GB2087868A - Amino-benzamides - Google Patents

Abstract

Antihypertensive and diuretic properties are exhibited by compounds of the formula <IMAGE> wherein: Ar and Ar' are independently alicyclic aryl or heterocyclic aryl groups; R1 is a substituent replacing a hydrogen on the ring and is independently hydroxy, alkyl, alkoxy, halogen, nitro, amino, monoalkylamino, dialkyl-amino, sulfhydryl, alkylmercapto, sulfonamido, carboxy, carbalkoxy, or trihalomethyl; n is an integer from 0 to 5 inclusive; R2 and R3 are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, phenyl, or cycloalkyl- alkyl; and R4 and R5 are independently hydrogen, halogen or trihalomethyl, with the proviso that when both Ar and Ar' are phenyl and n is 0, both R2 and R3 are not hydrogen.

Description

SPECIFICATION Amino-benzamides This invention relates to new organic compounds having valuable pharmaceutical activity. It particularly relates to compounds having anti hypertensive and diuretic activity and to a process for the preparation of said compounds.

The invention provides compounds of the formula

wherein: Ar and Ar' are independently alicyclic aryl or heterocyclic aryl groups; R, is a substituent replacing a hydrogen on the ring and is independently hydroxy, alkyl, alkoxy, halogen, nitro, amino, monoalkyl-amino, dialkyl-amino, sulfhydryl, alkyl-mercapto, sulfonamido, carboxy, carbalkoxy, or trihalomethyl; n is an integer from 0 to 5 inclusive; R2 and R3 are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, phenyl, or cycloalkyl-alkyl; and R4 and R5 are independently hydrogen, halogen or trihalomethyl; with the proviso that when both Ar and Ar' are phenyl and n is 0, both R2 and R3 are not hydrogen.

Preferably, the alkyl, alkenyl and alkynyl groups contain up to 6 carbon atoms, and may be straight chained or branched, the cycloalkyl groups contain from 3 to 7 carbon atoms, and Ar' is phenyl.

Preferably only one of R4 and R5 is hydrogen.

In accordance with this invention the compounds are prepared by the reaction of a sulfamylaroyl halide, preferably chloride, of the formula,

or equivalent acid acylating derivative, wherein X is halogen, preferably chlorine, with a hydrazine of the formula

wherein R1, R2, R3, R4 and R5 and Ar and n are the same as described above.

The hydrazines are readily prepared using standard methods by the nitrosation of an amine of the formula

where R2 is other than H, to form the nitrosamine

which is then reduced to the hydrazine of the formula

When R3 is other than hydrogen, R3 can then be introduced by standard methods by reaction with R3-halide, e.g. alkylation with alkyl halides to introduce alkyl groups. or by use of equivalent reagent, such as the dialkyl sulfates known for such reactions.

For compounds of formula I wherein R2 and/or R3 is other than H, the corresponding compounds of formula I in which R2 and/or R3 is hydrogen are reacted with halides of the formula R2-halide and R3-halide respectively under the usual conditions employed for alkylating amines.

The aforementioned nitrosation reaction is accomplished by reacting the starting secondary amine with nitrous acid, formed by reaction of a soluble nitrite salt with mineral acid.

The reaction is normally effected at low temperature, e.g. below about 10"C., in an organic solvent which is preferably water-miscible since the sodium nitrite is usually added as an aqueous solution. Lower alkanols such as methanol and ethanol are convenient as solvents.

The reduction of the nitrosoamine compound of formula V is effected preferably by use of metal hydrides, such as lithium aluminum hydride and lithium borohydride in an organic solvent such as a dialkyl ether, e.g.

diethyl ether.

The aforesaid conversions of compounds wherein R2 and/or R3 are H to those wherein R2 or R3 are other than H as defined herein is accomplished by reaction with R2 halide or R3 halide, preferably in the presence of a hydrogen halide acceptor such as alkali metal alkoxides, hydroxides, carbonate or bicarbonates.

The reaction can be effected at from room temperature up to about the reflux temperature of the reaction solvent.

The reaction of compounds of formula Il with the hydrazine of formula Ill is an acylation reaction to form the corresponding hydrazide. For this purpose, any acylating derivative of the acid corresponding to the acid chloride of formula li can be employed. Such derivatives include the lower alkyl esters, anhydrides, mixed anhydrides, and the like, as well as the preferred acyl halide. Hydrazide formation, i.e. the acylation reaction, is preferably conducted in an organic solvent usually in the presence of a base such as alkali metal alkoxides, hydroxide, bicarbonates or carbonates, particularly when an acyl halide is employed as acylating agent.The acylation reaction is normally carried at or near room temperature e.g. from 25 , to as low as 5"C. Higher temperatures are not necessary but may be used to effect reaction digestion. The solvent employed is preferably a water-miscible organic solvent such as lower alkanols and equivalent organic solvents.

The invention will be more fully illustrated in the examples which follow. These examples are given by way of illustration and are not to be considered as limiting.

EXAMPLE 1 N-Nitroso-N-isopropylaniline A mixture of 36g (0.125 mol) N-isopropylaniline, 45 ml hydrochloric acid, and 100 g ice was maintained at 10'C while a solution of 259 (0.36 mol) sodium nitrite in 90 ml water was added over a 10 minute period.

After the addition was completed, the mixture was allowed to stir for 1 hour. When stirring was discontinued an oily layer separated. The oil was removed and combined with subsequent toluene washing of the aqueous layer.

The resultant toluene solution was dried over magnesium sulfate, filtered, and stripped of solvent under diminished pressure to yield the N-nitroso compound.

EXAMPLE 2 1 -Isopropyl- 1 -phenyl-hydrazine hydrochloride The N-nitroso compound of Example 1 was readily reduced by gradually adding a solution of 1 2.8g (0.08 mol) of said compound in 100 ml glacial acetic acid to a vigorously stirred suspension of 25g zinc dust in 35 ml water. Throughout this addition the temperature was maintained between 10"C and 20"C.

After the addition was completed, the mixture was stirred for 1 5 minutes at room temperature and was then warmed to 80 on a steam bath. Unreacted zinc was filtered from the hot reaction mixture and was washed with three 1 5 ml portions of warm 5% hydrochloric acid.

The combined washings and filtrate was cooled, and the zinc hydroxide which precipitated was redissolved by the addition of 1 50 ml of 40% sodium hydroxide. The oiiy layer which separated was removed and combined with ethereal washings of the aqueous layer.

This ethereal solution was dried over magnesium sulfate and filtered. Acidification with gaseous hydrochloric acid yielded the salt of the hydrazine which separated as an oil and was removed from the ethereal solution.

1 -Isopropyl- 1-phenyl-2-(3-sulfamyl-4-chlorobenzoyl)-hydrazine Neutralization of the hydrazine hydrochloride of Example 2 was effected by stirring with 19.6g (0.21 mol) sodium bicarbonate in 100 ml isopropanol. When gas evolution ceased (12 hours) the system was cooled in an ice-water bath, and 259 (0.1 mol) 3sulfamyl-4-chlorobenzoyl chloride was added in several portions. Throughout this addition the temperature was maintained between 5" and 20on. After the addition the reaction mixture was stirred at room temperature overnight. The reaction mixture was then cooled to 0-5"C., diluted with 80 ml water, and stirred for 2 more hours.

Solid material which precipitated was collected and was washed with three 40 ml portions of cold 60% isorpopanol. Recrystallization from methylene chloride/ether yielded crystals, mp 112-124".

EXAMPLE 4 1-Phenyl- -n-propyl-hydrazine N-nitroso-N-propylaniline, prepared from Nn-propylaniline by the same method as described in Example 1, was conveniently reduced with lithium aluminum hydride (LAH).

The LAH in 450 ml dry ether was heated under reflux for 1 5 minutes, and a solution of 32.8g (0.2 mol) crude nitroso compound in 250 ml dry ether was added dropwise. The reaction mixture was allowed to stir for 3 hours before it was quenched by the dropwise addition of 12 ml water and 14 ml 20% sodium hydroxide. The resultant suspension was filtered free of inorganic salts, dried and stripped of solvents under diminished pressure. Distillation of the residue yielded the desired compound bp 55"-57"/0.12mm.

EXAMPLE 5 1 -n-Propyl- 1 -phen yl-2-(3-sulfam y!-4 chlorobenzoyl)hydrazine A vigorously stirred mixture of 14.0g (0.1 mol) 1-phenyl-1-n-propylhydrazine, 8. 4g (0.1 mol) sodium bicarbonate, and 100 ml isopro panol was chilled to 0-5"C., 23g (0.09 mol) 3-sulfamyl-4-chlorobenzoyl chloride was added in one portion, and the reaction mix ture was allowed to stir for several hours, gradually warming to room temperature. Dilu tion with water and refrigeration overnight yielded solid material which was collected and recrystallized from acetone/water, mp. 11 2'C (d).

EXAMPLE 6 1-Cyclohexyl- 1-phenyl-hydrazone N-Cyclohexyl-N-n itrosoaniline, prepared from N-cyclohexylaniline by the method de scribed in Example 1 was subsequently re duced to the hydrazine by the lithium alumi num hydride method described in Example 4.

1 -Cyclohexyl-1 Ophenyl-hydrazine distilled at 102-105"C/0.2 mm.

EXAMPLE 7 1 -Cyclohexyl- 1 -ph en yl-2-(3-sulfam yl-4-chloro- benzoyl)-hydrazine A mixture of 8.59 (0.045 mol) 1-cyclo hexyl-1-phenyl hydrazine in 50 ml isopropanol and 4.7g (0.045 mol) sodium bicarbonate was stirred and chilled. Addition of 11.36g (0.045 mol) 3-sulfamyl-4-chlorobenzoyl chlo ride was made in several portions. The mix ture was stirred for 2 hours at room tempera ture and for 2.5 hours at 40-50"C. Dilution of the reaction mixture with water yielded a solid material which was recrystallized from aqueous ethanol. M.P. 216-217"C.

EXAMPLE 8 1 -Phen yl-2-(3-sulfamyl-4-chlorobenzoyl)-h ydra zine In a 1 liter round bottom flask were placed phenyl hydrazine (54.lg 0.5 mol), triethylam ine (50.5g, 0.5 mol), and 1 50 ml of 1,2 dimethyloxyethane. Then the mixture was cooled to ice-bath temperature and with good stirring and over 10 minutes a solution of 3 sulfamyl-4-chlorobenzoyl chloride 97.1% (619, 0.24 moi) in 150 ml 1,2 dimethoxyeth ane was added dropwise. The reaction was permitted to reach ambient temperature. After standing for 6 days the solvent was evapo rated under vacuum and the residue taken up in 500 ml of ethyl acetate. The organic phase was washed twice with 2N H2SO4, with water and finally with 1 molar sodium bicarbonate solution.The ethyl acetate phase was separ ated and dried with magnesium sulfate, clari fied and concentrated to crystallization. 359 of product mp 189-190"C. were obtained.

I EXAMPLE 9 1-Allyl- 1-phenyl-2-(3-sulfamyl-4-chloroben- zoyl)-hydrazine In a three necked 1 liter round bottom reaction vessel equipped with a mechanical stirrer and reflux condenser were placed 48.89 (0.1 5 mol) of the compound of Example 8 and 1 25 ml of hexamethylphosphorictriamide. The mixture was heated with stirring under nitrogen to 80-85"C. To this solution 1269 (1.5 mol) of sodium bicarbonate powder was added portionwise followed by 20g (0.17 mol) of allyl bromide. After 2.25 hours an additional 1.89 (0.015 mol) of allyl bromide was added. After 29 hours of heating the reaction mixture was cooled to room temperature diluted with 700 ml of ethyl acetate, and the slurry was cross washed with water and diluted brine.The ethyl acetate was separated, dried with magnesium sulfate, clarified and taken to dryness under vacuum. The crude reaction mixture was crystallized from chloroform yielding 26.29 of analytically pure product mp 99-101"C.

EXAMPLE 10 1 -Phenyl- 1-propynyl-2-(3-sulfamyl-4-chloro- benzoyl)-hydrazine In a three necked 1 liter round bottom reaction vessel equipped with a mechanical stirrer and reflux condenser were placed 97.59 (0.3 mol) of the compound Example 8 and 200 ml of hexamethylphosphoric-triamide. The mixture was heated with stirring under nitrogen at 80-90"C till the solid dissolved. To this solution was added with stirring 252g (3 mol) sodium bicarbonate powder. Over a period of about 0.5 hour 29.4 ml of an 80% w/w solution of propargyl bromide in toluene (0.315 mol propargyl bromide) were added with stirring. After the reaction had run for 21 hours an additional 4 ml of the propargyl bromide solution in toluene (0.043 mol propargyl bromide) was added and the reaction continued for an additional 68 hours.The reaction mixture was then cooled and diluted with 1 liter of ethyl acetate. The mixture was transferred to a separatory funnel, cross-washed with water/brine, then with a 2 molar aqueous citric acid and again with brine. The organic layer was dried over anhydrous magnesium sulfate, clarified and evaporated to yield 1089 of a dark oil which was purified by chromatography over silica gel to yield a solid which was recrystallized from ethyl acetate/hexane. M.p.

168-170"C.

EXAMPLE 11 1-Allyl- 1 -phenyl-2-(3-sulfam yl-4-chloroben- zoyl)-hydrazine 1 -Phenyl-2-(3-sulfamyl-4-chlorobenzoyl)-hydrazine 59 (0.015 mol) was dissolved in dimethylformamide (15 ml). To this was added allyl bromide 2.89 (0.023 mol) and the mixture was heated at 95-100"C for about 1.5 hours. The reaction mixture was cooled and diluted with 30 ml of isopropanol and added slowly to about 900 ml of cold water. The precipitate was collected by filtration, washed with water and dried under reduced pressure to provide 1-allyl-1 phenyl-2-(3-sulfamyl-4chlorobenzoyl)-hydrazine (m.p. 99-101"C).

EXAMPLE 12 1-Allyl- 1-phenyl-2-(3-sulfamyl-4-chloroben- zoyl)-hydrazine In a three necked 1 2 liter round bottom reaction flask equipped with a mechanical stirrer and reflux condenser was placed isorpopanol 6.1 liters and 1-phenyl-2-(3-sulfamyl-4chlorobenzoyl)-hydrazine 1.3 kg (4.1 mol), potassium iodide 68.0g (0.41 mol) sodium bicarbonate 1.67 kg (19.9 mol) and allyl bromide 7689 (8 mol). This mixture was stirred at gentle reflux for about 20 hours then suction filtered while still hot. The cake was washed with isopropanol 300 ml and the combined filtrate and wash were diluted with warm water 2.7 liters. Crystallization occured in about 0.5 hours.The crystals were filtered and washed with isopropanol-water (70% v/v) to provide the compound (m.p/99-1 01 'C) EXAMPLE 13 I -Phenyl- 1-propynyl-2-(3-sulfamyl-4-chloro- benzoyl)-h ydrazine 1 -Phenyl-2-(3-sulfamyl-4-chlorobenzoyl)-hydrazine 59 (0.015 mol) was dissolved in di methylformamide (20 ml). To this was added propargyl bromide 3.69 (0.03 mol) and the mixture heated at 95-100"C for about 2 hours. The reaction mixture was concentrated under reduced pressure at about 40-45"C on a rotary evaporator. The concentrate was then diluted with approximately 2 volumes of isor popanol and added slowly to about 600 ml of vigorously stirred water.The precipitate was collected by filtration, washed with water and dried under reduced pressure to provide 1 phenyl- 1 -propynyl-2-(3-sulphamyl-4-chloro benzoyl)-hydrazine (m.p. 168-170"C).

Using the procedures in the above exam ples compounds wherein R1 was hydroxy, alkyl, alkoxy, nitro, halo, amino, trifluoro-methyl, mercapto and alkyl mercapto, and R2 and R3 were alkyl, cycloalkyl and alkenyl can be prepared. Where R1 is hydroxy, amino or mercapto the group is protected in the usual manner prior to the reaction with the sulfamyl halobenzoyl halide and the protective group removed after the reaction.

By following the procedures in the above examples the following additional compounds may be prepared: 2-[(4-ch loro-3-sulfamyl)-benzoyl]-1 -crotyl- 1 - phenyl-hydrazine, 2-[(4-chloro-3-sulfamyl)-benzoyl3- 1 -(2-buty nyl)-1 0 phenyl-hydrazine, 2-t($ch loro-3-su lfamyl)-benzoyl]- 1 -(3-methyl-2-butenyl)- 1 -phenyl hydrazine, 2-[(4-chloro-3-sulfamyl)-benzoyl]-1 -phenyl- 1 cyclopropyl-methylhydrazine, 2-[(4-chloro-3-sulfamyl)-benzoyl]- 1 -phenyl1 0 cyclopentyl-methylhydrazine, 2-[(4-chloro-3-su lfamyl)-benzoyl- 1 -phenyl-1 cyclobutyl-methylhydrazine, 2-[(4-chlorn-3-sulfamyl)-benzoyl]-1 -(2, 6-dich lorophenyl)- 1 -cyclopropyl methyl hydrazine, and 2-[(4-chlorn-3-sulfamyl)-benzoyl-2-methyl- 1 -phenyl-1 Oallyl-tiydrazine.

The compounds of the present invention exhibited antihypertensive and diuretic activities which would make them useful in the treatment of hypertension. In particular, the compounds, 1 -allyl- 1 -phenyl-2-(3-sulfamyl-4 chlorobenzoyl)-hyd razine and 1 -propargyl-1 - phenyl-2-(3-sulfamyl-4-chlorobenzoyl)-hydrazine, showed both potent diuretic and antihypertensive activities in rats and other mammals. In spontaneously hypertensive rats, 1allyl-1 -phenyl-2-(3-sulfamyl-4-chlorobenzoyl)hydrazine exhibited an antihypertensive ED50 in the rat of 3 mg/kg i.p. and 30 mg/kg p.o.

The therapeutic agents of this invention may be administered alone or in combination with pharmaceutically-acceptable carriers, the proportion of which is determined by the solubility and chemical nature of the compound, chosen route of administration and standard pharmaceutical practice. For example, they may be administered orally in the form of tablets or capsules containing such excipients as starch, milk sugar, certain types of clay and so forth. They may be administered orally in the form of solutions which may contain coloring and flavoring agents or they may be injected parenterally, that is, intramuscularly, intravenously or subcutaneously. For parenteral administration, they may be used in the form of a sterile solution containing other solutes, for example, enough saline or glucose to make the solution isotonic.

The physician will determine the dosage of the present therapeutic agents which will be most suitable and it will vary with the form of administration and the particular compound chosen, and furthermore, it will vary with the particular patient under treatment. He will generally wish to initiate treatment with small dosages substantially less than the optimum dose of the compound and increase the dosage by small increments until the optimum effect under the circurnstances is reached. It will generally be found that when the composition is administered orally, larger quantities of the active agent will be required to produce the same effect as a smaller quantity given parenterally. The compounds are useful in the same manner as other diuretic and anti-hypertensive agents and the dosage level is of the same order of magnitude as is generally employed with these other therapeutic agents.

The therapeutic dosage will generally be from 10 to 750 milligrams per day and higher although it may be administered in several different dosage units. Tablets containing from 10 to 250 mg of active agent are particularly useful.

Claims (36)

1. A compound of the formula

wherein: Ar and Ar' are independently alicyclic aryl or heterocyclic aryl groups; R1 is a substituent replacing a hydrogen on the ring and is independently hydroxy, alkyl, alkoxy, halogen, nitro, amino, monoalkyl-amino, dialkyl-amino, sulfhydryl, alkyl-mercapto, sulfonamido, carboxy, carbalkoxy, or trihalomethyl; n is an integer from 0 to 5 inclusive; R2 and R3 are independently hydrogen, alkyl, alkenyl, alkenyl, cycloalkyl, cycloalkenyl, phenyl, or cycloalkyl-alkyl, and R4 and R5 are independently hydrogen, halogen or trihalomethyl, with the proviso that when Ar and Ar' are phenyl and n is 0, both R2 and R3 are not hydrogen.

2. A compound according to Claim 1 wherein Ar and Ar' are independently phenyl, naphthyl, pyridyl, thienyl, or furyl.

3. A compound according to Claim 1 wherein the R2 and R3 alkyl groups are straight chained or branched and have from 1 to 10 carbon atoms.

4. A compound according to Claim 1 wherein the R2 and R3 alkenyl and alkynyl groups are straight chained or branched and have from 2 to 10 carbon atoms.

5. A compound according to Claim 1 wherein the R2 and R3 groups cycloalkyl, cycloalkenyl and cycloalkyl-alkyl, have from 3 to 10 carbon atoms.

6. A compound according to Claim 2 wherein Ar and Ar' are phenyl.

7. A compound according to Claim 6 wherein R, is Cl and n is 1 or 2.

8. A compound according to Claim 1 wherein R4 is hydrogen and R5 is chloro or trifluoromethyl.

9. A compound according to Claim 8 wherein the

group is

10. A compound according to Claim 8 wherein the

group is

11. A compound according to Claim 9 wherein Ar is phenyl and n is 0.

1 2. A compound according to Claim 10 wherein Ar is phenyl and n is 0.

1 3. A compound according to either Claim 9 or 10 wherein Ar is phenyl, R1 is chloro and n is 1.

14. A compound according to Claim 9 wherein (R,)nAr is 2,6-dichlorophenyl.

1 5. A compound according to Claim 11 wherein R2 is allyl and R3is hydrogen.

16. A compound according to Claim 12 wherein R2 is allyl and R3is hydrogen.

1 7. A compound according to Claim 11 wherein R2 is propargyl and R3 is hydrogen.

1 8. A compound according to Claim 11 wherein R2 is cyclopropylmethyl and R3 is hydrogen.

19. A compound according to Claim 14 wherein R2 is propargyl and R3is hydrogen.

20. A compound according to Claim 11 wherein R2 is allyl and R3is methyl.

21. A compound according to Claim 11 wherein R2 is CH3-C = C-CH2- and R3is hydrogen.

22. A compound according to Claim 11 wherein R2 is (H3C)C = C(CH3)-CH2- and R3is hydrogen.

23. A compound according to Claim 9 wherein R2 is propyl and R3is hydrogen.

24. A compound according to Claim 2 wherein R2 is propyl and R3is hydrogen.

25. A method of treating hypertension which comprises administering to animals having hypertension an effective dose of compound of Claim 1.

26. A method according to Claim 25 in which compound Ar is phenyl, Ar' is phenyl, n is 0, R2 is allyl, R3 is hydrogen, R4 is 4-chloro, R5 is hydrogen, and the SO2NH2 group is in the 3-position.

27. A method according to Claim 25 in which compound Ar is phenyl, Ar' is phenyl, n is 0, R2 is propargyl, R3 is hydrogen, R4 is 4-chloro, R5 is hydrogen, and the SO2NH2 is in the 3-position.

28. The process of producing a compound of formula I herein which comprises the step of acylating a hydrazine of formula Ill herein with a suitable acylating derivative, to form the corresponding hydrazide and optionally reacting the resulting product to introduce R3 substituents other than hydrogen.

29. Process as in Claim 28 wherein said acylating derivative is an acylhalide, preferably chloride.

30. Process as in Claim 28 or 29 wherein said hydrazine is prepared by reduction of the corresponding nitrosamine.

31. Process as in Claim 30 wherein said reduction is accomplished with a metal hydride such as lithium aluminum hydride or lithium borohydride.

32. Process as in Claim 28 or 29 wherein said acylation is conducted at or near ambient temperature.

33. Process as in Claim 30 wherein said nitrosamine is prepared by reaction of the corresponding secondary amine with nitrous acid at a temperature below about 10"C.

34. A process as claimed in Claim 28 and substantially as hereinbefore described with reference to any of Examples 3, 5 and 7 to 13.

35. Compounds of formula I when produced by a process as claimed in any of Claims 28 to 34.

36. A pharmaceutical composition which comprises a compound as claimed in any of Claims 1 to 24 and 35 in association with a pharmaceutically acceptable carrier.