CS272723B1 - Oxigen-bridged tetrahydropyridines- parimidines and hexahydropyridines - Google Patents

Abstract

The invention concerns oxygen-bridged tetrahydropyridines, -pyrimidines and hexahydropyridines of formula I, where R represents hydrogen or the cyano group, X represents an atom of nitrogen or carbon, Z represents the alkoxy-carbonyl group with straight or branched alkyl C1 to C4, the group of cyano or acetyl, Y represents an oxygen atom, the group of methyl, amino, cyanoamino dicyanomethylene group or Y and Z together represent the group of formula II, and the method of their production. The compounds of formula I are prepared by the reaction of 4-(2-hydroxyphenyl)-3-butene-2-1 with the active compounds of formula III, where (A) represents the group of amino, dicyanomethylene, cyano, acetyl, methoxycarbonyl or (A) and (B) jointly represent the group of formula and (B) represents the alkoxyl group with straight or branched alkyl C1 to C4, the group of cyanomethyl, acetyl, cyano or trivalent nitrogen N = a0 and D is hydrogen or the amino group, while n is 0 to 2 and with ammonium acetate or ammoniac. Compound I is used as a raw material for medicaments for the circulatory system.

Description

The invention relates to oxygen-bridged tetrahydrapyridines, -pyrimidines and hexahydropyridines and to a process for their preparation. Conformationally enforced compounds for studying the geometric requirements for dihydropyridine receptors have been discovered by the Merch group (D.A. Claremon et al. Synthesis 1986, 144; G.D. Hartman et al. J. Org. Chem., 1985, 50, 2427).

The present invention provides oxygen-bridged tetrahydropyridines, pyrimidines and hexahydropyridines of formula I,

(I) wherein R is hydrogen or cyano, X is nitrogen or carbon, Z is C 1 -C 4 alkoxycarbonyl, cyano, or acetyl, Y is O, methyl, amino, cyanoamino , a dicyanomethylene group or Y and Z represent a common group of formula II

CH, CH,

- C - CH ₂ - C - CH ₂ (II), and the dotted line indicates that the derivative of formula I is saturated or unsaturated, and a process for preparing the same by 4- (2-hydroxyphenyl) -3-butene- 2-one is reacted in an organic solvent with the active compound of formula III, (A) - C (D) _n with CS) (III), wherein (A) is amino, dicyanomethylene, cyano, acetyl, methoxycarbonyl or (A); (8) together represent a group of formula IV,

CH, CH CH _2-C 3 CH ₂ (IV) and (8) represents an alkoxycarbonyl group, a straight or branched alkyl-C ^ group, cyanomethyl, acetyl, cyano, or trivalent nitrogen of the N =, and D is hydrogen or amino, wherein the N is 0 to 2 and with ammonium acetate or ammonia. Or, instead of 4- (2-hydroxyphenyl) -3-buten-2-one, salicylaldehyde and acetone are added to the reaction mixture, and 4- (2-hydroxyphenyl) -3-buten-2-one is formed in situ. Thus, 0.8 to 1.0 molar parts of 4- (2-hydroxyphenyl) JS are reacted

CS 272723 B1 2

-3-buten-2-one with 0.8 to 2.5 molar parts of the compound of formula III and 0.8 to 1.8 molar parts of ammonium acetate or ammonia. The reaction is carried out at 20 to 100 ° C for 1 to 5 hours.

These compounds are used as intermediates in the preparation of medicaments of the circulatory system, resp. to study the geometric requirements of the dihydropyridine-type drug receptors.

The process for the preparation of the compounds according to the invention is carried out by adding to 0.8 to 1 molar part of 4- (2-hydroxyphenyl) -3-buten-2-one in an organic solvent such as ethanol, tetrahydrofuran, dioxane, dimethylformamide 0.8 to 1.8 molar parts of ammonium acetate or ammonia and 0.8 to 2.5 molar parts of the active compound of the formula III are preferably added in an organic solvent. The mixing of the two components takes place at a temperature of 20 to 100 ° C, preferably 40 to 80 ° C. It takes 1 to 5 hours to react. The compounds of formula (I) are isolated by distilling off the solvent, preferably under vacuum, and purification by known methods such as e.g. chromatography or crystallization. 4- (2-Hydroxyphenyl) -3-buten-2-one can be prepared directly in the reaction medium by reaction of salicylaldehyde and acetone, followed by the procedure described above. according to the invention there is a one-step preparation of oxygen-bridged tetrahydropyridines, hexahydropyridines and tetrahydropyrimidines. The invention is further described in the examples. These examples further describe the possibilities of preparing the compounds of formula I without limiting the scope of the invention in any way. The structure of the compounds was confirmed by NMR, NMR, mass spectra and elemental analysis.

Example 1

7

Methyl R, 11-dimethyl-8-oxa-10-azatricyclo [7.3.1.0 ^z '] trideca-2,4,6,11-tetraene-12-carboxylate

To a stirred solution of 1.62 g (0.01 mol) of 4- (2-hydroxyphenyl) -3-buten-2-one and 0.85 g (0.011 mol) of ammonium acetate in 10 ml of ethanol was added 1.16 g ( 0.01 mol) of methyl acetoacetate. The reaction mixture was heated to reflux for 3 hours and then concentrated in vacuo. 10 ml of ether and hexane were added to the resulting oily residue. The resulting crystalline residue was filtered off and recrystallized from acetone. 1.2 g of methyl 9, ll-dimethyl-O-oxa-10-tricyclo [7.3.1.O ^{2 '7]} trldeka-2,4,6, ll-tetraene-12-carboxylate with mp 204-206 C.

¹ H-NMR (DMSO-d 6): 1.66 (3H, s, 9-Me), 1.77 and 1.93 (2H, m, AB part of the ABX system), 2.09 (3H, s, 11) -Me), 3.61 (3H, s, 0Me), 4.04 (1H, m, X part of ABX), 6.72 (2H, m, ArH), 6.98 (1H, m, ArH), 7.17 (1H, brs, NH).

Example 2

12-Acetyl-9, ll-dimethyl-8-oxa-10-tricyclo [7.3.1.0 ^{2 '7]} trideca-2,4,6,11-tetraene

Analogously to Example 1 except that pentane-2,4-dione was used, 0.87 g of 12-acetyl-9,11-dimethyl-8-oxa-10-azatricyclo [7.3.1.0 ² ' ⁷ ] was obtained. trideka-2,4,6,11-tetraene with mp

Mp 244-245 ° C.

¹ H-NMR (DMSO-d 6): Z = 1.67 (3H, s, Me), 1.72 (1H, dd), 1.95 (1H, ddd), 2.12 (3H, s, Me) 1.24 (3H, s, Me), 4.24 (1H.dd), 6.71 (2H, m, ArH), 6.97 (1H, ddd, ArH), 7.21 (1H, dd, ArH), 7.70 (1H, brd, NH).

Example 3

9,13,13-Trimethyl-8-oza-10-azatetracyclo [7.7.1.0 ² '7.0] heptadeca-2,4,6,11 (16) -tetraen-15-one

To a solution of 1.62 g (0.01 mol) of 4- (2-hydroxyphenyl) -3-buten-2-one and 0.85 g (0.011 mol) of ammonium acetate in 10 ml of ethanol was added 1.40 g under reflection. (0.01 mol) of dimedone. By operating as in example 1, 1.64 g 9,13,13-trimethyl-8-oxa-10-azatetracyclo [7.7.1.0 ^{2 '7} .θ' ¹¹ '_ heptadecaethyleneoxycetanol 2,4,6, ll (16 -tetraen-15-one, mp 246-247 ° C.

¢,

EN 272 723 BI ¹ H-NMR (DMSO-d₆) (7 ^ = 0.75 (3H, s, Me), 0.97 (3H, s, Me), 1.70 (3H, s, Me), 1.75 (1H, dd), 1.99 (1H.ddd), 1.96 and 2.05 (2H, d), 2.11 and 2.18 (2H, d), 4.12 (1H (dd), 6.67 (1H, dd, ArH), 6.68 (1H.ddd, ArH), 6.84 (1H.ddd, ArH), 7.14 (1H, dd, ArH), 7, 96 (1H, brs, NH).

Example 4

9-Methyl-11-axo-8-oxa-10-azatricyclo [7.3.1.0 ^2,7 ] trideca-2,4,6-thien-12-carbonitrile Analogous to Procedure 3 except that methyl cyaneacetane is obtained 0.7 g of 9-methyl-l-oxo-8-oxa-10-tricyclo [7.3.1.0 ^{2 '7]} trideca-2,4,6-trien-12-carbonitrile, mp 210 ° C.

@ 1 H-NMR (DMSO-d6): .delta. = 1.62 (3H, s, Me), 2.14 and 2.28 (2H, m), 3.50 (1H, m), 4.53 ( 1H, d), 6.82 (1H, m, ArH), 6.96 (1H, m, ArH), 7.26 (2H, m, ArH), 8.97 (1H, brs, NH).

EXAMPLE II 5-amino-9-methyl-8-oxa-10,12-diazatricyclo [7.3.1.0 ^{2 '7]} trideca-2,4,6,11-tetraene

A mixture of 3.24 g (0.02 mol) of 4- (2-hydroxyphenyl) -3-buten-2-one, 1.0 g (0.024 mol) of cyanamide a1, 6 g (0.021 mol) of ammonium acetate in 60 ml of ethanol is stirred at 60 ° C for 2 hours. The solvent was distilled off and the residue triturated with ether, crystallizing 1.4 g of 11-amino-9-methyl-8-oxa-10,12-diazatricyclo (7.3.1.0 ^2,7 ) trideca-2,4,6,11- tettaene with tt 248 to

251 ° C.

¹ H-NMR (DMSO-d 6): Z = 1.72 (3H, s, Me), 2.14 (2H, m), 4.57 (1H, t), 6.82 (1H, m, ArH) ), 6.91 (1H,

m. Ar H), 7.21 (1H, m.ArH), 7.23 (H, m, Ar H), 7.60 (3H, br s, _NH2 and NH).

Example 6

N ^{1 'I'} -cyano-9-methyl-8-oxa-10,12-diazatricyclo [7.3.1.0 ^{2 '7]} trideca-2,4,6,11-tetraene-l-amine

A solution of 1.62 g (0.01 mol) of 4- (2-hydroxyphenyl) -3-buten-2-one, 8.8 g (0.015 mol) of cyanamide in 25 ml of 1,2-dimethoxyethane together with 4 drops of piperidine was added. reflux for 5 hours. The crystals precipitated by standing overnight are aspirated and washed with ether. This gave 0.84 g H ^ -kyano9-methyl-8-oxa-10,12-diazatricyclo [7.3.1.0 ^{2 '7]} trideca-2,4,6,11-tetraene-l-amine mp

Mp 271-273 ° C.

⁷ H-NMR (DMSO-d₆): / = 1.68 (3H, s, Me), 2.15 (2H, d), 4.50 (H, t), 6.80 (lH, dd); 6.91 (1H, ddd, ArH), 7.22 (2H, m, ArH), 8.58 (1H, brs, NH).

Example 7 11-Amino-9-methyl-8-oxa-10,12-diazatricyclo [7.3.1.0 ^217] trideca-2,4,6,11-tetraene-10-carbonitrile

A solution of 1.62 g (0.01 mol) of 4- (2-hydroxyphenyl) -3-buten-2-one, 0.8 g (0.015 mol) of cyanamide in 30 ml of ethanol together with 4 drops of piperidine was heated at 50-50 ° C. 60 ° C for 5 hours. After distilling off the solvent, the oily residue was dissolved in a mixture of dialkyl ether and acetone. On standing at 0 ° C for 2-3 hours, 0.11 g of 11-amino-2-methyl-8-oxa-10,12-diazatricyclo [7.3.1.0 ^2,7- trideca-2,4,6,11] precipitated. -tetraene-10-carbonitrile, mp 186-188 ° C.

¹ H-NMR (DMSO-d 6): Z = 1.85 (3H, s, Me), 2.11 and 2.20 (2H, m), 4.44 (1H, m), 5.80 (2H , br s, NH);

6.89 - 6.98 (2H, m.ArH), 7.16 - 7.23 (2H, m.ArH).

Example 8 IL-dicyanomethylene-9-methyl-8-oxa-10-tricyclo [7.3.1.0 ^{2 '7]} trideca-2,4,6,11-trien-12-carbonitrile

To a solution of 1.62 g (0.01 mol) of 4- (2-hydroxyphenyl) -3-buten-2-one in 30 ml of ethanol was added

1.32 g (0.01 mol) of dimeric malononitrile and 0.85 g (0.011 mol) of ammonium acetate. The reaction mixture was refluxed for 3 hours and still free of polymeric impurities by filtration. 2.0 g of 11-dicyanomethylene-9-methyl-8-oxa-10-aza-tricyclo crystallized from the filtrate upon cooling. 272723 B1 [7.3.1.0 ^2,7 ] trideca-2,4,6-triene-12-carbonitrile mp above 230 ° C (decomposition).

¹ H-NMR (DMSO-d 6): 1.85 (3H, s, Me), 2.24 and 2.33 (2H, m), 3.72 (1H, m), 4.47 (1H, dd) ), 6.83 (1H, dd, ArH), 6.99 (1H, ddd, ArH), 7.25 (1H, ddd, ArH), 7.53 (1H, dd, ArH), 10.07 ( H, br s, NH).

Example 9

9-Methyl-11-amino-12-cyano-8-oxa-10-azatricyclo [7.3.1.0 ² 'trideca-2,4,6,11-tetraene

A solution of 2.2 g (0.033 mol) of malonodinitrile, 4.0 g (0.033 mol) of salicylaldehyde, 2.7 g (0.04 mol) of ammonium acetate and 1.9 g (0.033 mol) of acetone is refluxed for 1 hour. The recovered precipitate was filtered off. The filtrate was precipitated 0.8 g of 9-methyl-l-amino-12-cyano-8-oxa-10-tricyclo [7.3.1.0 ^{2 '7]} trideca-2,4,6,11-tetraene, mp 273 to 275 ° C.

¹ H-NMR (DMSO-d 6): δ 1.64 (3H, s, Me), 1.94 (1H, m), 1.99 (1H, m), 3.42 (1H, m), δ , 31 (2H, s, _NH2), 6.72 (2H, m, Ar H), 7.03 (2H, m, Ar H), 7.16 (lH, s, NH).

Claims (5)

OBJECT OF THE INVENTION Oxygen bridged tetrahydropyridines, -pyrimidines and hexahydropyridines of formula (I), (I) wherein R is hydrogen or cyano, X is nitrogen or carbon, Z is straight or branched (C až-C alko) alkoxycarbonyl, cyano or acetyl, Y represents oxygen, methyl, amino, cyanoamino, dicyanomethylene or Y and Z together represent a group of formula II, CH, CH, IN - C - CH, - C - CH, - (II), II ^{2 2} o and the dotted line indicates that the derivative of formula I is saturated or unsaturated. 2. A process for the preparation of compounds of the formula I according to claim 1, characterized in that 4- (2-hydroxyphenyl) -3-buten-2-one is reacted in an organic solvent with the active compound of the formula III, (A) C ( D) _n ; (B) (III) wherein (A) is amino, dicyanomethylene, cyano, acetyl, methoxycarbonyl or (A) and (8) together are a group of formula IV, CS 272723 Bl CH, CH, \ / - C - CH _Z - C - CH ₂ (IV), and (B) is an alkoxy group, a straight or branched alkyl C ^ to C ^ group, cyanomethyl, acetyl, cyano, or trivalent nitrogen of the N =, and D is hydrogen or an amino wherein n is 0 to 2 with ammonium acetate or ammonia. 3. The process of claim 2 wherein salicylaldehyde and acetone and 4- (2-hydroxyphenyl) -3-butene-2 are added to the reaction mixture instead of 4- (2-hydroxymethyl) -3-buten-2-one. -on arises in situ. 4. A process according to claim 2, wherein 0.8 to 1.0 molar parts of 4- (2-hydroxyphenyl) -3-buten-2-one are reacted with 0.8 to 2.5 molar parts. and 0.8 to 1.8 molar parts of ammonium acetate or ammonia. 5. Process according to claim 2, characterized in that the reaction is carried out at a temperature of 20 to 100 ° C for 1 to 5 hours.