Process and intermediates for the preparation of oxophthalazinyl acetic acids and analogs thereof

Oxophthalazinyl acetic acids having benzothiazole side chains are prepared by reacting an oxophthalazinyl thioacetamide acetate with hydrogen sulfide and a nitrophenyl compound having a reactive group such that the benzothiazole side chain may be formed by ring closure involving the thioacetamide group. The oxophthalazinyl thioacetamide may be prepared by reacting the corresponding cyanomethyloxophthalazinyl acetate with hydrogen sulfide in the presence of tertiary amines. Analogous indazole and oxopyridopyridazinone acetic acids may be prepared similarly, as well as oxophthalazinyl, indazole and oxopyridopyridazinone acetic acids having thiazolopyridinyl side chains.

BACKGROUND OF THE INVENTION 
The present invention relates to processes and intermediates for the 
preparation of oxophthalazinyl acetic acids and analogues thereof. The 
latter compounds are aldose reductase inhibitors and are useful in 
preventing or alleviating chronic complications associated with diabetes. 
Aldose reductase inhibitors that may be prepared by the processes of the 
present invention are disclosed in U.S. Pat. Ser. No. 07/263,577, filed 
Oct. 27, 1988 and European Patent Application Publication Number 222576. 
Nitriles that are used as starting materials in the processes of the 
present invention are disclosed in European Patent Application Publication 
Number 0295051. 
West German Patent Application DE No. 3337859 refers to preparation of 
benzothiazole derivatives by cyclization of 2-substituted aniline or 
nitrobenzene compounds with thioamide derivatives. 
International Application PCT/US88/00110, filed January 19, 1988 refers to 
lH-indazole-3-acetic acids as aldose reductase inhibitors. 
SUMMARY OF THE INVENTION 
The present invention relates to a process for preparing a compound of the 
formula 
##STR1## 
wherein X and Y are independently CH or N; Z is N or CR.sup.6 ; A is a 
covalent bond or C.dbd.O; R.sup.1 is C.sub.1 -C.sub.6 alkyl; R.sup.3 and 
R.sup.4 are the same or different and are hydrogen, fluoro, chloro, bromo, 
trifluoromethyl, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, C.sub.1 
-C.sub.4 alkylthio, C.sub.1 -C.sub.4 alkylsulfinyl, C.sub.1 -C.sub.4 
alkylsulfonyl, or nitro, or R.sup.3 and R.sup.4 taken together are C.sub.1 
-C.sub.4 alkanedioxy; and R.sup.5 and R.sup.6 are the same or different 
and are hydrogen, fluoro, chloro, bromo, trifluoromethyl, nitro, cyano, 
C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, C.sub.1 -C.sub.4 
alkylthio, C.sub.1 -C.sub.4 alkylsulfinyl, C.sub.1 -C.sub.4 alkylsulfonyl, 
trifluoromethyl, trifluoromethoxy, or trifluoroacetyl, with the proviso 
that when X or Y is N, then R.sup.3 and R.sup.4 are the same or different 
and are hydrogen, CF.sub.3 or C.sub.1 -C.sub.4 alkyl, which comprises 
reacting a compound of the formula 
##STR2## 
wherein W is --CN or 
##STR3## 
and X, Y, A, R.sup.1, R.sup.3 and R.sup.4 are as defined above, with a 
compound of the formula 
##STR4## 
wherein Z and R.sup.5 are as defined above, and B is F, Cl, Br, I, SCN or 
OSO.sub.2 R.sup.7 wherein R.sup.7 is C.sub.1 -C.sub.4 alkyl, phenyl, 
methylphenyl, nitrophenyl or bromophenyl, in the presence of hydrogen 
sulfide, with the proviso that when W is CN, the reaction is conducted in 
the presence of a tertiary amine. 
Substituents R.sub.3 and R.sub.4 when other than trifluoromethyl or C.sub.1 
-C.sub.4 alkyl can not be directly across or immediately flanked by X or Y 
when they are nitrogen. 
In a preferred embodiment of the invention, the reaction is also conducted 
in the presence of a tertiary amine when W is 
##STR5## 
The present invention also relates to a compound of the formula 
##STR6## 
wherein W is 
##STR7## 
or --CN; R.sup.1 is C.sub.1 -C.sub.6 alkyl; R.sup.3 and R.sup.4 are the 
same or different and are hydrogen, fluoro, chloro, bromo, 
trifluoromethyl, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, C.sub.1 
-C.sub.4 alkylthio, C.sub.1 -C.sub.4 alkylsulfinyl, C.sub.1 -C.sub.4 
alkylsulfonyl, or nitro, or R.sup.3 and R.sup.4 taken together are C.sub.1 
-C.sub.4 alkanedioxy; and X and Y are independently CH or N, and A is a 
covalent bond or C.dbd.O, with the proviso that when X or Y is N, then 
R.sup.3 and R.sup.4 are the same or different and are trifluoromethyl or 
C.sub.1 -C.sub.4 alkyl, and with the proviso that when W is CN and A is 
C.dbd.O, then X and Y are not both CH. 
The invention further relates to a compound of the formula 
##STR8## 
wherein X and Y are independently CH or N; Z is N or CR.sup.6 ; R.sup.1 is 
C.sub.1 -C.sub.6 alkyl; R.sup.3 and R.sup.4 are the same or different and 
are hydrogen, trifluoromethyl, or C.sub.1 -C.sub.4 alkyl; and R.sup.5 and 
R.sup.6 are the same or different and are hydrogen, fluoro, chloro, bromo, 
trifluoromethyl, nitro, cyano, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 
alkoxy, C.sub.1 -C.sub.4 alkylthio, C.sub.1 -C.sub.4 alkylsulfinyl, 
C.sub.1 -C.sub.4 alkylsulfonyl, trifluoromethylthio, trifluoromethoxy, or 
trifluoroacetyl; with the proviso that X and Y are not both CH. 
Also included in the invention are a composition for inhibition of aldose 
reductase activity comprising a compound of formula VI in an amount 
effective in the inhibition of aldose reductase activity, in admixture 
with a pharmaceutically acceptable carrier; and a method of inhibiting 
aldose reductase activity comprising administering to a diabetic host an 
effective amount of a compound of formula VI. 
DETAILED DESCRIPTION OF THE INVENTION 
The processes of the present invention are illustrated in Scheme I. 
The compound of the formula IIB is reacted with the compound of the formula 
III to prepare a compound of the formula I. Generally, the reaction is 
conducted in a polar solvent. Suitable solvents include sulfolane 
(tetrahydrothiophene-1,1-dioxide), pyridine, diethylene glycol dialkyl 
ethers (e.g. diethylene glycol diethyl ether), N-methyl pyrrolidone, and 
mixtures thereof. The preferred solvent is dimethylformamide. The reaction 
temperature is generally between about 110.degree. C. and about 
180.degree. C., preferably the reflux temperature of the solvent. The 
reaction pressure is not critical. Generally, the pressure will range from 
about 0.5 to about 2 atmospheres, and will preferably be ambient pressure 
(i.e. about one atmosphere). The compound of formula IIB when W is CN is 
reacted with the compound of the formula III in the presence of a tertiary 
amine. Suitable tertiary amines are tri(C.sub.2 -C.sub.6)alkylamines, e.g. 
triethyl amine. 
The compound of the formula I may be hydrolyzed in aqueous base to prepare 
a compound of the formula V. 
##STR9## 
When R.sup.1 is tertiary butyl, the hydrolysis to a compound of the 
formula V is more conviently performed in concentrated sulfuric acid or 
trifluoroacetic acid. 
The compound of the formula IIB wherein W is cyano may be prepared by 
reacting a compound of the formula IIA with a compound of the formula 
L--CH.sub.2 CN wherein L is chloro, bromo, --OSO.sub.2 (C.sub.1 -C.sub.4 
alkyl), or --OSO.sub.2 aryl wherein aryl is phenyl or naphthyl optionally 
substituted by C.sub.1 -C.sub.4 alkyl, halogen, or nitro, in the presence 
of a base. Examples of suitable bases include alkali metal hydride such as 
sodium hydride, alkali metal carbonates such as potassium carbonate, 
alkali metal hydroxides such as sodium or potassium hydroxide, and alkali 
metal alkoxides such as potassium tertiary butoxide and sodium methoxide. 
The reaction may be conducted in a solvent which is inert under the 
reaction conditions. Suitable solvents are inert solvents such as 
dimethylformamide, dimethylacetamide, acetone, and diglyme. The reaction 
is generally at temperatures of between about 0.degree. C. and about 
100.degree. C. Preferably, the reaction temperature is between about 
40.degree. to 60.degree. C. 
The compound of the formula IIB wherein W is --C(S)NH.sub.2 may be prepared 
by reacting a compound of the formula IIB wherein W is CN with hydrogen 
sulfide in the presence of tertiary amines such as tri(C.sub.2 
-C.sub.6)alkyl amines, e.g. triethyl amine, in the presence of a solvent 
such as pyridine or dimethylformamide. Preferably, the reaction is 
conducted in dimethylformamide. Generally, the reaction is conducted at 
temperatures between about ambient temperature and about 100.degree. C. 
Preferably, the reaction temperature is between about 40.degree. and 
60.degree. C. 
The novel compounds of formula V and the pharmaceutically acceptable salts 
thereof are useful as inhibitors of the enzyme aldose reductase in the 
prevention and alleviation of chronic complications of diabetes, such as 
diabetic cataracts, retinopathy, nephropathy and neuropathy. The compound 
may be administered to a subject in need of treatment by a variety of 
conventional routes of administration, including orally, parenterally and 
topically. In general, these compounds will be administered orally or 
parenterally at dosages between about 0.5 and 25 mg/kg body weight of the 
subject to be treated per day, preferably from about 1.0 to 10 mg/kg. 
However, some variation in dosage will necessarily occur depending on the 
condition of the subject being treated. The compound may be administered 
alone or in combination with pharmaceutically acceptable carriers, in 
either single or multiple doses. Pharmaceutical compositions formed by 
combining a novel compound of the formula I or a pharmaceutically 
acceptable salt thereof and pharmaceutically acceptable carriers may be 
administered in a variety of dosage forms such as tablets, powders, 
lozenges, syrups, and injectable solutions. 
Compounds of formula I and pharmaceutically acceptable salts thereof may 
also be employed for the treatment of diabetic cataracts by topical 
administration. The ophthalmic preparation will contain a compound of 
formula I or a pharmaceutically acceptable salt thereof in a concentration 
from about 0.01 to about 1% by weight, preferably from about 0.05 to about 
0.5% by weight, in a pharmaceutically acceptable solution, suspension or 
ointment. Some variation in concentration will necessarily occur, 
depending on the particular compound employed and the condition of the 
subject to be treated. 
The activity of the compounds of formula VI of the present invention as 
agents for the control of chronic diabetic complications may be determined 
by a number of standard biological or pharmacological tests. Suitable 
tests include (1) measuring their ability to inhibit the enzyme activity 
of isolated aldose reductase; (2) measuring their ability to reduce or 
inhibit sorbitol accumulation in the sciatic nerve and lens of acutely 
streptozotocinized, i.e. diabetic, rats; (3) measuring their ability to 
reverse already-elevated sorbitol levels in the sciatic nerve and lens of 
chronic streptozotocin-induced diabetic rats; (4) measuring their ability 
to prevent or inhibit galactitol formation in the lens of acutely 
galactosemic rats; (5) measuring their ability to delay cataract formation 
and reduce the severity of lens opacities in chronic galactosemic rats; 
(6) measuring their ability to prevent sorbitol accumulation and cataract 
formation in isolated rat lens inclubated with glucose; and (7) measuring 
their ability to reduce already elevated sorbitol levels in isolated rat 
lens incubated with glucose.

The following Examples illustrate the processes of the present invention. 
All melting points are uncorrected. 
EXAMPLE 1 
Ethyl-3-thioacetamido-4-oxo-phthalazin-1-ylacetate 
Hydrogen sulfide was bubbled through a solution of 
ethyl-3-cyanomethyl-4-oxo-phthalazin-1-ylacetate (54.2 g) in 
dimethylformamide (200 ml) containing triethyl amine (1 ml) maintained at 
60.degree. C. After 15 minutes, the hydrogen sulfide bubbling was 
discontinued and heating was continued for 2 hours. The solution was 
cooled to room temperature and then poured slowly over ice-water (2000 
ml). The granulated thick precipitate was filtered, washed with water 
(2.times.200 ml) and then air-dried to obtain the title compound (yield 
57.8 g; m.p. 149.degree.-151.degree. C.). 
EXAMPLE 2 
Ethyl-3-(5-trifluoromethylbenzothiazol-2-ylmethyl)-4-oxo-3-H-phthalazin-1-y 
lacetate 
Procedure A 
A solution of ethyl-3-cyanomethyl-4-oxophthalazin-1-ylacetate (10.84 g) and 
a catalytic amount of triethylamine (0.2 g) in dimethylformamide (40 ml) 
maintained at 50.degree.-55.degree. C. was bubbled with hydrogen sulfide 
for 15 minutes. After hydrogen sulfide bubbling was discontinued, the 
reaction was continued for 3 hours. At this stage, the solution was 
resaturated with hydrogen sulfide and 4-chloro-3-nitrobenzotrifluoride 
(9.47 g) was added to the reaction mixture. The reaction mixture 
immediately turned light orange in color and it was then heated to 
140.degree. C. for 2.5 hours. The solution was cooled to room temperature 
and then was added dropwise to a mixture of ice-water and ethanol (800 ml; 
4:1). The pH of the aqueous ethanol was adjusted to about 2.0 with a few 
drops of 6N hydrochloric acid. The resulting granulated solid was filtered 
and the residue was crystallized from a 3:1 mixture of ethanol-methylene 
chloride (50 ml). The solid was collected by filtration and was then 
air-dried to obtain the title compound (yield 12.2 g). The mother liquor 
contained an additional quantity (analytical estimate, about 1.0 g) of the 
title compound. 
Procedure B 
To a solution of ethyl-3-thioacetamido-4-oxophthalazin-1-ylacetate (6.1 g) 
in dimethylformamide (30 ml) saturated with hydrogen sulfide was added 
4-chloro-3-nitrobenzotrifluoride (4.5 g) and the resulting solution was 
heated slowly to reflux. When the reflux temperature was reached, a slow 
current of hydrogen sulfide was passed through the solution and the 
refluxing continued for 4 hours. The reaction mixture was then cooled and 
poured onto ice-water (500 ml). The resulting gum was separated by 
decantation and then triturated with ethanol (75 ml). The granulated light 
yellow solid was filtered and the precipitate was collected and 
crystallized from ethanol (200 ml) to obtain the title compound (yield 4.1 
g). 
In a similar manner was prepared 
ethyl-3-(7-chlorobenzothiazol-2-ylmethyl)-4-oxo-3-H-phthalazin-1-ylacetate 
, m.p. 119.degree. C and ethyl-3-(5-chloro-7-fluoro- 
benzothiazol-2-ylmethyl)-4-oxo-3-H-phthalazine-1-ylacetate, m.p. 
202.degree.-204.degree. C. using 2,3-dichloronitrobenzene and 
2,5-dichloro-3-fluoro-nitrobenzene, respectively, in place of 
4-chloro-3-nitrobenzotrifluoride. 
EXAMPLE 3 
I. Methyl 1H-Indazole-3-ylacetate 
A solution of 1H-indazole-3-acetic acid (1.0 g) prepared according to J. 
Am. Chem. Soc., 79, 5245 (1957), in methanol (30 ml) containing five drops 
of concentrated sulfuric acid was refluxed for 8 hours. The reaction 
mixture was then concentrated to a low volume and diluted with ethyl 
acetate (20 ml). The organic layer was washed with water (2.times.10 ml) 
and then with sodium bicarbonate solution (10 ml, 10%). The ethyl acetate 
layer was collected and then dried to obtain the title compound (yield: 
0.8g; m.p. 146.degree. C.). 
II. Methyl-(1-cyanomethyl)-1-H-indazole-3-ylacetate 
To a solution of methyl-1-H-indazole-3-ylacetate (1.9 g) in 
dimethylformamide (4 ml) was added sodium hydride (0.58 g; 50% by weight 
dispersed in oil) and the mixture stirred for 15 minutes at room 
temperature. Chloroacetonitrile (1.9 g) dissolved in dimethylformamide (2 
ml) was then added and the reaction mixture stirred for 6 hours. The 
mixture was then poured onto ice-water (20 ml), the pH was adjusted to 
about 3 by the addition of sufficient dilute HCl, and the resulting 
precipitate was collected and air-dried (yield 1.87 g) m.p. 
128.degree.-134.degree. C. 
EXAMPLE 4 
3-(7-Chlorobenzothiazol-2ylmethyl)-4-oxo-3-H-phthalazin-1-ylacetic acid 
To a solution of 
ethyl-3-(7-chlorobenzothiazol-2-ylmethyl)-4-oxo-3-H-phthalazin-1-ylacetate 
(800 mg) in a 2:1 mixture of ethanol and tetrahydrofuran (30 ml) was added 
5 ml of 1% aqueous potassium hydroxide solution and the mixture was 
stirred at room temperature for 2 hours. The reaction mixture was 
concentrated by evaporation under vacuum and the resulting residue was 
diluted with water (10 ml). Upon adjusting the pH of the solution to 
around 2 with sufficient 10% HCl,a white precipitate was obtained. The 
precipitate was collected by filtration, air-dried and then crystallized 
from methylene chloride (10 ml) to obtain the title compound (yield, 273 
mg), m.p. 168.degree. C. 
Similarly, 
ethyl-3-(5-chloro-7-fluoro-benzothiazol-2-ylmethyl)-4-oxo-3-H-phthalazin-y 
lacetate was hydrolyzed to 
3-(5-chloro-7-fluoro-benzothiazol-2-ylmethyl)-4-oxo-3-H-phthalazanin-1-yla 
cetic acid (m.p. 207.degree.-207.5.degree. C.). 
EXAMPLE 5 
I. 3-Oxo-pyrido[3,2-c]and 3-oxo-pyrido[2.3-c]furan-1-ylidene acetic acid 
t-butyl ester 
A mixture of the commercially available 2,3-pyridinedicarboxylic anhydride 
(29.8 g), (t-butoxycarbonylmethylene)triphenyl phosphorane (75.2 g) and 
methylene chloride (1000 ml) was stirred at room temperature for 60 hours. 
The mixture was evaporated to dryness and the residue chromatographed over 
silica gel (2.0 kg). Upon careful elution with a solution of methylene 
chloride in ethyl acetate (49:1) and monitoring of the eluent fractions by 
thin layer chromatography, two products were isolated. The less polar 
product designated A was identified as a mixture (1:1) of E or Z 
3-oxo-pyrido[2,3-c]furan-1-ylidene acetic acid t-butyl ester [.sup.1 H 
NMR(CDCl.sub.3, 250 MHz); 1.5 (s, 9H), 6.1 (s, 1H), 7.8 (dd, J=6Hz, 1H), 
8.40 (dd, J.sub.1= 6Hz, J.sub.2 =Hz, 1H), 9.1 (dd, J.sub.1 =6H, J.sub.2 
=1H, 1H) and E 3-oxo-pyrido[3,2-c)furan-1-ylidene acetic acid t-butyl 
ester [.sup.1 H NMR(CDCl.sub.3, 250 MHz): 1.5 (s, 9H), 6.2 (s, 1H), 7.9 
(dd, J=6Hz, 1H), 9.0 (dd, J=6Hz, IH), 9.2 (d, J=12Hz, 1H). 
The more polar product designated B was identified as a mixture (about 
1:10) of E 3-oxo-pyrido[3,2-c]furan-1-ylidene acetic acid t-butyl ester 
and E or Z 3-oxopyrido [2,3-c]furan-1-ylidene acetic acid t-butyl ester. 
The less polar product A was not separated into pure components. The more 
polar product B was rechromatographed over silica gel (500 g) and eluted 
with a solution of methylene chloride in ethyl acetate (9:1). Evaporation 
of the early fractions gave pure E 3-oxo-pyrido[3,2-c]furan-1-ylidene 
acetic acid t-butyl ester (1.8 g, m.p. 113.degree.-114.degree. C.). 
Evaporation of the later fractions gave pure E or Z 
3-oxo-pyrido[2,3-c]-furan-1-ylidene acetic acid t-butyl ester (11.5 g, 
m.p. 118.degree. C.). 
II. t-Butyl 8-oxo-7H-pyrido[2,3-d]pyridazine-5-yl acetate 
To a solution of E 3-oxo-pyrido[3,2-c]furan-1-ylidene acetic acid t-butyl 
ester (1.85 g) in ethanol (10 ml) was cautiously added hydrazine hydrate 
(1.3 ml) and the mixture was then gently refluxed for 1 hour. The solution 
was concentrated to remove ethanol and the residue was diluted with water 
(20 ml). Sufficient 10% HCl was then added to adjust the pH to about 2.0. 
The precipated solid was collected and the collected solid was air-dried 
(1.36 g, m.p. 186.degree.-188.degree. C). 
EXAMPLE 6 
I. t-Butyl 5-oxo-6H-pyrido[2,3-d]pyridazine-8-yl acetate 
To a solution of E or Z 3-oxo-pyrido[2,3-c]furan-1-ylidene acetic acid 
t-butyl ester (m.p. 118.degree. C.; 10.0 g) in ethanol (25 ml) was added 
hydrazine hydrate (10 ml) dropwise and the resulting solution was refluxed 
for 10 minutes. The solution was evaporated to remove ethanol, the residue 
was diluted with water (20 ml) and sufficient 10% HCl was added to adjust 
the pH to about 6. The precipated solid was filtered and the collected 
solid was air-dried (8.9 g, m.p. 178.degree.-179.degree. C.). 
II. t-Butyl 
6-(5-trifluoromethylbenzothiazole-2-ylmethyl)-5-oxo-6H-pyrido[2,3-d]pyrida 
zine-8-ylacetate 
To a solution of t-butyl 5-oxo-6H-pyrido[2,3-d]- pyridazine-8-yl acetate 
(0.5 g) in dimethylformamide (5 ml) containing potassium t-butoxide (0.25 
g) was added 5-trifluoromethyl-2-chloromethylbenzothiazole (0.55 g). The 
solution was stirred at room temperature overnight and then poured over 
ice-water (20 ml); sufficient 10% HCl was added to adjust the pH to about 
5.0 and the precipitated crude solid was collected. The solid was 
chromatographed over silica gel using a 1:1 mixture of methylene chloride 
and ethyl acetate as eluent to obtain the product (0.66 g, m.p. 
121.degree.-122.degree. C.).