IL25356A - Aminoethyl ethers of cyclohexanol derivatives,their preparation and use - Google Patents

Description

'jiiDJi in□ TJinrn n PATENT ATTORNEYS ■ □ ' Q 1 D 3 ' ' □ 1111 0». REINHOLD COHN I Π D TJinj · * n ■ Π DR. MICHAEL COHN 2s m ISRAEL SHACHTER B.Sc. *3 3 ZJ *1 D 3 III "J N 1 HI ' FlleC/ 24161 PATENTS AND DESIGNS ORDINANCE SPECIFICATION Novel anilnoethyl ethers of cyclohexanol derivatives, their preparation and use N.V. KOKINKLIJKE PHABMACEUTISCHE FABHIEBN v/h BROCADSS STHEEMAH & PHABEACIA, a Dutch company, of looiersgracht 27~39> Amsterdam, 3¾e Netherlands do hereby declare -the nature of this invention and in what manner' the same is to be performed, to particularly described, and ascertained in and "by t following statement ': - THIS INVENTION relates to new therapeutically useful aminoethyl ethers of cyclohexanols and acid addition salts thereof, to processes for their preparation and to pharmaceutical compositions containing them.

In one aspect the invention comprises aminoethyl ethers of cyclohexanols of the general formula: '.iherein R is a lower alkyl group, R is a lot/er alkyl group, 1 *i J is a hydrogen atom or a lower alkyl group, ^ is a lower alkyl group , and R_ is a hydrogen atom or a lower alkyl group, or -N is a saturated, unsubstituted 5- or 6-membered heterocyclic nucleus which apart from the nitrogen atom already present may contain a further hetero atom in the ring, such as pyrrolidino, piperidino, morpholino and piperazino, and acid addition salts thereof.

By the term "lower alkyl" as used in this specification and accompanying claims is meant straight or branched chain alkyl groups having at most 6 (preferably at most 4) carbon atoms.

The compounds of formula I have valuable therapeutic properties they have coronary blood vessel dilating activity coupled a positive inotropic action and increase the refractory period.

Moreover, they have sedative, hypnotic and/or muscle relaxant properties. Their very low toxicity and the combination of sedative properties and strong coronary dilating activity, which is coupled with a positive inotropic action in therapeutically active dosesj They also possess properties resembling those of such well knovm benzhydryl ethers as diphenhydramine and orphenadrine - especially the latter. Preferred compounds are those in which R is hydrogen, 3 and, more particularly, those in which R. and are methyl, and ¾ 5 their acid addition salts.

For use as therapeutics the compounds of formula I may be used as bases or as acid addition salts containing pharmaceutically acceptable non-toxic anions, e.g. the hydrohal des , sulphates, oxalates, tartrates, fumarates, acetates, citrates, maleates, succinates, lactates and pamoates.

According to a further feature of the invention, the compounds of formula I are prepared by reacting a cyclohexanol derivative of the general formula: with an aminoethyl halide of the general formula: wherein R , R , R , R, and R^ have the meanings hereinbefore defined, and X is a halogen atom, preferably chlorine or bromine. The reaction is preferably carried out in the presence of a condensing agent such as sodamide, which suitably is used in quantities about equimolar with the cyclohexanol derivative of formula II. Preferably also the reactants are heated in the presence of an inert organic solvent such as an aromatic hydrocarbon, for example benzene, toluene or xylene.

In lieu of the aminoethyl halide of formula III its acid addition salts can be used without material influence either on reaction conditions or on yield.

In another method of making the new compounds a cyclohexanol derivative of formula II is first reacted with a 1 , 2-dihaloethane of the formula X-CH -CH -X, wherein X is as hereinbefore defined, and the resulting compound of the formula: is reacted with an amine of the formula: wherein the various symbols are as hereinbefore defined.

The reactions are carried out in a manner known er se for reactions of the same general type. It is preferable to add the cyclohexanol reactant, which may be dissolved in an inert organic solvent, to an excess of the 1 ,2-dihaloethane, so as to prevent the formation of appreciable quantities of a product containing two phsnylcyclohexyl groups by reaction of both halogen atoms of the dihalide with a hydroxyl group each of a phenylcyclohexanol molecule of formula II, The cyclohexanol derivatives of general formula II can be prepared by the process described and claimed in the specification of our copending Application No.25355 · According to another feature of the invention, the compounds of formula I are prepared by reduction of the carbonyl group cf an acetamide derivative of the formula: wherein the various symbols are as hereinbefore defined, to methylene (i.e. -CHg-) by methods known per se, for reducing a carbonyl group in an amide to -CH for example with lithium aluminium hydride or diborane. The reduction is preferably carried out in an inert organic solvent such as diethyl ether or tetrahydrofuran. By the term "methods known per se" as used in this specification and accompanying claims is meant methods heretofore used or described in the chemical literature.

The starting materials of formula VI can be obtained by the following methods: (a) Reaction of a cyclohexanol derivative of the formula: with an acetamide derivative of the formula: wherein K is a hydrogen or alkali metal atom and X is a halogen, preferably chlorine or bromine, atom and the other symbols are as hereinbefore defined. The reaction may be carried out in an inert organic solvent medium, e.g. diethyl ether or tetrahydrofuran, and preferably in the presence of an acid-binding agent such as an alkal (b) Reaction of an acetic acid derivative of the formula: COO , with an amine of the formula HNR^R , wherein is a lov/er alkyl group, and the other symbols are as hereinbefore defined. The reaction is preferably carried out -in the presence of an inert organic solvent such as benzene, toluene, dimethylsulphoxide or tetrahydrofuran.

The following E amples illustrate the invention.

SXAMPLB I To a suspension of 12 g. of finely powdered sodamide in about 30 ml. of anhydrous toluene a solution of 6ΐ·5 g« of l-(o-tolyl)- 2-methylcyclohexan-l-ol in about 100 ml. of anhydrous toluene is slowly added. The mixture is stirred at room temperature for about 30 minutes, and is thereafter heated under reflux for 4 hours. 3 .I5 g. of β-dimethylaminoethyl chloride is then added, and the mixture is stirred at room temperciture for 1 hour, and thereafter boiled under reflux for about l6 hours.

After being cooled, the mixture is poured into water, the toluene layer is separated and the water layer is extracted with diethyl ether. The toluene and ether solutions are combined, washed with water and dried with sodium sulphate. After filtration, diethyl ether and toluene are distilled off, and the content of 1- (o-tclyl )-2-methylcyclohex-l-yl β-dimethylaminoethyl ether in the residue is determined by titration. The calculated amount of hydrogen chloride in diethyl ether is then added, and the precipitated hydrochloride is filtered off and washed with diethyl ether. 66.6 g. of the product EXAMPLE II Following the general procedure described in Example I, but substituting different 1- (o-alkylphenyl )-2-alkylcyclohexan-l-ols for the l-(o-tolyl) -2-methylcyclohexan-l-ol, the l-(o-alkylphenyl) -2-alkylcyclohex-l-yl β-dimethylaminoethyl ethers shown below are obtained in the form of their hydrochlorides: lting Point Yield Rl ¾ Me R3 H 170.5-172 49 C2H5 CH3 H 175-177 53 C2H5 H I66-I69 65 C2H5 C2H5 t,"c4H9 H 201-201.5 49 C2H5 CH3 isoC_H_ H I9 -I9 . 54 3 7 isoC^ H 195 (sublimation) 8 C2H5 isoC^H^, isoC^H,, H 224-226 56 The invention includes within its scope pharmaceutical compositions containing, as active ingredient, at least one of the therapeutically active compounds of general formula I, or a nontoxic acid addition salt thereof, in association with a pharmaceutically acceptable carrier. The preparations may take: any of the forms customarily employed for administration of therapeutically active substances, but the preferred types are those suitable for oral administration, and especially tablets, pills and capsules including the substance. The tablets and pills may be formulated in the usual manner with one or more pharmacologically acceptable diluents or excipients, for example lactose or starch, and may include materials of a lubricating nature, for example calcium stearate.

Capsules made of absorbable material, for example gelatin, may contain the active substance alone or in admixture with a solid or liquid diluent.

Liquid preparations may be in the form of suspensions, emulsions, syrups or elixirs of the active substance in water or other liquid medium commonly used for making orally acceptable pharmaceutical formulations, such as liquid paraffin, or a syrup or elixir base. The active substance may also be made up in a form suitable for parenteral administration, i.e. as a suspension, emulsion or solution in sterile water, or an organic liquid usually employed for injectable preparations, for example a vegetable oil such as olive oil, or a sterile solution in an organic solvent.

The following Example . illustrates pharmaceutical cc-npositions according to the invention.

EXAMPLE III Ampoules containing 2 ml. of injectable liquid containing 2 mg. of active compound are prepared from the following materials ( o-tolyl )-2-methylcyclohexan-l-y1 β-dimethylaminoethyl ether hydrochl 2 mg, a2HP04.2H20 about 8 mg. H2P04 about l.l4 mg.

NaCl 13„8 rag. later (free from pyrogens) make up to 2 ml.

The sodium chloride and phosphates are dissolved in distilled water and the pH is settled between 7· 3 and 7. km The solution is saturated with nitrogen gas and then the active substance is dissolved. The solution is filtered and the ampoules are filled under nitrogen and sterilised. The injectable liquid obtained is suitable for intravenous or intrape itoneal administration.

Claims (22)

HAVING NOW particularly described and ascertained the nature of our said invention and in what manner the same is'^fco be performed, we declare that what we claim is

1. Aminoethyl ethers of cyclohexanols of the general formula: wherein R is a lower alkyl group, R is a lower alkyl group, R 1 3 is a hydrogen atom or a lower alkyl group, R. is a lower alkyl group and R^ is a hydrogen atom or a lower alkyl group, or -N / k is a saturated, unsubstituted 5- or 6-inenibered heterocyclic 5 nucleus, which apart from the nitrogen atom already present may contain a further hetero atoa in the ring, and acid addition salts thereof.

2. Aminoethyl ethers of cyclohexanols according to claim 1 wherein the alkyl groups within the definitions of ^, ^i R_, Ri and R_ contain UD to 4 carbon atoms. 5 ½ 5

3. Aminoethyl ethers of cyclohexanols according to claim 1 or 2 wherein is hydrogen.

4. Aminoethyl ethers of cyclohexanols according to any one of the preceding claims wherein R, and R_ are methyl groups.

5. l-(o-Tolyl)-2-methylcyclohex-l-yl p-dimethylarainoethyl ether.

6. l-(o-Tolyl)-2-ethylcyclohex-l-yl β-dimethylaminoethyl ether.

7. l-(o-Sthylphenyl)-2-methylcyclohex-l-yl β-dimethylamino-ethyl ether.

8. l-(o-Ethylphenyl)-2-ethylcyclohex-l-yl β-dimethylamino-ethyl ether.

9. · l-(o-Ethylphenyl)-2-t.-butylcyclohex-l-yl β-dimethyl-aminoethyl ether.

10. 1- (o-Isopropylphenyl )-2-methylcyclohex-l-yl β-diraethyl-aminoethyl ether.

11. · l-(o-Isopropylphenyl)-2-ethylcyclohex-l-yl β-dimethyl-aminoethyl ether.

12. , l-(o-Isopropylphenyl)-2-isopropylcyclohex-l-yl. β-dimethyl-aminoethyl ether.

13. · Acid addition salts of the ether claimed in any one of claims 5 to 12.

14. l4« Process for the preparation of aminoethyl ethers of cyclohexanols as claimed in claim 1 which comprises reacting a cyclohexanol derivative of the general formula: with an aminoethyl halide of the general formula: v/herein X represents a halogen atom, and the other symbols are as defined in claim 1.

15. · Process according to claim 14 in which the reaction is carried out in an inert organic solvent in the presence of a condensing agent .

16. l6. Process for the preparation of aminoethyl ethers of cyclohexanols as claimed in claim 1 which comprises reacting a cyclohexanol derivative of the general formula specified in claim l4 with a 1 ,2-dihaloethane of the formula X-CH -CH -X, wherein X represents a halogen atom, and reacting the resulting compound of the formula: with an amine HNR, R_. wherein R, . R„, R_, R, and R_ are as defined ¾ 5 1 -J ¾ p in claim i.

17. · Process for the preparation of aminoethyl ethers of cyclohexanols as claimed in claim 1 v/hich comprises reducing the carbonyl group of an acetainide derivative of the general formula: wherein the various symbols are as defined in claim 1, to methylene by methods known per se for reducing a carbonyl group in an amide to -CH2-.

18. l8. Process according to claim 17 wherein the reduction is effected with lithium aluminium hydride or diborane.

19. Process for the preparation of aminoethyl ethers of cyciohexanols of the formula specified in claim 1 substantially as hereinbefore described with especial reference to Example I.

20. Aminoethyl ethers of cyciohexanols of the formula specified in claim 1 when prepared by the process claimed in any one of claims 14 to 19.

21. Pharmaceutical compositions which comprise at least one aminoethyl ether of a cyclohexanol derivative as claimed in any one of claims 1 to 12, or non-toxic salt thereof, in association with a pharmaceutically acceptable carrier.

22. Pharmaceutical compositions according to claim 21 substantially as hereinbefore described with especial reference to Example III. Dated this 9th day of March, 1966