US3778442A - Heterocyclic amine esters of 2-phenylcyclohexen-3-carboxylic acid - Google Patents

Abstract

THIS INVENTION RELATES TO ALKYLAMINE AND HETEROCYCLIC AMINE ESTERS OF 2-PHENYL-CYCLOHEXEN-3-CARBOXYLIC ACID AS WELL AS PHYSIOLOGICALLY ACCEPTABLE SALTS THEREOF. THESE NEW COMPOUNDS HAVE BEEN FOUND TO HAVE ANTISPASTIC AND ANTIULCER ACTION. THE INVENTION ALSO RELATES TO THE PRODUCTION OF THESE COMPOUNDS.

Description

United States Patent Ofice 3,778,442 HETEROCYCLIC AMINE ESTERS OF Z-PHENYL- CYCLOHEXEN-S-CARBOXYLIC ACID Luigi Turbanti, Via B. da Padule 10, Pisa, Italy No Drawing. Original application Oct. 2, 1968, Ser. No. 766,029, now Patent No. 3,699,109, dated Oct. 17, 1972. Divided and this application June 15, 1972, Ser. No. 262,985

Claims priority, application Italy, Oct. 7, 1967, 21 367/67 U.S. Cl. 260-247.2 B 1 Claim ABSTRACT OF THE DISCLOSURE This invention relates to alkylamine and heterocyclic amine esters of 2-phenyl-cycloheXen-3-carboxylic acid as well as physiologically acceptable salts thereof. These new compounds have been found to have antispastic and antiulcer action. The invention also relates to the production of these compounds.

CROSS REFERENCE TO RELATED APPLICATION This application is a divisional of my copending application Ser. No. 766,029, filed Oct. 2, 1968, now US. Pat. No. 3,699,109 granted on Oct. 17, 1972, for the Tropyl Ester of 2-Phenyl-CycloheXen-3-Carboxylate.

BACKGROUND OF THE INVENTION SUMMARY OF THE INVENTION Generally speaking, the present invention provides compounds of the following general Formula 1:

3,778,442 Patented Dec. 11, 1973 N Am Within the scope of this invention there are also included the salts of these basic esters with inorganic and organic acids (such as hydrochloric, sulphuric, citric,

tartaric, and malonic acids), as well as the quaternization compounds of the above basic esters with inorganic alkyl esters (such as CH I; C H Br;

C,H Br) of the type C H X, wherein C H is a linear or branched aliph'atic chain having from 1 to 10 carbon atoms and X is a chlorine, bromine or iodine atom.

2-phenyl-cyclohexen 3 carboxylic acid (Formula I), wherein R=-H has been obtained by heating 2-phenyl- 2 hydroxy cyclohexen carboxylic acid (Formula II below) in organic solvents, such as carbon tetrachloride, in the presence of catalytic amounts of mineral acids (such as sulphuric acid),,accordi.ng to the scheme:

o 0031 00 on The amino esters have been obtained by the following methods as shown in Scheme I;

(a) by treating the sodium or potassium salt of acid (I) with the corresponding amino-alkyl halide in alcohol medium (such as in isopropanol);

(b) by reacting the chloride of acid (I), being prepared in turn by heating said acid with SOCl or by chlorination with PCl with the desired amino-alcohol or its potassium salt;

(c) by transesterification reaction from ethyl-2-phenylcyclohexen-3-carboxylate with the selected amino-alcohol, in the presence of traces of alkaline ethylates.

0000K oi-a' 000R Oooorv 0000mm HO-R' Et-ONa COOR' wherein R is the same as R excepted where R=-H.

The antispastic activity of the esters has been determined on segments of various isolated organs and it could be appreciated that the most tested products inhibit or prevent the contraction as due to several spasmodic agents both of hormonal and humoral essence and of a different essence; for some of the tested products, such as 2-phenylcyclohexen-tropyl carboxylate this inhibiting or preventive activity is already apparent at concentrations of 1 10 to 1X g./m1. The pharmacological features and the collateral effects of the compounds are substantially superimposable to those of atropine, so that the products are particularly suitable for the therapy of spasms in the smooth musculature of the biliary, urogenital and digestive system tracts. Such curative use is useful with respect to atropine on account of the higher therapeutic ratio as provided by the compounds of this invention.

The antiulcer activity has been determined through many tests, such as histamine ulcer, contention ulcer, desamethazone ulcer and pylorus ligature ulcer. Some of these products proved to eflectively inhibit ulcers from being arisen, whereby they can be considered as useful agents in the therapy of gastric and duodenal ulcers.

DESCRIPTION OF PREFERRED EMBODIMENTS The following examples are given to further illustrate the present invention. The scope of the invention is not, however, meant to be limited to the specific details of the examples.

(Formula I, wherein R=- 4 EXAMPLE 1 2-phenyl-cyclohexene-3-carboxylic acid (Formula I, wherein R=H) A mixture comprising 50 g. of Z-phenyl-Z-hydroxy-cyclohexan-carboxylic acid, prepared in accordance with the method as described in literature, 2 ml. of concentrated sulphuric acid and 500 ml. of carbon tetrachloride is refluxed for 24 hours and thoroughly stirred.

The solvent is removed and the residue is treated with a 10% aqueous solution of sodium bicarbonate and after ether wash the alkaline solution is acidified with dilute hydrochloric acid. 30 g. of crystalline product melting at 76-80 C. are obtained (as crystallized from ligroin). The yield is 65% of the theoretical value.

Method (a).-2-phenyl cyclohexene-3-carboxylate of 3-diethylamino-2,2-dimethyl-propyl:

5 g. (0.0248 mol) of 2-phenyl-cyclohexene-3-carboxylic acid, 20 cc. of isopropanol, and 0.97 g. (0.0248 mol) of potassium dissolved in 10 cc. methanol are introduced into a three-neck flask and 4.4 g. (0.0248 mol) 3-diethylamino-2,Z-dimethyl-propyl chloride are added to the solution.

The reaction mixture is stirred and reflux heated for 3 hours, the precipitated potassium chloride is filtered and the solvent removed under vacuum.

The oily residue obtained is dissolved in ether, the ether solution is washed with 10% sodium hydroxide and then with water until the alkalinity is removed, then dried with anydrous sodium sulphate and vacuum evaporated.

The yellow oily product thus obtained is purified by reduced pressure distillation, thereby obtaining 3 g. yellow oil B.P. mm, Hg 162-166 C.

Method (b).Tropyl 2 phenyl cyclohexen-S-carboxylate:

(Formula I, wherein R= N CH, L

A mixture comprising 4.4 g. of tropine, 1.2 g. potassium and 40 ml. toluol is reflux heated under stirring until complete dissolving. To the toluene suspension obtained, a solution of 2-phenyl-cyclohexen-3-carboxylic acid chloride (Formula I, wherein R=H) (as prepared by treating 6.26 g. acid with 19 ml. thionyl chloride and then evaporating to dryness) in 30 ml. of toluol is added, and the mixture is reflux heated under stirring for 12 hours.

The solvent is vacuum evaporated, the residue is treated with dilute HCl, the acid solution is ether washed and then alkalinized and accurately extracted with ester.

Afer dehydration, the ether solution is evaporated, yielding a maroon dense oil, which is purified by fractional distillation at a reduced pressure, B.-P. Hg 168 C.

Method (c).N methyl 3 piperidine-Z-phenylcyclohexen-3-carboxylate:

Formula I, wherein R= carboxylate, 5.4 g. (0.047 mol) 3-hydroxy-N-methylpiperidine, 0.13 g. (0.0057 mol) sodium dissolved in the EXAMPLE 2 3-diethylamino-2,2-dimethy1-propyl-2-phenyl-cyclohexen-3-carboxylate methyliodide Into a flask, provided with a reflux freezer having a tube filled with CaCl there are introduced 0.8 g. 3-diethylamino-2,2-dimethyl-propyl 2 phenyl cyclohexen- 3-carboxylate, 0.4 g. methyl iodide and 3 cc. methanol. The mixture is heated for 7 days in an oil bath at 45 C. Crystal separation not being obtained by cooling, the solvent is vacuum removed, thus obtaining a yellow resinous residue attaining a resinous appearance after ether washes; the compound thus obtained shows analytical features corresponding to the product expected.

The following compounds having the characteristics indicated were prepared in accordance with the above described methods:

3 (N morpholine) 2,2, dimethyl-propyl-Z-phenylcyc1ohexene-3-carboxylate, obtainable by methods (a), (b), (c): colourless dense oil, B.P. mm Hg 177178 C.

2 diethylamino 1 methylethyl-2-phenyl-cyclohexen- 3-carboxylate, obtainable by methods (a), (b), (0): light yellow Oil, B.'P.o 2 Hg 140 C.

2 dimethylaminoethyl 2 phenyl-cyclohexen-B-carboxylate, obtainable by methods (a), (b), (c): colourless fluid oil, B.P. mm Hg 130-132 C.

2 (2' diethylaminoethoxy) ethyl-2-pheny1-cyclohexen-S-carboxylate, obtainable by methods (b), (c): orange-yellow oil, B.P. mm Hg l71-172 C.

N,N' [2 (2' phenyl-cyclohexen-3-carboxyl)-ethy1]- piperazine, obtainable by methods (b), (c): light yellow crystals, M.P. (Kofler) 145-147 C.

Tropyl 2 phenyl cyclohexen-B-carboxylate methyliodide, colourless crystals, M.P. (Kofler) 272275' C.

While the invention has been described in particular with respect to the production of certain specific compounds and specific methods used in the production thereof, it is apparent that variations and modifications can be made without departing from the spirit and scope of the invention.

What is claimed is:

1. A compound selected from the group consisting of compounds of the formula:

wherein R is selected from the group consisting of UNITED STATES PATENTS 7/ 1969 Caldwell et a1. 260292 OTHER REFERENCES Burger, Medicinal Chemistry, second edition, Interscience Publishers, pp. 464, 465, 471 and 497 (1960).

ALAN L. ROTMAN, Primary Examiner US. Cl. X.R.