6-benzoxazinyl- and 6-benzothiazinyl-2,3,4,5- tetrahydropyridazin-3- ones, their preparation and pharmaceutical compositions containing them

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6-בנזוקםאזיניל- ו 6-בנזותיאזיניל-5,4,3,2טטראהידרופירידאזין־-3-אונים, הכנתם ותכשירי רוקחות המכילים אותם

6-BenzoxazinyI- and G-benzothiazinyl-ZjS^jS-tetrahydropyridazin-3-ones, their preparation and pharmaceutical compositions containing them

ORTHO PHARMACEUTICAL CORPORATION

C. 73489

BACKGROUND OF THE INVENTION

Field of the Invention

The present invention relates to compounds of the formula:

<img file="IL84832A_D0001.tif" />

as further defined herein. The compounds are useful as cardiotonic and vasodilating agents and as inhibitors of phosphodiesterase fraction III and platelet aggregation. In addition, the compounds are active as smooth muscle relaxants and bronchodilators The present invention further relates to intermediates of these compounds as further defined herein.

Description of the Prior Art

Quinoline substituted pyridazin-3-ones have been shown to be cardiotonic agents and platelet aggregation inhibitors. Published European Patent Application No. 155,798 and British Patent No. 2,031,404 describe compounds of the formula:

ORTH 534

<img file="IL84832A_D0002.tif" />

^•0 where R. , R_n and R, may be H or lower alkyl. 1 J J

U.S. Patent 4,562,190 describes benzothiazole substituted pyridazin-3-ones of the formula &lt;

where R, is C -C. alkyl and R_ is H, C -C. alkyl or aryl. 11b 4 lb

SUMMARY OF THE INVENTION

The present invention is directed to 6-benzoxazinyl- and 6־benzothiazinyl-2,3,4,5-tetrahydropyridazin-3-ones of the general formula:

.\N

<img file="IL84832A_D0003.tif" />

where

ORTH 534 ^C3-6

X may be H₂ or O;

Y may be O or S;

R₁ may cycloalkyl;

R₂ may cyclo alkyl or

R₃ may cycloalkyl, benzoyl, phenylalkanoyl such alkanesulfonyl such as methanesulfonyl;

be H C, straight- or branched-chain alkyl or ’ 1-6 be H, C, . straight- or branched-chain alkyl, 1-6

C- . alkenyl;

ώ^-0 be H, C straight- or branched-chain alkyl or 1-6 _____ and when X is H₂, R₃ may also be C_{2 6} alkanoyl, phenylalkanoyl such as phenylacetyl, or ^C36־ ^C3-6

R₄ may be H, halogen, C_p6 straight- or branched-chain alkyl or C alkoxy;

R and R. may each be H, C _R straight- or branched-chain

6 alkyl or C, cycloalkyl; and the dotted line may be a single or double bond between C4 and C5 of the pyridazine ring.

The compounds of formula I are useful as cardiotonic agents having a long duration of activity and are very potent inhibitors of phosphodiesterase fraction III. __ —

Intermediates useful in the preparation of the compounds of formula I of the present invention are those of the general formulas of

<img file="IL84832A_D0004.tif" />

where

ORTH 534

R , R , R , R₅ and Κθ may independently be H, straight- ־/branched-chain alkyl or C₃.₆ cycloalkyl;

M may be -CN or mono- or di-C₁_₆ alkyl amino;

X may be Hg or 0;

Y may be 0 or S;

r W and Z may independently be Η, straight- or branched-chain alkyl, C₂.₆ acyl or -C(O)CHR₄CH₂C(O)OR₇־ and r₇ may be H or C_p6 straight- or branched-chain alkyl.

The intermediates of the general formula IV may also include the quaternary ammonium salts thereof.

In the. intermediate? of the general formula V, R₃ may also be C alkanoyl, benzoyl, phenylalkanoyl or alkylsulfonyl when X is ¾. In addition, when one of R, W and Z is C(O)CHR₄CH₂C(O)OR₇, then the other cannot be the same substituent.

detailed description of THE INVENTION to pyridazinone compounds platelet anti-aggregatory inhibitory activity.

The invention in its broadest aspects relates which exhibit cardiotonic activity, vasodilating activity, activity and phosphodiesterase fraction III

- ,* The pyridazinone compounds of the invention d־m־A־/w «h-־ activities are shown by form־»״-⁰^ ־!״η pyridszi־״־״ compounds ־ ״!־»״־־ _tida2inone compounds, further relates to intermediates of the py ״

The preferred compounds of the present invention are th־־־ • .d γη R and R״ are hydrogen, R₄, R5 ^R6 ^areΓοΓοΗ,,¹ X is 0 or H and the pyridazinone ring is attached at C-7 of the benzoxazine ring.

The starting material־ for preparing the compounds of present invention can be prepared as shown in Scheme 1.

ORTH 534

SCHEME 1

<img file="IL84832A_D0005.tif" />

wherein R' is RCO or RSO , wherein R is lower alkyl and the alkyl group contains 16־ carbon atoms, and R_4׳ R₅ and R_g are as previously defined.

The benzoxazinone or benzothiazine 2 is prepared from compound 1 by the procedure of Shridhar, OrgPrep.Proc.Int. 14, 195 (1982). Compound 2 is refluxed for several hours in one equivalent of diborane in tetrahydrofuran to produce the benzoxazine or benzothiazine 3. Compound 3, where R^ is H, is treated with a sulfonyl or acyl compound such as methanesulfonyl chloride or acetyl chloride and pyridine in a solvent such as dichloromethane and refluxed for several hours to produce the benzoxazine or benzothiazine 4.

The compounds of formula I can be prepared as shown in Schemes 2, 3 and 4.

ORTH 534

SCHEME 2

<img file="IL84832A_D0006.tif" />

The benzoxazine or benzothiazine 2 or 4 is acylated by the method of Thyes, J.Med.Chem. 26, 800 (1983) using succinic anhydride to produce the compound 5^ Compound 5 is refluxed for 18־ hours with 2.2 equivalents of hydrazine in an alcohol solvent such as methanol to give compound 6. Alternatively, compound 6 can be prepared by first esterifying compound 5 in alcoholic HC1 to form compound 8 and then reacting compound 8 with hydrazine. Compound 6 can be alkylated at the 2-position of the pyridazinone ring by treatment in an inert solvent such as dimethylformamide with an alkali metal base such as sodium hydride and subsequent treatment with an alkyl halide, RjX wherein Rj is as defined above and X is chloro, bromo or iodo, at about 0-40°C for about 0.58־ hours to give compound 7. Alternatively,

ORTH 534 compound 5 (when R״ is H) can be alkylated at the 4-position as “ u described above to give compound 8. Compound 8 is refluxed with hydrazine to produce compound 6. The N-acylated derivative 7 (X = H₂; Rj = acyl or sulfonyl) was prepared from 6 (X = H₂; R, = H) by treatment with a base, such as triethylamine, and the appropriate acid chloride, such as acetyl chloride, methanesulfonyl chloride, benzoyl chloride, for example; as described above.

SCHEME 3

<img file="IL84832A_D0007.tif" />

To prepare a 5־alkylated pyridazinone, . the benzoxazine or benzothiazine 2 or 4 is acylated with propionyl chloride by the method of Thyes, supra, and the resulting product is converted to compound 9 by the method of McEvoy and Allen, J.Org.Chem. 38, 4044 (1973). Compound 9 is reacted with hydrazine or alkylated as described above to produce compounds 10 and 11, respectively. Compound 11 can be reacted with hydrazine to give compound 10.

ORTH 534

Compound 10 can be alkylated at the 2-position of the pyridazinone ring or acylated at the 4-position of the benzoxazine or benzothiazine ring as described previously.

SCHEME 4

<img file="IL84832A_D0008.tif" />

The benzoxazine or benzothiazine 2 or 4, when R. is -- 4

-C-CH--R. at the 7-position of the ring, is converted to compound Ζ X by the method of McEvoy and Allen, supra. Compound 12 is reacted with hydrazine or alkylated as described above to produce compounds 13 and 14, respectively. Compound 14 can be reacted with hydrazine to give compound 13. Compound 13 can be alkylated at the 2-position of the pyridazinone ring or acylated at the 4-position of the benzoxazine or benzothiazine ring as previously described.

Pharmaceutical compositions containing a compound of the present invention as the active ingredient in intimate admixture with a pharmaceutical carrier can be prepared according to

ORTH 534 conventional pharmaceutical compounding techniques. The carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., intravenous, oral or parenteral. The composition may also be administered by means of an aerosol. In preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like in the case of oral liquid preparations (such as, for example, suspensions, elixirs and solutions); or carriers such as starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like in the case of oral solid preparations (such as, for example, powders, capsules and tablets). Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be sugar-coated or enteric-coated by standard techniques. For parenterals, the carrier will, usually comprise sterile water, though other ingredients, for example, to aid solubility or for preservative purposes, may be included, injectable suspensions may also be prepared, in which case appropriate liquid carriers, suspending agents and the like may be employed. The pharmaceutical compositions will generally contain dosage unit, e.g., tablet, Capsule, powder, injection, teaspoonful and the like, from about 0.001 to about 10 mg/kg, and preferably from about 0.01 to about 0.1 mg/kg of the active ingredient.

The following examples describe the invention in greater particularity and are intended to be a way of illustrating but not limiting the invention.

EXAMPLE 1

3,4-Dihydro-7-(l-oxopropyl)3־oxo-1,4( 2H)-benzoxazine

4-Amino-3-hydroxypropiophenone (32 g) was dissolved in 250 ml of methyl isobutyl ketone and 250 ml of water containing 40 g of

ORTH 534 sodium bicarbonate. Chloroacetyl chloride (17 ml) was added to the rapidly stirring mixture at 0°C. The mixture was then heated at reflux for four hours. Upon cooling, the title compound was isolated by filtration and washed with ether. Yield: 35 g (88%), mp 174.5-176°C.

The following compounds were prepared by the above procedure, using the appropriate starting materials:

3.4- dihydro-3-oxo-l,4(2H)-benzoxazine, mp 170-171°C;

3.4- dihydro6־-methyl-3-oxo-l,4(2H)-benzoxazine, mp 204.5-

205.5°C;

3.4- dihydro-7-methyl-3-oxo־l,4(2H)-benzoxazine, mp 193-195°C;

3.4- dihydro-2-methyl-3-oxo-l,4(2H)-benzoxazine, mp 143-145°C;

3.4- dihydro-2,2-dimethyl-3-oxo-l,4(2H)-benzoxazine, mp 161163°C;

3.4- dihydro-2,7-dimethyl-3-oxo-l,4(2H)-benzoxazine, mp 152-

153°C;

3.4- dihydro-4-(1-methylethyl) -3-oxo-1,4(2H)-benzoxazine, oil;

3.4- dihydro4־-cyclopentyl-3-oxo-l,4(2H)-benzoxazine, oil;

3.4- dihydro-2-methyl4־-(l-methylethyl)-3-oxo-l, 4 (2H) benzoxazine, oil;

3.4- dihydro-2-methyl-4-cyclopentyl-3-oxo-l,4(2H)-benzoxazine, oil; and

3.4- dihydro-7-(l-oxoethyl)-3-oxo-l,4(2H)-benzoxazine, mp 193-196°C.

The following compounds were prepared by the above procedure, using the appropriate starting materials:

3.4- dihydro-3-oxo-1,4 [2H ]benzothiazine;

3.4- dihydro-3-oxo7־- (l-oxopropyl)-l, 4 [ 2H ] benzothiazine;

3.4- dihydro-2-methyl-3-oxo-l, 4[2H]benzothiazine; and

3,4־dihydro-2,2-dimethyl-3-oxo-l, 4 [ 2H ] benzothiazine.

ORTH 534 ־11EXAMPLE 2

3,4-Dihydro-l. «^2H)־^benWX2־ine !-1,4 (2H) ־benzoxazine several hours in one eq¹Excess sodium hydroxide extracted with ether and title compound as an oil.

was refluxed for ₃₃.Dlhydr־---׳-״.1-»־-3-־--_otane ._{n te״ahydroiB}״״.

ληοΗ the product was solution was added, th P . _{ent wa8} evaporated to give the the solvent was «׳ל“׳י

- _The following ״.” - —־־*:T ^{the ־b0Te PWed}' ־״, using th־ ־W-pnst״»״*־ ־g י .dihyd«-«-»^-‘.«״‘“״״׳״'-«¹־' ^a״d

3',4.dihydr2-־-n־thyl־l.‘<^2H>־^ben^e.

EXAMPLE •3 “:'.״־XX׳״-־.״,״,, “ך.“,—,.»,., r־^d “ ^tha ° _{with wa}t־^dd־ ־» triethylamine

- ־־ 7. :X Evaporation ״־' saturated NaHCOj provided the product, mp .

P P »־» following compounds ־_Th ־’— ng»״.־ ־using the apP^t .־_ur ^—־—4-־ydr-־.,3 .82°C־80 mp

The mixture was refluxed , and then with organic layer above procedmp 74.5-77°C;

; and

EXAMPLE 4

4-Oxo3,4) -4־-dihydro2־-methyb3־oxol,4(2H)-benzoxazin6־-yl)butync acid

4-Dlhydro-2-methyl-3-ox2)1.4-־H)-b־n־oxari״e (4.״ g> succinic anhydride (7 g) ״״ “*ded ” ^{93 e 0£}and 15.3 ml of dimethylformamide. The mixture «־״< ־ ־־ ,o־c for 2.3 hours and th״־ poured onto 1־־, giving ־ «hd wtach collected by filtration ״־< — * with water. Drpng ״>״״ of the title compound (90% yield), P was vacuum gave 16.5 g ^{2 8״}!he following compounds were prepared by the above procedure, using the appropriate starting materials:

4-oxo-4-(3,4-dihydro-3-oxo-1.4(2H)-be״zox־־in-6-yl)butyric acid.mp 206208°*־C;

4-oxo-4-(3.4־dihydro-2,2-dimethyl־3־oxo-l,4(2H)-benzoxaz1n6־yl)butyric acid;

4-ox3.4>-4-־-dihydr7-־-m־thyl-3-־x2)1.4-־H>-b־־״־x״־n-

6-yl)butyric acid, mp 226-228^QC;

״ ״ u. ׳i-nxo-1 4( 2H)-benzoxazin4-oxo3,4)-4־-dihydro-2,7-d1methyl 3 oxo רל׳-yl)butyric acid;

₄-oxo-4-(3.4־dihydr־4־־methanesulfonyl-1.4(2H)-be״zoxazm6־yl)butyric acid, mp 184-187°C;

4-oxo-4-(3,4-dihydro־4־(l־oxoethyl)־l,4(2H)-benzoxaz1־״

6- yl)butyric acid, mp 143144.5°־C,

2)4 ,4 יH)־benzoxaz1n25 4-oxo-4-(3,4־dihydro-6-methyl 3 oxo , t 8-yl)butyric acid; and

״.;,״ ״ι-'ΐ-ηγη-Ι 4(2H)־benzoxaz1n4-oxo3,4)־4־-d1hydro6־-methyl 3 oxo 1, 1

7- yl)butyric acid.

ORTH 515

EXAMPLE 5

Methyl 4-oxo-4-(3,4-dihydro-4-methyl-3-oxol,4(2H)-benzoxazin-6־yl)butyrate

3,4-Dihydro-3־oxo־l,4(2H)-benzoxazine was alkylated by dissolving the acid in dimethylformamide and adding two equivalents of 60% sodium hydride in oil suspension. After one-half hour, two equivalents of methyl iodide were added. The mixture was stirred under nitrogen for 12 hours, then poured into water. The product was collected by extraction into ethyl acetate and evaporation of the solvent, mp 139-140°C.

The following compounds were prepared by the above procedure, using the appropriate starting materials:

methyl 4-oxo-4-(3,4-dihydro-2,4־dimethyl-3-oxo־l,4(2H)benzoxazin-6-yl)butyrate, oil;

methyl 4-oxo-4-(3,4-dihydro-4,7־dimethyl3־-oxo-l,4(2H)benzoxazin-6-yl)butyrate, oil;

methyl 4-oxo3,4)-4־-dihydro-2,4,7-trimethyl-3-oxo-l, 4(2H)benzoxazin-6־yl)butyfate, oil;

methyl 4-oxo-4-(3,4-dihydro-4,6-dimethyl-3-oxo-l,4(2H)benzoxazin-8-yl)butyrate, oil;

methyl 4-oxo-4-(3,4-dihydro-4,6-dimethyl-3-oxo-l,4(2H)benzoxazin-7-yl)butyrate, oil;

methyl 4-oxo-4-(3,4-dihydro2,4־-trimethyl-3-oxo-l,4(2H)benzoxazin-6-yl)butyrate, oil;

methyl 4־oxo3,4)־4־-dihydro-4־methyl־3־oxo־l,4(2H)benzoxazin-6-yl)3־-methylbutyrate, oil;

methyl 4-oxo־3,4)־4־dihydro-2,4-dimethyl-3-oxo-l,4(2H)benzoxazin-6-yl)3־-methylbutyrate, oil;

methyl 4-oxo-4-(3,4-dihydro4,7־-dimethyl-3-oxo-l,4(2H)benzoxazin-6-yl)3־-methylbutyrate, oil;

methyl 4-oxo-4-(3,4-dihydro-2,4,7-trimethyl-3־oxo-l,4(2H)benzoxazin-6-yl)-3-methylbutyrate, oil;

ORTH 534 methyl 4-oxo-43,4)־-dihydro-4,6-dimethyl-3-oxo-l,4(211)benzoxazin-8-yl)-3-methylbutyrate, oil; and methyl 4-oxo-4-(3,4-dihydro4־-methyl-3־oxo-l,4(2H)benzoxazin-7-yl)-3-methylbutyrate, oil.

EXAMPLE 6

- Oxo- 4 - (3,4 -dihydro- 7 - m ethyl- 3-oxo-l,4(2H)benzoxazin-6-yl) -3-methylbutyric acid

A. 3,4-Dihydro-7-methyl-3-oxo-l,4(2H)-benzoxazine was acylated with propionyl chloride by the method of Example 4 in 85% yield. The product of this operation was converted to the title compound as follows:

B. 3,4-Dihydro7־-methyl-6-(l-oxopropyl)3־-oxo-l,4(2H)-benzoxazine (23.7 g) was added to a mixture of 13 g of dimethylamme hydrochloride and 15 ml of 37% aqueous formaldehyde solution in 68 ml of acetic anhydride. After heating on a steam bath for three hours, 50 ml of acetone was added and heating was continued for 15 minutes. The solvents were removed by evaporation at reduced pressure and the residue was dissolved in IN HCl and washed with ethyl acetate. The aqueous layer was basified with sodium hydroxide and the resultant crystals were collected by filtration. This product was dissolved in 500 ml of acetone and 10 ml of iodomethane were added. After heating at reflux overnight, the solid which formed was collected by filtration and washed with acetone. The product was dissolved in 400 ml of 50% aqueous methanol and 18 g of potassium cyanide in 200 ml of water was added. After stirring overnight at room temperature, the solid was collected and washed with water. The damp filter cake was suspended in 500 ml of 6N HCl and heated at reflux for 1.5 hours. Upon cooling a white precipitate formed which was collected by filtration and washed with water to give 19.4 g (81% yield) of the title compound, mp 169.5-172°C.

ORTH 534

The following compounds were prepared by the above procedure, using appropriate starting materials:

4-oxo-4-(3,4-dihydro-l, 4(2H)-benzoxazin-6-yl)-3methylbutyric acid;

4-oxo-4-(3,4-dihydro-2-methyl-l,4(2H)-benzoxazin-6-yl)-3methylbutyric acid;

4-oxo-4-(3,4־dihydro-3-oxo-l,4(2H)-benzoxazin-6-yl)-3methylbutyric acid;

4-oxo-4- (3,4-dihydro-2-methyl-3-oxo-l, 4 (2H) -benzoxazin6-yl)-3-methylbutyric acid;

4-oxo-4-(3,4-dihydro-2,7־dimethyl-3-oxo-l,4(2H)-benzoxazin6-yl)־3־methylbutyric acid;

4-oxo-4-(3,4-dihydro-4-(l-methylethyl)-2-methyl-3-oxo-l, 4(2H)benzoxazin-6-yl)-3-methylbutyric acid;

4-oxo-4-(3,4-dihydro-4-cyclopentyl-2-methyl-3-oxo-l,4(2H)benzoxazin-6-yl)3־-methylbutyric acid;

4-oxo3.4)־4־-dihydro6־-methyl-3-oxo-l, 4(2H)-benzoxazin-

8-yl)3־-methylbutyric acid; and

4-0X0-4- (3,4-dihydro-6-methyl-1,4 (2 H) -benzoxazin-8-yl) -3methylbutyric acid.

EXAMPLE 7

4-Oxo-4-(3,4-dihydro-3-oxo-l,4(2H)benzoxazin-7-yl)-3-methylbutyric acid

3,4-Dihy dro-7 - (1 -oxop ropy 1) 3 ־ -oxo-1,4 (2 H) -benzoxazine (from Example 1) was converted to the title compound by the method of Example 6B.

ORTH 534

־16־

EXAMPLE fi- (3 4-Dihvdro-4-methanesulfonyl־l, 4 (2H) ־ benzoxazin-5-yO -2,3,4, 5-tetrahydropyridaz1n-3-one

4-(3,4-dihy dro-4־methanesulfonyl־l, 4- (2H) -benzwas suspended in methanol and 2.2 equivaThe mixture was brought to

Ethyl 40־x0oxazin־6־yl)butyrate lents of hydrazine were added, reflux and stirred for 24 hours. Upon cooling, crystals of the desired product formed and were collected by flitration. Recrystallization from ethanol gave P״r־ title compound, mp 245־C.

Theor. C_uH_wH_$O₄S:

Found:

C, 50.47; H, 4.90; N, 13.59

C, 50.46; H, 4.85; N, 13.67

When in the above procedure, ethyl 4-oxo-4-(3,4-dihydro-4methanesulfonyl-l.4(2H)-benzoxazin-6-yl)-3-ethylbutyrate; ethy oxo-4-(3,4-dihydro-4-m־than־sulf־nyl-l,4&lt;2H)-b״־zoxaz1n-6-yl3־hexylhutyrate; or ethyl 4-־x3.4)-4-־-dihydr4-־-m־th־n־־ulf־nyl! 4(2H)-benz־x־zin-6-yl)-3-(l-n־thyl־thyl)butyr.te ¹⁹ ״ the starting material, the ' corresponding 5-ethyi-. 5-h־xyl- or -5-d-methylethyl) -pyridazin-3-one derivative is obtatned.

EXAMPLE 9 a &lt;3 4-Dihydro-4-methanesulfonyl-1.4(2H)-ben־oxa1־n6-y5 .2,3,4-״-tetrahydro-2-m־thylpyndaz1n-3-one

6-(3 4-Dlhydr4-־-meth־n־sult־nyl-l,4(2H)־b־n־oxa־in-6-yl)־ &lt;3,4 uiny suspended in 50 ml of

2,3,4,5-tetrahydropyndaz1n-3-one ( g) .

, pmiivalent of 60% sodium hydride in oil dimethylformamide and one equi . .

was added. When gas evolution ceased, one iodide was added and the mixture allowed to followed by one hour at 40־C. The mixture poured into 200 ml of ice water, giving a . j with water and recrystallized from collected by filtration, washed with water a equivalent of methyl stand for 1.5 hours was cooled and then precipitate that was

ORTH 534 ethanol. The material was further purified by chromatography on silica gel eluted with 1:1 EtOAc:Et₂O yielding 0.97g of the title product, mp 162-165°C.

Theor. C, .H.N.OS: 14 17 3 4

Found:

C, 51.99; H, 5.31; N, 13.00

C, 51.92; H, 5.32; N, 12.96

EXAMPLE 10

6-(3,4-Dihydro-4-methanesulfonyl-l, 4(2H)-benzoxazin6-yl)-2,3,4,5-tetrahydro-2-pentylpyridazin-3-one

6-(3,4-Dihydro-4-methanesulfonyl-l, 4 (2H) -benzoxazin-6-yl)-

2,3,4,5-tetrahydropyridazin-3־one was reacted with pentyl bromide in place of methyl iodide following the procedure of Example 9. The title compound was recovered, yield 1.46 g, mp 138-139°C.

Theor. C,.H.,N,OS: C, 56.96; H, 6.65; N, 11.07

25 3 4 _Found; C, 56.67; H, 6.49; N, 11.05

When in the above־ procedure, bromocyclohexane or 2-bromopropane is utilized in place of pentyl bromide, the corresponding 2-cyclohexyl or 2-(l-methylethyl)pyridazinone is obtained.

EXAMPLE 11

6-(3,4-Dihydro-4-methanesulfonyl-l, 4(2H j.-benzoxazin6-yl)-2,3,4,5-tetrahydro-2-(2-propenyl)pyridazin-3־one

6-(3,4-Dihydro4־-methanesulfonyl־l, 4 (2H) -benzoxazin-6-yl)-

2,3,4,5-tetrahydropyridazin-3-one was reacted with allyl bromide instead of methyl iodide, following the procedure of Example 9. The title compound was recovered, yield 2.03 g, mp 153-155°C.

Theor. C₁₆H₁₉N₃O₄S:

Found:

C, 54.99; H, 5.49; N, 12.03

C, 54.94; H, 5.58; N, 11.92

ORTH 534

EXAMPLE 12

6-(3,4-Dihydro-l, 4(2H)-benzoxazin-6־yl)־

2,3,4.5-tetrahydropyridazm-3-one

The method of Example 8 was followed using 4-oxo-4-(3,4dihydro-1,4-(2H)-benzoxazin-6-yl)butyric acid as the starting material to give the title compound in 60% yield, mp 198-199 C.

Theor. C_1־H₁₃N₃O₂:

Found ־.

C, 62.31; H, 5.68; N, 18.17

C, 62.35; H, 5.72; N, 18.18

EXAMPLE 13

6-<4-Acetyl-3,4-dihydro-l,4(2H)-benzoxazin-6-yl>2,3,4,5־tetrahydropyridazin-3-one

The method of Example 8 was f־H־״־d 4 8‘־״-ox3,4)-4-־dihydro-3,4-i starting material to 156-158°C.

_acet_yl-l,4-(2H)־benzoxazin-6־yl)butync acid as the yield the title compound in 40% :־־’^J yield, mp

Theor.

Found: .

C, 61.52; H, 5.54; N, 15.38

C, 61.49; H, 5.55; N. 15.24

EXAMPLE 14

1) ״-Dihvdro-4-(3,4-dimethoxyphenylcarbonyl)-M(2H)⁶־⁽ benzoxLin-6-yl)2.3,4,5־-tetrahydropyndaz1n-3-one

6-(3 4-Dihydro-l,4(2H)־benzoxazin-6-yl)2,3,4,5־-tetrahydrosolution and then evaporated to dry־־־״. The residue ־־״

ORTH 534 chromatographed on silica gel eluting with 1:1 ethyl acetate: ethyl ether. The title compound was collected as white needles, mp 207-208°C.

Theor. C₂₁H₂₁N₃O₅:

Found:

C, 63.78; H, 5.36; N, 10.63

C, 63.78; H, 5.40; N, 10.64

EXAMPLE 15

6-(3,4־Dihydro־l,4(2H)-benzoxazin6־-yl)2,3,4, 5־tetrahydro-5-methylpyridazin-3-one

The method of Example 8 was followed using 4-oxo-4-(3,4־ dihydro-1,4(2H)-benzoxazin-6-yl)-3-methylbutyric acid as the starting material to produce the title compound, mp 166-168°C.

Theor. C.H.X0.: C, 63.65; H, 6.18; N, 17.13

Found: C, 63.47; H, 6.22; N, 16.90

When in the above procedure, 4-oxo-4-(3,4-dihydro-l,4(2H)benzoxazin-6־yl)3־-ethylbutyric acid; 4-oxo-4-(3,4־d1hydrol,4(2H)-benzoxazin-6-yl)-3-hexylbutyric acid or 4-oxo-4-(3,4dihydro-1, 4(2H)-benzoxazin-6-yl)־3־(l־methylethyl)butyric acid is utilized, the corresponding 5-ethyl-, 5-hexyl- or -5-(l-methylethyl)-pyridazin-3-one derivative is obtained.

EXAMPLE 16

6-(4-Acetyl-3,4-dihydro-l,4(2H)-benzoxazin-6־yl)-

2,3,4,5-tetrahydro-5־methylpyridazin-3־one

6-(3,4-Dihydro-l, 4(2H)-benzoxazin6־-yl)2,3,4,5־-tetrahydro-

5-methylpyridazin-3-one was suspended in tetrahydrofuran and one equivalent of acetyl chloride was added. After one half hour at

ORTH 534 °C, the solvent was removed in vacuo, and the product was crystallized from ethanol in 61% yield, mp 185.5186°־C.

Theor. CHNO: 10 1ί u o

Found:

C, 62.69; H, 5.97; N, 14.63

C, 62.85; H, 6.03; N, 14.64

EXAMPLE 17

6-(3,4-Dihydro-4-methanesulfonyl-l, 4 (2H )־benzoxazin6-yl)-2,3,4,5-tetrahydro-5-methylpyridazin3־-one

The method of Example 16 was followed using methanesulfonyl chloride instead of acetyl chloride. Pyridine was added to the mixture. After one hour at 0°C, the mixture was warmed to room temperature and allowed to stir for 48 hours and then refluxed for 24 hours. Acetonitrile was added and the mixture was adsorbed onto silica gel and eluted with ethyl acetate. The title compound was crystallized from ethanol to give a 25% yield, mp 207-212°C.

Theor. ^C!4^H17^N3°4^S:

Found:

C, 51.99; H, 5.31; N, 13.00

C, 52.42; H, 5.31; N, 13.39

EXAMPLE 18

6-(3,4-Dihydro-2-methyl־l, 4(2H)-benzoxazin6-yl) 2,3,4,5־-tetrahydropyridazin3־-one

The method of Example 8 was followed using 4-oxo3,4)-4־dihydro-2-methyl־l,4(2H)benzoxazin-6-yl)butyric acid as the starting material to give the desired product in 10% yield, mp

294.5-295.5°C.

Theor. 1J 13 j z

Found:

C, 63.65; H, 6.18; N, 17.13

C, 63.37; H, 6.16; N, 17.41

ORTH 534

When in the above procedure, 4-oxo-4-(3,4-dihydro-2-methyl-

7-pentyl-l,4(2H)-benzoxazin-6-yl)butyric acid; 4-oxo-4-(3,4-dihydro-2-hexyl-7־isopropyl-l,4(2H)-benzoxazin-6-yl)-2-hexylbutyric acid; 4-oxo-4-(3,4-dihydro-2-methyl-7-cyclohexyl-l,4(2H)-benzoxazin-6-yl)butyric acid; 4-oxo-4-(3,4-dihydro-2-isobutyl-7-methoxyl,4(2H)-benzoxazin-6-yl)butyric acid or 4-oxo-4-(3,4-dihydro-2cyclopentyl-l,4(2H)-benzoxazin-6-yl)butyric acid is used, the corresponding pyridazinone derivative is obtained.

EXAMPLE 19

6-(3,4-Dihydro-2-methyl-l, 4(2H)-benzoxazin6-yl)-2,3,4,5-tetrahydro-5-methylpyridazin-3-one

The method of Example 8 was followed using 4-oxo-4-(3,4dihydro-2-methyl-l,4(2H)benzoxazin-6-yl)-3-methylbutyric acid as the starting material. The product was further purified by chromatography on silica gel, mp 179-182°C.

Theor. C, 64.83; H, 6.62; N, 16.21 _Found: ׳ C, 64.51; H, 6.64; N, 15.84

When in the above procedure, 4-oxo-43,4)־-dihydro-2-methyll,4(2H)-benzoxazin-6-yl)3־-ethylbutyric acid; 4-oxo-43,4)־-dihydro-2-methyl-l,4(2H)benzoxazin-6-yl)3־-hexylbutyric acid or 4oxo-4-(3,4-dihydro-2-methyl-l,4(2H)benzoxazin-6-yl)-3-(l-methylethyl)butyric acid is utilized, the corresponding 5-ethyl.5 ,־-hexyl_or-(1-methylethyl)-pyridizin-3-one derivative is obtained.

EXAMPLE 20

6-(3,4-Dihy dro-3-oxo-l, 4 (2H)-benzoxazin6-yl)-2,3,4,5-tetrahydropyridazin-3-one

Following the method of Example 8, but using methyl 4-0X0-4(3,4-dihydro-3-oxo-l,4(2H)benzoxazin-6-yl)butyrate, the title comORTH 534 ־22pound was obtained and was recrystallized from ethanol and then from acetonitrile as a hydrate, mp 274275°־C.

Theor. Ο^Η^Ο^Ο: C, 57.70; H, 4.65; N, 16.83

Found: C, 57.54; H, 4.50; N, 16.79

EXAMPLE 21־

6-(3,4-Dihydro-4־methyl-3־oxo־l,4(2H)־benzoxazin6-yl)-2,3,4,5-tetrahydropy ridazin-3-one

The method of Example 8 was followed using methyl 4-0X0-4־ (3,4-dihydro-4-methyl-3-oxo-l,4(2H)benzoxazin-6-yl)butyrate as the starting material. The product was purified by column chromatography followed by several recrystallizations from acetonitrile, mp 247247.5°־C.

Theor. C₁₃H₁₃N₃O₃: C, 60.21; H, 5.06; N, 16.21

Found: C, 59.85; H, 4.98; N, 16.26

EXAMPLE 22

6-(3,4-Dihy dro-3-oxo-l, 4 (2H) -benzoxazin6-yl)-2,3,4,5-tetrahydro-5-methylpyridazin3־-one

The method of Example 8 was followed using methyl 4-0x04־(3,4-dihydro-3-oxo-l,4(2H)benzoxazin-6-yl)3־-methylbutyrate as the starting material. The product was purified by crystallization from acetonitrile, followed by column chromatography on silica gel and eluted with 5% methanol in dichloromethane, mp 265267°־C.

Theor. ^1/4^י₃0₃א₃^3ן H^O: C, 59.19; H, 5.17; N, 15.93

Found: C, 59.22; H, 4.98; N, 15.92

ORTH 534

When in the above procedure, 4-oxo-4-(3,4-dihydro-3-oxol,4(2H)-benzoxazin6־-yl)3־-ethylbutyrate; 4-oxo־3,4)-4־dihydro-3oxo-1 _t4(2H)־benzoxazin-6-yl)3־-hexylbutyrate or 4-oxo-4-(3,4-dihydro-3-oxo-l,4(2H)benzoxazin-6־yl)-3-(l-methylethyl)butyrate is utilized, the corresponding 5-ethyl-, 5-hexyl- or -5־(l-methylethyl)-pyridazin-3-one derivative is obtained.

EXAMPLE 23

6-(3,4-Dihy dro-4-methyl-3-oxo-1,4 (2H) -benzoxazin6-yl)-2,3,4,5-tetrahydro-5-methylpyridazin-3-one

The method of Example 8 was followed using methyl 4-0X0-4(3,4-dihydro-4-methyl-3-oxo-l, 4( 2H)benzoxazin-6־yl)3־-methylbutyrate as the starting material. The product was purified by chromatography and eluted with 5% methanol in dichlorornethane, mp 215-218°C.

Theor C Η N 0 . C, 61.52; H, 5.54; N, 15.34

L5 ineor. .^₁₄^π14^1Ν3^ν₃.

_Found; C, 61.80; H, 5.75; N, 15.63

EXAMPLE 24

6-(3,4-Dihydro-2-methyl־3־oxo-l, 4 (2H) -benzoxazin6-yl)2,3,4,5־-tetrahydropyridazin-3-one ₂₀ The method of Example 8 was followed using 4-oxo-4-(3,4dihydro-2-methyl-3-oxo-l,4(2H)-benzoxazin6־-yl)butyric acid as the starting material, to produce the title compound in 75% yield,

C, 60.21; H, 5.06; N, 16.21

C, 60.02; H, 5.22; N, 16.08 mp 275-276°C.

Theor. C₁₃H₁₃N₃O_j:

Found:

ORTH 534

EXAMPLE 25

6-( 3,4-Dihydro-2,4-dimethyl-3-oxo-l, 4( 2H)-benzoxazin6-yl) 2,3,4,5־-tetrahydropyridazin-3-one

The title compound was produced in 25% yield, by following 5 the method of Example 8, using methyl-4-oxo-4-(3,4-dihydro-2,4dimethyl-3-oxo-l,4(2H)-benzoxazin-6-yl)butyrate as the starting material, mp 210211°־C.

Theor. C. .Η״Ν,Ο1/2.״ H״O: C, 59.56; H, 5.72; N, 15.16

15 3 3 2

Found: C, 59.93; H, 5.48; N, 15.16

EXAMPLE 26

6-(3,4-Dihy dro- 2-methyl-3-oxo-1,4 (2 H) -benzoxazin6-yl) 2,3,4,5־-tetrahydro-5-methylpyridazin-3-one

The method of Example 8 was followed using 4-oxo-4-(3,4dihydro-2-methyl-3-oxo-l,4(2H)-benzoxazin-6-yl)-3־methylbutyric acid as the starting material, to yield the title compound in 50% yield, mp 271-272°C.

Theor. CHNO: C, 61.52; H, 5.54; N, 15.38

15 0 0

Found: C, 61.34; H, 5.59; N, 15.41

When in the above procedure, 4-oxo-4-(3,4־dihydro-2-methyl2q 7-pentyl-3-oxo-l,4(2H)-benzoxazin-6-yl)butyric acid; 4-0Χ0-4(3,4-dihydro-2-hexyl-7-isopropyl-3-oxo-l, 4(2H)-benzoxazin-6-yl)butyric acid; 4-oxo-4-(3,4-dihydro-2-methyl-7-cyclohexyl3־-oxol,4(2H)-benzoxazin-6-yl)butyric acid; 4-oxo-4-(3,4-dihydro-2-isobutyl-7-methoxy-l,4(2H)-benzoxazin-6-yl)butyric acid or 4-0Χ0-49= (3,4-dihydro2־-cyclopentyl-3-oxo-l, 4(2H)-benzoxazin-6-yl)butyric acid is used, the corresponding pyridazinone derivative is obtained.

ORTH 534

EXAMPLE 27

6-(3,4-Dihydro-2,4-dimethyl-3-oxo-l, 4 (2H)-benzoxazin6-yl)-2,3,4, 5-tetrahydro-5-methylpyridazin-3-one

Following the method of Example 8, using methyl 4-0X0-4(3,4-dihydro-2,4-dimethyl-3-oxo-l,4(2H)-benzoxazin-6-yl)-3-methylbutyrate as the starting material, the title compound was obtained, in 40% yield, mp 184-185°C.

Theor. C_1eH._N,0,: C, 62.70; H, 5.98; N, 14.63

17 J 0

Found: C, 62.75; H, 5.95; N, 14.79

EXAMPLE 28

6-(3,4-Dihydro-7-methyl3־-oxo-l,4(2H)-benzoxazin6-yl)-2,3,4, 5-tetrahydropyridazin-3-one

The method of Example 8 was followed, using 4-oxo-4-(3,4־dihydro-7-methyl-3-oxo-l,4(2H)-benzoxazin6־-yl)butyric acid as the starting material, to produce the title compound in 55% yield, mp 255-257°C.

Theor. C^H^N^:

Found:

C, 60.21; H, 5.06; N, 16.21

C, 59.90; H, 5.26; N, 15.95

When in the above procedure, 4-oxo-4-(3,4-dihydro7־־-pentyl3-oxo-l,4(2H)-benzoxazin-6-yl)butyric acid; 4-oxo-4-(3,4-dihydro2-hexyl-7-isopropyl-3-oxo-l,4(2H)-benzoxazin-6-yl)butyric acid; 4oxo-4- (3,4-dihy dro-7-cyclohexyl-3-oxo-1,4 (2H) -benzoxazin-6-yl) butyric acid; 4-0x0-47(3,4-dihydro-2-isobutyl-7־methoxy-3-oxol,4(2H)benzoxazin-6-yl)butyric acid or 4-oxo-4-(3,4-dihydro-2cyclopentyl-3-oxo-l,4(2H)-benzoxazin-6-yl)butyric acid is used, the corresponding pyridazinone derivative is obtained.

ORTH 534

EXAMPLE 29

6-(3,4-Dihydro-4,7-dimethyl-3-oxo-l,4(2H)-benzoxazin6-yl)2,3,4,5־-tetrahydropyridazin-3-one

The title compound was obtained, in 47% yield, by following the method of Example 8, using methyl 4-oxo-4-(3,4-dihydro-4,7dimethyl-3־oxo-l,4(2H)-benzoxazin-6־yl)butyrate as the starting material, mp 227-228.5°C.

Theor. C H N.O.: C, 61.52; H, 5.54; N, 15.38

15 3 3

Found: C, 61.65; H, 5.57; N, 15.26

EXAMPLE 30

6-(3,4-Dihy dro-7 -methyl- 3-oxo-1,4 (2 H) -benzoxazin6-yl)-2,3,4,5-tetrahydro-5-methylpyridazin-3-one

The method of Example 8 was followed, using 4-oxo-4-(3,4dihydro-7-methyl-3-oxo-l,4(2H)-benzoxazin-6-yl)-3-methylbutyric acid as the starting material, to give the title compound in 51% yield, mp 163-166°C.

Theor. C. .H.N.O.-1/4 H״O: C, 60.52; H, 5.63; N, 15.13

15 3 3 4

Found: C, 60.65; H, 5.62; N, 15.03

EXAMPLE 31

6-(3,4-Dihy dro-4,7-dimethyl-3-oxo-l, 4( 2H) -benzoxazin6-yl) ־2,3,4,5־tetrahydro-5-methylpyridazin-3-one

Following the method of Example 8, using 4-oxo-4-(3,4-dihydro-4,7-dimethyl-3־oxo-l,4(2H)-benzoxazin-6־yl)3־-methylbutyrate

ORTH 534 as the starting material, the title compound was produced, mp 180-182°C.

Theor. C,_eH,״N_nO . C, 62.70; H, 5.98; N, 14.63

17 0 0

Found: C, 62.77; H, 6.06; N, 14.57

EXAMPLE 32

6-(3,4-Dihydro-2,7-dimethyl-3-oxo-l, 4( 2H)-benzoxazin6-yl)-2,3,4, 5-tetrahydropyridazin-3-one

The method of Example 8 was followed, using 4-oxo-4-(3,4-dihydro-2,7-dimethyl-3-oxo-l, 4( 2H)-benzoxazin-6-yl)butyric acid to give the title compound, mp 252-254°C.

Theor. C״H״N_O.-l/4 H,O: C, 60.52; H, 5.64; N, 15.13

15 3 3 Z

Found: C, 60.50; H, 5.45; N, 15.63

EXAMPLE 33

6-(3,4-Dihydro-2, 4,7־-trimethyl-3-oxo-l ,4(2H)-benzoxazin6-yl) -2,3,4,5-tetrahydropyridazin-3-one

Following the method of Example 8, using methyl 4-0Χ0-4(3,4-dihydro-2,4,7-trimethyl-3-oxo-l, 4(2H)-benzoxazin-6-yl)butyrate as the starting material, the title compound was obtained, mp 210-212°C.

Theor. C, 62.70; H, 5.98; N, 14.63

1/ u 0

Found: C, 62.85; H, 6.11; N, 14.93

ORTH 534

EXAMPLE 34

6-(3,4-Dihydro-2,7-dimethyl-3-oxo-l,4(2H)-benzoxazin6־yl)2,3,4,5־-tetrahydro-5-methylpyridazin-3-one

The method of Example 8 was followed, using 4-oxo3,4)־4־-dihydro-2,7-dimethyl-3-oxo-l, 4( 2H)-benzoxazin-6-yl)3־-methylbutyric acid, to yield the title compound, mp 190-191°C.

Theor. C H N O •1/2 HjO: C, 60.80; H, 6.14; N, 14.18

Found: C, 61.18; H, 6.42; N, 13.78

EXAMPLE 35

6~(3,4-Dihydro־2,4,7־trimethyl-3-oxo-l,4(2H)-benzoxazin’6-yl) 2,3,4,5־-tetrahydro-5-methylpyridazin-3-one

Following the method of Example 8, using methyl 4-oxo4-(3,4-dihydro-2,4, 7-trimethyl-3-oxo-l, 4(2H)-benzoxazin-6-yl)3־methylbutyrate as the starting material, the title compound was produced, mp 190-192°C.

Theor. C ,״Ν,Ο,-1/2 H O: C, 61.91; H, 6.51; N, 13.54 _Found; י’ C. 2.02־; H. 0.52; N, 13.86

When in the above procedure, 4-oxo-43,4)־-dihydro-2,4-dimethyl-7-pentyl-3-oxo-l,4(2H)־benzoxazin-6-yl)-3-methylbutyrate; 4-oxo-4-(3,4־dihydro-2-hexyl-4-methyl7־-isopropyl-3-0xo-l,4-(2H)benzoxazin-6-yl)3־-methylbutyrate; 4-oxo-(3,4-dihydro-2,4-d1methyl-7-cyclohexyl3־-oxo-l,4(2H)-benzoxazin-6-yl)-3-methylbutyrate; 4-oxo-4-(3,4-dihydro-2-isobutyl-4־methyl-7-methoxy-3-oxo1,4(2H)benzoxazin-6-yl)3־-methylbutyrate; or 4-oxo3,4)-4־-dihydro-2-cyclopentyl-4,7-dimethyl-3-oxo-l,4(2H)-benzoxazin6־-yl)3־methylbutyrate is used, the corresponding pyridazinone derivative is obtained.

ORTH 534

EXAMPLE 36

6-(3,4-Dihydro-2-methyl-4-(l-methylethyl)-3-oxo

1,4 (2H)-benzoxazin6־-yl)-2,3,4,5־ tetrahydro-5-methylpyridazin-3-one

The method of Example 8 was followed, using 4-oxo-4-(3,4-di- hydro-4-(l-methylethyl)-3-oxo-l,4(2H)-benzoxazin-6-yl)-3-methylbutyric acid as the starting material to give the title compound, mp 204-205°C.

Theor. C״H N 0 ־ C, 64.73; H, 6.72; N, 13.33

Found: C, 64.67; H, 6.66; N, 13.42

EXAMPLE 37

6-(3,4-Dihy dro- 4 -cyclopentyl- 2- m ethyl- 3 -oxo1,4(2H)-benzoxazin-6-yl)2,3,4,5־tetrahydro-5-methylpyridazin-3־one

Following the method of Example 8, using 4-oxo-4־3,4)־dihydro-4-cyclopentyl-2-methyl-3-oxo-l,4(2H)-benzoxazin-6-yl)3־-methylbutyric acid as the Starting material, the title compound was obtained, mp 220-223°C.

Theor. C₁₉H₂₃N₃O₃:

Found:

C, 66.84; H, 6.80; N, 12.31

C, 64.61; H, 6.78; N, 12.29

EXAMPLE 38

6-(3,4-Dihydro-6-methyl-3-oxo-l, 4(2H)-benzoxazin8-yl) -2,3,4,5-tetrahy dropyridazin-3-one

The method of Example 8 was followed, using 4-oxo-43,4)־-dihydro-6-methyl-3-oxo־l,4(2H)-benzoxazin-8־yl)butyric acid as the starting material to give the title compound, mp 266-270°C.

Theor. C₁₃H₁₃N₃O₃:

Found:

C, 60.21; H, 5.06; N, 16.21

C, 60.13; H, 5.26; N, 16.28

ORTH 534

EXAMPLE 39

6-(3,4-Dihydro-4,6-dimethyl-3-oxo-l, 4( 2H) -benzoxazin8-yl)2,3,4,5־-tetrahydropyridazin-3־one rf

Following the method of Example 8, using 4-oxo-4-(3,4-dihydro-4,6-dimethyl-3-oxo-l,4(2H)-benzoxazin-8-yl)butyrate as the starting material, the title compound was obtained in 16% yield, mp 266-270°C.

Theor.

Found:

C, 61.52; H, 5.54; N, 15.38

C, 61.18; H, 5.64; N, 15.36

EXAMPLE 40

6-(3,4-Dihydro-6-methyl-3-oxo-l,4(2H)-benzoxazin8—yl)—2,3,4,5-tetrahy dro-5-methylpyridazin-3-one

The method of Example 8 was followed, using 4-oxo-4-(3,4-d1hydro-6-methyl-3-oxo-l,4(2H)-benzoxazin-8־yl)butyric acid as the starting material, to give the title compound in 31% yield, mp 252-253.5°C.

Theor. θ₁₄Η₁₅Ν₃Ο₃: Found:

C, 61.52; H, 5.54; N, 15.38

C, 61.11; H, 5.68; N, 15.26

EXAMPLE 41

6-(3 4-Dihydro-4,6-dimethyl-3-oxo-l,4(2H)-benzoxazin8-yl)-2,3,4,5-tetrahy dro-5-methylpyridan-3-one

The method of Example 8 was followed, using methyl 4-0X0-4. (3,4-dihydro-4,6-dimethyl-3-oxo-l,4(2H)-benzoxazin-8-yl)-3-methylbutyrate as the starting material, to produce the title com

ORTH 534 pound in 15% yield after column chromatography on silica gel eluted with 5% methanol in dichloromethane, mp 212-213°C.

Theor. C₁₅H₁₇N₃O₃:

Found:

C, 62.69; H, 5.98; N, 14.63

C, 62.27; H, 5.92; N, 14.57

EXAMPLE 42

6-(3,4-Dihydro-6-methyl-l, 4(2H)-benzoxazin8-yl)-2,3,4,5-tetrahydro-5־methylpyridazin3־-one

Following the method of Example 8, using ethyl 4-oxo-4-(3,4dihydro-6-methyl-l,4(2H)־benzoxazin-8-yl)-3־methylbutyrate as the starting material, the title compound was prepared in 60% yield, mp 160-162°C.

Theor. C₁₄H₁₇N₃O₃;

Found:

C, 64.83; H, 6.62; N, 16.21

C, 64.87; H, 6.66; N, 16.31

When in the above procedure, 4-oxo3,4)-4־-dihydro-6-methyl1,4(2H)-benzoxazin-8-yl)-3-ethylbutyrate; 4-oxo-4-(3,4-dihydro-6methyl-l,4(2H)-benzoxazin-8־yl)־3־hexylbutyrate or 4-oxo-4-(3,4dihydro-6-methyl-l,4(2H)-benzoxazin8־-yl)-3-(l-methylethyl)butyrate is utilized, the corresponding 5-ethyl-, 5-hexyl- or -5-(1methylethyl )-pyridazin-3-one derivative is obtained.

EXAMPLE 43

6-(3,4-Dihy dro-4,6-dimethyl-3-oxo-l, 4 (2H) benzoxazin-7-yl)-2,3,4,5-tetrahydropyridazin-3-one

The method of Example 8 was followed, using methyl 4-0X0-4(3,4-dihydro-4,6-dimethyl-3-oxo-l, 4(2H)-benzoxazin-7-yl)butyrate

ORTH 534 as the starting material to produce the title compound, mp

211-213°C.

Theor. C^H^N^:

Found:

C, 61.52; H, 5.54; N, 15.38

C, 61.57; H, 5.49; N, 15.28

EXAMPLE 44

-6-(3,4-Dihydro-2,2-dimethyl-3-oxo-l,4(2H)benzoxazin-6-yl) -2,3,4,5־tetrahydropyridazin-3־one

The method of Example 8 was followed, using 4-oxo-4-(3,4-dihydro-2,2-dimethyl-3-oxo-l,4(2H)-benzoxazin-6-yl)butyric acid as the starting material, to give the title compound, mp 251-254°C.

Theor. ^c1a^H1=^Na°Q^:14 13 J 0

Found:

C, 61.52; H, 5.54; N, 15.38

C, 61.40; H, 5.58; N, 15.74

EXAMPLE 45

6-(3,4-DihydrO-2,2,4-trimethyl-3-oxo-l, 4 (2H) benzoxazin-6-yl)2,3,4,5־-tetrahydropyridazin-3-one

Following the method of Example 8, using methyl 4-0X0-4(3,4-dihydro-2,2,4-trimethyl-3-oxo-l, 4( 2H) -benzoxazin-6-yl)butyrate, the title compound was produced, mp 169-171°C.

Theor. C₁₅H₁₇N₃O₃

Found:

C, 62.69; H, 5.98; N, 14.63

C, 62.79; H, 5.86; N, 14.40

EXAMPLE 46

6-(3,4־Dihydro-3-oxo-l,4(2H)-benzoxazin7-yl)-2,3,4,5-tetrahydro-5־methylpyridazin3־-one

The method of Example 8 was followed, using 4-oxo-4-(3,4-dihydro-3-oxo-l,4(2H)-benzoxazin-7-yl)-3-methylbutyric acid as the

ORTH 534 starting material. The title compound was obtained and recrystallized from dimethylformamide-water, then ethanol, mp >300°C.

Theor. C₁₃H₁₃N₃O₃-l/4 ¾0: C, 59.18; H, 5.17; N. 15.93 ״ _A C, 58.88; H, 5.04; N, 16.03

Found: ’

When in the above procedure, 4-oxo-4-(3,4-dihydro-3-oxo-

1,4 (2H) -benzoxazin-7-yl-3-ethylbutyrate ., 4-oxo-4-(3,4-dihydro-3oxo-1,4(2H)-benzoxazin-7-yl)-3-hexylbutyrate or 4-oxo-4-(3,4-dlhydro-3-oxo-l,4(2H)-benzoxazin-7-yl)-3-(l-methylethyl)butyrate is utilized, the corresponding 5-ethyl-, 5-hexyl- or -5-(l-methylethyl)-pyridazin-3-one derivative is obtained.

EXAMPLE 47

6-(3,4-Dihydro-4-methyl-3-oxo-l,4(2H)-benzoxazin7-yl)-2,3,4,5-tetrahydro-5-methylpyridaz1n-3-one

The method of Example 8 was followed, using methyl 4-0X0-4(3,4-dihydro-4-methyl-3-oxo-l,4(2H)-benzoxazin-7-yl)3־-methylbutyrate. The product was purified by chromatography on silica gel eluted with 5% CHjOH in 0¾¾. mp 188-190־C.

C, 61.52; H, 5.54; N, 15.38

C, 61.45; H, 5.68; N, 15.15

Theor. C₁₄H₁₅N₃O₃:

Found:

EXAMPLE 48

6-(3,4־Dihydro-2־methyl3־-oxo-l, 4(2H) -benzoxazin7-yl)-2,3,4,5־tetrahydropyndaz1n-3־one

The method of Example 8 was followed, using 4-oxo-4-(3,4-d1h_ydro2־-methyl-3-oxo-l,4(2H)-benzoxazin־7־yl)butyric acid The product was purified by column chromatography on silica ge e u e

ORTH 534 with 5% CH,OH in CH,Cl״. Trituration with water gave the product 3 Lu as a hydrate, mp 294-295°C.

Theor. C.,H.,N,0,-1/4 H״O: C, 59.18; H, 5.15; N, 15.93 u 0 4

Found: C, 59.15; H, 4.93; N, 15.83

The corresponding 2-alkyl-pyridazinone derivatives of the compounds prepared in any of the preceding examples are prepared in accordance with the procedures of Examples 9 and 10. The corresponding 4-acyl, 4-arylacyl or 4-alkane sulfonylbenzoxazinyl derivatives of the compounds prepared in the preceding examples where R, = H are prepared in accordance with the o procedures of Examples 14, 16 and 17.

EXAMPLE 49

4-(3,4-Dihy dro- 3-oxo-l, 4 [ 2 H ] -benzothiazin-6-yl)-4-oxobutyric acid

To 100 g of aluminum chloride was added 15.6 ml of dimethylformamide. To the hot slurry was added an intimate mixture of 17 g of 3,4-dihydro-3-oxo-l,4(2Hl-benzothiazine and 10 g of succinic anhydride. After 15 minutes at 75°C, the mixture was poured into 600 ml of ice and the precipitate collected by filtration and washed with water then acetone to give 20 g (73% yield) of named compound decomposing at 215°-218°C.

Theor. C,,H₁₁NO.S-l/2 H״O: C, 52.54; H, 4.42; N, 5.11

11 ״ י _Found. C, 52.54; H, 4.20; N, 5.18

The following compounds are prepared by the above procedure, using the appropriate starting materials:

4-(3,4-dihydro-2-methyl-3-oxo-l,4[2H]-benzothiazin-6-yl־oxobutyric acid, and

4-(3,4-dihydro-2, 2-dimethyl-3-oxo-l, 4 [ 2H] -benzothiazin-6-yl-oxobutyric acid.

ORTH 534

EXAMPLE 50

Methyl 4-(3,4-dihydro-4-methyl-3-oxol,4[2H]-benzothiazin-6-yl)-4-oxobutyrate

4-(3,4-Dihydro-3-oxo-l, 4 [ 2H] -benzothiazin6־-yl) -4-oxobutyric acid (3 g) was suspended in 50 ml of dimethylformamide and 2.2 equivalents of 60% sodium hydride (1.0 g) were added. After 30 minutes at room temperature, 2.2 equivalents of methyl iodide (3.5 g) were added and the mixture stirred overnight. The mixture was poured into ice water and the precipitate collected by filtration. The solid was characterized by 1H NMR and used in the next reaction (see Example 54).

The following compounds are prepared by the above procedure, using the appropriate starting materials:

Methyl 4-(3,4-dihydro-2־methyl3־-oxo-l,4[2H]-benzothiazin-6-yloxobutyrate, and

Methyl 4-(3,4-dihydro-2,2-dimethyl-3-oxo-l,4[2H]-benzothiazin6-yl-oxobutyrate.

EXAMPLE 51

4-(3,4-Dihydro-3־oxo-l, 4[ 2H]-benzothiazin7-yl)-3-methyl-4-oxobutyric acid

3,4-Dihydro-3-oxo-7-(l־oxopropyl)-l,4[2H]־benzothiazine (5.0 g) was added to a mixture of 2.25־ ml of formalin solution and 2.72 g of dimethylamine hydrochloride in 7.5 ml of acetic anhydride and heated to 100°C overnight. Acetone (20 ml) was added and the mixture heated at reflux for 15 minutes before the volitiles were removed at reduced pressure. The residue was taken up in IN HC1 and washed with ethyl acetate. The aqueous portion was chilled in ice and basified with 12.5 N NaOH. The basic solution was extracted with ethyl acetate and dried over sodium sulfate. The solvent was removed and the residue taken up in acetone and

ORTH 534

־36- ml ot methyl iodide added. The mixture was heated at reflux for three hours, then cooled, and the precipitate collected by flitration and washed with acetone to give 6.6 g of the quaternary ammonium salt of the mannich product.

The quaternary salt (6.6 g). was dissolved in 20% methanol/ water and 3.8 g of potassium cyanide in 30 ml of water was added. The mixture was stirred at room temperature for 48 hours and the resultant precipitate collected by suction filtration to give 4-(3,4-dihydro-3־oxo-l,4[2H]־benzothiazin-7-yl)3־-methyl4־-oxobutyronitrile. The nitrile was heated to reflux in 200 ml of 6N HC1 for 30 minutes, then cooled and diluted with an equal volume of ice water. The solid collected was used in Example 55.

EXAMPLE 52

Methvl 43,4)־-dihydro4־-methyl3־-oxo-l,4[2H]־ benzothiazin-7־yl)3־-methyl4־-oxobutyrate

4-(3 4-Dihydro-3-oxo-l,4[2Hl־benzothiazin-7-yl)־3־methyl-4oxobutyric ־־id (1.7 g) «־־־» ־־'ved in 50 ml ot dimethylformamid־ and 0.23 g ot 60% sodium hydride was added. After 30 minutes, 0.7 ml of methyl iodide was added and the mixture star־ at room temperature for three hours, then poured into 100 ml of ice water and extracted with ethyl acetate. The organic layer ־־״ washed with brine and dried over sodium sulfate and evaporated The residue was chromatographed on a silica gel ־ ״״׳״1־־luted with 5% methanol in methylene chloride. The solvent was removed and the oil obtained was used in Example 56.

EXAMPLE 53

6-(3 4-Dihydro3־-oxo־l,4[2H]_rbenzothiazin6-yl)-2,3,4,5־tetrahydropyridaz1n 3־one

4-(3 4-Dihydro3־-oxo-l,4[2H]־benzothiazin6־-yl)־4־oxobutync acid (2.0’g) was suspended in 60 ml of ethanol and 1 ml of hydrazine added. The mixture «־־ heated at reflux for three hours.

ORTH 534 then cooled slowly. Filtration gave 1.85 g of the title compound, mp 299°-302°C.

Theor. C. _H. N,O״S-1/2 H״O: C, 53.32; H, 4.48; N, 15.55

1Z 11 J Z Z

Found: C, 53.02; H, 4.26; N, 15.94

The following compounds are prepared by the above procedure, using the appropriate starting materials:

4-(3,4-dihydro-2-methyl3־-oxo-l, 4 [ 2H ] -benzothiazin-6-yl-oxobutyric acid, and

4-(3,4-dihy dro-2,2-dimethyl-3-oxo-l, 4 [ 2H ] -benzothiazin-6-yl-oxobutyric acid.

EXAMPLE 54

6-(3,4-Dihy dro-4-methyl-3-oxo-l, 4 [ 2 H ] -benzothiazin6-yl)-2,3,4,5-tetrahydropyridazin-3-one

Methyl 4-(3,4-dihy dro-4-methyl-3-oxo-l, 4[2H]-benzothiazin-6yl)-4-oxobutyrate (2.5 g) was heated at reflux in 70 ml of ethanol containing 1 ml of hydrazine for three hours. Filtration gave

1.5 g of the named compound, melting at 241°-242°C.

Theor. C^H^N^S-1/4 H₂O: C, 55.80; H, 4.88; N, 15.02

Found: C, 55.64; H, 4.87; N, 15.06

The following compounds are prepared by the above procedure, using the appropriate starting materials:

4-(3,4-dihydro-2,4-dimethyl-3־oxo-l, 4 [ 2H] -benzothiazin-6-yl-oxobutyric acid, and

4-(3,4-dihydro-2,2,4-trimethyl-3-oxo-l, 4[ 2H] -benzothiazin-6-yloxobutyric acid.

ORTH 534 ־38EX AMPLE 55

6-(3 4-Dihydro-3-oxo-l,4[2H]-benzothiazin-7-yl2,3,4.5-tetrahydro-5-methylpyridazin-3-one

4-(3,4-Dihydro3־-oxo-l,4(2H]-benzothiazin-7-yl)4־-oxo-3methylbutyric acid (1.2 ¢) was heated at reflux overnight in 50 ml of ethanol containing 0.2 ml of hydrazine. Filtration gave a white chromatographed on silica gel eluted with 5% yielding 180 mg of the title powder which was methanol in methylene chloride, compound melting >300°C.

Theor. ^c₁o^H1q^N3°2^S‘^{1/4 H}2°^:

Found:

C, 55.80; H, 4.88; N, 15.02

C, 56.13; H, 4.75; N, 15.00

EXAMPLE 56

6-(3 4-Dihydro-4-methyl3־-oxo־l, 4[2H]־benzoth1azm7-yl)2,3,4,5־-tetrahydro-5-methylpyridaz1n־3־one

Methyl 4-(3,4-dihydro-4-methyl-3-oxo-l,4(2Hl-benzothiaz1n-7vl)-4-oxo-3-methylbutyrate (1.7 g) «as heated at reflux overnight with 0.3 ml of hydrazine in 50 ml of ethanol. ™ration gave a white powder which was chromatographed on silica gel eluted with 5% methanol in methylene chloride, yielding 110 mg of compound, mp 193°-194.5 C.

the named

Theor. C₁₄H₁₅N₃O₂S:

Found:

C, 58.10; H, 5.24;

C, 57.81; H, 5.42;

N, 14.52

N, 14.15

EXAMPLE 57

3,4-Dihydro-3-oxo6־-oxopropyll,4[2Hlbenzothiazine

4-Amino-3-thiocyanatopropriophenone (prepared by the 1method of K.D. Luess and R. Pohloudek-Fabini in Arch-Pharm. 29909),

ORTH 534

-884 (1966)) (35 g) was heated to reflux in 250 ml of water containing 90 g of sodium sulfide nonahydrate. The solution was cooled to room temperature and 60 ml of acetic acid was added. The precipitate that formed was collected and washed with water giving the mercapto compound.

4-Amino-3-mercaptopropiophenone was stirred in 200 ml of water containing 8.5 g of sodium hydroxide. The resultant mixture was filtered and 22 g of sodium chloroacetate added to the filtrate in 150 ml of water. After 30 minutes, 4 ml of acetic acid was added and the mixture heated to reflux. After 10 minutes, heat was removed and the mixture stirred at room temperature overnight. The yellow precipitate was collected by filtration and washed with water to give, after drying, 18.5 g of benzothiazine melting at 215°-220°C.

4-(3,4-Dihydro-3-oxo-l,4[2H]benzothiazin-7-yl)-4-oxobutyric acid was prepared by the same method as above. The starting material for this preparation was 4-aminophenyl-4-oxobutyric acid which is described by Thyes in J.Med.Chem. 26, 800 (1983). Thiocyanation was carried out by the method of K.D. Luess and R. Pohloudek-Fabini in Arch.Pharm. 299(10), 878-882 (1966).

EXAMPLE

Cardiotonic Activity

The cardiotonic activity of the compounds was determined in accordance with the method of Alousi, A.A., et al., J.Cir.Res. 45, 666 (1979). Basically, adult mongrel dogs were anesthetized with sodium pentobarbital and artificially respired. Arterial pressure was recorded via a femoral artery and the pressure pulse used to trigger a cardiotachometer for heart rate. Left ventricular pressure was measured with a Millar catheter and dP/dt was derived. Cardiac output was determined by measuring ascending aortic blood flow with an electromagnetic flow probe and myocardial contractile force was measured with a Walton Brodie strain gauge sutured to the right ventricle. Lead II EKG was also recorded.

ORTH 534

A standard dose of dopamine was administered to assess myocardial responsiveness. Test compounds were administered by i.v. infusion or bolus administration and the effects on cardiovascular parameters were determined. Dose-related effects of the test compound on BP, HR, dP/dt max., C.F. and C.O. were compared to pretreatment control values and expressed as a percentage change. The results are shown in Table I.

EXAMPLE

Phosphodiesterase Inhibitory Activity

The phosphodiesterase inhibitory activity was determined in accordance with the method of Thompson, W.J. et al., in Adv. Cycli.Nucleotide Res., Ed. Brooker, G. et al., Vol. 10, pp. 69-92 (1979). This assay measures the ability of compounds to inhibit cyclic nucleotide phosphodiesterase. This enzyme converts either cyclic AMP or cyclic GMP to the noncyclized AMP or GMP, respectively. Compounds were tested at various concentrations in the presence of cyclic AMP (0.10-1.0 pM containing 0.2 pCi H-cyclic AMP), enzyme, and 0.05M Tris-Cl buffer (pH 7.4, containing 5mM MgClj). After a specified time, the reaction was stopped by heating to 100°C for one minute. After cooling, 0.10 ml of a solution containing snake venom (1 mg/ml) was added and the reaction was allowed to proceed for 30 minutes. Termination of this reaction was accomplished by the addition of 1.0 ml of 33% Dowex slurry to separate the product from unconverted substrate. An aliquot was removed from the supernatant and quantitated by liquid scintillation spectrometry. The results are shown in Table I as the IC₅₀ which is the concentration (pM) of compound required to inhibit 50% of the cyclic nucleotide phosphodiesterase activity.

ORTH 534

TABLE 1

<td></td><td> Compound</td><td> . . .a</td><td> ״.lb</td><td>_Tr, ^c</td>

<td></td><td> (Example)</td><td> Dose (mpk)</td><td> CF</td><td> IC50__</td>

<td></td><td> A</td><td> .. 1.87 ....</td><td> 98 ..</td><td> 9.5</td>

<td></td><td> 9</td><td> 1.87</td><td> 62</td><td> 100</td>

<td> e</td><td> 10</td><td> 1.87</td><td> 18</td><td>⁵⁰ d</td>

<td> כ</td><td> 11</td><td> 1.87</td><td> 41</td><td> N.T.</td>

<td></td><td> 12</td><td> 1,87</td><td> 92</td><td> 50</td>

<td></td><td> 13 .</td><td> .. 1.87 ....</td><td> 71 ..</td><td> .. 100</td>

<td></td><td> 14</td><td> 1.87</td><td> 30</td><td> 80</td>

<td> ח ו</td><td> 15</td><td> 1.87</td><td> 125</td><td> 8</td>

<td> 1 u</td><td> 16</td><td> 1.87</td><td> 173</td><td> 30</td>

<td></td><td> 17</td><td> 1.87</td><td> 62</td><td> 4</td>

<td></td><td> 1 ft</td><td> . 0.47 ...</td><td> 50 ..</td><td> 8</td>

<td></td><td> 19</td><td> 0.47</td><td> 98</td><td> 40</td>

<td> 15</td><td> 20</td><td> 1.87</td><td> 71</td><td> 630</td>

<td></td><td> 21</td><td> 0.47</td><td> 74</td><td> 18</td>

<td></td><td> 22</td><td> 0.47</td><td> 136</td><td> 2</td>

<td></td><td> 0Q</td><td> . 0.47 ...</td><td> 134 ..</td><td> 8</td>

<td></td><td> 24</td><td> 0.47</td><td> 54</td><td> 14</td>

<td> 20</td><td> 25 • 26</td><td> 0.47 0.47</td><td> 31 156</td><td> 13 5</td>

<td></td><td> 27</td><td> 0.47</td><td> 117</td><td> 6</td>

<td></td><td></td><td> 0.47 ...</td><td> 46 ..</td><td> 15</td>

<td></td><td> 29</td><td> 0.47</td><td> 12</td><td> 56</td>

<td> 25</td><td> 30</td><td> 0.47</td><td> 124</td><td> 20</td>

<td></td><td> 31</td><td> .0.47</td><td> 33</td><td> 38</td>

<td></td><td> 33</td><td> 0.47</td><td> 8</td><td> 30</td>

<td></td><td> oc</td><td> 0.47 ...</td><td> 40 ..</td><td> 24</td>

<td></td><td> 37</td><td> 0.47</td><td> 4</td><td> 8</td>

<td> 30</td><td> 38</td><td> 0.47</td><td> 24</td><td> 31</td>

<td></td><td> 39</td><td> 0.47</td><td> 18</td><td> 28</td>

<td></td><td> 40</td><td> 0.47</td><td> 22</td><td> 26</td>

<td></td><td> 41</td><td> 0.47 ...</td><td> 60 ..</td><td> 7</td>

<td></td><td> 42</td><td> 0.47</td><td> 15</td><td> 100</td>

<td> 35</td><td> 43</td><td> 0.47</td><td> 104</td><td> 35</td>

<td></td><td> 46</td><td> 0.075</td><td> 130</td><td> 0.3</td>

<td></td><td> 47</td><td> 0.075</td><td> 109</td><td> 0.3</td>

<td></td><td> co</td><td> 0.075 ...</td><td> 21 ..</td><td></td>

<td></td><td> 54</td><td> 0.075</td><td> 11</td><td> 22</td>

<td> 40</td><td> 55</td><td> 0.035</td><td> 160</td><td> &lt;0.1</td>

<td></td><td> 56</td><td> 0.027</td><td> 32</td><td> &lt;0.1</td>

a I.V. dose used for cardiotonic activity assay.

b Percent increase in cardiac force.

c Micromolar concentration for 50% inhibition of cyclic nucleotide activity.

d Not tested.