CS228943B2 - Production of substituted 1,4-dihydropyridine derivative - Google Patents

Description

R ⁵ represents a C 1 -C 4 alkyl, aryl, C 1 -C 4 arylalkyl or benzhydryl group, and pharmaceutically acceptable acid addition salts thereof.

The compounds of formula I containing one or more centers of asymmetry exist in the form of one or more pairs of enantiomers and these pairs or individual isomers may be separated by physical methods, for example, by traction crystallization of the free bases or suitable salts or ehromatography of the free bases. The invention includes both separated pairs and mixtures thereof, racemic mixtures, or separated D- and L- optically active isomeric forms.

The pharmaceutically acceptable acid addition salts of the compounds of formula I are non-toxic acid addition salt salts containing pharmaceutically acceptable anions such as hydrochlorides, hydrobromides, hydroiodides, sulfates or hydrogensulfates, phosphates or hydrogenphosphates, acetates, maleates, fumarates, lactates, tartrates, citrates. , gluconates and saccharates.

The term "aryl" as used herein means a phenyl radical optionally substituted by one or two substituents selected from the group consisting of nitro, halogen, C1-C4alkyl, C1-C4alkoxy, trifluoromethyl, and cyano. or is 1-naphthyl or 2-naphthyl.

The term "heteroaryl" as used herein means benzofuranyl, benzothienyl, pyridyl, optionally monosubstituted methyl or cyano, quinolyl, benzoxazolyl, benzthiazolyl, furyl, pyrimidinyl and thienyl, optionally monosubstituted or halo or optionally substituted with halogen or alkyl. C 1 -C 4.

The term "halogen" refers to fluorine, chlorine, thunder or iodine.

C 3 or C 4 alkyl and alkoxy groups may be straight or branched.

Preferred are those compounds of formula (I) above wherein:

R is 1-naphthyl, phenyl optionally monosubstituted with halogen, trifluoromethyl, cyano or nitro, thienyl optionally monosubstituted with halogen, pyridyl or quinolyl, and

R ³ and R ⁴ are each independently C 1 -C 4 alkyl or benzyl, optionally monosubstituted on aromatic, fused halogen or C 1 -C 4 alkoxy, or

R ³ and R ⁴ together with the nitrogen atom to which they are attached form the remainder of the formula

-ti

O or r \ z

N N-R $ \ - / where

R ⁵ represents a C 1 -C 4 alkyl group, a phenyl group optionally monosubstituted with halogen, a benzyl group optionally monosubstituted on an aromatic ring with a halogen, or a benzhydryl group.

Most preferred are those compounds of formula (I) above wherein:

Y is (CH2) z,

R is 1-naphthyl or 2-chlorophenyl,

R ¹ and R ² independently represents a methyl or ethyl group and

R ³ and R ⁴ represent methyl groups.

The anti-ischemic activity of the compounds of formula I is demonstrated by their activity in one or more of the following tests:

(a) delaying the onset of residual stress rise (also known as stiffness or contracture in isolated ischemic guinea pigs), and (bj reducing in vivo guinea pig ischemic damage by intraventricular injection of microspheric particles.

In Test (a), isolated, electrically controlled, guinea pig hearts are washed with physiological saline at 37 ° C according to Langendorff. The test compound or vehicle is added to the physiological saline solution and after some time (usually 20 minutes) the heartwash flow is reduced to zero (ischemic phase).

During the ischemic phase, the residual cardiac tension is increased, which is recorded by means of an extensometer attached to the heart tip. The test compound at the concentration used is considered to be able to prevent or delay the consequences of ischemia if the residual stress increase over a period of time (usually 35 minutes) is less than 4 g.

To determine the approximate minimum effective dose, the compounds are tested at different concentrations on different cardiac preparations.

In test (b), a suspension of microspheres is injected into the left ventricle of the anesthetized guinea pig. Some of these particles are transported by the blood to the coronary circulation, causing the blockage of some small vessels. The consequences of this ischemia can be detected by changes in the electrocardiogram over a thirty minute interval or by accumulation of tritium-labeled tetracycline in the damaged cardiac tissue, or by releasing enzymes from the heart into the blood. In the latter two procedures, the animals may be allowed to change for a longer period of time (for example, 24 hours J) after recovery from anesthesia.

The test compound or vehicle is administered either to anesthetized animals or administered prior to anesthesia.

The amtihypertensive activity of the disclosed compounds is evaluated after their oral administration to spontaneously hypertensive rats or orally hypertensive dogs.

The ability of the compounds of the invention to antagonize the effect of Ca ⁺⁺ ions in various tissues such as the rat aorta is also examined.

The present invention provides a process for the preparation of the compounds of formula (I) and pharmaceutically acceptable acid addition salts thereof, characterized in that the compound of formula (IV):

R

(IV) wherein

R and R ¹ have the above meanings, is reacted with a compound of formula V

COÓR ² ·

CH 11 _N H _i ^{x C} '' CH £ Oy-Nf? ^R R * in which

R ² , R ³ , R ⁴ and Y are as defined above, in an organic solvent at a temperature of 60 to 130 ° C, after which optionally the resulting compound of formula I is converted by reaction with a suitable acid into its pharmaceutically acceptable acid addition salt.

The crotonate of formula (V) is usually prepared in situ by reacting the corresponding acetacetate of formula (VI) / COOR *

O-CH 2 -O-NR 4 (Vil with ammonium acetate, for example refluxing in a suitable organic solvent such as a C 1 -C 4 alkanol, for example ethanol, for about 1 hour. Crotonate of formula It is then reacted with a compound of formula (IV) by heating in a solvent at a temperature of 60 to 130 ° C for about 5 hours and then isolated and purified in a conventional manner.

The starting materials of formula IV are either known or can be prepared by methods analogous to those known in the art (see, for example, Can. J. Chem. 1967, 45, 1001).

Pharmaceutically acceptable acid addition salts may be prepared by adding a solution of the appropriate acid in a suitable organic solvent to a solution of the free base in a suitable organic solvent. The acid addition salt may be precipitated from solution or isolated by other conventional means.

The compounds of formula (I) may be administered as such, but are usually administered in the form of pharmaceutical compositions in which they are present in admixture with a pharmaceutical carrier selected with regard to the intended route of administration and standard pharmaceutical practice. For example, the compounds may be administered orally in the form of tablets containing starch or lactose as carriers, or in the form of capsules in which they are contained either alone or in admixture with carriers or excipients, or in the form of elixirs or suspensions containing flavorings; dyes. The active compounds according to the invention can be administered by parenteral injection, for example by intravenous, intramuscular or subcutaneous injection. For parenteral administration, the disclosed compounds are most preferably used in the form of a sterile aqueous solution which may contain other soluble substances, such as salts or glucose, to render the solution isotonic.

For administration in human medicine for the curative or prophylactic treatment of cardiac disorders and hypertension, the doses of the compounds when administered orally to an average adult patient (70 kgj range from 2 to 50 mg per day). 10 mg of the active ingredient in combination with a pharmaceutically acceptable carrier For intravenous administration, the dosage for a single dose will be in the range of 1 dq of 10 mg as needed.

The invention is illustrated by the following non-limiting examples.

Example 1

Preparation of 4- (2-chlorophenyl) -2- (3- (dimethylamino) propoxymethyl) -3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine

CHCOOCH, CH. II ^of '

g of ethyl 1-4- [3- (dimethylamino) propoxy] acetoacetate with heating for 20 minutes in 50 ml of ethanol with 8 g of ammonium acetate is converted to the corresponding 3-aminocrotonic acid ester, then 26 g of methyl 2- (2-chlorobenzylidine) is added Acetoacetate and heating to reflux was continued for 2.5 hours. The reaction mixture is evaporated to dryness and the residue is partitioned between 200 ml of toluene and 100 ml of saturated aqueous sodium carbonate solution to remove acetic acid. The toluene layer is extracted first with 200 ml and then with 100 ml of 2N hydrochloric acid, the combined acidic aqueous extracts are neutralized to pH 6 with solid sodium carbonate, saturated with sodium chloride and extracted thoroughly three times with 200 ml of ethyl acetate each. The combined ethyl acetate extracts were dried over sodium carbonate and evaporated to dryness after filtration. The residue was applied to a column of 27 g of silica gel prepared in petroleum ether (bp 60-80 ° C) containing 20% methylene chloride using a small amount of toluene. The column was eluted with the above solvent mixture, which was gradually replaced with pure methylene chloride. Appropriate fractions were combined, evaporated to dryness and the residue crystallized from a mixture of ether and petroleum ether (b.p. up to 60 ° C) (2: 1). 6.3 g of the title compound are obtained as colorless crystals of m.p. 77-78 ° C.

Analysis for:

C23H31ClN2O5 calculated:

% C, 61.26;% H, 6.93;% N, 6.21;

found:

H, 6.90; N, 6.30. Examples 2 to 8

The following compounds were also prepared in an analogous manner to Example 1:

H R

C ^ OOC ^ y ^ COOR ^2,

Cl · N CH-OY-NR ³ R H Example RR ² Y — NR ³ R ⁴ Isolated Temperature Analysis (%) Number Melting Form (° C) Found (calculated)

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X

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Claims (3)

the subject of the invention A process for the preparation of substituted 1,4-dihydropyridine derivatives of the general formula I Y a known group - (CH 2) 2 - or - (CH 2) -, R is an aryl or heteroaryl radical, R @ ¹ and R @ ² are each independently C1 -C4 alkyl or 2-methoxyethyl; R ³ and R ⁴ are each independently C 1 -C 4 alkyl or C 1 -C 4 arylalkyl, or R ³ and R ⁴ together with the nitrogen atom to which they are attached form the remainder of the formula -o or where R ⁵ is C 1 -C 4 alkyl, aryl, C 1 -C 4 arylalkyl or benzhydryl, wherein the aforementioned aryl is a phenyl radical optionally substituted by one or two substituents selected from the group consisting of nitro halogen, C1-C4alkyl, C1-C4alkoxy, trifluoromethyl and cyano; , optionally monosubstituted methyl or cyano, quinolyl, henzoxazolyl, benzthiazolyl, furyl, pyrimidinyl and ethienyl, optionally monosubstituted halogen or C 1 -C 4 alkyl, and pharmaceutically acceptable salts thereof The compound of formula (IV) is an acid addition salt thereof R γ l R OOC2 CH CHj O tivl in which R and R ¹ have the above meanings, is reacted with a compound of formula V X CH COOR * NH 4 - Ctyo-Y-NRW (V) wherein R ² , R ³ , R ⁴ and Y are as defined above, in an organic solvent at a temperature of 60 to 130 ° C, after which optionally the resulting compound of formula I is converted by reaction with a suitable acid into its pharmaceutically acceptable acid addition salt. 2. A process according to claim 1, wherein the corresponding compounds of the formulas (IV) and (V) are used as starting materials to produce the compounds of formula (I) in which: R is 1-naphthyl, fernyl, optionally monosubstituted with halogen, trifluoromethyl, cyano or nitro, thienyl, optionally monosubstituted with halogen, pyridyl or quinolyl, R ³ and R ⁴ are each independently C 1 -C 4 alkyl or benzyl optionally monosubstituted on the aromatic ring with halogen or C 1 -C 4 alkoxy, or R ³ and R ⁴ together with the nitrogen atom to which they are attached form a radical of formula or -N OV where R ⁵ represents a C 1 -C 4 alkyl group, a phenyl group optionally monosubstituted with halogen, a benzyl group optionally monosubstituted on an aromatic ring with a halogen, or a benzhydryl group, and pharmaceutically acceptable acid addition salts thereof. 3. A process according to claim 1 or 2, characterized in that the corresponding compounds of the formulas IV and V are used as starting materials to give compounds of the formula I in which: Y is [CH 2} z, R is 1-naphthyl or 2-chlorophenyl, R ¹ and R ^z independently ^of one another are methyl or ethyl and R ³ and R ⁴ represent methyl groups, and pharmaceutically acceptable acid addition salts thereof.