IE54988B1 - Benzhydrylsulfinylacetamide derivatives - Google Patents

Benzhydrylsulfinylacetamide derivatives

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IE54988B1
IE54988B1 IE1277/83A IE127783A IE54988B1 IE 54988 B1 IE54988 B1 IE 54988B1 IE 1277/83 A IE1277/83 A IE 1277/83A IE 127783 A IE127783 A IE 127783A IE 54988 B1 IE54988 B1 IE 54988B1
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crl
benzhydrylsulfinylacetamide
derivative
formula
represent
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IE1277/83A
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Lafon Labor
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/182—Radicals derived from carboxylic acids
    • C07D295/185—Radicals derived from carboxylic acids from aliphatic carboxylic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/26—Psychostimulants, e.g. nicotine, cocaine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
    • C07C29/36—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring increasing the number of carbon atoms by reactions with formation of hydroxy groups, which may occur via intermediates being derivatives of hydroxy, e.g. O-metal
    • C07C29/38—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring increasing the number of carbon atoms by reactions with formation of hydroxy groups, which may occur via intermediates being derivatives of hydroxy, e.g. O-metal by reaction with aldehydes or ketones
    • C07C29/40—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring increasing the number of carbon atoms by reactions with formation of hydroxy groups, which may occur via intermediates being derivatives of hydroxy, e.g. O-metal by reaction with aldehydes or ketones with compounds containing carbon-to-metal bonds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C321/00—Thiols, sulfides, hydropolysulfides or polysulfides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C33/00—Unsaturated compounds having hydroxy or O-metal groups bound to acyclic carbon atoms
    • C07C33/18—Monohydroxylic alcohols containing only six-membered aromatic rings as cyclic part
    • C07C33/24—Monohydroxylic alcohols containing only six-membered aromatic rings as cyclic part polycyclic without condensed ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/08—One of the condensed rings being a six-membered aromatic ring the other ring being five-membered, e.g. indane
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/10—One of the condensed rings being a six-membered aromatic ring the other ring being six-membered, e.g. tetraline

Abstract

For the Contracting States : BE, CH, DE, FR, GB, IT, LI, LU, NL, SE 1. A novel benzhydrylsulfinylacetamide derivative characterized in that it is selected from the group consisting of compounds of the general formula : see diagramm : EP0097071,P21,F1 wherein - X1 and X2 , which may be identical or different each represent H, Cl or F, - Z1 represents CH3 , CH2 CH3 , CH(CH3 )2 or C(CH3 )3 , Z1 may represent the hydrogen atom when at least one of X1 and X2 is different from H, - Z2 represents H ; NZ1 Z2 considered together may represent a piperidino or morpholino group. For the contracting state AT 1. A method for the preparation of a novel benzhydrylsulfinylacetamide derivative of the general formula : see diagramm : EP0097071,P22,F1 wherein : - X1 and X2 which may be identical or different each represent H, Cl or F, - Z1 represents CH3 , CH2 CH3 , CH(CH3 )2 or C(CH3 )3 , Z1 may represent the hydrogen atom when at least one of X1 and X2 is different from H, - Z2 represents H ; NZ1 Z2 considered together may represent a piperidino or morpholino group, characterized in that an acid chloride of general formula see diagramm : EP0097071,P22,F2 wherein X1 and X2 are as defined above, is reacted with an amine of general formula HNZ1 Z2 wherein Z1 and Z2 have the above definition, to a benzhydrythiocetamide derivative of general formula see diagramm : EP0097071,P22,F3 wherein X1 , X2 , Z1 and Z2 are as defined above, and the obtained benzhydrylthiocetamide derivative of formula (IV) is oxidized.

Description

2 5 4 9 8 8 The present invention relates to benzhydrylsulfinylacetaniide derivatives as industrial products. It relates also to the use of these derivatives in therapeutics, particularly as medicaments active on the central nervous system (CHS).
From U.3. Patent No. 4 177 290, it is known that benzhydrylsulfinylacetamide (described in Example 1 and having the code No. "CEL 40 476") has a particular neuro-psychophamacological spectrum: - presence: 10 excitation with hyper-reactivity hypermotillty, and - absence: 15 of stereotypies (except at high doses), potentiation of apomorphine and amphetamine effects. Derivatives of benzhydrylsulfinylacetaniide arc now recognised which have interesting pharmacological properties.
The derivatives of benzhydrylsulfinylacetaniide according to the invention correspond to the general formula a (I) in which - X^ and X„, which may be identical or different, each - 3 - 54988 represent H, Cl or F, - Z1 represents CHy CHgCEj, CH(CH3)2 or C(CH3)3, and Z1 can represent in addition a hydrogen atom when at least one of X1 and X2 is different from Hf - Z2 represents H, and NZ^Zg considered together can represent a piperidino or morpholino group.
The preferred groups X1 and X2 are H, 4-C1 and 4-F.
In Table 1 below, are given, in non-limiting manner, a certain number of compounds according to formula I, stating their essential activity on the CNS.
The products of formula I can be prepared by a method knov/n in itself by the application of conventional reaction mechanisms, for example, by employing one of the two methods described in the aforesaid U.S. Patent. The process recommended here consists: 1) of reacting an acyl chloride of the forraula (where X1 and Xg are defined as above) with an amine HNZ.J Zg (III) (where Z1 and Zg are defined as above) to obtain a derivative of benzhydrylsulfinylacetamide of the formula .(IV) - 4 - 54988 (where , X?, Z1 and Zg are defined as above), and 2) subjecting the above-said derivative of benxhydrylthio-acetamide to an oxidation reaction preferably by msans of no-130 volume. Ho02 (i.e. a solution in water containing from about 5 32 g/l to 40 g/l of hydrogen peroxide) at a temperature below or equal to 45°C, The compounds of formula I all act on the CNS. The products of Examples 1-3 and 7-8 are stimulant agents, on the other hand the products of Examples 4-6 are sedative agents, lo A therapeutic composition is recommended which contains in association with a physiologically-acceptable excipient at least one compound of formula I as active ingredient. This active ingredient is, of course, used in a pharmaceutically effective amount. - 5 - 54988 C0Sοaο χΗ S2 Η p P P P P P £ £ £ o 0 © a £ £ <0 d d ?* ;> > d d d H H H •H Ή •H H H H g £ 3 P P P 2 g g « •H g •H •5 id -d ri ♦d d »d •H £ •H ¢3 •S P +3 P OJ X Η £* β3 Ο ο Ο ΙΛ Ο °? 8 Ο Η CO O o o 0 0 0 ϋ ϋ VO OJ O VO 0 0 sr O 0 VO a O H H σι r—{ in i 1 l I in 1 t-i ΙΛ H H C\J CVI CM OJa a a a a a a a O Cl, t,a a a a a i t i oao τ) O O < < 9σισινοσισ>ίοο® OICJcOCOCOCOTH ^^cno't'tcri^oooooooooo Ό <ί· $ ao P ϋ 3 8PU r-C\JcO^"lrtVOt>COai (U ©> •rt 4-> P «3 © _ &· ft B1 & sr· - Qa i i s I I I a s sS - 6 - 5 4 9 8 8 The compounds of the formula X according to the invention mainly differ from previously known benzhydrylsulfinylacetamide (CRL 40476) in view of their action on sleep induced by a barbituric compound: the 5 compounds of formula I diminish the sleep duration induced in male mice (batch of ten animals per doses and per product to be tested) by pentobarbital (50mg/kg I,P. administered 0.5h after administration byI.P. route of product to be tested) while CEL 40476 does not modify the pentobarbital sleep 10 duration. This difference which is therapeutically useful is illustrated by Table IV. -7- 54988 TABLE IV Product Code No Action on Pentobarbital (50mg/kh j.P.) sleep duration dose effect Example 1 CEL 40920 128wg/kg l.P. (a) Example 2 CEL 40929 256mg/ldi l.P. (a) Example 4 CEL 40936 64mg/lch l.P. (a) Example 4 CEL 40936 128mg/kg l.P. (a) Example 4 CEL 40936 256mg/kg l.P. (a) Example 5 CEL 40489 128mg/kg l.P. U) Example 7 CEL 40933 ,8mg/kg l.P. (a) Example 8 CEL 40940 32mg/kh l.P. (a; Example 9 CEL 41018 16mg/kh l.P. (a) Comparative product CEL 40476 from 8 to 256mg/kh I.P. (b) Notes: (a) important diminution of sleep duration. (b) no significant modification of sleep duration. • Below are given some examples of the preparation, which are in no way limiting hut given purely by way of illustration, of compounds according to the invention. PREPARATION I Obtaining of 4-N-methyl-benzhydrylsulfinylacetamide (Example 1; code nos CRI 40920) 1) Benzhydrylthioacetic acid Into a triple-necked flask, are placed 91.2 g (1.2 mole) of thiourea in a mixture of 520 ml of 485S (w/v) HBr and 80 ml of water. The reaction medium is brought to 60°C and 484 g (1 mole) of benzhydrol is added in one batch. The temperature is raised to 95°C and then cooled : the thiouronium hydrobromide precipitates in the form of small orange beads. The latter are filtered and made into a paste several times in water.
The thiouronium salt thus obtained is introduced into a tripled-necked flask with 320 ml of caustic soda (d = 1.38; 3«2 moles); it is brought to 70°C and drop by drop a solution of 103.95 g (1·1 mole) of chloracetic acid in 200 ml of water are added drop by drop. After the addition, it is brought to reflux and kept there for 30 min; an insoluble material is formed, and the latter is separated by filtration hot, then the filtrate is cooled and acidified with concentrated HC1 : the benzhydrylthioacetic acid precipitates. The latter is drained and washed with water.
The benzhydrylthioacetic acid is purified by redissolving hot in a dilute soda solution ; the alkaline - 9 - - 9 - 54988 solution thus obtained is filtered on charcoal, cooled and acidified with concentrated HCl. The precipitate so obtained is drained and washed with water. 90.4 g of benzhydrylthioacetic acid is collected 5 (yield = 35*) (MP-inst. = 130°C). 2) Benzhydrylthioacetic acid chloride Into a triple-necked flask, are placed 25.8 g (0.1 mole) of benzhydrylthioacetic acid in 150 ml of benzene, the mixture is heated and drop by drop under 10 reflux 25 ml (0.343 mole) of thionyl chloride added.
Once the addition is terminated, the reflux is continued for about 1 h-1.5 h, cooled, and the excess benzene and thionyl chloride evaporated. In this way a clear orange oil is collected. 3) N-methyl-benzhydrylthioacetamide Into a tripled-necked flask provided with a condenser,a thermometer and a dropping funnel, are introduced to 28 ml (about 0.3 mole) of methylamine in 50 ml of water and drop by drop the previously obtained acid 20 chloride (about 0.1 mole) dissolved in about 100 ml of methylene chloride, is added.
The mixture is left in contact over night ; the next day the organic phase is washed with water, then with a dilute soda solution and again with water. It is 25 dried over Na^SO^, and the methylene chloride evaporated, the precipitate so obtained being taken up again with diisopropyl ether.
After recrystallisation in isopropanol 22.3 g (yield = 82f£) of N-methyl-benzhydrylthioacetamide are obtained,(IIP.inst = 101-102°C) which is in the form of a white powder. 4) CR1 40920 Into a. round-bottomed flask are placed 16.26 g (0.06 mole) of the acetamide previously obtained, 60 ml of acetic acid and 6.6 ml of HgOg (at about 130 volumes), are added; the temperature rises to 40°C and then drops again. When all the sulfide has disappeared, the acetic acid is evaporated, and. it is taken up again with water ; the N-methyl-benzhydrylsulfinylacetamide precipitates.
The latter is drained and washed several times with water.
.After recrystallisation in ethyl acetate 13.8 g (yield = 80^) are collected ; CEL 40920 (HP. = 80-85°C).
CEL 40920 is a white powder, insoluble in ether and ethyl acetate, soluble in methanol, ethanol and acetone. Its solubility in water is less than 1 g/l. PREPARATION II Preparation of N-(benzhydrylsulfinylacetyl)-piperidine (Example 5jCodeN.o: CRL 40489) 1) N-(benzhydrylthipacetyl)-pip eridine Into a triple-necked flask provided with a condenser and a dropping funnel, are placed 29 ml (0.3 mole) of piperidine in about 50 ml of ether and drop by drop 27.2 g (Ο.Ο98 mole) of benzhydrylthioacetic acid chloride in solution in about 100 ml of benzene are added. Once the addition is finished, water is added to the reaction mixture. The organic phase is washed with a - 11 - - 11 - 54988 dilute solution of soda, dilute. HC1, then with water, dried over Na2S0^, the solvent evaporated, it is taken up again with a mixture of diisopropyl-ether-petroleum ether. The expected product crystallises. After recrystallisation in ethyl acetate,?1,? g are collected (yield - 68,··) of U-(benr/.hydrylthioacetyl)-piperidirie. ^•inst. = «?-83°C). 2) CRl· 4048-9 Into a flask are placed 16.25 £ (0.05 mole) of N-(benzhydrylthioacetyl)-piperidine and 50 ml of acetic acid and 5-3 ml of H202 (at about 110 volumes) are added. The reaction mixture is left overnight at 15-25°C, then the acetic acid is evaporated. The residue after evaporation is taken up with ether to crystallise the expected product. 3y recrystallisation in ethyl acetate 12.7 g (yield = 77^) ore obtained of CRl 40489 (^P'inst = 150°0). The solubility of this product in water is less than 1 g/1.
PREPARATION III Preparation of 4-chlorobenzhydrylsulfinylacetamide (Example 7; Code No: CRl 40933)· 1) 4-chlorobensh^drol Into a solution of 0.35 mole of phenylmagnesium bromide in 300 ml of anhydrous ether, are run at 20°C a solution of 49.? £ (Ο.35 mole) of parachlorobenzeldehyde in 300 ml of anhydrous ether. After 2 h reflux and standing overnight, the precipitate is drained, washed twice with 50 ml of ether and the resulting filtrate is - 12 - 5 4988 poured into a vigorously stirred mixture of 200 ml of 6H HC1 and 500 g of ice. The precipitate is drained, washed with water, dried and recrystallised in the mixture methanol-water (80t20) v/v; the 4-chlorobenzhydrol 5 in obtained (HP = 60-61°C) with a 70yield. 2) 4-chlorohenzhydrylthioacetic acid 7.6 g (0.1 mole) of thiourea are dissolved in 50 ml of 48$ HBr. It is heated to 40°C and simultaneously 50 ml of ethanol and 17.5 g (0.08 mole) of 4-chloro-10 benzhydrol added, then it is heated 0.25 h under reflux.
The alcohol is evaporated under vacuum, 50 ml of cold water added, the thiouroniura salt is drained and washed twice with 20 ml of cold water. The moist precipitate is resuspended in 100 ml of water, a solution of 16 g of 15 caustic soda in 100 ml of water added and it is heated 0.25 h on a boiling water bath. Then drop by drop at 60-70°C are added a solution of 9.45 g (0.1 mole) of chloroacetic acid, 5g of Ma^CO-j and 100 ml of water. It is heated for 1 h on a boiling water bath, acidified with 20 3ΐί HC1, extracted with ether, the ether phase extracted with dilute bicarbonate, the alkaline solution is filtered over charcoal, it is precipitated with 3N HC1, drained, washed with water, dried and the expected acid obtained (HP = 101-102°C) with a 9C# yield. 3) 4-chlorobenz^drylthioacetamide A. solution of 11.7 g (0.04 mole) of 4-chloro-benzhydrylthioacetic acid in 60 ml of benzene and 12 ml of S0C1?, are heated for 1 h under reflux, evaporated - 13 - - 13 - 54988 under vaccuum, the oil is taken up again with 50 ml ether and poured slowly, cold, with stirring into 50 ml of 28$ ammonia. It is stirred 1 h, the ether is decanted, washed with water, dried, the ether driven off under vaccuum, the residue crystallised in petroleum ether and the expected amide is obtained (MP= 52-53°C) with a 90$ yield. 4) CRL 40933 1?.3 g (0.049 mole) of 4-chiorohenshydrylthiosceta-mide in solution in 40 ml of acetic acid are oxidised at 40-45°C with 4.2 ml of 110 volume hydrogen peroxide. The acetic acid is evaporated under vacuum, the residue is crystallised in diisopropyi ether and recrystallised in ethyl acetate. In this way CRL 40933 is obtained with a 5 2$ yield. MP = 145-146°C.
PREPARATION IV Preparation of 4,4l-difluorobeng:hydrylsulfinylacetamide (Example 8; Code No: CRL 40940) 1) 4_j41 -di Into a solution at 50°C of 11.4 g (0.15 mole) of thiourea in 75 ml of 485¾ HBr, are added simultaneously' 75 ml of ethanol and 26.4 g (0.12 mole) of 4,4’-difluoro-benzhydrol. It is heated 0.25 h under reflux, the alcohol evaporated under vacuum, 50 ml of cold water added, it is drained and washed twice with 20 ml of cold water, The precipitate is collected, then suspended in 150 ml of water. The resulting mixture is treated with a solution of 20 g (0.5 mole) of caustic soda in 100 ml of water. - 14 - 54988 It is brought to reflux 0.25 h and then at 70-75°C, are added drop by drop a solution of 18 g of chloroacetic acid, 100 ml of water and 9 g of sodium carbonate.
After 1 h under reflux, it is acidified with 3N HC1, 5 drained, washed with water. It is taken up again in water, treated with sodium bicarbonate, filtered over charcoal and precipitated with 3N HC1. After draining, washing with water and then drying, the expected acid is obtained (MP = 117-118°C) with 87$ yield. 2) 4,4 * -Mf luor ohenzhydrylthioacetamide A solution of 14.7 g (0.05 mole)) of 4,4'-difluorobenzhydrylthioacetic acid in 75 ml of benzeme and 15 ml of thionyl chloride are heated 1 h under reflux.
It is evaporated under vacuum, taken up again with 50 ml of ether and run into a mixture of 60 ml of 28$ ammonia and· 100 g of ice, with stirring. It is stirred 2 h, the ether decanted, washed with water, dried, evaporated to dryness trader vacuum, the residue 20 taken up again with petroleum ether and drained. The expected amide is obtained (MP = 73-74°C) with a 98$ yield. 3) CRL 40940 13 g (0.046 mole) of 4,4-difluorobenzhydryl-thioacetamide in solution of 40 ml of acetic acid are 25 oxidized with 4.6 ml of 110 volume H20?· It is evaporated under vacuum, taken up again with water, drained, the precipitate washed with water. By recrystallisation in ethanol, CRL 40 940 is obtained with an overall yield of 64$ (MP. = 101-102°C). - 15 - £4988 Below are summarised the results of the pharmacological tests which have been undertaken with the products according to the present invention. In these tests, the products of formula I under study were administered intraperitonealLy, suspended in an aqueous gum srebic solution, in a volume of 20 ml/kg in the male mouse and in a volume of 5 ml/k£ in the male rat.
I TOXICITY, OVERALL BEHAVIOUR AND HEM3TIVITIES The toxicity was studied in the male mouse. The results relating to the ID (Minimal non-lethal dose) are given in Table II below.
To evaluate the overall behaviour and the reactivities the batches of six animals (male mice or male rats) were observed before administration of each product, then 15 min, 30 min, lh, 2h, 3h and 24h after administration of each product. The results are reported in Table III below.
TABLE II Product Code No Exan.pl e 1 CRL 40920 greater than 256mg/kg Example 2 CRL 40929 greater than 513ng/kg Example 4 CRL 40936 greater than 512mg/kg Example 5 CRL 40489 greater than 1024mg/kg Example 7 CRL 40933 greater than 256mg/kg Example 8 CRL 40940 greater than 256mg/kg Example 9 CRL 41018 greater than 5iang/kg - 16 - 54988 TABLE III OVERALL BEHAVIOUR AND REACTIVITIES Product (Code No) Observations 5 a) a mouse at 256iaff/kg: -dyspnea, excitation, no mortality at 128ii\g/k.q: 10 -excitation Example 1 -hypothermia (-1.5°C) £or0.5h (CRL 4092D) at 64iagAg: -excitation b) a rat 15 at 64ir.g/kg: -mydriasis for 3h 54988 - 17 - TABLE III (contd) Product (Code No) Observations Example 2 (CRL 40929) a) mouse at 512mg/kg: -shortness of breath, dyspnea, sedation, diminution of reactivity on touching, no excitation after 3h -no mortality at 256mg/kg: -sedation for 0.5h with diminution of respiratory frequency -hypo-reactivity on touching for 2h -moderate hypothermia (-1°C) for 0.5h -excitation 3h after administration at 128mg/kg: -sedation, then excitation 3h after adJiiinistration b) rat at 128mg/kg: -mydriasis for 3h - 18 54988 TABLE III (Contd) Product (Code No) Observations a) mouse 5 • at 10 24m.g/kg: -abdominal cramps, sedation and hypo-reactivity on touching, shortness of breath -slow mortality (66¾ of the 10 Example 7 animal) 24h after administration (CRL- 40933) at 512mg/kg: -abdominal cramps, sedation and hypo-reactivity on touching -slow mortality (33¾ of the 15 animal) 24h after administration at 256mg/kg: -abdominal cramps, shortness of breath then -e:-ccitation appearing 1.5h after 20 ad> .ini strati on at'128n\g/kg: -excitation appearing 1.5h after administration and for 3h -reactivity on touching - 19 - 54988 TABLE III (CoKtd) Product (Code No) Observations b) rat at 64mg/kg: 5 -muscular hypotonia for 3h Example 7 -shortness of breath for 3h (CSL 40933) -mydriasis for 2 to 3h at I6mg/kg: -mydriasis Ih after administration 10 a) mouse at 512mg/kg: - staggering gait -convulsions {66%. of the animals) for 0.75h 15 -mortality (4 animals in 6 in lhf then 2 animals in 6 in 24h) Example 8 (CEL 40940) at 256mg/kg: - -excitation starting 0.5h after administration 20 -stereotypi es -no mortality 20 - 54988 TABLE III (Contd) Product (Code Ho) Observations 5 at 128mg/kg: -excitation with stereotypies for 3h -increase in reactivity 0» touching for 24h -hypothermia (-1.3°C) for 3h 10 at 32ng/kg: Example 8 -late excitation beginning lh after administration and for 2h -stereotypies 3h after administ- (CRL 40940) ration 20 -reactivity on touching for 24h at 8i.'.g/kg: -late excitation starting 2h after administration 25 -reactivity on touching for 2h at 2iug/kg: 30 -reactivity on touching for 2h b) rat at 64rng/lcg: -excitation -reactivity on touching -increased respiratory frequency for 24h 21 TABLE III (Contd) Product (Code Ho) Observations Example 8 at I6mg/kg: -excitation (CR1 40940) -reactivity on touching for 2h Example 9 a) mouse at 256mg/kg: -excitation appearing in 30 minutes and maximum 2 to 3h after administration -presence of distinct but late stereotypies -reactivity on touching for 3h at 64mg/kg: (CRL 41018) -excitation appearing in 30 minutes and maximum after 2h and for 24h -late appearance (2-3h) - 4 stereotypic movements of lour \ 1 intensity -reactivity on touching for 2-3h at 16mg/kg: -excitation for Ih in 33Ji of the 1 1 _l animals - 22 - 54988 TABLE III (End) Product (Code No) Observations Example 9 (CRL 41018) b) a rat at 128mg/kg: -excitation for 2h with hyperreactivity on touching for 0.5h at 32mg/kg: -fleeting diminution (0.5h) of the reactivity on touching and of the' muscular tonus at 8mg/kg: -fleeting hypo-reactivity (0.5h) and diminution of muscular tonus II TESTS ON THE CHS Results of the tests relating to CRL 40933 (product of Exai-£le_7) A - INTERACTION WITH APOMORPHINE 1) Mouse 20 Batches of 6 mice per dose received · CRL 40933 0.5h before sub-cutaneous injection of apomorphine administered at the dose of 1 or 1 S.-rig/kg.
It is observed that, at a high dose (128ii.g/kg), CRL· 40933 modifies to the hypothermic action of 25 16 mg/kg of apomorphine without modifying the behaviour of verticalisaion and stereotypies. - 23 - 5 4 9 8 8 2) Rat The CRL 40933 is administered to batches of 6 rats 0.5h before sub-cutaneous injection of 0,5mg/kg of aporaorphine.
It is observed that the CRL 40933 does not modify the stereotypic behaviour induced by apomorphine in the rat.
B - INTERACTION WITH AMPHETAMINE •Amphetamine (2 mg/kg) is injected intraperitoneally into batches of 6 rats, 30 min after administration of CRL 40933.
It is observed that CRN 40933 does not modify substantially the amphetamine stereotypies; the diminutions observed are probably due only to the existence of a relatively high index of stereotypies which is observed in the control batch.
C - INTER.ACTION WITH RESERPINE Four hours after intraperitoneal injection of 2.5 mg/kg of reserpine, batches of 6 mice received CRL 40933.
At doses of 32 mg/kg and 128 mg/kg, it was observed that CRL 40933 was weakly opposed to the reserpine hypothermia without modifying the ptosis.
D - INTERACTION WITH OkD ΤΕΞ-IQ RIME The CRL 40933 was administered in batches of 6 nice 0.5 h before intraperitoneal injection of 0.5mg/kg of oxotremorine. The following was observed; 1) Effect on temperature: at high doss (128mg/kg) the CRL 40933 is weakly opposed to the hypothermic effect of oxotremorine; 2) Action on trembling: the trembling induced by oxotrenorine is not influenced by CRL 40933; 3) Effect on peripheral cholinergic symptoms; CRL 40933 does not Modify the signs of peripheral cholinergic stimulation due to oxotrenorine.
E - EFFECT PIT THE FOUR PLATE TEST, TRACTIO'.I AMD ELECTRO SHOCK The tests were carried out on batches of 10 Mice (per dose)0.5 h after adjainistration of CRL 40933.
It was observed that CRL 40933 did not result in a distinct increase in the number of passages punished; it does not cause a major motor deficit and, at high dose (3 2 -ig/' F - EFFECT ON SPONTANEOUS 1.0TILITY One half-hour after having received CRL 40933, the mice (6 per dose, 12 controls) were placed in an activity fteter where their motility was recorded for 30 mins.
It was observed that, at doses of 3 2n’.g/kg and 128 ug/kg, CRL 40933 resulted in a distinct increase in the spontaneous motor activity of the mouse. A diminution of motility was observed at the lowest dose used (2 -g/kg).
G - EFFECT OH INTERGROPP AGRSSSIVITY After a three-week sojourn in each of the halves of a cage separated by an opaque partition, groups of 3 mice received CRL 40933. 30 mins later, the two groups from the sane cage were combined by withdrawing the partition and the number of fights which ensued in 10 minutes was noted - 25 - 54988 It /was observed that CEL· 40933 does not distinctly modify intergroup agressivity.
H - ACTIOII WITH RESPECT TO 33ME PI STUBBED BEHAVIOUR BY VARIOUS AGECTS 1) deduced j_otility-by_becoi^in2_accustowcd_to_the_enclosure 5 After 18h of dwelling in the actimetres, the laice (6 per dose, 12 controls) received CEL 40933. They were iiijaediatcly replaced in their respective enclosure and, 30 mins later, their motility was recorded for 30 mins.
It is observed thatCRL 40933 causes a resumption lo in activity in the mouse accustomed to its enclosure. This· effect, hardly perceptible at 2 mg/kg and at 8 ing/kg,is distinct at a high dose (from 32 mg/kg to 128 mg/kg). 2) Reduced-Motility by hypoxic aggression Half an hour after having received CRL 40933, 15 1 the mice (10 per dose, 20 controls) are subjected to an acute hypobarie anoxia [low pressure'of 600« m Hg' (i.e. .about 8 x 10^ Pa) i-n 90 s,then relaxation for 45 s], then they are placed in an activitymeter where their motility is recorded for 10 mins.
It is observed that, at a high, dose (128 mg/kg), CRL 40933 brings about a distinct improvement in the motor recovery in the mouse whose activity had been depressed following a brief spell in an enclosure at reduced pressure. 3) Asphyxic Anoxia Batches of 10 mice receive CEL 40933 30 min before intraperitoneal administration of 32 mg/kg of gallamine triiodosthylate.
At a high dose (128 mg/kg), the CRL 40933 shortens the time of the appearance of convulsions and death consecutive to an asphyxic anoxia caused by a curare type agent.
I - INTERACTION WITH BARBITAL- Half an hour after admini strati on of CRL 40933, batches of 10 mice received an intrapetitoneal injection of 220 mg/kg of barbital.
It was observed that, from the dose of 8 mg/kg, CRL 40933 reduces the duration of sleep enduced by the barbital.
J - EFFECT OH "BEHAVIORAL DESPAIR" Half an hour after having received CRL 40933, batches of 10 mice per dose are placed in a restricted space filled with water up to a height of 6 cm; the period of immobility between the 2nd and the 6th minute'’following immersion is noted.
CRL 40933, at doses of 8 mg/kgf 32 mg/kg, but _> especially 128 mg/kg, reduces the duration of immobility.
K - CONCLUSION Neuropsychophaimacblogical study of CRL 40933 establishes in the male mouse: a) stimulant type effects: - excitation and hyperreactivity, - hypenuotility, - resumption of motor activity in the mouse accustomed to its enclosure, - improvement in motor recovery after hypobaric hypoxia - 27 - - 27 - 5 4 9 8 8 - antagonism of barbituric sleep; b) effects of antidepressor type which are weak; - antagonism of hypothermias induced by amomorphine, oxotremorine and reserpine, - reduction in "despair" immobility; c) anticonvulsant effects: - antagonism to electric convlusions.
According to tne operational methods given above, study of the action on the CNS \vith the other products has given the results reported below# Results of tests relating to CRL 40920 (the product of Example 1) A - INTERACTION WITH APOMORPHINE 1) Mouse At the dose of 128 mg/kg, CRL 409 2D is hypothermic and not opposed to hypothermia induced by apomorphine. CRL 4092D does not modify the behaviours of verticalisation and stereotypies. 2) Rat CRL 40920 leaves unchanged stereotypies induced by apomorphine.
B - INTERACTION WITH AMPHETAMINE CRL 4092D, ati.the doses used, practically does not modify amphetaminic stereotypies.
C - INTERACTION WITH RESBRPINE At the dose of 128 mg/kg, CRL· 409 2D antagonises hypothermia induced by reserpine·1 without modifying ptosis. - .28 - 54988 D - INTERACTION WITH O/PTRS-.ORIHE 1) Action on temperature At doses of 8 mg/kg to 128 mg/kg CRL 40920 is moderately opposed to the hypothermic action of oxotremorine. 2) Action on trembling CRL- 40920 does not modify the intensity of trembling caused by oxotremorine. 3) Action on peripheral cholinergic symptoms CEL 40923 leaves practically unchanged the signs 10 of peripheral cholinergic stimulation which appear after oxotremorine administration.
E - ACTION OR THE FOUR PLATE, TRACTION AND ELECTRO SHOCK TESTS CRL 409 2D does not result in any increase in the number of passages punished’; it does not cause any major 15 motor incapacity and does not modify the convulsant effects of electroshock.
F - ACTION ON SPONTANEOUS ROTILITY CRL 40920, at doses of 32 and 128 mg/kg results in a moderate increase in·, .the spontaneous motility of 20 the ...cuss.
G - ACTION OH INTERGROUP AGGRSSSIVITY CRL 409 2D does not distinctly modify the number ' of combats.
H - ACTION VJITH RESPECT TO SOME BEHAVIOURS DISTURBED BY 25 VARIOUS AGENTS ' 1) Motility reduced by · habituation to the enclosure At doses of 8 mg/kg, 32 mg/kg and especially 128 mg/kg, CRL 409 2D causes a resumption of motor activity in the mouse 30 accustomed to its enclosure. - 29 - - 29 - 54988 2) Motility reduced by hypoxic aggression CRL 4092D, at the dose of 128 mg/kg, results in a moderate improvement ( but not significant) in motor recovery in the mouse whose motility has been depressed following a brief sojourn in an enclosure at reduced pressure. 3) Asphyxic Anoxia CRL 40920 does not modify the delay in the appearance of convulsions and of death consecutive to asphyxic anoxia caused by a curarising agent such as gallamine triiodoothylete.
I - I INTERACT ION TOTH' BARBITAL- At the dose of 128 mg/kg, CRL 40920 distinctly reduces the duration of barbituric sleep. At a lower dose (32 mg/kg), CRL 40920 does not result in appreciable modification in the duration of sleep but in a distinct reduction in the number of sleeping mice.
J - ACTION ON "BEHAVIORAL DESPAIR11 At doses of 32 mg/kg and 128 mg/kg, CRL 4092D distinctly reduces the duration of immobility of the mouse placed in forced immersion.
K - CONCLUSION Ncuropsychophaimacological study of CRL 4092D reveals essentially than exciting component which results from - moderate increaseln motor activity; - resumption of motor activity in the mouse accustomed to its enclosure; - 30 - 54988 5 10 15 20 25 - antagonism to barbituric sleep; - reduction in imobility in the behavioral despair tost. Moreover, it could be that the antagonisms of certain hypothermias are only a reflection of motor stimulation. Results of tests relating to CEL· 40929 (product of Example 2) A - INTERACTION WITH AP01.0EPHINE 1) House CRL 40929 leaves -.hypothermia, behaviour of verticalisation and stereotypies produced by apomorphine, unchanged in the raouse. 2) Rat Stereotypies induced by apomorphine are not modified by CRL 40929. B - INTERACTION WITH AMPHETAMINE CRL 40929, at doses of 8 mg/kg to 128 mg/kg, seem to potentiate weakly araphetaminic stereotypies. C - INTERACTION TOTH RESERPIHE At high dose (256 mg/kg), CRL 40929 very moderately reduces reserpinic ptosis. D - INTERACTION WITH 0N3TRB.0RINE 1) Effect on temperature CRL 40929 practically does not modify the y hypothermic effect of oxotreir.orine· 2) Effect on tretabling At strong doses (256 mg/kg), CRL 40929 seems to reduce moderately the intensity of trembling caused by oxotremorine. - 31 - 54988 3) Effect on peripheral cholinergic symptoms At high doses (from 64 mg/kg to 255 mg/kg), CEL 40929 seems to result in a reduction in signs of peripheral cholinergic stimulation, particularly defecation.
E - ACTION ON THE POUR PLATE, TRACTION AND ELECTED STOCK TEST CEL 40929 docs not result in an increase of the nu..ber of passages punished; it does not cause a major motor deficiency but, at strong doses (from 64 mg/3cg to 256 mg/kg), modifies the convulsant effect of electroshock.
P - ACTION OH SPONTANEOUS MOTILITY At the dose of 256 mg/kg, CEL 40929 does not result in distinct-hypermotility· . · G - ACTION ON INTEEGEOUP AGGRESSIVITY It was observed that CEL 40929 is weakly anti-aggressive, since it very moderately reduces intergroup aggressivity in the mouse.
H - ACTION WITH EESPECT TO 3DME BSHAVIOUES DISTURBED BY VARIOUS AGENTS 1) Motility reduced by habituation to the enclosure At doses of 4 mg/lcg, 64 mg/kg and 256 mg/kg, CEL 409 29 seems to cause a resumption in activity in the v.ouse accustomed to its enclosure. Such an effect is not observed at the intermediate dose of 16 mg/kg. 2) Motility reduced by hypoxic aggression At doses of 64 mg/kg and especially 256 mg/kg, CRL 40929 results in a distinct improvement in motor recovery in the mouse accustomed to its enclosure. - 32 - 54988 3) Asphyxic Anoxia At doses of 64mg/kg and 256 mg/kg, CEL 40929 moderately retards the appearance of anoxic convulsions caused by gallamine triiodoethylate, I - INTERACTION TOTH BARBITAL At high doses (256 mg/kg), CEL 40929 reduces distinctly the duration of barbituric sleep.
J - ACTION ON " BEHAVIORAL· DESPAIR11 It was observed that, from the dose of 16 ‘‘mg/kg, 10 CEL· 40929 distinctly reduces the duration of immobility.
K - CONCLUSION Neuropsychopharmacoligical study establishes that CRL 40929 is a psychotropic agent due to the fact of: - its stimulant effect on spontaneous motility, motility 15 reduced by habituation, - its improvement of motor recovery after hypoxic aggression, its effect in the so-called "behavioral despair" test. Results of tests relating to CEL· 40936 (product of Example 4) 2o CRL 40936 shows at low and average doses in the mouse, a group of effects of the sedative (sedation, hypo-reactivity, hypoaggresivity, hypothermia) type as well as antagonism to the convulsant effect of electroshock.
The effects are observed however in the absence of any 25 reduction in motor activity.
On the other hand, at high doses, CRL 40936 causes the appearance of discrete hypermotility, moderate resumption of activity in the mouse habituated to its enclosure and an appreciable improvement in motor recovery 30 after hypoxia. - 33 - S4988 In addition, an antagonistic effect to barbituric sleep and a reduction in hypomotility of "despair" are bbserved.
Results of tosts relating to CRL 40489 (product of Example 5) CRL· 40489 shows itself to be an active agent on CNS, of the sedative type. In the course of the test relating to spontaneous motility, it was observed that CRL 40489 causes hypor.iotility at all the doses used (8 mg/kg to 256 mg/kg), the intensity of this hypomotility increasing with the dose. On the other hand, CR1 40489 does not act distinctly on reducing r..obility (habituation to the enclosure and hypoxic aggression). CRL 40489 has besides an anti-aggressive effect. At the dose of 32 rag/kg, it reduces by half intergroup 'aggressivity.
Results of tests relating to CRL- 40949 (product of Example 8) A - INTERACTION WITH APOi-ORFHINE 1) Mouse At doses of 32 nig/kg and 128 >»g/kgt CRL· 40949 is hypothetic and aggravates the hypothermia induced by loses of 1 and 16 i:.g/kg of apomorphine, on the other hand, it does not modify the behaviour of verticalisation and stereotypies. 2) Rat At the dose of 6 mg/kg, CRL 40949 increases the stereotypies induced by apoicozphine.
B - INTERACTION WITH AMPHETAMINE At the dose of 64 mg/kg, CRL 40940 results in a potentiation of amphetaminic stereotypies. - 34 - 54888 C - INTERACTION WITH RE SEEP I HE At doses of 32 mg/kg, 64 mg/kg and 128 mg/kg, CRL-40949 has a sluggish antagonisra to reserpinic hyp.othem.-iia; it also antagonises reserpinic ptosis moderately to 24 h.
D - INTERACTION WITH ONDTRB'.ORINE 1) Effect on temperature At doses of 2 mg/kg, 8 mg/kg, 32 mg/kg and 128 mg/kg, CRL 40949 antagonises moderately and sluggishly the hypothermia, induced by oxotremorine. 2) Effect on trembling Trembling due to oxotremorine is practically unmodified. 3) Effect on peripheral cholinergic symptoms CRL 40949 does not modify the signs of peripheral 15 cholinergic stimulation due to oxotremorine.
E - EFFECT ON THE TOUR PLATE, TRACTION AND ELECTROSHOCK TEST CRL 40949 does not result in an increase in the number of passages punished; it does not cause major motor incapacity and practically does not modify the convulsant 2o effects of electroshock.
F - ACTION ON SPONTANEOUS UTILITY CRL 40940, at doses of 8 mg/kg, 32 mg/kg and 128 mg/kg, results in a distinct increase ih.-the spontaneous motility of the mouse.
G - EFFECT ON INTERGROUP AGGRESSIVITY The tests carried out show that GEL 40940 has no antiaggressivs effect. - 35 - 54988 Η - EFFECT WITH RESPECT TO SOME BEHAVIOURS DISTURBED BY VARI&Us~AGEHT 3 ' 1) Motility reduced by habituation to the enclosure Fro:.; the dose of 8 mg/kg and especially at 32 mg/kg 5 and 128 mg/kg, CRL 40940 causes a very distinct resumption in motor activity in the mouse habituated to its enclosure. 2) Motility reduced by hypoxic aggression CRL 40940, at doses of 32 mg/kg, but especially 128 :..g/kg, results in · a significant iii.prover.ent in motor lo recovery in the mouse whose motility has been depressed following a brief sojourn in an enclosure under reduced pressure. 3) Asphyxic Anoxia CRL- 40940 does not modify the delay in the appearance 15 of convulsions and death consecutive to asphyxic anoxia caused by a curarising agent such as gallamine triiodeothylate.
I - INTERACTION WITH BARBITAL At the doses of 32 mg/kg and 128 mg/kg, CRL 40940 distinctly reduces the duration of barbituric sleep.
J - ACTION ON 11 BEHAVIORAL DESPAIR" At doses of 8 mg/kg, 32 mg/kg and 128 mg/kg, CRL 40940 distinctly reduces the duration of immobility of the mouse placed.in forced immersion.
JC - CONCLUSION Neuropsychopharmacological study of CRL 40940 establishes essentially an exciting component which results from; - excitation with hyporeactivity, - increase in motor activity, - 36 - 54988 - resumption of motor activity in the mouse habituates to its enclosure, - antagonism to barbituric sleep, - reduction in isaaobility in the "behavioral despair" 5 - test, and - improvement in the motor recovery after asphyxic anoxia.
These effects, different from amphetaminic stimulants, appear in the absence of particular toxicity in the groups of mice, and of signs of peripheral sympathetic stimulation. 15 The appearance and relatively sliovr development of a certain number of effects ( hyperreactivity, antagonism to hypothermia and rescrpinic ptosis, antagonism to hypothermia induced by oxotremorine) permit slow resorption of CRL 40940 to be presumed. This suppositionaca.is confirmed by akinetic study of the stereotypies.
Results of tests relating to CRL 4*1013 (product of Example 9) A - INTERACTION WITH APOhORPHSffB In the mouse, at the>,dose of 256 rng/kg, CRL 41018 opposes the hypothermic effect of aporaorphine without modifying the behaviour of verticalisation and stereotypies.
B - INTERACTION WITH RESERPIN3 At a dose of 256 mg/kg it is observed that CRL 41018 slowly modifies rsserpinic hypothermia (1.5h) and ptosis (24 h).
C - INTERACTION V7ITH OIPTREt-DRINE 1) Effect on temperature At the highest dose used, CRL 41018 modifies the drop in temperature caused by oxotremorine. - 37 - 54988 2) Effect on troubling The intensity o'f trembling caused by oxotremorine is practically unmodified by CEL· 41018. 3) Effect on peripheral cholinergic symptoms CEL· 41018 does not r.iodify the signs of peripheral cholinergic stimulation induced byoxotrsmorine.
D - EFFECT OK THE FOUR PLATE, TRACTION AND ElECTRSHOCK TEST At doses of 64 mg/kg, CRL· 41018 results in a distinct increase in passages punished; it does not cause a motor deficit; and at a high dose (256 mg/kg) it partly opposes the convulsant effects of electroshock.
E - ACTION OH SPONTANEOUS i-OTILITY It is observed that CEL 41018 causes from the dose of 16 :..g/lcg a hypenaotility; it is observed in addition that the hypeimotility is a maximum 0.5 h after administration and that the duration of hypermotility is at least 4 h.
F - EOTILITY EEDUCED BY HABITUATION TO THE EI-fCLO SURE It is noted that at doses of 64 mg/kg apd 256mg/kg, CEL 41018 causes a resumption in motor activity in the mouse habituated to its enclosure.
G - INTERACTION WITH BARBITAL At doses of 16 mg/kg, 64 mg/kg and 256 mg/kg, CRL 41018 distinctly reduces the duration of barbituric sleep.
H - ACTION ON "BEHAVIORAL DESPAIR" It is observed that CRL 41018 at doses of 16 mg/kg, 64 mg/kg and 256 mg/kg considerably reduces the duration of immobility. - 33 - 54988 I - CONCLUSION Hcuropsychophar;,.acological study of CRL· 41018 establishes a stimulant effect on the CNS which:is essential, and at strong doses only an anti-depressant effect on the 5 CNS.
Ill CLINICAL TRIALS Clinical studies bore on disorders of vigilance, wakening and confused states, on the one hand, and on disorders of affectivity, contact and depression , on the 10 other hand.
In man, particularly in old people, it was observed that CRL 40239, CRL 40933, CRL 40940 and CRL 41018 administored in the for.’, of gelules or tablets (each containing 100 to 200iag of active ’ingredient at the rate of 1 to 15 . 3 gelules or tablets per day), have given excellent results as arousing medicaments. It has also been observed that these four products act effectively against enuresis.

Claims (7)

1. A benzhydrylsulfinylacetamide derivative of the general formula : 5 wherein - X1 and x2, which may be identical or different each represent H, Cl or F, - Z1 represents CH3, CH2CH3, CH(CH3)2 or CiCH3)3, Z1 may represent H when at.least one of X1 and Xg is different from H, 1° - Z2 represents H; or KZ^Z2 considered together may represent a piperidino or morpholine group. 2) A benzhydrylsulfinylacetamide derivative of formula I according to claim 1, in which X^ and X2, which may be identical or different, and each represent H, 4-C1 or 4-F. 15 3) A benzhydrylsulfinylacetamide derivative according to claim I which is selected from : , Il-methyl-beiizhydrylsulfinylacetarnice, . N-ethyl-benzhydrylsulfinylacetamide, . N-isopropyl-benzhydrylsulfinylacetamide,
2. 0. N-tertiobutyl-benzhydrylsulfinylacetamide, • 4-chloro-benzhydrylsul£inylacetam.idet • 4o4'-difluoro-benzhydrylsulfinylacetamide, . N-(benzhydrylsulfinylacetyl)-pip eridine, - 40 - 54988 . K-(benzhydrylsulfinylacetyl)-morpholine and « 4~£luoro-benzhydrylsul£inylacetamide.
3. 4. N-Isopropyl-benzhydrylsul£inylacetamide. 5· 4-Ghloro-benzhyarylsulfinylacetami de. 5 6. 4.4’-Difluoro-benzhydrylsulfinylacetamide.
4. 7. II- (Benzhydryl sul finylacetyl) -p ip eridine. 3. 4-Fluoro-benzhydrylsulfinylacetarftide. ·
5. 9. N-Ethyl-benzhydrylsulfinylacetamido.
6. 10. A therapeutical composition, which comprises in association 10 with a physiologically acceptable excipient, a pharmaceutically effective amount of a bcnzhydrylsulxinylacstamidc- derivative of formula I according to any ono of claims 1 to 9. 15
7. 11. A method for preparing a benshydrylsulfinylacetomide derivative of formula I according to claim 1, which comprises 1) reacting an acyl chloride of the formula with an amine of the formula III mz^z2 (wherein and Z2 are as defined in claim 1) so as to obtain a bonzhydrylthioacetamide derivative of the formula 20 - 41 - 5 10 15 (v/herein X^, Xg, and Z2 arc 1 and, (IV) 54968 as defined in claim 2. oxidising the benzhydrylthioaceta:..irfe derivative thus obtained v/ith. 12. A method according to claim 11, wherein the oxidation of the derivative of formula (IV) is carried out in the presence of 110 - 130 volume Η-,Ο-, at a temperature lower than or equal to 45°C. 13. A benzhydrylsulfinylacetamide derivative of the general formula I given and defined in claim 1, which is any one of those specifically hereinbefore mentioned other than those specifically claimed in-any one of claims 3-9. 14. A therapeutical composition according to claim 10, substantially as hereinbefore described. 15. A method for preparing a benzhydrylsulfinylacetamide derivative of the general formula I given and defined in claim 1, substantially as hereinbefore described with particular reference to the accompanying Preparatory Examples. 16. A benzhydrylsulfinylacetamide derivative of the general formula I given and defined in claim 1, whenever prepared by a method claimed in a preceding claim. F.R. KELLY & CO AGENTS FOR THE APPLICANTS 20
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