AU607609B2 - 2-phenylthiobenzylamine derivatives and acid addition salts thereof - Google Patents

Description

I' I r 1 i 6Ui 7 COMMONWEALTH OF AUSTRALIA PATENTS ACT 1952 COMPLETE SPECIFICATION FOR OFFICE USE Form Short Title: Int. Cl: Application Number: Lodged: Complete Specification-Lodged: Accepted: Lapsed: Published: e Priority: .11 Im~rdmrm- N Related Art: TO BE COMPLETED BY APPLICANT 4 Name of Applicant: Address of Applicant: Actual Inventor: SPOFA spojene podniky pro zdravotnickou vyrobu 1la Husinecka, PRAHA 3,

CZECHOSLOVAKIA

Miroslav Protiva; Martin Valchar; Jiri Jilek; Karel Sindelar; Antonin Dlabac; Jirina Metysova; Josef Pomykacek and Natasa Dlohzkova Address for Service: GRIFFITH HACK CO.

71 YORK STREET SYDNEY NSW 2000

AUSTRALIA

Complete Specification for the invention entitled: 2-PHENYLTHIOBENZYLAMINE DERIVATIVES AND ACID ADDITION SALTS THEREOF The following statement is a full description of this invention, including the best method of performing it known to mr./us:- 1099A:rk i 1 i i j i ;i 1 i

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.i The invention relates to 2-phenylthiobenzylamine derivatives, more particularly to N,N-dimethyl-2-(3-hydroxyand 3-methoxyphenylthio)benzylamine (compounds IA and IB, respectively) and their addition salts with pharrnaceutically acceptable organic or inorganic acids.

Said compound IA of formula I CHNSCHj CH 2N(CH 3)2 C C C cc r r r C t rcc t T C C C C C C t t C C C CII C in which'R is a hydroxy group, and its acid addition salts show properties of highly selective inhibitors of (5-HT) re-uptake in mammalian brain structures and are expected to find therapeutic use as 20 potent central antidepressant.

The above compound was selected as a structure of choice from numerous related new substances on the basis of pharmacological evaluation. Thus, standard biochemical tests on rat hypothalamus with the use of tritium-labeled 25 imipramine (IP) and desipramine (DP) antidepressants (4 nM concentration) proved remarkably higher affinity of compound IA to IP receptors, which indicates selectively serotonergic mechanism of its action (whereas affinity to DP receptors indicates adrenergic route, and conventional nonselective 30 antidepressants have the two affinity values of approx.

equal order of magnitude).

The reported selective action of compound IA was verified by direct comparison of 3 H-5-HT (10 nM) and 3 H-noradrenaline (NA, 10 nM) re-uptake in rat brain cortex; again the two sets of values Irmm y differentiated in the sense of predominant 5-HT re-uptake inhibition.

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C C CCC C -2- UKlrF~H 'H HACK CU SYDNEY OFFICE MELBOURNE OFFICE G.P.O. BOX 4164 G.P.O. BOX 1285K SYDNEY. N.S.W. 2001 MELBOURNE. VIC. 3004 Also, standard pharmacological tests of antireserpine activity (on experimental hypothermia, eyelid ptosis and gastric ulceration) and potentiation of yohimbine toxicity in mice are indicative of pronounced antidepressant properties of compound IA.

The substances under study were tested in the form of salts administered p.o. The results are conventionally expressed as medium inhibition concentrations IC 50 (nM) and effective doses ED (eliciting a first statistically significant response) or medium effective doses ED50 (mg per kg); the concentrations and effective doses are calculated as the corresponding amounts of the base.

Acute toxicity was tested in mice p.o. and medium lethal dose LD 50 is given. Thus compound IA hydrogen S 15 maleate LD0 232 mg/kg. Imipramine and desipramine 00 0 50 o"o binding inhibition IC 50 respectively 4.24 and 12947 nM; 0oooo° 5-HT and NA re-uptake IC 5 0 0.58 and 505543 nM. Reserpine 0o hypothermia ED 10, ptosis 25, ulceration 50 mg/kg.

0:0 Yohimbine, ED50 54.7 mg/kg.

.00 20 The compounds of the invention, i.e.

N,N-dimethyl-2-(3-hydroxyphenylthio)benzylamine (compound IA) and the respective 3-methoxy-phenylthio-analog (compound ccc IB), are available by different per se known preparative routes, such as e.g. reduction of the corresponding amide of the general formula II

R

C S (II)

CON(CH

3 )2 in which R has the same meaning as in formula I, with hydride agents, e.g. lithium aluminium hydride, or with nascent diborane (from NaBH 4

+BF

3 The subject methoxy-compound can advantageously be prepared by Leuckart 7107S/LN -3- ~1~17- I.il-. .:-11ir reaction from 2-arylthiobenzaldehydes of the general formula

III,

R

CHO

in which again R is the same as in formula I, with dimethylformamide and formic acid at approx. 170 to 1800C.

S 15 The desired hydroxy-compound IA is then obtained by demethylation of the preceding by per se known methods, e.g.

by heating with pyridine hydrochloride at approx. 180 to oa 220 0 C, boiling with concentrated hydrobromic acid or by reaction with boron tribromide in aprotic polar solvents 000 0..0 20 such as chloroform at ambient temperature.

00 Starting amides of formula II are novel compounds which can be prepared by current techniques starting with the o 00 respective carboxylic acids; these are known materials and 0Q 0 0 w are manufactured mostly by reaction of 2-iodobenzoic acid with 3-hydroxy- or 3-methyoxythiophenol in boiling aqueous potassiumhy~ a solution in the presence of copper. In case of said hydroxy-intermediate the resulting 2-(3-hydroxyphenylthio)benzoic acid is immediately reacted a..t with dimethylamine, e.g. in the presence of triphenylphosphine-tetrachloromethane complex in tetrahydrofuran.

0 r The structure of the novel products was verified using 4" common analytical and spectral methods. For preparing the respective medicinal dosage forms and pharmacological 35 evaluation the base of compound 1 is advantageously converted into crystalline, more readily water-soluble addition salts with pharmaceutically acceptable organic or inorganic acids.

71 7 -4- U-1 T o oli'o'a~t a 1 Ci **jpt s i mi&dd^f ouio nt ep eec fcp e I 1.1~ iil. 1 -1 I-I-'YY. I~ 1II_1I i 00 0 0900 oo 0 0000 0 0 00 0 00 o o 000 0000 00 00 0 0 0 0 0 0tt C c r r c C c C Further particulars of the procedure are illustrated by subsequent nonlimitative examples.

Example 1 a/ 2-(3-Methoxyphenylthio)benzoyl chloride To a stirred solution of 30 g of 2-(3-methoxyphenylthio)benzoic acid (Bartl V. et al., collect.Czech.Chem.Commun. 38, 2301, 19731) in 250 ml of benzene there are added 2 drops of dimethylformamide, 45 g of thionyl chloride is dropped in and the mixture is refluxed for 2 hours. The volatiles are evaporated, the residue is dissolved while hot in 55 ml of cyclohexane and the solution is rapidly filtered and allowed overnight to crystallize to yield 30.4 g of 2-(3-methoxyphenylthio)benzoyl chloride, m.p. 101 101.5 0

C.

15 b/ N,N-Dimethyl-2-(3-methoxyphenylthio)benzylamide A solution of the preceding acyl chloride (24.1 g) in 180 ml of benzene is added dropwise at 10 0 C under vigorous stirring to 160 ml of 20% aqueous ne. Stirring is continued for 2 hours at room temperature and the benzenic 20 layer is separated, washed with water, filtered and evaporated under reduced pressure to give an oily residue (23.1 g, 93%) which crystallizes spontaneously on standing, m.p. 42 43 0 C (petroleum ether).

c/ N,N-Dimethyl-2-(3-methoxyphenylthio)benzylamine -Procedure A A solution of the preceding benzamide (22.1 g) in 350 ml of ether is added during 40 minutes to a stirred solution of 8.7 g of lithium aluminium hydride in 150 ml of ether. The mixture is refluxed for 6 hours and on cooling 30 it is decomposed by slow addition successively of 9 ml of water, 9 ml of 15% sodium hydroxide solution and 27 ml of water. After stirring for 20 minutes the solid material is filtered off, washed with ether and the filtrate is dried and evaporated to give oily crude product (19.5 g, its neutralization with a solution of hydrogen chloride in ether affords the crystalline hydrochloride, m.p. 149 150 0

C

(ethanol ether).

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cC ~~1 rr- .i I -I :iz ixr -I -e C LII-- c/ N,N-Dimethyl-2-(3-methoxyphenylthio)benzylamine -Procedure B To a solution of 68.7 g of N,N-dimethyl-2-(3-methylphenylthio)-benzamide in 470 ml of tetrahydrofuran are added with stirring under nitrogen 13.1 g of sodium borohydride, and 68.7 g (61 ml) of boron trifluoride etherate are dropped in within 1 hour at 20 to 27 0 C. The mixture is stirred for another hour at room temperature and then refluxed for 3 hours. On cooling it is acidified, under continuous stirring, by slow addition (within 30 minutes) of 190 ml of dilute hydrochloric acid (1:1 by vol.). The mixture is refluxed for 3 hours, cooled and made alkaline with 400 ml of a 20% sodium hydroxide solution. The aqueous phase is diluted with 200 ml of water and extracted with 1,2-dichloroethane, the combined organic t C extracts are dried and evaporated, thet eside is dissolved i in 40 ml of ethanol, slight excess of ethanolic hydrogen chloride solution and 40 ml of cyclohexane are added, and the solution is inoculated and allowed in a refrigerator to 4. 20 crystallize the yield is 58.9 g of N,N- ~fti -2-(3-methoxyphenylthio)-benzylamine hydrochloride, m.p. 147.5 150 0 C, which is int-eF with rtr the product of the preceding Procedure A.

Example 2 a/ 2-(3-Methoxyphenylthio)benzaldehyde Su' A mixture of 20.0 g of 3-methoxythiophenol (Mauthner Ber. Dtsch.Chem.Ges. 39, 3596, 1906), 40 ml of 20 g of potassium carbonate and 20.1 g of .2ct. 2 ~-4oben Ioaie is stirred for 5 hours at 90 0 C. After that it is diluted with 200 ml of water and extracted with benzene. Processing of the extract and crystallization of i" the crude product from 25 ml of methanol affords 28.5 g of the desired material, m.p. 63.5 64.5 0

C.

b/ N,N-Dimethyl-2-(3-methoxyphenylthio)benzylamine A mixture of 28.5 g of 2-(3-methoxyphenylthio)benzaldehyde, 43 g of Cc I -6dimethylformamide and 26.8 g4E- formic acid is refluxed under stirring for 6.5 hours (bath temperature 180 0 On cooling there is added 5% hydrochloric acid (170 ml), the solution is washed with ether, the aqueous acidic portion is made alkaline with 20% sodium hydroxide and the liberated base is separated by extraction with 1,2-dichloroethane.

Processing of the extract gives 30.3 g of the crude product, which is then converted into the hydrochloride (27.1 g, m.p. 149 150 0

C.

Example 3 N,N-dimethyl-2-(3-hydroxyphenylthio)benzylamine A mixture of 214 g of N,N-dimethyl-2-(3-methoxyphenylthio)-benzylamine hydrochloride and 850 ml of 47% hydrobromic acid is refluxed under stirring for 8 hours at 120 0 C. On cooling it is poured into 1.85 liter of water and made alkaline to pH 9 by a slowly adding 1200 ml of 20% sodium hydroxide solution.

°o Extraction with 2.5 liter of 1,2-dichloroethane and 20 processing of the extract yields 170 g of the desired crystalline base, m.p. 107 108 0 C (methanol); hydrogen maleate, m.p. 123 -124 0 C (ethanol ether), hydrochloride, 0 gj m.p. 165 166 0 C (ethanol), hydrobromide, m.p. 150 151°C (ethanol ether).

C C] i S 7S/LN -7t <rr

Claims (2)

1.

2-Phenylthiobenzylamine derivatives of the general formula I R ~CH 2 N(CH 3 2 in which R is a hydroxy or methyoxy group, and addition salts thereof with pharmaceutically acceptable organic or S%15 inorganic acids. *too 0.002. N,N-Dimethyl-2-(3-hydroxyphenylthio)benzylamine and acid addition salts thereof. 0 0 ct3. N,N-Dimethyl-2-(3-methoxyphenylthio)benzylamine 0 4 -,Poo and acid addition salts thereof. 0)0 00 0" 20 4. 2-Phenylthiobenzylamine derivatives substantially as disclosed herein in conjunction with any one of the examples. 64 t bo~ DATED this 11th day of May 1989 spoien6 Podniky Pro zdravotnickou vvsrobu By their Patent Attorneys GRIFFITH HACK CO. 710 7S/LN