NL8302067A - 1,4-DIHYDROPYRIDINE DERIVATIVES, IN OPTICALLY ACTIVE OR RACEMIC FORM, METHODS FOR PREPARING THESE DERIVATIVES AND PHARMACEUTICAL PREPARATIONS CONTAINING THEM. - Google Patents

Description

1, u-Dihydropyridine derivatives, in optically active or in racemic form, methods of preparing these derivatives and pharmaceutical preparations containing them.

The invention relates to novel 1,1-dihydro-pyridine derivatives in optically active or in racemic form, methods for their preparation and pharmaceutical preparations containing these derivatives.

US Pat. No. 150 describes a broad class of 1,1-dihydropyridine derivatives. A number of other examples of this class are described in British Patent Application 2,037,766 A.

It has now been found that a special group of hitherto unknown optically active and racemic 1,1H-dihydropyridine derivatives not specifically disclosed or proposed herein possess particularly interesting pharmacological properties.

The present invention provides compounds of the formula 1 wherein one of the substituents represents a methyl group and the other represents an isopropyl, n-butyl, iso-butyl, cyclopentyl or iso-propoxyethyl group and R 1 represents a hydrogen atom or represents an optionally substituted alkyl group of 1 to 6 carbon atoms, either in optically active form when R 1 is a hydrogen atom, or in racemic or optically active form when R 2 has a meaning other than hydrogen, and their acid addition salts, hereinafter referred to as compounds of the invention.

The molecules of the compounds of the formula I have a chiral carbon atom at the position of the 1,1-dihydropyridine ring due to the presence of the two different carboxylic acid ester groups COOR and COQR.

An alkyl group of 1 to 6 carbon atoms, when substituted, is preferably substituted by hydroxyl, acetyloxy, methoxy, ethinyl, dimethylamino or morpholino. Recommended connections

-----A

8302067 "2 '♦ * are those compounds in which one of the substituent and and R 1 represents a methyl group and the other is an isopropyl group, especially those in which further R 1 is an alkyl group of 1 to 6 carbon atoms or a hydrogen atom especially a methyl group or a hydrogen atom, especially a methyl group.

Another aspect of the present invention pertains to a method of preparing a compound of the invention comprising the following steps: a) 1-N-alkylation of a compound of formula 1a, wherein R 1 and R 8 are the previously defined have meanings, b) exchange of the R ^ group in an optical isomer of a compound of formula 2, wherein R ^ and R ^ have the previously defined meanings and R ^ is a cleavable group, against a group of formula ORg, wherein Rg has a previously defined meaning and, if the compound of formula 1 is basic, recovering this compound as such or in the form of an acid addition salt.

The 1-N-alkylated products of step a) can be prepared in a conventional manner, using suitable alkylating agents, for example an alkyl halide, preferably in the presence of a base, for example sodium hydroxide. If the alkyl group is substituted and the substituent would react with the halide function, it is preferably protected and the protecting group is cleaved after the alkylation.

The 1-N-alkylated products can be recovered in a conventional manner. If the 1N-alkyl groups contain a salt-forming group, such as the dimethylamino or the morpholino group, then the 1-N-alkylated products can be used as acid addition salts, for example as salts of organic acids, such as fumaric acid, or with inorganic acids, for example hydrogen halide acids such as HCl are obtained. The starting compounds in step a) are known or can be prepared from known compounds by methods known per se. The starting compounds 35 in step a) can be prepared analogously to step b) insofar as they are optically 8302067 3.

The products of step b) can also be obtained in a conventional manner, using, for example, starting materials of formula 2, wherein R 1 represents a cleavable group, for example a hydroxyl group or an azolide group. Suitable azolide groups include the imidazolide group of formula 2a. It is known that in the underneath the azolide groups, such as those of formula 2b, are very active and readily exchange their azolyl moiety, for example the 1H-imidazol-1-yl group, against an ester group, for example that of the ORg type, for example by adding an alcohol of formula RgOH and reacting the ingredients at an elevated temperature, for example between 60 and 150 ° C. Other suitable azolide groups are, for example, the 1,2,3 "triazolide-> 1,2, U-triazolide, benzotriazolide, benzimidazolide and tetrazolide group.

The products of step b) can also be obtained in another conventional manner, using starting materials of formula 2, wherein a QR 2 group is and R 2 is a chiral hydrocarbon group containing virtually none of its epimeric forms and which have one or represents a number of electron-attracting groups or a hydrocarbon group in which an amino group is present.

Electron attracting groups include the phenyl group, the methoxy group, and a quaternized amino group.

Recommended amino groups are di C ^) alkylamino groups. Recommended quaternized amino groups are tri-C 1 -alkylamino groups.

Preferred R groups are ethyl groups, the S-position of which is substituted by electron-attracting groups or by an amino group, such as the 2- (R) -CH 2 O 2 -phenyl-ethyl group or the trimethylammonioethyl or dimethylaminoethyl group.

Due to the presence of electron-attracting groups or of the amino group, the carboxylic ester group -COR can easily be converted into a -COR group. 0 d - 8302067 «..... k" ^ for example by reaction with an alcohol of formula RgOH, preferably under basic conditions The compounds in which R 1 represents a hydroxyl group and other compounds of formula 2 can react in a corresponding manner The final products can be separated and purified by methods known per se, if desired and possibly in the form of an acid addition salt.

ia,. ,

Preferably, the optically active compounds of formula 2 of step b) R ^ are an azolide group or the like group OR ^, wherein R ^ is a chiral hydrocarbon group containing substantially none of the epimeric forms thereof and in which one or more electron attracting groups are present is presents.

Representative starting materials of formula 2 can be prepared according to reaction schemes 15 A and B, reaction scheme A on the formula sheet, for preparing compounds of formula 2, wherein R ^ is the isopropyl group, R ^ is an OR ^ 3 * group, R ^ is a hydrogen atom and R * a 2- (R) -CH_0-2-phenylethyl group and 5.3 reaction scheme B for the preparation of compounds of formula 2 wherein R1 is an isopropyl group, R1 is a 1-H-imidazol-1-yl group and R1 is a hydrogen atom proposals explaining how two optically active forms IIb.1.1 and IIb.1.2 can be prepared by chromatographic separation or selective crystallization, respectively, are obtained.

While the optically active connections IIb.1.1.

25 of the reaction scheme A are prepared directly by chromatographic separation of the corresponding mixture of diastereoisomeric esters, the optically active compounds IIb.1.3 of the reaction scheme B arise from a mixture of diastereoisomeric salts IIb.1.2, the components of which can be crystallized by selective crystallization. be separated.

Crystallization is more recommended as a separation method than chromatography when operating on an industrial scale.

After separation, the same working method is applied to compounds IIb.1.1 and IIb.1.2 to obtain the final compounds of formula 1 8302067 · 5.

Both the chiral ester group of the compounds IIb.1.1 and the proton-dimethylaminoethyl ester groups of the compounds IIb.1.2 can be converted into an ester group OR2, but in reaction scheme B on indirect mode, which preparation method is especially recommended.

Although it is possible in principle to obtain directly from the compounds IIb.1.2 or, preferably from the compounds of formula 11, the final products of formula 1 directly by transesterification, a more recommended route is the formation (via compounds of formula 11 ) of a more powerful electron-attracting group by quateralization (compounds of formula 12), allowing a second salt crystallization and purification.

Like compounds IIb.1.2, those of the type of formula 12 can be directly esterified to compounds of formula 1. However, it is possible to hydrolyze the ester group and convert the 3-carboxylic acid compounds (compounds of formula 13) either directly or via the 3-azolide compounds IIb.1.3 into the final products of formula 1, which reactions can be carried out in a conventional manner and allow the preparation of the compounds of formula 1 in both a good yield and in a very pure state.

In the following examples, the preparation of the intermediates disclosed in reaction schemes A and B is also described.

Example II

The isopropyl ester of U- (2,1,3-benzoxadiazol-4-yl) -1,5-dihydro-5-methoxycarbonyl-1,2,6-trimethyl-3 "pyridine carboxylic acid (of formula 1, racemate process , step a)) ._

1.5 g of solid, crushed potassium hydroxide and 0.8 U ml of methyl iodide in a nitrogen atmosphere were added to a solution of 2.5 g of the isopropyl ester of k- (2,1,3-benzoxadiazol-U-yl) -35 l , k-dihydro-5-methoxycarbonyl-2,6-dimethyl-3-pyridinecarboxylic acid ______ Λ 8302067% 6 in 1 * 0 ml dimethyl sulfoxide. The mixture was then stirred at room temperature. After 1.5 hours, the mixture was poured onto ice water and extracted with methylene chloride. The methylene chloride solution was dried over magnesium sulfate and evaporated under reduced pressure.

The title compound was purified by chromatography on silica gel using methylene chloride as eluent and crystallized from a mixture of ether and petroleum ether. M.p .: 125 ° C.

10 Example II:

The isopropyl ester of (-) - (S) - and (+) - (R) -U- (2,1,3 "benzoxadiazol-U-yl) -1,1 * dihydro-5" methoxy carbonyl-1, 2,6-trimethyl-3-pyridinecarboxylic acid (formula 1, antipodes) ._ 15 a) (+) - (R) - and (-) - (S) -U- (2,1,3-benzoxadiazole-1 *) -yl) - 1,1 * -dihydro-5 "isopropoxycarbonyl-2,6-dimethyl-3-pyridinecarbonzuux (2- (R) -methoxy-2-phenylethyl) -ester ^" (+) IIb.1.1 and (- ) IIb.1.1 ?.

1) A solution of 10.5 g of the isopropyl ester of U- (2,1,3-benzoxadiazol-U-yl) -1, U-dihydro-5 "(1H-imidazol-1-yl-carbonyl) was heated -2,6-dimethyl-3-pyridinecarboxylic acid (formula 3) in 35 g of (R) -2-methoxy-2-phenylethanol / prepared according to W. Kirmse et al., Chem. Ber. 108.79 (1975) 7 hours at 120 ° C. The excess of the optically active alcohol was then distilled off under high vacuum at a temperature between 80 and 110 ° C. The resulting residue was dissolved in methylene chloride and the solution was washed with a cold 2N hydrochloric acid solution, dried and evaporated under reduced pressure.

2) A solution of 3.5 g of the isopropyl ester 30 of 2-acetyl-3 "(2,1,3-benzoxadiazol-U-yl) -2-propenoic acid (formula 7) i (z) or (E) or a mixture of the (Z) and (E) isomers 7 and 3.0 g of the (2- (R) -methoxy-2-phenylethyl) ester of 3-aminocrotonic acid (formula 8) in 100 ml of dioxane was added Refluxed for 20 hours and evaporated to dryness under reduced pressure. The mixture of diastereo 8302067 7 isomers obtained according to 1) or 2) is evaporated by chromatography on silica gel at 5 atmosphere with a mixture of hexane and ether (1.5: 1) separated as eluent.

The first compound that was eluted was crystallized from a mixture of ethyl acetate and hexane. M.p .: 89 °, 3 -92 ° (in ethanol).

The second compound that was eluted was crystallized from a mixture of ether and hexane or methanol and water. Mp. 127 ° / * + 77 ° (in ethanol).

B) the isopropyl ester of (+) - (S) -k- (2,1,3-benzoxadiazol-k-yl) -1, - dihydro ** 5-methoxycarbonyl-2,6-dimethyl-3-pyridinecarboxylic acid formula 1a, antipode, reaction step b | 7-

5.3 g of (-) - (S) - 15 ^ - (2,1,3-benzoxadiazole - ^ - yl) -1, U-dihydro-5 "isopropoxycarbonyl-2,6-dimethyl- were heated in a nitrogen atmosphere 3-Pyridinecarboxylic acid (2- {R) -methoxy-2-phenylethyl) ester / lll.1.1 (-_) 7 in a solution of 0.3 g of sodium in 100 ml of methanol under reflux for 50 hours. the solution under reduced pressure to 50% and 20 added 100 ml of ice water The mixture was extracted with methylene chloride The solution in methylene chloride was dried over magnesium sulfate and evaporated under reduced pressure.

The residue was purified by chromatography on silica gel at low pressure (vapor). A mixture of hexane and ether (1: 4) was used as the eluent. After crystallization from a mixture of ether and hexane, the melting point of the pure (+) - (Us) enantiomer was (1a) - (+ 27 '1 ^ 2 ° C).

/ a7 | Jg = + 9.9 ° (ethanol, c * 1.5 g / dl).

fa7 ^ ° = + 6.7 ° (ethanol, c = 1.5 g / dl) c) The isopropyl ester of (-) - (&) - l + - (2,1,3 "benzoxadia-sole-U-yl -1-U-dihydro-5 * methoxycarbonyl-1,2,6-trimethyl-3-pyridinecarboxylic acid [formula 1, antipode, reaction step

To a solution of 0.7 g of the iso-35 propyl ester of (+) - (US) - (2,1,3 "benzoxadiazole - ^ - yl)" 1, ^ "dihydro- ____ Λ 8302067 8 * 5 was added -methoxycarbonyl-2,6-dimethyl-3 "pyridinecarboxylic acid in 10 ml dimethyl sulfoxide 0.1 + 3 g crushed potassium hydroxide. After adding 0.23 ml methyl iodide, the mixture was stirred for 1 hour in a nitrogen atmosphere. Then the mixture was poured 5 on ice water and extracted with methylene chloride. The solution in methylene chloride was dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography on silica gel under low pressure (vapor). A mixture of methylene chloride and ether (1+) was added. 9: 1) used as eluent The title compound was crystallized from a mixture of ether and hexane.

Mp. 92 °, / "o57 | ° g =" 3 ° (ethanol), c 0.6γ g / dl, / "/ yyg 3" 25 ° »(chloroform, c = * 1.0 g / dl).

d) The isopropyl ester of (-) - (R) - + + (2,1,3-benzoxadiazol-1 + -yl) -1,1 + -dihydro-5 ”methoxycarbonyl-2,6-dimethyl-3 pyridine carboxylic acid, formula 1a, antipode, reaction step b | 7

This compound was prepared analogously as described in b) from the enantiomer (+) - (1 + R) under a). M.p .: 20 ll + 0 ° C (crystallized from a mixture of ether and hexane).

ZVfJs = -10.1 ° (ethanol, c = 1.67 g / dl). / “A7 ^ ° =“ 6.7 ° (ethanol, c = 1.67 g / dl), e) (e isopropyl ester of (+) - (R) -1 + - (2,1,3 "benzoxadiazole) -1 + -yl) -1,1 + -dihydro-5-methoxycarbonyl- 1,2,6,6-trimethyl-3-pyridinecarboxylic acid / formula 1, antipode, reaction step a} 7.

This compound was prepared analogously as described in c) from the enantiomer (") - (i + R) under d). M.p .: 93 ° C (crystallized from a mixture of ether and hexane).

30 ZVf ° 6 + 3.1 ° (ethanol, c = 0.83 g / dl). 3 + 23 ° (chloroform, cs 1.1 g / dl).

The imidazolide of formula 3 used in a) 1) has a melting point of 166 ° C and was prepared from 1 + - (2,1,3 "benzoxadiazol-1 + -yl) -1,1 + -dihydro ~ 5" isopropoxycarbonyl-2 6-35 dimethyl-3 "pyridinecarboxylic acid formula U which is reacted with a slight 8302067 9 excess 1,1'-carbonyldiimidazole at 50 ° C in dioxane.

The acid of formula 4 has a melting point of 213 ° C and is obtained from the (2-cyanoethyl) ester of 4- (2,1,3-5-benzoxadiazol-4-yl) -1,4-dihydro-5 ** isopropoxyearbonyl-2,6-dimethyl-3 "pyridine carboxylic acid of formula 5" which is hydrolyzed at room temperature with 3 moles of NaOH in a mixture of water and 1,2-dimethoxyethane (2: 1).

The ester of formula 5, mp .: 125 ° C, prepared by reacting the (2-cyanoethyl) ester of aminocrotonic acid of formula 6 with the isopropyl ester of 2-acetyl-3- (2,1,3-benzoxa- 2-diazol-4-yl) -7-propenoic acid of formula 7 in dioxane.

The ester of formula 6, mp .: 88 ° C, is obtained by reacting the corresponding (2-cyanoethyl) ester of acetoacetic acid 15 dissolved in benzene with gaseous ammonia.

The ester of formula 7 is obtained by condensing 2,1,3-benzoxadiazole-4-aldehyde in the presence of catalytic amounts of piperidine and acetic acid in boiling benzene with the corresponding ester of acetoacetic acid.

The ester of formula 7 crystallized as a mixture and can be separated into the E isomer, mp .: 75 ° C and the Z isomer, mp: 55 ° C.

Example III:

The isopropyl ester of (+) - (S) -4- (2,1,3-benzoxadiazol-25 4-yl) -1,4-dihydro-5-methoxycarbonyl-2,6-dimethyl-3-pyridinecarboxylic acid (Formula 1 ) / 1, reaction step b) ./.

a) The (2-dimethylaminoethyl) ester of 4- (2,1,3-benzoxadiazol-4-yl) -1,4-dihydro-5-isopropoxy-carbonyl-2,6-dimethyl-3 "pyridinecarboxylic acid 30 (formula 9).

a.1) 5 g of the isopropyl ester of 4- (2,1,3-benzoxadiazol-4-yl) -1,4-dihydro-5- (1H-imidazol-1-ylcarbonyl) -2, was heated 6-dimethyl-3 ”pyridinecarboxylic acid (formula 3) and 24.5 ml of 2-dimethylaminoethanol in 20 ml of dioxane at boiling temperature for 5 hours. The mixture was then extracted with ice maker 8302067 * 10 and ethyl acetate. The organic phase was dried over magnesium sulfate, under reduced pressure. evaporated to dryness and the residue was purified by chromatography on silica gel. As the eluent, a mixture of ethylene chloride and ether (1: 1) was used. The hydrochloride salt of the product was crystallized from a mixture of ethanol and ether. M.p .: 150 ° C.

a.2) 182.6 g of the isopropyl ester of 2-acetyl-3 "(2,1,3-benzoxadiazol-U-yl) -2-propenoic acid (formula 7) (mixture of Z and E isomers) were boiled and 11.7 g of the (2-dimethylamino-10 ethyl) ester of 3-aminocrotonic acid in 1 L of dioxane for 16 hours. The mixture was then evaporated to dryness under reduced pressure, the residue was converted into the hydrochloride salt and crystallized from a mixture of ethanol and ether.

b) The (2-dimethylaminoethyl) ester of (-) - (Ξ) —U— 15 (2,1,3-benzoxadiazole - ^ - yl) -1, U-dihydro-5 "isopropoxycarbonyl-2,6 Dimethyl-3-pyridinecarboxylic acid (formula 11).

52.6 g of the compound of formula 9 mentioned in the title under a) and 1 * 9 * 6 g (-) - di-0,0'-p-toluoyl- (L) -20 tartaric acid were dissolved in 200 ml of hot isopropanol and let this solution stand. Herein the di-0,0'-p-toluoyl- (L) -tartaric acid salt of formula 10 was formed. After cooling to room temperature, the crystals formed were filtered off and recrystallized twice from isopropanol. The product, the di-0, Q'-p-toluoyl (L) -25 tartaric acid salt, was dried under high vacuum at 90 ° C.

M.p .: 1U6 °, 1a / f = -122 ° (ethanol / c * 1 g / dl), j_ a7 ^ g = "156 ° (ethanol, c = 1 g / dl). The broth was added by adding a dilute sodium hydroxide solution converted to the title compound of formula 11 and extracted with ether It is an oily product j_ a / ^ = -1 + 5 ° (ethanol, c * 1 g / dl), l = “58 ° (ethanol, c * 1 g / dl).

8302067 «* 11 c) The iodide of the (2-trimethylamoethyl) ester of (-) - (S) -U- (2,1,3" benzoxadiazol-U-yl) "1, U-dihydro-5-isopropoxycarbonyl -2,6-dimethyl-3 "pyridinecarboxylic acid of formula 12.

12 µg of the title compound mentioned under b) of the formula II were dissolved in 120 ml of methanol. After adding 2.3 * 1 ml of methyl iodide, the solution was allowed to stand at room temperature for 15 hours. The crystals formed were filtered off and recrystallized from a mixture of methanol and ether.

10 mp. 222 °, / “a? ^ =» 75 °. (ethanol, o = 1 g / dl) ~ ~ ° (ethanol, c * 1 g / dl).

d) (+) - (S) -U- (2,1,3 "benzoxadiazol-U-yl)" 1, H-dihydro "5" isopropoxycarbonyl-2,6-dimethyl-3-pyridine - carboxylic acid of formula 13.

A solution of 15 g of the iodomethylate mentioned under c) of formula 12 in 150 ml of dioxane and 300 ml of a 2N solution of sodium hydroxide in water was allowed to stand at room temperature for 16 hours. While stirring and cooling, the solution is made acidic by dripping concentrated hydrochloric acid.

After stirring in an ice bath for 30 minutes, the crystals formed were filtered off, washed with ice water and dried under high vacuum at 80 ° C.

Mp. 168 °, Z * + 1 ° (ethanol, c 1 g / dl), ZVjJg = + 27 ° (ethanol, c = 1 g / dl).

E) The isopropyl ester of (-) - (S) -U- (2,1,3 "benzoxadiazol-U-yl) -1,1-dihydro-5" (1H-imidazol-1-yl carbonyl) -2,6-dimethyl-3 "pyridinecarboxylic acid (Ilb.1.3).

A mixture of 8.6 g of the acid 30 mentioned under d) (formula 13) and 9.75 g of 1,1'-carbonyldiimidazole was stirred in 190 ml of dioxane for 2 hours at a bath temperature of 50 ° C. The solution was then evaporated to dryness under reduced pressure and the residue was purified by chromatography on low pressure silica gel, using a mixture of methylene chloride and ethanol (19: 1) as eluent. The product was crystallized from a mixture of ice-8302067-12 of methylene chloride and ether. Mp. 182 °, L “7p ° =“ 50 ° (ethanol, c 3 1 g / dl). [α] ° ° g *? 1 ° (ethanol, c = 1 g / dl).

f) three isopropyl ester of (+) - (S) - ^ - (2,1,3-benzoxa-5-diazol-H-yl) -1, U-dihydro-5-methoxycarbonyl-2,6-dimethyl-3 " * pyridine carboxylic acid of formula 1.

A solution of 5 g of the imidazolide mentioned under e) (lib. 1.3) in 50 ml of methanol was refluxed for 16 hours and evaporated under reduced pressure.

The "residue was purified by chromatography on silica gel under low pressure using a mixture of hexane and ether (1: 3) as eluent.

The product was recrystallized from a mixture of ether and hexane. M.p .: 11 ° C / a7 ^ s + 8 ° (ethanol, c 3 1 g / dl), 15 ZV5J5 = + 12 ° (ethanol, c 3 1 g / dl).

In the same manner as described in Example I, the following compounds were prepared. The starting materials are known or can be obtained from known compounds by methods known per se.

20 8302067 13

For R R R racemate or image antipode IV CH3 n-buffyl CH ^ + m.p. 117 ° V CH-i-butyl CH, 1 ^ + "133 ° VI CH ^ cyclopentyl C 1-4 +" 1 ^ 3 VII CH_ - (CH) _- 0-i-propyl CH, 1 ^ + "106 ° VIII CH3 i-propyl - (CH ^ -OH '+ oil 2 3) IX CH3 i-propyl - (CHgJg-OC-Caj + oil X CH3 i-propyl - (CH ^ -O-CH ^ + mp. 106 ° XI CH3 i-propyl -CHg-CSCH5 ^ + "100 ° / -0¾61" XII CH i-propyl - (CHj -N + "179 5" (hydrogen fumarate) ™ 3 XIII CH i-propyl - (CH_) - 1/3 + 162 ° ^ (hydrogen fumarate) CH 8) / CH 3 q XIV CH i-propyl - (CH) -N + V 92 ° NCH 3 f ^ ° 3 + 15 °, ZV5f ^ o ° (methanol, c = 1 g / dl ) HBr salt: mp.2k3 ° / - 720 _ / / 720 L «V3 + 5 s / 5i, 6s + 8 ° (methanol, c = 0.6 g / dl) CH ^ / 3 _ XV CH i- propyl - (CH ,, LN - mp: 92 ° X pti / ”720- icO Γ 720 _ ® 3 Z s / D -15, Sat / 5W = -20 ° (methanol, c = 1 g / dl) HBr- salt: mp 2 ^ 3 ° / - y20_ o, - 720 _ Z 2 / d = “5, Z 2 / 51.6 -8 ° (methanol, 0 = 0.6 g / dl) ____, ^ 1 8302067

lU

Alkylation with CH 2 J

alkylation with Br-1 C 3 -g 3 -O-rOh and ether cleavage with HCl 3). . .

from the compound of Example VIII by reaction 5 with acetic anhydride alkylation with j- (CH 2) 2 -O-CH 3

alkylation with Br-CH 2 “C = CH

alkylation with C1- (CH2) g -N- (CH2) 2 / alkylation with C1- (CH2) 2 alkylation of the compound of Example III

according to example XII

9) alkylation of the compound of Example 11 according to Example XII.

The compounds of the invention have a pharmacological action.

The compounds exhibit effects characteristic of calcium agonist and. They have a pronounced muscle relaxing effect, especially on smooth muscles, as evidenced by vasodilatation and blood pressure reduction in standard tests.

For example, in the test on an anesthetized cat using tracer microspheres (R. Hof et al., Basic Res. Cardiol ^ Xi (1980) 7 ^ 7-756 and 76 (1981) 630-638; R. Hof and med., J. Cardiovasc.Pharmacol. 1 * (1982) 352-362) coronary vasodilation was observed upon administration of about 5 to about 200 µg / kg iv. or about 5 to about 1 * 00 jig / kg i.d. 1-alkylated compounds of formula 1 and about 5 to about 80 µg / kg i.v. or about 10 to about 200 µg / kg i.d. of compounds wherein R 1 represents a hydrogen atom and a drop in blood pressure was observed upon administration of about 5 to about 250 µg / kg i.v. for 1-alkylated compounds and about 5 to about 50 µg / kg i.v. for compounds in which R ^ is a hydrogen atom.

8302067 r 15

A drop in blood pressure has also been observed in conscious, spontaneously hypertensive rats (method of Gerold and Tschirki, Arzneimittelforsch. 18 (1968) 1285) when administered from about 0.1 to about 50 µg / kg s.c. of the 5 1-N-alkylated compounds and from about 0.1 to about 10 mg / kg s.c. of the compounds in which represents a hydrogen atom.

The compounds are therefore indicated for use as calcium channel blockers to prevent and treat coronary insufficiency, eg, angina pectoris, cerebrovascular insufficiency, such as cerebrovascular lesions, eg cerebral haemorrhage and cerebrovascular vascular cramps, eg peripheral circulation, such as in limbs, such as intermittently limping and cramping, for example, colic, - asthma, for example, exercise-related asthma and - hypertension.

An indicated daily dose is between about 5 and about ^ 00 mg for 1-N-alkylated compounds and from about 5 mg to about 200 mg for compounds in which R1 represents a hydrogen atom, suitably administered, for example, orally, in separated doses of about 1.25 mg to about 200 mg for the 1-N-alkylated compounds and from about 1.25 mg to about 100 mg for the compounds wherein R 1 represents a hydrogen atom, 2 to 1 times a day, or in a slowly released form. An example of a daily dose is from about 5 mg to about 200 mg, preferably from about 10 to about 50 mg of the compound of Example IIc.

Recommended are the title compounds of Examples Ilb and IIc.

Compounds of formula 1 which are 1-N-alkylated, in particular the compound of Example IIc, when administered intravenously 8302067 * * 16 have a beneficial * slow onset of action and a longer duration of action compared to intraduodenal administration.

They are approximately as powerful if they 5 i.d. or i.v. be administered.

The slow onset and long duration of action make these compounds, due to fewer side effects, safer than other 1, U-dihydropyridines for intravenous use.

The compounds of S-configuration, ie the compounds of examples Ilb and IIc, because of their action, have a better pharmacological profile than the corresponding R-forms and the racemic forms.

The compounds of the invention are administered in free form or, if possible and suitable, in pharmaceutically acceptable acid addition salt forms. Such salt forms have a similar degree of action to the free forms and are easily obtained in a conventional manner.

The present invention also provides pharmaceutical compositions containing one or more compounds of the invention in free form and / or, if possible and suitable, in a pharmaceutically acceptable salt form, optionally together with a pharmaceutical carrier and / or diluent. Such preparations can be, for example, solutions or tablets.

8302067

Claims (11)

1. Compounds of formula 1, wherein one of the substituents and R 1 represents a methyl group and the other an isopropyl, n-butyl, iso-butyl, cyclopentyl or isopropoxyethyl group and R 1 is a hydrogen atom or represents an optionally substituted alkyl group of 1-6 carbon atoms, either in optically active form when R 1 represents a hydrogen atom or in a racemic or optically active form when R 1 has a meaning other than hydrogen, and the acid addition salts thereof. Compounds according to claim 1, wherein one of the substituents R 1 and R 8 represents a methyl group and the other is an isopropyl group. A compound according to claim 2, wherein R 15 represents a methyl group. A compound according to claim 2, wherein R 1 is a hydrogen atom. 5. The isopropyl ester of U— (2,1,3-benzoxadiazol-4-yl) -1,4-dihydro-5-methoxycarbonyl-1,2,6-trimethyl-3 "pyridinecarboxylic acid 20 and the (-) - ( 4s) and the (+) - {4r) form thereof, the isopropyl ester of (2,1,3 "benzoxadiazol-4-yl) -1,4-dihydro-5" methoxycarbonyl-2,6-dimethyl-3-pyridinecarboxylic acid in the (+) - 4s and (-) - itR form thereof, dsn-butyl ester of 4- (2,1,3-benzoxadiazol-4-yl} -1,4-25 dihydro-5-methoxycarbonyl-1, 2,6-trimethyl-3-pyridinecarboxylic acid, the isobutyl ester of 4- (2,1,3 "benzoxadiazol-4-yl) - 1,4-dihydro-5" non-oxycarbonyl-1,2,6-trimethyl-3-pyridinecarboxylic acid, the cyclopentyl ester of 4-f2,1,3 "benzoxadiazol-4-yl) -1, U-dihydro-5" methoxycarbonyl-1,2,6-trimethyl-3-pyridinecarboxylic acid, the 2-isopropoxyethyl ester of 4- (2, 1,3-benzoxadiazol-4-yl) -1,4-dihydro-5-methoxycarbonyl-1,2,6-trimethyl-3-pyridine carboxylic acid, the isopropyl ester of 4- (2,1,3-benzoxadiazol-4-yl ) - 1,4-dihydro-1- (2-hydroxyethyl) -5-methoxycarbonyl-2,6-dimethyl-1-3 "____ ^ 8302067 <? 18 pyridinecarboxylic acid, the isopropyl ester of 1- (2-acetoxyethyl) -k- {2, J, 3 "benzoxadiazol-U-yl) -1, i + -dihydro-5" * with hoxycarbonyl-2,6-dimethyl- 3-pyridinecarboxylic acid, 5 isopropyl ester of U- (2,1,3-benzoxadiazol-U-yl) -1,1 * dihydro-5'-ethoxycarbonyl-1- (2-with hoxyethyl) -2,6-dimethyl -3-Pyridinecarboxylic acid, the isopropyl ester of - (2,1,3-benzoxadiazol-1 + -yl) -1, H-dihydro-5 ”inethoxycarbonyl-2,6-dimethyl-1- {2-propinyl) -3” 10 pyridinecarboxylic acid, the isopropyl ester of U— (2,1,3 "benzoxadiazol-U-yl) -1- (2-dimethylaminoethyl) -1,1-dihydro-5-methoxycarbonyl-2,6-dimethyl-3-pyridinecarboxylic acid and its acid addition salts , the isopropyl ester of U- (2,1 jS-benzoxadiazole-^-yl) -15 1, ^ -dihydro-5-methoxycarbonyl-2,6-dimethyl-1- / 2- (U-morpholinyl) ethyl / -3 pyridinecarboxylic acid and its acid addition salts, the isopropyl ester of (+) - (8) - ^ - (2,1,3-benzoxadiazol-k-yl) -1 - (2-dimethylaminoethyl) -1, ^ - dihydro-5- methoxycarbonyl-2,6-dimethyl-3-pyridinecarboxylic acid and its acid addition salts of 20 and the isopropyl ester of (-) - (R) -U- (2,1,3-benzoxadiazol-1-yl) -1- (2-dimethylaminoethyl) -1, U-dihydro-5 "with hoxycarbonyl- 2,6-dimethyl-3 "pyridinecarboxylic acid and its acid addition salts. 6. Process for preparing a compound according to claim 1, characterized in that a) a compound of formula 1a, in which and R 1 has the meanings defined here, is alkylated 1-N and, if desired, the compound obtained is converted into an acid addition salt thereof, b) the R ^ group in an optical isomer of a compound of formula 2, wherein R ^ and R ^ have the previously defined meanings and R ^ is a cleavable group, against an OR group, wherein R ^ has a previously defined meaning, ui changes. Process according to claim 6, defined in step b), characterized in that the compound of formula 2 contains an 8302067 '19 • JX »X substituent, each of which is an OR group, in which R 1 is a chiral hydrocarbon group which is free-form does not contain any of its epimeric forms and one or more of the electron-attracting groups are present and R1 represents a methyl or isopropyl-5 group. 8. Compounds according to any one of claims 1-5 for use as a medicine, in particular for use in the treatment of coronary insufficiency, cerebrovascular insufficiency, peripheral circulatory disorders, hypertension or asthma. Pharmaceutical preparations containing one or more compounds according to claims 1-5, desiccant together with a pharmaceutical carrier or diluent. 10. Compounds of formula 2, as defined in claims 6 and 7, in particular the (2- (R) -methoxy-2-phenylethyl) ester of (-) - (S) -U- (2,1 , 3-benzoxadiazol-U-yl) -1, U-dihydro-5-isopropoxycarbonyl-2,6-dimethyl-U-pyridinecarboxylic acid, the (2- (R) -methoxy-2-phenylethyl) ester of (+ ) - (R) -k- (2,1,3 "benzoxadiazol-U-yl) -1,4-dihydro-5" isopropoxycarbonyl-2,6-20 dimethyl-3-pyridinecarboxylic acid, the isopropyl ester of U- (2 1,3-benzoxadiazol-k-yl) -1, k-dihydro_5 "(1H) -imidazol-1-yl-carbonyl) -2,6-dimethyl-3" pyridinecarboxylic acid, the isopropyl ester of (-) - (S ) -U- {2,1,3 "benzoxadiazol-U- * yl) -1, U-dihydro-5" (1H) -imidazole-1-ylcarbonyl) -2,6-dimethyl-3-pyridinecarboxylic acid and the isopropyl -25 ester of (+) - (R) -U- (2,1,3 "benzoxadiazol-U-yl) -1,6- dihydro-5- (1H) -imidazol-1-ylcarbonyl) -2,6 -dimethyl-3-pyridinecarboxylic acid. 11. 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