NL8105035A - 4- (2,1,3-BENZOXADIAZOL-4-YL) -1,4-DIHYDRO-PYRIDINE DERIVATIVES, PROCESSES FOR THEIR PREPARATION AND PHARMACEUTICAL PREPARATIONS CONTAINING THEM. - Google Patents

Description

- 1 - 4- (2,1,3-Benzoxadiazol-4-yl) -1,4-dihydro-pyridine derivatives, methods of their preparation and of pharmaceutical preparations containing them.

The invention relates to 4- (2, 1,3-benz-oxadiazol-4-yl) -1,4-dihydro-pyridine derivatives, as well as to processes for their preparation and to pharmaceutical preparations containing these derivatives.

The present invention provides new compounds of formula 1, wherein COOR 1 and COOR 2 have the same or different carboxylic acid ester groups. and R 1 represents a hydrogen atom or an acyl group.

In particular, the present invention provides compounds of formula 1, wherein R 1 and R 1 independently of one another, an alkyl group having 1 to 12 carbon atoms, an alkenyl group having 3 to 6 carbon atoms, an alkynyl group of 3 to 6 carbon atoms, a cycloalkyl group of 3 to 7 carbon atoms, a (C 4 -gJ-cycloalkylalkyl group, a (C 1 ^ ^ ^) alkoxyalkyl group, a (C ^ ^) alkylthioalkyl group, a hydroxyalkyl group of 2 to M 6 carbon atoms, a (C. Q) hydroxyalkoxyalkyl group, a phenyl group or a (C ^ phenylalkyl group and R ^ a hydrogen atom or a -CR ^

O

group, wherein R 1 is a hydrogen atom, an alkyl group with 1 to 6 carbon atoms, an alkenyl group with 3 to 6 carbon atoms, an alkynyl group with 3 to 6 carbon atoms, a cycloalkyl group with 3 to 7 carbon atoms, a (C 1 -g) cycloalkylalkyl group, an alkoxy group with 1 to 6 carbon atoms, a (C 1) alkoxyalkyl group, a

J-O

(C 1-) alkylthioalkyl group. represent a phenyl group or a (C) phenylalkyl-25 group.

A group of compounds includes the compounds of formula la, wherein R 1a and R 1a, independently of one another, is an alkyl group. with 1 to 6 carbon atoms, an alkenyl group with 3 to 6 carbon atoms, an alkynyl group with 3 to 6 carbon atoms, a 30 cycloalkyl group with 3 to 7 carbon atoms, a (C. ö) cycloalkyl-4-8 alkyl group, a (C 1-6) alkoxyalkyl group, a (C 3 -g) alkylthioalkyl 8105035 2v *.

s.

<- 2 - group, a (C 2 -g) alkoxyalkyl group, a (C 3 -g) alkylthioalkyl group, a hydroxyalkyl group with 2 to 6 carbon atoms, a (C 1 -g) hydroxyalkoxyalkyl group, a phenyl group. or a phenylalkyl group and R_ is a hydrogen atom or -C-R. , wherein R, a 3a i, 4a 4a

.5 O

hydrogen atom, an alkyl group with 1 to 6 carbon atoms, an alkenyl group with 3 to 6 carbon atoms, an alkynyl group with 3 to 6 carbon atoms, a cycloalkyl group with 3 to 7 carbon atoms, a (C 1-6) cycloalkylalkyl group, represents a (C8-5) alkoxyalkyl group, a (C3-6) alkylthioalkyl group, a phenyl group, or a (C 1-4) phenylalkyl group.

In any of the aforementioned groups, an alkyl group of 1 to 12 carbon atoms is preferably an alkyl group of 1 to 6 carbon atoms and an alkyl group of 1 to 6 carbon atoms is preferably an alkyl group of 1 to 6 carbon atoms / m 4 carbon atoms, in particular with 1 or 2 carbon atoms. Each alkoxy or alkyl-thio group preferably contains 1 to 4, in particular 1 or 2, carbon atoms. The hydroxyl, alkoxy or hydroxyalkoxy group of the hydroxyalkyl, alkoxyalkyl or hydroxyalkoxyalkyl portion is preferably the most distant attached carbon atom. Each hydroxyalkyl, alkoxyalkyl or hydroxyalkoxyalkyl group preferably contains an ethyl or propyl moiety substituted by hydroxyl, alkoxy, or hydroxyalkoxy, respectively. It is recommended that the alkyl portion of cycloalkylalkyl 25 be methyl. Cycloalkyl or the cycloalkyl portion of cycloalkylalkyl is suitably cyclopropyl or cyclopentyl or cyclohexyl. The multiple bond of alkenyl or alkynyl is preferably not in the α, β position, Alkenyl or alkynyl preferably contain 3-5 carbon-

K

atoms. Alkenyl is suitable ally! or 2-methylallyl. Alkynyl is suitable propinyl. It is recommended that R 1 and R 2 represent an alkyl group having 1 to 12 carbon atoms, especially 1 to 6 carbon atoms. R 1 is preferably a hydrogen atom. It is recommended that R 1 be an alkyl group with up to 6 carbon atoms, especially the methyl group.

Another aspect of the invention relates to a method of preparing a compound of the invention and comprises the reaction of a compound of formula 2 with an amidine of formula 3, wherein R 1, R 9 and R 3 are the have the meanings indicated above and, if desired, acylation of the compound of the formula I obtained, wherein R 1 represents a hydrogen atom, whereby a compound of the formula 1 in which an acyl group is obtained.

The reaction of a compound of formula 2 with a compound of formula 3, a ring closure, can be performed in a conventional manner for the synthesis of analogous dihydropyridines, for example, according to Hantzsch. In a compound of formula 1, R ^ represents the acyl group -C-R. for which R has an ff H ** 0 as indicated above, the acyl group may be present in the compound of formula 2 or introduced after cyclization.

An organic solvent, for example ethanol, can be present. The reaction is arranged at a temperature between room temperature and the reflux temperature of the solvent. executed. The amidine can be added as an acid addition salt, for example as an HCl salt. If desired, the free base can be liberated from the salt by basic means, for example, alkali alcoholates, such as sodium ethanolate. The acylation can be carried out in a conventional manner for the synthesis of corresponding amidines.

Examples of suitable acylating agents are acid anhydrides and acid chlorides. The reaction can conveniently be carried out in solution, for example in excess of anhydride. If an acid chloride is used, chloroform as solvent and pyridine or triethylamine can be used to bind the strong acid obtained. A suitable reaction temperature can be room temperature or slightly elevated temperature.

The compounds of formula 1 can be separated and purified by known methods. The compounds of formulas 2 and 3 are known or may be by known methods v 8105035. . - .. - 4 -. 'are prepared, separated and purified. The compounds of formula II can be obtained, for example, by condensation of 2,1,3-benzoxadiazole-4-carbaldehyde with a suitable ester of acetoacetic acid. Preferably, about equivalent amounts of the reactants are used. The reaction can be carried out under usual conditions for the condensation of an aldehyde with an α-etoacetate ester, for example as described in Example 1. The Compound of formula 2 can be obtained as a mixture of Z and E isomers and both can be reacted with a compound of formula 3 can be used. The mixture can be further converted into the compound of formula 1 without separation and purification.

The temperatures given in degrees Celsius in the following examples have not been corrected.

15

Example I

The diethyl ester of 2-amino-4- (2,1,3-benzoxadiazol-4-yl) -1,4-dihy-), · dro-6-methyl-3,5-pyridine-dicarboxylic acid 0,1 Rj = Rj is the ethyl group).

A mixture of 18.4 g of 2,1,3-benzoxadiazole-4-carbaldehyde, 15.7 g of the ethyl ester of acetoacetic acid, 0.6 ml of piperidine, 0.7 ml of acetic acid and 400 ml of benzene 4 was boiled hours while separating water. The solution was then concentrated by evaporation under reduced pressure, after which the crude product was dissolved in chloroform, the solution was passed through 300 g of silica gel. filtered and the filtrate concentrated by evaporation under reduced pressure.

4.1 g of the ethyl ester of 2-acetyl-3- (2,1,3-benzoxadiazol-4-yl) -propenic acid thus obtained (formula 2, Rj = the ethyl group) (a mixture of the Z and E isomers) and 2.6 g of the hydrochloride of the ethyl ester of amidinoacetic acid (formula 3.

HCl 4 = the ethyl group) (lit .: H. Meyer et al., Liebiegs Ann. Chem. 1977, 1895) were dissolved in 20 ml of ethanol and this solution was added at a bath temperature of 90 ° C within 30 min. And stirring a solution of 0.36 g of sodium in 15 ml of ethanol with stirring. The mixture was stirred at this temperature for 15 minutes, filtered and the filtrate was concentrated by evaporation under reduced pressure. The product was crystallized from ether, melting point: 184 ° C.

In a similar manner as described in Example 1, the following compounds were prepared:

formula 1

Example Rj R2 Rj Mp.

10 - IX (ch3) 2chch2-ch3- H 177 ° III * C2H5 "C2H5" CH3C (= 0) - 188 ° IV CH3- (CH3) 2CHCH2- H 162 ° v (ch3) 2ch-ch3- H 180 ° VI CH3- (CH3) 2CH-H188 ° can also be prepared by acylating the compound of Example I overnight at room temperature with an excess of acetic anhydride.

20

The compounds of formula III have a pharmacological action and are therefore indicated for use as medicines, for example therapeutic. In particular, they cause dilation of the coronary vessels, as evidenced by an increase in blood flow through the coronary vessels and aorta of an anesthetized open-chest cat using the microsphere method f_ Rudolph A.M. and Heymann M.S .: Circulation Research 21, 163-184 (1967), modified by R.P. Hof, F. Wyler and G. Stalder, Basic Res. Cardiol., 75, 747-756 (1980) / when administering 10-350 g / kg i.v. or from 50-500 * * g / kg i.d. of the connections.

The compounds of the formula I according to the invention are therefore indicated for use in coronary insuffi ciency, in particular angina pectoris. The compounds of the invention of the formula 1 according to the invention increase the blood flow to the limbs # for example the muscles of the legs # as shown by the microsphere method performed according to the above-described test on anesthetized cats when the compounds are administered in a dose from about 10 to about 350 µg / kg iv or from .5 about 50 to about 500 µg / kg i.d ..

The compounds are therefore indicated for use in the treatment of interpreterial claudication and other peripherals. disturbances of blood flow ^ to the muscles of the limbs.

The compounds of the formula 1 of the invention also increase blood flow to the brain # as can be demonstrated by the microsphere method on the anesthetized cat described above when the compounds of the invention are administered at a dose of from about 10 to about 15 350} g / kg iv or from about 50 to about 500 jug / kg i.d ..

The compounds of the formula I according to the invention are therefore indicated for use in the treatment of cerebrovascular disorders. An indicated daily dose for all of the aforementioned indications is between about 15 and about 30 mg # arranged in separate doses 2-4 times daily or in a slow-release form and dosage forms suitable for oral administration which are about 4 mg to about 150 mg of the compounds of the invention mixed with a solid or a liquid pharmaceutical containing carrier or diluent administered * The compounds of the invention of the formula 1 also have a calcium antagonistic activity # as evidenced by standard * tests # for example by inhibition of a calcium-induced contraction of the isolated coronary arteries of a dog suspended in a depolarizing solution 30 at a concentration of 10 to 10 M of the compounds according to the method of Godfraind and Kaba # Brit. J. Pharm. 36, 549-560, 1969. The compounds can therefore be used as spasmolytics for the treatment of cramps in smooth muscles. An indicated daily dose is between about 15 and 300 #, preferably 30 to 300 # mg #, suitable in separate doses 2-4 times daily or in 8105035-7 JU. * A slow-release form and dosage forms suitable for oral administration containing from about 4 mg to about 150 mg of the compounds mixed with a solid or liquid pharmaceutical carrier or diluent.

Furthermore, the compounds according to the invention of the formula I have an antihypertensive activity, as evidenced by a blood pressure-lowering activity in standard tests. For example, the compounds exert a blood pressure lowering effect in the test on Grollman rats. See A. Grollman, Proc. Soc. 10 Expt. Biol. and Med. 57, 104 (1944) / at s.c. administration of 0.1-10 mg / kg or in an anesthetized open-chest cat at i.v. administration of 10-350 fig / kq animal body weight of the compounds * The compounds are therefore indicated for use as anti-hypertensive agents. An indicated daily dose is between about 30 and about 600, preferably 60 to 600 mg, suitably in separated doses 2-4 times a day or in a slow-release form and dosage units suitable for oral administration and containing about 7 mg to about 30 mg of the compounds mixed with a solid or liquid pharmaceutical carrier or diluent.

and*

The connections of the example). II and V are particularly important, especially the compound of Example V. The activity against coronary insufficiency and hypertension are the preferred indications.

The compounds of the formula I of the invention can be administered in free base form.

The invention also relates to pharmaceutical preparations containing one or a number of compounds of the invention of formula If, if desired, together with a pharmaceutical carrier and / or diluent. Such formulations may be prepared or prepared by conventional methods and have any customary forms, e.g., capsules, tablets. The invention also includes molded pharmaceutical preparations obtained by the aforementioned method.

35 8105035

Claims (21)

1. Compounds of formula 1., wherein COOR ^ and COORj represent the same or different carboxylic acid ester groups and Rg represent a hydrogen atom or an acyl group * 5 2. Compounds according to claim 1, wherein R ^ and ^ 2 »independently, an alkyl group with 1 up to 12 carbon atoms, an alkenyl group with 3 through 6 carbon atoms, an alkyl group with 3 through 6 carbon atoms, a cycloalkyl group with 3 through 7 carbon atoms, a (C4_g) cycloalkylalkyl group, a ^ C ^ ^ 3 ^ 03 ^ ”10 alkyl group, a (C8 ^) alkylthioalkyl group, a hydroxyalkyl group with 2 to 6 carbon atoms, a (C ^ _g) hydroxyalkoxyalkyl group, a phenyl group or a (C ^ phenylalkyl group and Rg) a hydrogen atom or a -CR- group, in which R. is a hydrogen atom, a 4-4 alkyl group O15 with 1 to 6 carbon atoms, an alkenyl group with 3 to 6 carbon atoms, an alkynyl group with 3 to 6 carbon atoms a cycloalkyl group with 3 to 7 carbon atoms, a (C 1 -g) cycloalkylalkyl group, an alkoxy group with 1 to 6 carbon atoms, aand ^ Cg_g) alkoxyalkyl group, a (Cg_g) alkylthioalkyl group, a phenyl group or a (C ^ _ ^ g) -20 phenylalkyl group, suggest · Compounds according to claim 1, wherein R 1 and R 1, independently of one another, an alkyl group of 1 to 6 carbon atoms, an alkenyl group of 3 to 6 carbon atoms, an alkynyl group of 3 to 6 carbon atoms, a cycloalkyl group with 3 to 7 carbon atoms, a (C4_g) cycloalkylalkyl group, a {Cg_g} alkoxyalkyl group, a (C, c) alkylthioalkyl group, a hydroxyalkyl group with 2 to 6 carbon atoms, a (C) hydroxyalkoxyalkyl group , a 4-q phenyl group or a (C 1 / 4g) phenylalkyl group and Rg a hydrogen atom or a -CR. group, in which R- is a hydrogen atom, an alkyl group II 4 ** 30 O with 1 to 6 carbon atoms, an alkenyl group with 3 to 6 carbon atoms, an alkynyl group with 3 to 6 carbon atoms, a cycloalkyl group with 3 to 7 carbon atoms, a (C4-8) cycloalkylalkyl group, represent a C 1-8 alkoxyalkyl group, a (C) alkylthioalkyl group, a phenyl group or a (C 1-8) phenylalkyl group. 8105035 ·· * '- 9 - Compounds according to claim 1, wherein and R 2 independently represent an alkyl group having 1 to 12 carbon atoms. Compounds according to claim 1, wherein 5 and R 1 independently represent an alkyl group having 1 to 6 carbon atoms. Compounds according to claim 1, wherein R 1 represents a hydrogen atom. Compounds according to claim 1, wherein R 10 represents a -C-R group, wherein R represents an alkyl group having 1 to 6 carbon atoms. Compounds according to claim 7, wherein R 1 represents a methyl group. 9. The diethyl ester of 2-amino-4- (2,1,3-benzoxadiazol-4-yl) -1,4-dihydro-6-methyl-3,5-pyridine dicarboxylic acid. 10. The methyl ester of 2-amino-4- (2,1,3-benzoxa-diazol-4-yl) -1,4-dihydro-6-methyl-3,5-isobutoxycarbonylpyridine-5-carboxylic acid. 11. The ethyl ester of 2-acetylamino-4- (2,1,3-benzoxadiazol-4-yl) -1,4-dihydro-6-methyl-3-ethyloxycarbonyl-pyridine-5-carboxylic acid. 12. The isobutyl ester of 2-amino-4- (2,1,3-benz-oxadiazol-4-yl) -1,4-dihydro-6-methyl-3-methoxycarbonyl-pyridine-5-carboxylic acid. 13. The methyl ester of 2-amino-4- (2,1,3-benzoxa-diazol-4-yl) -1,4-dihydro-6-methyl-3-isopropoxycarbonylpyridine-5-carboxylic acid. 14. The isopropyl ester of 2-amino-4- (2,1,3-benz-oxadiazol-4-yl) -1,4-dihydro-6-methyl-1-3-methoxycarbonyl-pyridine-5-carboxylic acid . 15. A process for the preparation of a heterocyclic compound, characterized in that a compound of formula 1, in which the substituents and symbols have the meanings set out in claim 1, is prepared by a compound with 8105035. '..' ', ·. :. - reacting formula 2 with an amidine of formula 3 # in which R 1, R 2 and R 3 have the meanings indicated above and, if desired, the compound of formula 1 in which R 1 represents a hydrogen, Λ J substance atom to acylate, whereby a compound of formula 5. is obtained in which represents an acyl group. 16. A method of preparing a pharmaceutical preparation #, characterized in that one or a number of compounds of formula 1 # in which the substituents and symbols have the meanings indicated in claim 1 are introduced into a dosage form suitable for such use. Process according to claim 16 #, characterized in that a compound according to claims 2-14 is used. 18. Process according to claim 16 #, characterized in that a compound according to example IX and / or V is used. Process according to Claim 16 #, characterized in that the pharmaceutical composition and / or diluent are also included in the preparation. 20. Shaped therapeutic compositions # obtained using a method according to claims 16-19. 21. A method of treating coronary insufficiency or cerebrovascular disease # smooth muscle cramps or hypertension # characterized in that a patient in need of such treatment is given a therapeutically effective amount of a composition according to claim 16 -20. 8105035