GB2086901A

GB2086901A - 2-amino-4-(2,1,3- benzoxadiazol-4-yl)-1,4-dihydro-6- methyl-pyridine 3,5-dicarboxylates and Their 2-acylamino Derivatives

Info

Publication number: GB2086901A
Application number: GB8133475A
Authority: GB
Original assignee: Sandoz AG
Current assignee: Sandoz AG
Priority date: 1980-11-10
Filing date: 1981-11-06
Publication date: 1982-05-19
Also published as: NL8105035A; DE3143649A1; FI813460A7; DK494781A; IL64244A0; ES506986A0; PT73943B; BE891032A; FI813460L; AU7732381A; IT1189050B; ZA817774B; PT73943A; FR2493847A1; IT8149677A0; JPS57108089A; SE8106633L; ES8304123A1; IT8149677A1

Abstract

New compounds of formula I <IMAGE> wherein COOR1 and COOR2 are the same or different carboxylic acid ester groups and R3 is hydrogen or an acyl group, are useful in the treatment of coronary insufficiency, cerebrovascular accidents, spasms in smooth muscles or hypertension.

Description

SPECIFICATION New 4-(2,1 ,3-benzoxadiazol-4-yl)-1 ,4-dihydro-pyridine Derivatives, Their Production and Pharmaceutical Compositions Thereof This invention relates to 4-(2,1,3-benzoxadiazol-4-yl)-1,4-dihydro-pyridine derivatives, their production and pharmaceutical compositions thereof.

The present invention provides a compound of formula I,

wherein COOR1 and COOR2 are the same or different carboxylic acid ester groups and R3 is hydrogen or an acyl group.

In particular the present invention provides a compound of formula I, wherein R1 and R2 independently of each other are (C1~12)alkyl, (C3-6)alkenyl, (C3-6)alkinyl, (C3-7)cycloalkyl, (C4-8)cycloalkylalkyl, (C3-12)alkoxyalkyl, (C3-12)alkylthioalkyl, (C2-6)hydroxyalkyl, (C4-8)hydroxyalkoxyalkyl, phenyl or (C7-10)phenylalkyl and R3 is hydrogen or

wherein R4 is hydrogen, (C1-8)alkyl, (C3-6)alkenyl, (C3-6)alkinyl, (C3-7)cycloalkyl, (C4-8)cycloalkylalkyl, (C1-6)alkoxy, (C3-6)alkoxyalkyl, (C3-8)alkythioalkyl, pheny or (C7-10)phenylalkyl.

One group of compounds comprises the compounds of formula la,

wherein $1a and $2a independently of each other are (C1-6)alkyl, (C3-8)alkenyl, (C3-6)alkinyl, (C3-7)cycloalkyl, (C4-8)cycloalkylakyl, (C3-6)alkoxyalkyl, (C3-6)alkylthioalkyl, (C2-6)alkoxyalkyl, (C3-6)alkylthioalkyl, (C2-6)hydroxyalkyl, (C4-8)hydroxyalkoxyalkyl, phenyl or (C7-10)phenylalkyl and R3a is hydrogen or

wherein R4a ishydrogen, (C1-6)alkyl, (C3-6)alkenyl, (C3-6)alkinyl, (3-7)cycloalkyl, (C4-8)cycloalkylalkyl, (C3-6)alkoxyalkyl, (C3-6)alkylthioalkyl, phenyl or (C7-10)phenylalkyl.

In any of the above radicals (C1-12)alkyl is preferably (C1-6)alkyl, and (C1-6)alkyl is preferably (C1-4)alkyl, especially (C1-2)alkyl atoms. Any alkoxy or alkylthio radical has preferably 1 to 4, especially 1 to 2 carbon atoms. The hydroxy, alkoxy or hydroxyalkoxy group of the hydroxyalkyl, alkoxyalkyl or hydroxyalkoxyalkyl moiety is preferably attached to the distant terminal carbon atom. Any hydroxyalkyl, alkoxyalkyl or hydroxyalkoxyalkyl radical preferably comprises an ethyl or propyl moiety substituted by hydroxy, alkoxy or hydroxyalkoxy respectively. The alkyl moiety of cycloalkylalkyl is conveniently methyl. Cycloalkyl or the cycloalkyl moiety of cycloalkylalkyl is conveniently cyclopropyl or cyclopentyl or cyclohexyl. The multiple bond of alkenyl or alkinyl is preferably not in the , position.

Alkenyl or alkinyl preferably has 3 to 5 carbon atoms. Alkenyl is conveniently allyl or 2methylallyl. Alkinyl is conveniently propinyl. R1 and R2 are preferably (C,~12)alkyl, particularly, (C,~,)alkyl. R3 is preferably H. R4 is preferably (C1~8)alkyl, especially methyl.

The present invention in another aspect provides a process for the production of a compound of + the invention which comprises a compound of formula II,

with an amidine of formula Ill,

wherein R1, R2 and R3 are as defined above, and if desired, acylating a resultant compound of formula I, wherein R3 is hydrogen, to produce a compound of formula I, wherein R3 is acyl.

The reaction of a compound of formula II and the compound of formula Ill, a ring closure, may be effected in conventional manner for the synthesis of analogous dihydropyridines, e.g. according to Hantzsch.

When R3 is a compound of formula I represents the acyl radical

in which R4 is as defined above, the acyl group may be present in the compound of formula II or introduced after ring closure.

An organic solvent, e.g. ethanol, may be present. The reaction is conveniently effected at from room temperature to the reflux temperature of the solvent. The amidine may be added as an acid addition salt, e.g. as the HCI salt. If desired, the free base may be liberated from the salt with basic agents, e.g. alkali alcoholates, such as sodium ethanolate, which may be found in the acylation may be effected in conventional manner for the synthesis of analogous amides.

Suitable acylation agents include acid anhydrides or acid chlorides. The reaction is conveniently effected in solution, e.g. in excess anhydride. When an acid chloride is used, chloroform may be used as solvent and pyridine or triethylamine to bind the resulting strong acid. A suitable reaction temperature may be room temperature or a slightly elevated temperature.

The compounds of formula I may be isolated and purified by known methods. The compounds of formulae II and Ill are known or may be produced, isolated and purified by known methods. The compounds of formula II may, e.g. by obtained by condensing 2,1 ,3-benzoxadiazole-4-carbaldehyde with an appropriate acetoacetic acid ester. Preferably roughly equivalent amounts of reactants are used. The reaction may be effected under conventional conditions for condensation of an aldehyde with an acetoacetate ester, e.g. as described in Example 1. The compound of formula II may be produced as a mixture of Z and E isomers and, both of which may be used for the subsequent reaction with a compound of formula Ill. The mixture may be converted further into the compound of formula I without isolation and purification.In the following Examples the temperatures are in degrees Centrigrade and are uncorrected.

Example 1 2-Amino-4(2,1 ,3-benzoxadiazol-4yI)-1 ,4dihydrn-6-methyl-3,5-pyridine-dicarboxylic Acid Diethyl Ester (IR,=R2=Et) A mixture of 18.4 g of 2,1 ,3-benzoxadiazole-4-carbaldehyde, 1 5.7 g of acetoacetic acid ethyl ester, 0.6 ml of piperidine, 0,7 ml of acetic acid and 400 ml of benzene is heated to boiling for 4 hours at a water separator. The solution is subsequently concentrated by evaporation in vacuo, the crude product is dissolved in chloroform, the solution is filtered through 300 g of silica gel and the filtrate is concentrated by evaporation in vacuo.

4.1 g of the thus resulting 2-acetyl-3-(2,1 ,3-benzoxadiazol-4-yl)propenic acid ethyl ester (II, R1=ethyl) (this is a mixture of the Z- and E-isomers) and 2.6 g of amidino-acetic acid ethyl ester hydrochloride (Ill-HCl R2=ethyl) (lit.: H. Meyer et al., Liebigs Ann. Chem. 1977, 1895) are dissolved in 20 ml of ethanol and to the solution there is added dropwise at 900 bath temRerature within half an hour with stirring a solution of 0.36 g of sodium in 15 ml of ethanol. Stirring is continued for 1 5 minutes at the same temperature, filtration is effected and the filtrate is concentrated by evaporation in vacuo. The product is crystallized from ether. M.P. 1840.

In analogous manner to Example 1 the following compounds are produced: Formula I

Example R1 R2 R3 M.P.

2 CH3- (CH3)2CHCH2- H 177 3* C2H6- C2H5- CH3C(=Q)- 1880 4 CH3- tcYi3)2CHCH2- H 1620 5 (CH3)2CH- CH3- H H 1800 6 OH3- (CH3)2CH- H 1880 *Can also be produced by subsequent acetylation of the Example 1 compound in excess acetic anhydride at room temperature overnight.

The compounds of formula I exhibit pharmacologicål activity and are therefore indicated for use as pharmaceuticals, i.e. for therapy. In particular, they lead to a dilation of the coronary vessels as indicated by an increase in coronary and aortic blood flow of an anaesthetised open chest cat by means of the microsphere method [Rudolph A. M. and Heymann M. S.: Circulation Research 21, 1 63-1 84, (1967) and modified by R. P. Hof, F. Wyler and G. Stalder, Basic Res. Cardiol., 75, 747-756 (1980)] upon administration of from 10 to 350 jug/kg i.v. or of from 50 to 500 jug/kg i.d. of the compounds.

The compounds of formula I are therefore indicated for use in the treatment of coronary insufficiency, in particular angina pectoris. The compounds of formula I increase the blood flow to the limbs, e.g. leg musculature, as can be shown by means of the microsphere method on the abovementioned anaesthetised cat test upon administration of the compounds at a dose of from about 10 to about 350 ug/kg i.v. or from about 50 to about 500 ug/kg i.d..

The compounds are therefore indicated for use for the treatment of intermittent claudication and other peripheral disturbances of blood flow to limb muscles.

The compounds of formula I increase cerebral blood flow, as can be shown by means of the microsphere method on the above-mentioned anaesthetised cat upon administration of the compounds at a dose of from about 10 to about 350 ,ug/kg i.v. or from about 50 to about 500 ,ug/kg i.d.. The compounds of formula I are therefore indicated for use in the treatment of cerebrovascular accidents. An indicated daily dosage for all the above indications is from about 1 5 to about 300 mg, conveniently administered in divided doses 2 to 4 times a day or in sustained release form and dosage forms suitable for oral administration comprise from about 4 mg to about 1 50 mg of the compounds admixed with a solid or a liquid pharmaceutical carrier or diluent.

The compounds of formula I possess calcium-antagonistic activity, as indicated in standard tests, for example by an inhibition of a calcium induced contraction of isolated dog coronary arteries suspended in a depolarizing solution at concentration of 10-10 to 10-5 M of the compounds according to the principles of Godfraind and Kaba, Brit. J. Pharm. 36, 549-560, 1969. The compounds are therefore useful as spasmolytic agents, for the treatment of spasms in smooth muscles. An indicated daily dosage is in the range from about 15 to 300, preferably 30 to 300, mg, conveniently administered in divided doses 2 to 4 times a day or in sustained release form and dosage forms suitable for oral administration comprise from about 4 mg to about 1 50 mg of the compounds admixed with a solid or a liquid pharmaceutical carrier or diluent.

Additionally, the compounds of formula I exhibit antihypertensive activity, as indicated by a blood pressure lowering activity in standard tests.

For example, the compounds exhibit a blood pressure lowering effect in the Grollman rat test [see A. Grollman, Proc. Soc. Expt Biol. and Med. 57,104(1944)] on s.c. administration offrom 0.1 to 10 mg/kg or in the open chest anaesthetised cat on i.v. administration of from 10 to 350 yg/kg animal body weight of the compounds.

The compounds are therefore indicated for use as anti-hypertensive agents. An indicated daily dosage is in the range from about 30 to about 600, preferably 60 to 600 mg, conveniently administered in divided doses 2 to 4 times a day or in sustained release form and dosage forms suitable for oral administration comprise from about 7 mg to about 300 mg of the compounds admixed with a solid or liquid pharmaceutical carrier or diluent.

The compounds of Examples 2 and 5 are particularly interesting, especially the compound of Example 5. The coronary insufficiency and the antihypertensive activities are the preferred indications.

A compound of formula I may be administered in free base form. The present invention also provides a pharmaceutical composition comprising a compound of formula I in association with a pharmaceutical carrier or diluent. Such compositions may be prepared by conventional techniques to be in conventional forms, for example, capsules or tablets.

Claims

1. A process for the production of a compound of formula I,

wherein COOR, and COOR2 are the same or different carboxylic acid ester groups and R3 is hydrogen or an acyl group, which comprises reacting a compound of formula II,

with an amidine of formula Ill,

wherein R,, R2 and R3 are as defined above, and if desired, acylating a resultant compound of formula wherein R3 is hydrogen, to provide a compound of formula I, wherein R3 is acyl.

2. A process for the production of a compound of formula I as hereinbefore described with reference to any one of the Examples.

3. A compound of formula I whenever produced by a process of claim 1 or 2.

4. A compound of formula I, as defined in claim 1.

5. A compound of claim 4 in which in formula I R1 and R2 independently of each other are (C~12)- alkyl, (C3-6)alkenyl, (C3-6)alkinyl, (C3-7)cycloalkyl, (C4-8)cycloalkylalkyl, (C3-12)alkoxyalkyl, (C312)alkylthioalkyl, (C26)hydrnxyalkyl, (C4-8)hydroxyalkoxyalkyl, phenyl or (C7~,0)phenylalkyl and R3 is hydrogen or

wherein R4 is hydrogen, (C1-6)alkyl, (C3-6)alkenyl, (C3-6)alkinyl, (C3-7)cycloalkyl, (C4-8)cycloalkylakyl, (C1-6)alkoxy, (C3-6)alkoxyalkyl, (C3-6)alkylthioalkyl, phenyo or (C7-10)phenylalkyl.

6. A compound of claim 4 in which in formula I R, and R2 independently of each other are (C1-6)alkyl, (C3-6)alkenyl, (C9~6)alkinyl, (C3-7)cycloalkyl, (C4-6)cycloalkylalkyl, (C3-6)alkoxyalkyl, (C3-6)alkylthioalkyl, (C2-6)hydroxyalkyl, (C48)hydrnxyalkoxyalkyl, henyl or (C7-10)phenylalkyl and R3 is hydrogen or

wherein R4 is hydrogen, (C1-6)alkyl, (C3-6)alkenyl, (C3-6)alkinyl, (C3-7)cycloalkyl, (C4-8)cycloalkylalkyl, (C3-6)alkoxyalkyl, (C36)aIkylthioalkyl, phenyl or (C710)phenylalkyl.

7. A compound of claim 4 wherein in formula IR1 and R2 are (C1-12)alkyl.

8. A compound of claim 4 wherein in formula I R1 and R2 are (C1-6)alkyl.

9. A compound of claim 4 wherein in formula I R3 is H.

10. A compound of claim 4 wherein in formula I R3 is

and R4 is (C1-6)alkyl.

11. A compound of claim 10 in which R4 is methyl.

12.2-Amino-4-(2,1,3-benzoxadiazol-4-yl)-1,4-dihydro-6-methyl-3,5-pyridine dicarboxylic acid diethyl ester.

13.2-Amino-4-(2,1,3-benzoxadiazol-4-yl)-1,4-dihydro-6-methyl-3-isobutoxycarbonyl-pyridine5-carboxylic acid methyl ester.

14.2-Acetylamino-4-(2,1,3-benzoxadiazol-4-yl)-1,4-dihydro-6-methyl-3-ethyloxycarbonylpyridine-5-carboxylic acid ethyl ester.

1 5. 2-Am ino-4-(2,1,3-benzoxadiazol-4-yl)- 1 ,4-dihydro-6-methyl-3-methoxycarbonyl-pyridine-5carboxylic acid isobutyl ester.

16.2-Amino-4-(2,1,3-benzoxadiazol-4-yl)-1,4-dihydro-6-methyl-3-isopropoxycarbonyl-pyridine5-carboxylic acid methyl ester.

17. 2-Am ino-4-(2, 1 ,3-benzoxadiazol-4-yl)- 1 ,4-dihydro-6-methyl-3-methoxycarbonyl-pyridine-5carboxylic acid isopropyl ester.

18. A compound according to any one of claims 5 to 17 for use as a pharmaceutical.

19. A compound according to any one of claims 5 to 17 for use in the treatment of coronary insufficiency, cerebrovascular accidents, spasms in smooth muscles or hypertension.

20. A pharmaceutical composition which comprises a compound of any one of claims 5 to 17 in association with a pharmaceutical carrier or diluent.

21. A method of treating coronary insufficiency or cerebrovascular accidents, spasms in smooth muscles or hypertension, which comprises administering a therapeutically effective amount of a compound of any one of claims 5 to 17 to a subject in need of such treatment.