GB2122192A

GB2122192A - Dihydropyridines

Info

Publication number: GB2122192A
Application number: GB08316054A
Authority: GB
Inventors: Arnold Vogel
Original assignee: Sandoz AG
Current assignee: Sandoz AG
Priority date: 1982-06-15
Filing date: 1983-06-13
Publication date: 1984-01-11
Also published as: IT8348488A0; DE3320616A1; DK271183A; CH660593A5; ZA834409B; ES8504179A1; SE8303385D0; NL8302067A; PT76870A; FI832072L; PT76870B; AU1575383A; WO1984000033A1; GB8316054D0; PH23436A; CA1208639A; DK271183D0; FR2528431A1; IT1178353B; ES538157A0

Abstract

Compounds having the formula (I) wherein one of the two residues R1 and R2 is the methyl group and the other one is a group selected among isopropyl, n-butyl, isobutyl, cyclopentyl or isopropoxy-ethyl groups and the residue R3 is hydrogen or an optionally substituted alkyl group; these compounds are either in an optically active form when R3 is hydrogen, or in a racemic form or in an optically active form when R3 is an alkyl residue with 1 to 6 atoms of carbon, optionally substituted. Such compounds are used for the treatment of the deficiency of coronaries, cerebro-vascular deficiency, troubles of peripheral circulation, hypertension or asthma.

Description

SPECIFICATION I 4-Dihydropyridine derivatives, in optically active or in racemate form and their production and pharmaceutical compositions The invention relates to novel 1 4-dihydropyridine derivatives in optically active or in racemic form and their production and pharmaceutical compositions.

European Patent No. 1 50 discloses a broad class of 1 4-dihydropyridine derivatives. UK Patent Application 2,037,766A discloses a number of further examples of this class.

We have now found that a particular group of hitherto unknown optically active and racemic 1,4dihydropyridine derivatives, not specifically disclosed therein or suggested thereby have particularly interesting pharmacological profiles.

The present invention provides compounds of formula I

wherein one or R1 and R2 is methyl and the other is isopropyl, n-butyl, iso-butyl, cyclopentyl or isopropoxyethyl and R3 is hydrogen or optionally substituted (C,~6)alkyl, either in optically active form when R3 is hydrogen or in racemic or optically active form when R3 is other than hydrogen, and their acid addition salts hereinafter referred to as compounds of the invention.

The molecules of the compounds of formula I contain in position 4 of the 1 4-dihydropyridine ring a chiral carbon atom, due to the existence of the two different carboxylic acid ester groups COOR1 and COOR2. (C1~6)alkyl is, if substituted, preferably substituted by hydroxy, acetyloxy, methoxy, ethynyl, dimethylamino or morpholino. Preferred compounds are those, in which one of R1 and R2 is methyl and the other is iso-propyl, especially those, in which additionally R3 is (C1~6)alkyl or hydrogen, especially methyl or hydrogen, particularly methyl.

The present invention in another aspect provides a process for the production of a compound of the invention which includes the step of a) 1-N-alkylating a compound of formula la

wherein R1 and R2 are as defined above, b) exchanging the radical R4 in an optical isomer of a compound of formula II

wherein R, and R3 are as defined above, and R4 is a leaving group by a radical OR2 wherein R2 is as defined above, and if the compound of formula I is basic, recovering it as such or in the form of an acid addition salt.

The 1-N-alkylated products of step a) may be prepared in conventional manner, using appropriate alkylating agents, for example an alkyl halide, preferably in the presence of a base e.g. 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 split off after the alkylation.

The 1 -N-alkylated products may be recovered in conventional 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, such as fumaric acid, or with inorganic acids, e.g. hydrohalic acids, such as HCI. The starting compounds in step a) are known or may be prepared by methods known per sue from known compounds. The starting compounds in step a) can be prepared analogously to step b), insofar as they are optically active.

The products of step b) may also be prepared in conventional manner, using for example starting compounds of formula II in which R4, is a leaving group, e.g. OH or an azolide radical. Suitable azolide radicals include the imidazolide radical

It is known that especially the azolide groups, such as

are very reactive and readily exchange their azolyl part, e.g. the 1 H-imidazol-1-yI, for an ester group, e.g.

such of the type OR2, for example by adding an alcohol P2OH and reacting the components at an elevated temperature, e.g. 60-1 500.

Other suitable azolide radicals are e.g. the 1 2,3-triazolide, 1 ,2,4-triazolide, benzotriazolide, benzimidazolide and tetrazolide radicals.

The products of step b) may also be prepared in another conventional manner, by using starting compounds of formula II, wherein R4 is a group OR5 and P5 is a chiral, hydrocarbon radical substantially free from any of its epimeric form and containing one or more electron attracting groups or a hydrocarbon radical containing an amino group.

Preferred electron attracting groups include the phenyl group, the methoxy group or a quaternised amino group. Preferred amino groups are di(C1~4)alkylamino groups. Preferred quaternised amino groups are tri-(C1~4)alkylamino groups. Preferred radicals R5 are ethyl radicals substituted in p-position with the electron attracting groups or with the amino group, like the 2-(P)-CH3O-2-phenyl-ethyl radical or the trimethylammonio-ethyl or the dimethylaminoethyl radical. The carboxylic acid ester group

is, due to the presence of electron attracting groups or of the amino group, easily convertible to a

group for example by reaction with an alcohol P2OH, preferably under basic conditions.The R4 = OH and other compounds of formula II may be reacted similarly. The final products can be isolated and purified by methods known per Se; if desired and possible, in acid addition salt form.

Preferably in the optically active compounds II of step b), R4 is an azolide radical or such a group OR*5, wherein R*5 is a chiral hydrocarbon radical substantially free from any of its epimeric form and containing one or more electron attracting groups.

Representative starting compounds II can be prepared as indicated by the following reaction schemes I and II, illustrating how two optically active forms ||B.1.1 and 11 b.1.2 can be obtained by way of a chromatographic separation or selective crystallisation respectively.

Reaction Scheme 1 for the production of compounds II, wherein R1=isopropyl, R4 = OR@@), R3 = H and R5* = 2-(R)-CH3O-2-phenylethyl

Reaction Scheme II for the production of compounds II wherein R1 = Isopropyl, R4 = 1-H-imidazol-1-yl und R3=H

# # IX X III R*H= Di-O-O'-p-toluoyl-(D)bzw, (L) tartaric acid # Crystallisation (+)-(4R) (-)-(4S) llb. 1.2 # NaOH 3-Dimethylaminoethyl esters (+)-(4R) #CH3# (-)-(4S) XI 3-Trimethylammonioethyl esters (+)-(4R) (-)-(4S) XII #NaOH 3-carboxylic acid compounds (-)-(4R) # (+)-(4S) XIII 3-(1H-lmidazol-1-ylcarbonyl)compounds lib.1.3 (-)-(4R) (1)-(4S) Whereas the optically active compounds 1 b. 1.1 of reaction scheme I are directly prepared by chromatographic separation of the corresponding diastereoisomeric ester mixture, the optically active compounds llb.1.3 of reaction scheme II originate from a diastereoisomeric salt mixture 11 b.1.2, the components of which can be separated by selective crystallisation.

Crystallisation is a more preferred separation method than chromatography, when carried out on an industrial scale.

After the separation the same working principle is applied to the compounds Rib.1 .1 and lob. 1.2 to obtain finally compounds of formula I.

Both, the chiral ester group of the compounds lob.1.1 and the protonated dimethylaminoethyl ester groups of the compounds llb.1.2 may be converted into an ester group OR2, however in reaction scheme II in an indirect way which is a more preferred mode of production.

Although it is in principle possible to produce starting from compounds llb.1.2 or, more preferably from compounds Xl, the final compounds I immediately by transesterification, a more preferred route is to create (via compounds Xl) a stronger electron attracting group by quaternisation (compounds XII), thus making possible a second salt crystallisation and purification.

Like the compounds llb.1.2, those of type XII can be transesterified immediately into compounds of formula I. However, it is possible to hydrolyse the ester group and to convert the 3-carboxylic acid compounds (compounds XIII) either directly or via the 3-azolide compounds llb.1.3. into the final compounds I, reactions which can be carried out in conventional manner and allow the preparation of the compounds of formula I in both a good yield and a very pure state.

The invention is illustrated by the following Examples, which also describe the production of the intermediate compounds indicated in the reaction schemes I and II.

EXAMPLE 1 4-(2, 1 ,3-benzoxadiazol-4-yl)- 1 ,4-dihydro-5-methoxycarbonyl- 1 ,2,6-trimethyl-3-pyridine carboxylic acid isopropylester (I, Racemate process step a)) 1.5 g of solid pulverised potassium hydroxide and 0.84 ml of methyl iodide are added in a nitrogen atmosphere to a solution of 2.5 g of 4-(2,1 ,3-benzoxadiazol-4-yl)-1 ,4-dihydro-5-methoxycarbonyl- 2,6-dimethyl-3-pyridine carboxylic acid isopropylester in 40 ml of dimethyisulphoxide. The mixture is stirred at room temperature. After 1 1/2 hours the mixture is poured into ice water and extracted with methylene chloride. The methylene chloride solution is dried with magnesium sulphate and evaporated in vacuo.

The title compound is purified by chromatography on silica gel, using methylene chloride as an eluant and is crystallised in a mixture of ether and petrolether, M.P. 1250.

EXAMPLE 2 (-)-(S)- and (+)-(R)-4-(2, 1 ,3-benzoxadiazol-4-yI)-1 ,4-dihydro-5-methoxycarbonyl-1 ,2,6-trimethyl-3 pyridine carboxylic acid isopropylester (I, Antipodes).

a) (+)-(R)- and (-)-(S)-4-(2,1 ,3-Benzoxadiazol-4-yI)-1 ,4-dihydro-5-isopropoxycarbonyl-2,6dimethyl-3-pyridine carboxylic acid (2-(R)-methoxy-2-phenylethyl)ester [(+) Ill.1 .1 and (-) llb.1.1].

1. A solution of 10.5 g of 4-(2,1 ,3-benzoxadiazol-4-yI)- 1 ,4-dihydro-5-( 1 H-imidazol-1-ylcarbonyl)- 2,6-dimethyl-3-pyridine carboxylic acid isopropylester (III) in 35.0 g of (R)-2-methoxy-2-phenylethanol [prepared according to W. Kirmse et al., Chem. Ber. 108, 79 (1975)] is heated 7 hours at 1200. The excess of the optically active alcohol is distilled off in high vacuum at 801 10 . The residue is dissolved in methylene chloride and the solution is washed with cold 2N hydrochloric acid, dried and evaporated to dryness in vacuo.

2) A solution of 3.5 g of 2-acetyl-3-(2,1 ,3-benzoxadiazol-4-yI)-2-propenic acid isopropylester (VII) I(Z) or (E) or a mixture of (Z) and (E) isomers] and 3.0 g 3-amino-crotonic acid (2-(R)-methoxy-2phenylethyl)ester (VIII) in 100 ml of dioxane is heated for 20 hours at reflux temperature and evaporated to dryness in vacuo.

The diastereoisomeric mixture obtained obtained according to 1) or 2) is separated by chromatography on silica gel at 5 atm. with hexane-ether (1,5:1 ) as the eluant.

The first compound eluted is crystallised from ethylacetatehexane, M.P. 890, [25045 = 920 (in ethanol).

The second compound eluted is crystailised from ether-hexane or methanol-water. M.P. 1270, [cr]2 6 = +77 (in ethanol).

b) (+)-( S)-4-(2, 1 ,3-benzoxadiazol-4-yl)- 1 ,4-dihydro-5-methoxycarbonyl-2,6-dimethyl-3-pyridine carboxylic acid isopropylester [la, antipode, reaction step b)] 5.3 g (-)-(S)-4-(2, 1 ,3-benzoxadiazol-4-yl)- 1 ,4-dihydro-5-isopropoxycarbonyl-2,6-dimethyl-3- pyridine carboxylic acid-(2-(R)-methoxy-2-phenylethyl)ester [llb.1.1 (-)] in a solution of 0.3 g sodium in 100 ml methanol are heated for 50 hours at reflux temperature under a nitrogen atmosphere. The volume of the solution is reduced 50% in vacuo and 100 ml of ice water are added. The mixture is extracted with methylene chloride. The methylene chloride solution is dried with magnesium sulphate and evaporated in vacuo.The residue is purified by chromatography on silica gel at low pressure (flash).

Hexane-ether (1 :4) is used as an eluant, M.p. of the pure (+)-(4S)-enantiomer [(la)-(+)] after crystallisation from ether hexane: 1420.

[a]6 = +99 (ethanol, c = 1,5 g/cl).

[a]D20= +6,70 (ethanol, c = 1,5 g/dl).

c) (-)-(S)-4-(2,1,3-benzoxadiazol-4-yl)-1,4-dihydro-5-methoxycarbonyl-1,2,6-trimethyl-3 pyridine carboxylic acid isopropylester [I, antipode, reaction step a)] To a solution of 0.7 g (+)-(4S)-(2,1,3-benzoxadiazol-4-yl)-1,4-dihydro-5-methoxycarbonyl-2,6- dimethyl-3-pyridine carboxylic acid isopropylester in 10 ml dimethyl-sulphoxide are added 0.43 g pulverised potassium hydroxide. After addition of 0.23 ml methyl iodide the mixture is stirred 1 hour under nitrogen. Then the mixture is poured into ice water and extracted with methylene chloride. The methylene chloride solution is dried with magnesium sulphate and evaporated in vacuo. The residue is purified by chromatography on silica gel at low pressure (flash). Methylene chloride-ether (49:1) was used as an eluant. The title compound was crystallised from ether-hexane.M.p. 920. []2546 = 30 (ethanol, c = 0,67 g/dl), [α]54620 =25 , (chloroform, c = 1,0 g/dl).

d) (-)-(R)-4-(2,1,3-benzoxadiazol-4-yl)-1,4-dihydro-5-methoxycarbonyl-2,6-dimethyl-3-pyridine carboxylic acid isopropylester [la, antipode, reaction step b)] This compound is prepared from the enantiomer (+)-(4R) under a) in a manner analogous to that described in b). M.p. 1400 (crystallised in ether-hexane). [α]54620 =-10,10 (ethanol, c = 1,67 g/dl).

[o]2O =-6.7 (ethanol, c = 1,67 g/dl).

e) (+)-(R)-4-(2,1,3-benzoxadiazol-4-yl)-1,4-dihydro-5-methoxycarbonyl-1,2,6-trimethyl-3 pyridine carboxylic acid isopropylester [I, antipode, reaction step a)] This compound is prepared from the enantiomer (-)-(4R) under d) in a manner analogous to that described in c). M.p. 930 (crystallised in ether-hexane).

[aC]346 = +3.10 (ethanol, c = 0,83 g/dl). []346 = +230 (chloroform, c = 1,1 g/dl).

The imidazolide (III), used in a)1) has a m.p. 1660 and is prepared from 4-(2,1 ,3-benzoxadiazol-4- yl)-1,4-dihydro-5-isopropoxycarbonyl-2,6-dlmethyl-3-pyridine carboxylic acid (IV), which is reacted with a small excess of 1,1 '-carbonyldiimidazole at 500 in dioxane.

The acid (IV) has a m.p. 2130 and is obtained from 4-(2,1,3-benzoxadiazol-4-yl)-1,4-dihydro-5- isopropoxycarbonyl-2,6-dimethyl-3-pyridine carboxylic acid -(2-cyanoethvl)ester (V) which is hydrolysed at room temperature with 3 mol NaOH in water-1,2-dimethoxyethane (2:1).

The ester (V) m.p. 1250 is prepared by reaction of the aminocrotonic-acid-(2-cyanoethyl)ester (VI) with 2-acetyl-3-(2,1 ,3-benzoxadiazol-4-yI)-2-propenic acid isopropylester (VII) in dioxane.

The ester (VI), m.p. 880, is obtained from the corresponding acetoacetic acid-(2-cyanoethyl)ester by reaction in benzene solution with gaseous ammonia.

The ester (VII) is obtained by condensation of 2,1 ,3-benzoxadiazol-4-aldehyde with the corresponding acetoacetic acid ester in boiling benzene in the presence of catalytic amounts of piperidine and acetic acid.

The ester (VII) crystallises as a mixture and can be separated in the E-isomer, m.p. 750 and the Z isomer, m.p. 55 .

EXAMPLE 3 (+)-(S)-4-(2,1,3-benzoxadiazol-4-yl)-1,4-dihydro-5-methoxycarbonyl-2,6-dimethyl-3-pyridine carboxylic acid isopropylester (I) [I, reaction step b)] a) 4-(2,1,3-benzoxadiazol-4-yl)-1,4-dihydro-5-isopropoxycarbonyl-2,6-dimethyl-3-pyridine carboxylic acid-(2-dimethylaminoethyl)ester (IX) a. 1 5.0 g of 4-(2,1,3-benzoxadiazol-4-yl)-1,4-dihydro-5-(1 H-imidazol-1 -ylcarbonyl)-2,6-dimethyl- 3-pyridine carboxylic acid isopropylester (III) and 24.5 ml of 2-dimethylaminoethanol in 20 ml of dioxane are heated 5 hours to boiling temperature. The mixture is extracted with ice water and ethyl acetate. The organic phase is dried with magnesium sulphate, evaporated to dryness in vacuo and the residue is purified by chromatography on silica gel. Methylenechloride-ether (4:1) is used as an eluant.

The hydrochloride salt of the product is crystallised from ethanol-ether. M.p. 1500.

a.2 182.6 g of 2-acetyl-3-(2,1 ,3-benzoxadiazol-4-yl)-2-propenic acid isopropylester (VII) (Z,E isomer mixture) and 114.7 g of 3-aminocrotonic acid-(2-dimethylaminoethyl)ester in 11 of dioxane are heated 16 hours to boiling temperature. The mixture is evaporated to dryness in vacuo, the residue is converted into the hydrochloride salt and crystallised from ethanol-ether.

b) (-)-(S)-4-(2, 1 ,3-benzoxadiazol-4-yl)- 1 ,4-dihydro-5-isopropoxycarbonyl-2,6-dimethyl-3- pyridine carboxylic acid-(2-dimethyla minoethyl)ester (XI) 52.6 g of the title compound under a) (IX) and 49.6 g of (-)-di-0,0'-p-toluoyl-(L)-tartaric acid dissolved in 200 ml of hot isopropanol and allowed to stand. The di-0,0'-p-toluoyl-(L)-tartaric acid salt (X) is formed. After cooling to room temperature the formed crystals are filtered and recrystallised twice from isopropanol. The product, the di-O,O'-p-toluoyl-(L)-tartaric acid salt, is dried in high vacuum at 900. M.p. 1460, [α]D20 =-122 (ethanol, c = 1 g/dl), [α]54620 =-156 (ethanol, c = 1 g/dl).The salt is converted into the title compound (XI) by addition of diluted sodium hydroxide and is extracted with ether. It is an oily substance. [a]20 = 450 (ethanol, c = 1 g/dl), [a]25046 = 580 (ethanol, c = 1 g/dl).

c) (-)-(S)-4-(2,1,3-benzoxadiazol-4-yl)- 1,4-dihydro-5- isopropoxycarbonyl-2,6-dimethyl-3-pyridine carboxylic acid-(2-trimethylam monioethyl)ester-iodide (XII) 12.4 g of the title compound under b) (Xl) are dissolved in 120 ml of methanol. After adding 2.34 ml of methyl iodide, the solution is allowed to stand 15 hours at room temperature. The formed crystals are filtered and recrystallised from methanol-ether. M.p. 2220, [α]D20 =-75 . (ethanol, c = 1 g/dl) [α]54620=-99 (ethanol, c = 1 g/dl).

d) (+)-(S)-4-(2,1,3-benzoxadiazol-4-yl)-1,4-dihydro-5-isopropoxycarbonyl-2,6-dimethyl-3pyridine carboxylic acid (XIII) A solution of 1 5 g of the iodo methylate under c) (XII) in 150 ml of dioxane and 300 ml 2n aqueous sodium hydroxide is allowed to stand 16 hours at room temperature. While stirring and cooling, the solution is acidified by dropwise addition of concentrated hydrochloric acid. After stirring 30 minutes in an ice bath, the formed crystals are filtered, washed with ice water and dried in high vacuum at 800.

M.p. 168 , [α]D20=+17 (ethanol, c = 1 g/dl), [α]54620 = +270 (ethanol, c = 1 g/dl).

e) (-)-(S)-4-(2,1 ,3-benzoxadiazol-4-yl)-1 ,4-dihydro-5(1 H-imidazol-1 -ylcarbonyl)-2,6-dimethyl-3pyridine carboxylic acid isopropylester (llb.1.3) A mixture of 8.6 g of the acid under d) (XIII) and 9.75 g of 1,1 '-carbonyldiimidazole in 1 90 ml of dioxane are stirred 2 hours at 50 bath temperature. The solution is evaporated to dryness in vacuo and the residue is purified by chromatography on silica gel under slight pressure, using methylene chlorideethanol (19:1) as an eluant. The product is crystallised from methylene chloride-ether.

M.p. 1820, [a]o20 = 50 (ethanol, c = 1 g/dl).

[a]254% = 710 (ethanol, c = 1 g/dl).

f) (+)-(S)-4-(2,1,3-benzoxadiazol-4-yl)-1,4-dihydro-5-methoxycarbonyl-2,6-dimethyl-3-pyridine carboxylic acid isopropylester (I) A solution of 5 g of the imidazole under e) (llb.1.3) in 50 ml of methanol is heated 16 hours at reflux temperature and is evaporated to dryness in vacuo. The residue is purified by chromatography on silica gel under slight pressure, using hexane-ether (1 :3) as the eluant.

The product is crystallised from ether-hexane. M.p. 141 0, [a]020 = +80 (ethanol, c = 1 g/dl), [α]54620=+12 (ethanol, c = 1 g/dl).

In analogous manner as described in Example 1 the following compounds are prepared. The starting compounds are known or may be prepared by methods known per se from known compounds.

Racemate or Ex. R, R2 R3 Antipode 4 CH3 n-butyl CH31) i M.p. 1170 5 CH3 i-butyl CH31) i M.p. 133 6 CH3 Cyclopentyl CH31) i M.p. 1430 7 CH3 (CH2)2{Wi-propyl CH31 ) i M.p. 1060 8 cH3 i-propyl -(CH2)2-OH2 i Oil 0 9 CH3 i-propyl -(CH2)2-C11---CH33 * Oil 10 CH3 i-propy I (CH2)2-o---CH34 i M.p. 1060 11 CH3 i-propyl -CH2-C""'CH5) i M.p. 1000 /Cr 6) 12 CH3 i-propyl (CH2)2N"CHaS) i M.p. 1790 (hydrogentumarate) 13 CH3 i-propyl -(Cli- i M.p. 1620 22 (I1drerl'1umarate) CHa8 14 CH3 i-propyl (CH2)2NsCH + M.p. 920 = + po 150 [al5246 = + 200 (methanol, c=1 g/dl) HBrsalt: M.p. 2430 bath = + 50 [aO = + 80 (methanol, c c = 0/6gdl)

Racemate or Ex. I Rl R2 R3 Antipode cH?) 5 CH3 i-propyl -. - M.p. 920 15 CH3 i-propyl ^ H2)2N -(OH,),--NI = 920 Gal524 6 =-20 v = 200 546 (methanol, c=1 gdl) HBr-salt: M.p. 2430 [a]20 = 50 [a]5246 = 50 (methanol, c c = 0,6 g/dl) 1) alkylation with Ch3l 2) alkylation with

and ether splitting with HCI 3) from the compound of Example 8 by reaction with acetanhydride 4) alkylation with l-(CH2)2-O-OH3 5) alkylation with Br-CH2-C=-CH 6) alkylation with Cl=(CH2)2-N=(CH3)2 7) alkylation with

8) alkylation of the compound of Example 3f according to Example 12 9) alkylation of the compound of Example 2d according to Example 12 The compounds of the invention possess pharmacological activity.

The compounds exhibit effects typical of calcium antagonists. They exhibit a pronounced musclerelaxing effect, particularly on smooth muscle, as indicated by vasodilating and blood pressure lowering activity in standard tests. For example in the anaesthetized cat test using tracer microspheres (R. Hof et al.,BasicRes. Cardiol. 75 [1980] 747-756 and 76 [1981] 630-638; R. Hofetal.,J. Cardiovasc.

Pharmacol. 4 [1982] 352-362) coronary vasodilation is observed upon administration of from about 5 to about 200 yg/kg i.v. or from about 5 to about 400 g/kg i.d. of 1 -N-alkylated compounds of formula I and from about 5 to about 50 yg/kg i.v. or from about 10 to about 200 yg/kg i.d. of compounds in which R3 = H and a fall in blood pressure is observed upon administration of from about 5 to about 250 ,ug/kg i.v. for 1-N-alkylated compounds and from about 5 to about 50 g/kg i.v. for compounds in which P3=H.

A fall in blood pressure is also observed in the conscious spontaneously hypertensive rat (method of Gerold and Tschirki,Arzneimittelforsch. 18 [1968] 1285) upon administration of from about 0.1 to about g/kg s.c. of the 1 -N-alkylated compounds and of about 0.1 to about 10 mg/kg s.c. of the compounds in which R3 = H.

The compounds are therefore indicated for use as calcium antagonists for the prevention and treatment of coronary insufficiency, e.g. Angina pectoris; cerebrovascular insufficiency, such as cerebrovascular insults, e.g. stroke, and cerebrovascular spasms; -disturbances in peripheral circulation e.g. in limbs such as intermittent claudication and spasms, e.g. colic; asthma, e.g. exertion-related asthma; and -hypertension.

An indicated daily dose is from about 5 to about 400 mg for 1 -N-alkylated compounds and from about 5 mg to about 200 mg for compounds in which Ra = H, suitably administered, e.g. orally, in divided dosages of from about 1.25 mg to about 200 mg of the 1 -N-alkyiated compounds and from about 1.25 mg to about 100 mg of the compounds in which R3 = H, two to four times daily, or in retard form. An example of a daily dosage is from about 5 mg to about 200 mg, preferably from about 10 to about 50 mg of the compound of Example 2c.

Preferred are the title compounds of Examples 2b and 2c.

The compound of formula I which are 1-N-alkylated, especially the compound of Example 2c, have, when i.v. administered, an advantageous slow onset and longer duration of activity, compared with intraduodenal administration.

They are approximately equipotent when administered i.d. or i.v.

The slow onset and long duration of the activity render these substances, due to less side effects, safer than other 1 4-dihydro-pyridines for intravenous use.

The compounds with S-configuration, e.g. the compounds of Examples 2b and 2c have, related to their activity a better pharmacological profile than the corresponding R- and the racemic forms.

The compounds of the invention are administered in free form or if possible and appropriate, in pharmaceutically acceptable acid addition salt form. Such salt forms exhibit the same order of activity as the free forms and are readily prepared in conventional manner.

The present invention also provides a pharmaceutical composition comprising a compound of the invention in free form or where possible and appropriate in pharmaceutically acceptable salt form, in association with a pharmaceutical carrier or diluent. Such compositions may be in the form of, for example, a solution or a tablet.

Claims

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

wherein one of R, and R2 is methyl and the other is isopropyl, n-butyl, iso-butyl, cyclopentyl or iso propoxyethyl and R3 is hydrogen or optionally substituted (C1~6)alkyl, either in optically active form when R3 is hydrogen or in racemic or optically active form when R3 is other than hydrogen, and their acid addition salts, which includes the step of a) 1-N-alkylating a compound of formula la

wherein R, and R2 are as defined above or b) exchanging the radical R4 in an optical isomer of a compound of formula II

wherein R, and R3 are as defined above, and R4 is a leaving group, by a radical OR2, wherein R2 is as defined above, and if the compound of formula I is basic, recovering it as such or in the form of an acid addition salt.

2. A process of claim 1, defined in step b), in which the compound of formula II has a substituent R4 which is an azolide radical or a group OR*5 wherein 5 is a chiral, hydrocarbon radical substantially free from any of its epimeric form and containing one or more electron attracting groups.

3. A process of claim 2 in which the compound of formula II R4 = OR*5 and R, is methyl or isopropyl.

4. A process for the production of a compound of formula I or its acid addition salts defined in claim 1 substantially as hereinbefore described with reference to any one of the Examples.

5. A compound of formula I and its addition salts, whenever produced by a process of claim 1.

6. A compound of formula I and its addition salts as defined in claim 1.

7. A compound of claim 6 wherein one of R, and R2 is methyl and the other is isopropyl.

8. A compound of claim 7, wherein R3 is (C,~6)alkyl.

9. A compound of claim 7, wherein R3 is methyl.

1 0. A compound of claim 7, wherein R3 is hydrogen.

11. 4-(2, 1 ,3-benzoxadiazol-4-yl)- 1 ,4-dihydro-5-methoxy-carbonyl-1 ,2,6-trimethyl-3-pyridine carboxylic acid isopropylester.

1 2. (-)-(S)-4-(2, 1 ,3-benzoxadiazol-4-yl)- 1 ,4-dihydro-5-methoxycarbonyl- 1 ,2,6-trimethyl-3 pyridine carboxylic acid isopropylester.

13. (+)-(R)-4-(2,1 ,3-benzoxadiazol-4-yl)- 1 ,4-dihydro-5-methoxycarbonyl- 1 ,2,6-trimethyl-3 pyridine carboxylic acid isopropylester.

14. (+)-(S)-4-(2, 1 ,3-benzoxadiazol-4-yl)- 1 ,4-dihydro-5-methoxycarbonyl-2,6-dimethyl-3-pyridine carboxylic isopropylester.

1 5. (--)-(R)-4-(2,1 ,3-benzoxadiazol-4-yl)- 1 ,4-dihydro-5-methoxycarbonyl-2,6-dimethyl-3-pyridine carboxylic acid isopropylester.

1 6. 4-(2,1 ,3-benzoxadiazol-4-yl)-1 ,4-dihydro-5-methoxycarbonyl-1 ,2,6-trimethyl-3-pyridine carboxylic acid n-butylester.

1 7. 4-(2,1 ,3-benzoxadiazol-4-yl)- 1 ,4-dihydro-5-methoxycarbonyl-1 ,2,6-trimethyl-3-pyridine carboxylic acid isobutylester.

1 8. 4-(2,1 ,3-benzoxadiazol-4-yl)- 1 ,4-dihydro-5-methoxycarbonyl- 1 ,2,6-trimethyl-3-pyridine carboxylic acid cyclopentylester.

19. 4-(2,1 ,3-benzoxadiazol-4-yl)- 1 ,4-dihydro-5-methoxycarbonyl- 1 ,2,6-trimethyl-3-pyridine carboxylic acid-2-isopropoxyethylester.

20. 4-(2, 1 ,3-benzoxadiazol-4-yl)- 1 ,4-dihydro- 1 -(2-hydroxyethyl)-5-methoxycarbonyl-2,6 dimethyl-3-pyridine carboxylic acid isopropylester.

21. 1 -(2-acetoxyethyl)-4-(2, 1 ,3-benzoxadiazol-4-yl)- 1 ,4-dihydro-5-methoxycarbonyl-2,6 dimethyl-3-pyridine carboxylic acid isopropylester.

22. 4-(2, 1 ,3-benzoxadiazoi-4-yl)- 1 ,4-dihydro-5-methoxycarbonyl- 1 -(2-methoxyethyl)-2,6 dimethyl-3-pyridine carboxylic acid isopropylester.

23. 4-(2,1 ,3-benzoxadiazol-4-yl)-1 ,4-dihydro-5-methoxycarbonyl-2,6-dimethyl-1 -(2-propinyl)-3- pyridine carboxylic acid isopropylester.

24. 4-(2,1 ,3-benzoxadiazol-4-yl)-1 -(2-dimethylaminoethyl)-1 ,4-dihydro-5-methoxycarbonyl-2,6 dimethyl-3-pyridine carboxylic acid isopropylester and its acid addition salts.

25. 4-(2,1 ,3-benzoxadiazol-4-yi)- 1 ,4-dihydro-5-methoxycarbonyl-2,6-dimethyl-1 -[2-(4- morpholinyl)ethyl]-3-pyridine carboxylic acid isopropylester and its acid addition salts.

26. (+)-(S)-4-(2, 1 ,3-benzoxadiazol-4-yl)- 1 -(2-dimethylaminoethyl)-1 ,4-dihydro-5-methoxy carbonyl-2,6-dimethyl-3-pyridine carboxylic acid isopropylester and its acid addition salts.

27. (-)-(R)-4-(2, 1 ,3-benzoxadiazol-4-yI)-1 -(2-dimethylaminoethyl)-1 ,4-dihydro-5- methoxycarbonyl-2,6-dimethyl-3-pyridine carboxylic acid isopropylester and its acid addition salts.

28. A compound of formula II, as defined in claim 1.

29. A compound of formula II, as defined in claim 3.

30. (-)-(S)-4-(2 , 1 ,3-benzoxadiazol-4-yl)- 1 ,4-dihydro-5-isopropoxycarbonyl-2,6-dimethyl-3- pyridine carboxylic acid-(2-(R)-methoxy-2-phenylethyl)ester.

31. (+)-(R)-4-(2,1,3-benzoxadiazol-4-yl)-1,4-dihydro-5-isopropoxyCarbonyl-2,6-dimethyl-3- pyridine carboxylic acid-(2-(R)-methoxy-2-phenylethyl)ester.

32. 4-(2,1 ,3-benzoxadiazol-4-yI)-1 1,4-dihydro-5-(1 H-imidazol-1 -ylcarbonyl)-2,6-dimethyl-3pyridine carboxylic acid isopropylester.

33. (-)-(S)-4-(2 1 ,3-benzoxadiazol-4-yl)- 1 ,4-dihydro-5-( 1 H-imidazol- 1 -ylcarbonyl)-2,6-dimethyl3-pyridine carboxylic acid isopropylester.

34. (+)-(R)-4-(2, 1 ,3-benzoxadiazol-4-yl)- 1 ,4-dihydro-5-( 1 H-imidazol- 1 -ylca rbonyl)-2,6-dimethyl3-pyridine carboxylic acid isopropylester.

35. A compound of any one of claims 5 to 27 for use as a pharmaceutical.

36. A compound of any one of claims 5 to 27 for use in the treatment of coronary insufficiency, cerebrovascuiar insufficiency, peripheral circulation disturbances, hypertension or asthma.

37. A pharmaceutical composition, which comprises a compound of any one of claims 5 to 27 in association with a pharmaceutical carrier or diluent.

38. A method of treating coronary insufficiency, cerebrovascular insufficiency, peripheral circulation disturbances, hypertension or asthma, which comprises administering a therapeutically effective amount of a compound of any one of claims 5 to 27 to a subject in need of such treatment.