US3838151A - Cycloalkyllactamimides - Google Patents

Abstract

NOVEL COMPOUNDS OF THE FOLLOWING FORMULA ARE USEFUL AS HYPOGLYCEMIC AND ANTIVIRAL AGENTS.

R-N=C<(-NH-(CH2)N-)

WHEREIN R REPRESENTS NORBORNYL OR ADAMANTANYL AND N IS AN INTEGER OF FROM 3 TO 11.

Description

United States Patent O 3,838,151 CYCLOALKYLLACTAMIMIDES J. Martin Grisar, George P. Claxton, Thomas R. Blohm, and Edward McC. Roberts, Cincinnati, Ohio, assignors to Richardson-Merrell Inc., New York, N.Y. No Drawing. Filed Aug. 11, 1972, Ser. No. 280,049 Int. Cl. C07d 27/04, 29/28, 41/02 US. Cl. 260-239 B 7 Claims ABSTRACT OF THE DISCLOSURE Novel compounds of the following formula are useful as hypoglycemic and antiviral agents- R-NzO (CH7) wherein R represents norbornyl or adamantanyl and n is an integer of from 3 to 11.

FIELD OF INVENTION This invention relates to novel cycloalkyllactamimides which are useful as hypoglycemic and antiviral agents.

SUMMARY OF INVENTION The novel compounds of this invention which possess hypoglycemic or antiviral properties are represented by the following general Formula I:

\ J FormulaI wherein R represents norbornyl or adamantanyl and n is a positive whole integer of from 3 to 11. This invention also includes pharmaceutically acceptable acid addition salts of the compounds of general Formula I.

DETAILED DESCRIPTION OF INVENTION For convenience and uniformity all the compounds of this invention are named and represented as 2-iminoperhydroazacarbocyclics, as represented by Formula I. It is known, however, that compounds of this type may also be represented by the tautomeric form illustrated by the following general Formula II:

E a W Formula II This tautomerism has been discussed by R. Kowk and P. Pranc, J. Org. Chem. 32, 740 (1967). When represented as in Formula II the compounds of this invention are named differently than when represented as in Formula I. In solution under the conditions of therapeutic utility the proportion of each tautomeric form, or the delocalization of the charge between the two nitrogens will be dependent upon numerous factors including the nature of the substituents, the pH of the medium, and the like. This equilibrium state is conveniently depicted by the following general Formula III:

H anion 1 Formula III This invention relates to compounds represented or named in either tautomeric form as illustrated by general Formulas I and II. In the above general Formulas II and III, R and n have the meanings defined hereinbefore.

As samples of compounds of this invention there may be mentioned for example,

'ice

2- Z-norbornylimino hexahydroazepine,

2- l-adamantanylimino) azacyclotridecane, 2- 2-norbornylimino azacyclododecane, hexahydro-2- Z-ad amantanylimino) azepine, 2-'(2-norbornylimino)piperidine,

2( l-adamantanylimino pyrrolidine,

2- l-norbornylimino) azacycloundecane, hexahydro-2-( l-adamantanylimino) azepine, 2- 2-norbornylimino hexahydroazepine, 2 (2-norbornylimino)pyrrolidine,

2-( l-adamantanylimino piperidine,

and the like.

Pharmaceutically acceptable acid addition salts of the base compounds of this invention are those of any suitable inorganic or organic acid. Suitable inorganic acids are, for example, hydrochloric, hydrobromic, sulfuric, or phosphoric acids and the like. Suitable organic acids are, for example, carboxylic acids such as acetic, propionic, glycolic, lactic, pyruvic, malonic, succinic, fumaric, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic, benzoic, hydroxybenzoic, phenylacetie, cinnamic, salicylic, 2-phen0xybenzoic and the like, or sulfonic acids such as methane sulfonic, 2-hydroxyethane sulfonic acid and the like.

The novel compounds of this invention and pharmaceutically acceptable acid addition salts thereof are useful as hypoglycemic and antiviral agents. The compounds of this invention can be administered to animals, mammals and humans either alone or in the form of pharmaceutical preparations which contain the novel compounds suitable for oral or parenteral administration. Pharmaceutical preparations containing novel compounds of this invention and conventional pharmaceutical carriers can be employed in unit dosage forms such as solids, for example, tablets and capsules, or liquid solutions, suspensions or elixirs for oral administration or liquid solutions suspensions, emulsions and the like for parenteral use. The quantity of compound administered can vary over a wide range to provide from about 1.0 mg./kg. (milligram per kilogram) to about mg./kg. of body weight of the patient per day to achieve the desired effect. Unit doses of these compounds can contain, for example, from about 25 to 500 mg. of the compound and may be administered, for example, from 1 to 4 times daily.

As hypoglycemic agents compounds of this invention may be used to control hyperglycemic conditions, for example, as occurs in diabetic patients. To illustrate the hypoglycemic activity of compounds of this invention, when each of 2-(2-norbornylimino)hexahydroazepine hydrochloride and Z-(Z-adamantanylimino)pyrrolidine hydrochloride were administered to glucose primed rats at 100 mg./kg. of body weight, the plasma glucose was reduced respectively to 78% and 77% of control.

To illustrate the antiviral activity of compounds of this invention, tail lesions were produced in mice by subcutaneous inoculation of vaccinia -(IDH) virus after which hexahydro-Z-(Z- adamantanylimino] azepine hydrochloride was administered at a dosage level of 20 mg./kg. in one test and at 5 tug/kg. in another test. In each test the number of lesions was decreased by 33% and by 43% respectively as compared to control.

The compounds of this invention are prepared by reacting an excess of a lactim ether of the formula wherein n and R have the meanings defined hereinbefore and lower alkyl may be methyl, ethyl, and the like in a manner similar to that reported by R. E. Benson and T. L. Cairns, J. Am. Chem. Soc. 70, 2115-8 (1943). This reaction may be carried out in the presence or absence of a solvent. Suitable solvents for this reaction include lower alcohols such as methanol or ethanol, benzene, toluene, and the like. Preferred solvents are lower alcohols. A basic or acidic catalyst such as a tertiary amine or hydrogen chloride may be added to the reaction mixture. In general it is preferred that the hydrochloride salt of the reactant primary amine be used in the reaction. The temperature of the reaction may vary from 40 C. to 180 C., and preferably the temperature is from about 15 to 25 C. The reaction time may vary from 1 hour to about 60 days depending upon the temperature of the reaction, the reactant primary amine, and more particularly the degree of steric hindrance of the amine since highly sterically hindered amines react very slowly.

The lactim ethers which find use in this reaction may be prepared from commercially available corresponding lactams by methods known in the art. For example, by reaction of the appropriate lactam with dimethyl sulfate in a solvent such as benzene, toluene, xylene or the like at the reflux temperature of the solvent for 224 hours the corresponding O-methyllactim ether is obtained.

The reactant primary amines as represented by Formula V are commercially available or may be prepared, for example, by reduction of the oxime of the corresponding ketone.

The above described reaction may also be carried out using known thiolactim ethers, such as, S-methylthiocaprolactim [I-I. Behringer and H. Meier, Ann. 607, 67- 91 (1957)], or by using thiolactams wherein it may be advantageous to employ a catalyst such as mercury or silver oxide or cyanide [J A. Gautier and J. Renault, C. R. Acad. Sci. 234, 2081 (1952)].

The compounds of this invention may also be prepared using a complex of an appropriate lactam with phosphorus oxychloride, phosgene, borontrifiuoride etherate, dimethyl sulfate, hydrogen halide or a combination of two or more such reagents. This reaction has been studied by H. Bredereck in a series of articles in Chem. Ber., 1953-1968, particularly in volume 94, 2278 (1969) and volume 97, 1403 (1964). The complex formed is reacted with an appropriate primary amine described hereinabove in an aromatic hydrocarbon solvent such as benzene, toluene, or xylene or an alkyl polyhalide solvent such as carbon tetrachloride, chloroform, methylene chloride, tetrachloroethylene or the like. The reaction temperature is limited by the boiling point of the solvent, however, in some cases it is advantageous to carry out the reaction at room temperature or with cooling at to -40 C. depending on the reactants.

The following specific examples are illustrative of this invention.

EXAMPLE 1 2-(2-Norbornylimino)hexahydroazeipne hydrochloride To a mixture, which is cooled in an ice bath, of 22.7 g. (0.178 mole) of O-methylcaprolactim and 50 ml. of ethanol is added 25.0 g. (0.17 mole) of Z-aminonorbornane hydrochloride and 50 ml. of ethanol. The reaction mixture is stirred overnight after which it is cooled in an ice bath for about 3 hours. The precipitate is collected, washed with ethanol, dried, recrystallized from acetonemethanol and dried to give 2-(2-norbornylimino)hexahydroazepine hydrochloride, M.P. 314315.5 C.

EXAMPLE 2 2- Z-Adamantanylimino pyrrolidine hydrochloride A mixture of g. (0.0533 mole) of Z-adamantanamine hydrochloride and about 10 ml. of O-methylbutyrolactim is allowed to stand 7 days at room temperature with occasional stirring during which time sufiicient ethanol is added to maintain the mixture as a slurry. The mixture is cooled to 20 C. for 2 hours. The precipitate is collected, washed with ether, recrystallized from acetonemethanol and ethanol-water and dried to give 2-(2-adamantanylimino)pyrrolidine hydrochloride, M.P. 300 C.

EXAMPLE 3 Hexahydro-Z- (2adamantanylimino aze pine hydrochloride A mixture of 10 g. (0.0533 mole) of 2-adamantanamine hydrochloride and about 10 ml. of O-methylcaprolactim is allowed to stand 7 days at room temperature with occasional stirring during which time sufficient ethanol is added to maintain the mixture as a slurry. The mixture is cooled at 20 C. after which the precipitate is collected and washed with ether, then recrystallized from acetone-methanol and ethanol-water and dried to give hexahydro-2-(2 adamantanylimino)azepine hydrochloride, M.P. 300 C.

EXAMPLE 4 2- l-Adamantanylimino pyrrolidine hydrochloride A mixture of 10 g. (0.0533 mole) of l-adamantanamine hydrochloride and about 10 ml. of O-methylbutyrolactim is allowed to stand 35 days at room temperature with occasional stirring during which time about 10 ml. of additional O-methylbutyrolactim and 10 ml. of ethanol is added. The precipitate is collected, washed with ether, recrystallized from acetone-methanol and ethanol and dried to give 2-(l-adamantanylimino)pyrrolidine hychloride, M.P. 300 C.

EXAMPLE 5 2-( l-Adamantanylimino piperidine hydrochloride A mixture of 15 g. (0.08 mole) of l-adamantanamine hydrochloride and 25 ml. of O-methylvalerolactim is allowed to stand 45 days at room temperature with occasional stirring during which time an additional 10 ml. of O-methylvalerolactim is added. The mixture is filtered and the residue is washed with ether, recrystallized from acetone-methanol and ethanol and dried to give 2-(1-adamantanylimino)piperidine hydrochloride, M.P. 300 C.

EXAMPLE 6 Hexahydro-Z- l-ad amantanylimino) azepine hydrochloride A mixture of 10 g. (0.0533 mole) of l-adamantanamine hydrochloride and about 10 ml. of O-methylcaprolactim is allowed to stand 39 days at room temperature with occasional stirring during which time about 40 ml. of O- methylcaprolactim is added. A solid forms and is collected, then washed with ether, recrystallized from acetone-methanol and ethanol and dried to give hexahydro- 2 (1 adamantanylimino)azepine hydrochloride, M.P. 300 C.

EXAMPLE 7 2- (Z-Norbornylimino) azacyclotridecane hydrochloride To 21.7 g. (0.11 mole) of 2-azacyclotridecanone in 200 ml. of dry benzene is added dropwise 16.9 g. (0.11 mole) of phosphorus oxychloride. The mixture is stirred at room temperature for 4 hours after which is added 14.7 g. (0.10 mole) of 2-aminonorbornane. Stirring is continued for 5 hours, then the mixture is refluxed for 12 hours. The mixture is acidified with 2N HCl and allowed to stand at room temperature for 4 weeks. Crystals form and are separated, and dissolved in chloroform. The chloroform solution is washed with 2N HCl and saturated sodium chloride solution then dried over sodium sulfate and evaporated to dryness. The residue is recrystallized from methylene chloride-benzene to give 2-(2-norbornylimino)azacyclotridecane hydrochloride, M.P. 235- 237 C.

5 We claim: 1. A compound selected from a base of the formula wherein R is selected from the group consisting of norbornyl and adamantanyl and n is a positive whole integer of from 3 to 11 and pharmaceutically acceptable acid addition salts thereof.

2. A compound of Claim 1 wherein R is norbornyl.

3. A compound of Claim 2 which is 2-(2-norb0rnylimino)hexahydroazepine and pharmaceutically acceptable acid addition salts thereof.

4. A compound of Claim 1 wherein R is adamantanyl.

5. A compound of Claim 4 which is Z-(Z-adamantanylimino)pyrrolidine and pharmaceutically acceptable acid addition salts thereof.

6. A compound of Claim 4 which is 2-( l-adamantanylimino)piperidine and pharmaceutically acceptable acid addition salts thereof.

7. A compound of Claim 4 which is heXahydro-2-(1- adamantanylimino)azepine and pharmaceutically acceptable acid addition salts thereof.

No references cited.

ALTON D. ROLLINS, Primary Examiner US. Cl. X.R.

260239 BE, 293.56, 296 R, 326.85, 326.9; 424-244, 263, 267, 274