DK160090B - ANALOGY PROCEDURE FOR PREPARING BENZHYDR YLSULPHINYLETHYLAMINE DERIVATIVE - Google Patents

Abstract

1. Derivatives of N-(benzhydrylsulfinylalkyl)- amine, characterized in that they are selected from among the group constituted by : a) the N-[2-(benzhydrylsulfinyl)ethyl]amines of general formula (I) see diagramm : EP0097546,P4,F2 (wherein R represents a C1 -C4 alkyl group), and b) their acid addition salts.

Description

in

DK 160090 B

The present invention relates to an analogous process for the preparation of a novel benzhydrylsulfinyl-ethylamine derivative as set forth in the preamble of claim 1. The present novel compound is useful in the treatment of depressive disorders, especially in the elderly.

The hydrochloride salt of N- [2- (benzhydrylsulfinyl) ethyl] amine is disclosed as an intermediate in the synthesis of 10 disulfide-sulfoxide derivatives by R.G. Hiskey et al., In J.

Org. Chem. 32, pp. 3191-3194 (1967), without examining the possible therapeutic properties of the compounds. French Patent Application No. 76-29137 and corresponding U.S. Patent No. 4,066,686 disclose derivatives of type N- (benzhydrylsulfinylalkyl) amines, especially as compounds active against the central nervous system (CNS).

Surprisingly, it is found that novel derivatives of N- (benzhydrylsulfinylalkyl) amine exhibit interesting neuropsychopharmacological properties as antidepressants compared to the compounds subject to Examples 4 and 5 of the above-mentioned patent, respectively N - [2- (benzhydrylsulfinylethyl] morpholine (CRL 40221) and N- [2- (benzhydrylsulfinyl) ethyl] piperidine (CRL)

40222).

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The compounds of the invention comprise: a) N- [2- (benzhydrylsulfinyl) ethyl] methylamine formula: 0. . CH-SO-CK -CH 2 -NH-CE, (i) 15 and b) acid addition salts thereof.

Suitable acid addition salts are non-toxic acid addition salts obtained by reaction between the free base of formula (I) and an organic or inorganic acid. Suitable acids for this are hydrochloric, hydrobromic, sulfuric, phosphoric, saline, picric, formic, acetic, propionic, fumaric, maleic, malic, tartaric, citric, oxalic, benzoic, cinnamic, ascorbic and ascorbic. , p-toluenesulfonic acid, aspartic acid and glutamic acid, especially hydrochloric acid.

The compound of formula (I) has an active effect on the CNS: it acts as an anti-depressant on the CNS and exhibits a useful anti-aggressive effect.

The compound of the code CRL 40883, which is a product made by the analogous process of the present invention, does not induce the excitation phenomenon as opposed to the product CRL 40221.

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The reactivities of CRL 40883 are relatively diminished relative to that of compounds CRL 40221 and CRL 40222.

5 CRL 40883 exhibits an anti-aggression effect on group dividing mice as opposed to CRL 40221 and CRL 40222; movement after hypoxia is not diminished by CRL 40883, while this is the case for the other two products.

10

When interacting with apomorphine, CRL 40883 elicits an antagonism of the hypothermia, while the other two do not.

It should be further noted that CRL 40221 and CRL 40222 at a dose of 50 mg per twice daily dose in humans causes abdominal pain, nausea and a feeling of heavy bones; Therefore, clinical trials of these two antidepressants have been stopped. In contrast, CRL 40883 is tolerated at doses of 50 and 100 mg per day. dose, and a good antidepressant effect has been demonstrated in the elderly, especially an awakening effect which is quite unexpected in relation to the effects of CRL 40221 and CRL 40222.

25

Thus, these are useful drugs in that they do not exhibit the drawbacks of tricyclic antidepressants (dryness of the mouth, shaking, constipation, confusion of the mind).

30

To summarize, the comparison table below illustrates these different conditions.

One may recommend a therapeutic composition containing in association with a physiologically acceptable excipient at least one compound of formula (I) or a non-toxic acid addition salt thereof as the active ingredient.

DK 160090 B

ingredient.

The subject compound of formula (I) is prepared by a method well known in itself using 5 classical reaction mechanisms. The process of the invention is illustrated by the reaction scheme: (c6h5) 2ch-sh (II) 10 +

Br-CH2 CH2-NHCH3 (III) (c6h5) 2ch-s-ch2ch2-nhch3 (IV) H2 ° 2 (CgHg) 2CH-SO-CH2CH2-NHCH3 (I) 20 and the process of the invention is characterized by the method of claim 1. characteristic part stated.

The compound Code CRL 40883 prepared by the analogous process of the invention has as the hydrochloride salt melting point 128-130 ° C.

The process of the invention and compounds of the invention are described in more detail in the following examples.

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DK 160090 B

PREPARATION I

Preparation of the Hydrochloride Salt of N- [2- (Benzhyd-ylsulfinyl) -ethyl] -methylamine 5 (Example 1; code no .: CRL 40883).

1) The hydrochloride salt of N- [2- (benzhydrylthio) -ethyl] -methylamine 10 g (0.075 mole) of diphenylmethanethiol in suspension in 75 ml of water is transferred to brine with 16 g (0.4 mole) of sodium hydroxide dissolved in 25 ml water. The mixture is heated to reflux and drop by drop in this mixture is added a solution of 17.6 g (0.08 mole) of hydrogen bromide salt of N- (2-bromethyl) methylamine in 50 ml of water. The mixture is kept under reflux for 1 hour, cooled, extracted with ether, washed with water. The ether solution is extracted with 100 ml of 2N hydrochloric acid and the base precipitates 20 with concentrated NaOH. The base is redissolved in ether, the ether phase is washed with water, dried, and the desired hydrogen chloride salt is precipitated by the addition of ethanolic hydrogen chloride. The precipitate is aspirated, washed with ethyl acetate and obtained by recrystallization from ethanol the hydrogen chloride salt of N- [2- (benzhydrylthio) ethyl] methylamine in a yield of 71%. Mp. = 121-122 ° C.

2) CRL 40883 14 g (0.05 mole) of hydrochloride salt of N- [2- (benzhydrylthio) ethyl] methylamine is oxidized in solution in 50 ml of acetic acid using 5 ml of H2 C> 2 with the strength of 110 volumes (i.e. a solution of H 2 O 2, which can release 110 times its volume in the form of gaseous H 2 O 2) for 1 hour at 40 ° C. The acetic acid is evaporated under vacuum, the residue is redissolved in acetone and the precipitate formed is aspirated. Recrystallization is obtained from a mixture of ethanol and ethyl acetate (1: 1) v / v CRL 40883 with a yield of 58%. Mp. = 128-130 ° C.

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In the following, results are obtained from neuropsychopharmacological tests conducted with CRL 40883 (the product of Example I). In these experiments CRL 40883 was dissolved in distilled water at pH 5 by intraperitoneal route in a volume of 20 ml / kg in male mice and in a volume of 5 ml / kg in male rats, or as indicated in the table material.

A - Toxicity

For male mice, the value of DL-30 at intraperitoneal ingestion of CRL 40883 is in the order of 250 mg / kg.

B - General behavior and reaction skills

Groups of 6 animals were observed before, and then after 15 mi-20 nuts, 30 minutes, 1 hour, 2 hours, 3 hours and 24 hours, all after administration of CRL 40883.

1) In mice 25 Compound CRL 40883 did not cause significant modifications in behavior and responsiveness at doses of 64 mg / kg, 16 mg / kg, 4 mg / kg and 1 mg / kg. A moderate sedative effect was observed, especially at the dose of 128 mg / kg.

2) In rats

At a dose of 32 mg / kg, a decreased responsiveness to touch and a muscular hypotony was observed for 30 minutes; at the dosage of 8 mg / kg, 2 mg / kg and 0.5 mg / kg no special symptoms were observed.

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Interaction with apomorphine 1 - Mouse

Holds on every 6 mice received CRL 40883 1/2 hour before subcutaneous injection of apomorphine at a dose of 1 or 16 mg / kg.

DK 160090 B

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At doses of 16 and 64 mg / kg, CRL 40883 partially counteracts the hypothermia induced by apomorphine without modifying the behavior in terms of verticality and stereotypes.

Interaction with amphetamine

Amphetamine (2 mg / kg) is injected by intraperitoneal administration to teams of 6 rats 1/2 hour after administration of CRL 40883.

I-1-1-1-1-1 I ICumulated | | | | ICRL 40883 IIndex Avg % of |% | Duration |

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I 0.5 I 21.50 I 108 I + 8 I 170 | I 2 I 23.17 I 117 I + 17 I 180 | I 8 I 22.83 [115 1 + 15 | 180 | I 32 I 43.33 I 218 | + 118 | 300 |

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With a high dose (32 mg / kg), CRL 40883 reinforces the amphetamine-induced stereotypes.

Interaction with reserpine 4 hours after intraperitoneal injection of 2.5 mg / kg reserpine received hold on 6 mice CRL 40883.

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At the dosages used, CRL 40883 very weakly counteracts the reserpine-induced hypothermia without modifying ptosis.

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Interaction with oxotremorine CRL 40883 was administered to 6 mice 1/2 hour before intraperitoneal injection of 0.5 mg / kg oxotremorine.

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At high doses (64 mg / kg), CRL 40883 counteracts the hypothermia-inducing effect of oxotremorine.

Impact on group aggressiveness

Groups of 3 mice received CRL 40883 after staying 3 weeks in each of their respective halves of a cage separated by opaque closure. The two groups in the same cage were united by removing the closure and recording the number of fights that lasted for 10 minutes.

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At the dosages used, CRL 40883 caused a reduction in the number of fights.

Comparative Table 5 I-1-1-1-1 I JCRL 40 221 I CRL 40 222 | CRL 40 883 | I-1-i-1-1 | Mg / kg / I / P 164 32 16 8 4 | 64 32 16 8 4 164 32 16 8 4 | 10 | -1-1-1-j | Excitations | + + + + J 0 | O [I-1-1-1-1 | Reactivities | + | + + + + + | | I-1-1-1-1 15 | Temperature [Decrease | | | in Ise | 0 | 0 | I-1-1-1-1 | 4-plate test | Increases mo- | | | | | derat number | | | 20 | The penalty of punishment | | | | | fairy passenger [0 | 0 | I-1-1-1-1 | Amphetamine- | Increases by | Decreases | Increases by | | stereotypes | 128 mg / kg | at 4 mg / kg | 64 mg / kg | 25 I-1-1-1-1 IAggressiveness I | [Decrease | | within | 0 | 0 | at dose of |

I group | | | 16 and 64 | I I I | mg / kg / I / P | 30 I-1-1-1-1 IB Mobility | Reducer | Reducer | 0 | In post hypoxia | | | | I-1-1-1-1 IV Interaction | | | Antagonism | 35 | ning with | | | against hypother- | | apomorphine | 0 | 0 | ant |

I_I

Claims (1)

GOSQB Patent claim: Analogous process for the preparation of a benzhydryl-sulfinylethylamine derivative of the formula: / TV 10 CR-SO-CH successively 20 a) reacting diphenylmethanethiol of formula (CgHg ^ CH-SH (II) and N-CH3-2-bromethylamine of formula Br-CJ of compound (III) per ml. 1 mole of the compound (II) in water in the presence of a base, preferably NaOH or KOH, under reflux for at least 1 hour to give a benzhydrylthioethylamine of the formula (CgHg 2 -CH-S-Cl -NHRCHg (IV) to b) subject the benzhydrylthioethyl-30 amine thus obtained to an oxidation reaction in acetic acid using hydrogen peroxide having a strength of 110-130 vol. with such a concentration of 2Q 2 'that it can release 110-130 times its own volume in the form of 1 2 O 2, at a temperature of 40-45 ° C for 1 hour, and then, if desired, convert the reaction product to an acid addition salt .