CH660593A5 - 1,4-DIHYDROPYRIDINE DICARBONIC ACID ESTER, METHOD FOR THE PRODUCTION THEREOF AND PHARMACEUTICAL COMPOSITION, CONTAINING THESE COMPOUNDS AS ACTIVE SUBSTANCE. - Google Patents

Description

The invention relates to new 1,4-dihydropyridine derivatives in optically active or in racemate form and their preparation and pharmaceutical compositions. 55 European Patent 150 describes an extensive group of 1,4-dihydropyridine derivatives. DE patent applications 2 949 464 and 2 949 491 describe a number of other compounds of this group. Chem. Ab-stracts 98, 7 (February 1983), reference 49 076 S describes the binding of the calcium antagonist NIMODIPIN and its ENANTIOMERS to the receptors of the calcium channels in skeletal muscle homogenates.

It has now been found that a special group of previously unknown optically active and racemic 1,4-dihy-65 dropyridine derivatives has a particularly interesting pharmacological profile.

The invention relates to compounds of the formula I.

3rd

660 593

where one of

Ri and R2 are methyl and the other isopropyl, n-butyl, iso-butyl, cyclopentyl or iso-propoxyethyl and

R3 represents hydrogen or an optionally substituted (C | .6) alkyl,

in optically active form when R3 is hydrogen, or in racemic or optically active form when R3 is an optionally substituted (C | 6) alkyl, and their acid addition salts, hereinafter referred to as compounds according to the invention.

The molecules of the compounds of the formula I contain a chiral carbon atom in position 4 of the 1,4-dihydropyridine ring due to the presence of the two different carboxylic ester groups COOR] and COOR2.

(C, 6) Alkyl, if substituted, is preferably substituted by hydroxy, acetyloxy, methoxy, ethynyl, dimethylamino or morpholino.

Preferred compounds are those in which one of R 1 and R 2 is methyl and the other is isopropyl. Those in which R3 (Q6) is alkyl or hydrogen, in particular methyl, are particularly preferred.

The invention also relates to processes for the preparation of the compounds of the formula I according to the invention as claimed in claim 1, one of which is characterized by 1-N-alkylation of a compound of the formula Ia,

wherein

R, and R2 have the meanings mentioned in claim 1 and, if the compound of the formula I obtained is basic, its isolation as such or as an acid addition salt, and the other (according to claim 8) by replacing the radical R4 in an optically isomeric form Compound of formula II,

wherein

R, and R3 have the meanings mentioned in claim 1 and R4 is a cleavable group by an ester radical OR2, in which R2 has the meaning mentioned in claim 1 and, if the compound of the formula I is basic, its isolation as such or as Acid addition salt.

The 1-N-alkylated products of the process according to claim 7 can be prepared in a manner known per se, using suitable alkylating agents. The alkyl group can be substituted by an alkyl halide as the alkylating agent, preferably in the presence of a base, e.g. sNaOH.

If it is substituted and the substituent would react with the halogen atom, it can be protected and the protecting group removed after the alkylation.

The 1-N-alkylated products can be isolated and purified in a known manner. If the 1-N-alkyl groups contain a salt-forming group such as the dimethylamino or the morpholino group, the 1-N-alkylated products can be obtained as acid addition salts, e.g. as salts with organic acids, e.g. Fumaric acid, or with inorganic acids, e.g. Hydrohalic acids such as HCl.

The starting products of this process are known or can be prepared from known compounds by known methods. The starting products of this 2o process, insofar as they are optically active, can be produced according to the process of claim 8.

The products of the process according to claim 8 can also be produced in a known manner, e.g. Starting materials of formula II are used, in which 25 R4 is a removable group, e.g. Is OH or an azolide residue.

Suitable azolide residues are e.g. the imidazolide residue

-G

Azolide groups, which are very reactive and their azolyl part, e.g. 1-H-imidazol-l-yl, slightly against an ester group, e.g. replace one of the type OR2 if e.g. an alcohol R2OH is added and the components at elevated temperature, e.g. 60-150 ° can be implemented.

Other possible azolide residues are e.g. the 1,2,3-triazo-lid, 1,2,4-triazolid, benzotriazolide, benzimidazolide and tetrazolide.

The products of the process according to claim 8 can also be prepared in a different conventional manner, using starting materials of the formula II, in which R4 denotes an OR5 group and R5 is a dural, uniformly configured hydrocarbon radical with one or more electron-withdrawing groups or a hydrocarbon radical, which contains an amino group.

Preferred electron-withdrawing groups are those such as the phenyl or methoxy group or a quaternized amino group. Preferred amino groups are di- (C] 4) alkylamino groups. Preferred quaternized amino groups are tri (C | 4) alkylamino groups. Preferred radicals R5 are ethyl radicals which are substituted in the β position with the electron-attracting groups or with an amino group, such as the 2- (R) -CH30-2-phenylethyl radical or the trimethylammonioethyl or dimethylaminoethyl radical.

The carboxylic acid ester group-C -0-R5 is

II O

Entity of the electron-withdrawing groups or the amino group, easily convertible into a -C-0-R2 group

II O

30th

It is known that particular

-C-N

35

i-Q

660 593

4th

by implementation with e.g. an alcohol R2OH Preferred chiral, uniformly configured hydrocarbon residue with wise under basic conditions. The R4 = OH and one or more electron-withdrawing groups.

their compounds of the formula II can be prepared in a similar manner. Representative starting products II can be prepared. The end products can be known as described in the following reaction

Way and, if desired and possible, as acid addition men I and II. These schemes show how two op-

salts isolated and cleaned. active forms IIb. 1.1 and IIb. 1.2 can be obtained

In the optically active compounds, R4 is preferably an azolide residue or such a group 0R5 *, where R5 * is a or a selective crystallization method by means of chromatographic separation.

Reaction scheme I for the preparation of compounds IIb, wherein Ri = isopropyl, R4 = 0R5, R3 = H and R5 = 2- (R) -CH30-2-phenylethyl

-> +

vi phenyl

-CHff- "

oh

IV

0-CH.

oh

ihenyl H

Q * phenyl fN) - ™ .- /

21 SH

Chromatography

III

(+) - (4R ^ ^ (-) - (4S) IIb. 1.1

Reaction scheme II for the preparation of compounds IIb, in which R] = isopropyl, R4 = 1-H-imidazol-l-yl and R3 = H

1 I A

Q! 0

i '^ \ 0- (CH2) 2-NC

vii +

, Ç0

->> -0 '

II 3I

VM.

H

3- (CH2 ^ 2 ^.

h r * ©

iii

R * H =>

- (ch2) 2-NÎ

Di-O-O'-p-toluoyl- (R) or (L) tartaric acid o- (chj2-n <^

t ^ Crystallization (+) - (4R) ~ "V) - (4S) IIb.1.2

J, NaOH

3-dimethylaminoethyl ester (+) - (4R) [CH-J (-) - f4S) XI

3-Trimethylammoni ethyl ester

(+) - (4R)

NaOH

(-) - (4s)

XII

3 — carboxylic acid compounds. (-) - (4R) | (+) - (4S) XIII

3r (lH -Imidazo1-l-v] carbonyl) compounds IIb.1.3 (+) - (4R) (-) - (4SJ

While the optically active compounds IIb. 1.1. of the reaction scheme I can be obtained directly by chromatographic separation of the corresponding diastereoisomeric mixture, the optically active compounds IIb. 1.3 of the reaction scheme II from a mixture of diastereoisomers IIb. 1.2 prepared, the components, since they contain a salt-forming group, can be easily separated by selective crystallization.

Compared to chromatography, crystallization is a preferred method of separation when carried out on an industrial scale.

After the separation, the same process principle is used in both reaction schemes I and II to prepare the compounds of the formula I, both the dural, uniformly configured ester groups of the compounds IIb. 1.1 as the protonated dimethylaminoethyl ester groups of the compounds IIb. 1.2 can be converted to an ester group OR2, but an indirect but preferred route is illustrated in Reaction Scheme II.

Although it is possible in principle, starting from compounds IIb. 1.2 or better of compounds XI to produce end products I directly by reaction, it is preferred (via compound XI) to allow a more electron-attracting group to be formed by quaternization (compounds XII), which makes a second salt crystallization and purification possible.

Like the compounds IIb. 1.2, the type XII can be converted directly into compounds of the formula I by transesterification. However, it is possible to hydrolyze the ester group and the free 3-carboxylic acid compounds (compounds XIII) either directly or via the 3-azolide compounds IIb. 1.3 to convert into the final products I.

The reactions can be carried out in a known manner and make it possible to obtain the compounds I in good yield and degree of purity.

The invention is illustrated by the following exemplary embodiments, which likewise describe the compounds in reaction schemes I and II.

example 1

4- (2, l, 3-benzoxadiazoI-4-yl) -l, 4-dihydro-5-methoxy-carbonyl-1,2,6-trimethyl-3-pyridinecarboxylic acid isopropyl ester [I, racemate, process step a)]

A solution of 2.5 g of isopropyl 4- (2, 1,3-benzoxadiozol-4-yl) -1,4-dihydro-5-methoxycarbonyl-2,6-dimethyl-3-pyridinecarbonate in 40 ml of dimethyl sulfoxide 1.5 g of solid, powdered potassium hydroxide and 0.84 ml of methyl iodide are added under nitrogen and the mixture is stirred at room temperature. After 1/2 hour the mixture is poured onto ice water, extracted with methylene chloride, the methylene chloride solution is dried with magnesium sulfate and evaporated in vacuo . The product is purified by chromatography on silica gel while eluting with methylene chloride and crystallized from ester petroleum ether. Mp 125 °.

Example 2

(-) - (S) - and (+) - (R) -4- (2, l, 3-benzoxadiazol-4-yl) -1,4-dihydro-5-methoxycarbonyl-1,2,6-trimethyl -3-pyridine-carbonic acid isoporpyl ester [I, antipodes]

a) (+) (R) - and (-) - (S) -4- (2,1,3-Benzoxadiazol-4-yl) - 1,4-dihydro-5-isopropoxycarbonyl-2,6-dimethyl- 3-pyridincarboxylic acid- (2- (R) -methoxy-2-phenylethyl) esther [(+) (IIb. 1.1) and (-) (IIb. 1.1)]

1) A solution of 10.5 g of 4- (2, l, 3-benzoxadiazol-4-yl) -l, 4-dihydro-5- (1H-imidazol-l-ylcarbonyl) -2,6-dimethyl -3-pyridinecarboxylic acid isopropyl ester (III) in 35.0 g of (-) - (R) -2-methoxy-2-phenylethanol [prepared by W. Kirmse et al., Chem. Ber. 108, 79 (1975)] is 7 hours

5 660 593

120 ° bath temperature heated. The excess optically active alcohol is then distilled off in a high vacuum at an air bath temperature of 80-110 °, the residue is dissolved in methylene chloride, the solution is washed with cold 2N hydrochloric acid 5, dried with magnesium sulfate and evaporated in vacuo.

2) A solution of 3.5 g of 2-acetyl-3- (2,1,3-benzoxadi-azol-4-yl) -2-propenoic acid isopropyl ester (VII) [(Z) or (E) or a mixture of (Z) and (E)] and 3.0 g of 3-aminocro-ionic acid (2- (R) -methoxy-2-phenyl ether) ester (VIII) in 100 ml of dioxane is heated to boiling under reflux for 20 hours and then evaporated in vacuo.

The diastereomer mixture obtained according to 1) or 2) is separated by chromatography over silica gel under 4 atm 15, hexane ether (1.5: 1) being used as the mobile phase.

The first eluted compound is crystallized from ethyl acetate-hexane, mp. 89 °. It shows an optical rotation of [a] 20546 = -92 ° (ethanol).

20 The second eluted compound crystallizes from ether-hexane or methanol-water, mp. 127 ° [ct] 20546 = + 77c (ethanol).

b) (+) - (S) -4- (2, l, 3-benzoxadiazol-4-yl) 1,4-dihydro-5-methoxycarbonyl-2,6-dimethyl-3-pyridinecarboxylic acid isoprop-

25 py les ter [la, antipode, process step b)]

5.3 g (-) - (S) -4- (2, l, 3-benzoxadiazol-4-yl) -1,4-dihydro-5-isopropoxycarbonyl-2,6-dimethyl-3-pyridinecarboxylic acid- (2nd - (R) -methoxy-2-phenylethyl) ester [(-) (IIb. 1.1)] are refluxed in a solution of 0.3 g of sodium in 100 ml of methanol for 50 hours under nitrogen under reflux for 30 hours. The solution is then concentrated in vacuo to half its volume, mixed with 100 ml of ice water and extracted several times with methylene chloride.

The methylene chloride solution is dried with magnesium sulfate 35, evaporated in vacuo and the product is purified by chromatography on silica gel under weak pressure (flash), hexane-ether (1: 4) being used as eluent.

The pure (+) - (4S) -enantiomer [(+) (Ia)] melts after 40 crystallizations from ether-hexane at 142 °.

[œ] 20546 = + 9.9 ° (ethanol, c = 1.5 g / dl)

[a] D20 = + 6.7 ° (ethanol, c = 1.5 g / dl)

c) (~) - (S) -4- (2, l, 3-benzoxadiazol-4-yl) -1,4-dihydro-5-methoxy-carbonyl-1,2,6-trimethyl-3-pyridinecarboxylic acid- iso-

45 propyl ester [I, antipode, process step a)]

A solution of 0.7 g (+) - (4S) -4- (2, l, 3-benzoxadiazole-

4-yl) -l, 4-dihydro-5-methoxycarbonyl-2,6-dimethyl-3-pyri-dincarboxylic acid isopropyl ester, [a] 20546 = + 9.9 ° (ethanol, c = 1.5 g / gl ), in 10 ml of dimethyl sulfoxide with 0.43 g of

50 stem, powdered potassium hydroxide was added and after adding 0.23 ml of methyl iodide stirred under nitrogen for 1 hour. Then the mixture is poured onto ice water, extracted with methylene chloride, the methylene chloride solution is dried with magnesium sulfate and evaporated in vacuo. 55 The product is purified by chromatography under light pressure (flash) over silica gel, eluting with methylene chloride ether (49: 1). The compound melts at 92 ° after crystallization from ether-hexane.

[a] 20546 = -3 ° (ethanol, c = 0.67 g / dl)

60 [a] 20546 = - 25 ° (chloroform, c = 1.0 g / dl)

d) (-) - (R) -4- (2, l, 3-benzoxadiazol-4-yl) -l, 4-dihydro-

5-methoxycarbonyl-2,6-dimethyl-3-pyridinecarboxylic acid isopropyl ester [Ia, antipode, process step b)]

This compound is prepared from the enantiomer (+) - (4R) 65 under a) in a manner similar to that described under b).

The (-) -enantiomer obtained is crystallized from ether-hexane, mp. 140 °.

660 593 6

[a] 20546 = -10.1 ° (ethanol, c = 1.67 g / dl) Then it is evaporated in vacuo, the product in the

[a] D20 = —6.7 ° (ethanol, c = 1.67 g / dl) hydrochloride transferred and this crystallized from ethanol ether

e) (+) - (R) -4- (2, l, 3.Benzoxadiazol-4-yl) -1,4-dihydro-5 installed.

methoxycarbonyl-l, 2,6-trimethyl-3-pyridinecarboxylic acid-iso- b) (-) - (S) -4- (2, l, 3-benzoxadiazol-4-yl) -1,4-dihydro-5-

propyl ester [I, antipode, process step a)] s isopropoxycarbonyl-2,6-dimethyl-3-pyridinecarboxylic acid

This compound is obtained analogously to c) from the (2-dimethylaminoethyl) ester (XI) obtained under d)

tenen (-) - (4R) -enantiomers, mp (from ether- 52.6 g of base a) (IX) and 49.6 g (-) - di-0,0'- p-toluene

Hexane) = 93 ° yl- (L) -tartaric acid are dissolved hot in 200 ml of isopropanol

[a] 20546 = + 3.1 ° (ethanol, c = 0.83 g / dl) and the solution was left to stand. The Di-0,0'-o- forms

[a] 20546 = + 23 ° (chloroform, c = 1.1 g / dl) io toluoyl- (L) - tartaric acid salt (X). After cooling to room

The imidazolide (III) used under a), mp. 166 °, temperato, the crystals formed are filtered off and is prepared twice from 4- (2, l, 3-benzoxadiazol-4-yl) -1,4-dynocl1 recrystallized from isopropanol. The "pro-

hydro-5-isopropoxycarbonyl-2,6-dimethyl-3-pyridine product, the di-0,0'-p-toluoyl- (L) - tartaric acid salt, is in the bonic acid (IV) by reaction with a slight excess high vacuum dried at 90 °, mp. 146 °.

shot l, l'-carbonyldiimidazole in dioxane at 50 °. 15 (ethanol, c = 1 g / dl), [a] 20546 = -156 ° (ethanol, c = 1

The acid (IV), mp. 213 °, is obtained from the g / dl) -

4- (2, l, 3-benzoxadiazol-4-yl) -1,4-dihydro-5-isopropoxycar- By shaking with dilute sodium hydroxide solution and bonyl-2,6-dimethyl-3-pyridinecarboxylic acid- (2-cyanoethyl) - The salt is converted into the title compound in ether. It ester (V), mp 125 °, by hydrolysis with 3 moles of sodium is oily.

hydroxide in water / 1,2-dimethoxyethane (2: 1) at room temperature - 20 MD 0 = - 45 ° (ethanol, c = 1 g / dl), [a] 20546 = - 58 °

temperature. (Ethanol, c = 1 g / dl).

The ester (V), mp. 125 °, is by reaction of c) (-) - (S) -4- (2, l, 3-benzoxadiazol-4-yl) -l, 4-dihydro-5-

Aminocrotonic acid (2-cyanoethyl) ester (VI) with 2-acetyl-3-isopropoxycarbonyl-2,6-dimethyl-3-pyridinecarboxylic acid-

(2,1,3-benzoxadiazol-4-yl) -2-propenoic acid isopropyl ester (2-trimethylaminoethyl) ester iodide (XII)

(VII) made in dioxane. 25 To dissolve 12.4 g of the title compound under b) (XI)

The ester (VI), mp. 88 °, is obtained by adding 2.34 ml of methyl iodide to 120 ml of methanol, and the corresponding acetoacetic acid (2-cyanoethyl) ester in benzene oil is left to stand for 15 hours at room temperature . Then solution is reacted with gaseous ammonia. the crystals formed are filtered off and extracted from methanol

The ester (VII) is recrystallized by condensation of 2,1,3-ben ether. Mp 222 °. [a] D20 = -75 ° (ethanol,

zoxadiazol-4-aldehyde with the corresponding acetoacetic acid 30c = 1 g / dl), [a] 20546 = -99 ° (ethanol = 1 g / dl).

reester in boiling benzene in the presence of catalytic d) (+) - (S) -4- (2, l, 3-benzoxadiazol-4-yl) -l, 4- dihydro-5-

get piperidine and acetic acid. isopropoxycarbonyl-2,6-dimethyl-3-pyridinecarboxylic acid

The ester (VII) crystallizes as a mixture and can be converted into the (XM)

E-isomers, mp. 15 °, and the Z-isomer, mp. 55 °, split- The solution of 15 g of the iodomethylate under c) (XII) in ten. 35 150 ml of dioxane and 300 ml of 2N aqueous sodium hydroxide solution are left to stand at room temperature for 16 hours. Then the solution is stirred and cooled by dropping

Example 3 acidified concentrated hydrochloric acid. After '/ z hours of

(+) - (S) -4- (2, l, 3-Benzoxadiazol-4-yl) -1,4-dihydro-5-methyl stirring in an ice bath, the deposited crystals are

xycarbonyl-2,6-dimethyl-3-pyridinecarboxylic acid isopropyl ester 40 filtered, rinsed with ice water and in a high vacuum at 80 °

[I, process step b)] dried. Mp 168 °. [a] D20 = + 17 ° (ethanol, c = 1 g / dl),

a) 4- (2, l, 3-Benzoxydiazol-4-yl) -1,4-dihydro-5-isopropo- [ct] 20546 = + 27 ° (ethanol, c = 1 g / dl).

xycarbonyl-2,6-dimethyl-3-pyridinecarboxylic acid- (2-dimethyl-e) (-) - (S) -4- (2, l, 3-benzoxadiazol-4-yl) -l, 4-dihydro-5 -

amino-ethyl) ester (IX) (lH-ìmidazol-1-ylcarbonyl) - 2,6-dimethyl-3-pyridinecarbon-

a. 1 5.0 g of 4- (2,1,3-benzoxadiazol-4-yl) -1,4-dihydro-5- 45 isopropyl acid ester (IIb.1.3)

(1H) - imidazol-l-ylcarbonyl) - 2,6-dimethyl-3-pyridinecarbon- A mixture of 8.6 g of the acid under d) (XIII) and acid isopropyl ester (III) in 20 ml of dioxane with 24 , 5 9.75 gl, l'-carbonyldiimidazole in 190 ml of dioxane becomes 2

ml of 2-dimethylaminoethanol heated to boiling for 5 hours. Stirred for hours at 50 ° bath temperature. Then the solution

Then it is shaken with ice water and ethyl acetate, the solution is evaporated in vacuo and the residue is

organic phase dried with magnesium sulfate, chromatographed in a gel of 50 under light pressure. It is evaporated under vacuum and the product is eluted through chromatographic methylene chloride-ethanol (19: 1) and the product is crystallized from silica gel (eluent: methylene chloride ether methylene chloride ether. Mp. 182 °. [A] D20 =

4: 1) cleaned. The hydrochloride of the product is obtained from -50 ° (ethanol, c = 1 g / dl), [a] 20546 = -71 ° (ethanol, c =

Ethanol ether crystallized. Mp 150 °. 1 g / dl).

a.2 182.6 g of 2-acetyl-3- (2, l, 3-benzoxydiazol-4-yl) - 2-pro- 55 In an analogous manner as in Example 1, the following isopropyl pensate (VII) (Z, E -Mixed, crystalline) and compounds prepared by 1-N-alkylation. From-

114.7 g of 3-aminocrotonic acid (2-dimethylaminoethyl) ester products are known or can be heated to boiling in 1 liter of dioxane for 16 hours. Methods are made from known products.

7

660 593

e.g. r1

4th

ch3

5

ch3

6

ch3

7

ch3

8th

ch3

Racemate or

Antipode

15

n-butyl i-butyl cyclopentyl - (CH2) 2-0-i-propyl CH. ^

CH315

CH

CH31}

ch

CH.

CH.

ch.

ch.

CH.

i-propyl i-propyl i-propyl i-propyl i-propyl i-propyl i-propyl

ch.

i-propyl

3)

(ch2) 2-oh2)

O

(ch2) 2-0-c-ch

(ch2) 2-o-ch34)

ch, -c = ch5) 2 6)

ch.

'2J2'

CH

- (^ Î .- ^ ch3

<C "2V'Q

'3 7)

8th)

"(CH) -NC ^ H3 CH

3rd

9)

^ Alkylation with CH, J

21 0.

'Alkylation with Br- (CH2) 2 "0- |'

° o

• HCl

3) auç Hof connection of example R through

4)

5)

6)

Mp 117 ° mp 133 ° mp 143 ° mp 106 ° oil

Oil

Mp 106 ° mp 100 °

Mp 179 ° (as hydrogenfuma-rat)

Mp 162 ° (as hydrogenfuma-rat)

Mp 92 °

K «-, ar

(Methanol, c = 1 g / dl) as HBr-SaU: s "ip. 243e

M? "« •

[a] ^ fi = + 8 °

546

(Methanol, c = 0.6 g / dl]

Mp 92 °

Ca] p ° = -15 °

^ 5 ° 6-'20 °

(/ ethanol,

M 20

c = 1 g / dl ') as HBr sow: Sc

Ca]

D

, 20th

Cal '

546 (methanol, c = 0.6 g / dl)

and ether cleavage with Urnse ^ 'urn nn't acetic anhydride

'Alkylation with J- (CH2) 2 "0-CH3 ^ alkylation with Br-CH2" C = CH

Alkylation with C1- (CII2) 2-N = (CH3), ^ alkylation with Cl- (CH2) ,, - t /

O\

'Alkylation of the compound of example g) »H H (u H

3f according to example 12 2d "

660 593

8th

f) (+) - (S) -4- (2, l, 3-benzoxadiazol-4-yl) -l, 4 isopropyl dihydro-5-methoxycarbonyl-2,6-dimethyl-3-pyridinecarboxylate (I )

The solution of 5 g of the imidazolide under e) (IIb.1.3) in 50 ml of methanol is heated to boiling under reflux for 16 hours, then evaporated in vacuo and the residue is chromatographed on silica gel under gentle pressure, with hexane ether (1: 3) is eluted. The product is crystallized from ether-hexane. Mp 141 °. [a] D20 = + 8 ° (ethanol, c = 1 g / dl), [a] 20546 = + 12 ° (ethanol, c = 1 g / dl).

The compounds according to the invention have pharmacological activity.

The compounds have typical effects for calcium antagonists. They have a pronounced muscle-relaxing effect, especially on smooth muscles, demonstrable through vasodilation and lowering blood pressure in standard tests, e.g. the microsphere method in which anesthetized cats (R. Hof et al., Basic. Res. Car-diol. 75 [1980] 747-756 and 76 [1981] 630-638; R. Hof et al., J. Cardiovasc. Pharmacol. 4 [1982] 352-362), wherein coronary nasodilation is perceived after administration of 5 to about 200 xg / kg iv or from about 5 to about 400 Hg / kg i.d. from 1-N-alkylated compounds of formula I and from about 5 to about 50 (ig / kg iv or from about 10 to about 200 (ig / kg id of compounds I wherein R] = H and a drop in blood pressure is observed after administration from about 5 to about 250 xg / kg iv of 1-N-alkylated compounds and from about 5 to about 50 Hg / kg iv of compounds wherein R3 = H.

A reduction in blood pressure is also perceived in the awake, spontaneously hypertensive rat (method by Gérais M. Tschirki, Arzneimittelforschung 18 [1968] 1285 after administration of about 0.1 to about 50 mg / lg sc of 1-N-alkylated compounds I and of about 0.1 to about 10 mg / kg sc of compounds I, wherein R3 = H.

The compounds are therefore useful as calcium antagonists for the prevention or treatment of

Coronary insufficiency, e.g. Angina pectoris,

Cerebrovascular insufficiency, e.g. cerebrovascular insults, such as stroke, and cerebrovascular spasms,

Peripheral circulatory disorders, e.g. in the

Limbs, like intermittent limping, and cramps, like colic,

Asthma, e.g. asthma and hypertension due to exertion.

5 A reasonable daily dose is from about 5 to about 400 mg of 1-N-alkylated compounds and from about 5 mg to about 200 mg of compounds where R3 = H suitably e.g. orally in partial doses from about 1.25 mg to about 200 mg of the 1-N-alkylated compounds and from about io 1.25 mg to about 100 mg of the compounds, wherein R3 = H administered 2 to 4 times a day or in a delayed release form .

A daily dose is from about 5 to about 200 mg, preferably from about 10 to about 50 mg of compound 15 of Example 2c.

Preferred compounds are those of Examples 2b and 2c.

The compounds of formula I which are 1-N-alkylated, especially the compound of example 2c, have 20 when i.v. administered, an advantageous, slowed increase and a longer duration of action compared to intraduonal administration.

They are equipotent if they i.d.i.v. be administered.

The slow increase and long duration of action make these substances safer than other 1,4-dihydropyridines in i.v. Use.

The connections with S configuration, e.g. the compounds of Examples 2b and 2c have a better pharmacological profile in terms of their activity than the corresponding compounds with R configuration and racemates.

The compounds according to the invention are administered in free form or, if possible and suitable, in pharmaceutically acceptable salt form. Such salt forms have the same activity in magnitude as the free forms and are produced in a known manner.

The invention also relates to pharmaceutical compositions which contain a compound according to the invention, together with a pharmaceutical carrier or diluent. Such compositions can e.g. available as a solution or as a tablet.

C.

Claims (9)

660 593 PATENT CLAIMS 1. Compounds of formula I, R, 00C. Ia where one of Rj and R2 are methyl and the other isopropyl, n-butyl, iso-butyl, cyclopentyl or iso-propoxyethyl and R3 represents hydrogen or an optionally substituted (C, _c) -alkyl, in optically active form when R3 is hydrogen, or in racemic or optically active form when R3 is optionally substituted (Q 6) alkyl, and their acid addition salts. 2. Compounds of formula I according to claim 1, wherein one of R! and R2 is methyl and the other is isopropyl. 3.4- (2, l, 3-benzoxadiazol-4-yl) -l, 4-dihydro-5-metboxy-carbonyl-l, 2,6-trimethyl-3-pyridinecarboxylic acid isopropyl ester and its (-) - (4S) and / or (+) - (4R) form, as a compound of the formula I according to claim 1. 4. 4- (2, l, 3-benzoxadiazol-4-yl) - l, 4-dihydro-5-methoxy-carbonyl-2,6-dimethyl-3-pyridinecarboxylic acid isopropyl ester in (+) - (4S) or (- ) - (4R) form as a compound of formula I according to claim 1. 5. 4- (2, 1,3-benzoxadiazol-4-yl) -1,4-dihydro-5-methoxycarbonyl-1,2,6-trimethyl-3-pyridinecarboxylic acid n-butyl ester, 4- (2nd , l, 3-Benzoxadiazol-4-yl) -l, 4-dihydro-5-methoxycarbonyl-1,2,6-trimethyl-3-pyridinecarboxylic acid isobutyl ester, 4- (2, l, 3-benzoxadiazol-4-yl ) - l, 4-dihydro-5-methoxycarbonyl-l, 2,6-trimethyl-3-pyridinecarboxylic acid cyclopentyl ester and 4- (2, l, 3-benzoxadiazol-4-yl) - l, 4-dihydro-5- methoxy-carbonyl-l, 2,6-trimethyl-3-pyridic acid-2-isopropoxy-ethyl ester, 4- (2, l, 3-benzoxadiazol-4-yl) - l, 4-dihydro-l- (2-hydroxyethyl ) -5-methoxycarbonyl- 2,6-dimethyl-3-pyridine-carboxylic acid isopropyl ester, 1- (2-acetoxyethyl) -4- (2,1,3-benzoxadiazol-4-yl) -1,4-dihydro- 5-methoxycarbonyl-2,6-dimethyl-3-pyridinecarboxylic acid isopropyl ester, 4- (2, l, 3-benzoxadiazol-4-yl) -l, 4-dihydro-5-methoxycarbonyl-l- (2-methoxyethyl) - 2,6-dimethyl-3-pyridinecarboxylic acid iso-propyl ester and 4- (2, l, 3-benzoxadiazol-4-yl) -l, 4-dihydro-5-methoxycarbonyl-2,6-dimethyl-l- (2nd -propinyl) -3-pyridinecarbonic acid isopropyl ester as V Compounds of the formula I according to claim 1. 6. 4- (2, l, 3-benzoxadiazol-4-yl) -l- (2-dimethylamino-ethyl) -l, 4-dihydro-5-methoxycarbonyl-2,6-dimethyl -3-pyridicarboxylic acid isopropyl ester, 4- (2,1,3-benzoxadiazol-4-yl) -1,4-dihydro-5-methoxycarbonyl-2,6-dimethyl-1 - [2- (4-morpholinyl) ethyl] -3-pyridinecarboxylic acid - Isopropyl ester, (+) - (S) -4- (2, l, 3-benzoxadiazol-4-yl) -l- (2-dimethylamino-ethyl) -l, 4-dihydro-5-methoxycarbonyl-2,6 - Isopropyl dimethyl-3-pyridincarboxylate, (-) - (R) -4- (2,1,3-benzoxadiazol-4-yl) -l- (2-dimethylaminoethyl) -l, 4-dihydro -5-methoxycarbonyl-2,6-dimethyl-3-pyridinecarboxylic acid isopropyl ester and its acid addition salts as compounds of the formula I according to claim 1. 7. A process for the preparation of compounds of the formula I according to claim 1, characterized by 1-N-alkylation of a compound of the formula Ia, 10th wherein R] and R2 have the meanings mentioned in claim 1 under formula I and, if the compound of formula I obtained is basic, its isolation as such or as an acid addition salt. 8. A process for the preparation of compounds of the formula I according to claim 1, characterized by replacement of the radical R4 in an optically isomeric form of a compound of the formula II, 20th 25 R ^ OC. 30th II 35 wherein R, and R3 have the meanings mentioned in claim 1 under formula I and R4 is a cleavable group, by an ester radical -OR2, in which R2 has the meaning mentioned in claim 1 under formula I and, if the compound of formula I obtained is basic , their isolation as such or as an acid addition salt. 9. Pharmaceutical composition containing as 4o active ingredient a compound of formula I according to claim 1 and a pharmaceutical carrier or a pharmaceutical diluent. 10. Use of compounds of the formula I according to claim 1 for the preparation of medicaments which are used for 45 treatment of coronary insufficiency, cerebravascular insufficiency, peripheral circulatory disorders, high blood pressure or asthma. 50