(3-{[Methanesulfonyl-(4-pentyl-benzyl)-amino]-methyl}-phenyl)-acetic acid

1H NMR (4.31(400 MHZ,CDCl3) δ7.34-7.13(m,8h),(s,2H), 4.28(s,2H), 3.66(S,2H),

2.75(S,3H), 2.58(t,2H), 1.59(m,4H), 1.31(m,4H), 0.88(t,3H); MS 402 (Ml).

Example 161

(3-{[(4-Isopropoxy-benzyl)methanesulfonyl-amino]-methyl}-phenyl)-aceticacid

Step A:

(3-[(4-Isopropoxy-benzvlamino ymethyl]-phenyl}-acetic acid methyl ester 1H NMR(400MHZ, CDCI3) δ 7.29-7.15(m,6H)&gt; 6.84(d,2H), 4.52(m,lH) ), 3.78(s,

2H), 3.72(s,2H), 3.68(s,3H), 3.61(s,2H), 1.32(d,6H).

Step (B):

(3-( [(4-Isopropoxy-benzyl)-methanesulfonyl-amino]-methtl}phenyl)-acetic acid methyl ester

1H NMR(400 MHZ, CDCI3) δ 7.32-7.19(m,6H), 6.84(d,2H), 4.53(m,lH), 4.3(s,2H),

4.25(s,2H), 3.69(s,3H), 3.66(S,2H), 3.62(S)2H), 2.75(S,3H), 1.32(d,6H).

Step (c):

(3-{[ (4-Isopropoxy)-benzyl)-methanesulfonyl-amino]-methyl}-phenyl)-acetic acid

IH NMR(400MHZ, CDCI3) δ 7.33-7.17(m,6H), 6.83(d,2H)1 4.52(m,lH), 4.29

(S,2H), 4.24(S,2H), 3.65(S,2H), 2.74(S,3H), 1.32(d,6H); MS 390 (Ml).

Example 162

(3-{[Methanesulfonyl-(4-pyrimidin-5-yl-benzyl)-amino]-methyl}phenyl)-acetic

acid

Step A:

{3-t4-Pryimidin-5-yl-benzylamino)-methyl]-phenyl)-acetic acid

1H NMR (400MHz, CDCI3) δ 9.19(s,lH), 8.95(s,2H), 7.52(m,4H), 7.32-7.15

(m,4H), 3.88(s,2H), 3.82(s,2H), 3.69(s,3H), 3.63(s,2H).

Step (B):

(3-{[Methanesulfonyl-(4-pyrimidin-5-yl-benzyl)-amino]-methyl}-phenyl)-acetic acid methyl ester

MS 425 (M+).

Step (c):

(3-{[Methanesulfonyl-(4-pyrimidin-5-yl-benzyl)-amino)-methyl}-phenyl)-acetic

acid

1H NMR(400MHz, CDC13) δ 9.2(s,lH), 8.95(s,2H), 7.52(d,2H), 7.43(d) 2H), 7.34-7.15(m,4H), 4.41(s,2H ), 4.37(s,2H), 3.65(S,2H), 2.86(s,3H); MS 410 (Ml).

Example 163

-3{[Methanesulfonyl-(4-methyl-benzyl)-amino]-methyl}-phenyl)-acetic acid) Reductive Amination) Step (A):

(3-[{4-Methyl-benzyl)-amino]-methyl)-phenyl)-acetic acid ethyl ester Stir for several hours at room temperature a solution of 4-methylbenzylamine (0.097. ml, 0.76 mmol) 3-formyl-phenyl)-acetic acid ethyl ester (138 mg, 0.72 mmol) in MeOH (2 mL). The reaction was cooled to 0°C and NaBH (43 mg, 1.15 mmol) was added. After stirring at room temperature for 10 minutes, add a 1:1 mixture of saturated aqueous NaHCO3:water. The product was extracted in CH2CI2 (3 times), the organic solution was dried over MgSO4, filtered, and concentrated to produce the title compound (231

1H NMR(400MHZ, CDCL3) δ 7.13-7.3(m,8H),4.14(q,2H),3.83(d,4H),3.78(s,2H), 2.34(s,3H), 1.25(t,3H ); MS 298 (M+l).

Step (b): Sulfonamide formation

)3-{[-Methanesulfonyl-(4-methyl-benzyl)-amino]-methyl]-pheny)-acetic acid ethyl

ester

Add methanesulfonyl chloride (0.03 mL, 0.405 mmol) to a solution of 3-{[(4-methyl-benzyl)-amino]-methyl}-phenyl)-acetic acid ethyl ester (119 mg, 0.401 mmol) triethylamine (0.61 mL, 0.726 mol) in CH2CI2 (2 mL) at 0 C. Stir the reaction at room temperature for two and a half hours and add 1 m HCl. The product was extracted in CH2Cl2 (3 times). Dry the solution

Organic MgSO4, filtered and concentrated by suction. The product was purified by medium pressure chromatography (1:3 EtOAc:hexanes) to provide the title compound (101.4 mg). 3.6 (1 NMR(400 MHz, CDCI3) δ 7.13-7.36(m,8H), 4.27-4.3(m,4H), 4.14 (q,2H H

MS 376 (M+l). ;(S,2H), 2.74(s, 3H), 2.33(S,3H)

Step C: Hydrolysis of the Ester

)3{[-Methanesulfonyl-(4-methyl-benzyl)-aminol-methyl}-phenyl)-acetic acid Add aqueous NaOH (2 m, 0.4 ml) to a solution of 3-{[Methanesulfonyl-(4-methyl). -benzyl)-amino]-methyl}-phenyl)-acetic acid ethyl)

ester

(1.104 mg, 0.27 mmol) in MeOH (3 mL). Stir the reaction at room temperature for 1 hour and dilute with a 1:1 mixture of 1 N HCl and water. The product was extracted in CH2CI2 (3 times), the organic solution was dried over MgSO4, filtered, and concentrated to provide the title compound (87 mg).

1H NMR(400MHZ,CDCl3) δ7.13-7.34(m,8H),4.28(d,4H),3.65(s,2H),2.75(S,3H),

(2.33(s,2H); MS 346 (Ml

Examples 164-170

Examples 164-170 are prepared in a manner similar to Example 163 by starting with the appropriate aldehyde amine reagents in step (a), followed by formation of the desired sulfonamide in step (b) and hydrolysis of the ester in step (c).

Example 164

(3-{[-tert-Butyl-benzyl)-methanesulfonyl-amino]-methyl}-phenyl)-aceticacid

Step A:

{3-[(4-tert-Butyl-benzylamino)-methyl]-phenyl}-acetic acid ethyl ester 1H NMR (400MHz, CDCI3) s 7.32-7.34(m,2H), 7.24-7.27(m,5H), 7.15-7.16(m,

1H), 4.13(q,2H), 3.77(d,4H), 3.59(S,2H), 1.3(s,9H), 1.21-1.26(m,3H); MS 340 (M++l).

Step (B):

(3-{[(4-tert-Butvyl-benzyl)-methanesulfonyl-amino]-methyl}-phenyl)-acetic acid ethyl ester

1H NMR(400MHz, CDCI3) δ 7.2-7.37(m,8H), 4.3(d,4H), 4.14(q, 2H), 3.6(s,2H), 2.76(s,3H), 1.31(s,9H ), 1.25(t,3H).

Step (c):

(3-{[(4-tert-Butyl-benzyl)-methanesulfonyl-amino]-methyl} -phenyl)-acetic acid 1H NMR(400MHz, CDCI3) δ 7.2-7.36(m,8H), 4.31(s,2H ), 4.28(s,2H), 3.64(s,2H), 2.75(s,3H), l,3(s,9H); MS 388 (M+-l).

Example 165

(3-{[4- tert-Butyl-benzyl)-methanesulfonyl-amino]-methyl}-phenoxy)-acetic acid

Step A:

{3-[(4-tert-Butyl-benzylamino)-methyl]-phenoxy}-acetic acid methyl ester

Step (B):

(3-{[(4-tert-Butyl-benzyl)-methanesulfonyl-amino]-methyl}-phenoxy)-acetic acid methyl ester

Step (c):

(3-{[(4-tert-Butyl-benzyl)-methanesulfonyl-aminol-methyl} -phenoxy)acetic acid 1H NMR(400MHz, CDCI3) δ 7.2-7.36(m,5H), 6.84-6.95(m,3H ), 4.66(s,2H), 4.3(s,4H), 2.77(s,3H), 1.3(s,9H); MS 404 (Ml).

Example 166

(3-{[Methanesulfonyl-(4-trifluoromethoxy-benzyl)-amino]-methyl}-phenyl)acetic

acid

Step A:

3-{[4-Trifluoromethoxy-benzyl)-amino]-methyl-phenyl)-acetic acid ethyl ester 1HNMR(400MHz, CDCl3) δ7.34-7.36(m,2H), 7.14-7.16(m,3H), 7.21 -7.32(m,3H)4.1-4.16(m,2H), 3.77(d,4H), 3.6(s,2H), 1.21-1.25(m,3H); MS 368 (M+1).

Step (B):

(3-{[Methanesulfonyl)-4-trifluoromethoxy-benzyl)-amino]-methyl}-phenyl)-acetic

acid ethyl ester

1H NMR(400 MHZ, CDCl3) δ7.15-7.33(m,8H), 4.31(d,4H), 4.14(q,2H), 3.58(s,2H),

2.81(S,3H), 1.25(t,3H); MS 446 (M+l).

Step (C-):

(3-{[Methanesulfonyl-(4-trifluoromethoxy-benzyl)-amino)-methyl}-pheny)-acetic

acid

1H NMR(400MHZ, CDCl3) δ7.1-7.32(m,8H), 4.3(s,4H), 3.62(s,2H), 2.8(s,3H); MS

416 (Ml).

Example 167

[3-({[4-Chloro-phenyl)-propyl]-methanesulfonyl-amino}-methy-phenyl]-acetic acid

Step A:

[3-({[3-(4-Chloro-phenyl)-propyl]-amino}-methy)-phenyl]-acetic acid ethyl ester

Step (B):

[3-({[3-Chloro-phenyl)-propyl]-methanesulfonyl-amino}-methyl)-phenyl]-acetic acid ethyl ester

1H NMR(400 MHZ, CDCl3) δ7.18-7.31(m,6H), 6.95(d,2H), 4.34(s,2H),4.11(q,2H),

3.59(s,2H), 3.13-3.19(m,2H), 2.8(s3H), 2.49(t,2H), 1.74-1.82(m,2H), 1.23(t,3H); MS 424 (M+l).

Step (c):

[3-({[3-(4-Chloro-phenyl)-propyl]-methanesulfonyl-amino}-methyl)-phenyl]-acetic

acid

MS 393.9 (Ml).

Example 168

(3-{[Mthanesulfonyl-(3-trifluoromethoxy-benzyl)-amino]-methyl}-phenyl)-acetic

acid

Step A:

(3-{[(3-trifluoromethoxy-benzyl)-amino]-methyl}-phenyl)-acetic acid ethyl ester

Step (B):

(3-{[Methanesulfonyl-(3-trifluoromethoxy-benzyl)-amino]-methyl]-phenyl)-acetic

acid ethyl ester

1H NMR(400MHz, CDCl3) δ7.13-7.4(m,8H), 4.33(d,4H), 4.14(q,2H), 3.59(s,2H), 2.82(S,3H), 1.25(t, 3H); MS 446 (MH+).

(3-{[Methanesulfonyl-(3-trifluoromethoxy-benzyl)-amino]-methyl}-phenyl)-acetic

acid

MS417(M-1).

Example 169

[3-({[2-(3-Chloro-phenylsulfanyl)-ethyl]-methanesnlfonyl-aminno)-methyl)-

phenyl]-acetic acid

1H NMR(400MHz, CDCl3) δ 6.98-7.37(m,8H), 4.32(S,2H), 3.6(s,2H), 3.28(m,2H), 2.81-2.93(m,5H); 412 (ml).

Example 170

[3-({[4-(2-Benzo[1.3]dioxol-5-yl)-benzyl)-methanesulfonyl-amino}-methyl)-

phenyl]-acetic acid MS 478 (Ml).

Example 171

(3-{[Mrthanesulfony-(4-thiazol-2-yl-benzyl)-amino]-methyl}-phenoxy)-acetic acid

-

{3-[(4-Thiazol-2-yl-benzvlamino)-methy-phenoxy}-acetic acid tert-butyl ester

25 Stir at room temperature for an hour and a half a solution of 3-aminomethyl-phenoxy-acetic acid tert-butyl ester (0.14 g' 0.59 mmol) 4-thiazol-2-yl-benzaldehyde (0.105 g, 0.55 mmol). ) in 2

Milliliters of MeOH. After cooling to 0°C, NaBH4 (0.033 g, 0.88 mmol) is added and the reaction is stirred for 10 minutes. The mixture is cooled by saturated aqueous NaHCO3:water (1:1) and MeOH is removed by vacuum. The mixture was extracted in CH2Cl2, the organic solution was dried over MgSO4, filtered and vacuum concentrated to provide a brown oil. The product was purified by flash chromatography on silica gel (4/6 hexanes /EtOAc) to provide the title compound of step (a) (0.140 g). 1HNMR (400MHz, CDCl3) δ), 7.82(s,lH), 7.4(d,2H), 7.23-7.38(m,2H), 411 1.45(s,9H); MS ,(6.78(d,lH), 4.49(s,2H), 3.8(s,2H), 3.76(s,2H ,(6.94(m,2H)

l+M).)

Step (b): Sulfonamide formation

3)}]MethanesuIfonyl-(4-thiazol-2-yl-benzyl)-amino)-methyl)-phenoxy)acetic acid

tert-butyl ester

Stir at room temperature for two hours solution of

}3-[(4-Thiazol-2-yl-benzylamino)-methy]-phenozyacetic acid tert-butyl ester{-(45 g, 0.109 mmol), triethylamine (16.8 ml, 0.120 mmol) and chloride methanesulfonyl (8.6 ml, 0.11 mol) in 2 ml

CH2CI2. Cool the mixture with water. The aqueous solution was washed with CH2CI2, the organic solution was dried over Na2SO4, filtered and concentrated. The product was purified by flash chromatography on silica gel (1/1 hexanes /EtOAc) to provide the compound of the title of step (b) as a pure oil. -6.8(1H NMR(400MHz, CDCl3) δ 7.97(d,2H), 7.85(s,lH), 7.35(s,3H), 7.32(m, lH 489 6.9(m,3H), 4.48(s, 2H), 4.36(s,2H), 4.29(s,2H), 2.79(s,3H), 1.47(s,9H);

M+l).)

Step C: Hydrolysis of the Ester

3-{[Methanesulfonyl-(4-thiazol-2-yl-benzyl)-amino]-methyl}-phenoxy)-acetic acid)

Cool to 0 °C solution of

(3-{[Methanesulfonyl-(4-thiazol-2-yl-benzyl)-amino]-methyl}-phenoxy)-acetic acid tert-butyl ester

Stir the acetic acid tert-butyl ester and add 2 milliliters of CH2C12 per milliliter (0.074 g) of reaction at room temperature for two hours. The solvent is removed by evaporation by boiling at 100°C

The title compound (40 mg) is available. CH2C12 constant heat with

1HNMR (400MHz, CDCl3) δ 9.94(bs,lH), 8.14(s,lH), 7.81(d,2H), 7.55(s,lH), 7.37(d,2H), 7.18(m,lH), 6.9 (d,lH), 6.8(d,lH), 6.63(s,lH), 4.58(s,2H), 4.35(s,2H), 4.29(s,2H), 2.93(S,3H); MS 431 (Ml).

Examples 172-178

Examples 172-178 are prepared in a manner similar to Example 171 by starting with the appropriate aldehyde reagent in step (a) followed by formation of the desired sulfonamide in step (b) and hydrolysis of the ester in step (c).

Example 172

3-([Methanesulfonyl-(4-pyridin-2-vl-benzyl)-amino}-methyl}-phenoxy)acetic)

acid hydrochloride salt

The TFA salt isolated in step (c) is converted to HCl salt by adding 2 equiv of 1 M HCl, then removing water and drying by vacuum.

MS 427 (M+1), 425 (M-1).

Example 173

5-{3-[(2-Benzylsulfanyl-ethyl)-methanesulfonyl-amino]-propyl)-thiophene-2-carboxylic acid

Step A:

5-{3-[(2-Benzylsulfanyl-ethyl-aminol-propyl}-thiophene-2-carboxylic acid tert-butyl ester

1HNMR(400MHz, CDCl3) δ7.52(d,lH), 7.19-7.29(m,5H), 6.73(d,lH), 3.68(s, 2H), 2.83(t,2H), 2.71(t,2H ), 2.53-2.59(m,4H),1.81(t,2H) 1.54(s,9H); MS 392

(M+1).

Step (B):

5-{3-[(2-Benzylsulfanyl-ethyl)-methanesulfonyl-amino-propyl}-thiophene-2-carboxylic acid tert-butyl ester

1H NMR(400MHz, CDCl3) δ 7.52(d,lH), 7.22- 7.3(m,5H), 6.74(d,lH), 3.71(s,2H), 3.23(t,2H), 3.06-3.15(m ,2H), 2.77-2.88(m,5H), 2.58(t,2H), 1.54(s,9H); MS 470 (M+l).

Step (c):

5-{3-[(2-Benzylsulfanyl-ethyl)-methanesulfonyl-amino]-propyl}-thiophene-2-

carboxylic acid

MS412(M-1).

Example 174

5-(3-{[2-(Biphenvl-2-yloxy)-ethyl]-methanesulfonyl-aminol-propyl)thiophene-2-carboxylic acid

Step A:

5-(3-{[2-(Biphenyl-2-yloxy)-ethy]-amino}-propyl)-thiophene-2-carboxvlic acid tert-butyl ester

1H NMR(400MHz, CDCl3) δ 7.49-7.52(m,3H), 7.24- 7.39(m,5H), 6.9-6.2(m,2H)

6.69(d,lH), 4.08(t,2H), 2.89(t,2H), 2.74(t,2H), 2.57 (t,2H), 2.22(bs,lH), 1.71-1.79 (m,2H) , 1.55(s,9H); MS 438 (M+l).

Step (B):

5-(3-{[2-(Biphenyl-2-yloxy)-ethyl)-methanesulfonyl-amino}-prppyl)-thiophene-2-carboxylic acid tert-butyl ester MS 460 (M-56).

Step (c):

5-(3-{[2-(Biphenyl-2-yloxy)-ethyl)-methanesulfonyl-amino)-propyl)thiophene-2-carboxylic acid MS 458 (Ml).

Example 175

5-(3-{[3-1H-Indol-3-yl)-propyl]-methasulfonyl-amino}-propl)-thiophene-2-carboxylic acid

Step A:

5-(3-}[3 -1H-Indol-3-yl-propyl]-aminol-propy)-thiophene-2-carboxylic acid tert-butyl ester

1H NMR(400MHZ, CDCl3) δ 8.11(s, lH), 7.49-7.57(m,2H), 7.32(d,lH), 7.07-7.18

(m,2H), 6.96(s,lH), 6.71(d,lH), 2.68-2.81(m,8H), 1.91-2.06(m,4H), 1.54(S,9H);

MS 399 (M+l).

Step (B):

5-(3-{[3-(1H-Indol-3-yl-propyl]-methanesulfunyl-aminoi-propyl)-thiophene-2-carboxylic acid tert-butyl ester

1HNMR(400MHz, CDCl3) δ 8.07(bs, IH), 7.5-7.55(m,2H), 7.34-7.36(m,lH), 7.08-7.2(m,2H), 6.98-6.99(m,lH), 6.7(d,1H), 3.66(S,2H), 3.15-3.25(m,4H), 3.05-3.11(m,1H), 2.73-2.85(m,6H), 1.88-2.04(m,4H), 1.55(S,9H); MS 475 (Ml).

Step B):

5-(3-{[3-(1H-Indol-3-yl)-propyl]-methanesulfonyl-amino}-propyl)thiopene-2-carboxylic acid MS 419 (Ml).

Example 176

5-{3-(4-tert-Butyl-benzyl)-methanesulfonyl-amino]-propyl}-thiophene-2-carboxylic acid

Step A:

5-{3-[(4-tert-Butyl-benzyl)-amino)-propyl}-thiophene-2-carboxylic acid tert-butyl ester

1H NMR(400 MHZ, CDCl3)δ 7.51(d,1H),7.33(d,2H), 7.23-7.25(m,2H), 6.72(d,

1H), 3.74(s,2H), 2.87(t,2H), 2.69(t,2H), 1.9(t,2H), 1.54(s,9H), 1.29(s,9H); MS 388 (M+l).

Step (B):

5-{3-[(4-tert-Butyl-benzyl)-methanesulfonyl-amino]-propyl}-thiophene-2-carboxylic acid tert-butyl ester

1HNMR(400MHz, CDCl3)δ7.47-7.49(m,lH),7.34-7.36(m,2H), 7.23-7.25(m,2H), 6.59(d,lH), 4.33(s,2H), 3.21 (t,2H), 2.81(s, 3H), 2.73(t,2H), 1.83(t,2H), 1.54(S,9H), 1.3(S,9H); MS 483 (M+18).

5-{3-[(4-tert-Butyl-benzyl)-methanesulfonyl-amino]-propyl)-thiophene-2-carboxylic acid

1H NMR(400MHz, CDCl3) δ 7.64(d,lH), 7.36(d,lH), 7.25-7.26(m,2H), 6.66(d,1H), 4.34(s,2H), 3.23(t,2H ), 2.82(s,3H), 2.77(t)2H), 1.79-1.87(m,2H), 1.3(S,9H);

MS 408 (Ml).

Example 177

5-(3-{[2-(3-Chloro-phenylsulfanyl)-ethyl]-methanesulfonyl-amino}-propyl)-thiophene-2-carboxvlic acid

Step A:

5-(3-{[2-(3-Chloro-phenylsulfanyl)-ethyl]-amino-propyl)-thiophene-2-carboxylic acid tert-butyl ester

1H NMR(400MHz, CDCl3)δ 7.48-7.53(m,1H), 7.12- 7.31(m,4H), 6.74(d,lH), 3.06

(t,2H), 2.85(q,4H), 2.65(t,2H), 1.8-1.87(m)2H), l.55(s,9H); MS 412 (MH+).

step (b);

5-(3-{[2-(3-Chloro-phenylsulfanyl-ethyl]-methanesulfonyltino}-propyl)-thiophene-2-carboxvlic acid tert-butyl ester

1HNMR(400MHz,CDCl3) δ7.52(d) IH),7.14-7.31(m,4H) , 6.75(d,lH), 3.31-3.35

(m,2H),3.21(t,2H),3.11-3.15(m,2H),2.82-2.87(m,2H),2.82(s,3H),1.94(t,2H),

l.54(s,9H);MS 508 (M+18).

Step (c):

5-(3-{[2-(3-Chloro-phenlysulfanyl)-ethyl)-methanesulfonyl-amino}-propyl)-thiophene-2-carboxylic acid

1HNMR(400MHZ, CDCl3)δ7.72(d,lH), 7.31(s,lH), 7.15-7.25(m,3H)) 6.97(d,lH), 3.34-3.42(m,2H), 3.24(t ,2H), 3.14(t,2H), 2.91(t,2H), 2.85(S,3H), 1.93-2.1(m,2H); MS 434 (M+l).

Example 178

(3-{[Methanesulfonyl-(4-pyridin-3-yl-benzyl)-amino]-methyl}-phenoxy)-acetic

acid

Step A:

{3-[(4-Pyridin-3-yl-benzylamino)-methyl]-phenoxy}-acetic acid tert-butyl ester 1H NMR(400MHz, CDCl3) δ 8.81(bs,2H), 7.59(d,2H), 7.47(m,2H), 7.41(m,2H), 7.22(t,lH), 6.94(m,2H), 6.78(m,lH), 4.5(S,2H), 3.82(S,2H), 3.78 (s, 2H), 1.45(s,9H); MS 405 (M+l).

Step (B):

(3-{[Methanesulfonyl-(4-pyridin-3-yl-benzyl)-amino]-methyl}-phenoxy)-acetic acid tert-butyl ester

1HNMR(400MHz, CDCl3) δ 8.83(bs,lH), 8.59(m,lH), 7.85(m,lH), 7.55(m,2H), 7.4(d,2H), 7.36(m,lH), 7.24 (m,lH), 6.91(d,lH), 6.86(m, IH), 6.82(dd,lH), 4.49 (s,2H), 4.39(s,2H), 4.32(s,2H), 2.81( s,3H), 1.48(s,9H); MS 483 (M+l).

Step (c):

(3-{[Methanesulfonyl-(4-pyridin-3-yl-benzyl)-amino]-methvl}-phenoxy)-acetic

acid

MS 425 (Ml).

Example 179

5-(3-{[3-(3-Br0m0-phenyl)-pr0pyl)-methanesulf0nyl-amin0}-pr0pyl)-thi0phene-2-carboxylic acid

Reductive Amination: (Step (A).

5-(3-{[3-(3-Br0m0-phenyl-pr0pyl]-amin0}-pr0pyl)-thi0phene-2-carb0xylic acid tert-butyl ester

Get the title compound from

5-(3-amino-propyl)-thophene-2-carbxoylic acid tert-butyl ester hydrochloride and 3-(3-br0m0-phenyl)-pr0pi0naldehyde

Following the methods described in step (a) of Example 141 1H NMR(400MHz, CDCl3) δ 7.5(d,lH), 7.28-7.3(m,2H),7.06-7.14(m,2H), 6.75.

(d,1H), 2.85(d,2H), 2.65-2.78(m,4H), 2.6(t,2H),1.92-2.04(m,4H),1.52-1.45(m,9H); MS 438 (M+).

Sulfonamide Step B: Composition

5-(3-{[3-(3-Br0m0-phenyl)-pr0pyl]-methanesulf0nyl-amin0l}-pr0pyl)-thi0phene-2-carboxylic acid tert-butyl ester

Get the title compound from

5-(3-{(3-(3-Br0m0-phenyl)-pr0pyl]-amin0}-propyl)-thi0phene-2-carb0xylicacid tert-butyl ester

Using the method described in step (b) of Example 141 1H NMR (400MHz and CDCl3) δ 7.52(d,lH), 7.3- 7.32(m,2H), 7.07-7.16(m,2H), 6.74

(d,lH), 3.15-3.2(m,4H), 2.84(t,2H), 2.8(S,3H) 2.59(t,2H), 1.85-1.98(m,4H),1.54

(S,9H); MS 533 (M+17).

Ester for Hydrolysis Step C: Hydrolysis of 5-(3-{[3-(3-Br0m0-phenyl)-pr0pyl]-methanesulf0nyl-aminol-propyl)-thi0phene-2-carboxylic acid

Get the title compound from

5-(3-{[3-(3-Br0m0-phenyl)-pr0pyl]-methanesulfonyl-amin0}-pr0pyl)-thi0phene-2-carboxylic acid tert-butyl ester

Using the method described in step (c) of Example 171.

1H NMR(400MHz,CDCl3)δ 7.71(d,1H), 7.31- 7.33(m,2H), 7.08-7.17(m,2H), 6.84

(d,lH), 3.11-3.22(m,4H), 2.9(t,2H), 2.81(S,3H), 2.6(t, 2H),1.82-1.99(m,4H);MS

458 (Ml).

Example 180

Example 180 is prepared in a manner similar to Example 179 by starting with the appropriate amine and aldehyde reagents in step (a) followed by formation of the desired sulfonamide in step (b) and hydrolysis of the ester in step (c).

Example 180

5-(3-{(Butane-l-sulfonyl)-[3-(3-Chloro-phenyl)-propyl]-amino)-propyl)-thiophene-

2-carboxylic acid

Step A:

5-(3{[3-(3-Chloro-phenyl)-propyl]-amino}-propyl)thiophene-2-carboxylic acid tert-butyl ester

The title compound is prepared following the procedure described in step (a) of Example 179 except that diisopropylethylamine is used instead of triethylamine. Step (B):

5-(3-{(Butane-l-sulfonyl)-(3-Chloro-phenyl)-propyl]-amino}-propy)-thiophene-

2-carboxylic acid tert-butyl ester MS 531(M+18).

Step (c):

5-(3-{(Butane-l-sulfonyl)-[3-(3-Chloro-phenyl)-propyl]-amino}-prPopy)-thiophene-

2-carboxylic acid

1H NMR(400MHz, CDCl3) δ 7.72(d,1H,J=4). 7.0-7.4(m,4H), 6.7(d,lH,J=4), 3.25

(m,4H), 2.82(m,4H), 2.6(rn,2H), 1.6-2.25(m,6H), 1.07 (t,3H,J=7); MS 457 (Ml).

Example 181

5-{3-[Cyclopropanecarbonyl-(2,3-dihydro-benzo[l.4]dioxin-6-ylmethyl)-amino]-

propyl}-thiophene-2-carboxylic acid

Reductive Amination: (a) step

5-{3-[(2,3-Dihydro-benzo[1,4]dixoin-6-ylmethyl)-amino]-propyl}-thiophene-2-carboxylic acid methyl ester

Step (A) is performed in a similar manner to Step (A) of Example 163. Step B: Amide formation

5-{3-[Cyclopropanecarbonyl-(2,3-dihydro-benzo[1,4]1dioxin-6-ylmethyl)-aminol

pronyl}-thiophene-2-carboxylic acid methyl ester

Stir at room temperature for 16 hours solution of

-2-5-{3-[(2,3-Dihydro-benzo[l,4]dioxin-6-ylmethyl)-amino]-propyl}-thiophene

Carboxylic acid methyl ester (0.435 g, 0.125 mmol) in DCC (0.0284 g, 0.137 mmol) and cyclopropanecarboxylic acid (0.0119 g, 0.137 mmol) in 10 mM CH2Cl2. The mixture is filtered and the original liquid is concentrated by vacuum. The residue was dissolved in 15 ml EtOAc and filtered. The organic solution is washed with water and then with a saline solution, dried over magnesium sulphate, filtered, and concentrated by vacuum to provide the compound described in step (b) as oil (53 mg).

MS 416 (M+).

Ester for Hydrolysis Step (C): Hydrolysis of 5-{3-[Cyclopropanecarbonyl-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)amino]-propyl}-thiophene-2-carboxylic acid

take place . (c) In a manner similar to step (c) in Example 141.

1HNMR(400MHz,CDCl3)δ7.7(bs,lH),6.5-7.0(m,4H),4.5(s,2H),4.2(bs 4H), 3.32(m,2H), 2.7(m,2H) ,1.7-1.8(m,2H),l.0-0.7(m,4H), MS 402 (M+l), 400 (Ml).

Questions 182-184

Examples 182-184 are prepared in a manner similar to Example 181 by starting with suitable aldehyde and amine reagents in step (a) followed by formation of the desired amide in step (b) and hydrolysis of the ester in step (c).

Example 182

5-[3-(Benzofuran2-ylmethyl-cyclopropanecarbonyl-amino)propyl]-thiophene-2-

carboxylic acid

1HNMR(400MHZ,CDCl3)δ7.7(bs,1H) 7.0-7.6(m,4H), 6.6-6.95(m,2H), 4.6(s,2H),

3.2(m,2H), 2.7(m,2H), 1.8(m,2H), 1.0-0.7(m,4H); MS 384 (M+l), 382 (Ml).

Example 183

5-(3-{[3-(3-Chloro-phenyl)-propyl]-propionyl-amino}-propyl)-thiophene-2-carboxylic acid

1H NMR(400MHZ,CDCl3)δ 7.3-7.0(m,4H), 6.73(d,lH), 3.2(rn,4H),

2.92(m,2H), 2.71(m,2H), 2.2(m,2H), 1.89-1.7(m,4H), 1.2(t,3H); MS 392 (Ml).

Example 184

5-(3-{Acetyl-[3-(3-Chloro-phenyl)-propyl]-aminol-propyl)-thiophene-2-carboxylic

acid

Step A:

5-(3-{[3-(3-Chloro-phenyl)-propyl)-amino}-propyl)-thiophene-2-carboxylic methyl ester

MS 352 (Mtl).

Step (B):

5-(3-{Acetyl-[3-(3-Chloro-phenyl)-propyl)-amino]-propyl)-thiophene-2-carboxylic acid methyl ester MS 394 (M+l).

Step (c):

5-(3-(Acetlyl-[3-(3-Chloro-phenly)-propyll-amino]-propyl)-thiophene-2-carboxylic

acid

1H NMR(400MHZ, CDCl3) δ7.7 (d,lH,J=4), 7.0-7.6(m,4H), 6.8 (d,lH,J=4), 3.25

(m,4H), 2.82(m,2H), 2.6(m,2H), 2.2(s,3H), 1.6-2.0(m,2H); MS 378 (Ml), 380

(M+l).

Example 185

{3-5(4-Butyl-benzyl-(propane-l-sulfonyl)-amino]-propyl-thiophene-2-

carboxylic acid

Step (A): Reductive Amination

5-{3-[(4-Butyl-benzyl)-aminol-propyn-thiophene-2-carboxvlic acid methyl ester heated with re-condensation of steam for several four and a half hours a thread of 4-butylbenzaldehyde

(0 mg, 1.54 1 mmol),

5-(3-amino-propyl)-thiophene-2-carboxylic acid methyl ester hydrochloride

(4.03 mg, 1.695 mmol), Na2SCO and (2.189 g, 15.41 mmol) in MeOH (1.0 ml) and add an additional (2.19 g) of Na2SO4. The mixture was heated with steam re-condensed for one hour and cooled to room temperature. Solids are separated by filtration with the help of MeOH and volatiles are removed by suction. The residue is dissolved in THF (10 ml) and CH2Cl2 (10 ml) and the solution is cooled to 0°C. Add acetic acid (185 mg, 3,082 mmol) then sodium triacetoxyborohydride (653 mg, 3,082 mmol) and stir the reaction at room temperature for 16 hours. The reaction was diluted with EtOAc and the organic solution was washed with aqueous NaHCO3 and then with brine. The organic solution was dried on MgSO4, filtered and concentrated. Purification by flash chromatography (CHCl31:99:MeOH to 97.5:2.5 MeOH:CHCI3) provided the title compound (300 mg).

MS 346 (MH+).

Step (b): Sulfonamide formation

5{3-[(--Butyl-benzyl-(propane-l-sulfonyl)amino]-propyl{-4thiophenel

carboxylic acid methyl ester

The title compound is prepared using the method described in step (b) of Example 141 except that N-methylmorpholine is used instead of triethylamine. Step C: Hydrolysis of the Ester

-Butyl-benzyl)-(propane-l-sulfonyl)-amino]-propyl}thiophene5-{3-[4

carboxylic acid

The title compound is prepared using the method described in step (c) of Example 141.

1HNMR(400MHZ, CDCl3)δ 7.72(7.4-7.0 =(d,1H,J),7.0-7.4 (m,4H),6.7(d,lH,J=4), 3.22 (t,2H,J=6.8 ) 2.65(t,2H,J=6.8), 1.6-2.25(m,6H), 1.02-1.l(m,6H) MS 436 (Ml),

438 (p+l).

Example 186

3-{[(Benzo[1,2,5]oxadiazole-4-sulfonyl)(4-butyl-benzyl)amino]-methyl}-)

phenvl)acetic acid

Step A: Formation of Sulfonamide

-{-Benzol [1,2,5]oxadiazole-4-sulfonyl)-butyl-benzyl)-amino]methyl} [(3

phenyl)acetic acid methyl ester Add benzofurazan-4-sulfonyl Chloride (109 mg, 0.5 mmol) to a solution of 3-[(4-butyl-benzylamino)methyl]-phenyl}-acetic acid methyl ester (163 mg). (0.5 mmol) N,N-diisopropylethylamine (65 mg, 0.5 mmol) in 1,2-dichloroethane. Stir the reaction mixture at room temperature for 20 hours.

The reaction was diluted with EtOAc and the organic solution was washed with water and then with saline. The organic solution was dried over MgSO4, filtered, and concentrated to be available

(3)-{[(Benzo[1,2,5[oxadiazole-4-sulfonyl)-(4-butyl-benzyl)-amino[-methyl}-

phenyl)-acetic acid methyl ester.

7.06-7.1(1H NMR(400MHz, CDCl3)δ 7.95(d, lH), 7.88(d,lH), 7.37-7.41(m,lH 2.48(t) 6.9-6.97(m,6H), 4.56( s,2H), 4.51(S,2H), 3.66(s,3H), 3.45(S,2H ,(m,2H).(18+,2H), 1.45-1.53(m,2H), 1.23-1.32 (m,2H), 0.89(t,3H); MS 508 (M) Step B: Hydrolysis for Ester

3-1 Benzor[1,2,5]oxadiazole-4-sulfonyl)4-butyl-benzyl)-aminol-methyl}]}-)

phenyl)-acetic acid

The title compound is prepared by hydrolysis of the compound

(3-{[(Benzo[l,2,5]oxadiazole-4-sulfonyl)-(4-butyl-benzyl)-amino]-methyl}-phenyl)- methyl ester

By following the procedure described in step (b) of Example 138.

1H NMR(400MHz, CDCl3) δ 7.93(d,lH), 7.87(d,lH), 7.34-7.38(m,lH), 7.07-7.09(m,2H), 6.9-6.96(rn,6H), 4.54 (s,2H), 4.49(s,2H), 3.47(s,2H), 2.46(t,2H), 1.44-1.51(m,2H), 1.22-1.31(m,2H), 0.88(t,3H) ); MS 492 (Ml).

Examples 188-187

Examples 87 1-188 are prepared in a manner similar to Example 186 by formation of the sulfonamide from the appropriate amine in step (a) followed by hydrolysis of the ester in step (b).

Example 187

(3-{](4-Butyl-benzyl)propane-l-sulfonyl)-amino]-methyl}-phenyl)-acetic acid

Step A:

(3_{[(4-Butyl-benzyl)-(propane-l-sulfonyl)-amino]-methyl}-phenyl)-acetic acid methyl ester

1H NMR(400MHZ, CDCl3) δ 4.3(d,4H), 3.69(s,3H), 3.61(s,2H), 2.82-2.86(m,2H),

2.59(t,2H), 1.78-1.84(m,2H), 1.58(t,2H).

Step (B):

(3-{[(4-Butyl-benzyl)-(propane-1-(propane-1-sulfonyl)-amino]-methyl}-phenyl)-acetic acid

1H NMR(400MHZ, CDCl3) δ 7.12-7.32(m,8H), 4.3(d,4H), 3.64(S,2H), 2.81-2.9

(m,2H),2.59(t,2H), 1.47-1.83(m,2H), 1.54-1.61(m,2H), 1.31-1.4(m,2H),0.87-0.97

(m,6H); MS416(M+-l).

Example 188

(3-{[(Butyl-benzyl)-thiophenelsulfonyl)amino]-methyl)-phenyl)-acetic acid

Step A:

(3-{[(4-Butyl-benzl)-(thiophene-2-sulfonyl)-amino]-methyl}-phenyl)-acetic acid methyl ester

1H NMR(400MHz, CDCl3) δ7.51-7.57(m,2H), 7.12-7.2(m)2H), 6.95 -7.08(m,7H), 4.3(d,4H), 3.68(S,3H), 3.52(S,2H), 2.55(t,2H), 1.51-1.58(m,2H), 1.27 -1.36(m,2H), 0.91(t,3H); MS 472 (M+l).

:(Step (b

(3-{[(Butyl-benzyl)-thiophene-2-sulfonyl)-amino]-methyl}-phenyl-acetic acid 1H NMR(400MHz, CDCl3) δ7.5-7.54(m,2H), 7.1-7.18( m,2H), 6.89-7.05(m,7H), 4.27(d,4H), 3.52(s,2H), 2.52(t,2H), 1.48-1.56(m,2H), 1.21-1.34(m, 2H), 0.89(t,3H); MS 456 (Ml).

Example 189

3-)3-{[3-(3-Chloro-phenyl)-propyl]-methanesulfonyl-amino}-propyl)-benzoic acid

Step A: Sulfonamide formation

3-(3-{[3-(3-Chloro-phenyl)-propyl]-methanesulfonyl-amino}-propyl)-benzoic acid

methyl ester

Add methanesulfonyl chloride (18.3 mg, 0.16 mmol)

Zero Celsius to a solution of

3-(3-([3-(3-Chloro-phenyl)-propyl]-amino}-propyl)-benzoic acid methyl ester

(50.3 mg, 0.145 mmol) trirthylamine (32.4 mg, 0.32 mmol) in CH2C12 (10 ml). The reaction mixture was stirred for 24 h at room temperature and diluted with CH2C12. The organic solution was washed sequentially with aqueous HCl (5.5%, one time), water (one time), NaHCO3 (one time) and brine (one time). The organic solution was dried over MgSO4, filtered, and concentrated to provide the compound of step (a) as oil (71 mg).

(1+MS 424 (M.)

Step B: Hydrolysis of the Ester

3-(3-{[3-(3-Chloro-phenyl)-propyl]-methanesulfonyl-amino}-propyl)-benzoic acid

The title compound is prepared by hydrolysis of the compound

3-(3-{[3-(3-Chloro-phenyl)-propyl]-methanesulfonyl-amino}-propyl)-benzoic acid methyl ester

By following the procedure described in step (b) of Example 141.

1HNMR(400MHz, CDCl3) δ 7.0-8.0(m,8H), 3.19(m,4H), 3.0(s,3H), 2.7(m,2H), 2.6(m,2H), 1.79-2.03(m, 4H); MS 408 (Ml), 410 (Mtl).

Examples 190-197

amine from sulfonamide Examples 190-197 are prepared in a manner similar to Example 189 in the formation

In step (b). The appropriate ester in step (a) is followed by hydrolysis of example 190

5-(3-{[3-(3-Chloro-phenyl)-propyl)-methanesulfonyl-amino)-furan-2-carboxylic

acid

Step A:

5-(3-{[3-(3-Chloro-phenyl)-propyl]-methanesulfonyl-amino}-propyl)-furan-2-carboxylic acid methyl ester MS 414 (M+l).

Step (B):

5-(3-{[3-(3-Chloro-phenyl)-propyl]-methanesulfonyl-amino)-furan-2-carboxylic

acid

1H NMR(400MHZ, CDCl3) δ6.75-7.5(m,5H), 6.2(d,lH,J=4), 2.95(S,3H), 2.8(m,

2H), 2.65(m,2H), 1.8-2.0(m,4H); MS 398 (Ml), 400 (M+l).

Example 191

5-(3-{[3-(3-Chloro-phenyl)-propyl)-methanesulfonyl-amino)-propyl)-tetrahydrofuran-2-carboxylic acid

Step A:

5-(3-{[3-(3-Chloro-phenyl)-propyl)-methanesulfonyl-aminol-propyl)-tetrahydrofuran-2-carboxylic acid methyl ester MS 418 (M+l).

Step (B):

5-(3-{[3-(3-Chloro-phenyl)-propyl)-methanesulfonyl-amino)-propyl)-tetrahydrofuran-2-carboxylic acid

1H NMR(400MHz, CDCl3) 7.3-7.0 δ(m,14 H), 3.2 (t,2H,J=6.8), 2.85(s,3H), 2.65 (t,2H,J=6.7), 1.9(m ,2H); MS 402 (Ml), 404 (M+l).

Example 192

5-(3-{[3-(3-Chloro-pheny )propyl]-ethanesulfonyl-amino}-propyl)-furan-2-

carboxylic acid

:(a) A step

5-)-(3-{[3-(3-Chloro-phenyl)prooyl]-ethanesulfonyl-amino}-propyl)-furan-2-

Carboxylic acid methyl ester MS 428 (M+l).

Step (B):

5-(3-{[3-(3-Chloro-phenyl)-propyl]-ethanesulfonyl-amino}-propyl)-furan-2-

carboxylic acid

H1 NMR(400MHz, CDCl3) δ 6.8-7.7(m,5H), 6.21(d,1 H,J= 4), 3.22(m,4H), 2.81(m,2H), 2.62(m,2H), 1.8-2.2(m,6H), 1.05(t,3H,J=7); MS 412 (Ml), 414 (M+l).

Example 193

5-(3-[(4-Butyl-benzyl)ethanesulfonyl-aminol-propyl}-thiophene-2-carboxylic acid

Step A:

5-}3-[(4-Butyl-benzyl)-ethanesulfonyl-amino]-propyl}-thiophene-2-carbpxylic acid

methyl ester MS 457 (M+18).

Step (B):

5.(3_[(4-Butyl-benzyl)-ethanesulfonyl-amino]-propyl}-thiophene-2-carboxylic acid

lHNMR(400MHz, CDCI3) 7.7δ(d,lH,J=3.9), 7.0-7.4(m,4H), 6.72(d) lH,J=3.8), 3.22(t,2H,J=6.9), 2.6 (t,2H,J=7), 1.72-2.3(m,6H), 1.03-1.09(m,6H); MS 422 (Ml).

Example 194

5-(3-{[3-(3-Chloro-phenyl)propyl]-ethanesulfonyl-amino)-propyl)-thiophene-2_:

carboxylic acid

Step A:

5-(3-{[3-(3-Chloro-phenyl)-propyl)-ethanesulfonyl-amino}-propyl)-thiophene-2-

carboxylic acid methyl ester

MS 461 (M+18).

Step (B):

5-(3-{[3-(3-Chloro-phenyl)-propyn-ethanesulfonyl-amino}-propyl)-thiophene-2-carboxylic acid

1HNMR(400MHz,CDCl3)δ6.62-7.71(m,6H),3.26(m,4H), 2.83(m,2H), 2.63(m,2H), 1.6-2.25(m,6H), 1.06(t ,3H,J=7); MS 428 (Ml), 429 (M+l).

Example 195

3-(3-{[3-(3-Chloro-phenyl)-propyl]-ethanesulfonyl-amino}-propyl)-benzoic acid

Step A:

3-(3-{[3-(3-Chloro-phenyl)-propyn-ethanesulfbnyl-amino}-propyl)-benzoicacid methyl ester MS 438 (Ml).

Step (B):

3-(3-{[3-(3-Chloro-phenyl)-propyn-ethanesulfonyl-amino}-propyl)-benzoic acid 1HNMR(400MHz,CDCl3)δ7.0-8.0(m,8H)) 3.21(m, 4H), 2.78(m,2H), 2.5(m,2H), 1.82-2.2(m,6H), 1.05(t,3H,J=7.0); MS 422 (Ml), 424 (M+l).

Example 196

5-{3-[[3-(3-Chloro-phenyl)-propyn-(propane-l-sulfonyl)-amino]-propyn-thiophene-2-carboxylic acid

Step A:

5-{3-[[3-(3-Chloro-phenyl)-propyl]-(propane-l-sulfbnyl)-amino]-propyl)-thiophene-2-carboxylic acid methyl ester MS 476 (M+18).

Step (B):

5-{3-[[3-(3-Chloro-phenyl)-propy1)-(propane-1 -sulfonyl)-amino]-propyl 1 -thiophene-2-carboxylic acid

1H NMR(400MHz,CDCl3) δ 7.7(d,lH,J=4.0), 7.0-7.3(m,4H), 6.8(d,lH,J=4.0), 3.2(m,4H), 2.7(m, 4H), 2.5(m,2H),1.7-2.0(m.6H), 1.0(t, 3H,J=7.0); MS 444 (M+l),

442 (Ml).

Example 197

5--{3-[[3-(3-Chloro-phenyl)-propyl]-(3-chloro-propane-l-sulfonyl)-amino]-propyl_}-

thiophene-2-carboxylic acid

Sulfonamide Step A: Composition

5-{3-[[3-(3-Chloro-phenyl)-propyl]-(3-chloro-propane-l-sulfonyl)-amino]-propyl}:

thiophene-2-carboxyliaidt-butyl ester

The compound of step (a) is prepared from appropriate starting materials in a manner similar to the method described in step (a) of Example 189. Step (b): Hydrolysis of the Ester

5-{3-[[3-)3-Chloro-phenyl)-propyl]-)3-chloro-propane-1-sulfonyl)-amino]-propyl}-thiophene-2-carboxylic acid

The title compound is prepared by hydrolysis of the compound

5-{3-[[3-(3-Chloro-phenyl)-propyll-(3-chloro-propane-l-sulfonyl)-amino]-propyl}-

thiophene-2-carboxylic acid tert-butyl ester

in a manner similar to the method described in step (c) of Example 171.

1H NMR(400MHZ,CDCl3) δ 6.6-7.72(m,6H), 3.19(m,4H), 2.79(m,2H), 2.6(m,2H),

1.6-2.2(m,6H): MS 477 (Ml).

Example 198

5-(3-{[3-(3-Chloro-phenyl)-propyl-hydroxyacetyl-amino}-propyl)-thiophene-2-

carboxylicacd

Amide Step A: Composition

5-(3-{[3-Chloro-phenyl)-propyl)-hydroxyacetyl-amino)-propyl)-thiophene-2:

earhoxylic acid methyl ester

Stir for 24 hours at room temperature solution of

5-(3-{[3-(3-chloro-phenyl)-propyl]}-propyl)-thiophene-2-carboxylic acid methyl

ester

(80.7 mg, 0.23 mmol), acetoxyacetic acid (30 mg, 0.25 mmol) DCC, and (52 mg, 0.25 mmol) in CH2C12 (0.1 mmol). The reaction mixture is filtered and the filtrate is concentrated. The residue is dissolved in EtOAc (1.5 ml) and filtered. The filter cloth is washed with HCl (5.5%, once), water (once). NaHCO3 (once), brine (once). The organic solution was dried over MgSO4, filtered, and concentrated until the product was available as oil (0.9 mg).

MS 452 (M+1).

Ester for Hydrolysis Step B: Hydrolysis

5-(3{[3-Chloro-phenyl)-propl]-hdyroxyacetyl-amino}-propyl)-thiophene-2-

carboxylic acid

The title compound is prepared by hydrolysis of the compound

5-(3-{[3-(3-Chloro-phenyl)-propyl]-hydroxyacetyl-amino}-propyl)-thiophene-2-

carboxylic acid methyl ester

in a manner similar to the method described in step (c) of Example 141

H1 NMR(400MHZ,CDCL3) S 6.7-7.8(m,6H), 3.24(m,4H), 2.81(m,2H), 2.6(m,2H),

1.2-2.02(rn,4H); MS 394 (Ml), 396 (M+1).

Examples 199-205

Examples 199-205 are prepared by a method similar to Example 198 by forming the amide from the appropriate amine in step (a) followed by hydrolysis of the ester in step (b).

Example 199

5-(3-{[3-(3-Chloro-phenyl)-propyl]-cyclopropanecarbonyl-amino}-propyl)-tbiophene-2-carboxylic acid

Step A:

5-(3-{[3-(3-Chloro-phenyl)-propyl]-cyclopropanecarbonyl-aminol-propyl)-

thiophene-2-carboxylic acid methy ester

Step (B):

5-(3-{[3-(3-Chloro-phenyl)-propyl1-cyclopropanecarbonyl-amino]-oropy]thiophene-2-carboxylic acid

1H NMR(400MHz,CDCl3) δ 6.6-7.8(m,6H), 3.25(m,4H), 2.75(m,2H), 2.6(m,2H), 1.8-2.0(m,4H), 0.7-1.0 (m,4H); MS 406 (Ml), 406 (M+l).

Example 200

5-(3-{[3-(3-Chloro-phenyl)-propyl)-cyclobutanecarbonvl-amino}-propyl)-thiophene-2-carboxylic acid

Step (A):

5-(3-{[3-(3-Chloro-phenyl)-propyl]-cyclobuticarbonyl-amino}-propyl)-thiophene-2-carboxylic acid methyl ester

Step (B):

5-(3-{[3-(3-Chloro-phenyl)-propyl]-cyclobuticarbonyl-amino}-propyl)-thiophene-2-carboxylic acid

1H NMR(400MHz,CDCl3) δ 6.6-7.7(m,6H), 3.22(m,4H), 2.86(m,2H), 2.66(m,2H), 1.66-1.99(m,10H); MS 418 (Ml), 420 (M+l).

Example 201

5-(3-{[3-(3-Chloro-phenyl)-propyl)-methoxyacetyl-amino}-propyl)-thiophene-2-

carboxylic acid

Step A:

5-(3-{[3-(3-Chloro-phenyl)-propyl]-methoxyacetyl-amino}-propyl)-thiophene-2-carboxylic acid

Step (B):

5-(3-{[3-(3-Chloro-phenyl)-propyl)-propyl]-methoyvacetvyl-amino}-pronyl)-thiophene-2-carboxylic acid

1H NMR(400MHz,CDCl3) δ 6.6-7.82(m,6H), 3.25(m,4H), 3.2(s,3H), 2.8(t,2H,J=

7.0),2.6(t,2H,J=7.0), 1.6-2.0(m,4H); MS 408 (Ml), 410 (M+l).

Example 202

5-(3-{Butyryl-[3-(3-chloro-phenyl)-propyl]-amino}-propyl)-thiophene-2-carboxylic

acid

Step A:

5-(3-{Butyryl-[3-(3-chloro-phenyl)-propyl]-amino}-propyl)-thiophene-2-carboxylic acid methyl ester MS 422 (M+l).

Step (B):

5-(3-{Butyryl-[3-(3-chloro-phenyl)-propyl]-amino}-propyl)-thiophene-2-carboxylic

acid

1H NMR(400MHZ,CDCL3) δ 6.66-7.7(m,6H), 3.2(rn,4H), 2.81(m,2H), 2.62(m,2H),

1.7-2.2(m,6H), 1.04(t,3H,J=6.7); MS 408 (M+l), 406 (Ml).

Example 203

5-(3-{[3-(3-Chloro-phenyl)-propyl)-propionyl-amino}-propyl)-furan-2-carboxylic

acid

Step A:

MS 392 (M+l).

Step (B):

5-(3-{[3-(3-Chlor-phenyl)-propyl)-propionyl]-amino}-propyl)-furan-2-carboxylic

acid

1H NMR(400MHZ,CDCL3)δ 6.8-7.7(m,5H), 6.21(d,lH,J=3.9), 3.2(m,4H), 2.83

(m,2H), 2.6(m,2H),1.8-2.2(m,6H),1.04(t,3H,J=6.8); MS 376(M-1),378(M+1).

Example 204

5(3-{[Chloro-phenyl)-propyl(-cyclopropanecarbonyl-amino}-propyl)-furan-2-carboxylic acid

Step A:

5-(3-{[3-(3-Chloro-phenyl)-propyl]-cylopropanecarbonyl-amino)-propyl)-furan-2-carboxylic acid methyl ester MS 404 (M+l).

Step (B):

5-(3-{[3-(3-Chloro-phenyl)-propy1]-cyclopropanecarbonyl-amino}-propyl)-furan-2-carboxylic acid

1H NMR(400MHz,CDCl3) δ 6.8-7.4(m,5H), 6.19(d, lH,J=4.0), 3.25(m,4H), 2.81

(m,2H), 2.6(rn,2H), 1.6-2.0(m,4H); MS 388 (Ml), 390 (M+l).

Example 205

5-(3-{Acetyl-[3-(3-chloro-phenyl)-propyl]-amino}-propyl)-furan-2-carboxylic acid

Step A:

5-(3-{Acetyl-[3-(3-chloro-phenyl)-propyl)-amino}-propyl)-furan-2-carboxylic acid methyl ester MS 378 (M+l).

Step (B):

5-(3-{Acetyl-[3-(3-chloro-phenyl)-propyl)-amin0}-propyl)-furan-2-carboxylic acid 1HNMR(400MHz,CDCl3)δ6.82-7.7(m,5H) , 6.2(d,lH,J=4), 3.2(m,4H), 2.8(m,

2H), 2.6(m,2H), 2.1(s,3H), 1.6-2.04(m,4H); MS 362 (Ml), 364 (M+l).

Example 206

-2-5-(3-{[3-(3-Chloro-phenyl)-propyl]-methanesulfonyl-amino}-propyl)-thiophene

carboxylic acid sodium salt

Add 3NaHCO (1.49 g, 17.74 mmol) to a solution of -2-5-(3-{[3-(3-Chloro-phenyl)-propyl]-methanesulfonyl-amino}-propyl)-thiophene

carboxylic acid

(7.378 g, 17.74 mmol) in MeOH (325 ml) and water (25 ml) and stir the reaction at room temperature for 3 hours. The reaction is concentrated by suction and the residue boils at

50 milliliters of sodium x2) to provide 50 milliliters of CHCI3 salt x2, then MeOH x2 provides a constant boiling point with

As a white solid (7.661 g).

1H NMR(400MHZ,CD3OD(δ 7.35(d,lH),7.28(m,2H),7.14(m,2H), 6.73(d,lH), 3.23(m,4H), 2.83(S,3H), 2.82(m,2H), 2.62(t,2H), 1.94(m)2H), 1.88(m,2H).

Examples 2.7-216

Following the general procedure described in Example 206, prepare the following sodium salts (Examples 207-216) with the variations as noted.

Example 207

)3-{[(-Butyl-benzyl)methanesulfonyl-amino]-methyl}-phenyl)-acetic acid sodium

salt

Following the procedure described for Example 06 2, the sodium salt is generated. The sodium salt is stirred in 3% EtOAc/EtOH at 45°C for 20 hours, cooled to room temperature and filtered to produce a white solid. Melting point 58 1. Celsius;

1HNMR(400MHz,CD3OD)δ7.26-7.11(m,8H),4.28(s,4H), 3.45(s,2H), 3.29(s,2H), 2.8(S,3H), 2.58(t,2H ), 1.57(m,2H), I.33(m)2H), 0.92(t,3H).

Example 208

[3-({[3-(3,5-Dichloro-phenyl)allyl]-methisulfonyl-amino}-methyl)-phenoxy]-acetic acidsodiumsalt

IH NMR(400MHZ,CD3DO δ7.29-7.21(m,4H), 6.94(m,2H), 6.84(d,lH), 6.44(d)

lH), 6.24(m,1H), 4.37(s,2H), 4.35(S,2H), 3.94(d,2H), 2.94(s,3H).

Example 209

[3-({[2-(3,5-Dichloro-phenoxy)-ethyl]-methanesulfonyl-amino}-methyl)-phenoxyl-acetic acid sodium salt

IH NMR(400MHz,CD30D) δ 7.21(m,lH), 6.96(m,3H), 6.83(m,3H), 4.44(s,2H), 4.35(s,2H), 4.01(t,2H), 3.56(t,2H), 2.97(s,3H).

Example 210

2-(3-{[2-3,5-Dichloro-phenoxy)ethy]-methanesulfonyl-amino}-propyl)-thiazol-4-

carboxylic acid sodium salt

IH NMR(400MHZ,CD3OD) δ 7.82(bs,lH), 6.99(m,lH), 6.92(m,2H), 4.15(t,2H).

3.62(m,2H), 3.36(m,2H), 3.03(m,2H), 2.94(S,3H), 2.14(m,2H).

Example 211

N-[2-(3,5-Dichloro-phenoxy)-ethyl]-N-[6-(lH-tetrazol-5-yl-hexyn]-

methanesulfonamide sodium salt

1H NMR(400MHZ,CD3OD)δ 6.93(s,2H), 4.14(t,2H), 3.58(t,2H), 3.23

(t,2H), 2.91(S,3H), 2.8(t,2H), 1.73(m,2H), 1.62(m,2H), 1.36(m)4H).

Example 212

7-ir2-(3.5-Dichloro-phenoxy)-ethyl]- methanesulfonyl-amino}heptanoic acid sodium salt

In 2% water in sodium, the sodium salt is stirred. Following the procedure described for Example 206, a salt is generated at 65°C for 20 hours. The mixture was cooled to room temperature and filtered providing EtOAc

Solid, white. Melting point: 166°C

1H NMR(400MHZ,CD3OD δ 7.0(s,lH), 6.94(s,2H), 4.14(t,2H), 3.59(t,2H), 3.29

(t,2H), 2.92(s,3H), 2.14(t,2H), 1.6(rn,4H), 1.35(m,4H).

Example 213

7-[(4-Butyl-benzyl)-methanesulfonyl-amino]-heptanoic acid sodium salt

Following the procedure described for Example 6 0 2 sodium salt is generated. Stir the sodium salt in 10% EtOH in EtOAc at 65°C for 20 hours. The mixture is cooled to room temperature and filtered to provide a white solid. Melting point 37 1. Celsius;

1H NMR(400MHZ,CD3OD) δ 7.27(d,2H), 7.15(d,2H), 4.32(S,2H), 3.12(t,2H), 2.85

(S,3H), 2.6(t)2H), 2.09(t,2H), 1.6-1.2(m,12H), 0.92(t,3H).

Example 214

(3-{[4-Cyclohexyl-benzyl)methanesulfonyl-amino]-methyl}-phenyl)-aceticacid sodium salt

1H NMR(400MHz,CD30D) 7.15-7.33 δ(m,8H), 4.31(S,2H), 4.28(S,2H), 3.64(s,

2H), 2.74(s,3H), 2.48(m,lH), 1.84(m,4H), 1.74(m,lH), 1.38(m)4H),

Example 215

3-{[4-tert-Butyl-benzyl)-methanesulfonyl-amino]-methyl}-phenoxy)-aceticacid sodium salt

In 2% water in sodium, the sodium salt is stirred. Following the procedure described for Example 206, a salt is generated at 65°C for 20 hours. The mixture was cooled to room temperature and filtered to provide EtOAc

Solid white colour. Melting point 4 8 1-86 1C; 1H NMR(400MHz,D3O) δ7.19(d,2H), 7.04(m,3H), 6.71(d,lH), 6.63(d)lH), 6.49(S1H),4.2(S,2H),4.18 (S,2H), 4.17(S,2H), 2.88(S,3H), 1.08(S,9H).

Example 216

5-(3-{[2-(3,5-Dichloro-phenoxy)-ethyl]-methanesulfnyl-amino}-propyl-thiophene-

2-carboxylic acid sodium salt

1HNMR(400MHz,CD3OD) δ7.34(d,lH), 6.99(t,lH), 6.9(d,2H), 6.72(d,lH), 4.12(t,2H), 3.6(t,2H), 3.31(t,2H), 2.92(s,3H), 2.83(t,2H), 2.0(rn,2H).

Preparations (C4-C6)

Preparations (C4-C6) are prepared from appropriate starting materials in a manner similar to the preparation

(Part 1).

Product (Part 4)

N-[3-(5-Methyl-thiophene-2-yl)propyl]-methanesulfonamide 1H NMR(400MHz,CDCl3) δ 6.57-6.53(m,2H) 4.35(m,lH), 3.17(m,2H), 2.93(s,

3H), 2.83(t,2H), 2.42(S,3H), 1.9(m,2H).

Preparation (Part 5)

[3-(3-Methanesulfonylamino-propyl)-phenyl]-acetic acid methyl ester

1HNMR(250MHz,CDCl3)δ7.3-7.06(m,4H),4.34(m,1H),3.7)(s,3H),3.61(s,2H),

3.27(m,2H), 2.94(S,3H), 2.72(t,2H), 1.93(m,2H).

Product (Part 6)

[2-(3-Methanesulfonylamino-propyl)phenyl]-acetic acid methyl ester

1H NMR(400MHZ,CDCl3) δ 7.24-7.16(m,4H) 4.58(m,lH), 3.69(s,3H), 3.66(s, 2H),

3.17(q,2H), 2.94(S,3H), 2.72(t,2H), 1.88(m,2H).

Preparers (D3-D4)

Preparations (D3-D4) are prepared from appropriate starting materials in a similar manner to preparation (D1).

Preparation (D3)

l-Bromomethvl-4-propyl-benzene

1HNMR(400MHz,CDCl3)δ7.3-7.25(m,2H), 7.14(m,2H), 4.48(s,2H), 2.56(t,2H), 1.62(m,2H), 0.93(t,3H ).

Preparation (D4)

1- Bromoethyl-4-ethyl-benzene

1HNMR(400MHz,CDCl3)δ7.28(m,2H), 7.16(d,2H), 4.48(S,2H), 2.43(q,2H), 1.22(t,3H).

Preparations (and 3 and 4)

Preparations (F3-F4) are prepared from appropriate starting materials in a manner similar to preparation (F1).

Preparation (and 3)

2- Bromo-methyl-benzofuran

Preparation (and 4)

6-Chloro-2-bromomethyl-quinoline

Lotions (L4-L17)

Preparations (L4-L17) are prepared from appropriate starting materials in a manner similar to preparations (L1).

Preparation (for 4)

1-(2-Bromo-ethoxyl-3-ethyl-benzene

Lotion (L5)

l-(2-Bromo-ethoxy)-3-isopropyl-benzene

Preparation (L6)

l-(2-Bromo-ethoxyb3-trlfluoromethyl-benzn

Preparation (L7)

l-(2-Br0m0-eth0xv)-3,5-diflu0r0-benzene 1H NMR(400MHz,CDCl3)s 6.42(m,3H), 4.24(t,2H), 3.62(t,2H).

Lotion (L8)

l-(2-Bromo-ethoxy)-3,5-dichloro-benezene

You will attend (for 9)

l-(2-Bromo-ethoxy)3-fluoro-benzene

Preparation (for 10)

l-(2-Bromo-ethoxy)-3-chloro-5-methoxy-benzene

Preparation (L 1 1)

l-(2-Bromo-ethoxy)-3-ethoxy-benzene

Preparation (L 2 1)

l-(2-Bromo-ethoxy)-3-chloro-benzene

Preparation(L13)

5-(2-Bromo-ethoxy)-benzo[1,3]dloxole

1HNMR(400MHz,CDCl3) δ6.69(d,lH), 6.5(s,lH), 6.33(dd,lH), 5.91(s,2H),4.2(t,2H), 3.59(t,2H).

Preparation (L 4 1)

l-(2-Bromo-ethoxy)3,5-bis-trifluoromethyl-benzene

Lotion (for 15)

l-(3-Bromo-propoxy)3-chloro-5-methoxy-benzene