NZ199437A - 4-(2,1,3-benzoxadiazol-4-yl)-2,6-dimethyl-1,4-dihydro-3-methoxycarbonylpyridine-5-carboxylic acid isopropyl ester and pharmaceutical compositions - Google Patents

Description

New Zealand Paient Spedficaiion for Paient Number 1 99437 I ; t ■: Tf'r:d: • • OR fc>b S -P 4 £& k... ... ..aifc ~~1 1 9 9437 a-#1 U!-;&r the provisions of RegC ^ , ■<> i ccd Ynbo " " ;*wion I1)tl'2 — , Dl,,; i4SEP,»?Of.... ; _ . . . '■Specific::1'- i h?.: been ante-date< -V;c /7..JP^c*-fn&'^£ |9 7f rap ^ pj, ^ r-5 &?> Mi$ ki'iI'd & A 'Lrr InrtiaJs ftbl K3>(/4-3S NEW ZEALAND PATENTS ACT, 19S3 Divided from No. 192422 No.: Date: COMPLETE SPECIFICATION fj ^ ~ / Jn h - 0 an 1,4-dihydropyridine derivative, its preparation and pharmaceutical compositions containing it * ^We, SANDOZ LTD., 35 Lichtstrasse, CH-4002 Basle, Switzerland, a Swiss Body Corporate, hereby declare the invention for which X / we pray that a patent may be granted to tttfe/us, and the method by which it is to be performed, to be particularly described in and by the following statement:- - 1 - - (followed by la) AN 1,4-DIHYDROPYRIDINE DERIVATIVE, ITS PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING IT The present invention provides 4-(2,1,3-benz-oxadiazolyl-4)-2,6-dimethyl-l,4-dihydro-3-methoxy-carbonyl-pyridine-5-carboxylie acid isopropyl ester of formula I, H3COOC COOCH(CH3)2 A J P The compound of formula I falls under the scope of copending New Zealand Patent Specification No. 187,617, but is Per.^f/^5. not specifically disclosed therein. It has now been 10 found that the compound of formula I has particularly valuable pharmacological properties, e.g. a long duration of action and its coronary and cerebral activities are particularly potent. Its calcium antagonistic activity i n r»~ i ^ . V. * : y V - 2 - -500 549g/ii J. P. & S. posseise-i >n y is particxiLarly potent.It also pgsgogoo a good tolerability.

The present invention also provides a process for the production of the compound of formula I, comprising replacing the moiety -HC=Y in a compound 5 of formula II, ii hc=y wherein -HC=Y is i) formyl, ii) a radical of formula -CH=C-C(=Z)CH.

I COOCHj or ^ COOCH(CH0)- I 3 2 HC-C l=Z) CH-, / 3 iii) a radical of formula -HC HC-C(=Z')CH3 cooch3 wherein Z and Z' are independently oxygen or NH, by a moiety of formula iii, h3cooc^^ cooch(ch3)2 III The process may be effected in conventional manner for analogous dihydropyridine syntheses, e.g. according to Hantzsch. When the moiety -HC=Y is formyl it is possible to react such a compound of for-5 mula II with the compound of formula IV ch3-co-ch2-cooch (c1i3) 2 iv and the compound of formula VII, ch3-c(nh2)=ch-cooch3 vii A compound of formula II, wherein -hc=y is a radical ii) or iii), may be formed as an intermediate in the above reactions. It may however be produced 10 by different processes.

Alternatively it is convenient to react a compound of formula II, wherein the moiety -HC=Y is a radical ii) with the compound of formula IV or VI, ch3-c(nh2)=ch-cooch(ch3)2 vi and where appropriate, with ammonia. A compound of 15 formula II, wherein the moiety -HC=Y is a radical iii) may be an intermediate. ■f C' C- 'A "7 r! V " . • ' "? J' ' - - 4 - 500 54D6- r -i' In the above reactions it is possible in certain instances that a mixture of dihydropyridines may be formed. If so these may be separated in conventional manner, e.g. by column or thin layer chro-5 matography.

When the starting material is a compound of formula II, wherein -HC=Y is a radical iii), the reaction is a ring cyclisation. When Z and Z' are both oxygen,then ammonia should be present. 10 However, all the above reactions may be effec ted under the same conditions.

The reaction may be effected conveniently in solution. A suitable solvent is water, ethanol, dio-xane, dimethyl formamide, dimethyl sulphoxide, pyri-15 dine or glacial acetic acid. Suitable reaction temperatures may be from 20 to 160°, preferably from 60 to 120°C.

Insofar as the production of starting materials is not particularly described these compounds are known 20 or may be produced in analogous manner to known compounds .

In the following Example the temperatures given are in degrees Centigrade and are uncorrected. 3 7 - 5 - -500 54DG/II Example: 4-(2,1,3-Benzoxadiazol-4-vl)-2,6-dimethyl-1, 4-dihydro-3-methoxv carbony ^pyridines'carboxy lie acid isopropyl ester 3 g of 2,l,3-benzoxadiazole-4-aldehyde, 2.9 g 5 of acetoacetic acid isopropyl ester, 2.3 g |3-amino-crotonic acid methyl ester and 10 ml of ethanol are stirred under reflux for 3 hours. The mixture is subsequently evaporated and the residue is chromatogra-phed on silica gel with chloroform/acetic acid ethyl 10 ester (8:1) to yield the title compound. The product is recrystallisea from cyclohexane and diisopropyl ether, m.p. 131-153°. The product may be purified in conventional manner, e.g. crystallisation or chromatography. M.p. 168-170°. n-z. patent off ice 1 7 FEBI982 RECEIVED O o n ~t - 6 - 500-54DG/II The compound of formula I exhibits pharmacological activity. In particular, the compound leads to a dilation of coronary vessels as demonstrated by the results of tests measuring the blood flow to the myo-5 cardium of an anaesthetised cat by means of the microsphere method (Rudolph A.M. and Heymann M.S.: Circulation Research 21, 163, 1967) upon administration of from 30 to 50 jig/kg i.v. or of from 50 to 150 pg/kg i.d. of the compound.

The compound of formula I also possesses a fa vourable effect against angina pectoris, as shown by the increase of the coronary flow of an anaesthetised cat upon administration of the compound.

The compound of formula I is therefore indi-15 cated for use in the treatment of coronary insufficiency.

The compound of formula I increases the blood flow to limbs, e.g. leg musculature, as can be shown by means of the microsphere method on the anaestheti-20 sed cat upon administration of from 30 to 50 pg/kg i.v. or from 50 to 150 pg/kg i.d. of the compound.

The compound of formula I is therefore indicated for use in the treatment of intermittent claudication and other peripheral disturbances of blood 25 flow to limb muscle.

Claims (5)

1 C/. a -T * :> -;*.! - vt-' - 7 - The compound of formula I increases cerebral blood flow, as can be shown by means of the microsphere method on the anaesthetised cat upon administration of from 30 to 50 pg/kg i.v. or from 50 to 5 150 \ig/kg i.d. of the compound. The compound of formula I is therefore indicated for use in the treatment of cerebrovascular insults . The compound of formula I possesses calcium-10 antagonistic activity as indicated in standard tests, for example by an inhibition of a calcium induced contraction of isolated dog coronary arteries suspended in a depolarizing solution at concentration of 10 ^ — 8 to 10 M of the compound according to the princi-15 pies of Godfraind and Kaba, Brit, J. Pharm. 3_6, 549-560, 1969. The compound of formula I is therefore indicated for use as spasmolytic agent for the treatment of spasms of muscles. For the above indications an in-20 dicated daily dose is from about 5 to 40 mg, conveniently administered in divided doses 2 to 4 times a day in unit dosage form containing from about 2.5 mg to about 10 mg, or in sustained release form. Additionally, the compound of formula I ex-25 hibits antihypertensive activity, as indicated in stan- 1994 - 9 - £00 S49G/II- » ' i \ , fj. v . -ii . , i. A process for the production of the compound of formula I, which comprises replacing the moiety -HC-Y in a compound of formula II, wherein -HC=Y is i) ii) II HC=Y forinyl, a radical of formula -HC=C-C (=Z)C'H. i COOCH_ - 8 - f}. /•. -y ■' - W / dard tests, e.g. in the Grollman rat test [see A. Grollman, Proc. Soc. Expt. Biol, and Ned. _57, 104 (1944)] on s.c. administration of from 0.1 to 10 mg/kg animal body weight of the compound. 5 The compound of formula I is therefore fur ther indicated for use as an antihypertensive agent. For this use an indicated daily dose is from about 5 to about 40 mg# conveniently given in divided doses 2 to 4 times a day in unit dosage form containing 10 about 2.5 mg to about io or in sustained release form. The compound of formula I may be administered in the form of a pharmaceutical composition. The present invention accordingly provides a pharmaceutical 15 composition comprising the compound of formula I in association with a pharmaceutical carrier or diluent. Such compositions may be formulated by conventional techniques to be in conventional forms, for example capsules or tablets. 20 The coronary insufficiency, the intermittent claudication, the cerebrovascular insufficiency and the spasmolytic activities are the p>. -Torred indications for the compound of formula I. Q O A ~Z - " ^ vJ / - 10 - «500-54»6/£J- or COOCK(CK )_ I 3 2 hc-c(=z)ck ~ / ^ iii) a radical of formula -HC nshc-c(=z,)ch3 cooch3 wherein z and z1 are independently oxygen or NH, by a moiety of formula III , h3cooc cooch(ch3)2 III

2. A process for the production of the compound of formula I, as stated in claim 1 substantially as hereinbefore described with reference to the Example^. 10

3. The compound of formula I, whenever produced by a process according to claim 1 or 2.

4. 4-(2,1,3-Benzoxadiazol-4-yl)-2,6-dimethyl-1#4-dihydro-3-methoxycarbonyl-pyridine-5-carboxylic acid isopropyl ester.

5. A pharmaceutical composition comprising the compound of claim 3 or 4 in association with a pharmaceutical carrier or diluent. DAV OF 19^2 K !. P.T, iC & SO.N f. // S- 111 AGENTS foh THE applicants