CA1215393A - Benzhydrylsulfinylethylamine derivatives - Google Patents
Benzhydrylsulfinylethylamine derivativesInfo
- Publication number
- CA1215393A CA1215393A CA000429260A CA429260A CA1215393A CA 1215393 A CA1215393 A CA 1215393A CA 000429260 A CA000429260 A CA 000429260A CA 429260 A CA429260 A CA 429260A CA 1215393 A CA1215393 A CA 1215393A
- Authority
- CA
- Canada
- Prior art keywords
- formula
- ethyl
- benzhydrylsulfinyl
- addition salts
- prepared
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
- SHMYXVVITSBKCM-UHFFFAOYSA-N 2-benzhydrylsulfinylethanamine Chemical class C=1C=CC=CC=1C([S+]([O-])CCN)C1=CC=CC=C1 SHMYXVVITSBKCM-UHFFFAOYSA-N 0.000 title claims abstract description 10
- 239000002253 acid Substances 0.000 claims abstract description 9
- 150000003839 salts Chemical class 0.000 claims abstract description 9
- ORKZATPRQQSLDT-UHFFFAOYSA-N diphenylmethanethiol Chemical compound C=1C=CC=CC=1C(S)C1=CC=CC=C1 ORKZATPRQQSLDT-UHFFFAOYSA-N 0.000 claims abstract description 5
- IZQAUUVBKYXMET-UHFFFAOYSA-N 2-bromoethanamine Chemical compound NCCBr IZQAUUVBKYXMET-UHFFFAOYSA-N 0.000 claims abstract description 3
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims abstract 3
- 238000000034 method Methods 0.000 claims description 13
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 8
- 150000001875 compounds Chemical class 0.000 claims description 7
- 238000010992 reflux Methods 0.000 claims description 4
- BIPNUYXEYOEPHN-UHFFFAOYSA-N 2-benzhydrylsulfanylethanamine Chemical compound C=1C=CC=CC=1C(SCCN)C1=CC=CC=C1 BIPNUYXEYOEPHN-UHFFFAOYSA-N 0.000 claims description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 3
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims 2
- 230000001590 oxidative effect Effects 0.000 claims 1
- 239000000935 antidepressant agent Substances 0.000 abstract description 3
- 229940005513 antidepressants Drugs 0.000 abstract description 3
- 230000001430 anti-depressive effect Effects 0.000 abstract description 2
- 239000003814 drug Substances 0.000 abstract description 2
- 230000005494 condensation Effects 0.000 abstract 1
- 238000009833 condensation Methods 0.000 abstract 1
- 238000007254 oxidation reaction Methods 0.000 abstract 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 239000000203 mixture Substances 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 241000699666 Mus <mouse, genus> Species 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 210000003169 central nervous system Anatomy 0.000 description 3
- QFOIDHLIVYBINE-UHFFFAOYSA-N 2-benzhydrylsulfanyl-n-methylethanamine Chemical compound C=1C=CC=CC=1C(SCCNC)C1=CC=CC=C1 QFOIDHLIVYBINE-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- 230000006399 behavior Effects 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- DNXIKVLOVZVMQF-UHFFFAOYSA-N (3beta,16beta,17alpha,18beta,20alpha)-17-hydroxy-11-methoxy-18-[(3,4,5-trimethoxybenzoyl)oxy]-yohimban-16-carboxylic acid, methyl ester Natural products C1C2CN3CCC(C4=CC=C(OC)C=C4N4)=C4C3CC2C(C(=O)OC)C(O)C1OC(=O)C1=CC(OC)=C(OC)C(OC)=C1 DNXIKVLOVZVMQF-UHFFFAOYSA-N 0.000 description 1
- QGCYWVJSFGJYEX-UHFFFAOYSA-N 1-(2-benzhydrylsulfinylethyl)piperidine Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)S(=O)CCN1CCCCC1 QGCYWVJSFGJYEX-UHFFFAOYSA-N 0.000 description 1
- ROKMFBRRUNPXTO-UHFFFAOYSA-N 4-(2-benzhydrylsulfinylethyl)morpholine Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)S(=O)CCN1CCOCC1 ROKMFBRRUNPXTO-UHFFFAOYSA-N 0.000 description 1
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 1
- BWGNESOTFCXPMA-UHFFFAOYSA-N Dihydrogen disulfide Chemical compound SS BWGNESOTFCXPMA-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- 206010021113 Hypothermia Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 208000007379 Muscle Hypotonia Diseases 0.000 description 1
- 208000027419 Muscular hypotonia Diseases 0.000 description 1
- RSDOPYMFZBJHRL-UHFFFAOYSA-N Oxotremorine Chemical compound O=C1CCCN1CC#CCN1CCCC1 RSDOPYMFZBJHRL-UHFFFAOYSA-N 0.000 description 1
- LCQMZZCPPSWADO-UHFFFAOYSA-N Reserpilin Natural products COC(=O)C1COCC2CN3CCc4c([nH]c5cc(OC)c(OC)cc45)C3CC12 LCQMZZCPPSWADO-UHFFFAOYSA-N 0.000 description 1
- QEVHRUUCFGRFIF-SFWBKIHZSA-N Reserpine Natural products O=C(OC)[C@@H]1[C@H](OC)[C@H](OC(=O)c2cc(OC)c(OC)c(OC)c2)C[C@H]2[C@@H]1C[C@H]1N(C2)CCc2c3c([nH]c12)cc(OC)cc3 QEVHRUUCFGRFIF-SFWBKIHZSA-N 0.000 description 1
- 206010039897 Sedation Diseases 0.000 description 1
- 206010042008 Stereotypy Diseases 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 230000008485 antagonism Effects 0.000 description 1
- 230000002539 anti-aggressive effect Effects 0.000 description 1
- VMWNQDUVQKEIOC-CYBMUJFWSA-N apomorphine Chemical compound C([C@H]1N(C)CC2)C3=CC=C(O)C(O)=C3C3=C1C2=CC=C3 VMWNQDUVQKEIOC-CYBMUJFWSA-N 0.000 description 1
- 229960004046 apomorphine Drugs 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 150000001510 aspartic acids Chemical class 0.000 description 1
- -1 benzhydrylthio-ethylamine Chemical compound 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid group Chemical group C(C1=CC=CC=C1)(=O)O WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 125000005998 bromoethyl group Chemical group 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 230000000875 corresponding effect Effects 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- LJQKCYFTNDAAPC-UHFFFAOYSA-N ethanol;ethyl acetate Chemical compound CCO.CCOC(C)=O LJQKCYFTNDAAPC-UHFFFAOYSA-N 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 150000002307 glutamic acids Chemical class 0.000 description 1
- 230000002631 hypothermal effect Effects 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- BJOIZNZVOZKDIG-MDEJGZGSSA-N reserpine Chemical compound O([C@H]1[C@@H]([C@H]([C@H]2C[C@@H]3C4=C([C]5C=CC(OC)=CC5=N4)CCN3C[C@H]2C1)C(=O)OC)OC)C(=O)C1=CC(OC)=C(OC)C(OC)=C1 BJOIZNZVOZKDIG-MDEJGZGSSA-N 0.000 description 1
- 229960003147 reserpine Drugs 0.000 description 1
- MDMGHDFNKNZPAU-UHFFFAOYSA-N roserpine Natural products C1C2CN3CCC(C4=CC=C(OC)C=C4N4)=C4C3CC2C(OC(C)=O)C(OC)C1OC(=O)C1=CC(OC)=C(OC)C(OC)=C1 MDMGHDFNKNZPAU-UHFFFAOYSA-N 0.000 description 1
- 230000036280 sedation Effects 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C317/00—Sulfones; Sulfoxides
- C07C317/26—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
- C07C317/28—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to acyclic carbon atoms of the carbon skeleton
-
- 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
- A61P25/20—Hypnotics; Sedatives
Landscapes
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Neurosurgery (AREA)
- Life Sciences & Earth Sciences (AREA)
- Neurology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Anesthesiology (AREA)
- Pharmacology & Pharmacy (AREA)
- Biomedical Technology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
ABSTRACT
The present invention relates as new industrial products to the N-[2-(benzhydrylsulfinyl)-ethyl]-amines of formula:
(C6H5)2 CH - SO - CH2CH2 - NHR (I) (wherein R is H or C1-C4-alkyl) and to the acid addition salts thereof.
These new products are useful in therapeutics, particularly as anti-depressants of the CNS. They may be prepared by condensation of diphenylmethanethiol with a 2-bromoethylamine of formula BrCH2CH2NHR (wherein R is defined as indicated hereinabove) then oxidization by means of H2O2.
The present invention relates as new industrial products to the N-[2-(benzhydrylsulfinyl)-ethyl]-amines of formula:
(C6H5)2 CH - SO - CH2CH2 - NHR (I) (wherein R is H or C1-C4-alkyl) and to the acid addition salts thereof.
These new products are useful in therapeutics, particularly as anti-depressants of the CNS. They may be prepared by condensation of diphenylmethanethiol with a 2-bromoethylamine of formula BrCH2CH2NHR (wherein R is defined as indicated hereinabove) then oxidization by means of H2O2.
Description
~.lS393 Benzhydrylsulfinylethylamine derivatives.
The present invention relates to benzhydrylsulfinylethylamines - as new industrial products. It also relates to the use of these products in therapeutics and to the method for preparing them.
The hydrochloride of N-[2-(benzhydrylsulfinyl)-ethyl]-amine 5 is known to have been described as intermediary of synthesis of disulfide -sulfoxide derivatives by R. C~. HISKEY et al., J. Org. Chem., 32, pages 3191-3194 (1967) without a study of its psssible therapeutical properties. It is also known that French Patent No. 2,326,1~1 and corres-ponding U.S. Patent No. 4 06~ 686 propose derivatives of the N-(benz-10 hydrylsulfinylalkyl)-amine type, particularly as substances active on the central nervous system tCNS). It has just been unexpectedly found that new derivatives of N-(benzhydrylsuJfinylalkyl)-amine present interesting neuropsychopharmacological properties with respect to the products of Examples 4 and 5 of the above-mentioned Patents, 15 namely N-[2-(benzhydrylsulfinyl)-ethyl]-morpholine and N-[2-(benzhydryl-sulfinyl)-ethyl]-piperidine.
The new N-benzhydrylsulfinylalkyl-amine derivatives according to the invention are characterized in that they are selected from the group consisting of:
a) N-[2-(benzhydrylsul~inyJ)-ethyl]-amines o~ the formula '' ~3\
CH - SO - CH2 - CH2 - NH - R (I) ~/
30 (wherein R is a Cl-C4-alkyl group), and-b) acid addition salts thereof.
Among the R groups included in the definition given herein-above, particular mention may be made of the CH3, C2H5, i-C3H7 and t-C4Hg groups.
The most interesting compound from the psychopharmeutical .
,.
;3~3 point of view is the compound R = CH3.
Among suitable acid addition salts, particular men-tion may be made of the non-toxic addition salts obtained by reacting the free base of formula I with an inorganic or organic acid. From those acids suitable to this end, particular mention may be made of hydrochloric, hydro-bromic, sulfuric, phosphoric, nitric, picric, formic, acetic, propionic, fumaric, maleic, malic, tartric, citric, oxalic, benzoic, cinnamic, ascorbic, methanesulfonic, paratoluenesulfonic, aspartic and glutamic acids.
The products of formula I are active on the CNS:
they act as antidepressants of the CNS and present an interesting anti-aggressive effect.
A therapeutical composition is recommended which is characterized in that it contains, in association with a physiologically acceptable excipient, at le~ast one compound of formula I or one of its non-toxic addition salts, as active ingredient.
The compounds of formula I may be prepared in accor-dance with a method known per se by application of conven-tional reaction mechanisms. The method recommended accor-ding to the invention which is illustrated by the scheme:
(C6H5)2CH - SH (II) +
Br-CH2CH2-NHR (III) (C6H5)2CH-S-CH2CH2-NHR (IV) 1, H22 (C6H5)2CH-SO-CH2CH2-NHR (I) is characterized in that, successively, a) diphenylmethanethiol (II) is reacted in water, in the presence of a base particularly selected from NaOH and KOH, with a 2-bromoe-thylamine of formula Br-CH2CH2-NHR
(III) - wherein R is defined as indicated hereinabove -under refluxing for at least I hour, using from l to l.2 mole of III, for l mole of II, to obtain a benzhydrylthio-ethylamine of formula:
;393 (C6H5)2CH - S - CH2C}12 - NHR (IV) then, b) the benzhydrylthioethylamine thus obtained is oxidized in acetic acid with H2O2 at 110-130 volumes, at a temperature of 5 40-45C for I hour.
A certain number of N-[2-(benzhydrylsulfinyl)-ethyl]-amines according to the invention are given in non-limiting manner in Table I hereinbelow:
TABLE I
(C6H5~2CH - SO - CH2CH2 - NHR
Product Code No. R Melting point Ex I (a) CRL 40883 CH3 128-130C
Ex 2 (a) CH(CH3)2 Ex 3 (a) _ C(CH3)3 Note: (a): hydrochloride Other advantages and features of the invention will be more readily understood on reading the following description of examples 25 of preparation which are in no way limiting.
Obtaining of the hydrochloride of N-[2-(benzhydrylsulfinyl)-ethyl]-__ methylamine (Example l; Code No.: CRL 40883).
1) - Hydrochloride of N-[2-(benzhydrylthio)-ethyl]-methylamine.
15 g (0.075 mol) of diphenylmethanethiol in suspension in 75 ml of water are salified wi~h 16 g (0.4 mol) of sodium hydroxide in pellet form in solution in 25 ml of water. The mixture is taken to reflux and a solution of 17.6 g (0.08 mol) of hydrobromide of N-(2-35 bromoethyl)-methylamine in 50 ml of water is poured drop by drop into this mixture. Reflux is maintained for I hour, the mixture is cooled, extracted with ether, washed in water. The ethereal solution is extracted with 100 ml of 2 N HCI acid, the base is precipitated with concentrated ~aO~. The base is taken up in ether, the ethereal 5 phase is washed in water, dried and the desired hydrochloride is precipi-tated by the addition of hydrochloric ethanol. The precipitate is drained, washed with ethyl acetate and, by recrystallization from ethanol, the hydrochloride of N-[2-(benzhydrylthio)-ethyl~-methylamine is ob-tained with a yielo of 71%. m.p. 121-122C.
The present invention relates to benzhydrylsulfinylethylamines - as new industrial products. It also relates to the use of these products in therapeutics and to the method for preparing them.
The hydrochloride of N-[2-(benzhydrylsulfinyl)-ethyl]-amine 5 is known to have been described as intermediary of synthesis of disulfide -sulfoxide derivatives by R. C~. HISKEY et al., J. Org. Chem., 32, pages 3191-3194 (1967) without a study of its psssible therapeutical properties. It is also known that French Patent No. 2,326,1~1 and corres-ponding U.S. Patent No. 4 06~ 686 propose derivatives of the N-(benz-10 hydrylsulfinylalkyl)-amine type, particularly as substances active on the central nervous system tCNS). It has just been unexpectedly found that new derivatives of N-(benzhydrylsuJfinylalkyl)-amine present interesting neuropsychopharmacological properties with respect to the products of Examples 4 and 5 of the above-mentioned Patents, 15 namely N-[2-(benzhydrylsulfinyl)-ethyl]-morpholine and N-[2-(benzhydryl-sulfinyl)-ethyl]-piperidine.
The new N-benzhydrylsulfinylalkyl-amine derivatives according to the invention are characterized in that they are selected from the group consisting of:
a) N-[2-(benzhydrylsul~inyJ)-ethyl]-amines o~ the formula '' ~3\
CH - SO - CH2 - CH2 - NH - R (I) ~/
30 (wherein R is a Cl-C4-alkyl group), and-b) acid addition salts thereof.
Among the R groups included in the definition given herein-above, particular mention may be made of the CH3, C2H5, i-C3H7 and t-C4Hg groups.
The most interesting compound from the psychopharmeutical .
,.
;3~3 point of view is the compound R = CH3.
Among suitable acid addition salts, particular men-tion may be made of the non-toxic addition salts obtained by reacting the free base of formula I with an inorganic or organic acid. From those acids suitable to this end, particular mention may be made of hydrochloric, hydro-bromic, sulfuric, phosphoric, nitric, picric, formic, acetic, propionic, fumaric, maleic, malic, tartric, citric, oxalic, benzoic, cinnamic, ascorbic, methanesulfonic, paratoluenesulfonic, aspartic and glutamic acids.
The products of formula I are active on the CNS:
they act as antidepressants of the CNS and present an interesting anti-aggressive effect.
A therapeutical composition is recommended which is characterized in that it contains, in association with a physiologically acceptable excipient, at le~ast one compound of formula I or one of its non-toxic addition salts, as active ingredient.
The compounds of formula I may be prepared in accor-dance with a method known per se by application of conven-tional reaction mechanisms. The method recommended accor-ding to the invention which is illustrated by the scheme:
(C6H5)2CH - SH (II) +
Br-CH2CH2-NHR (III) (C6H5)2CH-S-CH2CH2-NHR (IV) 1, H22 (C6H5)2CH-SO-CH2CH2-NHR (I) is characterized in that, successively, a) diphenylmethanethiol (II) is reacted in water, in the presence of a base particularly selected from NaOH and KOH, with a 2-bromoe-thylamine of formula Br-CH2CH2-NHR
(III) - wherein R is defined as indicated hereinabove -under refluxing for at least I hour, using from l to l.2 mole of III, for l mole of II, to obtain a benzhydrylthio-ethylamine of formula:
;393 (C6H5)2CH - S - CH2C}12 - NHR (IV) then, b) the benzhydrylthioethylamine thus obtained is oxidized in acetic acid with H2O2 at 110-130 volumes, at a temperature of 5 40-45C for I hour.
A certain number of N-[2-(benzhydrylsulfinyl)-ethyl]-amines according to the invention are given in non-limiting manner in Table I hereinbelow:
TABLE I
(C6H5~2CH - SO - CH2CH2 - NHR
Product Code No. R Melting point Ex I (a) CRL 40883 CH3 128-130C
Ex 2 (a) CH(CH3)2 Ex 3 (a) _ C(CH3)3 Note: (a): hydrochloride Other advantages and features of the invention will be more readily understood on reading the following description of examples 25 of preparation which are in no way limiting.
Obtaining of the hydrochloride of N-[2-(benzhydrylsulfinyl)-ethyl]-__ methylamine (Example l; Code No.: CRL 40883).
1) - Hydrochloride of N-[2-(benzhydrylthio)-ethyl]-methylamine.
15 g (0.075 mol) of diphenylmethanethiol in suspension in 75 ml of water are salified wi~h 16 g (0.4 mol) of sodium hydroxide in pellet form in solution in 25 ml of water. The mixture is taken to reflux and a solution of 17.6 g (0.08 mol) of hydrobromide of N-(2-35 bromoethyl)-methylamine in 50 ml of water is poured drop by drop into this mixture. Reflux is maintained for I hour, the mixture is cooled, extracted with ether, washed in water. The ethereal solution is extracted with 100 ml of 2 N HCI acid, the base is precipitated with concentrated ~aO~. The base is taken up in ether, the ethereal 5 phase is washed in water, dried and the desired hydrochloride is precipi-tated by the addition of hydrochloric ethanol. The precipitate is drained, washed with ethyl acetate and, by recrystallization from ethanol, the hydrochloride of N-[2-(benzhydrylthio)-ethyl~-methylamine is ob-tained with a yielo of 71%. m.p. 121-122C.
2) CRL 40883 14 g (0.05 mol) of hydrochloride of N-[2-(benzhydrylthio)-ethyl]-methylamine in solution in 50 ml of acetic acid are oxidized with 5 ml of H2O2 at 110 volumes for I hour at 40C. The acetic acid is evaporated in vacuo, the residue of evaporation is taken up in acetone and the precipitate formed is drained. By recrystallizatian from the ethanol-ethyl acetate (1:1) v/v mixture, CRL 40883 is obtained with a yield of 58%. m.p. = 128-130C.
The results of the neuropsychopharmacological tests undertaken with CRL 40883 (product of Example 1) have been summarized herein-after. In these tests, CRL 40883 in solution in distilled water at pH
5 was administered by the intraperitoneal route in a volume of 20 ml/kg in the male mouse and in a volume of 5 mJ/kg in the male rat.
A - TOXICITY
In the male mouse, the LD-30 of CRL 40883 by the IP route is of the order of 250 mg/kg.
B - OVERALL BEHAVIOUR AND REACTIVITIES
Batches of 6 animals are observed before, then IS minutes, 30 minutes1 I hr., 2 hrs., 3 hrs. and 24 hrs. after administration of CRL 40883.
I) In the mouse:
At the doses of 64 mg/kg, 16 mg/kg, 4 mg/kg and I mg/kg, CRL 40883 does not bring about any substantial changes in behaviour and reactivities. Moderate sedation is observed particularly at the dose of 128 mg/kg.
1~5393 2) In the rat:
At the dose of 32 mg/kg, a hyporeactivity to touch and a muscular hypotonia are observed for 30 minutes; at the doses of 8 mg/kg, 2 mg/kg and 0.5 mg/kg, no particular symptoms are observed.
CRL 40883 presents the effects of an antidepressant substance (antagonism of the hypothermias induced by apomorphine, reserpine or oxotremorine) as well as a potentialization of the amphetaminic stereotypies.
Furthermore, at tl-e doses of 16 mgtkg and 64 mg/kg, CRL
40883 brings about a considerable reduction in the number of fights in the groups of mice, according to the intergroup aggressiveness method.
The results of the neuropsychopharmacological tests undertaken with CRL 40883 (product of Example 1) have been summarized herein-after. In these tests, CRL 40883 in solution in distilled water at pH
5 was administered by the intraperitoneal route in a volume of 20 ml/kg in the male mouse and in a volume of 5 mJ/kg in the male rat.
A - TOXICITY
In the male mouse, the LD-30 of CRL 40883 by the IP route is of the order of 250 mg/kg.
B - OVERALL BEHAVIOUR AND REACTIVITIES
Batches of 6 animals are observed before, then IS minutes, 30 minutes1 I hr., 2 hrs., 3 hrs. and 24 hrs. after administration of CRL 40883.
I) In the mouse:
At the doses of 64 mg/kg, 16 mg/kg, 4 mg/kg and I mg/kg, CRL 40883 does not bring about any substantial changes in behaviour and reactivities. Moderate sedation is observed particularly at the dose of 128 mg/kg.
1~5393 2) In the rat:
At the dose of 32 mg/kg, a hyporeactivity to touch and a muscular hypotonia are observed for 30 minutes; at the doses of 8 mg/kg, 2 mg/kg and 0.5 mg/kg, no particular symptoms are observed.
CRL 40883 presents the effects of an antidepressant substance (antagonism of the hypothermias induced by apomorphine, reserpine or oxotremorine) as well as a potentialization of the amphetaminic stereotypies.
Furthermore, at tl-e doses of 16 mgtkg and 64 mg/kg, CRL
40883 brings about a considerable reduction in the number of fights in the groups of mice, according to the intergroup aggressiveness method.
Claims (8)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A method for preparing N-[2-(benzhydrylsulfinyl)-ethyl]-amines of the formula:
(I) wherein R represents a C1-C4-alkyl group and acid addition salts thereof, said method comprising successively a) reacting in water in the presence of a base selected from the group comprising NaOH and KOH, diphenyl-methanethiol of the formula:
(C6H5)2 CH-SH (II) with a 2-bromoethylamine of the formula:
BrCH2CH2NHR (III) wherein R is as defined above for obtaining a benzhydrylthioethylamine of the formula:
(C6H5)2 CH - S - CH2CH2 - NHR (IV) then, b) oxidizing said benzhydrylthioethylamine thus obtained to prepare a compound of formula (I) and optionally preparing acid addition salts of the prepared compound of formula (I).
(I) wherein R represents a C1-C4-alkyl group and acid addition salts thereof, said method comprising successively a) reacting in water in the presence of a base selected from the group comprising NaOH and KOH, diphenyl-methanethiol of the formula:
(C6H5)2 CH-SH (II) with a 2-bromoethylamine of the formula:
BrCH2CH2NHR (III) wherein R is as defined above for obtaining a benzhydrylthioethylamine of the formula:
(C6H5)2 CH - S - CH2CH2 - NHR (IV) then, b) oxidizing said benzhydrylthioethylamine thus obtained to prepare a compound of formula (I) and optionally preparing acid addition salts of the prepared compound of formula (I).
2. A method of claim 1, wherein step (a) is conducted under refluxing conditions for at least 1 hour using from 1 to 1.2 mole of formula (III) for 1 mole of formula (II).
3. A method of claim 1 or 2 wherein step (b), said compound of formula (IV) is oxidized with H2O2 at 110-130 volumes in acetic acid, at a temperature of 40-45°C for 1 hours.
4. A method of claim 1, wherein R is CH3, CH2CH3, i-C3H7 or t-C4H9.
5. A method of claim 1, wherein R is CH3.
6. N-[2-(benzhydrylsulfinyl)ethyl]-amines of the formula:
(I) wherein R represents a C1-C4-alkyl group and acid addition salts thereof, when prepared by the process of claim 1.
(I) wherein R represents a C1-C4-alkyl group and acid addition salts thereof, when prepared by the process of claim 1.
7. N-[2-(benzhydrylsulfinyl)ethyl]-amine of the formula (I) according to claim 6, wherein R is CH3, CH2CH3, i-C3H7 or t-C4H9, when prepared by the process of claim 4.
8. N-[2-(benzhydrylsulfinyl)ethyl]-amine and its acid addition salts, when prepared by the process of claim 5.
7.
7.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR8209804 | 1982-06-04 | ||
| FR8209804A FR2528040A1 (en) | 1982-06-04 | 1982-06-04 | BENZHYDRYLSULFINYLETHYLAMINES, PREPARATION METHOD AND THERAPEUTIC USE |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1215393A true CA1215393A (en) | 1986-12-16 |
Family
ID=9274665
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000429260A Expired CA1215393A (en) | 1982-06-04 | 1983-05-31 | Benzhydrylsulfinylethylamine derivatives |
Country Status (9)
| Country | Link |
|---|---|
| EP (1) | EP0097546B1 (en) |
| JP (1) | JPS591457A (en) |
| AT (1) | ATE15796T1 (en) |
| CA (1) | CA1215393A (en) |
| DE (1) | DE3360881D1 (en) |
| DK (1) | DK160090C (en) |
| ES (1) | ES522983A0 (en) |
| FR (1) | FR2528040A1 (en) |
| IE (1) | IE54987B1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8153667B2 (en) | 2004-04-13 | 2012-04-10 | Cephalon, Inc. | Tricyclic aromatic and bis-phenyl sulfinyl derivatives |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP4518637B2 (en) * | 2000-07-07 | 2010-08-04 | 住友精化株式会社 | Process for producing 2- (methylsulfonyl) ethylamine |
| EP2964611B1 (en) | 2013-03-08 | 2022-10-19 | The United States of America, as represented by The Secretary, Department of Health and Human Services | Potent and selective inhibitors of monoamine transporters; method of making; and use thereof |
| US11365195B2 (en) | 2017-11-13 | 2022-06-21 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Atypical inhibitors of monoamine transporters; method of making; and use thereof |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1520812A (en) * | 1975-10-02 | 1978-08-09 | Lafon Labor | Benzhydrylsulphinyl derivatives |
-
1982
- 1982-06-04 FR FR8209804A patent/FR2528040A1/en active Granted
-
1983
- 1983-05-26 AT AT83401048T patent/ATE15796T1/en not_active IP Right Cessation
- 1983-05-26 IE IE1249/83A patent/IE54987B1/en not_active IP Right Cessation
- 1983-05-26 DE DE8383401048T patent/DE3360881D1/en not_active Expired
- 1983-05-26 EP EP83401048A patent/EP0097546B1/en not_active Expired
- 1983-05-31 CA CA000429260A patent/CA1215393A/en not_active Expired
- 1983-06-03 ES ES522983A patent/ES522983A0/en active Granted
- 1983-06-03 DK DK253483A patent/DK160090C/en not_active IP Right Cessation
- 1983-06-04 JP JP58098796A patent/JPS591457A/en active Pending
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8153667B2 (en) | 2004-04-13 | 2012-04-10 | Cephalon, Inc. | Tricyclic aromatic and bis-phenyl sulfinyl derivatives |
Also Published As
| Publication number | Publication date |
|---|---|
| DE3360881D1 (en) | 1985-10-31 |
| FR2528040A1 (en) | 1983-12-09 |
| IE831249L (en) | 1983-12-04 |
| IE54987B1 (en) | 1990-04-11 |
| ES8403447A1 (en) | 1984-03-16 |
| DK160090B (en) | 1991-01-28 |
| FR2528040B1 (en) | 1984-12-28 |
| EP0097546B1 (en) | 1985-09-25 |
| DK253483A (en) | 1983-12-05 |
| ES522983A0 (en) | 1984-03-16 |
| EP0097546A1 (en) | 1984-01-04 |
| DK160090C (en) | 1991-06-24 |
| DK253483D0 (en) | 1983-06-03 |
| JPS591457A (en) | 1984-01-06 |
| ATE15796T1 (en) | 1985-10-15 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CS246080B2 (en) | Method of piperazine derivatives production | |
| FR2471968A1 (en) | BASIC ETHERS, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING SAME | |
| JPS6040428B2 (en) | Novel 3-aryl-2-oxazolidinone derivatives, their production methods, and antidepressants containing the derivatives | |
| FR2496102A1 (en) | 7-SUBSTITUTED BENZOPYRANES, THEIR PREPARATION AND THEIR APPLICATION AS MEDICAMENTS | |
| JP4156799B2 (en) | Phenylaminoalkylcarboxylic acid derivative and pharmaceutical composition containing the same | |
| CA1215393A (en) | Benzhydrylsulfinylethylamine derivatives | |
| JP2008526836A (en) | Sibutramine inorganic acid salt | |
| JPS6326099B2 (en) | ||
| FR2643634A1 (en) | NOVEL BENZOXAZOLINONIC DERIVATIVES, PROCESSES FOR PREPARING THEM AND PHARMACEUTICAL COMPOSITIONS CONTAINING SAME | |
| US6696489B1 (en) | 2-Methylpropionic acid derivatives and medicinal compositions containing the same | |
| FR2460294A1 (en) | NOVEL OXIME ETHERS, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING SAME | |
| EP0005091B1 (en) | Monosubstituted piperazines, processes for their preparation and pharmaceutical compositions containing them | |
| FR2651227A1 (en) | NOVEL AMINOPROPANOL DERIVATIVES, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING SUCH DERIVATIVES. | |
| FR2534915A1 (en) | New 2-(phenoxymethyl)morpholine derivatives, their therapeutic use and process for preparing them | |
| US4714699A (en) | 2-tolylmorpholine derivatives and pharmaceutical compositions | |
| IE43132B1 (en) | Cis-bicyclooctyl-alkyl-amine derivatives | |
| US4162327A (en) | N,N-Disubstituted-2-furylethyl amines | |
| US3904689A (en) | Alkanolamine derivatives | |
| US3452031A (en) | Aminoalkylcarbamate esters | |
| KR100857342B1 (en) | A novel sibutramine organic acid salt and manufacturing process thereof | |
| CA1215048A (en) | 2-(hexahydroazepino)-n-(2,6-dimethylphenyl)- acetamide, the hydrochloride thereof, a process for the preparation thereof and pharmaceutical compositions containing them | |
| CA1227808A (en) | Preparation of (-)-1-(2-fluorophenyl)-2- tertiobutylamino-1-ethanol | |
| CA1227220A (en) | 3-amino-1 phenoxy-2-propanol derivatives | |
| KR20220050002A (en) | High purification of technical grade triethylenetetramine | |
| CS216169B2 (en) | Method of making the new n-substituted n-2-+l2-furylethyl p-amines and the salts thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MKEX | Expiry |