DK145463B - PROCEDURE FOR PROCESSING ISOMERIZATION OF 2- (4-INDENYLOXYMETHYL) MORPHOLINE COMPOUNDS OR ACID ADDITION SALTS THEREOF TO THE ACID ADDITION SALTS THEREOF TO THE ACID ADDITION OXYLETHYLES OF THE TILS 7 - Google Patents

Description

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(21) Application No. 489/77 (81) IntCI.3 C 07 D 265/30 (22) Submission date 4 · 1977 (24) Running day 4 Feb. 1977 (41) Aim. available Oct. 1 1977 (44) Presented Nov. 22; 1982 (86) International application no.

(86) International Import Date (85) Continuation Day - (62) Stock Application No. "

(30) Priority 27 · Oct. 1976, 128962/76, JP

(71) Applicant YAMANOUCHI PHARMACEUTICAL CO. LTD., Tokyo, JP.

(72) Inventor Kozo Takahashi, JP: Masuo Murakami, JP: Tadao Kojima, JP: Kunihiro Niigata, JP: et al.

(74) Associate Engineer Hofman-Bang & Boutard.

(54) Process for the isomerization of 2- (4-indenyloxymethyl) morpholine compounds or acid addition salts thereof to acid addition salts of the corresponding 2- (7-in = denyloxymethyl) morpholine blooms.

The invention relates to a process for the isomerization of 2- (4-indenyloxymethyl) morpholine compounds with the formula III-b or acid addition salts thereof as set forth in the preamble to acid addition salts of the corresponding 2- (7-indenyloxymethyl) morpholine compounds. t compounds with the formula Ill-a specified in the preamble of the claim.

D

1 *

Antidepressants containing a morpholine ring are already known, e.g. from US Patents Nos. 3,714,167 and 3,712,890 and Danish Patent Nos. 120,543.

2 145463

The compound which is believed to have the hottest activity among the compounds disclosed in these patents is 2- (2-ethoxyphenoxymethyl) morpholine, commonly known as "Viloxazine" ("Nature"; 258, 157-158 ( 1972)). A series of studies by K. B. Mallion, A.H. Todd, R.W. Turner et al., The inventors of "Viloxazine", suggest the link between the chemical structures and the pharmacological activities of these compounds. Thus, it is preferred that the compound has one substituent at the 2-position of a phenoxy group attached to morpholine. Furthermore, if the phenoxy group forms a condensed ring, it is preferred that e.g. is a tetralin type ring formed by condensation of a tetramethylene group. However, if the condensed ring forms an indant-type ring upon condensation of a trimethylene group, the pharmacological effect becomes less.

The inventors have in a previously filed Danish patent application no.

352/76 proposed to prepare compounds of general formula I2 1 2 wherein R is hydrogen or methyl and R is hydrogen or alkyl of 1-6 carbon atoms and has found that these compounds have excellent antidepressant activity.

1 'Danish Patent Application No. 4709/79 - Divided from the present application - they have disclosed an industrially useful process for preparing a 2- (7-indenyloxymethyl) morpholine compound (hereinafter referred to as the 7 isomer) of the general formula O -CEL n οό X) I₂ and a 2- (4-indenyloxymethyl) morpholine compound (hereinafter referred to as the 4-isomer) of the general formula US463

FT

n in which formulas R is hydrogen, alkyl of 1-6 carbon atoms, cyclohexyl, phenyl or benzyl, as a mixture of the isomeric or acid addition salts thereof or as separate acid addition salts of the isomers.

P

When R in the indicated phonies means alkyl of 1-6 carbon atoms, these may be straight or branched chain and examples of such alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, neopentyl, hexyl and isohexyl.

It has been found that the acid addition salts of the 2- (7-indenyloxymethyl) -morpholine compounds have a better pharmacological effect than. ,. acid addition salts of the 2- (4-indenyloxymethyl) morpholine compounds and, therefore, can be used with greater advantage as drugs, and a method of isomerizing the 4-isomer to the 7-isomer has now been found.

The process according to the invention is characterized by the characterizing part of the claim.

The isomerization process of the invention can be illustrated by the following reaction scheme:

Free morpholine compound (4-isomer, possibly in admixture with 7-isomer)

Acid / \ Acid (stoichiometric or X (below stoichioma) leaching) / ^ Base (small amount) \ l

Morpholinium salt ---; - Morpholinium salt (4-isomer, optionally in the mixture of O (7-isomer) with 7-isomer)

Thus, the mixture of the acid addition salt of the 7 isomer and the acid addition salt of the 4 isomer, which is obtained by adding an acid to the mixture prepared according to the above methods, has the unexpected property that the 4 isomer can be isomerized to the 7 isomer. a small amount of base such that only the 7 isomer is obtained as the acid addition salt thereof by isomerizing the mixture of the two isomers (free bases) as obtained by the reaction or after purification by adding in an organic solvent an acid of slightly less than the stoichiometric amount to join the residual free base itself as the base or by adding the mixture of the isomers an acid in the stoichiometric or slightly excess amount to convert the entire isomer mixture to acid addition salts and then adding a small amount of a basic material to the salts in an organic solvent The purification of the mixture of the isomers can be carried out by a conventional method such as f. eg. filtration, concentration, extraction, distillation, column chromatography, recrystallization, etc.

As examples of the acid used to form the acid addition salts of the isomers, e.g. organic acids such as citric acid, acetic acid, lactic acid, maleic acid, fumaric acid, benzoic acid, tartaric acid, ascorbic acid, succinic and malic acids, and inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid and nitric acid are mentioned. Examples of basic materials which can be used for the isomerization include the free tautomeric mixture and other organic and inorganic bases such as pyridine, triethylamine, sodium hydroxide and barium hydroxide.

The compounds prepared by the process of the invention exhibit methamphetamine stereotypically increasing activity, which is one of the desired pharmacological properties of an antidepressant, and furthermore, the activity is stronger than the activity of the known antidepressant amitriptyline.

The compounds prepared by the process of the invention also exhibit antireserpine activity, which is one of the desired pharmacological properties of an antidepressant, and show it stronger than the known compounds.

145463 5

The acute toxicity of the compounds by oral administration is about half that of the known compounds, and the compounds prepared by the process according to the invention exhibit an excellent coefficient of safety in medical treatment given the potent activity of the compounds.

The compounds exhibit further enhancing activity on the action of 5-hydroxytryptophan, which is one of the desired effects of an antidepressant, and exhibits higher activity than the known compounds amitriptyline and imipramine.

Furthermore, the isolated acid addition salts of the 7 isomer exhibit a more advantageous pharmacological activity than the acid addition B salts. II; ne of the 4-isomer as shown in the following experiments: ./·

Experiment 1

The effects of the compounds on methamphetamine-Induced Stereo .....: type behavior in rats (male Wistar strain rats, age 8 weeks) were investigated according to the method described by Ueki et al. ·; (Folia Pharmacologies Japonica, 68, 716, 1972).

The rats were placed in separate plastic cages for one hour to become accustomed to the test conditions, after which the test compounds were administered intraperitoneally followed by one hour of intraperitoneal administration of methamphetamine (5 mg / kg). The test compounds in effect on the excited behavior of the rats were observed every 30 minutes until five hours had elapsed.

The test compound ED ^Q was 5 mg / kg i.p. for 2- (7-indenyloxymethyl) morpholine hydrochloride and 12.5 mg / kg i.p. for 2- (4-indenyl-: oxymethyl) morpholine hydrochloride. Thus, the former was 2.5 times more powerful than the latter. ; '

Experiment 2

The effects of the compounds on reserpine-induced hypothermia in mice (male mice of the ICR-JCL strain, age 5 weeks) were studied by that of Ueki et al. (ibid) method described. The mice were pretreated with reserpine (3 mg / kg s.c.) and kept in separate plastic cages for 17 hours. The room temperature was maintained at 23-1 ° C. The test compounds were administered orally and the rectal temperature of the mice was measured 5 hours after. The differences in the recalculation temperature (δΤ) between the treated rats and the rats in the control group, and the sum of the differences (Σ4Τ) were calculated, followed by graphical evaluation of EDT = 1 ^ oq. This ED value was 1.8 mg / kg p.o. for 2- (7-indenyloxymethyl) morpholine hydrochloride and 2.4 mg / kg p.o. for 2- (4-indenyloxymethyl) morpholine hydrochloride. Thus, the former was found to exert greater efficiency than the latter.

In the isomerization reaction, it is unnecessary to dissolve the tautomeric mixture (free bases, acid addition salts) in a solvent, since the tautomeric mixture can remain as it is in the reaction system and no complete dissolution is required.

The following examples serve to illustrate the method of the invention.

EXAMPLE 1 In 20 ml of acetone, 10 g of a mixture (3? 7) of 2- (4-indenyloxymethyl) morpholine hydrochloride and 2- (7-indenyloxy-methyl) morpholine hydrochloride were suspended, and after addition of 3 g of mixture (3: 7) of 2- (4-indenyloxymethyl) morpholine and 2- (7-indenyloxymethyl) morpholine, the resulting mixture was stirred for 24 hours at room temperature. The crystals thus precipitated were recovered by filtration, washed thoroughly with acetone, and 10 g of the recovered crude crystals were recrystallized from 40 ml of methanol to give 7.0 g of 2- (7-indenyloxy-methyl) morpholine hydrochloride. .

Elemental Analysis for Cj HjH₂ ^^NCll: C (° / o) H (%) N (9e) Cl (9e) Calculated: 62.80 6.78 5.23 13.24 Found: 63.01 6.75 ' 5.11 12.98

Nuclear Magnetic Resonance Spectrum (CDCl3 + Dg-DMSO): δ 145463 S (ppm): 3.0-3.4 (m, 4H,)

^ OH

4.0-4.2 (m, 4H, -OCHP-f NC)

Λ Λ S, '' 'H

4.3 (», ih,; 3.34 (2H, qqjS) 6.58 (doublet, 1H, JT ^ 1H J = 6 Hz) 6.84 (doublet, 1H, ^ Jpp J = 6 Hz) 6.78 (d, 1H,) 0-7.04 (d, 1H, one) l 7.20 (t, 1H,) 10 * 0 (1H,

H

EXAMPLE 2 In 20 ml of isopropyl alcohol, 10 g (0.043 mol) of a mixture of (3: 7) of 2- (4-indenyloxymethyl) morpholine and 2- (7-indenyl-oxymethyl) morpholine was dissolved and after the addition of 5.9 ml (0.032 mol) of 20% (w / v) hydrogen chloride in isopropyl alcohol was stirred for 24 hours at room temperature. The crystals thus precipitated were recovered by filtration, washed thoroughly with acetone and then recrystallized from 40 ml of methanol to give the title compound; 7.7 g of 2- (7-indenyloxymethyl) morpholine hydrochloride.

Elemental analysis for C 14 H 18 ° 2 NC 1: C (%) H (%) N (%) Cl (%) calculated: 62.80 6.78 5.23 13.24 found: 62.54 6.63 5.08 13.00 EXAMPLE 5 In 20 ml of methanol, 10 g of a mixture (3: 7) of 2- (4-indenyloxymethyl) morpholine hydrochloride and 2- (7-indenyloxymethyl) morpholine hydrochloride was suspended and after the addition of 0.3 g of triethylamine, the mixture was stirred for 24 hours at room temperature. The crystals thus precipitated were recovered by filtration, washed thoroughly with acetone and recrystallized from 40 ml of methanol to give 6.3 g of 2- (7-indenyloxymethyl) morpholine hydrochloride.

Elemental Analysis for CL ^H ^₂O₂NCl: C (#) H (ji) Ν (* 5) Cl (JÉ) calculated: 62.80 6.78 5 13.29