DE3143649A1 - NEW 4 (2,1,3-BENZOXADIAZOL-4-YL) -1,4-DIHYDROPYRIDINE DERIVATIVES, THEIR PRODUCTION AND PHARMACEUTICAL COMPOSITIONS - Google Patents

Description

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New 4- (2,1,3-benzoxadiazol-4-yl) -1,4-dihydropyridine derivatives, their preparation and pharmaceutical Compositions.

The invention relates to 4- (2,1,3-benzoxadiazol-4-y1) -1,4-dihydro-pyridine derivatives, their manufacture and pharmaceutical compositions. The invention relates to compounds of Formula I,

COOR.

NHR.

wherein COOR, and COOR- are the same or different carboxylic acid ester groups and R ^ hydrogen or represents an acyl group.

The invention, particularly compounds ■ the formula I wherein R, and R _{2 are} independently ^{(C l-12) alkyl /} _(C3-6) alkenyl, (C ₃ _ ₆₎ alkynyl, (C _3-7) -

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Cycloalkyl, (C _4-3 ) cycloalkylalkyl, (C _3-12 ) alkoxyalkyl, (C _3-13 ) alkylthioalkyl, (C _3-6 ) hydroxyalkyl, (C _4-8 ) hydroxyalkoxyalkyl, phenyl or (C _7-10 ) Phenylalkyl and
R _{3 is} hydrogen or -CR ₄ , in which R _{4 is} hydrogen,

(C _1-6 ) alkyl, (C _3-6 ) alkenyl, (C _3-5 ) alkynyl, (C _3-7 ) cycloalkyl, (C _4-8 ) cycloalkylalkyl, (C _1-6 ) alkoxy, ( C _3-6 ) alkoxyalkyl, (C _3-6 ) alkylthioalkyl, phenyl or (C _7-10 ) phenylalkyl.

One group of the compounds is especially one of the formula Ia,

Yes

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wherein R, and R ₂ are independently (C ,,) alkyl, (C _3-6) alkenyl, (C ₃ _ ₆₎ alkynyl, (C _3-7) cycloalkyl, (C ₄ _ ₈₎ cycloalkylalkyl, (C _{3 -6} ) alkoxyalkyl, (C _3-6 ) -alkylthioalky1, (C _3-6 ) hydroxyalkyl, (C _4-8 ) hydroxyalkoxyalkyl, phenyl or (C _7-10 ) phenylalkyl and

R- is hydrogen or -C-R, where R. is water * -

substance, (C _1-6 ) alkyl, (C _3-6 ) alkenyl, (C _3-6 ) alkynyl, (C _3-7 ) cycloalkyl, (C _4-8 ) cycloalkylalkyl, (C _3-6 ) alkoxyalkyl, (C _3-6 ) alkylthioalkyl, phenyl or ( ^c ₇ _io ^ ~ phenylalkyl.

In each of the above-mentioned radicals (C. ₁₂ ) alkyl is preferably (C._g) alkyl, and (C _1-6 ) alkyl is preferably ( C._.) Alkyl, especially (C .__) alkyl. An alkoxy or alkylthio radical preferably contains 1 to 4, especially 1 to 2, carbon atoms. The hydroxy, alkoxy or hydroxyalkoxy group of the hydroxyalkyl, alkoxyalkyl or hydroxyalkoxyalkyl radical is preferably connected to the terminal carbon atom. A hydroxyalkyl, alkoxyalkyl or hydroxyalkoxyalkyl radical preferably contains an ethyl or propyl radical which is substituted by hydroxy, alkoxy or hydroxyalkoxy. The alkyl radical of the cycloalkylalkyl is expediently methyl. The cycloalkyl or

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the cycloalkyl radical of the cycloalkylalkyl is conveniently cyclopropyl, cyclopentyl or cyclohexyl. The multiple bond of the alkenyl or alkynyl is preferably not in the α , β position.

Alkenyl or alkynyl preferably has 3 to 5 carbon atoms. Alkenyl is conveniently allyl or 2-methylallyl. Alkynyl is expediently propynyl. R, and R_ are preferably (C ._, ") alkyl, particularly (C, _ ₆₎ alkyl. R_ is preferably hydrogen. R- is preferably (C, _g ) alkyl, especially methyl.

The invention also relates to a process for the preparation of the compounds according to the invention, characterized in that a compound of the formula II,

II

with an amidine of the formula III,

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COOR ₂

HN

is reacted, wherein COOR _f COOR ₂ and R _{3 have} the abovementioned meanings, and if desired, a resulting compound of the formula I, in which R _{3 is} hydrogen, is acylated, whereby a compound of the formula I, in which R _{3 is} acyl, is formed.

The reaction of a compound of the formula II and the compound of the formula III, a ring closure, can be in for the synthesis of analogous dihydropyridines in the usual way, e.g. according to Hantzsch. If R_ in a compound of the formula I is the acyl radical -C-R., In which R. has the meaning mentioned above,

represents, the acyl radical can already be in the compound of the formula III may be present or only be introduced after the ring closure.

An organic solvent such as ethanol can be present. The implementation is expedient between room temperature and reflux temperature of the

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Running solvent. The amidine can be used as Acid addition salts can be added, e.g. as HCl Salt. If desired, the free base can be extracted from the salt with basic agents, e.g. alkali alcoholates, such as sodium ethanolate, are released and in situ are formed. The acylation can be carried out in a known manner in amides analogous to the synthesis will. Suitable acylating agents are, for example, acid anhydrides or acid chlorides. The reaction will expediently carried out in solution, e.g. in an excess of the anhydride. When using an acid chloride chloroform can be used as a solvent and pyridine or triethylamine to bind the strong Acid can be used. Room temperature or a slightly elevated temperature is sufficient as the reaction temperature.

The compounds of the formula I can be isolated and purified by known methods. The connections of the formulas II and III are known or can be prepared, isolated and purified by known methods will.

The compounds of formula II can, for example, by condensing 2, 1, 3-benzoxadiazole-4-carboxaldehyde with condensed with a suitable acetoacetic acid ester

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the. Preferably about equivalent amounts of the reagents are used. The implementation can take place under conditions as are customary for the condensation of an aldehyde with an acetoacetic acid ester, such as e.g. described in Example 1. The compound of formula II can be used as a mixture of Z and E isomers, both of which are suitable for subsequent reaction with a compound of formula III can be used. The mixture can be used without further isolation and purification be converted into the compound of formula I. In the following examples are the temperatures in degrees Celsius; they are not corrected.

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Example 1 ; 2-Αΐηχηο-4 -_ (2 _ζ 1 _ζ 3- ^ βηζοχ3αΪ3ζο1-4- ^ γ1) _ 1, ^ - di

A mixture of 18.4 g of 2, l, 3-benzoxadiazole-4-carboxaldehyde, 15.7 g of ethyl acetoacetate, 0.6 ml Piperidine, 0.7 ml of acetic acid and 400 ml of benzene are heated to boiling on a water separator for 4 hours. The solution is then evaporated in vacuo, the crude product dissolved in chloroform and the solution over 300 g of silica gel filtered and the filtrate in vacuo evaporated.

4.1 g of the 2-acetyl-3- (2,1,3-benzoxadiazol-4-yl) propenoic acid ethyl ester (II R - ethyl) obtained in this way (it is a mixture of the Z and E isomers) and 2.6 g of ethyl amidinoacetate hydrochloride (III-HCl R ² = ethyl) (Lit .: H. Meyer et al., Liebigs Ann. Chem. 1977 , 1895) are dissolved in 20 ml of ethanol and dissolved at 90 ° bath temperature A solution of 0.36 g of sodium in 15 ml of ethanol was added dropwise within 1/2 hour with stirring. Stirring is continued for 15 minutes at the same temperature, then filtered and the filtrate is evaporated in vacuo. The product is crystallized from ether. M.p. 184 °.

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The following compounds are produced analogously to Example 1:

Formula I.

Examples ^R l ^R 2 ^R 3 Sm. P. 2 (CHo) ^ CHCH ^ - CH ₃ - H 17 7 ^ö *
3 C ₂ H ₅ - C ₂ H ₅ - CH ₃ C (= 0) - 188 ° A. CH ₃ - (CH-.) ^ CHCH——
0 2. .2 H 162 ° 5 (CH ₃ ) ₂ CH- CH ₃ - H 180 ° 6th CH ₃ - (CH ₃ ) ₂ CH- H 188 °

Can also be obtained by subsequent acetylation of the compound of Example 1 can be prepared in an excess of acetoacetic anhydride overnight and at room temperature.

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The compounds of the formula I have pharmacological properties Effects and therefore can be used as a remedy. In particular, they widen the coronary arteries, what about the increase in blood flow in the coronary arteries and the aorta using the microsphere method [Rudolph A.M and Heymann M.S .: Circulation Research 21, 163-184, (1967) and modified by R.P. Hof, F. Wy ler. ' and G. Stalder, Basic Res. Cardiol., 75, 747-756 (1980] in an anesthetized "open chest" cat after administration of 10 to 350 μg / kg i.v. or from 50 to 500; ag / kg i.d. of the connections are established can.

The compounds of formula I are therefore useful for use in the treatment of coronary insufficiency, particularly angina pectoris. The compounds of the formula I further increase the blood flow to the limbs, for example the leg muscles, which is achieved by means of the microsphere method in the above-mentioned anesthetized "open chest" cat after administration of about 10 to about 350 jag / kg iv. or from about 50 to about 500 µg / kg id.

The compounds are therefore for use in intermittent limping and other peripheral circulatory disorders

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Disorders of the leg muscles useful. The compounds of formula I increase blood circulation of the brain by the microsphere method in the above-mentioned anesthetized cat after administration from about 10 to about 350 jug / kg i.v. or from about 50 to about 500 mg / kg i.d. of connections can be determined.

The compounds of formula I are therefore useful in the treatment of cerebrovascular accidents. The daily dose for all of the above indications is between about 15 to about 300 mg, and will conveniently administered 2 to 4 times a day in partial amounts or in delayed release form. Dosage forms, which are suitable for oral administration contain from about 4 mg to about 150 mg of the compounds and are mixed with a solid or liquid pharmaceutical carrier or diluent.

The compounds of the formula I have calcium antagonistic activity, which has been demonstrated in standard tests can be, e.g. by inhibiting a calcium-induced contraction of isolated coronary vessels of a dog, which are suspended in a depolarizing solution, which the compounds according to the invention in Contains concentrations of 10 ~ to 10 "M (method

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by Godfraind and Kaba, Brit. J. Pharm. _36_, 549-560, 1969). The compounds are therefore useful as antispasmodics for the treatment of smooth muscle spasms useful .. The daily dose is between about 15 and 300, preferably 30 to 300 mg, and is appropriate Administered 2 to 4 times a day in partial amounts or in a delayed release form. Dosage forms, which are suitable for oral administration contain from about 4 mg to about 150 mg of the compounds and are with a solid or liquid pharmaceutical carrier or diluents mixed. The compounds additionally exhibit an antihypertensive one Effect on what can be demonstrated by a hypotensive effect in standard tests, e.g. the compounds show a blood pressure-lowering effect in the test with the Grollmann rat [A. Resentment man, Proc. Soc. Expt. Biol. And Med. _5J7, 104 (1944)] s.c. Administration of about 0.1 to 10 mg / kg or in the anesthetized "open chest" cat after i.v. Administration of about 10 to 350 pg of the compounds per kg of animal body weight. The compounds are therefore useful as antihypertensive agents. The daily dose is between about 30 and about 600, preferably 60 to 600 mg, and is suitably 2 to

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Administered 4 times a day in partial or delayed delivery form. Dosage forms suitable for Oral administration are suitable contain from about 7 to about 300 mg of the compounds and are with a mixed solid or liquid pharmaceutical carriers or diluents. The connections of the Examples 2 and 5 are particularly interesting, especially the compound of Example 5.

Treatment of coronary insufficiency and high Blood pressure are the preferred indications. The compounds of the formula I can be in free base form administered. The invention also relates to pharmaceutical compositions composed of a compound of formula I with a pharmaceutical carrier or diluent. Such compositions can by means of conventional techniques in the usual forms, e.g. capsules or tablets.

Claims (6)

3U3649 Case 100-5507 SANDOZ-PATENT-GMBH 7850 Lörrach Patent claims: 1. Method of making compounds of formula I, CH COOR, NHR. in which COOR. and COOR _{2 are} identical or different carboxylic acid ester groups and R-. Represents hydrogen or an acyl group, characterized in that a compound of the formula II, 100-5507 II with an amidine of the formula III, HN H ₂ C COOR ₂ NHR. Ill is reacted, wherein COOR., COOR and R _{3 have} the abovementioned meanings and, if desired, a resulting compound of the formula I, in which R _{3 is} hydrogen, is acylated, whereby a compound of the formula I, in which R_ is acyl, is formed. 2. Compounds of the formula I prepared by the process according to claim 1. 3U3649 - 3 - 100-5507 3. Compounds of the formula I, reproduced in claim 1. 4. Compounds according to claim 3, for use as a pharmaceutical. 5.. Compounds according to claim 3 for use in the treatment of coronary insufficiency, cerebrovascular accidents, smooth muscle spasms, or high blood pressure. 6. Pharmaceutical composition, characterized by a compound according to claim 3 and a pharmaceutical carrier or diluent.