6-benzoxazinyl- and 6-benzothiazinyl-2,3,4,5-tetrahydropyridazin-3-ones

Descriptive Memory

BACKGROUND OF THE INVENTION

SCOPE OF THE INVENTION

The present invention relates to the compounds of formula:

<img file="PT86453B_D0001.tif" />

<img file="PT86453B_D0002.tif" />

cardiotonic agents and vasodilators and as inhibitors of phosphodiesterase fraction III and platelet aggregation.

In addition, the compounds are active as smooth muscle relaxants and as bronchodilators. The present invention also relates to intermediates of these compounds as defined below.

Description of the Prior Art

Quinoline-substituted pyridazin-3-ones have been shown to be cardiotonic agents and inhibitors of platelet aggregation. European latent application Published No £ 155798 and English Patent No. 2031404 describe compounds of the formula

<img file="PT86453B_D0003.tif" />

where βχ, ^and May be H or lower alkyl.

United States Patent no. 4,562,190 describes benzothiazole substituted pyridazin-3-ones of the formula;

<img file="PT86453B_D0004.tif" />

where is alkyl θ

III

-2 is H, (C1 -C6) alkyl or aryl

SUMMARY OF THE INVENTION

The present invention relates to 6-benzoxazinyl- and 6-benzothiazinyl-2,3,4,5-tetrahydro-pyridazin-5-ones of the general formula:

in

XY ^AND1 which may may may or cycloalkyl (G-G, -);

be be be

R_z^R3

<img file="PT86453B_D0005.tif" />

H₂ or 0; 0 or S;

H, alkyl (^Gj_^_Gg)

- 3 '6' * may be H, alkyl (^Gthat “^Gg) cycloalkyl (G 1 -C 6) ^or (C1 -C6) alkenyl; may be H, (C1 -C6) alkyl_r) of straight chain or cycloalkyl (G 1 -C 6), and when X is H₂, straight chain or branched or branched branched, branched may also and phenyl-ace ^R5th or be (C -C) acyl_r), aryl acyl such as benzoyl or

ethyl, or alkanesulfonyl such as methanesulfonyl; may be H, halogen, straight chain (C1 -C6) alkyl or the

branched or C1 -C6 alkoxy;

and e Εθ may be individually H, (C 1 -C 6) alkyl ⁱⁿ straight or branched chain or cyclo (C1 -C6) alkyl_r); it's the

the dotted line may be a single or double bond between C4 and 05 in the pyridazine ring.

The compounds of formula I are useful as

<img file="PT86453B_D0006.tif" />

cardiotonic agents having long-term activity and are very powerful inhibitors of phosphodi esterase fraction III.

The present invention also relates to intermediates of the compounds of formula I having the general formulas.

<img file="PT86453B_D0007.tif" />

<img file="PT86453B_D0008.tif" />

^R7

R 4, R 4 and R 6 may independently be H, straight or branched (C 1 -C 6) alkyl or cyclo (C 1 -C 6) alkyl;

being H, straight chain or branched chain alkyl (θρ-θζ), where ^R1’ ^5*

-°6⁾ can

-CN or mono- or di (C1 -C6) alkylamino

Can X be H? or 0;

Y may be 0 or S;

R, W and Z may be independently H, straight or branched chain (C1 -C4) alkyl, (C1 -C6) acyl or -C (O) CHR4 CH₂C (02 ORqJ and

Rg may be H or straight or branched chain (C1 -C6) alkyl

In the intermediates of formula IV, when R? for -CN or mono- or di-C 1 -C 6 alkylamino may also include its quaternary ammonium salts.

<img file="PT86453B_D0009.tif" />

<img file="PT86453B_D0010.tif" />

-sulfonyl when X is H₂· Also, when one of R, W and Z is -C (0) CHR₄CH₂C (0) 0R₈, so the others cannot be the same substitute.

DETAILED DESCRIPTION OF THE INVENTION

In its broadest aspects the present invention relates to pyridazinone compounds which exhibit cardiotonic activity, vasodilatory activity, platelet anti-aggregation activity and phosphodiesterase fraction III inhibitory activity. The pyridazinone compounds of the present invention demonstrating these activities are represented by formula I above. The pyridazine compounds contain a benzoxazine ring. The present invention also relates to intermediates of pyridazinone compounds.

Preferred compounds of the present invention are those wherein R3 is CH3, R3₂ and R ^ are hydrogen, R ^, R5 and Rg are H or GH ^, X is 0 or EL ·, and the pyridazinone ring is attached to C-7 of the benzoxazine ring.

Starting materials for the preparation of the compounds of the present invention may be prepared as indicated in Scheme I.

SCHEME 1

<img file="PT86453B_D0011.tif" />

<img file="PT86453B_D0012.tif" />

on what

R »is RCO or RSO_nowherein R is lower alkyl and the alkyl group contains 1-6 carbon atoms, and

R, R_r and R have the above meanings.

5 6

Benzoxazinone or benzothiazine 2 is prepared from compound 1 by the procedure of Shridhar, Org. Prep. Proc. Int. 14, 195 (1982). Compound 2 is refluxed for several hours in an equivalent of diborane in tetrahydrofuran to provide benzoxazine or benzothiazine. Compound 3 wherein H is treated with a sulfonyl or acyl compound such as methane chloride

sulfonyl or acetyl chloride and pyridine in a solvent such as dichloromethane and refluxed for several hours to provide benzoxazine or benzothiazine 4.

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

SCHEME 2

<img file="PT86453B_D0013.tif" />

<img file="PT86453B_D0014.tif" />

<img file="PT86453B_D0015.tif" />

<img file="PT86453B_D0016.tif" />

Benzoxazine or benzothiazine 2 or 4 is acylated by the method of Thyes, J, Med. Chem. 26, 800 (1983) using succinic anhydride to provide compound Compound 5 is refluxed for 1-8 hours with 2.2 equivalents of hydrazine in an alcoholic solvent such as methanol to provide compound 6. Alternatively, Compound 6 may be prepared by first esterifying compound 5 in H2 O allylic to provide compound 8 and then reacting compound 8 with hydrazine. 0 Compound 6 may be alkylated at the 2-position of the pyridazinone ring by treatment in an inert solvent such as dimethylformamide with an alkaline metal base such as sodium hydride and further treatment with an alkyl halide, R X wherein R 6 has the Earlier meanings and X is chlorine, bromine or iodine at a temperature of 0-40 ° C for 0.5-8 hours to provide compound 7. Alternatively, compound 5 (when R 2 is H) may be alkylated at position 4 as described above to provide compound 8. Compound 8 is refluxed with hydrazine to afford compound 6. 0 2 N-acylated derivative (X = Hgj = acyl or sulfonyl) was prepared from 6 (X = Hg; Rf = R) by treatment with a base such as triethylamine and the appropriate acid chloride, such as acetyl chloride, methanesulfonyl chloride, benzoyl chloride, for example as previously described.

SCHEME 3

<img file="PT86453B_D0017.tif" />

SCHEME 3

<img file="PT86453B_D0018.tif" />

To prepare a 5-alkylated pyridazinone, benzoxazine or benzothiazine 2 or β is acylated with proprionyl chloride by the method of Thyes, supra, and the resulting product is converted to compound β by the method of McEvoy and Allen, J. Org. Chem. 38, 4044 (1973). Compound Q is reacted with hydrazine or alkylated as described above to provide compounds 10 and 11, respectively. Compound 11 may be reacted with hydrazine to proportion. . Compound 10. 0 compound 10 may be alkylated at the 8-

<img file="PT86453B_D0019.tif" />

pyridazinone ring 2 or acylated at the 4-position of the benzoxazine or benzothiazine ring as previously described.

Scheme 4

<img file="PT86453B_D0020.tif" />

13 benzothiazine 2 ring, benzoxazine is converted to the position or

THE

-C-CHyR-L compound 12 by the method rot compound 12 with hydrazine or alkylate with McEvoy's R4 and

4, in

Allen, supra. Reame previously described to provide compounds 13 and

14 respectively. Compound 14 may be reacted with hydrazine to provide compound 13. Compound 13 may be alkylated at the 2-position of the pyridazinone ring or may be acylated at the 4-position of the benzoxazine or benzothiazine ring as described above.

<img file="PT86453B_D0021.tif" />

Pharmaceutical compositions containing a compound of the present invention as an active ingredient in admixture with a pharmaceutical carrier may be prepared according to conventional pharmaceutical composition techniques. The carrier may take a wide variety of forms depending on the desired preparation form for administration, for example intravenous, oral or parenteral. The composition may also be administered by aerosol. For the preparation of compositions in oral dosage form, any of the usual pharmaceutical media may be used, 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 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 lozenges). Because of their ease in administration, tablets and capsules represent the most advantageous oral soda unit form, in which case solid pharmaceutical carriers are of course employed. If desired, the tablets may be sugar coated or enteric coated according to standard techniques. For parenteral use, the carrier will normally consist of sterile water, although other ingredients may be included, for example to aid solubility or for preservative purposes, and injectable suspensions may also be prepared, in which case liquid carriers will be used. appropriate suspending agents and the like. The pharmaceutical compositions will generally contain a dosage unit, for example, tablet, capsule, powder, injection, teaspoon and the like, comprised between approximately 0.001 and 10 mg / kg, and preferably between 0.01 and 0.1 mg / kg. kg of active ingredient.

The following examples describe the present invention more particularly and are intended as a way of illustrating it without limiting it.

-10EXAMPLE 1

3,4-dihydro-7- (1-oxopropyl) -3-oxo-1,4 (2H) -benzoxazine

4-Amino-3-hydroxypropiophenone (32 g) was dissolved in 250 ml methyl isobutyl ketone and 250 ml water containing 40 g sodium bicarbonate. Chloride was added. chloroacetyl (17 ml) to the rapidly stirred mixture at 0 ° C. The mixture was then heated at reflux for 4 hours. On 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 according to the above procedure using appropriate starting materials:

3,4-dihydro-3-oxo-1,4 (2H) -benzoxazine, mp: 170-171 ° C;

3,4-dihydro-6-methyl-3-oxo-1,4 (2H) -benzoxazine, mp: 204.5-205.5 ° C;

3,4-dihydro-7-methyl-3-oxo-1,4 (2H) -benzoxazine, mp: 193-195 ° C;

3,4-dihydro-2-methyl-3-oxo-1,4 (2H) -benzoxazine, mp: 143-145 ° C;

3,4-dihydro-2,2-dimethyl-3-oxo-1,4 (2H) -benzoxazine, mp: 161-163 ° C;

5.4-dihydro-2,7-dimethyl-3-oxo-1,4 (2H) -benzoxazine, mp: 152-153 ° C;

5.4-dihydro-4- (1-methyl-ethyl) -3-oxo-1,4 (2H) -benzoxazine, oil

5.4-dihydro-4-cyclopentyl-3-oxo-1,4 (2H) -benzoxazine, oil;

3,4-dihydro-2-methyl-4- (1-methyl-ethyl) -3-oxo-1,4 (2H) -benzoxazine, oil;

5.4-dihydro-2-methyl-4-cyclopentyl-3-oxo-1,4 (2H) -benzoxazine, oil; and

3,4-dihydro-7- (1-oxo-ethyl) -3-oxo-1,4 (2H) -benzoxazine, mp 193-196 ° C.

The following compounds were prepared if

<img file="PT86453B_D0022.tif" />

following the above procedure using appropriate starting materials:

3,4-dihydro-3-oxo-1,4 / 2H7benzothiazine;

3.4-dihydrO-3-OXO-7- (1-oxo-propyl) -1,4 / 2H7benzothiazine;

3,4-dihydro-2-methyl-3-Oxo-1,4Z2H7benzothiazine; and

3,4-dihydro-2,2-dimethyl-3-oxo-1,4Z2H7henzothiazine.

<img file="PT86453B_D0023.tif" />

EXAMPLE 2

3,4-dihydro-1. 4 (2H) -benzoxazine

3,4-Dihydro-3-oxo-1,4 (2H) -benzoxazine was refluxed for several hours in an equivalent of diborane in tetrahydrofuran. Excess sodium hydroxide solution was added, the product was extracted with ether and the solvent was evaporated to afford the title compound as an oil.

The following compounds were prepared according to the above procedure using appropriate starting materials:

3,4-dihydro-6-methyl-1,4 (2H) -benzoxazine and

3,4-dihydro-2-methyl-1,4 (2H) -benzoxazine.

<img file="PT86453B_D0024.tif" />

EXAMPLE 3

3,4-dihydro-2,7-dimethyl-4- (1-oxo-ethyl) -1,4 (2H) -benzoxmna

3,4-Dihydro-2,7-dimethyl-1,4 (2H) -benzoxazine was dissolved in dichloromethane and one equivalent of acetyl chloride and one equivalent of triethylamine were added in that order. The mixture was refluxed for several hours, cooled and washed with water and then saturated NaHCO 3 solution. Evaporation of the organic layer afforded the product, mp: 60.5-63 ° C.

The following compounds were prepared according to the above procedure using appropriate

-12 Starting Tools:

3,4-dihydro-4-methanesulfonyl-1,4 (2H) -benzoxazine, mp: 74.5-77 ° C;

3,4-dihydro-4- (1-oxo-ethyl) -1,4 (2H) -benzoxazine, oil; and

3,4-dihydro-2-methyl-4- (1-oxo-ethyl) -1,4 (2H) -benzoxazine, mp: 80-82 ° C.

EXAMPLE 4

4-OxQ-4 (3,4-dihydro-2-methyl-3-Qxo-1,4 (2H) -benzoxazin-6-yl) -butyric acid

5.4 dihydro-2-methyl-3-oxo-1,4 (2H) -benzoxazine (11.4 g) and succinic anhydride (7 g) were added to 93 g of aluminum chloride and 15, 3 ml of dimethylformamide. The mixture was stirred at 70 ° C for 2.5 hours and then poured onto ice to give a solid which was collected by filtration and washed with water. Vacuum drying provided

16.5 g of the title compound (90% yield), mp: 198-200 ° C.

The following compounds were prepared according to the above procedure using appropriate starting materials:

4-β-4- (3,4-dihydro-3-oxo-1,4 (2H) -benzoxazin-6-yl) butyric acid, mp: 206-208 ° C;

4-β-4- (3,4-dihydro-2,2-dimethyl-3-oxo-1,4 (2H) -benzoxazin-6-yl) butyric acid;

4-β-4- (3,4-dihydro-7-methyl-3-oxo-1,4 (2H) -benzoxazin-6-yl) butyric acid, mp: 226-228 ° C;

4-oxo-4- (3,4-dihydro-2,7-dimethyl-3-oxo-1,4 (2H) -benzoxazin-6-yl) butyric acid;

4-OXO-4- (3,4-dihydro-4-methanesulfonyl-1,4 (2H) -benzoxazin-6-yl) butyric acid, mp: 184-187 ° C;

4-oxo-4 “(3,4-dihydro-4- (1-oxo-ethyl) -1,4 (2H) -benzoxazin-6-yl) butyric acid, mp: 143-144.5 ° C ° C;

4-OXO-4- (3,4-dihydro-6-methyl-3-oxo-1,4 (2H) -benzoxazin-8-yl) butyric acid; and

<img file="PT86453B_D0025.tif" />

4-Oxo-4- (3,4-dihydro-6-methyl-N-oxo-1,4 (2H) -benzoxazin-7-yl) butyric acid.

EXAMPLE 5

Methyl 4-oxo-4- (3,4-dihydro-4-methyl-3-oxo-1,4 (2H) -benzoxazin-6-yl) -butyrate

3,4-Dihydro-5-oxo-1,4 (2H) -benzoxazine was alkylated by dissolving the acid in dimethylformamide and adding two equivalents of 60% sodium hydride in oily suspension. After half an hour two equivalents of methyl iodide were added. The mixture was stirred under nitrogen for 12 hours and then poured into water. The product was collected by extraction with ethyl acetate and evaporation of the solvent, mp: 139-144 ° C.

The following compounds were prepared according to the above procedure using appropriate starting materials:

Methyl 4- [4- (3,4-dihydro-2,4-dimethyl-3-oxo-1,4 (2H) -benzoxazin-6-yl) butyrate, oil;

Methyl 4-oxo-4- (3,4-dihydro-4,7-dimethyl-3-oxo-1,4 (2H) -benzoxazin-6-yl) -butyrate, oil;

Methyl 4-oxo-4- (3,4-dihydro-2,4,7-trimethyl-3-oxo-1,4 (2H) -benzoxazin-6-yl) -butyrate, oil;

Methyl 4- [4- (3,4-dihydro-4,6-dimethyl-3-oxo-1,4 (2H) -benzoxazin-8-yl) butyrate, oil;

Methyl 4-oxo-4- (3,4-dihydro-4,6-dimethyl-3-oxo-1,4 (2H) -benzoxazin-7-yl) -butyrate, oil;

Methyl 4- [4- (3,4-dihydro-2,4-trimethyl-3-oxo-1,4 (2H) -benzoxazin-6-yl) butyrate, oil;

Methyl 4-β-4- (3,4-dihydro-4-methylethyl-5-oxo-1,4 (2H) -benzoxazin-6-yl) -3-methylbutyrate, oil;

Methyl 4- [4- (3,4-dihydro-2,4-dimethyl-3-oxo-1,4 (2H) -benzoxazin-b-yl) -3-methylbutyrate, oil;

Methyl 4-oxo-4- (3,4-dihydro-4,7-dimethyl-3-oxo-1,4 (2H) -benzoxazin-6-yl) -3-methylbutyrate, oil;

<img file="PT86453B_D0026.tif" />

4-methyl-4- (3,4-dihydro-2,4,7-trimethyl-3-oxo-1,4 (2H) -benzoxazin-6-yl) -3-methylbutyrate, oil ;

Methyl 4-oxo-4 '(3,4-dihydro-4,6-dimethyl-3-oxo-1,4 (2H) -benzoxazin-8-yl) -3-methylbutyrate, oil; and

Methyl 4-oxo-4- (3,4-dihydro-4-methyl-3-oxo-1,4 (2H) -benzoxazin-7-yl) -3-methylbutyrate, oil.

EXAMPLE 6

4-Oxo-4- (3,4-dihydro-7-methyl-3-oxo-1,4 (2H) -benzoxazin-6-yl) -3-methyl-butyric acid

A. 5,4-Dihydro-7-methyl-3-oxo-1,4 (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-Dihydro-7-methyl-6- (1-oxo-propyl) -3-oxo-1,4 (2H) -benzoxazine (23.7 g) was added to a mixture of 13 g of dimethylamine hydrochloride and 15 ml of a solution of 37% aqueous formaldehyde in 68 ml of acetic anhydride. After heating on a steam bath for 5 hours, 50 ml of acetone was added and heating was continued for 15 minutes. The solvents were removed by evaporation under reduced pressure and the residue was dissolved in 1 N HCl and washed with ethyl acetate. The aqueous layer was basified with sodium hydroxide and the resulting crystals were collected by filtration. The product was dissolved in 500 ml of acetone and 10 ml of iodomethane was added. After heating at reflux overnight, the solid formed was collected by filtration and washed with acetone. The product was dissolved in 400 ml of 50% aqueous methanol and potassium cyanide was added in 200 ml of water. After stirring overnight at room temperature, the solid was collected and washed with water. The wet filter cake was suspended in 500 ml of 6N HCl and refluxed for 1.5 hours. On cooling a white precipitate formed which was collected by filtration and washed with water to give 19.4 g (81% yield).

<img file="PT86453B_D0027.tif" />

of the title compound, mp 169.5-172 ° C.

The following compounds were prepared according to the above procedure using appropriate starting materials:

4-β-4- (5,4-dihydro-1,4 (2H) -benzoxazin-6-yl) -3-methyl-butyric acid;

4-0X0-4- (3,4-dihydro-2-methyl-1,4 (2H) -benzoxazin-6-yl) -3-methyl butyric acid;

4-β-4- (5,4-dihydro-3-oxo-1,4 (2H) -benzoxazin-6-yl) -3-methyl-butyric acid;

4-OXO-4- (3,4-dihydro-2-methyl-3-oxo-1,4 (2H) -benzoxazin-6-yl) -3-methyl-butyric acid;

4-OXO-4- (3,4-dihydro-2,7-dimethyl-3-oxo-1,4 (2H) -benzoxazin-6-yl) -3-methyl-butyric acid;

4-OXO-4- (3,4-dihydro-4- (1-methyl-ethyl) -2-methyl-3-oxo-1,4 (2H) -benzoxazin-6-yl) -3-acid methyl butyric;

4-OXO-4- (3,4-dihydro-4-cyclopentyl-2-methyl-3-oxo-1,4 (2H) -benzoxazin-6-yl) -3-methyl-butyric acid;

4-OXO-4- (3,4-dihydro-6-methyl-3-oxo-1,4 (2H) -benzoxazin-8-yl) -3-methyl-butyric acid; and

4-Oxo-4- (3,4-dihydro-6-methyl-1,4 (2H) -benzoxazin-8-yl) -3-methyl-butyric acid.

EXAMPLE 7

4-β-4- (3,4-dihydro-3-oxo-1,4 (2H) -benzoxazin-7-yl) -3-methyl-butyric acid

3,4-Dihydro-7- (1-oxo-propyl) -3-oxo-1,4 (2H) -benzoxazine (from Example 1) was converted to the title compound by the method of Example 6B.

EXAMPLE 8

6- (3,4-dihydro-4-methanesulfonyl-1,4 (? 2H) -benzoxazin-6-yl) -2,3,4,5-tetrahydropyridazin-3-one

<img file="PT86453B_D0028.tif" />

With ethyl 4-0X0-4- (3,4-dihydro-4-methanesulfonyl-1,4 (2H) -benzoxazin-6-yl) butyrate was suspended in methanol and added. 2.2 equivalents of hydrazine The mixture was refluxed and stirred for 24 hours. On cooling crystals of the desired product formed and collected by filtration. Recrystallization from ethanol afforded pure title compound, mp: 245 ° C.

Theory: C H -JLO.S: C, 50.47; H, 4.90; N, 13.59 j 4

Found: C, 50.46; H, 4.85; N, 13.67

When in the above procedure ethyl 4-β-4- (3,4-dihydro-4-methanesulfonyl-1,4 (2H) -benzoxazin-6-yl) -3-ethylbutyrate is used; Ethyl 4-oxo-4- (3,4-dihydro-4-methanesulfonyl-1,4 (2H) -benzoxazin-6-yl) -3-hexylbutyrate; or ethyl 4-oxo-4- (3,4-dihydro-4-methanesulfonyl-1,4 (2H) -benzoxazin-6-yl) -3- (1-methyl-ethyl) -butyrate as starting materials the corresponding 5-ethyl-, 5-hexyl- or 5- (1-methyl-ethyl) -pyridazin-3-one derivative is obtained.

EXAMPLE 9

6- (3,4-dihydro-4-methane-saifonyl-1,4 (2H) -benzoxazin-6-11) -2,3,4,5-tetrahydro-2-methyl-pyridazin-3 -ona

6- (3,4-Dihydro-4-methanesulfonyl-1,4 (2H) -benzoxazin-6-yl) -2,3,4,5-tetrahydro-pyridazin was suspended -3-one (3 g) in 50 ml of dimethyl formamide and an equivalent of 60% sodium hydride in oil was added. When gas evolution ceased, an equivalent of methyl iodide was added and the mixture was allowed to stand for

1.5 hours followed by an additional 1 hour at 40 ° C. The mixture was cooled and then poured into ice / water (200 ml) to provide a precipitate which was collected by filtration, washed with water and recrystallized from ethanol. The material was further purified by silica gel chromatography eluting with EtOAc: 0.5 ml yielding 0.97 g of the title product.

Mp 162-165 ° C.

<img file="PT86453B_D0029.tif" />

Theoretical: C

Found:

C, 51.99; H, 5.31; N, 13.00

G, 51.92; H, 5.32; U, 12.96

EXAMPLE 10

6- (3,4-dihydro-4-methanesulfonyl-1,4 (2 H) -benzoxazin-6-yl) -2,3,4,5-tetrahydro-2-pentyl-pyridazin -3-one

6- (3,4-Dihydro-4-methanesulfonyl-1,4 (2H) -benzoxazin-6-yl) -2,3,4,5-tetrahydropyridine-2-one 3-one with pentyl bromide instead of methyl iodide following the procedure of Example 9. The title compound was collected, yield 1.46 g, mp: 138-139 ° C.

Theoretical: 0.56.96; H, 6.65; I, 11.07

Found: C, 56.67; H, 6.49; 11.05

When the above procedure uses bromo-cyclohexane or 2-bromo-propane instead of pentyl bromide, the corresponding 2-cyclohexyl- or 2- (1-methyl-ethyl) -pyridazinone is obtained.

EXAMPLE 11

6- (3,4-dihydro-4-methanesulfonyl-1,4 (2H) -benzoxazin-6-yl) -2,3,4,5-tetrahydro-2- (2-propenyl) -pyridazin-3-one

6- (3,4-Dihydro-4-methanesulfonyl-1,4 (2H) -benzoxazin-6-yl) -2,3,4,5-tetrahydropyridine-2-one 3-one with allyl bromide instead of methyl iodide following the procedure of Example 9. The title compound was collected, yield 2.03 g, mp: 153-155 ° C.

Theory: C C HH ^ NN ^O ^S: C, 54.99; H, 5.49; N, 12.03

-18Found:

C, 54.94; H, 5.58; N, 11.92

EXAMPLE 12

6- (3,4-dihydro-1,4 (2H) -benzoxazin-6-yl) -2,3,4,5-tetrahydro-pyridazin-3-one

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

Theoretical: C

<img file="PT86453B_D0030.tif" />

Found:

C, 62.31; H, 5.68; N, 18.17

G, 62.35; H, 5.72; N, 18.18

EXAMPLE 13

6- (4-acetyl-3,4-dihydro-1,4 (2H) -benzoxazin-6-yl) -2,

3,4,5-tetrahydro-pyridazin-3-one

The method of Example 8 was followed using 4-oxo-4- (3,4-dihydro-3,4-acetyl-1,4 (2H) -benzoxazin-6-yl) -butyric acid as the starting material. to afford the title compound in 40% yield, mp_O: 156-158 ° C.

Theoretical: 0.61.52; H, 5.54; N, 15.38

Found: 0.61.49; H, 5.55; N, 15.24

EXAMPLE 14

6- (3,4-dihydro-4- (3,4-dimethoxy-phenylcarbonyl) - ?, 4 (2H) -benzoxazin-6-yl) -2,3,4,5-tetrahydro -pyridazin-3-one

6- (3,4-Dihydro-1,4 (2H) -benzoxazin-6-yl) -2,3,4,5-tetrahydro-pyridazin-3-one was dissolved in clo-19-

<img file="PT86453B_D0031.tif" />

methylene straight and 1.1 equivalents of triethylamine. 1.1 equivalents of 3,4-dimethoxybenzoyl chloride was added and the mixture was heated at reflux for 4 hours. The solution was washed with sodium bicarbonate solution and then evaporated to dryness. The residue was chromatographed on silica gel eluting with 1: 1 ethyl acetate: ethyl ether. The title compound was collected as white needles, mp: 207-208 ° C.

Theoretical: ^Ç21^H21^N3°5^{: Ç}’ ⁶⁵·^{78; H}» 5.36; ^1O·⁶³

Found:

0.63.78; H, 5.40; N, 10.64

EXAMPLE 15

6- (3,4-dihydro-1,4 (2H) -benzoxazin-6-yl) -2,3,4,5-tetrahydro-5-methyl-pyridazin-3-one

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

Theoretical: C

<img file="PT86453B_D0032.tif" />

Found:

G, 63.65; H, 6.18; N, 17.13

G, 63.47; H, 6.22; N, 16.90

When in the above procedure 4-oxo-4- (3,4-dihydro-1,4 (2H) -benzoxazin-6-yl) -3-ethyl-butyric acid is used; 4-oxo-4- (3,4-dihydro-1,4 (2H) -benzoxazin-6-yl) -3-hexyl butyric acid or 4-oxo-4- (3,4 -dihydro-1,4 (2H) -benzoxazin-6-yl) -3- (1-methyl-ethyl) -butyric gives the corresponding 5-ethyl-, 5-hexyl- or 5- ( 1-methylethyl). -pyridazin-3-one.

Example 16

6- (4-ac ethyl-3,4-dihydro-1,4 (2H) -benzoxazin-6-yl) -2 _f

3,4,5-tetrahydro-5-methyl-pyridazin-3-one

6- (5,4-Dihydrohydrate) was suspended.

<img file="PT86453B_D0033.tif" />

-1,4 (2H) -benzoxazin-6-yl) -2,3,4,5-tetrahydro-5-methyl-pyridazin-3-one in tetrahydrofuran and an equivalent of acetyl chloride was added . After half an hour at 0 ° C, the solvent was removed in vacuo, and the product was crystallized from ethanol in 61% yield, mp: 185.5-186 ° C.

Theoretical:

Found:

G, 62.69; H, 5.97; M, 14.63

G, 62.85; H, 6.03; N, 14.64

Example 17

6- (3,4-dihydro-4-methanesulfonyl-1,4 (2H) -benzoxazin-6-yl) -2,3,4,5-tetrahydro-5-methyl-pyridazin-3 -ona

The method of Example 16 was followed using methanesulfonyl chloride instead of acetyl chloride. Pyridine was added to the mixture. After 1 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 taken up in silica gel and eluted with ethyl acetate. 0 Title compound crystallized from ethanol to give 25% yield, mp: 207-212 ° C.

Theory: G, 51.99; H, 5.31; N, 13.00

Found: C, 52.42; H, 5.31; N, 13.39

EXAMPLE 18

6- (3,4-dihydro-2-methyl-1,4 (2H) -benzoxazin-6-yl) -2,

3,4,5-tetrahydro-pyridazin-3-oua

The method of Example 8 was followed using 4-oxo-4- (3,4-dihydro-2-methyl-1,4 (2H) -benzoxazin-6-yl) -butyric acid as a starting material to provide the desired product in a yield of 10 mp .: 294.5-295.5 ° θ ·

-21Theoretical: G ,, ,, EL t-lVzO ,,:

15 3 2

Found:

<img file="PT86453B_D0034.tif" />

0.63.37; H, 6.16; N, 17.41

When in the above procedure 4-oxo-4- (3,4-dihydro-2-methyl-7-pentyl-1,4 (2H) -benzoxazin-6-yl) -butyric acid is used; 4-oxo-4- (3,4-dihydro-2-hexyl-7-isopropyl-1,4 (2H) -benzoxazin-6-yl) -2-hexyl-butyric acid; 4-oxo-4- (3,4-dihydro-2-methyl-7-cyclohexyl-1,4 (2H) -benzoxazin-6-yl) -butyric acid; 4-oxo-4- (3,4-dihydro-2-isobutyl-7-methoxy-1,4 (2H) -benzoxazin-6-yl) -butyric acid or 4-oxo-4- ( 3,4-dihydro-2-cyclopentyl-1,4 (2H) -benzoxazin-6-yl) -butyric, the corresponding pyridazinone derivative is obtained.

Example 19

6- (3,4-dihydro-2-methyl-1,4 (2H) -benzoxazin-6-yl) -2,

3,4,5-tetrahydro-5-methyl-pyridazin-3-one

The method of Example 8 was followed using 4-oxo-4 '(3,4-dihydro-2-methyl-1,4 (2H) -benzoxazin-6'-J) -yl) - 3-methylbutyric as starting material. The product still was purified by silica gel chromatography, mp: 179-182 ° C.

Theoretical: 0_.Η_ΊO: C, 64.83; I, 6.62; N, 16.21

17 3 2

Found: C, 64.51; H, 6.64; N, 15.84

When in the above procedure 4-oxo-4- (3,4'-dihydro-2-methyl-1,4 (2H) -benzoxazin-6-yl) -3-ethyl-butyric acid is used; 4-oxo-4- (3,4-dihydro-2-methyl-1,4 (2H) -benzoxazin-6-yl) -3-hexylbutyric acid or 4-oxo-4- ( 3,4-dihydro-2-methyl-1,4 (2H) -benzoxazin-6-yl) -3- (1-methyl-ethyl) -butyric, the corresponding 5-ethyl- derivative is obtained,

5-hexyl or 5- (1-methylethyl) pyridizin-3-one.

EXAMPLE 20

226- (3,4-dihydro-3-oxo-1,4 (2H) -benzoxazin-6-yl) -2,

<img file="PT86453B_D0035.tif" />

3,4,5-tetrahydro-pyridazin-3-one

Following the method of Example 8, but using methyl 4-OXO-4- (3,4-dihydro-3-oxo-1,4 (2H) -benzoxazin-6-yl) -butyrate, gave the title compound and recrystallized from ethanol and then from acetonitrile as a hydrate, mp: 274-275 ° C.

Theory: C C HH- ^N ^ .H ^O: C, 57.70; H, 4.65; N, 16_O83 Found: C, 57.54; H, 4.50; N, 16.79

EXAMPLE 21

6- (3,4-dihydro-4-methyl-3-oxo-1,4 (2H) -benzoxazin-6-yl) -2,3,4,5-tetrahydro-pyridazin-3-one

The method of Example 8 was followed using methyl 4-0X0-4- (3,4-dihydro-4-methyl-3-oxo-1,4 (2yl) -benzoxazin-6-yl) -butyrate. as a starting material. The product was purified by column chromatography followed by several recrystallizations from acetonitrile, mp: 247-247.5 ° C.

Theoretical: C

15^H13^N3°3^:

C, 60.21; H, 5.06; N, 16.21

Found:

C, 59.85; H, 4.98; N, 16.26

EXAMPLE 22

6- (3,4-dihydro-3-oxo-1,4 (2H) -benzoxazin-6-yl) -2,

3,4,5-tetrahydro-5-methyl-pyridazin-3-one

The method of Example 8 was followed using methyl 4-oxo-4- (3,4-dihydro-5-oxo-1,4 (2H) -benzoxazin-6-yl) -3-methylbutyrate as a starting material. The product was purified by crystallization from acetonitrile, followed by silica gel column chromatography and eluted.^— with 5% methanol in dichloromethane, mp: 265-267 ° C.

<img file="PT86453B_D0036.tif" />

Theoretical 0 Η N_x0 · 1/4Η₉O: C, 59.19; Δ, 5.17; N, 15.95 13 15 5 5^ά

Found: C, 59.22; Η, 4 · 9θ; U, 15.92

When in the above procedure 4-oxo-4- (5,4-dihydro-3-oxo-1,4 (2H) -benzoxazin-6-yl) -3-ethylbutyrate is used; 4-oxo-4- (5,4-dihydro-3-oxo-1,4 (2H) -benzoxazin-6-yl) -3-hexylbutyrate or 4-oxo-4- (3,4-dihydro-3-oxo-1,4 (2H) -benzoxazin-6-yl) -5- (1-methyl-ethyl) -butyrate gives the corresponding 5-derivative. ethyl-, 5-hexyl- or 5- (1-methyl-ethyl) -pyridazin-3-one.

EXAMPLE 25

6- (5.4-dihydro-4-methyl-5-oxo-1,4 (2H) -benzoxazin-6-yl) -2,5,4,5-tetrahydro-5-methyl-pyridazin -3-one

The method of Example 8 was followed using 4-OXO-4- (3,4-dihydro-4-methyl-3-oxo-1,4 (2H) -benzoxazin-6-yl) -3-methyl methylbutyrate as a starting material. The product was purified by chromatography and eluted with 5% methanol in dichloromethane, mp: 215-218 ° C.

Theoretical: C

<img file="PT86453B_D0037.tif" />

Found:

C, 61.52; H, 5.54; N, 15.54

C, 61.80; H, 5.75; U, 15.65

EXAMPLE 24

6- (5,4-dihydro-2-methyl-3-oxo-1,4 (2H) -benzoxazin-6-yl) -2,3,4,5-tetrahydro-pyridazin-3 -ona

The method of Example 8 was followed using 4-oxo-4- (5,4-dihydro-2-methyl-3-oxo-1,4 (2H) -benzoxazin-6-yl) -butyric acid as a starting material to provide the title compound in 75% yield, mp: 275-276 ° C.

Theoretical: 0

15^H15^N5°5^í

C, 60.21; H, 5.06; I, 16.21

-24Found:

C, 60.02; H, 5.22; N, 16.08

HMLO 25

6- (3,4-dihydro-2,4-dimethyl-3-oxo-1,4 (2H) -benzoxazin-6-yl) -2,3,4,5-tetrahydropyridazin-3 -ona

The title compound was prepared in 25% yield following the method of Example 8 using 4-oxo-4- (3,4-dihydro-2,4-dimethyl-3-oxo-1). Methyl 4- (2H) -benzoxazin-6-yl) -butyrate as a starting material, mp: 210-211 ° C.

Theoretical: N ^ O ^ '1/2 H ^ O:

Found:

C, 59.56; H, 5.72; 11.15.16

0.59.93; H, 5.48; N, 15.16

EXAMPLE 26

6- (3,4-dihydro-2-methyl-3-oxo-1,4 (2H) -benzoxazin-6-yl) -2,3,4,5-tetrahydro-5-methyl-pyridazin -3-one

The method of Example 8 was followed using 4-oxo-4- (3,4-dihydro-2-methyl-3-oxo-1,4 (2H) -benzoxazin-6-yl) -acetic acid. 5-methylbutyric as a starting material to provide the title compound in 50 mp yield: 271-272 ° C.

Theoretical: 0_Ί.Η_ΊΕΔ 0: C, 61.52; H, 5.54; N, 15.38

15 3 5

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

When in the above procedure 4-oxo-4- (3,4-dihydro-2-methyl-7-pentyl-3-oxo-1,4 (2H) -benzoxazin-6-yl) -acetate is used. butyric; 4-oxo-4- (3,4-dihydro-2-hexyl-7-isopropyl-3-oxo-1,4 (2H) -benzoxazin-6-yl) -butyric acid; 4-oxo-4- (3,4-dihydro-2-methyl-7-cyclohexyl-3-oxo-1,4 (2H) -benzoxazin-6-yl) -butyric acid; 4-oxo-4- (3,4-dihydro-2-isobutyl-7-methoxy-1,4 (2H) -benzoxazin-6-yl) -butyric acid or

<img file="PT86453B_D0038.tif" />

4-OXO-4- (3,4-dihydro-2-cyclopentyl-3-oxo-1,4 (2H) -benzo.xazin-6-yl) -butyric acid gives the corresponding derivative of pi ridazinone.

Example 27

6- (3,4-dihydro-2,4-dimethyl-3-oxo-1,4 (2H) -benzoxazin-6-yl) -2.3.4.5-tetrahydro-5-methyl-pyridazin-3 -ona

Following the method of Example 8 using 4-oxo-4- (3,4-dihydro-2,4-dimethyl-3-oxo-1,4 (2H) -benzoxazin-6-yl). Methyl -3-methylbutyrate as a starting material gave the title compound in 40% yield, mp: 184-185 ° C.

Theory: C C-C, 62.70; H, 5.98; N, 14.65

Found: 0.62.75; H, 5.95; N, 14.79

EXAMPLE 28

6- (3,4-dihydro-7-methyl-3-oxo-1,4 (2H) -benzoxazin-6-yl) -2,3.4.5-tetrahydro-pyridazin-3-one

The method of Example 8 was followed using 4-oxo-4- (3,4-dihydro-7-methyl-3-oxo-1,4 (2H) -benzoxazin-6-yl) -butyric acid as a starting material to afford the title compound in 55% yield, mp: 255-257 ° C.

Theoretical: C

<img file="PT86453B_D0039.tif" />

Found:

C, 60.21; H, 5.06; N, 16.21

0.59.90; H, 5.26; N, 15.95

When in the above procedure 4-oxo-4- (3,4-dihydro-7-pentyl-5-oxo-1,4 (2H) -benzoxazin-6-yl) -butyric acid is used; 4-oxo-4- (3,4-dihydro-2-hexyl-7-isopropyl-N-oxo-1,4 (2H) -benzoxazin-6-yl) -butyric acid; the acid

<img file="PT86453B_D0040.tif" />

4-οχο-4- (5,4-dihydro-7-cyclohexyl-3-oxo-1,4 (2H) -benzoxazin-6-yl) -butyric; 4-oxo-4- (3,4-dihydro-2-isobutyl-7-methoxy-3-oxo-1,4 (2H) -benzoxazin-6-yl) -butyric acid or 4-oxo acid -4- (3,4-dihydro-2-cyclopentyl-3-oxo-1,4 (2H) -benzoxazin-6-yl) -butyric gives the corresponding pyridazinone derivative.

EXAMPLE 29

6- (3,4-dihydro-4,7-dimethyl-3-oxo-1,4 (2H) -benzoxa · zin-6-yl) -2,3,4,5-tetrahydropyridazin -3-one

The title compound was obtained in 47% yield following the method of Example 8 using 4-oxo-4- (3,4-dihydro-4,7-dimethyl-3-oxo-1,4 ( Methyl 2H) -benzoxazin-6-yl) -butyrate as starting material, mp: 227-228.5 ° C.

Theoretical: Ο, .Η, ΧΟ.

15 3 5

Found:

C, 61.52; H, 5.54, N, 15.38

C, 61.65; H, 5.57; N, 15.26

EXAMPLE 50

6- (3,4-dihydro-7-methyl-3-oxo-1,4 (2H) -benzoxazin-6-yl) -2,3,4,5-tetrahydro-5-methyl-pyridazin -5-one

The method of Example 8 was followed using 4-oxo-4- (3,4-dihydro-7-methyl-3-oxo-1,4 (2H) -benzoxazin-6-yl) -3-acid -methylbutyric as a starting material to provide the title compound in 51% yield, mp: 163-166 ° C.

Theoretical; O ^H- ^O ^ -lHH ^); 0.60.52; H, 5.63; N, 15.13 Found: C, 60.65; H, 5.62; N, 15.03

EXAMPLE 31

6- (3,4-dihydro-4,7-dimethyl-3-oxo-1,4 (2H) -benzoxa-27zin-6-yl) -2,3,4,5-tetrahydro- 5-methyl-pyridazin-3-one

<img file="PT86453B_D0041.tif" />

Following the method of Example 8 using 4-oxo-4- (3,4-dihydro-4,7-dimethyl-3-oxo-1,4 (2H) -benzoxazin-6-yl) as starting material -3-methylbutyrate, the title compound was obtained, mp: 180-182 ° C.

Theoretical:

°₁₅^H17^N5^O5^!

C, 62.70; H, 5.98; N, 14.63

Found:

G, 62.77; H, 6.06; I, 14.57

Example 32

6- (3,4-dihydro-2,7-dimethyl-3-oxo-1,4 (2H) -benzoxazin-6-yl) -2,3,4,5-tetrahydropyridazin-3 -ona

The method of Example 8 was followed using 4-0X0-4- (3,4-dihydro-2,7-dimethyl-3-oxo-1,4 (2H) -benzoxazin-6-yl) acid -butyric acid to provide the title compound, mp: 252-254 ° C.

Theorist: G

Found:

0.60.52; H, 5.64; H, 15.13

G, 60.50; H, 5.45; S, 15.63

Example 33

6- (3,4-dihydro-2,4,7-trimethyl-3-oxo-1,4 (2H) -benzoxazin-6-yl) -2,3,4,5-tetrahydropyridazin -3-one

Following the method of Example 8 using 4-OXO-4- (3,4-dihydro-2,4,7-trimethyl-3-oxo-1,4 (2H) -benzoxazin-6-yl) - Methyl butyrate as a starting material gave the title compound, mp: 210-212 ° C.

Theoretical: CHIO; C, 62.70; H, 5.98; I, 14.63

17 3 3

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

-28Example 34

6- (3,4-dihydro-2,7-dimethyl-3-oxo-1,4 (2H) -benzoxazin-6-yl) -2.3.4.5-tetrahydro-5-methyl-pyridazin-3 -ona

The method of Example 8 was followed using 4-oxo-4- (3,4-dihydro-2,7-dimethyl-3-oxo-1,4 (2H) -benzoxazin-6-yl) acid -3-methylbutyric to provide the title compound, mp: 190-191 ° C.

Theoretical I: C₁₅H₁₇N₃O₃-1 / 2H₂O: C, 60.80; H, 6.14; il, 14.18

Found: G, 61.18; H, 6.42; II, 13.78

EXAMPLE 35

6- (3,4-dihydro-2,4,7-trimethyl-3-oxo-1,4 (2H) -benzoxazin-6-yl) -2,3,4,5-tetrahydro-5 -methyl-pyridazin-3-one

Following the method of Example 8, using 4-0X0-4- (3,4-dihydro-2,4,7-trimethyl-3-oxo-1,4 (2H) -benzoxazin-6-yl) - Methyl 3-methyl butyrate as starting material | The title compound was prepared, mp: 190-192 ° C.

Theoretical: 0- ^ 11 - ^^ 0 ^ 1/2 H₂O: C, 61.91; H, 6.51; 1, 13.54 Found: G, 62.02; Δ, 6.52; K, 13.86

When in the above procedure 4-OXO-4- (3,4-dihydro-2,4-dimethyl-7-pentyl-3-oxo-1,4 (2H) -benzoxazin-6-yl) -benzamide is used. 3-methyl butyrate; 4-oxo-4- (3,4-dihydro-2-hexyl-4-methyl-7-isopropyl-3-oxo-1,4 (2H.) -Benzoxazin-6-yl) -3-methyl tilbutyrat 0; 4-oxo- (3,4-dihydro-2,4-dimethyl-7-cyclohexyl-3-oxo-1,4 (2H) -benzoxazin-6-yl) -3-methylbutyrate; 4-oxo-4- (3,4-dihydro-2-isobutyl-4-methyl-7-methoxy-3-oxo-1,4 (2H) -benzoxazin-6-yl) -3-methyl- butyrate; or 4-oxo-4- (3,4-dihydro-2-cyclo-pentyl-4,7-dimethyl-3-oxo-1,4 (2H) -benzoxazin-6-yl) -3- methyl. butyrate, the corresponding pyridazinone derivative is obtained. '

-29EXAMPLE 36

6- (3,4-dihydro-2-methyl-4- (1-methyl-ethyl) -3-oxo-1,4 (2H) -benzoxazin-6-yl) -2,3,4,5 -tetrahydro-5-methyl-pyridazin-3-one

The method of Example 8 was followed using 4-oxo-4- (3,4-dihydro-4- (1-methyl-ethyl) -3-oxo-1,4 (2H) -benzoxazin-4-oxide). 6-yl) -3-methylbutyric as a starting material to provide the title compound, mp: 204-205 ° C.

Theoretical:

<img file="PT86453B_D0042.tif" />

C, 64.73; H, 6.72; N, 13.33

Found:

0.64.67; H, 6.66; N, 13.42

Example 37

6- (3,4-dihydro-4-cyelo-pentyl-2-methyl-3-oxo-1,4 (2H) -benzoxazin-6-yl) -2,3,4,5-tetrahydro-5 -methyl-pyridazin-3-one

Following the method of Example 8 using 4-oxo-4- (3,4-dihydro-4-cyclopentyl-2-methyl-3-oxo-1,4 (2H) -benzoxazin-6-acid) yl) -3-methylbutyric as a starting material gave the title compound, mp: 220-223 ° C.

Theoretical:

25 5 5

C, 66.84; H, 6.80; N, 12.31

Found:

C, 64.61; H, 6.78; N, 12.29

Example 38

6- (3,4-dihydro-6-methyl-3-oxo-1,4 (2H) -benzoxazin-8-yl) -2,3,4,5-tetrahydro-pyridazin-3-one

The method of Example 8 was followed using 4-oxo-4- (3,4-dihydro-6-methyl-3-oxo-1,4 (2E) -ben acid

30·

<img file="PT86453B_D0043.tif" />

zoxazin-8-11) -Kutotoxic as a starting material to provide the title compound, mp: 266-270 ° C.

Theoretical:

<img file="PT86453B_D0044.tif" />

Found:

C, 60.21; E, 5.06; N, 16.21

C, 60.13; H, 5.26; N, 16.28

Example 39

6- (3,4-dihydro-4,6-dimethyl-3-oxo-1,4 (2H) -benzoxazin-8-yl) -2,3,4,5-tetrahydro-pyridazin-3 one

Following the method of Example 8 using 4-oxo-4- (3,4-dihydro-4,6-dimethyl-3-oxo-1,4 (2H) -benzoxazin-8-yl) -butyrate as starting material was obtained with

<td colspan="4">title with a yield of 16%,</td><td>Federal Police.:</td><td colspan="2">266-270 ° C.</td>

<td>Theory: C ^ H- ^ N ^ O ^:</td><td>ç,</td><td> 61.52;</td><td>H,</td><td> 5.54;</td><td>N</td><td> 15.38</td>

<td>Found:</td><td>ç,</td><td> 61.18;</td><td>H,</td><td> 5.64;</td><td>N</td><td> 15.36</td>

Example 40

6- (3,4-dihydro-6-methyl-3-oxo-1,4 (2H) -benzoxazin-8-yl) -2,3,4,5-tetrahydro-5-methyl-pyridazin-3 -ona

The method of Example 8 was followed using 4-oxo-4- (3,4-dihydro-6-methyl-3-oxo-1,4 (2H) -benzoxazin-8-yl) -butyric acid as a starting material to provide the title compound in 31% yield, mp 252-253.5 ° C.

Theoretical: C

<img file="PT86453B_D0045.tif" />

Found:

C, 61.52; H, 5.54; 15.38

C, 61.11; H, 5.68; N, 15.26

Example 41

6- (3,4-dihydro-4,6-dimethyl-3-oxo-1,4 (2H) -benzoxazin-8-yl) -2,3,4,5-tetrahydro-5-methyl -pyridan-3-one

The method of Example 8 followed by

<img file="PT86453B_D0046.tif" />

using 4-0X0-4- (5,4-dihydro0-4,6-dimethyl-3-oxo-1,4 (2H) -benzoxazin-8-yl) -3-methylbutyrate. methyl as a starting material to provide the title compound in 15% yield after column chromatography of silica gel eluted with 5% methanol in dichloromethane, mp: 212-213 ° C.

Theoretical: θ 62.69; Δ, 5.98; Ϊ'ϊ, 14.63

Found: C, 62.27; Δ, 5.92; N, 14.57

EXAMPLE 42

6- (3,4-dihydro-6-methyl-1,4 (2H) -benzoxazin-8-yl) ·

-2.3.4.5-tetrahydro-5-methyl-pyridazin-3-one

Following the method of Example 8 using ethyl 4-OXO-4- (3,4-dihydro-6-methyl-1,4 (2H) -benzoxazin-8-yl) -3-methylbutyrate as material The title compound was prepared in 60% yield, mp: 160-162 ° C.

Theoretical: 0

<img file="PT86453B_D0047.tif" />

Found:

C, 64.83; H, 6.62; N, 16.21

0.64.87; H, 6.66; N, 16.31

<img file="PT86453B_D0048.tif" />

When in the above procedure 4-β-4- (3,4-dihydro-6-methyl-1,4 (2H) -benzoxazin-8-yl) -3-ethylbutyrate is used; 4-oxo-4- (3,4-dihydro-6-methyl-1,4 (2H) -benzoxazin-8-yl) -3-hexyl butyrate or 4-oxo-4- (3,4- dihydro-6-methyl-1,4 (2H) -benzoxazin-8-yl) -3- (1-methyl-ethyl) -butyrate, the corresponding 5-ethyl-, 5-hexyl derivative is obtained. - or 5- (1-methyl-ethyl) -pyridazin-3-one.

Example 43

6- (3,4-dihydro-4,6-dimethyl-3-oxo-1,4 (2Η) -benzoxazin-7-yl) -2,3,4,5-tetrahydropyridazin-3 -ona

The method of Example 8 followed by

<img file="PT86453B_D0049.tif" />

using 4-oxo-4- (3,4-dihydr0-4,6-dimethyl-3-oxo-1,4 (2H) -benzoxazin-7-yl) -butyrate as a starting material to provide The title compound, mp: 211-215 ° C.

Theory: C, C, 61.52; H, 5.54; N, 15.38

Found: 0.61.57; Δ, 5.49; N, 15.28

6- (3,4-dihydr0-2,2-dimethyl-3-oxo-1,4 (2H) -benzoxazin-6-yl) -2,3,4,5-tetrahydropyridazin-3 -ona

The method of Example 8 was followed using 4-β-4- (3,4-dihydro-2,2-dimethyl-5-oxo-1,4 (2'-benzoxazin-6-yl) - butyric acid as a starting material to provide the title compound, mp: 251-254 ° C.

Theoretical: C_no .H_r-N „0„:

15 3 3

C, 61.52; H, 5.54; N, 15.38

Found:

C, 61.40; Δ 5.58; N, 15.74

EXAMPLE 45

6- (3,4-dihydr0-2,2,4-trimethyl-3-oxo-1,4 (2H) -benzoxazin-6-yl) -2,3,4,5-tetrahydropyridazin -3-one

Following the method of Example 8 using 4-0X0-4- (3,4-dihydr0-2,2,4-trimethyl-3-oxo-1,4 (2H) -benzoxazin-6-yl) -butyrate of methyl, the title compound was prepared, mp: 169-171 ° C.

Theoretical: C_ 0:

1/ 33

Found:

C, 62.69; H, 5.98; N, 14.63

C, 62.79; Δ, 5.86; N, 14.40

EXAMPLE 46

6- (3,4-dihydro-3-oxo-1,4 (2H) -benzoxazin-7-yl) -2,

3,4,5-tetrahydro-5-methyl-pyridazin-3-one

<img file="PT86453B_D0050.tif" />

The method of Example 8 was followed using 4-oxo-4- (3,4-dihydro-3-oxo-1,4 (2H) -benzoxazin-7-yl) -3-methyl-butyric acid as a starting material. The title compound was obtained and recrystallized from dimethylformamide / water and then from ethanol, mp:> 300 ° C.

Theoretical θ ^ - ^⁰^¹/^{4 H}₂^{0; 59.18; H}’ ^{5.17; N}’ ^15,95

Found: C, 58.88; H, 5.04; N, 16.03

When in the previous procedure it is used | 4-oxo-4- (3,4-dihydro-3-oxo-1,4 (2H) -benzoxazin-7-yl-3-ethyl butyrate; 4-oxo-4- (3,4- dihydro-3-oxo-1,4 (2H) -benzoxazin-7-yl) -3-hexylbutyrate or 4-ox: o-4- (3,4-dihydro-3-oxo-1 (2h) -benzoxazin-7-yl) -3- (1-methyl-ethyl) -butyrate, gives the corresponding 5-ethyl-, 5-hexyl- or 5- (1-methyl-ethyl) derivative. pyridazin-3-one.

EXAMPLE 47

6- (3,4-dihydro-4-methyl-3-oxo-1,4 (2Ξ) -benzoxazin-7-yl) -2,3,4,5-tetrahydro-5-methyl-2-one pyridazin-3-one

The method of Example 8 was followed using 4-oxo-4- (3,4-dihydrobut-4-methyl-3-oxo-1,4 (2H) -benzoxazin-7-yl) Methyl -3-methyl butyrate. The product was purified by silica gel chromatography and eluted with 5% CH 2 OH in CH 2.₂C1₂mp 188-190 ° C.

Theoretical: 0.61.52; H, 5.54; N, 15.38

Found: C, 61.45; H, 5.68; N, 15.15

EXAMPLE 48

6- (3,4-dihydro-2-methyl-3-oxo-1,4 (2H) -benzoxazin-7-yl) -2,3,4,5-tetrahydro-pyridazin-3 one

The method of Example 8 followed by

<img file="PT86453B_D0051.tif" />

using 4-oxo-4- (5,4-dihydro-2-methyl-3-oxo-1,4 (2H) -benzoxazin-7-yl) -butyric acid. The product was purified by column chromatography on silica gel and eluted with 5% CH 2 Cl 2 in CH 2 Cl 2. Trituration with water afforded the product as a hydrate, mp: 294-295%.

Theoretical: C _ί_η N Ο · 1 / 4Η₉0:

13 3 3 2

0.59.18; H, 5.15; 1Ϊ, 15.93

Found:

O, 59.15; H, 4.93; N, 15.83

The corresponding 2-alkylpyridazinone derivatives of the compounds prepared in any of the previous examples were obtained according to the procedures of Examples 9 and 10. The corresponding 4-acyl, 4-aryl acyl or 4-alkanesulfonyl benzoxazinyl derivatives of the compounds prepared in the foregoing Examples where = H were obtained according to the procedures of Examples 14, 16 and 17.

Example 49

4- (3,4-Dihydro-3-oxo-1,4,4-benzothiazin-6-yl) -4-oxobutyric acid

To 100 g of aluminum chloride was added 15.6 ml of dimethyl formamide. To the hot mass was added an intimate mixture of 17 g of 3,4-dihydro-3-oxo-1,4 / 2E7-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 was collected by filtration and washed with water and then acetone to afford 20 g (73% yield) of title compound which decomposes at 215 ° -218 ° C.

Theoretical: C HJO ^ J / 2 Η_£O: G, 52.54; H, 4.42; N, 5.11

Found; C, 52.54; H, 4.20; N, 5.18

The following compounds were prepared according to the above procedure using appropriate starting materials:

<img file="PT86453B_D0052.tif" />

4- (5,4-Dihydro-2-methyl-3-oxo-1,4Z2H7-benzothiazin-6-yl-oxo-butyric acid, and

4- (3,4-Dihydro-2,2-dimethyl-3-oxo-1,4-2H7-benzothiazin-6-yl-oxo-butyric acid.

EXAMPLE 50

Methyl 4- (3,4-dihydro-4-methyl-3-oxo-1,4Z2H-7-benzothiazin-6-yl) -4-oxo-butyrate

4- (3,4-Dihydro-3-oxo-1,4-2H7-benzothiazin-6-yl) -4-oxo-butyric acid (3 g) was suspended in 50 ml of dimethyl formamide and 2.2 equivalents of 60% sodium hydride (1.0 g) was added. After 30 minutes at room temperature 2.2 equivalents of methyl iodide (3.5 g) was added and the mixture was stirred overnight. The mixture was poured into ice / water and the precipitate collected by filtration. The solid was characterized by its 1 H NMR spectrum and used in the next reaction (see Example 54).

The following compounds were prepared according to the above procedure using appropriate starting materials:

Methyl 4- (3,4-dihydro-2-methyl-3-oxo-1,4 / 2H-benzothiazin-6-yl-oxo-butyrate, and

Methyl 4- (3,4-dihydro-2,2-dimethyl-3-oxo-1,4 / 2H-benzothiazin-6-yl-ox2-butyrate.

EXAMPLE 51

4- (3,4-dihydro-3-oxo-1,4,4H-benzothiazin-7-yl) -3-methyl-4-oxo-butyric acid

3,4-Dihydro-3-oxo-7- (1-oxo-propyl) -1,4Z2H-7-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 for

<img file="PT86453B_D0053.tif" />

during the night. Acetone (20 ml) was added and the mixture was heated at reflux for 15 minutes before removing volatile products under reduced pressure. The residue was extracted with 1 N HCl and washed with ethyl acetate. The aqueous portion was cooled with ice and made basic with 12.5N NaOH._O The alkaline solution was extracted with ethyl acetate and dried over sodium sulfate. The solvent was removed and the residue was extracted with acetone and 5 ml of methyl iodide was added. The mixture was heated at reflux for 3 hours, then cooled and the precipitate collected by filtration and washed with acetone to afford 6.6 g of quaternary ammonium salt of the main product.

The quaternary salt (6.6 g) was dissolved in 20% methanol / water and 3.8 g of potassium cyanide was added in 30 ml of water. The mixture was stirred at room temperature for 48 hours and the resulting precipitate collected by filtration suction to afford 4- (3,4-dihydro-3-oxo-1-4 / 2H7-benzothiazin-7- (1) -3-methyl-4-oxo-butyronitrile. The nitrile was heated at reflux in 200 ml 6N HCl for 30 minutes, then cooled and diluted with an equal volume of ice / water. 0 The solid collected was used in Example 55 »

EXAMPLE 52

Methyl 4- (3,4-dihydro-4-methyl-3-oxo-1,4Z2H / benzothiazin-7-yl) -3-methyl-4-oxo-butyrate

4- (3,4-Dihydro-3-oxo-1,4-2H7-benzothiazin-7-yl) -3-methyl-4-oxo-butyric acid (1.7 g) was dissolved in 50 ml of dimethylformamide and 0.23 g of 60% sodium hydride was added. After 30 minutes, 0.7 ml of methyl iodide was added and the mixture was stirred at room temperature for 3 hours, then poured into 100 ml of ice / water and extracted with ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate and evaporated. The residue was chromatographed on a silica gel column and eluted with 5% methanol in methylene chloride.

<img file="PT86453B_D0054.tif" />

The solvent was removed and the obtained oil was used in Example 56.

EXAMPLE 53

6- (3,4-dihydro-3-oxo-1,4 / 2S7-benzothiazin-6-yl) -2,

3,4,5-tetrahydro-pyridazin-3-one

4- (3,4-Dihydro-3-oxo-1,4-2H7-benzothiazin-6-yl) -4-oxo-butyric acid (2.0 g) was suspended in 60 ml of ethanol and 1 ml of hydrazine was added. The mixture was heated at reflux for 3 hours, then slowly cooled. Filtration afforded 1.85 g of the title compound, mp: 299-302 ° C.

Theorist: CH_{1] L}^ S · 1/2 H₂0: 0.53.52; H, 4-48; N, 15.55

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

The following compounds were prepared according to the above procedure using appropriate starting materials:

4- (3,4-dihydro-2-methyl-3-oxo-1,4zIM17-benzothiazin-6-yl-oxo-butyric acid, and

4- (3,4-Dihydro-2,2-dimethyl-3-oxo-1,4Z2H7 acid)^en2othiazin-6-yl-oxo-butyric.

EXAMPLE 54

6- (3,4-dihydro-4-methyl-3-oxo-1,4Z2H7-benzothiazin-6-yl) -2,3,4,5-tetrahydro-pyridazin-3-one

Methyl 4- (3,4-dihydro-4-methyl-3-oxo-1,4Z2H7-benzothiazin-6-yl) -4-oxo-butyrate (2.5 g) was heated at reflux at 70 ° C. ml of ethanol containing 1 ml of hydrazine for 3 hours. Filtration afforded 1.5 g of the title compound, mp 241-242 ° C.

Theoretical: C: HH ^ NN ^ OgSS.HAO: C,

55.80; H,

4.88; I, 15.02

4.87; li, 15.06

Found:

C, 55.64; H,

The following compounds were prepared according to the above procedure using appropriate starting materials:

4- (3,4-dihydro-2,4-dimethyl-3-oxo-1,4-2H7-benzothiazin-6-yl-oxo-butyric acid, and

4- (3,4-Dihydro-2,2,4-trimethyl-3-oxo-1,4,4 H 7 -benzothiazin-6-yl-oxo-butyric acid.

EXAMPLE 55

6- (3,4-dihydro-3-oxo-1,4-2H7-benzothiazin-7-yl-2,

3.4.5-tetrahydro-5-methyl-pyridazin-3-one

4- (3,4-Dihydro-3-oxo-1,4Z2H7-benzothiazin-7-yl) -4-oxo-3-methyl-butyric acid (1.2 g) was refluxed overnight. ) in 50 ml ethanol containing 0.2 ml hydrazine. Filtration afforded a white powder which was chromatographed on silica gel and eluted with 5% methanol in methylene chloride, affording 180 ml of the title compound, melting point> 300 ° C.

Theoretical; Ç₁₃H₁₃N₃O₂S.1 / 4HgO: C, 55.80; II, 4.88; N, 15.02

Found: C, 56.13; E, 4.75; E, 15.00

EXAMPLE 56

6- (3,4-dihydro-4-methyl-3-oxo-1,4Z2E7-benzothiazin-7-yl) -2.3.4.5-tetrahydro-5-methyl-pyridazin-3-one

Overnight reflux 4- (3,4-dihydro-4-methyl-3-oxo-1,4,4-benzothiasin-7-yl) -4-oxo-3-methylbutyrate methylene chloride (1.7 g) with 0.3 ml hydrazine in 50 ml ethanol. Filtration afforded a white powder which was chromatographed on silica gel and eluted with 5% methanol.

<img file="PT86453B_D0055.tif" />

in methylene chloride, providing 110

<img file="PT86453B_D0056.tif" />

title, mp: 193-194.5 ° C.

Theoretical: ^ç8.10; 1.24; N, 14.52

Found:

C, 57.81; II, 5.42; 11, 14.15

Example 57

3,4-dihydro-3-oxo-6-oxo-propyl-1,4Z2H7-benzothiazine

4-Amino-3-thio-cyanate-propriophenone (prepared by the method of KD Luess and R. Pohloudek-Fabini in Arch. Pharm. 299 (10), 878-884 (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 which formed was collected and washed with water affording the mercapto compound.

4-Amino-3-mercapto-propiophenone was stirred in 200 ml of water containing 8.5 g of sodium hydroxide. The resulting mixture was filtered and 22 g of sodium chloroacetate was added to the filtrate in 150 ml of water. After 30 minutes, 4 ml of acetic acid was added and the mixture was heated to reflux. After 10 minutes, the heat source was removed and the mixture was stirred at room temperature overnight. 0 The yellow precipitate was collected by filtration and washed with water to give, after drying, 18.5 g of benzothiazine with a melting point at 215 ° -220 ° C.

4- (5,4-Dihydro-5-oxo-1,4Z2H7-bicytothiazin-7-yl) -4-oxobutyric acid was prepared by the same method as above. The starting material for this preparation was 4-amino-phenyl-4-oxo-butyric acid described by Thyes in J. Med. Chem. 26, 800 (1983). Thiocyanation was performed by the method of KD Luess and R. Pohloudek-Fabini in Arch, Pharm. 299 (10), 878-882 (1966).

EXAMPLE 58

-40Oardiotonic Activity

The oardiotonic activity of the compounds was determined according to the method of Alousi, AA, et al., J. Cir. Res. 45, 666 (1979). Basically, adult hybrid dogs with sodium pentobarbital were anesthetized and subjected to artificial respiration. Blood pressure was recorded through the femoral artery and pulsation was used to send a cardiotaquimetzo to determine the heart rate. Left ventricular pressure was measured with a Millar catheter and the dP / dt derivative was calculated. Cardiac output was determined by measuring ascending aortic blood flow with an electromagnetic flow probe and the myocardial contraction force was measured with a Walton Brodie strain gauge attached to the right ventricle. The reading of the EKG II probe was also recorded. A standard dose of dopamine was administered to assess the myocardial reaction. Test compounds were administered by iv infusion or by injection and the effects on cardiovascular parameters were determined. The dose / effect values ​​associated with the test compound on BP, HR, max dP / dt, OF, and CO were compared with pre-treatment control values ​​and expressed as a percentage of variation. The results are presented in Table I,

EXAMPLE 59

Phosiodiesterase Inhibitory Activity

Phosphodiesterase inhibitory activity was determined according to the method of Thompson, VI. J. et al., In Adv. Cycli. Nucleotide Res., Ed, Brooker, G-. et al., Vol. 10, pages 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 uncyclic AMP or GMP, respectively. The

Compounds were assayed for various concentrations in the presence of cyclic AMP (0.10-1.0 containing 0.2 µCi cyclic H-AiP), enzyme, and 0.05 M tris-01 buffer (pH 7.4 containing 5 mL4 MgCl). After a certain time, the reaction was stopped by heating at 100 ° C for 1 minute. After cooling, 0.10 ml of a solution containing snake venom (1 mg / ml) was added and the reaction allowed to proceed for 30 minutes. This reaction was completed by the addition of 1.0 ml of 33% Dowex paste to separate the product from the unconverted substrate. An aliquot of the supernatant was removed and quantified by liquid scintillation spectrometry. The results are shown in Table I as values ​​representing the concentration (Compound) required for inhibiting 50% of cyclic nucleotide phosphodiesterase activity.

<img file="PT86453B_D0057.tif" />

-42 TABLE 1

<td>Compound</td><td></td><td>B</td><td>ç</td>

<td>(Example)</td><td>Serving (mpk)</td><td>CE</td><td> -1^50—</td>

<td> 8 .....</td><td> ..... 1.87 ......</td><td> ... 98</td><td> .... 9.5</td>

<td> 9</td><td> 1.87</td><td> 62</td><td>10th</td>

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

<td> 11</td><td> 1.87</td><td> 41</td><td>NT</td>

<td> 12</td><td> 1.87</td><td> 92</td><td> 50</td>

<td>Ί 5 ......</td><td> ..... 1.87 ......</td><td> ... 71</td><td> ....100</td>

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

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

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

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

<td> 18 ......</td><td> 0.47 ......</td><td> ... 50</td><td> .... 8</td>

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

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

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

<td> 22</td><td> 0.47</td><td> 156</td><td> 2</td>

<td> 9^ .....</td><td>0.Δ7 ......</td><td> ,.. 134</td><td> .... 8</td>

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

<td> 25</td><td> 0.47</td><td> 31</td><td> 15</td>

<td> 26</td><td> 0.47</td><td> 156</td><td> 5</td>

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

<td> 28 ......</td><td> ..... 0.47 ......</td><td></td><td> .... 15</td>

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

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

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

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

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

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

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

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

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

<td> 41 ......</td><td> ..... 0.4-7 ......</td><td> 60</td><td> .... 7</td>

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

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

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

<td> 47</td><td> 0.075</td><td> 109</td><td>0o3</td>

<td> 53 ......</td><td> ..... 0.075 ......</td><td> T</td><td> .... 25</td>

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

<td> 55</td><td> 0.035</td><td> 160</td><td> 40.1</td>

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

<img file="PT86453B_D0058.tif" />

a Dose IV used for cardiotonic activity assay b Percent increase in cardiac strength c Micromolar concentration to 50% inhibition of cyclic nucleotide activity d Not tested