CS218028B1 - Substituted 1-/amino-6,7-dimethoxychinazoline-2-yl/-3,4-dehydropiperidins and method of preparation thereof - Google Patents

Abstract

The present invention relates to novel antihypertensive effective substituted 1- (4-amino-6,7-dimethoxyquinazolin-2-yl) -3,4-dehydropiperidines of the general formula I wherein R is phenyl or phenyl substituted at the o-, m-, or p-position with chloro, fluoro, methyl- or tert-butylphosphine, their addition salts, and processes for the preparation thereof, wherein the 2-chloro- d-amino-BY-dimethoxyquinazoline with the corresponding 3,4-dehydropiperidine derivatives.

Description

The present invention relates to substituted 1- (4-amino-6,7-dimethoxyquinazolin-2-yl) -3,4-dehydropiperidines of formula I

(D wherein R is phenyl, 2-, 3- and 4-chlorophenyl-, m- and β-tolyl-, 4-fluorophenyl-, or

4-tert-butylphenyl, their addition salts with pharmaceutically acceptable inorganic or organic acids, and processes for their preparation.

The compounds of formula (I) are novel compounds which exhibit remarkable longer-lasting hypotensive efficacy at oral doses of 1 to 5 mg / kg in pharmacological tests in both DOCA hypertensive rats and normotensive monkeys, and their toxicity is relatively low (LD 50 from 300 to 4000 mg) / kg po in mice). Thus, they are expected to be useful in the treatment of certain forms of hypertensive disease in humans.

The invention also relates to a process for the preparation of compounds of the formula I, which comprises the condensation of the known 2-chloro-4-amift-6,7-dimethoxyquinazoline (U.S. Pat. No. 3,518,136; Chem. Abstr. 71, 91519 / 196.9 l) with a 3,4-dehydropiperidine derivative of the general formula II (II) in which the substituent R has the same meaning as in the formula I. The reaction is carried out in an alkanol having 4 or 5 carbon atoms in the molecule, preferably isoamyl alcohol, 6 h at the boiling point of the reaction mixture. On cooling, the hydrochloride of the product of formula I crystallizes and is isolated by suction. It is purified by crystallization from a lower alkanol such as methanol or aqueous ethanol, or is converted by basification of an aqueous suspension such as aqueous sodium hydroxide. The base of formula (I) is isolated by shaking it into a suitable, water-immiscible solvent such as chloroform and evaporating the solvent. The crude base may be recrystallized from, for example, ethanol and converted into addition salts, preferably hydrochlorides, which are usually crystallized from aqueous ethanol in the form of hydrates by neutralization with inorganic or organic acids in anhydrous or aqueous alkanol.

The substituted 3,4-dehydropiperidines II are predominantly known.

The synthesis of 4-phenyl-3,4-dehydropiperidine is described in C. J. Schmidle and R. C. Mansfield: J. Am. Chem. Soc., 78, 1702 (1956), the preparation of 3,4-dehydropiperidines substituted in the 4-position of ρ-tolyl-, 4-tert-butylphenyl- and

4-chlorophenyl is described in British Pat. No. 881,893 and the preparation of 4 * fluorophenyl 3-chlorophenyl derivatives were published in P. A. Jansen et al., J. Med. Pharm. Chem., 281 (1959).

The novel 4-m-tolyl-3,4-dehydropiperidine can be prepared analogously to the procedure described for the preparation of 4-p-tolyl-3,4-dehydropiperidine in British Pat. No. 881,893. Reaction of m-tolylmagnesium bromide with acetone in absolute ether affords 2-m-tolylpropan-2-ol which is dehydrated with potassium hydrogen sulfate at 200 ° C. The obtained 2-m-tolylpropene purified by distillation under reduced pressure is then converted to 4-m-tolyl-3,4-dehydroplperidine by heating with 37% aqueous formaldehyde and ammonium chloride in methanol to boiling for 20 h, acidifying the reaction mixture with hydrochloric acid. and boiling for 4 hours.

_4-m-tolyl-3! The 4-dehydropiperidine is isolated by basifying the reaction mixture with aqueous sodium hydroxide solution, shaking it into a suitable organic solvent, for example benzene, and distillation.

The new 4- (2-chlorophenyl) -3,4-dehydropiperidine is prepared in another way by reacting 2-chlorophenylmagnesium bromide with 1-ethoxycarbonyl-4-piperidoin (K. Sindelar et al .: Collection Czechoslov. Chem. Commun. 38, 3891). 1973) gave 1-ethoxycarbonyl-4- (2-chlorophenyl) -4-piperidinol which was hydrolyzed by boiling with a solution of potassium hydroxide in ethanol and the resulting 4- (2-chlorophenyl) -4-piperidinyl was dehydrated by heating to the next stage. with 85% phosphoric acid and

4- (2-Chlorophenyl) -3,4-dehydropyridine is isolated by alkalizing the cooled reaction mixture and shaking it into ether.

The details of the process according to the invention and the preparation of the novel intermediates are given in the examples, which, however, are merely illustrative of the possibilities of the invention but are not exhaustive. Example 1

1- (4-Amino-6,7-dimethoxyquinazolin-2-yl) -4-phenyl-3,4-dehydropiperidine

A mixture of 2.4 g of 2-chloro-4-amino-6,7-dimethoxyquinazoline and 1.7 g of 4-phenyl-3,4-dehydropiperidine in 50 ml of isoamyl alcohol is heated to boiling under stirring for 4 hours. of the mixture precipitated 2.9 g (72.5%) of the crude hydrochloride product which crystallized from aqueous ethanol as the hemihydrate and melted with decomposition at 240-242 ° C. In an analogous manner, prepare:

1- (4-amino-6,7-dimethoxyquinazolin-2-yl) -4- (4-fluorophenyl) -3,4-dehydropiperidine,

m.p. 2.32 ° C decomp. (75% ethanol);

1- (4-Amino-6,7-dimethoxyquinazolin-2-yl) -4- (4-chlorophenyl) -3,4-de-dropiperidine, m.p. hydrochloride hydrate 260 ° C with decomposition (75% ethanol),

1- (4-amino-6,7-dimethoxyquinazolin-2-yl) -4- (3-chlorophenyl) -3,4-dehydropiperidine, m.p. hydrochloride hydrate 2.25-233 ° C with decomposition (75% ethanol) )

1- (4-a, mino-6,7-dimethoxyquinazolin-2-yl) -4- (2-chlorophenyl) -3,4-dehydropiperidine, m.p. hydrochloride hydrate 252-253 ° C with decomposition (50%) ethanol)

1- (4-amino-6,7-dimethoxyquinazolin-2-yl) -4-m-tolyl-3,4-dehydropiperidine, hydrochloride hydrate alters the crystal modification at about 195 ° C and melts at 215 to 2.20 ° C with decomposition (85% ethanol)

1- (4-aimino-6,7,7-dimethoxychmazolin-2-yl) -4-p-tolyl-3,4-dehydropiperidine, hydrochloride crystallizes from methanol as a solvate with methanol and melts at 246-248 ° C with decomposition , and

1- (4-Amino-6,7-dimethoxyquinazolin-2-yl) -4- (4-tert-butylphenyl) -3,4-dehydropiperidine, m.p. hydrochloride hydrate 210-220 ° C with decomposition (50%) ethanol).

Example 2

1- (4-Amino-6,7-dimethoxyquinazolin-2-yl) -4-p-tolyl-3,4-dehydropiperidine

A mixture of 4.8 g of 2-chloro-4-amino-6,7-dimethoxyquinazoline and 3.7 g of 4-p-tolyl-3,4-dehydropiperidine in 150 ml of isoamyl alcohol is heated to boiling with stirring for 5 h. cooling, crystallized from the mixture with fine crystalline hydrochloride of the product which was filtered off with suction, suspended in 50 ml of chloroform, and the suspension was stirred with a solution of 2 g of sodium hydroxide in 20 ml of water. The separated chloroform solution was dried over anhydrous potassium carbonate and the chloroform was distilled off under reduced pressure. The residue (5.2 g, 69%) is the crude base of the product. It is converted to the hydrochloride by dissolving in methanol and acidifying the solution by introducing hydrogen chloride. The precipitated hydrochloride crystallizes from methanol as a solvate with the methanol molecule and has mp 246-248 ° C with decomposition.

EXAMPLE 3 3-Ethoxycarbonyl-4- (2-chlorophenyl) -4-piperidinol

To 3.2 g of magnesium in 30 ml of absolute ether was added iodine and about one fifth of the solution

25.2 g of 2-bromohlorobenzene in 170 ml of absolute ether. After initiation of the reaction by discolouration and heating of the mixture, the remainder of the 2-bromo-chlorobenzene solution is added dropwise with stirring so that the mixture slightly refluxes. The mixture is then heated to boiling for about 1 hour until all the magnesium has reacted. While stirring and cooling with cold water, a solution of 18 g of 1-ethoxycarbonyl-4-piperidone in 55 ml of absolute ether is added dropwise to the cooled solution. The mixture was then stirred at room temperature for 30 minutes, cooled with ice and water and quenched with dropwise addition of a solution of 21 g of ammonium chloride in 80 ml of water under stirring and ice-cooling. The ether solution was separated, dried over anhydrous potassium carbonate and the ether was evaporated. 24 g (80.4%) of crude product are obtained which, after recrystallization from 60% ethanol, has a melting point of 156-158 ° C.

Example 1 a d 4

4- (2-Chlorophenyl) -4-piperidinol

A mixture of 24 g of 1-ethoxycarbonyl-4- (2-chlorophenyl) -4-piperidinyl, 25 g of potassium hydroxide and 37 ml of ethanol is heated with stirring in a bath heated to 120 DEG C. for 2 hours. After cooling, 239 ml of water and 150 ml of water are added. ml of chloroform. After thorough mixing, the chloroform solution was separated and the aqueous layer was shaken with 150 ml of chloroform. The combined chloroform solutions were dried over anhydrous potassium carbonate and the chloroform was distilled off. The crude product residue is recrystallized from benzene. 11.6 g (81.8%) of the product with a melting point of 165 DEG-167 DEG C. are obtained.

Example 1 a d 5

4- (2-chlorophenyl) -3,4-dehydropiperidine

A mixture of 5.8 g of 4- (2-chlorophenyl) -4-piperidinol and 30 ml of 85% phosphoric acid was heated to 135 ° C with stirring for 45 minutes. After cooling, the mixture was diluted with 100 ml of water and basified with aqueous sodium hydroxide solution. The resulting oily product was shaken into ether. The ether solution was dried with anhydrous potassium carbonate. Acidification with a solution of hydrogen chloride in ether gives the hydrochloride. (5.2 g, 82.4%), mp 212-315 ° C (acetone-ether). The base is liberated from the hydrochloride by alkalization of the aqueous solution with sodium hydroxide, shaking into ether and evaporation.

Example 6

2- m-tolylpropene

To 11.8 g of magnesium in 50 ml of absolute ether was added a grain of iodine and a portion of the solution of 83 g

Of 3-bromotoluene in 10 ml of absolute ether. After the reaction has started to decolorize and heat the solution, the remainder of the 3-bromotoluene solution is added dropwise with stirring. The reaction mixture was then stirred and heated to boiling until virtually all of the magnesium had reacted. The solution was cooled and 28.2 g of dry acetone was added dropwise while cooling with water. The reaction mixture is left at room temperature for 16 hours and quenched by the dropwise addition of 600 ml of 10% hydrochloric acid under stirring and cooling with water and ice. The ether solution was separated, and the aqueous layer was shaken with ether. The combined ethereal solutions were shaken with 5% aqueous sodium hydroxide solution, dried over anhydrous potassium carbonate and the ether was evaporated. 83 g of crude 2-m-tolyl-2-proipanol are obtained, which is added dropwise to 5 g of potassium hydrogen sulphate heated in a bath at 20 ° C. At this temperature, the mixture of reaction water and product distilled off. The distillate was diluted with ether, dried over anhydrous sodium sulfate and the ether was evaporated. The residue is crude 2-m-tolylpropane which is purified by distillation under reduced pressure. A fraction between 70 and 85 ° C / 1.3 kPa (37.6 g) was collected.

Example 1 a d 7

4-Isobutyl-3,4-dehydropiperidine

30.7 g of ammonium chloride are dissolved in

107 ml of a 37% aqueous solution of fodmaidehyde, the solution is heated under stirring to ¹ 60 ° C and dropwise dropwise with stirring at this temperature

37.6 g of 2-m-tolylpropene. To the mixture was added 70 mL of methanol, and the reaction mixture was stirred and heated to 40 ° C for 20 h. Methanol was distilled off under reduced pressure and to the remaining solution was added 107 mL of concentrated hydrochloric acid. The mixture was then stirred and heated to 100 ° C for 4 hours. After cooling, it is diluted with water, basified with aqueous sodium hydroxide solution and shaken with benzene. The benzene solution was dried over anhydrous sodium sulfate, the benzene was evaporated, and the crude 4-m-tert-3,4-dehydropiperidine residue was fractionated under reduced pressure. The fraction boiling at 100-110 ° C / 90-133 Pa was collected.

Claims (3)

SUBJECT 1. A substituted l- (4-amino-6,7-dimethoxy-2-y1) -3,4-dehydroepiandrosterone dropiperidiny formula I <· _{| Wherein R is phenyl-, 2-, 3- and 4-chlorophenyl-, m- and p-tolyl-, 4-fluorophenyl- or 4-tert-butylphenyl, and their addition salts with pharmaceutically acceptable inorganic and organic acids. A process for the preparation of substituted 1- (4-amino-6,7-dimethoxyquinazolin-2-yl) -3,4-dehydropiperidines according to water 1 of the general formula I, wherein R is as defined above, characterized in that 2- chloro-4-amino-6,7-dimethoxyquinazoline with a 3,4-dehydropiperidine derivative of formula (II) of the invention wherein R is as defined in formula (I) in a C 4 -C 5 alkanol at the boiling point of the reaction mixture and the hydrochloride of the product of formula I, which is eliminated by cooling the reaction mixture, is either purified by crystallization from anhydrous or aqueous alkanol, preferably ethanol, or is converted by alkalization of an aqueous suspension which is neutralized, if desired, with pharmaceutically acceptable inorganic or organic acids. 3. The process of claim 2 wherein the reaction of 2-chloro-4-amino-6,7-dimethoxyquinazoline with the piperidine derivative of Formula II is carried out in isoamyl alcohol at the boiling point of the reaction mixture for 4 to 5 hours.