LT3612B

Therapeutic agents

Abstract

This invention includes a description for formula I<IMAGE>and their saline, useful in pharmacy; where R50 is hydrogen or Cl-4 alkyl, A51 is oxygen, sulphur or NR52 formula group; where R52 is hydrogen of C1-4 alkyl; A50 correspond to 1) mono- or bicyclic aromatic ring, which can have one or several nitrogen, oxygen or sulphur atoms, ii) cycloalkenyl group, iii) non-cyclical bridge with a one, two or three atoms chain, which is located between the cyclobutanedione group and Xso, described as a chain, this is one or two carbon atom chain, or a chain, made from one carbon atom and one or several nitrogen, oxygen and sulphur atoms or iv) connection; X 50 is a connection or interim group, connecting a chain of one or several atoms length between A50 and B50; where B50 is a mono- or bicyclic aromatic ring, which can have one or more nitrogen, oxygen or sulphur atoms, r is an integer number from 1 to 6; and Het is a ring system, which can have one or more nitrogen, oxygen and sulphur atoms or is phosphinite or amine formation (where A50, X50, B50 and Het can be substituted).The compounds include angiotensin II antagonist activation and are used for treating blood vessel disorders such as hypertension.

LT3612B, drawing sheet 1 — Sheet 1 of 107

Term

Term ended

Expired 13 July 2013, 13.2 years ago.

9 claims: 4 independent, 5 dependent

1
DEFINITION OF INVENTION IŠRADIMO APIBRĖŽTIS 1. Compound of Formula II:1. Junginys, kurio struktūrinė formulė II: arba jo farmaciškai tinkama druska: or a pharmaceutically acceptable salt thereof: kur where R310 is hydrogen or C1.4-alkyl;R310 yra vandenilis arba C1.4-alkilas;A190 is oxygen, sulfur or a group of the formula -NR319- in which R319 is hydrogen or C1_4-alkyl;A190 yra deguonis, siera arba grupė, kurios formulė -NR319-, kurioje R319 yra vandenilis arba C1_4-alkilas;R311, R3i2 < R3i3 and R3i4 is, independently of one another, hydrogen, fluorine, chlorine, bromine, C1_4-alkyl, C1_4-alkoxy, nitro, cyano, carboxyl, C2_4-alkoxycarbonyl, C1_4-alkylthio group, C1.4-alkylsulfinyl, C1.4-alkylsulfonyl, phenyl (which may alternatively be C 1-6 alkyl, Cx_4-alkoxy, fluorine, chlorine or bromine), C1_4-alkylsulfonylamino, or C 1-4 alkylaminosulfonyl;R311, R3i2< R3i3 ir R3i4 yra, nepri kl ausomai vienas nuo kito, vandenilis, fluoras, chloras, bromas, C1_4-alkilas, C1_4-alkoksigrupė, nitrogrupė, cianogrupė, karboksilas, C2_4-alkoksikarbonilas, C1_4-alkiltiogrupė, C1.4-alkilsulfinilogrupė, C1.4-alkįlsulfonilogrupė, fenilas (kuriame, kaip pakaitai, gali būti Cj.ų-alkilas, Cx_4-aikoksigrupė, fluoras, chloras arba bromas), C1_4-alkilsulfonilaminogrupė,arba C^-alkilaminosulfonilo grupė;R315 is hydrogen or C1_4-alkyl;and fTT R315 yra vandenilis arba C1_4-alkilas;ir fTT 119 119 R316, R3i7 ir R3i8 independently of one another is hydrogen, C 1-4 alkyl, nitro, fluoro, chloro, bromo, cyano, formyl or a group of the formula -SOgR320, ~ SO2NR321R322 or -COR323 (wherein R32o < R32i, R322, independently of one another, is hydrogen or C 1-4.4-alkyl, g is 1 or 2 and R is323 is C1.4-alkyl or a group of the formula -OR324 or -NR325R326in which R324, R325 and Rs326, independently of one another, are hydrogen or C1_4alkyl). R316, R3i7 ir R3i8, nepriklausomai vienas nuo kito, yra vandenilis, C1_4-alkilas, nitrogrupė, fluoras, chloras, bromas, cianogrupė, formilas arba grupė, kurios formulė -SOgR320, ~SO2NR321R322 arba -COR323 (kuriose R32o< R32i, R322, nepriklausomai vienas nuo kito, yra vandenilis arba C1_4-alkilas, g yra 1 arba 2, o R323 yra C1.4-alkilas arba grupė, kurios formulė -OR324 arba -NR325R326, kuriose R324, R325 ir R326, nepriklausomai vienas nuo kito, yra vandenilis arba C1_4-alkilas) .
5
Compound selected from:5. Junginys, pasirinktas iš: 3- [4 '- (2-Ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyrid-3-ylmethyl) -biphenyl-2-yl] -4-isopropoxycyclobut-3-en-1 , 2dione;3-[ 4 ' - (2-etil-5, 7-dimetil-3H-imidazo[ 4,5-b] pirid-3-ilmetil)-bifenil-2-il] -4-izopropoksiciklobut-3-en-l,2diono;3- [4 '- (2-Ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyrid-3-ylmethyl) -biphenyl-2-yl] -4-hydroxycyclobut-3-en-1 , 2-dione;3-[ 4 ' - (2-etil-5, 7-dimetil-3H-imidazo[ 4,5-b] pirid-3-ilmetil)-bifenil-2-il] -4-hidroksiciklobut-3-en-l,2-diono;3-Amino-4- [4 '- (2-ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyrid-3-ylmethyl) biphenyl-2-yl] cyclobut-3-en-1 , 2-dione;3-amino-4-[ 4 ' - (2-etil-5, 7-dimetil-3H-imidazo[ 4,5-b]pirid-3-ilmetil)bifenil-2-il] ciklobut-3-en-l,2-diono;z z 3- [4 '- (5,7-Dimethyl-2-propyl-3H-imidazo [4,5-b] pyrid-3-ylmethyl) -biphenyl-2-yl] -4-isopropoxycyclobut-3-en-1,2-dione ;3-[ 4 ' - (5, 7-dimetil-2-propil-3H-imidazo[ 4,5-b] pirid-3ilmetil)-bifenil-2-il] -4-izopropoksiciklobut-3-en-l,2diono;121 121 3- [4 '- (5,7-Dimethyl-2-propyl-3H-imidazo [4,5-b] pyrid-3-ylmethyl) -biphenyl-2-yl] -4-hydroxycyclobut-3-ene-1,2-dione ;3-[ 4'-(5, 7-dimetil~2-propil-3H-imidazo[ 4,5-b] pirid-3ilmetil)-bifenil-2-il] -4-hidroksiciklobut-3-en-l, 2diono;2-ethyl-3- [2-isopropoxy-3,4-dioxocyclobut-1-en-yl) biphenyl-4-ylmethyl] -5,7, N, N-tetramethyl-3H-imidazo [4,5-b] pyridine-6-sulfamide;2-etil-3-[ 2-izopropoksi-3,4-dioksociklobut-l-en-il)bifenil-4-ilmetil] -5,7, N, N-tetrametil-3H-imidazo[ 4,5-b] piridin-6-sulfamido;2- etil-3-[ 2’-(2-hidroksi-3,4-dioksociklobut-l-en-l-il)bifenil-4-ilmetil)-5,7,N,N-tetrametil-3H-imidazo[ 4,5-b] piridin-6-sulfamido;2-ethyl-3- [2 '- (2-hydroxy-3,4-dioxocyclobut-1-en-1-yl) biphenyl-4-ylmethyl) -5,7, N, N-tetramethyl-3H-imidazo [ 4,5-b] pyridine-6-sulfamide;3- [ 4’-(6-chlor-2-etil-5, 7-dimetil-3H-imidazo[ 4,5-b] pirid-3-il-metil) bifenil-2-il] -4-hidroks.iciklobut-3-en1,2-diono;3- [4 '- (6-chloro-2-ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyrid-3-ylmethyl) biphenyl-2-yl] -4-hydroxy. icyclobut-3-en1,2-dione;2- [ 4 ' - (2-etil-5, 7-dimetil-3H-imidazo[ 4,5-b] pirid-3-ilmetil)-bifenil-2-il]-3,4-dioksociklobut-l-en-l-il-oksimetilpivalato;2- [4 '- (2-Ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyrid-3-ylmethyl) -biphenyl-2-yl] -3,4-dioxocyclobut-1-ene -1-yl-oxymethyl pivalate;3- dimetilamino-4-[ 4'- (2-etil-5,7-dimetil-3H-imidazo[ 4,5-b] pirid-3-ilmetil)bifenil-2-ii] ciklobut-3-en-l,2-diono;3-Dimethylamino-4- [4'- (2-ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyrid-3-ylmethyl) biphenyl-2-yl] cyclobut-3-en-1 , 2-dione;1- [2- [4 '- (2-Ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyrid-3-ylmethyl) -biphenyl-2-yl] -3,4-dioxocyclobut-1 -en-1-yloxy] -ethyl pivalate;1—[ 2-[ 4’-(2-etil-5,7-dimeti l-3H-imidazo[ 4,5-b] pirid-3ilmetil)-bifenil-2-il] -3,4-dioksociklobut-l-en-l-iloksi]-etilpivalato;arba jų farmaciškai tinkamų druskų. or pharmaceutically acceptable salts thereof.
6
Farmacinė kompozicija, besiskirianti tuo, kad į ją įeina II, III arba IV formulės junginys pagal bet kurį iš ankstesnio punkto kartu su farmaciškai tinkamu nešikliu arba skiedikliu. 6th A pharmaceutical composition comprising a compound of formula II, III or IV according to any one of the preceding claims together with a pharmaceutically acceptable carrier or diluent.
9
Junginio, (II) , kurioje 9th The compound of (II) wherein R310 is hydrogen or Ci_4-alkyl; R310 yra vandenilis arba Ci_4-alkilas; A190 is oxygen, sulfur or a group of the formula -NR319- in which R319 is hydrogen or C 1-4 alkyl; A190 yra deguonis, siera arba grupė, kurios formulė -NR319-, kurioje R319 yra vandenilis arba C^-alkilas; R3n, R3i2z R313 it R314, independently of one another, are hydrogen, fluorine, chlorine, bromine, C1_4-alkyl, C1_4-alkoxy, nitro, cyano, carboxyl, C2-4-alkoxycarbonyl, C1_4-alkyl group, C1_4-alkylsulfinyl group, C1_4-alkylsulfonyl group, phenyl (which may be substituted with C1_4-alkyl, C3_4-alkoxy, fluorine, chlorine or bromine), C1_4-alkylsulfonylamino or C 1-4 alkylaminosulfonyl; R315 is hydrogen or C1.4-alkyl; and R3n, R3i2z R313 it R314, nepriklausomai vienas nuo kito, yra vandenilis, fluoras, chloras, bromas, C1_4-alkilas, C1_4-alkoksigrupė, nitrogrupė, cianogrupė, karboksilas, C2-4-alkoksikarbonilas, C1_4-alkiitiogrupė, C1_4-alkilsulfinilo grupė, C1_4-alkilsulf onilo grupė, fenilas (kuriame, kaip pakaitai, gali būti C1_4-alkilas, C3_4-alkoksigrupė, fluoras, chloras arba bromas) , C1_4-alkilsulfonilaminogrupė arba C^-alkilaminosulfonilo grupė; R315 yra vandenilis arba C1.4-alkilas; ir R316, r317 ir R3i8z independently of each other is hydrogen, C1_4-alkyl, nitro, fluorine, chlorine, R316, r317 ir R3i8z nepr i klau somai vienas nuo kito, yra vandenilis, C1_4-alkilas, nitrogrupė, fluoras, chloras, JI JI 123 bromine, cyano, formyl or a group of the formula -SOgR320, _SO2NR321R322 or -COR323 (where R32q, R32i, R322 <are independently hydrogen or C4_4alkyl, g is 1 or 2, and R is323 is C1_4-alkyl or a group of the formula -OR324 or -NR325R326, where R324, R325 and R326, independently of one another, are hydrogen or C1_4-alkyl); 123 bromas, cianogrupė, formilas arba grupė, kurios formulė -SOgR320, _SO2NR321R322 arba -COR323 (kur R32q, R32i, R322< nepriklausomai vienas nuo kito, yra vandenilis arba C4_4alkilas, g yra 1 arba 2, o R323 yra C1_4-alkilas arba grupė, kurios formulė -OR324 arba -NR325R326, kur R324, R325 ir R326, nepriklausomai’ vienas nuo kito, yra vandenilis arba C1_4-alkilas) ; arba jo farmaciškai tinkamos druskos gavimo būdas, b esiskiriantis tuo, kad junginį, kurio formulė LXX:or a pharmaceutically acceptable salt thereof, characterized in that the compound of formula LXX: (LXX), kurioje L yra atskylanti grupė, veikia junginiu, kurio formulė Het-H (Het-H) atliekant reakciją tirpiklyje, kuris yra inertiškas reakcijos sąlygoms. (LXX), wherein L is a leaving group, acts on a compound of formula Het-H (Het-H) by reaction in a solvent inert to the reaction conditions.

Independent claims4

1,245 paragraphs in 85 sections, as filed

and pharmaceutically acceptable salts thereof;

wherein R 50 is hydrogen or C 1-4 alkyl, A 51 is oxygen, sulfur or NR 52 is a group of formula; wherein R 52 is hydrogen or C 1-4 alkyl; A50 corresponds to (i) a mono or bicyclic aromatic ring which may have one or more nitrogen, oxygen or sulfur atoms, (ii) a cycloalkendenyl group, (iii) a non-cyclic bridge having one, two or three ring atoms between the cyclobutendione group and means a chain of one or two carbon atoms or a chain of one carbon atom and one or more atoms of nitrogen, oxygen or sulfur; or (iv) a bond; Χ50 is a bond or an intermediate group linking a one or two atom long chain between A50 and B50; B50 is a mono or bicyclic aromatic ring having one or more nitrogen, oxygen or sulfur atoms, r is an integer from 1 to 6; and Het is a ring system which may have one or more nitrogen, oxygen or sulfur atoms or is a derivative of a phosphonate, phosphinate or amino (where A50, Χ50, B50 and Het may be substituted).

The compounds have angiotensin II antagonist activity and are used to treat blood vessel disorders such as hypertension.

The present invention provides novel therapeutic agents as well as partially novel substituted cyclobut-3-en-1,2-diones, processes for their preparation, pharmaceutical compositions containing them, and their therapeutic activity in the treatment of blood vessel disorders.

Angiotensin II is the primary mediator of the reninangiotensin system. Angiotensin II is known to be a vasoconstrictor whose action is mediated through interaction with specific receptors on cell membranes. Recently, several non-peptide compounds have been reported as angiotensin II antagonists as useful antihypertensive agents.

The present invention describes compounds of formula I

H £ ti

(CHo) ri * fsc 0Ύ p and pharmaceutically acceptable salts thereof, wherein R50 is hydrogen or Cf_4 alkyl, A51 is oxygen, sulfur or -NR52- a group of formula wherein R52 is hydrogen or Cf_4 alkyl; A50 corresponds to (i) a mono or bicyclic aromatic ring which may have one or more nitrogen, oxygen or sulfur atoms, (ii) a cycloalkendenyl group, (iii) an acyclic bridge having a one, two or three atomic chain between the cyclobutendio.no group and X.50, the described chain is a chain of one or two carbon atoms or a single carbon atom and one or more atoms of nitrogen, oxygen or sulfur; or (iv) a bond; X50 is a bond or linking group linking a chain of one or two atoms in length between A50 and B50; Bs0 is a mono or bicyclic aromatic ring having one or more nitrogen, oxygen or sulfur atoms, r is an integer from 1 to 6; o Het is a ring system which may contain one or more nitrogen, oxygen or sulfur atoms or is a derivative of a phosphonate, phosphinate or amino (wherein A50, X50, B50 and Het may be substituted).

A50 group, it is best to select from groups (i) to (xi) given above (where in each case Z50 is a connection to X50, while other free valences are joined to the cyclobutendione group).

(i) in which R70 and R71 each independently is hydrogen, hydroxy, alkyl (may be substituted by halogen, C3_8 cycloalkyl or phenyl, C3.12 cycloalkyl or phenyl (both of which may be substituted by halogen), C1_6 alkyl or Ο3_6 alkoxy or R70 and R71 together form a 3 or 7 membered carbocycle (which may have one or two Ο7_6 alkyl, 0Σ_6 alkoxyl, phenyl, hydroxyl or halogen substituents);

Ar, * 81 * 60 (ii), * 80 in which A6U is nitrogen or methine; AS1 is imine, oxygen or sulfur, and R80 and R81 each is hydrogen, halogen, fluorine, nitro, cyano, alkyl, cOf 2 (preferably C2_4) alkenyl, alkylthio, mono-, di- or trihalogen- (C4.6 alkyl), hydroxyalkyl, oxoalkyl, carboxyl or esterified carboxyl group, or when R80 and R81 is adjacent to carbon atoms, it is R80 and R81 may together form 1,3-butadienylene, thereby fusing a fused aromatic ring;

(iii)

OR

in which R90-R9each is independently hydrogen, halo, fluoro, nitro, amino, C4_4 alkylamino, di {C4_4 alkyl) amino, trifluoromethyl, C4_4 alkyl, C4_4 alkoxyl or -SO2NHR98 a group of formula (where Rss is hydrogen, Cj_5 alkyl, aryl or arylmethyl);

(iv) wherein -A70-A71-A72-A73- is

- C (O) N (R103) C (R100) N-, -C (R100) NC (O) N (R103)-,

- N (R103) C (O) NC (R100) -, -NC (R100) N (R103) C (O) -,

- C (O) N (R103) NC (R 100) - or

- C (R100) NN (R103) C (O) -;

formula group in which Rioo_rio 2 is each independently hydrogen, halogen, fluoro, nitro, amino, C3_4 alkylamino, di {C1_4 alkyl) amino, trifluoromethyl, Cx_4 alkyl, C1-4 alkoxyl or SO2NHR104 a group of formula (wherein R104 is hydrogen, Cx_6 alkyl, aryl, arylmethyl or -CH2OC (O) CH3 formula group) or when two of R100, R101 and R102 being attached to adjacent carbon atoms, they can combine to form a phenyl or naphthyl ring; o R103 is hydrogen, Οχ_4 alkyl, phenyl or phenylmethyl (wherein phenyl or phenylmethyl may be substituted with one or two substituents, optionally halogen, fluorine, C1.4 alkyl, C3_4 alkoxyl, trifluoromethyl, amino, Cx_4 alkylamino, di {C3_4 alkyl) amino or -CO2R104 of formula '(wherein R104 is defined above);

A8O0)AS3 a81~a82 in which -AS0-A81-A82-A83- is “Y50-C (Ruo) C (Rm) C (Ζ82)

- C (R310) C (Rm) C (Z52) Y50-, a group of formulas in which Y50 is oxygen, sulfur, sulfinyl or sulfonyl; Rn0 and R1U each is independently hydrogen, halogen, fluoro, nitro, amino, formyl, C 1-4 alkylamino, di (Cx_4 alkyl) amino, trifluoromethyl, C1_7 alkyl, C 1-4 alkoxyl, C3_7 cycloalkyl or -SO2NHR112, -O (CH2) CO (CH2) dCH3, ~ (CH2)d O (CH2)dCH3, - (CH2) N (R112)2, -CH (OR112) (C 1-7 alkyl), -CO2R112,

-CH = CHR112, -CH2CRu2= C (R112)2, - (CH2) eNHC (O) R112 - (Cx_4) alkylaryl or -CH (R112)2 a group of formula (where R112 is hydrogen, Cx_6 alkyl, arylmethyl or aryl, c is an integer from 1 to 3, d is an integer from 1 to 5, oe is O or an integer from 1 to 2) or when R110 and Rin when attached to adjacent carbon atoms, they can be bonded to form a phenyl or naphthyl ring; and where Z52 represents the other free valence described above;

R120~~ A90 r121 (Vi) wherein A90 is a bond, oxygen, sulfur, sulfinyl or sulfonyl, methylene or -NR122 - a group of formulas, where (R122 is hydrogen, Cx_6 alkyl, aryl, aryl (C2_7) alkylcarbonyl, (C1_6) alkylcarbonyl, [(C2_5) alkenyl) methylene, [(C2_5) alkynyl] methylene or arylmethylene); o R120 and R121 each is hydrogen, 0χ_6 alkyl (may be aryl or C2_7 cycloakyl substituted), aryl (capable of up to 5 substituents optionally selected from halogen, fluorine, C 1-8 alkyl, (C2_5 alkenyl) methylene, (C2_5 alkynyl) methylene, CTs alkoxyl, alkylthio, nitro, trifluoromethyl, hydroxyl, nitro or -CO2R123 groups of formula (where R123 is hydrogen, Ο2_6 alkyl, aryl or arylmethylene)), or aryl (C1_2) alkyl (capable of up to 5 »substituents optionally selected from halogen, fluorine, Ο3_6 alkyl, (C2_5 alkenyl) methylene, (C2-5 alkynyl) methylene, (Τ5 alkoxy, alkylthio, nitro, trifluoromethyl, hydroxyl or -CO2R123 groups of formula (where R123 is as previously described), or C3_7 cycloalkyl.

Rm.

(vii) wherein R130, Ri31 and R132 each independently hydrogen, halogen, fluorine, nitrogen, amino, Cx_4 alkylamino, di {CL_4 alkyl) amino, trifluoromethyl,4 alkyl, Cx_4 aiLT 3612 B ί

coxyl or -SO2NHR133 a group of formula (where R133 is hydrogen, C1_5 alkyl, aryl or arylmethyl);

R

OR \ - {k

R141

100 (viii), 'Ί4 2 in which R140 is hydrogen, alkyl, aryl (denoting phenyl which may be substituted by halogen, fluorine, alkyl, alkoxyl, alkylthio, hydroxyl, alkanoyl, nitro, amino, dialkylamine, -trifluoromethyl, C3_7 cycloalkyl or arylalkyl; A100 is nitrogen (where the dashed line represents a bond,) or nitrogen substituted as an independently selected group from R140 a list of values (where the dotted line is not a connection); o R141 and R142 each independently hydrogen, halogen, fluorine, nitro, amino,4 alkylamino, di (C 1-4)4 alkyl) amino, trifluoromethyl, Cx_4 alkyl, C3_4 alkoxyl or -SO2NHR143 group of formula (where hydrogen, Ο7_5 alkyl or arylmethylene);

R143 is

r150 (ix) in which R1S0 is hydrogen, C7_6 alkyl or Y60 a group of formula wherein Y60 is phenyl or 1- or 2LT 3612B naphthyl (each may be methyl, methoxy, hydroxyl, bromine, chlorine, fluorine, nitro, amino, diethylamino, methylthio or sulfhydryl substituted), Cx_6 alkyl-Y60formula group (wherein Y60 is described above), Y61 formula group (wherein Y61 is a 5- or 6-membered ring or an 8-, 9- or 10-membered bicyclic ring containing one or more heteroatoms optionally selected from nitrogen, oxygen and sulfur (including, but not limited to, pyrrole, imidazole, thiophene, furan, pyridine, thiazole) , indole, morpholine and isoquinoline)) which can be replaced by halogen, fluorine, Cx_6 alkyl, Cx_6 alkoxyl or hydroxyl; or a C 1 -C 6 -alkyl-Y 4 - formula group (wherein Y61 is described above);

*111 Z50 Ano (x), in which Am is oxygen, sulfur imine or methylene; if Am is oxygen, sulfur or imine, then A110 is -CR160R161- a group of formulas, and if A1U is methylene, it is A110 is either nitrogen or -CR160Ri6i_ a group of the formula wherein R160 and R161 each independently is hydrogen, C 1-4 alkyl, C3_10 alkenyl, C3_10 alkynyl, C3_8 cycloalkyl, C4_10 c'cycloalkylalkyl, C5_10 cycloalkylalkenyl, C5.10 cycloalkylalkynyl or aryl which may have one or two halogen, Cx_4 alkyl or Cx_4 alkoxyl substituent;

OH (CH2) b '50? 50

-V (xi) wherein b is 2, 3 or 4; or o

j'V ·

N— Z (xii), '171 wherein R171 is hydrogen, halogen, fluorine, alkyl or Cx_4 alkoxyl; o R170 is hydrogen, halogen, fluorine, C4_4 alkyl, C4_4 alkoxyl, nitro, C4_4 acyloxy, carboxy (can be esterified), phenyl, furyl or -NHSO2Me, the NHSO2CF.3, -SO?NH2 or -CONHR172 a group of formula (wherein R172 is hydrogen, methyl or benzyl).

Accordingly, when X50 is a linking group, it being carbonyl, oxygen, sulfur, vinylene, difluorvinylene, monofluorvinylene, ethylene, perfluoroethylene, oxymethylene, thiomethylene or -NR53-, -CONR54-,

-NR54CO-, -nhcr55r56-, no55so2-, -so2no55-, CR55R56NH-,

-CH (OR57) ~, -CH (OCOR58) or -C (NR59) - a group of formulas (where R53 is hydrogen, C2_4 acyl, C4_6 alkyl, allyl, C3_6 cycloalkyl, phenyl or benzyl, R54 is hydrogen or C4_4 alkyl, R55 is hydrogen, Ci_5 alkyl, phenyl or benzyl, R56 is hydrogen or C4_14 alkyl, R57 is hydrogen, C ^ .g alkyl, Ο7_8 perfluoroalkyl, C3_6 cycloalkyl, phenyl or benzyl, R58 is hydrogen, Ο4_6 alkyl, C3_6 cycloalkyl, phenyl or benzyl, R59 is -NR55R56, -OR56, NHC (O) NH2, -NHC (S) NH2, -NHSO2 benzyl or -NHSO2 a phenyl group of formula (wherein R55 and R56 are described above);

B50 group is best selected from the groups xv xxii described above (where, in each case, Z51 is a connection to

X50, and the other free valence is combined with - {CH2) R-Het group);

in which R180 is hydrogen, halogen (preferably bromine), fluorine, Cx <_6> alkyl, C2_6 alkenyl, C3_g fluoroalkyl, C1_6 alkoxyl, formyl, carboxyl or -COR183 a group of formula (where R183 means C3_g alkyl, C2_6 alkenyl, alkoxyl or -NR184R185 formula group (where

R184 and R185 each being hydrogen or alkyl, or taken together to form a saturated heterocyclic ring containing. 5 or 6 ring members and capable of having one oxygen atom in the ring)); R181 and R182 each independently hydrogen, halogen, fluorine, nitro, amino, C3_4 alkylamino, di {C3_4 alkyl) amino, trifluoromethyl, Cy-4 alkyl, C3_4 alkoxyl or -SO2NHR191 a group of the formula (containing hydrogen, alkyl, aryl or arylmethyl); o A120 is oxygen, sulfur or -NR186a group of the formula wherein R186 is hydrogen or a group selected from C 1-4 alkyl, C3_6 alkenyl, C 1-46 alkoxyl or -COR19? or -SO2R188 a group of the formula [wherein R187 and Ri88 each is Cj.g alkyl, C2_6 alkenyl, C 1-8 alkoxyl or -NR189R190 a group of formula (wherein R189 and R190, which may be the same or different, each represents a hydrogen atom or a Ci4 alkyl group, or together form a saturated heterocyclic ring having 5 or 6 ring members which may have one oxygen atom in the ring)]} and wherein the free valence described above is preferably in the 5 position of the ring;

KjoO

(xvi) wherein R200 and R20each individually selected from R above180 and R202 and R 203 k are each independently selected from the preceding R181 defining a designated list and wherein the free valence described above is preferably at the 5-position of the ring;

(xvii) wherein R210, R2n and R 212 are each independently van 25 denyl, halogen, fluoro, nitro, C 1-4 alkyl, C 1-4 acyloxy, C3_6 cycloalkyl, C2_6 alkoxyl, hydroxy -C3_4 ally, ^ _4 alkylthio, Cx_4 alkylsulfinyl, C2_4 alkylsulfonyl, trifluoromethyl, aryl, furyl or

-NHSO2R213, -SO2NHR213 or -NR213R214 a group of the formula wherein R213 and R214 each independently is hydrogen, C 1-8 alkyl, benzyl or phenyl, or when R210 and ^ • 211 are attached to adjacent carbon atoms so that together they can form an aromatic ring; o A130 is carbonyl, methylene or -CH (CO2 C3_4 alkyl) -, -CH (CO2H) -,

-CH (CN) -, -CH (tetrazolyl) - or -CH (CONHSO2R2i5) - a group of formula wherein R215 is aryl, heteroaryl, C3_7 cycloalkyl or C4_4 alkyl (which may be substituted by aryl, heteroaryl, hydroxyl, sulfhydryl, alkyl,4 alkoxyl, C4_4 alkylthio, methyl, halogen, fluoro, nitro, carboxyl, carboxy (C4_4 alkyl), amino, di (C4_4 alkyl) amino or -PO3H or -PO (OH) [O- (C 1-6 alkyl)], and wherein the free valence described above is preferably in the 5-position of the ring;

140 (xviii) wherein R22and R 221 are each hydrogen, halogen, fluoro, nitro, amino, C4.4 alkylamino, di {C4_4 alkyl) amino, trifluoromethyl, C4_4 alkyl, C3_4 alkoxyl or -SO2NHR228 a group of formula (wherein R228 is hydrogen, C3-5 alkyl, aryl or arylmethyl); o A140-A141- is -N = CR222-, -CR222= CR223- or -CHR222-CHR223- a group of formulas;

in which R222 and R223 each is independently hydrogen, halo, fluoro, alkyl, haloalkyl; C3_7 cycloalkyl or arylalkyl (wherein aryl is phenyl which may be substituted by halogen, fluoro, alkyl, alkoxyl, alkylthio, hydroxyl, alkanoyl, nitro, amino, trifluoromethyl, alkylamine or dialkylamine or a group of formula -COR224 (wherein R224 is hydrogen, C4_6 alkyl, C3_6 cycloalkyl or -OR225 or -NR226R227th a group of the formula wherein R225 is oxygen, C4_6 alkyl, C3.6 cycloalkyl, aryl, arylalkyl or a 5-7 membered carbocyclic ring which may have another 5-7 membered carbocyclic ring attached thereto and R226th and R 227 are each independently hydrogen, C4_4 alkyl, phenyl, benzyl, α-methylbenzyl, or together form C3_4 a cyclic group which may contain nitrogen and / or oxygen in the ring) and wherein the free valence described above is in the 5 position of the ring;

in which R230 and R231 each independently hydrogen, halogen, fluorine, nitro, amino, C4_4 alkylamino, di {Cx_4 alkyl) amino, trifluoromethyl, Cf-4 alkyl, Cj.4 alkoxyl or -SO2NHR234 a group of formula (where R234 is hydrogen, alkyl, aryl or arylmethyl);

A15o and A151 each independently is oxygen, sulfur or -NR232- or -CR232R233- a group of formulas in which R232 and R233 each is hydrogen, C4_6 alkyl, C3_6 cycloalkyl, phenyl or benzyl and wherein the free valence described above is in the 5-position of the ring;

(xx) wherein -A160-A161is = C {R232) -N = or = NC (R232) = a group of the formula and wherein R230z R23i have R232 each independently hydrogen, halogen, fluorine, nitro, amino, C4_4 alkyl, Cf_4 alkylamino, di {C4_4 alkyl) amino, Cf-4 alkoxyl, trifluoromethyl or -SO2NHR233 a group of formula (wherein R233 is hydrogen, Cf_5 alkyl, aryl or arylmethyl);

in which R240 ~ R243 each independently hydrogen, halogen, fluorine, Cx_6 alkyl, Cx_6 perfluoroalkyl, Cx_6 alkoxyl or Cx_6 alkoxylalkyl-az; or

in which -A170= A171 - is -C {R250) = N- or -C (R251) = C (R252) a group of the formula wherein R250 is hydrogen or Cx_7 alkyl, and R251 and R252 each is hydrogen, halogen, fluorine, Cx_7 alkyl, Cx_7 alkoxyl, C2_7 alkenyloxyl, phenoxyl, benzyloxyl, trifluoromethyl or -S (O)f-R253 a group of the formula (wherein f is O or an integer from 1 to 2 and R253 is hydrogen or Cx_7 alkyl).

Preferably, r is 1.

Het is preferably a single group of any given formula, wherein in each case the symbols are as defined in the corresponding patent publication cited in brackets. The disclosed and / or specific heterocycles are as defined in the relevant patent publication (s):

(DE-A-3928177, EP-A-0392317; THOMAE)

(DE-A-4006692; SCHERING)

(DE-A-4031287, DE-A-4105324 and EP-A-0468470; THOMAE) R\ (DE-A-4031601, DE-A-4105827 »(and EP-A-0470543; THOMAE)

........ n, (DE-A-4032522 and DE-A-4034728; SCHERING) cn r ~ σι σ

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Het is accordingly a heterocyclic group which forms a closed organic ring system whose ring system contains one or more oxygen, nitrogen or sulfur atoms. Het primarily forms a stable monocyclic ring having a 5- to 7-membered or saturated or unsaturated bicyclic heterocyclic ring having from 7 to 10 members and containing up to five, preferably three, nitrogen, oxygen and / or sulfur atoms (wherein any nitrogen atom may be a ketine chain), and including any bicyclic group in which any of the mono-heterocyclic rings defined above is linked to a benzene ring, and wherein the ring may be substituted. The following heterocyclic groups include, but are not limited to: thienyl, furyl, pyranyl, chromenyl, xanthenyl, pyrrolyl, 2H-pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, indolyl, indazolyl, purinyl, chinolyl, chinolyl , quinoxalinyl, quinazolinyl, cinolinyl, pteridinyl, isothiazolyl, isoxazolyl, furazanyl, piperazinyl, pyrrolidinyl, oxazolyl, triazolyl and tetrazolyl and any of their isomers, and where appropriate in the context, dihydro, tet25 rahydro, and their mono-, di- and tri-derivatives. Heterocyclic groups in the present invention also include fused rings based on any combination of up to three ring rings and / or benzene or naphthalene rings discussed above. Preferably, these heterocycles are based on benzimidazole and imidazopyridine.

Groups of formulas i, ii, iii, iv, viii, ix, x, xi and xii are described in (a) (Bayer); b) EP-A-0480204 (Fujisawa); c) (Merck); d) EP-A-0512676 (Merck); e) EP-A-0512675 (Merck);

f) WO-A-9112001 (Merck); g) WO-A-9215577 (Searle);

V, VI, VII, EP-A-0513533 US-A-5124335

h) EP-A-0501269 (Matter); i) WO-A-9206081 (Warner Lambert); j) US-A-5191086 (Matter); k) DE-A-4006693 (Schering) and 1) EP-A-0253310 (Du Pont) respectively, and preferably when these groups are as described in these publications.

Groups of formulas xv, xvi, xvii, xviii, xix, xx, xxi and

0514193,

0514197, (Glaxo);

(Merck);

(Squibb) (Merck) preferably xxii are described m) WO-A-9209600, EP-AEP-A-0514192, EP-A-043709, EP-A-0514198, EP-A-

<td>n)</td><td>EP-A-0429257</td><td>(Glaxo);</td><td> 0)</td><td>EP-A-0517357</td>

<td>P)</td><td>EP-A-0488532</td><td>(Squibb);</td><td>q)</td><td>US-A-5190942</td>

<td>; r)</td><td>EP-A-0508393</td><td>(Searie);</td><td>S)</td><td>EP-A-0400974</td>

<td>and t)</td><td>EP-A-0528762</td><td>(Ciba Geigy)</td><td colspan="2">respectively, and</td>

wherein said groups are as described in these publications.

Het is preferably one of the groups of formula xxv, xxvi, xxvii or xxviii, shown below:

br, f

. FU-,:26i (XXV), in which R260 is hydrogen or alkyl and R261, R262 and R2£ 3 each is hydrogen, C1_4 alkyl, nitro, fluoro, chloro, bromo, cyano, formyl or -sonr264 , -so2no265r266 or -COR267 a group of formula (wherein R264 , R265 and R266 each is independently hydrogen or alkyl, n is 1 or 2, and R is267 yr3

C! _4 alkyl or -OR268 or -NR269R270 a group of the formula wherein R268z R269and REach is independently hydrogen or C 1-4 alkyl);

T --- 36

UIR28! (xxvi) in which R28o Yra hydrogen or Cx_6 alkyl; R281 is * hydrogen, chlorine, fluorinated (preferably perfluorinated) Cx_2 alkyl (preferably trifluoromethyl or pentafluoroethyl, aryl, Cx_4 alkyl, Cx_4 alkylsulfinyl, Cx_4 alkylsulfonyl, Cx_4 alkylthio, arylsulfinyl, arylsulfonyl, arylthio, arylmethylsulfinyl, arylmethylsulfonyl phenyl or arylmethylthio (wherein aryl represents phenyl or 1-; or 2-naphthyl, each of which may be substituted by Cr_4 alkyl, Cx_4 alkoxyl or fluorine, chlorine or bromine; and R282 is hydroxymethyl, formyl, carboxyl, C2_4 alkoxymethyl, C2-4 alkoxycarbonyl or bacarboxymethyl 20;

R290

/ 291 pR292 (xxvii) in which R290 is hydrogen or Cx_6 alkyl, and R291 and 30 ^ 292 are each independently hydrogen, Cx_4 alkyl or phenyl (may be substituted by Cx_4 alkyl, Cx_4 alkoxyl, fluorine, chlorine or bromine, or R291 and R292 together with the carbon atom to which they are attached form C3_6 a spirocycloalkyl ring; orR30I

XN5>^-R300 IP Ί

I £ lS0 (xxviii), in which A180 is oxygen, sulfur or -NR302 - a group of formulas in which R302 is Cx_6 alkyl, A181 is nitrogen or methine,300 is hydrogen, Cx.4 alkyl, Cx_4 alkylthio or aryl Cx_4 alkyl (where aryl represents phenyl which may be substituted by Cx_4 alkyl, Cx_4 alkoxyl, or fluorine, chlorine or bromine; and R30I is hydrogen, carboxyl, carbamoyl or -C (O) NR303R304 a group of formula (wherein R303 and R304 each individually is Cx_4 alkyl or hydroxy-substituted Cx_4 alkyl, or Cx_4 alkyl).

In groups of formula xxv, R260 better is ethyl, R262 is hydrogen, and R261 and R263 both are methyl.

In groups of formula xxvi, R280 better is butiias, and R281 is chlorine.

In groups of formula xxvii, R290 better is butiias, and R291 and R292 together with the carbon atom to which they are attached form a ring of spirocycloheptane.

In groups of formula xxviii, A1S0 preferably is -NBu Formula group, R300 is hydrogen, and R301 is a carboxyl group.

In the priority compounds of formula I A50 is a group of formula (iii) above, X50 is a bond, B50 is a group of the formula (xxi) given above, and the Het heterocyclic ring is as previously defined.

T

Priority compounds of formula I are compounds of formula II

in which R130 is hydrogen or Cx_4 alkyl;

Ai9o is oxygen, sulfur or -NR319- a group of formulas in which R319 is hydrogen or Cx_4 alkyl;

and R314 each is individually vandeCx_4 alkoxyl, nitro, cyano, carboxyl, C2-4 alkoxycarbonyl, Cx_4 alkylthio, Cx_4 alkylsulfinyl, Cx_4 alkylsulfonyl, phenyl (can be substituted by Cx_4 alkyl, Cx_4 alkoxyl, fluorine, chlorine or bromine, Cx_4 alkylsulfonylamino or Cx_6 alkylaminosulfonyl group; R315 is hydrogen or Cx_4 alkyl; o R316, R31- and R318 how many311 *

312 * '313 Nile, Fluorine, Chlorine, Bromine, Cx_4 alkyl, ^x_4 one individually fluorine, chlorine, - SO2NR321R322 or hydrogen, 0χ_4 alkyl, nitro, bromine, cyano, formyl or -SOSORq gx'32O *

-COR323 a group of formula (wherein R320 * R321 * R322 are each independently hydrogen or C)x_4 alkyl, g is 1 or 2, and R is323 is Cx_4 alkyl or -OR324 or -NR325R326th a group of the formula wherein R324, R325 and R 326 are each independently hydrogen or Cx_4 alkyl);

and pharmaceutically acceptable salts thereof.

Particularly preferred compounds of formula I are represented by formula III

III in which A19o, R310, R315, R316, R317 and R318 each as defined above;

and pharmaceutically acceptable salts thereof.

Particularly preferred compounds of formula I are represented by formula IV:

paIV, in which A190 and R310 is as defined above;

and pharmaceutically acceptable salts thereof.

Priority compounds of formulas II, III and IV contain oxygen and R310 is hydrogen.

Further preferred compounds of formula I are represented by formula V

and pharmaceutically acceptable salts thereof;

in which R330 is C2.x0 alkyl, C3_x0 alkenyl or (CH2)hC3.6 cycloalkyl or - (CH2) h-phenyl groups wherein h is O or an integer from 1 to 8 (capable of having up to three Cx_6 alkyl, nitro, cyano, halo, fluoro, Cx_3 perfluoroalkyl, Cx_3 perfluoroalkylsulfonyl, Cx_6 alkylsulfonyl, Cx_6 alkylthio, hydroxyl, Cx_6 alkoxyl, or - NR33.jP.335, —CO2R334 , —CONR334R335, - PO {OR334) 2,

-NR334CHO, -NR334O (Cx_6 alkyl) or -NR334COR336 of the formula groups (where R334 and R335 each independently is hydrogen or Cx_4 alkyl, and R336 is Cx_3 perfluoroalkyl);

A200 is a bond, sulfur or oxygen; R33x is hydrogen, halogen, fluorine, formyl, nitro, Cx_3 perfluoroalkyl, cyano, Cx_6 alkyl, phenyl, hydroxymethyl or -CO2R338, -CONR338R339 or -NR338R339 a group of formula (wherein R338 and R339 each independently is hydrogen or Cx_4 alkyl);

m is O or an integer from 1 to 4;

B60 is 1,4-phenylene, 1,4-naphthylene or 2,5-pyridylene, which may contain one or more halogens,

I fluoro, Cf_4 alkyl, nitro, hydroxyl, Cx_4 alkoxyl, Cf_4 alkylsulfonyl, Cx_3 perfluoroalkyl, nitrile or -SO2NiIR338, -NHSO2R338 or -CONR338R33g of the formula (where R338 and R33s each is as defined above);

A201 is oxygen, sulfur or -NR337- a group of formulas (in which R337 is hydrogen or Cx.4 alkyl);

R333 is hydrogen or Cf_4 alkyl;

0 r332 Yra group selected from the xxxxxxiii groups above:

R34O'X ____ ^R341 <342 (XXX), nitro, Cj., 3 Cf_6 in an alkyl radical R340 and R341 each is hydrogen, Cf_6 alkyl, C3_6 cycloalkyl or phenyl-Y70-, biphenyl-Y70-, naphthyl-Y70-, thienil-Y70-, furyl-Y70-, pyridyl-Y70-, pyrazolyl-Y70-, imidazolyl-Y70-, pyrrolyl-Y70-, triazolyl-Y70-, oxazolyl-Y70-, isoxazolyl-Y70-, thiazolyl-Y70- or tetrazolyl-Y70- a group of the formula wherein each aryl or heteroaryl group may contain hydroxyl, perfluoroalkyl, Cx_3 perfluoroalkylsulfonyl, thio, Cfg alkylsulfonyl, Cx_6 alkyl, Cx_6 alkoxyl, halogen, fluorine or -NR343R344 , -CO2R343, -SO2NHR343, -SO3K, -CONR343R344 , -NR343CHO, -NR343CO (Cf_3 perfluoroalkyl) or -NR343CO (Cj_6 alkyl) substituents on the formula wherein R343 and R344 each independently is hydrogen or Cx_6 alkyl; Y70 is a bond, oxygen, sulfur or Cx_6 alkylene which may be substituted by phenyl or benzyl (wherein each phenyl or benzyl group may contain halogen, nitro, trifluoromethyl, Cx_6 alkyl, Οχ_6 alkokT silyl, cyano or -CO2R345 a group of the formula wherein R345 is hydrogen or Cx_4 alkyl); R342 is

-Y71-COOR346 (where R346 is hydrogen, C4_6 alkyl or

2-di (C 1-6 alkyl) amino-2-oxoethyl); -Y71-CONR347R348 (where R347 and R348 each independently is hydrogen or C7_6 alkyl), or -Y71-tetrazol-5-yl (where Y71 is a bond, vinylene, methylenoxymethylene, methylene (each may be substituted as C3_e alkyl, one or two benzyl groups, thienylmethyl, furylmethyl), or -C (O) NHCHR349- a group of formulas (where R349 is hydrogen, Cx_6 alkyl, phenyl, benzyl, thienylmethyl or furylmethyl));

^ 350 ^ 351 - {CH2) n - -N - to -R352r353 (xxxi) in which R350 and R351 each individually hydrogen or Ο4_6 alkyl; R352 is hydrogen, Ci_8 alkyl or thienyl-Y80~, furyl-Y80-, pyrazolyl-Y80-, imidazolyl-YB0-, thiazolyl-Y80-, pyridyl-Y80-, tetrazolyl-Y80-, pyrrolyl-Y80-, triazolyl-Y80, oxazolyl-Y80-, isoxazolyl-Y80- or phenyl-Y80- formula group (where Y80 is a bond or C3_6 alkylene) in which each aryl or heteroaryl group may have Cx_6 alkyl, C4_6 alkoxyl, C4-4 perfluoroalkyl, C7_6 alkylthio, C7_6 alkylsulfonyl, C3_4 perfluoroalkylsulfonyl, halogen, hydroxyl, nitro or -nr354r355, -co2r354, -so2nhr354, -so3h, -conr354r355,

-NR354CHO, -NR354COR356 or -NR354COC1_6 alkyl group substitution (where R354 and R355 each independently is hydrogen or C3_4 alkyl, and R356 is C4_4 perfluoroalkyl); R353 is -CO2R358, -CONR358R357 or a group of the formula tetrazol-5il (wherein R357 and R358 each is hydrogen or C 1-4 alkyl); on is O or an integer from 1 to 5;

^ 3 60 - (CH2) nN -------- j—K?, ;; 2 tCH2 3 pU36, (xxxii) in which R360 is hydrogen, C4_6 alkyl, C3.6 alkenyl, alkylcarbonyl or ~ (CH2)0_3 phenyl group of formula;

R361 is hydrogen, C4_6 alkyl, C3_6 alkenyl or - (CH2)0-3-phenyl; R362 is -CO2R364 , -CONHR364R365 a group of formula (where R364 and R365 each independently is hydrogen or C4_6 alkyl) or tetrazol-5-yl;

n and p are each independently O or an integer from 1 to 4; o

R363 is phenyl, naphthyl, thienyl, furyl, pyridyl, pyrimidyl, imidazolyl, thiazolyl, triazolyl, tetrazolyl, pyrazolyl, pyrrolyl, oxazolyl or isoxazolyl, wherein each aryl or heteroaryl group may be substituted by C4_6 alkyl, Cj_6 alkoxyl, halogen, fluorine, hydroxyl, nitro, Cx_4 perf skeletal bone, C4_6 alkylsulfonyl, C4_4 perfluoroalkylsulfonyl, C1.6 alkylthio or -NR366R367, -CO2R366,

-CONR366R

366^367,

-SO3H, -SO2NHR366, -NR366CHO; -NR36eCO (C4_4 perfluoroalkyl) or -NRCOC1G6 alkyl (where R366 and R367 each independently is hydrogen or C4.6 alkyl);

(xxxiii) in which R370 is -CO2R373, CONR373R374 or a tetrazol-5-yl group of the formula; A210 is a bond or a carbonyl group; R371 is hydrogen, Cx_8 alkyl, C3_6 cycloalkyl, phenyl, phenyl Cx_4 alkylene or biphenyl or biphenyl Cx_3 alkylene, wherein each phenyl group may be substituted with up to three substituents selected from Cx_6 alkyl, nitro, halogen, fluoro, hydroxyl, Cx_6 alkyl or NR375R376 '-CO2R376 or -CONR375R376 formula groups (where

R375 and R376 each independently is hydrogen or Cx_4 alkyl); R372 is hydrogen or Cx_6 alkyl; R373 and R374 each is hydrogen, Cx_4 alkyl or - (CH2)O_4 phenyl group of formula; on is C or an integer from 1 to 4.

In priority compounds of formula V B60 is 1,4-phenylene which may be substituted as defined above.

Priority compounds of formula V are represented by formula VI:

VI R333~ α201 in which R330, A200, R331, R332, A201 and R333 each individually as defined above, and R400 and R401 each is hydrogen, halogen, fluorine,

Cx_4 alkyl, nitro, hydroxyl, Cx_4 alkoxyl, Cx_4 alkylsulfonyl, Cx_3 perfluoroalkyl, nitrile or

-SO2NHR402, -NHSO2R402 or -CONR402R403 a group of formula (wherein R402 and R403 each independently is hydrogen or Cx_4 alkyl); and the other substituents are as previously defined.

Unless otherwise indicated, the previously used alkyl, alkenyl and alkynyl mean linear or branched radicals having from 1 to 10 carbon atoms, preferably from 1 to 6 carbon atoms, and more preferably from 1 to 4 carbon atoms.

Unless otherwise indicated, the term aryl as used herein refers to phenyl or naphthyl which may contain halogen, fluorine, Cx_4 alkyl, Cx_4 alkoxy, nitro, trifluoromethyl, Cx_4 alkylthio, hydroxy, amino, di (Cx_4 alkyl) amino, carboxyl or esterified Cx_4 alkyl carboxyl groups as substituents.

Unless otherwise indicated, the term heteroaryl as used herein refers to a five or six membered aromatic ring containing up to 3 oxygen, nitrogen and / or sulfur atoms and capable of containing hydroxyl, sulfhydryl, Cx_4 alkyl, Cx_4 alkoxyl, trifluoromethyl, halogen, fluoro, nitro, carboxyl, esterified Cx.4 alkyl carboxyl, amino, Cx_4 alkylamino or di {Cx_4 alkyl) amino substituent.

It will be understood that a group having 3 or more carbon atoms may be linear or branched, for example, propyl includes n-propyl and isopropyl and butyl includes n-butyl, secondary, butyl, isobutyl and tertiary, butyl. the term halogen means bromine, chlorine or iodine.

T

Specific compounds of the present invention include:

3- [4 '- (2-ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyrid-3-ylmethyl) biphenyl-2-yl] -4-isopropoxycyclobut-3-en-1, 2dion;

3- [4 '- (2-Ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyrid-3-ylmethyl) biphenyl-2-yl] -4-hydroxycyclobut-3-en-1, 2-dione;

3-Amino-4- [4 '- (2-ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyrid-3-ylmethyl) biphenyl-2-yl] cyclobut-3-en-1 , 2-dione;

3- [4 '- (5,7-Dimethyl-2-propyl-3H-imidazo [4,5-b] pyrid-3-ylmethyl) -biphenyl-2-yl] -4-isopropoxycyclobut-3-ene-1,2-dione;

3- [4 '- (5,7-dimethyl-2-propyl-3H-imidazo [4,5-b] pyrid-3-ylmethyl) biphenyl-2-yl] -4-hydroxycyclobut-3-ene-1,2-dione;

2-ethyl-3- [21-isopropoxy-3,4-dioxocyclobut-1-en-yl) biphenyl-4-ylmethyl] -5,7, N, N-tetramethyl-3H-imidazo [4,5-b] pyridine-6-sulfonamide;

2-ethyl-3- [2 '- (2-hydroxy-3,4-dioxocyclobut-1-enyl) biphenyl-4-ylmethyl] -5,7, N, N-tetramethyl-3H-imidazo [4 , 5-b] pyridine-6-sulfonamide;

3- [4 '- (6-Chloro-2-ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyrid-3-ylmethyl) -biphenyl-2-yl] -4-hydroxy-cyclobut-3-ene , 2-dione;

2- [4 '- (2-Ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyrid-3-ylmethyl) -biphenyl-2-yl] -3,4-dioxocyclobut-1-en- l -yloxymef 'til pivalate;

4-ethyl-1- [2 '- (3,4-dioxo-2-isopropoxycyclobut-1-enyl) biphenyl-4-ylmethyl] -2-propyl-1H-imidazole-5-carboxaldehyde;

4-ethyl-1- [2 '- (2-hydroxy-3,4-dioxocyclobut-1-en-1-yl) biphenyl-4-ylmethyl] -2-propyl-1H-imidazole-5-carboxaldehyde;

3-Dimethylamino-4- [4 '- (2-ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyrid-3-ylmethyl) biphenyl-2-yl] cyclobut-3-en-1 , 2dion;

1- [2- [4 '- (2-Ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyrid-3-ylmethyl) biphenyl-2-yl] -3,4-dioxocyclobut-1-ene -1-yloxy] -ethyl pivalate;

ethyl 4- [N-butyl-N- [2- (2-isopropoxy-3,4-dioxocyclobut-1-en-1-yl) biphenyl-4-ylmethyl] amino] pyrimidine-5-carboxylate;

ethyl 4- [N-butyl-N- [2 '- (2-hydroxy-3,4-dioxocyclobutyl-en-1-yl) biphenyl-4-ylmethylamino] pyrimidine-5-carboxylate;

4- [N-butyl-N- [2 '- (2-hydroxy-3,4-dioxocyclobut-1-en-yl) -biphenyl-4-ylmethylamino] pyrimidine-5-carboxylic acid;

3- [4 '- (2-Butyl-5-oxo-2-imidazoline-4-spirocyclopent-1-ylmethyl) biphenyl-2-yl] -4-isopropoxycyclobut-3-ene-1,2-dione;

3- [4 '- (2-Butyl-5-oxo-2-imidazolin-4-spirocyclopent-1-ylmethyl) biphenyl-2-yl] -4-hydroxycyclobut-3-ene-1,2-dione;

T

2-Butyl-4-chloro-1- [2 '- (2-isopropoxy-3,4-dioxocyclobut-1-en-1-yl) biphenyl-4-ylmethyl)] -1H-imidazole-5-carboxaldehyde;

2-butyl-4-chloro-1- [2 '- (2-hydroxy-3,4-dioxocyclobuten-1-yl) biphenyl-4-methyl)] -1H-imidazole-5-carboxaldehyde;

3- [4 '- (2-Butyl-4-chloro-5-hydroxymethyl-1H-imidazol-1-ylmethyl) biphenyl-2-yl] -4-isopropoxycyclobut-3-ene-1,2-dione;

methyl 2-butyl-4-chloro-1- [2 '- (2-isopropoxy-3,4-dioxocyclobut-1-en-1-yl) biphenyl-4-ylmethyl] -1H-imidazole-5-carboxylate;

methyl 2-butyl-4-chloro-1- [2 '- {2-hydroxy-3,4-dioxocyclobut-1-en-1-yl) biphenyl-4-methylmethyl] -1H-imidazole-5-carboxylate;

2-Butyl-4-chloro-1- [2 '- (2-hydroxy-3,4-dioxocyclobuten-1-yl) biphenyl-4-ylmethyl] -1H-imidazole-5-carboxylic acid; and (E) -2-Benzyl-3- [2-butyl-4-chloro-1- [4- (2-hydroxy-3,4-dioxocyclobut-1-en-1-ylbenzyl] -1H-imidazol-5-yl ] -propenoic acid;

and, where appropriate, pharmaceutically acceptable salts and / or solutions thereof, such as alkali metal salts, preferably sodium salts, and hydrochlorides.

The present invention also provides compounds of Formulas I-VI wherein Ay, A190 and A201 each is oxygen modified wherein R50, R310 and R333 is each group which can be hydrolyzed in vivo to leave compounds of formula I-VI wherein R50, R310 and

R333 is hydrogen, such groups including the groups xxxv of formula -choco ~ r411 1 r4) 0 (xxxv) in which R410 is hydrogen or C3_4 alkyl, and R411 is Cx_4 alkyl or C3_6 cycloalkyl; xxxvi formula groups

(χχχνί) in which R412 and fyn are each independently hydrogen or Cx_4 alkyl; and xxxvii formula groups

(χχχνϋ) in which R414 is hydrogen or Cx_4 alkyl.

Compounds containing such groups are generally described as pro-drugs. Scientists should be aware that many other groups that can be eliminated in vivo can be used in these pro-drugs. Examples of these groups and methods of introducing them can be found in H. Bundgaard's article (Drugs of the Future (1991), 16, 443) and in Design of Prodrugs (editor H. Bundgaart, 1985 Elsevier Science Publishers BV, Biomedical Division) and Pro-drugs as Novel Drug Delivery Systems (T. Higuchi and V. Stella, 1975, ACS Symposium Series 14, American Chemical Society, Wasbington DC). Except as otherwise stated, all of the above references to compounds of Formulas I-VI include, where possible, the following formulations of Formula I-VI compounds.

The compounds of formula I-VI with acids and alkalis form salts. The following references to compounds of formula I-VI include all of these pharmaceutically acceptable salts of compounds of formula I-VI. Particularly suitable salts of the compounds of the formula I-VI are, for example, alkali metal salts (such as sodium and potassium salts), alkaline earth metal salts (such as magnesium and calcium salts), aluminum and ammonium salts, salts with suitable organic bases such as such as alkylamines, N-methyl-D-glutamine, and salts with amino acids such as arginine and lysine. Inorganic acid salts such as hydrochlorides, hydrobromides, sulfates and phosphates, and organic acid salts such as maleate and fumarate are also suitable.

Scientists should be aware that certain compounds of Formulas I-VI, or salts thereof, have one or more chiral centers. When a compound of formula I-VI has a single chiral center, it can exist in two enantiomeric forms which can be obtained separately by methods known to the art. These methods typically involve the separation of diastereoisomeric salts or complexes by reformulation, which may be separated, for example, by crystallization; formation of diastereomeric derivatives which can be separated, for example, by crystallization, gas-liquid or liquid chromatography; selective isolation of one enantiomer by reaction with a specific enantiomeric reagent, such as enzymatic oxidation or reduction; or gas-liquid or liquid chromatography in a chiral environment, for example on a chiral support or in the presence of a chiral solvent. Optionally, specific enantiomers may be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts, or solvents, or by converting one enantiomer into another by asymmetric transformation. The present invention includes all enantiomers of Formulas I-VI and mixtures thereof. When a compound of formula I-VI has more than one chiral center, it may exist in diastereoisomeric forms. Diastereoisomers may be separated by methods known to those skilled in the art, such as chromatography or crystallization. The present invention includes all diastereoisomers of the compounds of Formulas I-VI and mixtures thereof. It will be appreciated that where the active phase is transformed using the separation procedures described above, a further step is required to convert the product into the active phase.

Certain compounds of Formulas I-VI or salts thereof may have more than one crystalline form and the present invention includes all crystalline forms and mixtures thereof.

Certain compounds of Formulas I-VI may have the form of zwitterions, and the present invention includes zwitterionic forms and mixtures thereof.

Certain compounds of Formulas I-VI, or salts thereof, may also exist in the form of solvates, for example, hydτ wheels, and the present invention includes all solvates and mixtures thereof.

The present invention also provides pharmaceutical compositions comprising the compounds of Formulas I-VI or salts thereof in association with a pharmaceutically acceptable diluent or carrier. Specific compounds that may be included in the compositions of the present invention are the novel compounds described above.

The term active compound as used hereinbefore refers to a compound of formula I-VI, more preferably of formula II. When used therapeutically, the active compound may be administered orally, rectally, parenterally or topically, preferably orally. Thus, the pharmaceutical compositions of the present invention may be any known pharmaceutical composition for oral, rectal, parenteral or topical administration. The compositions may be formulated according to methods known to those skilled in the art to control the administration of the compounds of this invention. Pharmaceutically acceptable carriers suitable for use in these compositions are well known in the pharmaceutical art. Accordingly, the compositions of the invention contain 0.190% by weight of the active compound. The compositions of the invention are usually formulated in unit dosage form.

Formulations for oral administration are the preferred compositions of the invention and are in the form of conventional forms such as tablets, capsules, syrups, and aqueous or oily suspensions. The excipients used in preparing these pharmaceutical compositions are known in the pharmaceutical art.

Tablets may be prepared by mixing the active compound with an inert diluent such as lactose or calcium phosphate in the presence of disintegrating agents such as magnesium stearate, and preparing the tablet from the mixture by known methods. If desired, these tablets may be enteric-coated by known techniques, for example, using cellulose acetate phthalalate. Generally, capsules, for example hard or soft gelatin capsules, containing the active compound with or without added excipients, may be formulated in conventional manner and, if desired, enteric-coated in a known manner. Enteric-coated compositions of the present invention may be superior depending upon the nature of the active compound. The tablets and capsules may each contain between 1 and 500 mg of the active compound. Other compositions for oral administration include, for example, aqueous suspensions comprising a compound of Formulas I-VI in aqueous medium in the presence of a non-toxic suspending agent such as sodium carboxymethylcellulose, and oily suspensions comprising a compound of the present invention in a suitable vegetable oil. such as in arachis oil.

The present invention includes compositions for rectal administration in the form of known pharmaceutical forms for this use, for example, suppositories with semisynthetic glycerides or polyethylene glycol base.

The compositions of the present invention for parenteral administration include sterile solutions of known pharmaceutical forms for such administration, such as sterile suspension in aqueous or oily medium in a suitable solvent.

Compositions for topical administration may be comprised of a binding agent in which the active compound is dispersed so as to be in contact with the skin for the transdermal effect of the compound of formula I-VI.

The active compound may be dispersed optionally in a cream or ointment base.

In some technologies, it would be useful to use the compounds of the present invention in the form of very fine particles, such as those obtained by vigorously grinding liquids.

In the compositions of the present invention, the active compound may, if desired, be associated with other similar pharmacologically active ingredients, such as a β-adrenoceptor antagonist such as atenolol, propranol, oxoprenolol, nadolol or timolol and / or a diuretic such as co-fluazide, ethacrylic acid. or frusemide and / or an angiotensin converting protein inhibitor such as captopril or enalapril and / or vasodilators, such as hydralazine hydrochloride, flosechinone, sodium nitroprusside, glyceryl trinitrate or molzidomine and / or potassium channel activators such as lemacalin or pinacidil and / or an adrenoceptor antagonist such as prazosin or labetalol and / or other hypotensive agents such as chloridine, α-methyldopa or ketanserin and / or inhibitors of positive inotropes such as milrinone, digitalis or dobutamine, such as zaprinast, cif bradycardic agents such as alinidine or phalipamil, an endothelin antagonist and / or an endothelin converting protein inhibitor, and / or a renin inhibitor, and / or a thrombolytic agent such as streptokinase.

and / or PDE and / or specific therapeutic activity of the compounds of formulas I to VI was demonstrated in standard laboratory animals. This test includes, for example, oral administration of compounds to spontaneously hypertensive rats. Thus, compounds of Formulas I-VI may be used to reduce blood pressure in hypertensive mammals. Regardless of the exact amount of active compound consumed, its use depends on many factors, such as the age of the patient, the severity of the medical history, and the limits of its use must be correctly determined by the prescribing physician. For mammals, including humans, a suitable dose for the small intestine is usually in the range of 0.01 to 25 mg / kg / day, more typically 0.2 to 10 mg / kg / day in single or divided doses. For parenteral administration, the dose is usually in the range of 0.001 to 2.5 mg / kg / day, more typically 0.005 to 1 mg / kg / day in single or divided doses or in continuous administration. Oral administration is a priority.

The compounds of formulas I-VI and their salts contain angiotensin

II antagonists are therefore used in the treatment of hypertension in mammals, including humans. Compounds of Formulas I-VI are also nurgically compatible with acute and chronic persistent heart failure, glaucoma, primary and secondary hyperaldosteronism, primary and secondary pulmonary hypertension, cor pulmonale, renal failure, renal vasohypertension, angina, migraine, left ventricular blood vessel diseases (such as Raynaud's disease), scleroderma, treatment of diabetic nephropathy and prophylaxis of coronary insufficiency after myocardial infarction.

Accordingly, the present invention further provides the use of any of the compounds of Formulas I to VI for the treatment of said disorders and the use of any of the compounds of Formulas I to VI in the manufacture of a medicament for the treatment of said disorders.

T

Methods of preparing compounds of Formulas I-VI will now be described.

These methods form a further aspect of the present invention.

Compounds of formula I wherein R5Â is Cx_4 alkyl, A51 is oxygen, or is 1, may be obtained by reacting a compound of formula X, ch2l

wherein f. is a leaving group such as halogen (e.g., bromine); o R50 is Cx_4 alkyl; with a corresponding compound of formula Het-H wherein Het is as defined in the above list of structural formulas; inert to the reaction conditions in the solvent; better at base.

The compounds of Formula Het-H may be prepared by the methods outlined in the corresponding patent publications above. In particular, compounds of formula Het-H wherein Het is a group of formula xxv, xxvi and xxvii may be prepared as described in EP-A-0400974 (Merck), WO-A9114679 (Sanofi) and EP-A-0475206 (Abbott). respectively.

Compounds of formula Het-H where Het is a group of formula xxvi can be obtained by Schunack [Arch. Pharmaz. (1974) Vol. 307, p. 46] (for compounds wherein R8 is hydrogen), EP-A-0253310 (for compounds wherein R8 is chlorine or trifluoromethyl), EP-A-0324337 (for compounds wherein R8 is pentafluoroethyl), WO-A-9200977 (for compounds where R8 is Cx_4 alkyl) and EP-A-0465368 (for compounds wherein R8 is Cx_4 alkylsulfinyl, alkylsulfonyl, Cx_4 alkylthio, arylsulfinyl, arylsulfonyl, arylthio, arylmethylsulfinyl, arylmethylsulfonyl or arylmethylthio group [wherein aryl represents phenyl which may be Cx_4 alkyl, Cx_4 alkoxy or fluorine, chlorine or bromine substituted])

Compounds of formula X wherein L is a halogen such as chlorine or bromine may be prepared by reacting a compound of formula XI

with a chlorinating agent such as benzitriethylammonium tetrachlorododate or with a brominating agent such as N-bromosuccinimide; inert to the reaction conditions in the solvent.

Compounds of formula XI wherein X50 is a connection such that A50 and B50 are directly connected through a carbon - carbon bond (eg when A50 is a group of formula ii, iii, iv or v as defined above, and B50 is a group of formula xv, xix, xx, xxi or xxii) can be obtained by reacting compound XII

XII,

<td>where Hal with formi</td><td>is flaps</td><td>halogen, respectively Compound XIII CH3 - b50 - q50</td><td>bromine or</td><td>iodine; XIII,</td>

<td>in which</td><td>B50</td><td>is xv, xix, xx, xxi</td><td colspan="2">or xxii formulas</td>

<td>group,</td><td>how</td><td>stated above; o</td><td>Q.50 means</td><td>of course</td>

an aromatic ring linking group, such as a boronic acid group of formula -B (OH)2 or a boric acid derivative of the formula -B (OAlk)2 (where Alk is Cx_4 alkyl group) or a trialkyl tin group having the formula -Sn (Alk)3 (where Alk is Cx_4 alkyl group); inert to the reaction conditions in the solvent; a better reaction in the presence of a base such as sodium carbonate; respectively, in the presence of a metal catalyst such as palladium (O) or nickel (O), or by reacting the compounds of formula XII and XIII in a similar manner, modifying them in the substituents Q50 and Hal are interchangeable.

Compounds of formula XIII wherein B50 is a group of the formula xv, xix, xx, xxi, or xxii as above, is either known from the patent publications designated by the letters (m) and (q) to (t) as above, or is readily derived from those described therein. of compounds of the formula XIII such that Q50 is a lithium or MgHal group of formula (where Hal is halogen) by reaction with trialkylborate (such as triisopropylborate at -100 ° to 0 ° C) in an inert reaction to a solvent (such as tetrahydrofuran). To obtain -B (OH) in the compound of formula XIII2 As an alternative to the formula, hydrolysis can be performed in the presence of an acid (such as hydrochloric acid).

Compounds of formula XII may be prepared by reacting a compound of formula XIV

wherein T is a trialkyl tin group of the formula -Sn (Alk)3, where Alk stands for Cx_4 an alkyl group (preferably a butyl group); with a compound of formula XV

Fish - A5C - I XV wherein Hal is bromine or iodine, preferably bromine; inert to the reaction conditions in a solvent, preferably in the presence of a metal catalyst such as palladium (O) or nickel (O).

Compounds of formula XIV may be prepared as described by Liebeskind and Fengl in Journal of Organic Chemistry (1990) Vol. 55 pp. 5359/5364.

The compounds of Formula XV are either known from the above-mentioned patent publications designated letters (b) to (e) or are readily derived from the compounds described therein, for example by the halogenation reactions described above, respectively.

Compounds of formula XI may also be prepared by reacting a compound of formula XVI

CH3 - B50 - X50 - A50 - Met

XVI wherein Met is lithium or a group of the formula MgX wherein X is chlorine, bromine or iodine; with a compound of formula XVII

XVII wherein Alk is alkyl; followed by treatment with an acylating agent such as trifluoroacetic anhydride; inert to the reaction conditions in the solvent.

Compounds of Formula XVII are available from Aldrich Chemical Co. (In the United Kingdom).

Compounds of formula XVI may be prepared by reacting a compound of formula XVIII

CH3 - B50 - X50 - A50 - Hal XVIII wherein Hal is halogen, preferably bromine; with Cx_4 alkyl-lithium compound or metal magnesium; inert to the reaction conditions in the solvent.

Compounds of Formula XVIII, wherein X50 is such a connection that A50 and B50 are connected through a carbon - carbon bond (eg A50 is a group of formula ii, iii, iv or v above, and B50 is a group of formula xv, xix, xx, xxi or xxii) may be obtained by reacting a compound of formula XIII with a compound of formula XIX as described above

Fish - A50 - I XIX wherein Hal is halogen or iodine and A50 is a group of formula ii, iii, iv or v above; inert to the reaction conditions in the solvent; preferably in the presence of a base such as sodium carbonate; a better reaction in the presence of a metal catalyst such as palladium (O) or nickel (O); or by reacting compounds of formula XII and XIX in the same manner, modifying them so that Q is substituted50 and Hal are interchangeable.

Compounds of Formula XVIII, wherein X50 is such a connection that A50 and E50 are connected through a carbon - carbon bond (eg when A50 is a group of formula ii, iii, iv or v of the formula given above, and B50 is a group of formula xv, xix, xx, xxi or xxii) may also be obtained by reacting a compound of formula XIII wherein Q50 is a group of formula -MgHal (wherein Hal is bromine or chlorine) with a compound of formula XX

Fish - A50 - Hal XX, in which A50 is a group of formula ii, iii, iv or v as previously described and each Hal is independently chloro, bromo or iodo; inert to the reaction conditions in the solvent; a better reaction in the presence of a base such as sodium carbonate; preferably in the presence of a metal catalyst such as palladium (O) or nickel (0) or by reacting the compounds of formula XIII and XX in the same manner, modifying them so that Q50 and Hal are interchangeable therein.

Compounds of formula XIX and XX are either known from the above-mentioned patent publications designated letters (b) to (e) or readily derived from the compounds described therein.

Compounds of Formula I wherein A50 is oxygen, r is 1 and R50 is Cx_4 alkyl may also be prepared by reaction of a compound of formula XXI

Het - CH2 - B50 - X50 - Aso - I XXI with the above compound of formula XIV; inert to the reaction conditions in the solvent; preferably in the presence of a metal catalyst; for example palladium (O) or nickel (O) catalyst.

Compounds of formula XXI may be prepared by reacting a compound of formula XXII

LCH2 - B50 - X50 - A50 - I XXII wherein L is a leaving group, preferably halogen (e.g. bromine or chlorine) with a Het-H compound of the formula as previously described; inert to the reaction conditions in the solvent; better at base.

Compounds of formula XXI may also be prepared by reacting a compound of formula XXII (or a corresponding compound wherein L is an amine) with a precursor of the corresponding Het group of the formula and subsequently generating the Het residue in situ. Suitable methods are described in the aforementioned patent publications.

Compounds of formula XXII wherein L is bromine or chlorine may be prepared by reacting a compound of formula XXIII

CH3 - B50 - X50 - A50 - I XXIII f

with a chlorinating agent, such as benzyltriethylammonium tetrachloroiodate, or with a brominating agent, for example, N-bromosuccinimide; inert to the reaction conditions in the solvent.

The foregoing compounds of formula XXIII wherein X is a bond such that A50 and B50 are connected through a carbon - carbon bond (eg when A50 is a group of formula ii, iii, iv or v above, and B50 is a group of formula xv, xix, xx, xxi or xxii) may be obtained by reacting a compound of formula XIII above with a compound of formula XIX above; inert to the reaction conditions in the solvent; preferably by reaction with a base such as sodium carbonate; preferably in the presence of a metal catalyst, such as palladium (O) or nickel (O), or by reacting the compounds of formula XIII and XIX in the same manner, modifying them so that Q50 and Hal are interchangeable.

It will be appreciated that when a readily reactive substituent, such as a carboxyl, is present in a compound of formula Het-H or in a Het group of the formula, it is necessary to block this substituent (e.g., in this case by esterification of the carboxyl group). Following such a reaction, the unit may be removed (for example, by acidic or alkaline hydrolysis) to provide a free substituent if required.

Compounds of Formula I wherein A50 is a group of formula vii given above, R50 is Cx_4 alkyl, X50 is a bond, r is 1, and A51 is oxygen which may be produced by reaction of a compound of formula XL with ι

XL wherein L is a leaving group such as halogen (e.g., bromine); o R50 is Cys_4 alkyl; with a corresponding compound of formula Het-H wherein Het is as defined in the above list of structural formulas; inert to the reaction conditions in a solvent (such as dimethylformamide); preferably in the presence of a base such as sodium hydride.

Formulas xt, compounds wherein R50 is Ci_4 alkyl and L is a halogen, for example chlorine or bromine, can be obtained by reacting a compound of formula XLI

\ V (.3 'r132

XLI with a chlorinating agent such as benzyltriethylammonium tetrachloroiodate or with a brominating agent such as N-bromosuccinimide; inert to the reaction conditions in the solvent.

Compounds of formula XLI may be prepared by reacting a compound of formula XLII

K130 \\ [_7/ r132

XLII with a compound of formula XVII above, followed by treatment with an acylating agent such as trifluoroacetic anhydride; in an inert solvent under reaction conditions.

Compounds of formula XLII may be prepared by reacting a compound of formula XLIII

XLIII with C 1-4 alkylthiol reagent (such as butylitis); inert to the reaction conditions in the solvent.

Formula XLIII compounds are known from WO-A-9215577 (Searie).

Compounds of formula I wherein X50 is a non-linker, but a linking group as previously described may be obtained by the reactions described above, modified by appropriate alternative aromatic or aliphatic linkage reactions as described in FR-A-2669928 (Labs UPSA), EP-A-0323841 (Du Pont), EP-A-0475206 (Abbot),

EP-A-0449699 (Labs UPSA), US-A-5091390 (Du Pont), US-A4880804 (Du Pont) and US-A-5043349 (Du Pont) and references therein.

Compounds of formula V wherein A20X is oxygen, and R333 is Cx_4 alkyl, may be prepared by reacting a compound of formula L _ανΊΓΚ331r330 * 200 \ 'L.

N r332 L (CK?): n

I zB60~yeah with the above compound of formula XIV (wherein R50 is R333) inert to the reaction conditions in the solvent; preferably in the presence of a metal catalyst such as palladium (O) or nickel (O).

Compounds of formula L wherein R332 is a group of formula xxx, which may be obtained by dehydrating a compound of formula LI R330 * 200 \ .OK R3i? n - e— <

<CH2lrn r? <5OR34X LI b60 —Cal for example, by reaction with a salivating agent such as acetic anhydride followed by treatment with a base,

Such as diazobicyclo [5.4.0] undec-7-enu in the reaction inert to the solvent.

Compounds of formula Ll may be prepared by reacting a compound of formula LII

LII with R34iCH2R342 in a solvent inert to the reaction conditions in the presence of a base such as lithium diisopropylamide. Formulas R34] CH2R342 the compounds are well known in the art (e.g., from EP-A-0425211; Smithkline Beecham).

Compounds of formula LII may be prepared by reacting a compound of formula Lili

Lili with a compound of formula LIV

L (CH2)ra - B60 - Hal

LIV wherein Hal is bromine or iodine and L is a leaving group such as bromine or chlorine; inert to the reaction conditions in the solvent; preferably in the presence of a base such as potassium carbonate. This reaction results in a mixture of isomeric products which can be separated by conventional techniques such as column chromatography.

Compounds of formula Lili are known from EP-A-0425211 (Smithkline Beecham) or are readily derived from the compounds described herein by methods well known in the art.

The compounds of formula LIV are well known.

Compounds of formula L wherein R332 is a group of formula xxxi, which may be prepared by reacting a compound of formula LV

(CH2) m I 2

B60- Hal

LV wherein Hal is bromine or iodine with an LVI compound of the formula R350 H —N *? 351 j ~R352 r3S3

LVI under inert reaction conditions preferably in the presence of a catalyst, succinimide.

in a solvent; such as N-hydro69

Formula LV compounds may be prepared as described in EP-A-0437103 (Smithkline Beecham).

Compounds of Formula LVI EP-A-0437103 may be obtained (Smithkline Beecham).

as described

Compounds of formula L wherein R332 is a group of formula xxxii which may be prepared by reacting a compound of formula LVII R330~A200

I (CH2) ro B60~ Hal

LVII wherein Hal is bromine or chlorine and L is a leaving group such as chlorine; with a compound of formula LVIII

363

LVIII in a reaction inert solvent such as dimethylformamide; preferably in the presence of a base such as triethylamine.

Compounds of Formula LVIII may be prepared as described in EP-A-0427463 (Smithkline Beecham).

Compounds of Formula LVII wherein n is greater than 1 are known from US-A-4340598 (Takeda) or are readily derived from compounds described herein by methods well known in the art.

Compounds of Formula LVII wherein L is halogen, on is 1, may be prepared by reacting a compound of Formula LIX

LIX wherein Hal is bromine or chlorine; with a halogenating agent such as thionyl chloride; inert to the reaction conditions in the solvent.

Compounds of formula LIX may be prepared by reacting a compound of formula LX r330 a2Cu

I (CK! M I 2

LX with a reducing agent such as sodium borohydride;

inert to the reaction conditions in the solvent.

T

Formula LX compounds may be prepared as described in EP-A-0427463 (Smithkline Beecham).

Compounds of formula L wherein R332 is a group of formula xxxiii wherein R370 is carboxyl, A210 is carbonyl, and R372 Yra ci-6 alkyl may be obtained by hydrolysis of a compound of formula LXI

LXI in which R372 is Cx_6 alkyl, and R373 is as previously defined, but not hydrogen; for example, with a base such as aqueous sodium carbonate solution; inert to the reaction conditions in the solvent.

Compounds of Formula LXI wherein R372 is C1_6 alkyl may be prepared by reaction of the corresponding compound wherein R372 is hydrogen, with a base such as sodium hydride followed by Cx_6 alkyl halide in a solvent inert to the reaction conditions.

Compounds of Formula LXI wherein R372 is hydrogen, may be prepared by reacting the above compound of formula LVII, wherein L is chlorine, with the compound of formula LXII, jGto73ccG>2-c ··

Well

LXII in which R373 is as previously defined, but not hydrogen; inert to the reaction conditions in a solvent (such as dimethylformamide).

Compounds of formula LXII may be prepared as described in WO-A-9200068 (Smithkline Beecham).

Compounds of formula L wherein R332 is a group of formula xxxiii wherein R370 is -CO2R373 formula group, A210 is a bond, and R371 and R372 both are hydrogen, can be obtained by hydrolysis of a compound of formula LXIII

Ph Ph (CH-Air! *

B6c- Hal

LXIII in which R373 is as defined above but not hydrogen, for example by hydrolysis with a dilute acid such as hydrochloric acid; inert to the reaction conditions in the solvent.

Compounds of formula LXIII may be prepared by reacting a compound of formula LVII wherein L is chlorine with a compound of formula LXIV

Ph / = N-HH-co2-R27J Ph bi

LXIV in which R373 is as previously defined, but not hydrogen; inert to the reaction conditions in a solvent (such as tetrahydrofuran).

Compounds of formula LXIV may be prepared as described in WO-A-9200068 (Smithkline Beecham).

Compounds of formula II (in particular compounds of the present invention) wherein R310 is alkyl, o

A190 is oxygen, may be obtained by reacting a compound of formula LXX

wherein L is a leaving group such as halogen and R310 is C3_4 alkyl; with a corresponding compound of formula Het-H wherein Het is a group of formula xxxviii

(xxxviii) in a solvent inert to the reaction conditions; better at base.

Compounds of formula LXX wherein L is a halogen such as chlorine or bromine may be prepared by reacting a compound of formula LXXI

R311

LXXI in which R310 is Cx_4 alkyl; with a halogenating agent such as a chlorinating agent such as benzyltriethylammonium tetrachloroiodate, or with a brominating agent such as N-bromosuccinamide in a solvent inert to the reaction conditions.

Compounds of formula LXXI may be prepared by reacting a compound of formula LXXII

LXXII wherein Hal is halogen, preferably bromine or iodine, and R310 Yra C 1-4 alkyl; with a compound of formula LXXIII

LXXIII, ° 50 in which Q50 represents a boronic acid group of the formula -B (OH)2 or a trialkilstanyl group of formula -Sn (Alk) 3 (where Alk stands for Cx_4 alkyl group); inert to the reaction conditions in the solvent; a better reaction in the presence of a base such as sodium carbonate; preferably in the presence of a metal catalyst such as palladium (O) or nickel (O).

The compounds of formula LXXIII are well known.

Compounds of formula LXXII may be prepared by reacting a compound of formula LXXIV

LXXIV in which R310 is Cx_4 alkyl and T is a trialkyl tin group of the formula -Sn (Alk)3, where Alk stands for C2_4 an alkyl group (preferably a butyl group); with a compound of formula LXXV

LXXV wherein Hal is bromine or iodine, preferably bromine, in a reaction inert solvent, preferably in the presence of a metal catalyst such as palladium (O) or nickel (O).

Compounds of formula LXXIV may be prepared as described by Liebeskind and Fengl, Journal of Organic Chemistry (1990) Vol. 55 pp. 5359/5364.

Formula LXXV compounds are well known and available from Lancaster Synthesis Ltd or Aldrich Chemical Co. (United Kingdom).

Compounds of formula LXXI may also be prepared by reacting a compound of formula LXXVI

LXXVI wherein Met is lithium or a group of the formula MgX wherein X is chlorine, bromine or iodine; with compound of formula LXXVII n

Alko

LXXVII in which R310 is C3_4 alkyl and Alk is Cx_4 alkyl; followed by reaction with an acylating agent such as

T with trifluoroacetic anhydride; inert to the reaction conditions in the solvent.

Compounds of formula LXXVII are well known and are available from Aldrich Chemical Co. (United Kingdom).

are obtained by reacting

Compounds of Formula LXXVI may be of Formula LXXVIII

CH,

U '312 Γ J

LXXVIII, KWherein Hal is halogen, preferably by a fused silica or a metal bromine; with almagnesium; inert to the reaction conditions in the solvent.

Compounds of formula LXXVIII are described by Gomberg and Pernert (J. Am. Chem. Soc. (1926) Vol 48, p. 1373) and may be prepared as described therein.

They can also be obtained by reacting formulas

LXXIII, modifying it so that Q50 is a group of formula MgHal (where Hal is chloro, bromo or iodo) with 1,2-diiodobenzene, 1,2-bromoiodobenzene, 1,2-dibromobenzene or 1,2-bromo-chlorobenzene (substituted with R, respectively)311 and / or R312 groups) inert to the reaction conditions in a solvent in the presence of palladium (O) or nickel (0) catalyst.

Compounds of formula LXXIII by modifying them such that Q50 is a group of the formula MgHal, which can be obtained by reacting the corresponding compounds wherein Q5Â is chlorine, bromine or iodine with metallic magnesium; inert to the reaction conditions in the solvent.

Compounds of Formula II wherein A190 is oxygen, and R310 is lower alkyl, and may also be prepared by reaction of a compound of formula LXXIX

LXXIX wherein Het is a group of formula xxxviii above; with a compound of formula LXXIV above, in an inert reaction solvent, preferably in the presence of a metal catalyst such as palladium (O) or nickel (O).

Compounds of formula LXXIX may be prepared by reacting a compound of formula LXXX

LXXX,

Where L is a leaving group, preferably halogen {e.g. bromine or chlorine); with a compound of formula Het-H (wherein Het is a group of formula χχχνίϋ above) in an inert reaction solvent, preferably in the presence of a base.

Compounds of formula LXXX wherein L is bromine or chlorine may be prepared by reacting a compound of formula LXXX1

CH-,

LXXXI with a chlorinating agent, such as benzyltriethylammonium tetrachlorododate, or with a brominating agent, such as / Nbromo-succinimide.

Compounds of formula LXXXI are known from Hammerschmidt and Vogtle (Chem. Ber. (1979) Vol. 112, p. 1785) and may be prepared as described therein.

Compounds of formula Het-H wherein Het is a group of formula χχχνίϋ as previously described, wherein R316, R317 and R318 each is hydrogen, Cx_4 alkyl, nitro, fluoro, chloro, bromo, cyano or formyl may be prepared by methods described in EP-A-0400974 (merck).

Compounds of formula Het-H wherein Het is a group of formula χχχνίϋ above, wherein R317 is -SO2NR320R321 a group of formula (I) may be prepared by reacting a corresponding compound of formula 3612 B Het-H with modification R317 is a sulfonyl chloride group; with HNR320R321 an amine of the formula or a salt thereof; inert to the reaction conditions in the solvent.

Compounds of formula Het-H in which Het is a group of formula xxxviii by modifying them such that R317 is a sulfonyl chloride group which may be prepared by reaction of the corresponding compound of formula Het-H, wherein R317 is an amino group; with a diazotizing agent such as an alkali metal nitrite under appropriate conditions (e.g., concentrated hydrochloric acid at a temperature below 5 ° C); by adding a source of copper (I) ions (e.g., by adding copper chloride) and sulfur dioxide in an inert solvent to the reaction conditions.

Compounds of formula lt-s Het-H wherein Het is a group of formula xxxviii wherein R317 is an amino group, may be obtained by reduction of the corresponding compound, wherein R317 is a nitro group with an appropriate reducing agent such as hydrogen. gas with a catalyst such as metal palladium catalyst.

Compounds of Formula I, modified so that R50 is a group of the above formula χχχν, xxxvi or χχχνίί (e.g., so-called pro-drugs) can be obtained by reacting an alkali metal salt of a compound of formula I above, wherein A51 is oxygen, and R50 is hydrogen, with the above compounds of the formulas χχχν, χχχνί or χχχνίί, wherein in each of the foregoing structures the free valence is bound to a halogen, preferably chlorine, in an inert reaction solvent; preferably in the presence of an alkali metal iodide such as potassium iodide.

T

Compounds of Formula I wherein A51 is oxygen, and R50 is hydrogen, may be obtained by hydrolysis of a compound of formula I wherein A51 is oxygen, and R50 is lower alkyl (obtained as previously described), for example, when heated under acidic or alkaline conditions.

In addition, compounds of formula I wherein A51 is oxygen, and R 50 is hydrogen, may be obtained by deprotection of compounds of formula I wherein A51 is oxygen by modifying them so that R50 is a protecting group, for example:

1) an aralkyl group during ether decomposition, for example by using hydrobromic acid in a reaction inert to the liquid;

2) an aralkyl group (e.g. benzyl or trityl), for example, by hydrogenolysis such as hydrogen over palladium on carbon; or

3) a trialkylsilyl group (e.g. t-butyldimethylsilyl) by known silicon removal methods, for example by reaction with a fluoride source; such as tetrabutylammonium fluoride).

Experts should be aware of the many protecting groups that can be used. Examples of these protecting groups and methods for their attachment and removal can be found in TW Greene, John Wiley & Sons, 1981 textbook, Protective Groups in Organic Synthesis.

It should also be known that reactions previously described with compounds wherein R50 is alkyl, and may also be carried out using the appropriate compounds, modifying such that R50 they contain a protecting group as previously described.

Therefore, on the other hand, the present invention provides novel intermediates of formula XC.

XC wherein Z is a protecting group of the type described above.

Compounds of Formula I wherein A51 is sulfur or -NR52may be prepared by reacting a compound of formula XCI (CH2)r- Het ^ 50 o * 50 a50

XCI wherein Hal is halogen, preferably bromine or chlorine; with HSR respectively50 or HNR50R52 a compound of the formula (or alkali metal salts thereof); inert to the reaction conditions in a solvent (such as pyridine). When A51 is sulfur, followed by an interaction with a strong acid such as concentrated hydrochloric acid. In order to obtain the corresponding free acid, any salt formed, if desired, must be neutralized.

Compounds of Formula I wherein A51 is sulfur or -NR52a group of formula, and R51 is Cx_4 alkyl may also be present

It is prepared by reacting a compound of formula XCI with hydrogen sulfide or ammonia, respectively, followed by treatment with an alkylating agent, if necessary.

Compounds of formula XCI may also be prepared by reacting a salt of a compound of formula I, preferably an alkali metal salt, wherein A51 is oxygen, and R50 is hydrogen; with a halogenating agent, preferably a chlorinating agent such as oxalyl chloride; inert to the reaction conditions in the solvent.

Compounds of Formula I wherein A61 is -NR52- where R52 are, as previously described, also obtainable by carrying out the reaction of a compound of formula I wherein A51 is oxygen, and R50 is Ο4_4 alkyl, by interaction with HNR50R52 or a alkali metal salt thereof in a solvent inert to the reaction conditions.

All novel intermediates described herein containing a cyclobutendione ring in the present invention are key mediators and form an additional aspect of the invention.

Novel intermediates corresponding to the above structures of Formula I (e.g., Formulas II, III and IV) are also provided, modified so that R310 is a protecting group as described previously).

Salts of the compounds of Formula I, which are also encompassed by the present invention, may be prepared by conventional methods, such as reaction of the free acid or free basic form of the compound of Formula I with one or more equivalents of the corresponding acid or base.

The therapeutic activity of the compounds of formula I was demonstrated in these experiments. In Assay A, retention of angiotensin II reT receptor on the adrenal membrane was determined in vitro, and in Assays B and C, the antihypertensive effect of the compounds was measured in vivo. The tests are described in more detail below.

Test A

1) Preparation of membranes

New Zealand white rabbit male adrenal glands were homogenized on ice in 20 mM aqueous sodium bicarbonate solution containing 50 μΜ PMSF (phenylmethanesulfonyl fluoride) (2 mL / g wet weight) using a Polytron (brand) homogenizer, 3x15 seconds, adjusted to 8. The homogenate was centrifuged at 900 g for 10 min at 4 ° C and the precipitate was removed. The supernatant was centrifuged again at 30,000 g for 30 minutes at 4 ° C and the resulting pellet was suspended in assay buffer (50 mM Tris-HCl, pH 7.4 containing 1 mM EDTA,

6.5 mM UgCl, 125 mM NaCl, 50 μΜ PMSF, 5 pg / mL pepstatin and 50 pg / mL each leupeptin, antipain, aprotinin and chymostatin): 10 mL per gram of starting wet tissue. Polyethylene glycol (30% final concentration) was added as a cryopreservant, and the membrane preparation was divided into samples stored at -80 ° C as needed. The protein was determined by a modified Lowry method. (Markwell et al., (1978) Anai. Biochem., 87: 206-210).

2) Binding assay

Rabbit adrenal membrane specimens containing 10-30. μρ of protein were incubated with 0.05 nM [I] -angiotensin II in the presence or absence of a potential angiotensin II antagonist in 1 ml polyamide tubes in a total volume of 200 μΐ of assay buffer. After incubation for 60 minutes at 25 ° C, the reaction was stopped by the addition of chilled ice assay buffer, and bound and free radioactivity were separated through Skatron (brand) receptor binding filters after pre-moistening with assay buffer using the Skatron cell cutter. The filters were washed with chilled ice-phosphate-buffered saline, dried, and radioactivity was determined using a gamma counter. Nonspecific binding, as measured with 2 μΜ unlabeled angiotensin II, was subtracted from total binding to obtain specific binding. Radioligand binding curves were assayed using EBDA and LIGAND (Cambridge Bioscit). Binding pull values were obtained by non-linear regression analysis of non-transformed data.

The activities of the compounds described in the examples herein are reported in Table A, column 1, below.

Test B

Female Aoki-Okamoto strains of self-hypertensive rats, weight range 180-240 g were used. Groups of four rats were fasted overnight prior to study compound administration. Blood pressure was measured this way. The rats were placed in a box kept at 38 ° C and their tails protruded through the holes in the box. After 30 min, blood pressure in the box was measured using a swollen cuff placed around the base of the tail, and arterial pulsations were controlled by a pneumatic pulse transducer. Pressure greater than the expected blood pressure was applied to the cuff and this pressure was gradually reduced. Cuff pressure, which recurs with arterial pulsation, was taken as blood pressure. Rats were removed from the box and each group was orally dosed with a fixed dose of the test compound in solution or suspension in 0.25% aqueous carboxymethylcellulose. With no additive before dosing, blood pressure was measured 1.5 and 5.0 hours after dosing. The degree of blood pressure reduction required to achieve a significant p <0.01 level comparable to control was 9% after correction for control changes over time. Thus, in this test, compounds were considered active if, after a correction of 9% or more, they caused a drop in blood pressure.

Limit doses of antihypertensive compounds of formula I were determined as follows. The compounds were initially tested at different dose levels, for example 90 mg / kg. If the compound was considered to be sufficiently active (yielding a blood pressure reduction of 16% or more after correction), it was re-tested at a lower dose level, for example 30 mg / kg. During testing, further low dose levels were used to determine the threshold antihypertensive dose (the dose that causes a reduction in blood pressure between 9% and 16% after correction). Inactive at a certain dose level, compounds causing a blood pressure decrease equal to or greater than 16% after correction were classified at the next higher dose level as having a marginal antihypertensive dose within two dose levels.

The activity of the compounds described in the examples below is given in Table A, column 2, below.

Test C

The modification procedure was performed in the above procedure B of test B after pretreatment with rats with cofluidide 10 mg / kg (oral diuretic) to ensure activation of reninangiotensin sisLT 3612 B, 16 and 2 hours before the test compound dose.

The activity of the compounds 5 described in the examples below is given in Table A, column 3, below.

The antihypertensive activity of the compounds of the present invention may also be demonstrated in rats in which the renin-angiotensin system has been activated by surgical intervention.

TABLE A

<td>FINAL</td><td> 1</td><td>COLUMN</td><td>COLUMN 2</td><td>COLUMN 3</td>

<td>EXAMPLE</td><td>(Off</td><td>in test A)</td><td>(Limit antihiper-</td><td>(Limit antihiper-</td>

<td>PRODUCT</td><td></td><td>(x10 '9M)</td><td>tensile dose in test B) (mg / kg)</td><td>tensile dose in test C) (mg / kg)</td>

TABLE A (cont'd)

<td>FINAL</td><td> 1</td><td>COLUMN</td><td>COLUMN 2</td><td>COLUMN 3</td>

<td>EXAMPLE</td><td>(Off</td><td>in test A)</td><td>(Limit antihiper-</td><td>(Limit antihiper-</td>

<td>PRODUCT</td><td></td><td>(x10 '9M)</td><td>tensile dose in test B) (mg / kg)</td><td>tensile dose in test C) (mg / kg)</td>

The invention is illustrated by the following non-limiting examples in which the mixed solvent compositions are provided by volume. The novel compounds were characterized by one or more of the following methods: elemental analysis, nuclear magnetic resonance and infrared spectroscopy.

Flash chromatography was carried out according to the method described by Stili et al., J. Org. Chem. (1978), Vol. 43, pp. 2923-5.

An example

Mixture of 3-isopropoxy-4-tributyltin cyclobut-3-en-1,2-dione (4.68 g; preferably as described by Liebeskind and Fengl, Journal of Organic Chemistry (1990), Vol. 55, pp. 5359/5364). , l-bromo-2-iodobenzene (3.54 g), dry dimethylformamide (15 mL), tetrakis (triphenylphosphine) palladium (O) (0.606 g) and copper iodide (0.196 g) were stirred under nitrogen at room temperature for about 2.5 hours and then it is kept at room temperature for 3 days. Diethyl ether (225 mL) was added and the resulting mixture was washed first with saturated aqueous ammonium chloride solution (225 mL) followed by 10% aqueous potassium fluoride solution (3x225 mL). The organic phase was filtered through a pad of silica (5 cm diameter x 1 cm height) and the collected dry residue was washed with diethyl ether (50 mL). The resulting orange filtrate and washings were combined and evaporated. A semi-liquid brown oil was obtained, which was purified by flash chromatography on silica gel (eluting with dichloromethane and washing with 20% diethyl ether in petroleum ether (boiling point 40-60 ° C)). The resulting intermediate was 3- (2-bromophenyl) -4-isopropoxycyclobut-3-ene-1,2-dione - a yellow oil (2.16 g).

The product of Example 1 above (2.16 g) was dissolved in toluene (170 mL) and 4-methylbenzene boronic acid (1.94 g), tetrakis (triphenylphosphine) palladium (O) (0.53 g), ethanol (8.3 mL) and aqueous solution were added to the solution. sodium carbonate solution (2M; 8.3 mL). The resulting mixture was heated in a flask with a rectification column under nitrogen for 3.5 hours. The resulting dark reaction mixture was left to cool to room temperature and then washed with water (2X50 mL). The organic phase was dried over magnesium sulfate and then evaporated. Obtained a brown oil (3.37 g) which was purified by flash chromatography on silica gel (dichloromethane washing). A yellow oil (1.48 g) was obtained and this oil was mixed with petroleum ether (boiling point 40-60 ° C): diethyl ether mixture 1: 1. A yellow suspension was obtained. The solution was filtered and the resulting solid residue was washed with petroleum ether (boiling 40-60 ° C) and dried in vacuo. Further intermediate was obtained

3-Isopropoxy-4- (4'-methylbiphenyl-2-yl) cyclobut-3-ene-1,2-dione-pale yellow solid (0.96 g; m.p. 120-130 ° C).

3- Isopropoxy-4- (4'-methylbiphenyl-2-yl) cyclobut-3-ene-1,2-dione (1.24 g; more preferably as described in the example).

1 (b)), carbon tetrachloride (40 ml), recrystallized N-bromosuccinimide (0.79 g) and AIBN (azobis (isobutyronitrile)) (40 mg) were heated in a rectifying column flask for 4.5 hours. AIBN (23 mg) was then added and the mixture heated for a further 4.5 hours. The mixture is kept at room temperature for about 16 hours and then quenched with ice-water. The yellow supernatant was separated. The resulting off-white solid was washed with cold carbon tetrachloride (about 3 mL). The resulting yellow supernatant and washings were combined and evaporated. The resulting yellow gum was dried in vacuo. The intermediate is obtained

3- (4'-Bromomethyl-biphenyl-2-yl) -4-isopropoxy-cyclobut-3en-1,2-dione (1.74 g).

2-Ethyl-5,7-dimethyl-3H-imidazo [4.5-b] pyridine (0.66 g; obtained as described by Mantio et al., J. Med. Chem. 34, (1991), pp. A-0400974; Merck) and anhydrous potassium carbonate (1.02 g) were added to 3- (4'-bromomethylbiphenyl-2-yl) -4-isopropoxycyclobut3-en1,2-dione (1.88 g preferably as described in Example 1 (c)). dry dimethylformamide 910 mL) and the resulting mixture was stirred at room temperature for about 16 hours. To the resulting dark reaction mixture was added 2-ethyl-5,7-dimethyl-3H-imidazo [4.5-b] pyridine (0.33 g) and stirred for a further 24 hours at room temperature. The resulting dark mixture was partitioned between ethyl acetate (100 mL) and water (50 mL). The organic layer was separated, washed with water (50 mL) and dried over magnesium sulfate. The resulting solution was evaporated. A dark oil was obtained, which was purified by flash chromatography on silica gel (elution with 1% technical alcohol in dichloromethane), repeated chromatography on silica gel (elution with ethyl acetate), and chromatography again on silica gel (elution with 0% to 2% methanol in dichloromethane). The active compound of this invention, 3- [4'-2 (ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyrid-3-ylmethyl) -biphenyl-2-yl] -4-isopropoxycyclobut-3-en-1, was obtained. 2- Dione - yellow foam slowly melting at 60 ° C or below.

An example

A mixture of 1,2-diiodobenzene (6.6 g) and tetrakis (triphenylphosphine) palladium (O) (0.34 g) was stirred at room temperature in AR toluene under a nitrogen atmosphere. An aqueous solution of sodium corbonate (2 g) (15 mL) was added. The resulting orange mixture was heated under stirring in a flask with a screaming flask, and after 40 minutes, a solution of 4-methylbenzobenzoic acid (1.36 g) in technical methyl alcohol was added in portions. The resulting mixture was heated in a flask with a rectifying column for a further 4 hours, then cooled to room temperature. Aqueous hydrogen peroxide (30%; 1 mL) was added and the resulting mixture was stirred at room temperature for 1 hour. Saturated sodium chloride solution was added and the organic phase separated. The aqueous phase is extracted with ethyl acetate (2 x 50 mL) and the combined organic phases are washed with saturated sodium chloride solution (1 x 70 mL) and dried over magnesium sulfate. An orange gum was obtained. This resin was mixed with petroleum ether (boiling point 40-60 ° C) (200 mL). The resulting resin was partially purified by silica gel flash chromatography (petroleum ether (boiling 40-60 [deg.] C.): ethyl acetate (4: 1)) and further purified by flash column chromatography on silica gel (petroleum ether (boiling). 60-80 ° C) 200 ml / min). The intermediate 2'-iodo-4-methylbiphenyl was obtained as a colorless oil (1.3 g).

The product of Example 2 (a) above (1.23 g) was dissolved in carbon tetrachloride (30 mL). N-Bromosuccinimide (0.82 g) was added followed by AIBN (33 mg). Heat the resulting mixture in a flask with a rectifying column for 4.5 hours and then keep it at room temperature for approximately 16 hours. The resulting bright pink supernatant solution was separated and the resulting solid white residue was mixed with additional carbon tetrachloride (about 3 mL). The supernatant and subsequent washings were combined and then evaporated. Further intermediate 4- (bromomethyl) -2'-iodobiphenyl is obtained as a bright pink / red oil (1.69 g).

2-Ethyl-5,7-dimethyl-3H-imidazo [4.5-b] pyridine (0.731 g) and anhydrous potassium carbonate (1.15 g) were stirred in dry dimethylformamide (10 mL) for 10 min. A solution of the product of Example 2 (b) (1.65 g) in dry dimethylformamide (10 mL) was added portionwise over about 5 minutes. The resulting suspension was stirred at room temperature for about 16 hours and then partitioned between diethyl ether (50 mL) and water (50 mL). The layers were separated and the aqueous phase was further extracted with diethyl ether (25 mL). The combined organic phases were dried over magnesium sulfate and evaporated. Obtained a brown oil. This π

the oil was purified by flash chromatography on silica gel (eluting with acetate) followed by vacuum drying. The intermediate 2-ethyl-3- (2'-iodobiphenyl-4-ylmethyl) -5,7-dimethyl-3H-imidazo [4.5-b] pyridine was obtained as a brown oil (1.07 g).

A portion of the product of Example 2 (c) (97 mg) was dissolved in dry dimethylformamide (1 mL). 3-Isopropoxy-4-tributyl tin cyclobut-3-ene-1,2-dione (91 mg) was added followed by tetrakis (triphenylphosphine) palladium (O) (20 mg) followed by copper iodide (8 mg). and stirred under nitrogen for 70 minutes. Thereafter, tetrakis (triphenylphosphine) palladium (O) (16 mg) and copper iodide (9 mg) were added and stirring was continued at room temperature for another 50 minutes. Thereafter, 3-isopropoxy-4-tributyltin-cyclobut-3-ene-1,2-dione (41 mg) was added and stirring was continued for a further 72 hours. The solution was then combined treated (see f below).

The residue of the product of Example 2 (c) (0.94 g) was dissolved in dry dimethylformamide (4 mL) and the resulting solution was stirred at room temperature under nitrogen until 3-isopropoxy-4-tributyltin cyclobut-3-ene-1,2-dione was added. 1.29 g), tetrakis (triphenylphosphine) palladium (O) (0.143 mg) and copper iodide (40 mg). The resulting mixture was stirred at room temperature for 5.5 hours. Tetrakis (triphenylphosphine) palladium (O) (0.14 g) and copper iodide (0.12 g) were then added. After stirring under nitrogen for a further 72 hours, the resulting solution was combined treatment (see f below).

The two red-brown reaction solutions of (d) and (e) above were combined, diluted with diethyl ether (75 mL) and washed with saturated aqueous ammonium chloride solution (50 mL) followed by 10% aqueous potassium fluoride solution (3 x 30 mL). ). A gray solid, insoluble in both phases, was obtained. The organic phase was filtered through diatomaceous earth (trade name Celite), separating the small aqueous phase. The organic phase was evaporated. An orange oil was obtained, which was partially purified by flash chromatography on silica gel (eluting with methanol in dichloromethane 0 to 4% in ascending order). Further purification was carried out by chromatography on silica gel (eluting with diethyl ether). A semi-liquid foam was obtained, which was disintegrated and vacuum dried. The resulting active compound of the present invention is 3- [4 '- (2-ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyrid-3-ylmethyl) biphenyl-2-yl) -4-isopropoxycyclobutyl-. The 3-en-l, 2dione yellow solid (0.42 g) was substantially identical to the product of Example 1 (d).

An example

To a solution of 1-bromo-2-iodobenzene (200 g) and 4-methylbenzene boronic acid (105 g) in toluene (1 L) was added sodium carbonate (164.8 g), technical methyl alcohol (165 ml), water (165 ml) and after all, tetrakis (triphenylphosphine) palladium (O) (40.8 g). The resulting mixture was stirred at 95-100 ° C under nitrogen for hours. After cooling to room temperature, water (1 L) was added and the resulting mixture was stirred for minutes. The organic layer was separated and dried over magnesium sulfate 3612. The solvent was evaporated under reduced pressure to give a crude product.

The above reaction was repeated at x0.45, and the crude products of both reactions were combined and stirred in hexane (1 L) for 30 min. The insoluble material was filtered off and the solvent c was evaporated under reduced pressure through a fractionation column,; filled with glass spirals. The intermediate is obtained

2-Bromo-4'-methylbiphenyl (241.7 g) as a colorless oil (boiling point 98-102 ° C at 0.8 mmHg).

To a solution of 2-bromo-4'-methylbiphenyl (9.0 g; prepared as described in Example 3 (a) and Gomberg and Pernert, J. Am. Chem. Soc. (1926) Vol 48p 1373) in tetrahydrofuran (60 mL) was added. Butyl lithium (2.5M in hexane,

15.3 mL). The mixture was stirred at -70 ° C for 10 minutes and then a solution of 3,4-diisopropoxycyclobut-3-en-1,2-dione (7.6 g) in tetrahydrofuran (100 mL) was added over 1 minute at -70 ° C. ). The resulting solution was stirred for an additional 30 minutes at -70 ° C and then treated with trifluoroacetic anhydride (6.4 mL) and saturated aqueous ammonium chloride (40 mL). The resulting mixture was allowed to warm to room temperature and then partitioned between diethyl ether (300 mL) and aqueous sodium bicarbonate (5%, 300 mL). The aqueous layer was extracted once more with diethyl ether (200 mL) and the combined organic layers were washed with brine, dried over magnesium sulfate and evaporated. A yellow oily solid was obtained, which was purified by flash chromatography on silica gel (eluting with a gradient of 10% to 20% ethyl acetate in petroleum ether (boiling point 60-80 ° C)). The intermediate 3-isopropyl 3612B oxy-4- (4'-methibiphenyl-2-yl) cyclobut-3-ene-1,2-dione is obtained as a yellow solid substantially identical to the product of Example 1 (b). The above method is described in Reed et al., Journal of Organic Chemistry (1988) Vol. 53, p 2477.

It is understood that this intermediate may react as described, for example, in Examples 1 (c) and 1 (d) to form the active compounds of the present invention, such as the active compound of Example 1.

An example

The final products of Examples 1 and 2 (0.35 g), glacial acetic acid (7.5 ml), and water (7.5 ml) were heated at 95-100 ° C under nitrogen for 5 hours. The resulting yellow solution was filtered through cotton wool and evaporated. A glassy brown oil was obtained. This oil was mixed with ethyl acetate (5 mL) to give a yellow solid which was dried in vacuo at 70 ° C. The resulting active compound of the present invention is 3- [4 '- (2-ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyrid-3-ylmethyl) biphenyl-2-yl] 4-hydroxycyclobut-3-en-1, 2-dione (0.23 g; m.p. 245-247 ° C).

An example

3- [4 '- (2-Ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyrid-3-ylmethyl) biphenyl-2-yl] -4-hydroxycyclobut-3-en-1, 2-Dione (1.3 g; preferably as described in Example 4) was suspended in distilled water (10 mL) and aqueous sodium hydroxide solution (0.1 M; 29 mL) was added portionwise under ice-cooling. The resulting mixture was evaporated under reduced pressure (bath temperature% C or lower). A brown oil was obtained which was mixed with diethyl ether (50 mL). A yellow solid was obtained. This solid was collected and dried under vacuum at 60 ° C. The dried material was then mixed with diethyl ether (100 mL) and dried again in vacuo at 70 ° C. The resulting active compound of the present invention is 3- [4'- (2-ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyrid-3-ylmethyl) biphenyl-2-yl] -4-hydroxycyclobut-3 -en-i, 2-dione sodium salt (1.18 g). The cauldron melts slowly at temperatures of 180 ° C or lower.

An example

3- [4 '- (2-Ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyrid-3-ylmethyl) -biphenyl-2-yl) -4-isopropoxy-cyclobut-3-ene -1.2dione (0.44 g; more preferably as in Example 2) was stirred in saturated ammonia ethanol solution (10 mL) for 3 hours at room temperature and then left at room temperature for an additional 16 hours. The solvent was evaporated and the resulting residue was mixed with diethyl ether. An off-white solid was obtained, which was dried in vacuo. The resulting active compound of the present invention is 3-amino20 4- [4 '- (2-ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyrid-3-ylmethyl) biphenyl-2-yl]. cyclobut-3-ene-1,2-dione (0.25 g; mp 217 ° C).

An example

To a stirred suspension of sodium hydride (0.15 g; 60% in mineral oil) in dry dimethylformamide (10 mL) was added 5,7-dimethyl-2-propyl-3H-imidazo- [4,5-b] pyridine (0.69 g) over 15 minutes. ) (preferably as described by Mantio et al., J. Med. Chem. 34, (1991), pp. 2919/2922 and EP-A-0400974; Merck) Stirring was continued for another 30 minutes. The resulting solution was added to a stirred solution of 3- (4'-bromomethylbiphenyl-2-yl) -4-isopropoxycyclobut-3-en-1,2-dione (1.46 g; preferably as described in Example 1 (c) in dry dimethylformamide (10 mL)). Stirring at 0-5 ° C was continued for Ϊ an hour The resulting dark solution was poured into ethyl acetate (75 mL) and the resulting mixture was washed with water (60 mL) The aqueous phase was extracted with ethyl acetate. (60 ml) and the combined organic phases are washed with water (3x6 ml) and dried over magnesium sulfate. The solvent was evaporated under reduced pressure and the resulting residue was purified by flash chromatography on silica gel (ethyl acetate / petroleum ether (boiling point 4060 ° C) (4: 1)). The resulting active compound of the present invention is 3 [4 '- (5,7-dimethyl-2-propyl-3H-imidazo- [4,5-b] pyrid-3-ylmethyl) -biphenyl-2-yl] -4-isopropoxycyclobutyl-. 3-en-l, 2-dione - yellow gum (0.73 g).

An example

A solution of the final product of Example 7 in a mixture of acetic acid (30 mL) and water (17 mL) (0.73 g) was stirred at 95-100 ° C under nitrogen for 18 hours. The solvent was evaporated under reduced pressure and the resulting residue was mixed with ethyl acetate (20 mL). The active compound of the present invention is 3- (4 '- (5,7-dimethyl-2-propyl-3H-imidazo [4,5-b] pyrid-3-ylmethyl) biphenyl-2-yl] -4-hydroxycyclobut-3. -en-1,2-dione-yellow solid (0.44 g; mp 240 ° C, liquid from 210 ° C).

An example

The final product of Example 8 (0.40 g) was dissolved in a mixture of aqueous sodium hydrochloride solution (2.5M; 15 mL) and technical methyl alcohol (15 mL) and the resulting solution was extracted with dichloromethane (2 x 15 mL). The combined extracts were dried over magnesium sulfate and the solvent evaporated. 3- (4- (5,7-Dimethyl-2-propyl-3H-imidazo [4,5-b] pyrid-3-ylmethyl) -biphenyl-2-yl] -4-hydroxycyclobut-3-en-1, m.p. Sodium 2-dione (0.4 g; m.p. 182 ° C, with slight decomposition) is the active compound of this invention.

TT

10 'Example

2-Ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyridine was added to the stirred sulfuric acid (2.17 g) and the resulting solution was heated to 80 ° C. Potassium nitrate (3.0 g) was added portionwise over 10 minutes and the resulting mixture was heated at 95-100 ° C for 10 minutes, cooled and then poured onto ice (about 25 g). The mixture was neutralized with concentrated ammonia solution and then extracted with dichloromethane (2 x 50 mL). The combined extracts were dried over magnesium sulfate and then the solvent was evaporated. The resulting residue was recrystallized from ethyl acetate (15 mL) to give the intermediate 2-ethyl-5,7-dimethyl-6-nitro-3H-imidazo [4,5-b] pyridine (1.01 g; m.p. 146-). 149 ° C).

A solution of the product of Example 10 (a) (1.01 g) in technical methanol (75 ml) was shaken at room temperature under a hydrogen palladium on carbon (10%; 120 mg) and pressure for 7 hours. The resulting mixture was filtered through diatomaceous earth (trade name 'Celite') and the ro filtrate was evaporated. A viscous pale brown oil was obtained. Trituration of this oil in diethyl ether (30 mL) gave the intermediate 6-amino-2-ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyridine (0.88 g; mp 153-155 ° C). ).

6-Amino-2-ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyridine (1.89 g; more than 10 (b)) was dissolved in concentrated hydrochloric acid (2.6 mL) and water (2.6) by stirring. ml) in the mixture and the mixture was cooled to below 5 ° C. In support of the lower, neLT 3612 B

100 After 5 ° C, a solution of sodium nitrite (0.76 g) in water (2.2 ml) was added portionwise. The resulting solution (A).

Copper iodide (0.26 g) was dissolved in saturated sulfuric acetic acid (10 mL) and the resulting solution (B) was cooled to 10 ° C. To 1 stirred cooled solution (B) at 0-10 ° C, add solution (A) in portions over 10 minutes. The resulting mixture was stirred for 3.5 hours at 10-15 ° C, ice (100 g) was added, followed by extraction with dichloromethane (3X50 ml). The combined extracts were dried over magnesium sulfate and the solvent evaporated. A pale yellow solid was obtained which was added portionwise at room temperature to an aqueous solution of dimethylamine (30%; 20 mL). The solvent was evaporated under reduced pressure and the resulting residue was stirred with water (5 mL). Intermediate 2-ethyl-5,7, N, N-tetramethyl-3H-imidazo [4,5-b] pyridine-6-sulfonamide (0.21 g; m.p. 179-182 ° C) was obtained.

To a solution of the product of Example 10 (c) (0.19 g) in dry dimethylformamide (2 mL) under nitrogen was added sodium hydride (60% dispersion in mineral oil; 25 mg) and the resulting mixture was stirred for 10 minutes. The resulting solution was added dropwise at 0-5 ° C to stirred 3 (4'-bromomethyl-biphenyl-2-yl) -4-isopropoxycyclobut-3-ene-1,2-dione (0.289 g; preferably as in Example 1 (c)). solution in dry dimethylformamide (2 ml). ' The resulting mixture was stirred at room temperature for 1.5 hours, poured into ethyl acetate (50 mL) and then washed with water (2 x 25 mL). The washings were then extracted with ethyl acetate (40 mL). The combined organic solutions were dried over magnesium sulfate and the solvent evaporated under reduced pressure. The resulting residue was purified by silica gel flash chromatography (eluting with ethyl acetate / petroleum ether (boiling point 40-60 ° C) (4: 1)). Gau-r

101 that active compound of this invention is 2-ethyl-3- [2 '- (2-isopropoxy-3,4-dioxycyclobut-1-en-1-yl) biphenyl-4-ylmethyl] -5,7,7N, N-hetramethyl -3H-imidazo [4,5-b] pyridine-6-sulfonamide (0.2 mp 80 ° C with slow decomposition).

Example A solution of the final product of the sample (0.19 g) in a mixture of acetic acid (8.3 ml) and water (3.7 ml) was heated at 95-100 ° C for 15 hours. The solvent was evaporated under reduced pressure and the resulting residue was mixed with ethyl acetate (5 mL). The resulting solid was collected and dried under vacuum at 70 ° C. The resulting active compound of the present invention is 2-ethyl-3- [2 '- (2-isopropoxy-3,4-dioxocyclobut-1-en-1-yl) biphenyl-4-ylmethyl] -5,7, N, N-tetramethyl-3H. - Imidazo [4,5-b] pyridine-6sulfonamide monoethyl acetate solvate (0.15 g; m.p. 195-197 ° C (by decomposition)).

6-Amino-2-ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyridine (0.85 g; more preferably as in Example 10 (b)) was stirred with concentrated hydrochloric acid (1.15 ml) and water (1.15). ml> in a mixture, and the resulting solution was cooled to 0 [deg.] C. A solution of sodium nitrite (0.34 g) in water (1 ml) was added portionwise while maintaining the internal temperature below 5 [deg.] C. The resulting solution was stirred at this temperature for 10 minutes and then added to a stirred solution of copper chloride (0.48 g) in concentrated hydrochloric acid (1.7 ehI) while maintaining the temperature below 10 ° C. The resulting mixture was stirred at 70 ° C for 2 hours, then cooled to room temperature. The precipitate was collected and washed with water (5 ml). Recrystallization of this residue from methanol gave a second portion (70 mg) of the intermediate identified above.

102

To a suspension of the product of Example 12 (a) (0.28 g) in dry dimethylformamide (4 mL) was added sodium hydride (60% dispersion in mineral oil; 91 mg), and the resulting mixture was stirred at room temperature under nitrogen for 30 minutes. The resulting mixture was added portionwise to a solution of 3- (4'-bromomethylbiphenyl-2-yl) -4-isopropoxycyclobut-3-en-1,2-dione (0.548 g; more preferably as described in Example 1 (c)) in dry dimethylformamide (5). ml). The resulting mixture was stirred at room temperature for 5 hours and then poured into ethyl acetate (70 mL). The resulting mixture was washed with water (2 x 25 mL) and the washings were extracted with ethyl acetate (20 mL). The combined organic phases were dried over magnesium sulfate and the solvent evaporated under reduced pressure. Intermediate 3- [4 '- <6-chloro-2-ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyrid-3-ylmethyl) biphenyl-2-yl] -4-isopropoxycyclobut-3 was obtained. -en-l, 2-dione - a viscous oil (0.65 g).

The product of Example 12 (b) (0.65 g) was heated for 18 hours in a mixture of acetic acid (7 mL) and water (2.5 mL) at 95-100 ° C under a nitrogen atmosphere. The solvents were evaporated under reduced pressure and the resulting residue was mixed with ethyl acetate (20 mL). Resin formed. An aqueous sodium hydroxide solution (5 ml) was added to the resin. The resulting suspension was acidified with concentrated hydrochloric acid. A yellow solid was obtained which was collected on a filter and purified by flash chromatography on silica gel (eluting with ethyl acetate / 7: 3 methanol). The resulting active compound of the present invention is 3 [4 '(6-chloro-2-ethyl-5,7-dimethyl-3H-imidazol-4,5-b] pyridin-3-ylmethyl) biphenyl-2-yl] -4-hydroxycyclobut-3- en-1,2-dione hydrochloride, a yellow solid (70 mg; mp 205 ° C with decomposition).

ΤΤΓ

103

An example

To the stirred 3- [4 '- (2-ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyrid-3-ylmethyl) biphenyl-2-yl] -4-hydroxycyclobut-3-ene, To a suspension of 2-dione (4.21 g; preferably as in Example 4) in dry N, N-dimethylacetamide (40 ml) was added portionwise chloromethyl pivalate (3.22 g) at room temperature. Potassium iodide (2.5 g) was added to the resulting mixture and it was stirred at room temperature for a further 2 days. Chloromethyl pivalate (3.7 g) was added and stirred for a further 2 days. The resulting mixture was poured into diethyl ether (500 mL). A resin was obtained, which was separated and dissolved in a mixture of acetone (100 mL) and ethyl acetate (300 mL). The resulting solution was washed with a saturated aqueous solution of sodium bicarbonate (2 x 400 mL) followed by water (2 x 400 mL) and dried over magnesium sulfate. The solvents were evaporated under reduced pressure and the resulting residue was purified by flash chromatography on silica gel (ethyl acetate washing). The resulting active compound of the present invention is 2- [4 '- (2-ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyrid-3-ylmethyl) biphenyl-2-yl] -3,4-dioxocyclobut. -1-en-1-yloxymethyl] pivalate as a yellow foam (0.54 g), mp 60-80 ° C.

An example

Sodium hydride (60% dispersion in mineral oil; 36 mg) was added to a stirred solution of 4-ethyl-2-propyl-11 Himidazole-5-carboxaldehyde (0.15 g; preferably as described in WO92 / 00977; Dupont) in dry dimethylformamide (3 ml) and stirred. for another 45 minutes. The resulting solution was then added to a stirred solution of 3- (4-bromomethylbiphenyl-2-yl) -4-isopropoxycyclobut-3-ene-1,2-dione (0.35 g; preferably as in Example 1 (c)) in dry dimethylformamide (3 mL). . After stirring for 1 hour, 2-propanol (0.1 mL) was added. The resulting mixture was poured into ethyl acetate (20 mL) and then washed with water (15 mL). Wash waters ext. 3612 B

104 The reaction mixture was quenched with ethyl acetate (10 mL) and the organic phases were washed with water (5 x 15 mL) and dried over magnesium sulfate. The solvent was evaporated under reduced pressure and the resulting residue was purified by flash chromatography on silica gel (eluting with ethyl acetate / petroleum ether (boiling point 60-80 ° C) (75:25)). The resulting active compound of the present invention is 4-ethyl-1- [2'- (3,4-dioxo-2-isopropoxycyclobut-1-en-1-yl) biphenyl-4-ylmethyl] -2-propyl-1H-imidazole-5 -Carboxaldehyde in the form of foam (0.194 g).

Sample product (0.19 g), acetic acid (2 mL), and water (2 mL) were heated at 95-100 ° C under nitrogen for about 5 hours and then left at room temperature for a further 17 hours. The solvents were evaporated under reduced pressure and the resulting residue was mixed with ethyl acetate (2 x 15 mL) and dried in vacuo at 80 ° C. The resulting active compound of the present invention is 4-ethyl-1- [2 '- (2-hydroxy-3,4-dioxocyclobuten-1-yl) biphenyl-4-ylmethyl] -2-propyl-1H-imidazole-5-carboxaldehyde. yellow solid (0.12 g; m.p. 241-245 ° C).

An example

The final product of Example 5 (0.463 g; dried under vacuum since it is a hygroscopic compound) was dissolved in dry dimethylformamide (3 mL). The resulting solution was added to a solution of chloromethyl pivalate (0.19 g) in dry dimethylformamide (3 mL). The resulting mixture was stirred for about 17 hours and then potassium iodide (21 mg) was added and stirred for a further 3 days. Additional chloromethyl pivalate (98 mg) was added and stirred for a further 4 days. The resulting solution was partitioned between water (25 mL) and diethyl ether (25 mL). The aqueous layer was separated and extracted with diethyl ether (2 x 25 mL).

T

105

The combined organic layers were dried over magnesium sulfate, the solvent was distilled off and the resulting residue was purified by flash chromatography on silica gel (ethyl acetate followed by ethyl acetate / 9: 1 methanol). The fractions containing the higher content of the two main products were combined and evaporated under reduced pressure. The resulting residue was mixed with diethyl ether (2 mL). The resulting solid was collected and washed with diethyl ether (1 mL) and then dried. The active compound of the present invention is obtained [4 '- (2-ethyl-5,7-dimethyl-3H-imidazo [4,5-f] pyrid-3-ylmethyl) biphenyl-2-yl] cyclobut-3-en-1, 2dione - colorless solid (34 mg; m.p. 140142 ° C).

An example

The final product of Example 4 (1.01 g; dried under vacuum since it is a hygroscopic compound) was suspended in dry N, N-dimethylacetamide (10 mL). 1-Chloroethyl pivalate (0.9 g; preferably as described in J. Med. Chem. (1978), Vol. 21, p. 753) is added with stirring, followed by potassium iodide (0.77 g). Stirring is continued at room temperature for a further 3 days. The resulting suspension was diluted with ethyl acetate (50 mL) and washed with sodium bicarbonate solution (5%; 50 mL) followed by water (4 X 50 mL). The organic layer was dried over magnesium sulfate, the organic solvents evaporated under reduced pressure and the resulting residue was purified by flash chromatography on silica gel (ethyl acetate washing). The resulting active compound of the present invention is 1- [2- [4 '- (2-ethyl-5,7-dimethyl-3H-imidazo [4,5-b] pyrid-3-ylmethyl) biphenyl-2-yl] -3 , 4-Cyclobut-l-en-1-yloxy] ethyl pivalate 0.22 ethyl acetate solvate (0.55 g) as a yellow foam which is liquid and slowly melts at about 80 ° C.

106

An example

A solution of 4-bromomethyl-2'-iodobiphenyl (4.0 g; preferably 2 (b)) and butylamine (40 mL) in dry tetrahydrofuran (55 mL) was stirred in a flask with a rectification column at room temperature for 45 minutes. The solvent was evaporated under reduced pressure and the resulting residue was dissolved in dichloromethane (100 mL). The resulting solution was washed with aqueous potassium hydroxide solution (1M; 2X50 mL), water (50 mL), followed by hydrochloric acid (5M; 2X50 mL). The organic layer was dried over magnesium sulfate and the organic solvent evaporated. The resulting residue was purified by flash chromatography on silica gel (dichloromethane / methanol (9: 1)). The intermediate N- (2'-iodobiphenyl-4-ylmethyl) butylamine (1.9 g; mp 134-136 ° C) was obtained.

b) '

To a solution of the product of Example 18 (a) (1.9 g) and triethylamine (2.5 mL) in dry tetrahydrofuran (10 mL) was added ethyl 4-chloropyrimidine-5-carboxylate (0.9 g, preferably as described by Bredereck et al., Chem. Ber.). 1962), Vol, 95, p 803) in dry tetrahydrofuran (2 mL) and the resulting mixture was stirred at room temperature for about 1.5 hours. The solvent was evaporated under reduced pressure and the resulting residue was dissolved in dichloromethane (50 mL), washed with saturated sodium bicarbonate solution (2 x 25 mL) and then dried over magnesium sulfate. The solvent was evaporated and the resulting residue was purified by flash chromatography on silica gel (eluting with ethyl acetate). The intermediate 4-tert-butyl-N- (2'-iodobiphenyl-4-ylmethyl) amino] pyrimidine-5-carboxylate was obtained as a viscous oil (1.5 g).

• ΗΓ

107

3-Isopropoxy-4-tributylstanylcyclobut-3-ene-1,2-dione (1,626 g), tetrakis (triphenylphosphine) palladium (O) (0.348 g), copper iodide (0.138 g) and the product of Example 18 (b).

After stirring for 23.5 hours at room temperature under nitrogen, dry dimethylformamide (20 ml) was added. After dilution with ether (100 mL), the mixture was washed with saturated ammonium chloride solution (2 x 25 mL), aqueous potassium fluoride solution (10%; 2 x 25 mL), and water (2 x 25 mL). The organic phase was dried over magnesium sulfate and the solvent evaporated under reduced pressure. A brown solid was obtained. This solid is purified by flash chromatography on silica gel eluting with petroleum ether (boiling in water). 40-60 ° C) / ethyl acetate (1: 1). The resulting active compound of the present invention is ethyl 4- [N-butyl-N- [2 '- (2-isopropoxy-3,4-dioxocyclobut-1-en-1-yl) biphenyl-4-ylmethyl] amino] -pyrimidin-5 -Carboxylate - yellow oil (0.77 g).

Example (c) The product of Example (0.67 g) was heated at 96-100 ° C in a mixture of acetic acid (30 mL) and water (15 mL) under a nitrogen atmosphere for 22 h. The resulting solution was cooled and filtered. The solvents were evaporated under reduced pressure. The resulting active compound of the present invention is ethyl 4- [N-butyl-N- [2 '- (2-hydroxy-3,4-dioxocyclobut-1-en-1-yl) biphenyl-4-ylmethyl] amino] -pyrimidine-5-carboxylate. - Brown solid (0.59 g; m.p. 95 ° C (with decomposition)).

Example A solution of the final product of the sample (0.59 g) and sodium hydroxide (0.51 g) was stirred at room temperature for 7 hours in a mixture of methanol (20 ml) and water

108 (6 mL). The stirred solution was left at room temperature for a further 18 hours and then acidified to pH 2 by the addition of concentrated hydrochloric acid. The resulting mixture was diluted with water (20 mL) and filtered. A solid product (400 mg) was obtained, which was then stirred in a solution of sodium hydroxide (0.5 g) and water (10 ml) at room temperature for 6 hours, and the resulting mixture was acidified to pH 2 with concentrated hydrochloric acid. A pale brown precipitate was obtained. This precipitate was collected and dried. The resulting active compound of the present invention is 4- [N-butyl-N- [2'-hydroxy-3,4-dioxocyclobut-1-en-1-yl) biphenyl-4-ylmethyl] amino] -pyrimidine-5-carboxylic acid 0.6. hydrochloride (0.2 g; mp 172-175 ° C (with decomposition)).

An example

To a stirred solution of 2-butyl-2-imidazolin-4-spirocyclopentan-5 (1 H) -one (3.9 g; preferably as described in WO 91/14679; Sanofi) in dry dimethylformamide (68.5 mL) was added sodium hydride (68.5 mL) at room temperature. 60% dispersion in mineral oil; 0.804 g). Stirring was continued for another 45 minutes. The resulting solution was then added to a stirred solution of 3 (4'-bromomethylbiphenyl-2-yl) -4-isopropoxycyclobut-3-en1,2-dione (11.17 g; preferably as described in Example 1 (c)) in dry dimethylformamide and stirring was continued. for another 2 hours. 2-Propanol (2.6 mL) was added and the resulting mixture was poured into ethyl acetate (450 mL) and washed with water (250 mL). The aqueous layer was separated and extracted with ethyl acetate (300 mL). The combined organic layers were washed with brine (5 x 200 mL) and dried over magnesium sulfate. The organic solvent was evaporated under reduced pressure and the resulting residue was purified by flash chromatography on silica gel (eluting with ethyl acetate / petroleum ether (boiling point 60-80 ° C) (7: 3)). Obtained akLT 3612 B

109 3- [4 '- (2-Butyl-5-oxo-2-imidazolin-4-spirocyclopent-1-ylmethyl) -biphenyl-2-yl] -4-isopropoxycyclobut-3-ene-1,2-dione - yellow resin (3.6 g).

Example A mixture of the sample product (3.6 g) in acetic acid (35.2 ml) and water (35.2 ml) was heated at 95-100 ° C under a nitrogen atmosphere for about 4.5 hours. The solvents were evaporated under reduced pressure. The resulting resin was mixed with ethyl acetate (2 x 90 mL) and dried in vacuo at 60 ° C. The resulting active compound of the present invention is 3- [4 '- (2-butyl-5-oxo-2-imidazolin-4-spirocyclopent-1-ylmethyl) biphenyl-2-1] -4-hydroxycyclobut-3-ene-1,2-dione (1.91 g; m.p. 197199 ° C).

An example

To a stirred mixture of 2-butyl-4-chloro-1H-imidazole-5-carboxaldehyde (preferably as described in Drugs of the Future (1991), Vol. 16, p. 305), anhydrous potassium carbonate (6.9 g) and dry dimethylformamide (100 mL) ) at room temperature was added 4- (bromomethyl) -2'-iodobiphenyl (9.23 g; preferably as described in Example 2 (b)) in dry dimethylformamide (50 mL). Stirring was continued at room temperature for another 24 hours. Water (200 mL) was added and the resulting mixture was extracted with diethyl ether (500 mL then 200 mL). The combined extracts were washed with water (2 x 100 mL) and dried over magnesium sulfate. The organic solvent was evaporated and the residual orange oil was purified by silica gel thin layer chromatography (eluting with 5% then 30% ethyl acetate in petroleum ether (boiling point 60-80 ° C)).

110

The intermediate 2-butyl-4-chloro-1- (2'-iodobiphenyl-4-ylmethyl) -1H-imidazole-5-carboxaldehyde was obtained as a yellow oil (8.06 g).

To a solution of Example 23 (a) (0.5 g) in dry dimethylformamide (5 mL) was added 3-isopropoxy-4-tributyltin cyclobut-3-ene-1,2-dione (0.67 g; preferably as described by Liebeskind & Fengl, Journal of Organic Chemistry (1990), Vol 55, pp 5359/5364)), tetrakis (triphenylphosphine) palladium (O) (0.145 g) and copper iodide (48 mg). The resulting mixture was stirred at room temperature. in a nitrogen atmosphere for 24 hours. Diethyl ether (50 mL) was added and the resulting mixture was washed with saturated aqueous ammonium chloride solution (35 mL) followed by aqueous potassium fluoride solution (10%; 3 x 20 mL) and the organic layer was dried over magnesium sulfate. The organic solvents were evaporated in vacuo and the remaining orange / brown oil was purified by flash chromatography on silica gel (20% ethyl acetate in petroleum ether (boiling 60-80 ° C)). The resulting active compound of the present invention is 2-butyl-4-chloro-1- [2 '- (2-isopropoxy-3,4-dioxocyclobut-1-en-1-yl) biphenyl-4-ylmethyl)] -1H-imidazole. 5-Carboxaldehyde - Semi-solid yellow oil (0.22 g).

Example A solution of the final product of the sample (0.20 g) in a mixture of glacial acetic acid (5 ml) and water (5 ml)

Heat at 95-100 ° C for 4.5 hours. Glacial acetic acid (2 mL) and water (2 mL) were added and the mixture was heated for a further 5 hours. The resulting solution was cooled to room temperature and filtered. The solvents were evaporated in vacuo. The resulting active compound of the present invention is 2-butyl-4-chloro-1- [2 '- (2-hydroxy-3,4-dioxocyclobuten-1-yl) biphenyl-4-ylmethyl)] -1H-imidazol-5-one. carboxaldeLT 3612 B

111 hydra is a yellow solid that melts and melts at 50 ° C or below.

An example

To a solution of the product of Example 23 (a) (0.5 g) in methanol (5 ml) at room temperature was added sodium borohydride (39 mg) and the resulting solution was stirred for 1.5 hours. The solvent was evaporated in vacuo and water (50 mL) was added to the resulting residue. The resulting mixture was extracted with ethyl acetate (2 x 50 mL) and the combined extracts dried over magnesium sulfate. The solvent was evaporated in vacuo. The intermediate 2-butyl-4-chloro-5-hydroxymethyl-1- [2'-iodobiphenyl-4-ylmethyl] -1H-imidazole was obtained as a yellow oil (0.33 g).

To a solution of the product of Example 25 (a) above (0.30 g) in dry dimethylformamide (5 mL) under nitrogen was added 3-isopropoxy-4-tributyltin cyclobut-3-ene-1,2-dione (0.402 g), tetrakis (triphenylphosphine). palladium (O) (86 mg) and copper iodide (28 mg). The resulting mixture was stirred for 40 hours. Diethyl ether (50 mL) was added and the resulting mixture was washed with saturated aqueous ammonium chloride solution (30 mL) followed by aqueous potassium fluoride solution (10%; 2x20 mL). The organic solution was dried over magnesium sulfate and the solvents evaporated in vacuo. The resulting residue was dissolved in diethyl ether (10 mL), the insoluble material was removed by filtration, and the solvent was again evaporated in vacuo. The resulting residue was purified by silica gel flash chromatography (eluting with ethyl acetate / petroleum ether (boiling point 60-80 ° C) (1: 1)). The resulting active compound of the present invention is 3- [4 '- (2-butyl-4-chloro-5-hydroxymethyl-1H-imi [beta]

112 dazol-1-ylmethyl) -biphen1-2-yl] -4-isopropoxycyclobut-3en-1,2-dione - yellow oil (80 mg).

Example A solution of sodium hydride (60% dispersion in mineral oil; 35 mg) in dry dimethylformamide (2 ml) was added methyl 2-butyl-4-chloro-1H-imidazole-5-carboxylate under nitrogen at room temperature and stirring was continued for another 30 minutes. . 3- (4'-Bromomethylbiphenyl-2-yl) -4-isopropylcyclobut-3-ene-1,2-dione (0.64 g; better than 1 (c)) in dry dimethylformamide (3 mL) was then added. ) and stir for another 24 hours. The reaction mixture was partitioned between water (20 mL) and diethyl ether (20 mL). The aqueous layer was separated and extracted with diethyl ether (20 mL). Combined ethereal. the solutions were dried over magnesium sulfate and the solvent evaporated in vacuo. The residue obtained was purified by flash chromatography on silica gel (eluting with 20% ethyl acetate in petroleum ether (boiling point 4060 [deg.] C.) (1: 1)). The resulting active compound of the present invention is 2-butyl-4-chloro-1- [2 '- (2-isopropoxy-3,4-dioxocyclobut-1-en-1-yl) biphenyl-4-ylmethyl] -1H-imidazole-5-carboxylate - yellow oil (0.17 g).

An example

(a) A solution of sodium chlorite (1.02 g) and sodium dihydrogen phosphate (1.02 g) in water (24 ml) is added at room temperature to a solution of product 23 (0.5 g) in t-butanol and the resulting mixture is stirred vigorously for 40 hours. Subsequently, enough sodium metabisulphite is added to make the solution yellow. Then, most of the solvents were evaporated in vacuo. Water (75 mL) was added to the resulting residue and the resulting mixture was added

T

113 extracted with dichloromethane (2X50 mL). The combined extracts were dried over magnesium sulfate and the organic solvent was evaporated in vacuo. Trituration of the resulting residue with diethyl ether (5 mL) gave the intermediate 2-butyl-4-chloro-1- (2'-iodobiphenyl-4-ylmethyl) -1H-imidazole-5-carboxylic acid as a colorless solid (0.27 g; m.p. mp 175 ° C).

To a stirred suspension of sodium hydride (60% dispersion in mineral oil; 41 mg) in dry dimethylformamide (5 mL) was added methyl 2-butyl-4-chloro-1- (2'-iodobiphenyl-4-dimethyl) -1- at room temperature under nitrogen. imidazole-5-carboxylic acid (0.43 g; preferably as described in Example 27 (a)), and stirring was continued for another 30 minutes. Iodomethane (0.06 mL) was then added and stirred for a further 2 hours. Diethyl ether (20 mL) was then added and the resulting mixture was washed with water (20 mL). The washings were extracted with diethyl ether (2 x 20 mL) and the combined organic phases dried over magnesium sulfate. The organic solvent was evaporated. Another intermediate methyl 2-butyl-4-chloro-1- (2'-iodobiphenyl-4-ylmethyl) -1H-imidazole-5-carboxylate was obtained as an oil (0.43 g).

To a solution of the product of Example 27 (b) (0.42 g) in dry dimethylformamide at room temperature under nitrogen was added 3-isopropoxy-4-tributyltin cyclobut-3-ene-1,2-dione (0.53 g), tetrakis (triphenylphosphine) palladium (O). (0.12 g) and copper iodide (38 mg).

The mixture is stirred for 18 hours. Diethyl ether (30 mL) was added and the resulting mixture was washed with saturated aqueous ammonium chloride solution (20 mL) followed by aqueous potassium fluoride solution (10%; 2 x 20 mL). OrLT 3612 B

114 the organic phase was dried over magnesium sulfate and the solvent evaporated in vacuo. The resulting residue was purified by flash chromatography on silica gel eluting with a gradient of 20% to 50% ethyl acetate in petroleum ether (boiling at 40-60 ° C) to give the active compound of the present invention (substantially identical to Example 26) methyl 2-butyl. -4-Chloro-1- [2 '- (2-isopropoxy-3,4-dioxocyclobut-1-en-1-yl) biphenyl-4-ylmethyl] -1H-imidazole-5-carboxylate - yellow oil (0.1 g) ).

An example

Methyl 2-butyl-4-chloro-1- [2'-isopropoxy-3,4-dioxocyclobut-1-en-1-yl) biphenyl-4-ylmethyl] -1H-imidazole-5-carboxylate (0.26 g; preferably as described in Example 27 (c)) was heated in a mixture of glacial acetic acid (5 ml) and water (5 ml) at 95-100 ° C for 5 hours. The solvents were evaporated in vacuo and the resulting residue was purified by flash chromatography on silica gel (eluting with 10% to 30% ascending order in technical methyl alcohol in ethyl acetate). The resulting active compound of the present invention is methyl 2-butyl-4-chloro-1- [2 '- (2-hydroxy-3,4-dioxocyclobut-1-en-1-yl) biphenyl-4-ylmethyl] -1H-imidazol-5-one. Carboxylate - yellow oil (0.1 g).

An example

To a solution of the product of Example 28 (90 mg) in methanol (3 mL) was added aqueous sodium hydroxide solution (2M; 1 mL) at room temperature. The resulting mixture was stirred for 2 hours. The solvent was evaporated in vacuo and water (2 mL) was added to the resulting residue and the resulting solution acidified to pH 1 with hydrochloric acid (5M). The resulting yellow precipitate was filtered off, washed with water and dried. The resulting active compound of the present invention is 2-butyl-4-chloro-1- [2 '- (2-hydroxy-3,4-dioxocyclobut-1-en-1-yl) biphenyl-4-ylmethyl] -1H-imidazol-5 -karLT 3612 B

115 Boxylic acid 0.4 hydrochloride is a pale yellow solid (70 mg; m.p. 168 ° C).

An example

A mixture of 2-butyl-4-chloro-1H-imidazole-5-carboxaldehyde (4.0 g; preferably as described in Drugs of the Future (1991), Vol. 16, p. 305), potassium carbonate and dry dimethylformamide (50 ml) was stirred at room temperature for 15 minutes. at temperature. To the resulting mixture was added 4-iodobenzyl bromide (6.34 g) and stirring was continued for about 17 hours. The solvent was then evaporated under reduced pressure at 80 ° C. Water (200 mL) was added to the resulting residue, which was then extracted with diethyl ether (2 x 100 mL). The combined extracts were washed with water (50 mL) and dried over magnesium sulfate. The solvent was evaporated. The resulting residue was purified by flash chromatography on silica gel (eluting with dichloromethane / methanol (80: 1)). The intermediate 2-butyl-4-chloro- (4-iodobenzyl) -1H-imidazole-5-carboxaldehyde was obtained as an oil (6.9 g).

b) To a stirred solution of lithium diisopropylamide tetrahydrofuran adduct (16.4 ml; 1.5M in cyclohexane) in dry tetrahydrofuran (50 ml) at -70 ° C under nitrogen was added methyl 3-phenylpropanoate (4.03 g) in dry tetrahydrofuran (50 ml) over 15 minutes. ). Stirring at -70 ° C is continued for about 1 hour. A solution of the product of Example 30 (a) (6.6 g) in dry tetrahydrofuran (50 mL) was then added over 15 minutes and the resulting mixture was stirred at -70 ° C for 4 hours. The mixture was allowed to warm to 0 ° C and was poured into a saturated aqueous solution of ammonium chloride (250 mL) and extracted with ethyl acetate (3 x 150 mL). Combine

116 the extracts were washed with brine (50 ml), dried over magnesium sulfate and evaporated to dryness under reduced pressure. The resulting residue was mixed with petroleum ether (boiling 60-80 ° C; 2 x 100 mL) and further purified by flash chromatography on silica gel (eluting with dichloromethane / methanol (50: 1)). The intermediate methyl 2-benzyl-3- [2-butyl-4-chloro- (4-iodobenzyl) -1H-imidazol-5-yl] -3-carboxypropenoate (5.7 g, mp 155-159 ° C) is obtained. ) - a solid mixture of diastereomers.

A solution of the product of Example 30 (a) (5.7 g), acetic anhydride (11 ml) and 4-dimethylaminopyridine (0.5 g) in dichloromethane (250 ml) was stirred at room temperature for about 17 hours and then washed with saturated sodium bicarbonate solution (2 x 300 ml). ). The organic layer was dried over magnesium sulfate and the solvent evaporated. The resulting residue was dissolved in dry toluene (300 mL) and added

1,8-Diazabicyclo [5.4.0] talc-7-eno (6 mL). The resulting mixture was heated to 95-100 ° C under nitrogen for about 8 hours and then cooled. The solvent was then evaporated under reduced pressure and the resulting residue was purified by flash chromatography on silica gel (60: 1 dichloromethane / methanol). The intermediate (E) -methyl 2-benzyl-3- [2-butyl-4-chloro-1- (4-iodobenzyl) -1H-imidazol-5-yl] propenoate was obtained as an oil (3.5 g).

A mixture of the product of Example 30 (c) '(0.8 g), 3-isopropoxy-4-tributyltin cyclobut-3-ene-1,2-dione (0.9 g), tetrakis (triphenylphosphine) palladium (O) (0.2 g) ), copper iodide (0.1 'g) and dry dimethylformamide (5 mL) were stirred at room temperature under nitrogen for about 17 hours. The solvent was evaporated under reduced pressure and the resulting residue was dissolved in diethyl ether iii

117 (150 mL). The resulting solution was washed with a saturated aqueous ammonium chloride solution (50 mL) followed by a saturated aqueous potassium fluoride solution (2X50 mL) and dried over magnesium sulfate. The solvent was evaporated and the resulting residue was purified by flash chromatography on silica gel (eluting with dichloromethane / methanol (50: 1)). The intermediate (E) -methyl 2-benzyl-3- [2-butyl-4-chloro-1- [4- (2-isopropoxy-3,4-dioxocyclobut-1-en-yl) benzyl] -1H-imidazole is obtained. 5-yl] Propenoate - Oil (0.4 g).

(E) -methyl 2-benzyl-3- [2-butyl-4-chloro-1- [4- (2-isopropoxy-3,4-dioxocyclobut-1-en-1-yl) benzyl] -1H- imidazol-5-yl] propenoate (1.2 g; preferably as described in Example 30 (d)) and aqueous acetic acid (50%; 20 ml) was heated at 95-100 ° C for 6 hours. The solvents were evaporated under reduced pressure and the resulting residue was mixed with diethyl ether (2 x 20 mL). The resulting solid was dissolved in technical methyl alcohol (20 mL). Aqueous sodium hydroxide solution (0.5M, 22 ml) was then added and the resulting mixture was stirred at room temperature for 1 hour and then neutralized with hydrochloric acid (5 M). The solvent was evaporated under reduced pressure and the resulting residue was extracted with aqueous sodium hydroxide solution (1M; 60 mL) and then acidified with hydrochloric acid (5M). The resulting precipitate was collected, washed with water (2 x 10 mL) and dried. The active compound of the present invention is obtained (E) methyl 2-benzyl-3- [2-butyl-4-chloro-1- [4- (2-hydroxy-3,4-dioxocyclobut-1-en-1-yl) benzyl] -1H. -imidazol-5-yl] propenoic acid - solid (0.54 g; m.p. 155160 ° C).

Contents85

Every citation, both ways

Citations
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US5043349A	Cites	United States of America	Applicant
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38 members in 27 offices

This recordMember, by publication datePriority claim17 more offices are in the list below

Priority claims3

Priority claims
Document	Office	Kind	Date
9218449	United Kingdom	A	1992-08-29
9218449	–	–	–
GB19920018449	–	–	–

Members38

Family members, oldest first
Document	Office	Kind
GB9214690D0	United Kingdom	D0	1992-08-19
GB9218449D0	United Kingdom	D0	1992-10-14
GB9218848D0	United Kingdom	D0	1992-10-21
GB9218849D0	United Kingdom	D0	1992-10-21
IL106283D0	Israel	D0	1993-11-15
CA2139930A1	Canada	A1	1994-01-20
WO9401436A1	World Intellectual Property Organization (WIPO)	A1	1994-01-20
AU4565893A	Australia	A	1994-01-31
ZA934909B	South Africa	B	1994-02-11
MX9304151A	Mexico	A	1994-02-28
LTIP787A	Lithuania	A	1994-11-25
NO950082D0	Norway	D0	1995-01-09
FI950089A	Finland	A	1995-03-07
NO950082L	Norway	L	1995-03-09
HU9500043D0	Hungary	D0	1995-03-28
EP0649424A1	European Patent Office (EPO)	A1	1995-04-26
PL307127A1	Poland	A1	1995-05-02
SK2895A3	Slovakia	A3	1995-07-11
CZ4795A3	Czechia	A3	1995-07-12
KR950702560A	Republic of Korea	A	1995-07-29
JPH07508740A	Japan	A	1995-09-28
BG99337A	Bulgaria	A	1995-09-29
LT3612BThis record	Lithuania	B	1995-12-27
HUT72086A	Hungary	A	1996-03-28
AU673183B2	Australia	B2	1996-10-31
IN177310B	India	B	1996-12-28
HRP931044A2	Croatia	A2	1996-12-31
YU48193A	Yugoslavia, later Serbia and Montenegro (until 2006)	A	1997-01-08
RU95105969A	Russian Federation	A	1997-01-10
US5627191A	United States of America	A	1997-05-06
NZ254112A	New Zealand	A	1997-06-24
KR0137885B1	Republic of Korea	B1	1998-04-27
EP0649424B1	European Patent Office (EPO)	B1	1998-10-07
AT171946T	Austria	T	1998-10-15
ATE171946T1	Austria	T1	1998-10-15
DE69321471D1	Germany	D1	1998-11-12
DE69321471T2	Germany	T2	1999-03-04
MY131465A	Malaysia	A	2007-08-30