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(11) | EP 0 000 150 A1 |
| (12) | EUROPEAN PATENT APPLICATION |
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| (54) | Dihydropyridine derivatives, process for their production and pharmaceutical compositions containing them. |
| (57) Compounds of formula I,
wherein R, is hydrogen, alkyl of 1 to 6 carbon atoms, alkenyl or alkinyl of 3 to 6 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, cycloalkylalkyl of 4 to 8 carbon atoms, phenylalkyl of 7 to 9 carbon atoms or phenylalkenyl of 9 to 12 carbon atoms, the phenyl ring being unsubstituted or mono-, di- or trisubstituted independently by halogen, hydroxy or alkyl or alkoxy of 1 to 4 carbon atoms, R2 and Rs, independently, are hydrogen or alkyl of 1 to 6 carbon atoms, R3 and R4, independently, are alkyl of 1 to 6 carbon atoms, alkenyl or alkinyl of 3 to 6 carbon atoms, cycloalkyl of to 7 carbon atoms, cycloalkylalkyl of 4 to 8 carbon atoms, alkoxy of 1 to 6 carbon atoms, hydroxyalkoxy of 2 to 6 carbon atoms, alkoxyalkoxy of 3 to 6 carbon atoms, hydroxyalkoxyalkoxy of 4 ro 8 carbon atoms, alkenyloxy or alkinyloxy of 3 to 6 carbon atoms, cycloalkyloxy of 3 to 7 carbon atoms or cycloalkylalkoxy of 4 to 8 carbon atoms, R6 is hydrogen, halogen, alkyl or alkoxy or alkylthio or alkylsulfonyl, each of 1 to
4 carbon atoms, trifluoromethyl, nitro or hydroxy, and is oxygen or sulphur |
[0002] The present invention provides compounds of formula I,
wherein R1 is hydrogen, alkyl of 1 to 6 carbon atoms, alkenyl or alkinyl of 3 to 6 carbon atoms, cycloalkyl of 3 to 7.carbon atoms,cycloalkylalkyl of 4 to 8 carbon atoms, phenylalkyl of 7 to 9 carbon atoms.or phenylalkenyl of 9 to 12 carbon atoms, the phenyl ring being unsubstituted or mono-, di- or trisubstituted independently by halogen, hydroxy or alkyl or alkoxy of 1 to 4 carbon atoms,
R2 and R5, independently, are hydrogen or alkyl of 1 to 6 carbon atoms,
R3 and R41 independently, are alkyl of 1 to 6 carbon atoms, alkenyl or alkinyl of 3 to 6 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, cycloalkylalkyl of 4 to 8 carbon atoms, alkoxy of 1 to 6 carbon atoms, hydroxyalkoxy of 2 to 6 carbon atoms, alkoxyalkoxy of 3 to 6 carbon atoms, hydroxyalkoxyalkoxy of 4 to 8 carbon atoms, alkenyloxy or alkinyloxy of 3 to 6 carbon atoms, cycloalkyloxy of 3 to 7 carbon atoms or cycloalkylalkoxy of 4 to 8 carbon atoms,
R6 is hydrogen, halogen, alkyl or alkoxy or alkylthio or alkylsulfonyl, each of 1 to 4 carbon atoms, trifluoromethyl, nitro or hydroxy, and X is oxygen or sulphur.
[0003] In any of the above radicals alkyl of 1 to 6 carbon atoms is preferably of 1 to 4 carbon atoms, especially of 1 or 2 carbon atoms.. Any alkyl, alkoxy, alkylthio or alkylsulfonyl radical of 1 to 4 carbon atoms is preferably of 1 or 2 carbon atoms. The alkyl moiety of cycloalkylalkyl or cycloalkylalkoxy is conveniently methyl. Halogen means fluorine, chlorine or bromine and is especially chlorine. Cycloalkyl or the cycloalkyl moiety of cycloalkylalkyl or cycloalkylalkoxy is conveniently cyclopropyl or cyclopentyl or cyclohexyl. The multiple bond of alkenyl, alkinyl alkenyloxy, alkinyloxy or phenylalkenyl is preferably not in the a, position. Alkenyl, alkenyloxy, alkinyl or alkinyloxy preferably has 3 to 5 carbon atoms. Alkenyl or the alkenyl moiety of alkenyloxy is conveniently allyl or 2-methylallyl. Alkinyl or the alkinyl moiety of alkinyloxy is conveniently propinyl. Phenylalkenyl preferably has the trans-configuration and is for example cinnamyl. When R1 is optionally substituted phenylalkyl, the phenyl group is preferably unsubstituted. When the phenyl group is di- or tri-substituted, preferably the substituents are the same. When R3 and/or R4 is alkoxy, this is preferably ethoxy or methoxy. When R3 and/or R4 is alkoxyalkoxy or hydroxyalkoxyalkoxy, preferably the carbon chain between the two ether oxygen atoms is of 2 carbon atoms. The hydroxy group of hydroxyalkoxy or of hydroxyalkoxyalkoxy is preferably not attached to the carbon atom attached to an ether oxygen atom. R1 is preferably hydrogen. R2 is conveniently identical to R5. R2 and/or R5 is preferably methyl. R3 and/or R4 is preferably alkoxy or alkoxyalkoxy, especially n-butyloxyethoxy. R6 is conveniently halogen, alkyl or alkoxy, or especially hydrogen. R6 is conveniently adjacent to the dihydropyridine moiety which in turn is conveniently in the 4-position.
[0004] The present invention also provides a process for the production of a compound of formula I as defined above, comprising replacing the moiety -HC=Y in a compound of formula II,
wherein R6 and X are as defined above, and
-HC=Y is i) formyl,
ii) a radical of formula
or
iii) a radical of formula -
wherein Z and Z' are independently oxygen or NR1, and R1 to R5 are as defined above, by a moiety of formula III,
wherein R1 to R5 are as defined above.
[0005] The process may be effected in conventional manner for analogous dihydropyridine syntheses, e.g. according to Hantzsch. When the moiety -HC=Y is formyl and when it is desired to produce a compound of formula I, wherein R2 is identical to R5 and R3 is identical to R4, it is convenient to react a compound of formula II with a compound of formula IV,
wherein R4 and R5 are as defined above, in the presence of a compound of formula V,
wherein R1 is as defined above.
[0006] Preferably at least 2 moles of a compound of formula IV per mole of a compound of formula II are present. Alternatively a compound of formula II may be reacted with a compound of formula VI,
wherein R1, R4 and R5 are as defined above.
[0007] Preferably at least 2 moles of a compound of formula VI per mole of a compound of formula II are present. Preferably also R1 is hydrogen.
[0008] When the moiety -HC=Y is formyl and preferably when it is desired to produce a compound of formula I wherein R2 is different to R5 and/or R3 is different to R41 it is also possible to react such a compound of formula II with a compound of formula IV and a compound of formula VII,
wherein R2, R1 and R3 are as defined above.
[0009] It will be appreciated that a compound of formula VI may be formed as an intermediate during the reaction of a compound bf formula IV and a compound of formula V. A compound of formula II, wherein -HC=Y is a radical ii) or iii), may be formed as an intermediate in the above reactions. They may however be produced by different processes.
[0010] Alternatively or particularly for the production of a compound of formula I, wherein R2 is different to R5 and/or R3 is different to R41 it is convenient to react a compound of formula.II, wherein the moiety -HC=Y is a radical ii) with a compound of formula IV or VI, and where appropriate, with a compound of formula V. A compound of formula II, wherein the moiety -HC=Y is a radical iii) may be an intermediate.
[0011] In the above reactions it is possible in certain instances when R2, R31 R4 and R5 are not identical that more than one isomer of formula I may be formed. If so these may be separated in conventional manner, e.g. by thin layer chromatography.
[0012] 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 an amine of formula V should be present.
[0014] The reaction may be effected conveniently in solution. A suitable solvent is water, ethanol, dioxane, dimethyl formamide, dimethyl sulphoxide, pyridine or glacial acetic acid. Suitable reaction temperatures may be from 20 to 160° C, preferably from 60 to 120° C.
[0015] Insofar as the production of starting materials is not particularly described these compounds are known or may be produced in analogous manner to known compounds.
[0016] In the following Examples the temperatures given are in degrees Centigrade and are uncorrected.
Example 1: 4-(2,1,3-Berizoxadiazol-4-yl)-2,6-
dimethyl-1,4-dihydro-pyridine-3,5-dicarboxylic acid diethyl ester
[0017] 3.2 g of 2,1,3-benzoxadiazole-4-aldehyde, 5.7 g of acetoacetic acid ethyl ester, 2.5 ml of concentrated ammonia and 10 ml of ethanol are refluxed for 6 hours. The mixture is subsequently evaporated and the residual oil is chromatographed on silica gel with chloroform/ acetic acid ethyl ester (91) to yield the title compound. The product is recrystallised from toluene, m.p. 153-155°.
[0018] By using the process described in Example 1, and corresponding starting compounds, e.g. a compound of formula II, wherein -HC=Y is a radical i) and compounds of formula IV and V, and for Examples 18 and 19 a compound of formula II, wherein -HC=Y is a radical ii), wherein Z is oxygen and a compound of formula VI, the following compounds of formula I may be obtained, wherein y indicates the position of the dihydropyridine moiety:
[0019] The compounds of formula I exhibit pharmacological activity. In particular, they lead to a dilation of the coronary vessels as demonstrated by the results of tests measuring the blood flow to the myocardium of an anaesthetised cat by means of the microsphere method upon administration of the active substance i.v. or i.d. The compounds of formula I also possess a favourable effect against angina pectoris, as shown by the increase of the coronary flow of an anesthetised cat upon administration of the active substance.
[0020] The compounds of formula I are therefore indicated for use in the treatment of coronary insufficiency. For this use an indicated daily dose is from about 5 to 100 mg, conveniently administered in divided doses 2 to 4 times a day in unit dosage form containing from about 1.25 to about 50 mg, or in sustained release form.
[0021] Additionally, the compounds of formula I exhibit antihypertensive activity, as indicated in standard tests, e.g. in the Grollman rat test [see A. Grollman, Proc. Soc. Expt. Biol. and Med. 57, 104 (1944)] on s.c, admini-. stration of from 0.1 to 10 mg/kg animal body weight of the compounds.
[0022] The compounds are therefore further indicated for use as anti-hypertensive agents. For this use an indicated daily dose is from about 5 to about 1000 mg, conveniently given in divided doses 2 to 4 times a day in unit dosage form containing about 1.25 mg to about 500 mg, or in sustained release form.
[0023] The compounds of formula I may be administered in the form of a pharmaceutical composition. The present invention accordingly provides a pharmaceutical composition comprising a compound of formula I in association with a pharmaceutical carrier or diluent. Such compositions may be prepared by conventional techniques to be in conventional forms, for example capsules or tablets.
[0024] The compounds of Examples 1 and 2 are the preferred compounds. The coronary insuffiency utility is the preferred utility.
[0025] In a group of compounds R1 is hydrogen, alkyl, alkenyl, cycloalkyl of 3 to 6 carbon atoms or phenylalkyl; the phenyl ring being unsubstituted or substituted by one,two or three substituents chosen from one or two halogen radicals, one or two alkyl groups of' 1 to 4 carbon atoms, one to three alkoxy groups of 1 to 4 carbon atoms; R3 and R4, independently, are alkyl, alkenyl, cycloalkyl of 3 to 6 carbon atoms, alkoxy, hydroxyalkoxy of 2 to 6 carbon atoms, alkoxyalkoxy of 3.to 6 carbon atoms, hydroxyalkoxyalkoxy of 4 to 8 carbon atoms, alkenyloxy, or cycloalkoxy of 3 to 6 carbon atoms, and R6 is other than alkylsulfonyl.
[0026] Conveniently R1 is hydrogen, R2 and R5 are each alkyl, especially methyl, R3 and R4 are each alkoxy, especially ethoxy, R6 is hydrogen or halogen, especially chlorine, especially in the 4 position, the dihydropyridine moiety is in the 4 or 5 position, and X is S.
[0027] Alternatively conveniently R1 is hydrogen, R2 and R5 are each alkyl, especially methyl, R3 and R4 are each alkyl or alkoxy, especially methyl, ethyl, tert. butyl, methoxy, ethoxy or tert. butyloxy, R6 is hydrogen or halogen, especially chlorine,or alkoxy, especially metthoxy, the dihydropyridine moiety is in the 4 or 5. position and R6 is in the 4, 5 or 7 position.
wherein R1 is hydrogen, alkyl of 1 to 6 carbon atoms, alkenyl or alkinyl of 3 to 6 carbon atoms, cycloalkyl of 3 to 7 carbon atoms,cycloalkylalkyl of 4 to 8 carbon atoms, phenylalkyl of 7 to 9.carbon atoms or phenylalkenyl of 9 to 12 carbon atoms, the phenyl ring being unsubstituted or mono-, di- or trisubstituted independently by halogen, hydroxy or alkyl or alkoxy of 1 to 4 carbon atoms,
R2 and RSO independently, are hydrogen or alkyl of 1 to 6 carbon atoms,
R3 and R4, independently, are alkyl of 1 to 6 carbon atoms, alkenyl or alkinyl of 3 to 6 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, cycloalkylalkyl of 4 to 8 carbon atoms, alkoxy of 1 to 6 carbon atoms, hydroxyalkoxy of 2 to 6 carbon atoms, alkoxyalkoxy of 3 to 6 carbon atoms, hydroxyalkoxyalkoxy of 4 to 8 carbon atoms, alkenyloxy or alkinyloxy of 3 to 6 carbon atoms, cycloalkyloxy of 3 to 7 carbon atoms . or cycloalkylalkoxy of 4 to 8 carbon atoms,
R6 is hydrogen, halogen, alkyl or alkoxy or alkylthio or alkylsulfonyl, each of 1 to 4 carbon atoms, trifluoromethyl, nitro or hydroxy, and
X is oxygen or sulphur,
which comprises replacing the moiety -HC=Y in a compound of formula II,
wherein R6 and X are as defined above, and
-HC=Y is i) formyl,
ii) a radical of formula
or
iii) a radical of formula
wherein Z and Z' are independently oxygen or NR1, and
R1 to R5 are as defined above, by a moiety of formula III,
wherein R1 to R5 are as defined above.