FI64938B - PROCEDURE FOR THE FRAMEWORK OF THERAPEUTIC THERAPEUTIC BENSOX A- AND OX BENZOTIADIAZOLYL-1,4-DIHYDROPYRID DERIVATIVES - Google Patents

Description

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Jgag | L] (11> uTLÄGGNI NGSSKAIFT 6 4 938 ^ "(51) Kv.ik.3 / im.CL3 C 07 D 417/04, 413/04 FINLAND I — FINLAND (21) PtMflUlhakamus - Patanauueknlng 701867 (22) H« k * m) «cloud — Ameknlnpdag 12.06.78 '* (23) Primary cloud — Glltlghttsdtg 12.06.78 (41) Become public - Bllvlt offentllg 21.12.78

Patent and register held · ............., ,,., _. (441 Date of Nihtivikslpunon I · kuulululaun— οί in Οο

Patent- och regittentyrelaen '7 Aieekan utla «d och utl.tkriftM pubiicmd 01: 5 (32) (33) (31) Requested # tuofk * u« —Begird prlorltec 20.06.77 l6.03.78 Switzerland-Switzerland (CH) 7520 / 77, 2865/78 (71) Sandoz AG, Basel, Switzerland-Switzerland (CH) (72) Peter Neumann, Bern, Switzerland-Switzerland (CH) (71 *) Oy Kolster Ab C53 *) Method for the development of new therapeutically useful benzox and The present invention relates to benzoxadiazolyl-1,1'-dihydropyridine derivatives.

The present invention relates to a process for the preparation of new therapeutically useful benzoxa- and benzothiadiazolyl-1,4-dihydropyridine derivatives of the formula> γ \

R, 0C / COR, I

R 1, wherein R 1 is hydrogen or C 1-8 alkyl, R 2 and R 5 are independently C 64938 alkyl, and are independently C 1-6 alkyl or C 1-6 alkoxy, R 1 is hydrogen, halogen or C 1-6 alkyl; alkoxy, and X is oxygen or sulfur.

Of the alkyl groups having 1 to 6 carbon atoms, alkyl groups having 1 to 4 carbon atoms and especially 1 to 4 carbon atoms are preferable. Of the alkoxy groups having 1 to 4 carbon atoms, groups having 1 to 2 carbon atoms are preferable. Halogen means fluorine, chlorine or bromine and especially chlorine. When R 1 and / or R 4 is alkoxy, it is preferably ethoxy or methoxy.

R 1 is preferably hydrogen. R e is suitably the same as R <-, and R 2 and / or R t - is preferably methyl. R 1 and / or R 2 are preferably alkoxy.

Rg is suitably halogen or alkoxy or especially hydrogen. The position of R 1 is preferably adjacent to the dihydropyrine group, which in turn is preferably in the 4-position.

The process according to the invention for the preparation of a compound of formula I is characterized in that the compound of formula II

The compound of formula Rf> HC = O / is reacted with the compounds of formulas III, IV and V by reacting all four components with each other stepwise

III IV V

R.OC-CH, H „C-COR, H_N-R, 4 | 2 21 3 2 1 R5 o \ 2 in which formulas and X have the same meaning as above.

The process can be carried out by reacting all four components with each other or in stages, for example as follows: a) II is reacted with III and then with IV and V 3 64938 / b) li is reacted with III and then IV with the reaction product of III and V (enamine), c) II is reacted with the reaction product of III and V (enamine) and then with IV, or d) II is reacted with the reaction product of III and V (enamine) and then with the reaction product of IV and V (enamine).

Preferably the reaction is carried out according to procedure a), b) or c), most preferably according to procedure a) or b).

a) and b) as a final step in the process, a compound of formula R 1

B

R40c “G VI

% is reacted with an acetoacetic acid ester of the formula H2C-COR3 // \ c r2

and an amine of the formula H 2 N-R 2

or with their reaction product of formula HC-COR-,

Il 3 c / \ HN R ~ I 2 R1

Preferably, the reaction is carried out between compounds of formula VI and formula VII.

The above reaction can be carried out by a conventional method used in the synthesis of dihydropyridines, for example by Hantzsch synthesis.

R 1 is preferably hydrogen.

4,64938

In the above reactions, in certain cases when 1 * 2 * R 1, R 2 and R 2 are not identical, several isomers of the formula I can be obtained. These can be separated by conventional methods, for example by thin layer chromatography.

The above reactions can all be carried out under the same conditions.

The reaction is conveniently carried out in solution. A suitable solvent is water, ethanol, dioxane, dimethylformamide, dimethyl sulfoxide, pyridine or glacial acetic acid. A suitable reaction temperature is 20 to 160 ° C, preferably 60 to 120 ° C.

Unless the preparation of the starting compounds is specifically described, these are known or can be prepared analogously to the preparation of known compounds.

In the following examples, all temperatures are reported in degrees Celsius and are uncorrected.

Example 1 4- (2,1,3-Benzoxadiazol-4-yl) -2,6-dimethyl-1,4-dihydro-pyridine-3,5-dicarboxylic acid diethyl ester 3.2 g of 2,1,3-benzoxadiazole-4 aldehyde, 5.7 g of acetic acid ethyl ester, 2.5 ml of concentrated ammonium hydroxide and 10 ml of ethanol are refluxed for 6 hours. The mixture is then evaporated to dryness and the residue is chromatographed on silica gel with chloroform / ethyl acetate (9: 1) to give the title compound. Crystallized from toluene, it has m.p. 153-155 ° C.

Following the procedure of Example 1 and using the corresponding starting materials, for example a compound of formula II and compounds of formula III and V, and in Examples 12-13 a compound of formula VI and a compound of formula VII, the following compounds of formula I are obtained. In Table y, denotes the position of the dihydropyridine group.

For example, R · ^ R2 R3 R4 Rj Rg X y Sp. ° C

2 H CH3 OC2H5 OC2H5 CH3 h S 4 146-148 3 "" OC (CH3) 3 OC (CH3) 3 "" "" 193-199 4 "" OCH3 OCH3 "7-C1O" 207-211 5 "" " "" HS * 215-216 6 "" OC2H5 OC2H5 "5-OCH3" "201-203 7" "" "7-C1" "I135-155 j repeats ...

Il 5

The table continues ... 64 938

Eg r2 r3 r4 r5 R6 X y Sp. ° C

8! H CH3 OC2H5 ° C2H5 CH3 HS 5 152-153 9 "'" "" "4-C1" "198-200 10:" i "CH3 CH3" H "4 225-228 11 |"' "" "" "O "218-222 12 j" · "" OC2H5 "" "" "186-188 13 1" i "|" "" "" S "146-148

The compounds of formula I have pharmacological activity. In particular, they have a cardiovascular dilating effect, as has been shown in experiments measuring the blood flow to the myocardium of an anesthetized cat by the microsphere method, in which the active compound was administered i.v. or i.d. The compounds of formula I also have a beneficial effect on angina pectoris disease, as has been shown in an experiment in an anesthetized cat upon administration of the active compound.

The compounds of formula I can thus be used for the treatment of heart failure. The daily dose is then about 5 to 100 mg, which is suitably administered in 2 to 4 sub-doses per day in unit doses containing about 1.25 to about 50 mg of active compound, or as a slow-release formulation of the active compound.

In addition, the compounds of formula I have s.c. at doses of 0.1 to 10 mg / kg body weight, the antihypertensive activity as demonstrated by standard experiments, for example the Grollman rat test / see. A. Grollman, Proc. Soc. Exp.t. Biol. and Med. 57, 104 (1944) / ·

The compounds of the formula I can thus be used as antihypertensive drugs. The daily dose is then about 5 to about 1,000 mg, which is suitably administered 2 to 4 times a day in unit doses containing about 1.25 to about 500 mg of active compound, or as a sustained-release pharmaceutical preparation.

Dihydropyridines with a similar structure are known, for example, from DE-A-2 117 571. However, the coronary-dilating and antihypertensive effects of the compounds according to the invention are clearly greater than those of the asymmetric 4-phenyl-1,4-dihydropyridine-carboxylic acid carboxylic acid group disclosed in DE-2 117 571 substituted with N 2 -C 2 or azido or SQN alkyl groups (n = 0-2).

Claims (2)

64938 A process for the preparation of novel therapeutically useful benzoxa- and benzothiadiazolyl-1,4-dihydropyridine derivatives of the formula R 6 R 4 OC 2 COR-, 43 R, N R 1 -, R 1 wherein R 1 is hydrogen or C C 1-6 alkyl, R 6 and R 6 are independently C 1-6 alkyl, R 6 and R 6 are independently C 1-6 alkyl or C 1-6 alkoxy, R 4 is hydrogen, halogen or C 1-6 alkyl; alkoxy and X is oxygen or sulfur, characterized in that the compound of the formula II R6 II HC = O ^ is reacted with the compounds of the formulas III, IV and V by reacting all four components with each other or in stages III IV VR, 0C-CHo HoC -C0Ro H ^ NR. 4 j 2 2 | 3 2 1 JC = 0 C r5 / \ in which the formulas R1 -R1 and X have the same meaning as above. Process according to Claim 1, characterized in that the compound of the formula Li reacting with an acetoacetic acid ester of the formula H 2 -C-COR., wherein R 2 and R 2 are as defined above, and with an amine of the formula H 2 NR 1 v or a reaction product thereof of the formula H 1 -COR 3 , C VII / \ HM R „R1 where R · ^, R2 and have the same meaning as above.