CA1098524A - Process for the preparation of new derivatives of piperazincarbodithioic acid - Google Patents
Process for the preparation of new derivatives of piperazincarbodithioic acidInfo
- Publication number
- CA1098524A CA1098524A CA305,059A CA305059A CA1098524A CA 1098524 A CA1098524 A CA 1098524A CA 305059 A CA305059 A CA 305059A CA 1098524 A CA1098524 A CA 1098524A
- Authority
- CA
- Canada
- Prior art keywords
- acid
- radical
- sodium salt
- piperazine
- thiazolyl
- 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
- IDIICHZCEIGXGB-UHFFFAOYSA-N 1-piperazinecarbodithioic acid Chemical class SC(=S)N1CCNCC1 IDIICHZCEIGXGB-UHFFFAOYSA-N 0.000 title claims abstract 4
- 238000000034 method Methods 0.000 title claims description 24
- 238000002360 preparation method Methods 0.000 title claims description 4
- -1 monosubstituted piperazines Chemical class 0.000 claims abstract description 27
- DXHPZXWIPWDXHJ-UHFFFAOYSA-N carbon monosulfide Chemical compound [S+]#[C-] DXHPZXWIPWDXHJ-UHFFFAOYSA-N 0.000 claims abstract description 25
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 11
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 10
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 9
- 150000003839 salts Chemical class 0.000 claims abstract description 9
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 6
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims abstract description 5
- 239000011593 sulfur Substances 0.000 claims abstract description 5
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 4
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 4
- 239000001301 oxygen Substances 0.000 claims abstract description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract 7
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 48
- 159000000000 sodium salts Chemical class 0.000 claims description 18
- 239000002253 acid Substances 0.000 claims description 17
- 125000004432 carbon atom Chemical group C* 0.000 claims description 8
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 7
- 229910052799 carbon Inorganic materials 0.000 claims description 7
- 125000005843 halogen group Chemical group 0.000 claims description 6
- 125000004434 sulfur atom Chemical group 0.000 claims description 6
- 125000000335 thiazolyl group Chemical group 0.000 claims description 6
- UCKMPCXJQFINFW-UHFFFAOYSA-N Sulphide Chemical compound [S-2] UCKMPCXJQFINFW-UHFFFAOYSA-N 0.000 claims description 4
- CIUQDSCDWFSTQR-UHFFFAOYSA-N [C]1=CC=CC=C1 Chemical compound [C]1=CC=CC=C1 CIUQDSCDWFSTQR-UHFFFAOYSA-N 0.000 claims description 4
- 239000000126 substance Substances 0.000 claims description 4
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 3
- 125000004429 atom Chemical group 0.000 claims description 2
- UGUHFDPGDQDVGX-UHFFFAOYSA-N 1,2,3-thiadiazole Chemical compound C1=CSN=N1 UGUHFDPGDQDVGX-UHFFFAOYSA-N 0.000 claims 6
- 238000001311 chemical methods and process Methods 0.000 claims 6
- AEJARLYXNFRVLK-UHFFFAOYSA-N 4H-1,2,3-triazole Chemical compound C1C=NN=N1 AEJARLYXNFRVLK-UHFFFAOYSA-N 0.000 claims 3
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 claims 3
- WCPAKWJPBJAGKN-UHFFFAOYSA-N oxadiazole Chemical compound C1=CON=N1 WCPAKWJPBJAGKN-UHFFFAOYSA-N 0.000 claims 3
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 claims 2
- 150000001875 compounds Chemical class 0.000 abstract description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 abstract description 2
- 201000010099 disease Diseases 0.000 abstract description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 2
- 231100000334 hepatotoxic Toxicity 0.000 abstract description 2
- 230000003082 hepatotoxic effect Effects 0.000 abstract description 2
- 229910052739 hydrogen Inorganic materials 0.000 abstract 3
- 239000001257 hydrogen Substances 0.000 abstract 3
- 229910052736 halogen Inorganic materials 0.000 abstract 2
- 150000002367 halogens Chemical group 0.000 abstract 2
- 150000002431 hydrogen Chemical class 0.000 abstract 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 abstract 2
- 125000003545 alkoxy group Chemical group 0.000 abstract 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 abstract 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 abstract 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 abstract 1
- 238000002560 therapeutic procedure Methods 0.000 abstract 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 19
- 239000011734 sodium Substances 0.000 description 19
- 229910052708 sodium Inorganic materials 0.000 description 19
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- 238000000354 decomposition reaction Methods 0.000 description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 10
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 8
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 7
- 239000000243 solution Substances 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 5
- 241000700159 Rattus Species 0.000 description 4
- 231100000566 intoxication Toxicity 0.000 description 4
- 230000035987 intoxication Effects 0.000 description 4
- YUKQRDCYNOVPGJ-UHFFFAOYSA-N thioacetamide Chemical compound CC(N)=S YUKQRDCYNOVPGJ-UHFFFAOYSA-N 0.000 description 4
- DLFVBJFMPXGRIB-UHFFFAOYSA-N thioacetamide Natural products CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 3
- QGJOPFRUJISHPQ-UHFFFAOYSA-N Carbon disulfide Chemical compound S=C=S QGJOPFRUJISHPQ-UHFFFAOYSA-N 0.000 description 3
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 3
- 239000000460 chlorine Substances 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- 230000002443 hepatoprotective effect Effects 0.000 description 3
- 231100000572 poisoning Toxicity 0.000 description 3
- 230000000607 poisoning effect Effects 0.000 description 3
- 235000011121 sodium hydroxide Nutrition 0.000 description 3
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 3
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- AMQJEAYHLZJPGS-UHFFFAOYSA-N N-Pentanol Chemical compound CCCCCO AMQJEAYHLZJPGS-UHFFFAOYSA-N 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- 230000001989 choleretic effect Effects 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- 239000012153 distilled water Substances 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000008194 pharmaceutical composition Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 108010082126 Alanine transaminase Proteins 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 206010016654 Fibrosis Diseases 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 208000015924 Lithiasis Diseases 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 240000007817 Olea europaea Species 0.000 description 1
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 230000002690 anti-lithiasic effect Effects 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000000731 choleretic agent Substances 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 230000007882 cirrhosis Effects 0.000 description 1
- 208000019425 cirrhosis of liver Diseases 0.000 description 1
- 229940110456 cocoa butter Drugs 0.000 description 1
- 235000019868 cocoa butter Nutrition 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 159000000011 group IA salts Chemical class 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000003223 protective agent Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- KUAZQDVKQLNFPE-UHFFFAOYSA-N thiram Chemical compound CN(C)C(=S)SSC(=S)N(C)C KUAZQDVKQLNFPE-UHFFFAOYSA-N 0.000 description 1
- 229960002447 thiram Drugs 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 239000010463 virgin olive oil Substances 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Hematology (AREA)
- Diabetes (AREA)
- Obesity (AREA)
- Gastroenterology & Hepatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Thiazole And Isothizaole Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
Abstract
. De nouveaux dérivés de l'acide pipérazinecarbodithioîque de formule I : I dans laquelle :- un des symboles A et B est azote et l'autre représente oxygène, soufre ou ? N-Y dans lequel Y est hydrogène DU méthyle, ou B est soufre et A est dans lequel R' est hydrogène, alkyle de C1 à C5, phényle ou benzyle,- R est hydrogène, halogène, alkyle de C1 à C5 ou phényle, ou,- R et R' représentent ensemble - CH = CH - CH = CH - éventuellement substitué par un halogène et un ou plusie??s alkyle ou alkoxy de C1 à C5, et leurs sels d'addicion avec des agents alcalins compatibles, sont préparés en faisant réagir les pipérazines N monosubstituées de formule II : II dans laquelle : A, B et R ont les significations énoncées précédemment, avec un excès de sulfure de carbone. Ces nouveaux composés et leurs sels physiologiquement tolérables peuvent être utilisés en thérapeutique,notamment dans le traitement des mala dies hépatotoxiques.. New piperazinecarbodithioic acid derivatives of formula I: I in which: - one of the symbols A and B is nitrogen and the other represents oxygen, sulfur or? NY in which Y is hydrogen DU methyl, or B is sulfur and A is in which R 'is hydrogen, C1 to C5 alkyl, phenyl or benzyl, - R is hydrogen, halogen, C1 to C5 alkyl or phenyl, or, - R and R 'represent together - CH = CH - CH = CH - optionally substituted by a halogen and one or more alkyl or alkoxy of C1 to C5, and their addicion salts with compatible alkaline agents, are prepared by reacting the monosubstituted piperazines N of formula II: II in which: A, B and R have the meanings set out above, with an excess of carbon sulfide. These new compounds and their physiologically tolerable salts can be used in therapy, in particular in the treatment of hepatotoxic diseases.
Description
La présente invention a pour objet le procédé de prépa-ration des nouveaux dérivés de l'acide pipérazinecarbodithio~que de formule génerale I :
A- -N
~ BY-- :
dans laquelle:
un des symboles A et B représente un atome d'azote et l'autre représente un atome d'oxygene, de soufre ou un radical ~ N - Y dans lequel Y est un atome d'hydrogene ou un radical méthyle, ou B est un atome de soufre et A est un radical ~ C - R' -~
dans lequel R' est un atome d'hydrogene, un radical alkyle ayant de 1 a 5 atomes de carbone, un radical phényle ou un radical benzyle, R est un atome d'hydrogène, un atome d'halogene tel que par exemple un atome de fluor, de chlore ou de brome, un groupe alkyle ayant de 1 à 5 atomes de carbone ou un radical ph~nyle, ou lorsque B est soufre et A est ~ C - R', R et R' représen-tent ensemble le groupe, - CH = CH - CH ~ CH - qui peut être éven-tuellement substitué par un atome d'halogene tel que par exempleun atome de fluor, de chlore ou de brome ou par un ou plusieurs radicaux alkyle ou alcoxy ayant chacun de 1 à 5 atomes de carbone, afin de former avec le groupe thiazolyle auquel ils sont liés un radical benzothiazolyle éventuellement substitué.
La présente invention inclut aussi la préparation des sels d'addition des dérivés de formule générale I et plus parti-culierement, les sels d ! addition qui sont physiologiquement tolé-rables.
La présente invention a pour objet le procédé de prépa-ration des dérivés de formule générale I caractérisé en ce que .~
~0~3SZ4 l'on fait reagir les piperazines N-monosubstituees de ~ormule générale II :
A N
R ~ ~ N NH II
dans laquelle A, B et R ont les significations définies ci-dessus, avec un excès de sulfure de carbone.
Il est avantageux d'effectuer la réaction dans un solvant approprié, tel que par exemple un alcool ayant de 1 a 3 atomes de carbone, a la température ambiante, de préférence en présence d'un léger exces d'un agent alcalin tel que, par exemple, l'hydroxyde de sodium, l'éthylate ou le méthylate de sodium.
Les piperazines N-monosubstituées II de départ ont ~té
préparees en chauffant a reflux, pendant 5 a 7 heures, 1 mole de dérivé hétérocyclique halogéné de formule :
A -N
R ~ ~ Hal B
dans laquelle A, B et R ont les significations précédemment défi-nies et Hal représente un atome de chlore ou de brome, avec 4 molesde pipérazine anhydre/ dans un solvant approprie tel que par exem-ple le butanol ou le pentanol.
Les dérivés de formule générale I sont amphoteres. Ils donnent, avec les agents alcalins, des sels alcalins cristallisés et ætables ce qui permet une purification aisée.
En milieu neutre, les composés de l'invention existent sous une forme cristalline relativement stable de formule :
A N
R ~ ~ ~ N C S~
,,, ~
-10!~85Z4 En milieu acide, toutefois, ils se decomposent avec for-mation de sulfure de carbone.
Les dérivés de formule générale I et leurs sels physio-logiquement tolérables possedent des propriétés pharmacologiques et thérapeutiques intéressantes, notamment des propriétés hépato-protectrice, cholérétique, antilithiasique et hypocholestérolé-miante. Ils peuvent, en conséquence, être utilisés comme médica-ment, notamment dans le traitement des maladies hépatotoxiques, de la cirrhose, de la lithiase et de l'hypercholestérolémie.
Leur toxicité est faible et leur DL50 déterminée chez la souris par voie orale varie de 250 à plus de 4000mg/kg.
Leurs propriétés hépatoprotectrices ont été mises en évi-dence par voie orale chez le rat vis a vis d'intoxications causées par le tétrachlorure de carbone ou le thioacétamide, selon la méthode suivante :
. des rats SD~CD mâles d'environ 200g reçoivent une in-jection intrapéritonéale de lml/kg de CC14 dilué a 40% dans l'huile d'olive vierge. 24h. après, le degré d'intoxication est évalué d'une part en pratiquant chez tous les rats un test à la Brome Sulfone Phtaléine (BSP) selon la technique de G. BOURDON
et R. FAUVERT (Revue Intern. Hépatol. 8 : 473-524, 1958) d'autre part en évaluant l'activité transaminase SGPT du sérum ~Kit de dosage BIO-MERIEUX).
. a chaque test est pratiqué un lot contrôle ne recevant que le CC14 et un lot témoin non intoxiqué ne recevant que l'huile d'olive. Le traitement par les agents protecteurs a lieu 48, 24, 18 et 4 heures avant l'injection de BSP.
Pour plusieurs dérivés de la présente invention, l'acti-vité hépatoprotectrice vis a vis d'une intoxication au tétra-chlorure de carbone est significative des la dose de 0,50mg/kg ~0~85Z4 per os. Une protection totale contre les perturbations bio-chimiques entraînées par l'intoxication au CC14 est observée pour des doses variant de 3 à 50mg/kg per os selon les composés.
L'activité hépatoprotectrice vis à vis d'une intoxication causée par le thioacétamide a eté mise en évidence en utilisant la technique ci-dessus décrite, l'intoxication étant dans ce cas provoquée par une injection intrapéritonéale de thioacétamide, à
la dose de 75mg/kg, en solution dans de l'eau distill~e. On observe une hépatoprotection significative contre une intoxica-tion au thioacétamide à des doses qui varient de 3 à 30mg/kg per `
os selon les dérivés.
L'activité cholérétique des dérivés de la présente inven-tion a ét~ mise en évidence chez le rat a des doses qui, pour certains dériv8s, peuvent descendre jusqu'a 10mg/kg par voie intraduodénale.
La présente invention comprend également la préparation des compositions pharmaceutiques contenant, comme principe actif, un dérivé de formule générale I ou un de ses sels physiologique-ment tolérables, mélangé ou associé a un excipient pharmaceutique approprie tel que, par exemple, l'eau distillée, le glucose, le lactose, l'amidon, le talc, le stéarate de magnésium, l'~thyl cellulose ou le beurre de cacao.
Les compositions pharmaceutiques ainsi obtenues se pré-sentent par exemple sous forme de comprimés, dragées, gélules, suppositoires, solutions injectables ou buvables, et peuvent être administrées par voie orale, rectale ou parentérale a la dose de 10 à 100 mg, 1 a 3 fois par jour.
Les exemples suivants illustrent l'invention, les points de fusion étant d~terminés dans un tube capillaire.
.. , .., . . .. .., .. . _ . .. . .
... , . ,- .. : - :. : - ~ .
EXEMPLE 1 :
(thiazolyl-2)-4 pipérazinecarbodithioate-l de sodium ~s 3 N ~ _ fi s Na On prépare une solution d'~thylate de sodium ~ partir de 300ml d'éthanol anhydre et 7,5g de sodium. A la solution obtenue, on ajoute successivement 49,3g de (thiazolyl-2)-1 pipérazine et 22,8g de sulfure de carbone. La température interne croit de 25 a 50C durant l'addition de sulfure de carbone. On maintient l'agi-tation pendant deux heures, puis on concentre la solution a la moitié de son volume initial. Le sel de sodium cristallise.
On l'essore et le lave a l'éther. On obtient 29g de cristaux de sel de sodium qui, recristallisés dans 220ml d'isopropanol en présence de lml d'une solution concentrée de soude, donnent 14,5g de (thiazolyl-2~-4 pipérazinecarbodithioate-l ~e sodium, fondant a 320-322C en se décomposant.
EXEMPLES 2 a 19 :
Les dérivés suivants ont été préparés selon le procédé
décrit dans l'exemple 1 : The subject of the present invention is the process for preparing ration of new derivatives of piperazinecarbodithio acid that of general formula I:
A- -N
~ BY--:
in which:
one of the symbols A and B represents a nitrogen atom and the other represents an oxygen, sulfur atom or a radical ~ N - Y in which Y is a hydrogen atom or a radical methyl, where B is a sulfur atom and A is a radical ~ C - R '- ~
in which R 'is a hydrogen atom, an alkyl radical having from 1 to 5 carbon atoms, a phenyl radical or a radical benzyl, R is a hydrogen atom, a halogen atom such that for example a fluorine, chlorine or bromine atom, a group alkyl having from 1 to 5 carbon atoms or a ph ~ nyl radical, or when B is sulfur and A is ~ C - R ', R and R' represent together try the group, - CH = CH - CH ~ CH - which can be event-you substituted by a halogen atom such as for example a fluorine, chlorine or bromine atom or by one or more alkyl or alkoxy radicals each having from 1 to 5 carbon atoms, in order to form with the thiazolyl group to which they are linked a optionally substituted benzothiazolyl radical.
The present invention also includes the preparation of addition salts of derivatives of general formula I and more especially, the salts of! addition that are physiologically tolerated rables.
The subject of the present invention is the process for preparing ration of derivatives of general formula I characterized in that . ~
~ 0 ~ 3SZ4 we react N-monosubstituted piperazines of ~ ormule general II:
YEAR
R ~ ~ N NH II
in which A, B and R have the meanings defined above, with an excess of carbon sulfide.
It is advantageous to carry out the reaction in a solvent suitable, such as for example an alcohol having from 1 to 3 atoms of carbon, at room temperature, preferably in the presence of a slight excess of an alkaline agent such as, for example, hydroxide sodium, ethyl ethylate or sodium methylate.
The starting N-monosubstituted piperazines II were ~ t prepared by heating at reflux, for 5 to 7 hours, 1 mole of halogenated heterocyclic derivative of formula:
A -N
R ~ ~ Hal B
in which A, B and R have the meanings previously defined nies and Hal represents a chlorine or bromine atom, with 4 moles of anhydrous piperazine / in an appropriate solvent such as for example-ple butanol or pentanol.
The derivatives of general formula I are amphoteric. They together with the alkaline agents, give crystalline alkaline salts and stables which allows easy purification.
In neutral medium, the compounds of the invention exist in a relatively stable crystalline form of formula:
YEAR
R ~ ~ ~ NCS ~
,,, ~
-10! ~ 85Z4 In an acidic environment, however, they decompose with-carbon sulfide.
The derivatives of general formula I and their physiological salts logically tolerable have pharmacological properties and interesting therapeutics, in particular of the hepato-protective, choleretic, antilithiasic and hypocholesterolated-crumbling. They can therefore be used as a medicine.
particularly in the treatment of hepatotoxic diseases, cirrhosis, lithiasis and high cholesterol.
Their toxicity is low and their LD50 determined in the Oral mice range from 250 to over 4000mg / kg.
Their hepatoprotective properties have been highlighted.
Oral dence in rats against poisoning caused with carbon tetrachloride or thioacetamide, depending on the following method:
. male SD ~ CD rats weighing approximately 200 g receive an intraperitoneal junction of lml / kg of CC14 diluted to 40% in virgin olive oil. 24h. after, the degree of intoxication is evaluated on the one hand by carrying out in all the rats a test with Brome Sulfone Phthalein (BSP) according to the technique of G. BOURDON
and R. FAUVERT (Revue Intern. Hépatol. 8: 473-524, 1958) other part by evaluating the SGPT transaminase activity of the serum ~ Kit BIO-MERIOUS dosage).
. each test is carried out a control batch not receiving that CC14 and a non-intoxicated control batch receiving only the oil olive. Treatment with protective agents takes place 48, 24, 18 and 4 hours before the BSP injection.
For several derivatives of the present invention, the acti-hepatoprotective life with respect to tetra poisoning carbon chloride is significant for the dose of 0.50 mg / kg ~ 0 ~ 85Z4 per os. Total protection against bio- disturbances chemicals caused by CC14 poisoning is observed for doses varying from 3 to 50 mg / kg per os depending on the compounds.
Hepatoprotective activity against intoxication caused by thioacetamide has been demonstrated using the technique described above, intoxication being in this case caused by an intraperitoneal injection of thioacetamide, the dose of 75 mg / kg, in solution in distilled water. We observes significant hepatoprotection against intoxication thioacetamide at doses ranging from 3 to 30 mg / kg per `
bone according to derivatives.
The choleretic activity of the derivatives of the present invention tion has been demonstrated in rats at doses which, for some derivatives, can go down to 10mg / kg per channel intraduodenal.
The present invention also includes the preparation pharmaceutical compositions containing, as active ingredient, a derivative of general formula I or a physiological salt thereof-tolerable, mixed or combined with a pharmaceutical excipient suitable such as, for example, distilled water, glucose, lactose, starch, talc, magnesium stearate, ~ thyl cellulose or cocoa butter.
The pharmaceutical compositions thus obtained are pre-smell for example in the form of tablets, dragees, capsules, suppositories, injectable or oral solutions, and may be administered orally, rectally or parenterally dose of 10 to 100 mg, 1 to 3 times a day.
The following examples illustrate the invention, the points of fusion being terminated in a capillary tube.
.., ..,. . .. .., ... _. ... .
...,. , - ..: -:. : - ~.
EXAMPLE 1:
(2-thiazolyl) -4 sodium piperazinecarbodithioate-1 ~ s 3 N ~ _ fi s Na A solution of ~ sodium thylate ~ is prepared from 300ml of anhydrous ethanol and 7.5g of sodium. At the solution obtained, 49.3 g of (2-thiazolyl) -1 piperazine are successively added and 22.8g of carbon sulfide. The internal temperature increases by 25 a 50C during the addition of carbon sulfide. We maintain the agi-for two hours, then the solution is concentrated to the half of its original volume. The sodium salt crystallizes.
It is wrung and washed with ether. We get 29g of crystals sodium salt which, recrystallized from 220ml of isopropanol in the presence of lml of a concentrated soda solution, give 14.5 g of (thiazolyl-2 ~ -4 piperazinecarbodithioate-l ~ e sodium, melting at 320-322C as it decomposes.
EXAMPLES 2 to 19:
The following derivatives were prepared according to the process described in Example 1:
2. (méthyl-4 thiazolyl-2)-4 pipérazinecarbodithioate-l de sodium hydraté, P.F. 325-330C (éther anhydre), à partir de (méthyl-4 thiazolyl-2)-1 pipérazine, Eb./0,05mmHg 125-128C, et de sulfure de carbone. 2. (sodium methyl-4 thiazolyl-2) -4 piperazinecarbodithioate-l hydrated, PF 325-330C (anhydrous ether), from (methyl-4 thiazolyl-2) -1 piperazine, Eb./0.05mmHg 125-128C, and sulfide of carbon.
3. (diméthyl-4,5 thiazolyl-2)-4 pipérazinecarbodithioate-l de sodium hydraté, P.F. 320-340C, avec décomposition (éthanol anhydre) a partir de (diméthyl-4,5 thiazolyl-2)-1 pipérazine, Eb./0,Olmm Hg : 133-136C, et de sulfure de carbone. 3. (4,5-dimethyl-2-thiazolyl) -4 piperazinecarbodithioate-1 sodium hydrate, PF 320-340C, with decomposition (ethanol anhydrous) from (4,5-dimethyl-2-thiazolyl) -1 piperazine, Eb./0,Olmm Hg: 133-136C, and carbon sulfide.
4. (phényl-4 thiazolyl-2)-4 pipérazinecarbodithioate-l de sodium hydraté, P.F. 270-275C avec décomposition (isopropanol anhydre) ~ ~ .
~;)98524 partir de (phényl-4 thiazolyl-2)-1 pipérazine, Eb./0,05mmHig :
195-201C, et de sulfure de carbone. 4. (4-phenyl-2-thiazolyl) -4 sodium piperazinecarbodithioate-1 hydrated, PF 270-275C with decomposition (anhydrous isopropanol) ~ ~.
~;) 98524 from (4-phenyl-2-thiazolyl) -1 piperazine, Eb./0.05mmHig:
195-201C, and carbon sulfide.
5. (benzothiazolyl-2)-4 pipérazinecarbodithioate-l de sodium, P.F. 320C, avec décomposition (éthanol) à partir de (benzothia-zolyl-2)-1 pip~razine, P.F. 78-80C, et de sulfure de carbone. 5. (2-benzothiazolyl) -4 sodium piperazinecarbodithioate-1, PF 320C, with decomposition (ethanol) from (benzothia-zolyl-2) -1 pip ~ razine, PF 78-80C, and carbon sulfide.
6. (chloro-4 benzothiazolyl-2)-4 pipérazinecarbodithioate-1 de sodium~hydraté,P.F. 290-295C (~thanol a 97%), a partir de (chloro-4 benzothiazolyl-2)-1 pip~razine, Eb./0,07mmHg : 200-206C, et de sulfure de carbone. 6. (4-chloro-benzothiazolyl-2) -4 piperazinecarbodithioate-1 sodium hydrated, PF 290-295C (~ thanol at 97%), from (4-chloro-benzothiazolyl-2) -1 pip ~ razine, Eb./0,07mmHg: 200-206C, and carbon sulfide.
7. (méthoxy-6 benzothiazolyl-2)-4 pipérazinecarbodithioate-l de sodium hydraté, P.F. ~ 300C (éthanol a 90%), a partir de (métho- ~;
xy-6 benzothiazolyl-2)-1 pipérazine, P.F. 142-144C, et de sulfure de carbone. 7. (6-methoxy-2-benzothiazolyl) -4 piperazinecarbodithioate-1 hydrated sodium, PF ~ 300C (90% ethanol), from (metho- ~;
xy-6 benzothiazolyl-2) -1 piperazine, PF 142-144C, and sulfide of carbon.
8. diméthyl-5,6 benzothiazolyl-2)-4 pipérazinecarbodithioate-1 de sodium, P.F. 310-320C (éthanol), a partir de (diméthyl-5,6 benzo~
thiazolyl-2)-1 pipérazine, P.F. 120-122C, et de sulfure de carbone. 8. dimethyl-5,6 benzothiazolyl-2) -4 piperazinecarbodithioate-1 sodium, PF 310-320C (ethanol), from (5.6 dimethyl benzo ~
thiazolyl-2) -1 piperazine, PF 120-122C, and carbon.
9. (thiadiazol-1,3,4 yl-2)-4 pipérazinecarbodithioate-l de sodium -hydraté, P.F. 230-240C avec décomposition (méthanol a 98%), a partir de (thiadiazol-1,3,4 yl-2)-1 pipérazine, P.F. de son dichlo-rhydrate : 234-240C, et de sulfure de carbone. 9. (thiadiazol-1,3,4 yl-2) -4 sodium piperazinecarbodithioate-l -hydrated, PF 230-240C with decomposition (98% methanol), a from (thiadiazol-1,3,4 yl-2) -1 piperazine, PF of its dichlo-hydrate: 234-240C, and carbon sulfide.
10. (méthyl-5 thiadiazol-1,3,4 yl-2)-4 pipérazinecarbodithioate-l de sodium hydraté, P.F. 210C avec décomposition (méthanol a 98~
~ partir de (méthyl-5 thiadiazol-1,3,4, yl-2)-1 pip~razine, P.F.
de son dichlorhydrate 240-242C, et de sulfure de carbone. 10. (5-methyl thiadiazol-1,3,4 yl-2) -4 piperazinecarbodithioate-1 hydrated sodium, PF 210C with decomposition (methanol 98 ~
~ from (5-methyl-thiadiazol-1,3,4, yl-2) -1 pip ~ razine, PF
its 240-242C dihydrochloride, and carbon disulfide.
11. (méthyl-3 oxadiazol-1,2,4 yl-5)-4 pipérazinecarbodithioate-l de sodium hydraté, P.F. 240C avec décomposition (méthanol), ~
partir de (méthyl-3 oxadiazol-1,2,4 yl-5)-1 pipérazine, P.F. de son dichlorhydrate : 240-245C, et de sulfure de carbone.
. . .
10~!8524 . 11. (3-methyl-oxadiazol-1,2,4 yl-5) -4 piperazinecarbodithioate-1 sodium hydrate, PF 240C with decomposition (methanol), ~
from (3-methyl-oxadiazol-1,2,4 yl-5) -1 piperazine, PF from its dihydrochloride: 240-245C, and carbon sulfide.
. . .
10 ~! 8524 .
12. (méthyl-3 thiadiazol-1,2,4 yl-51-4 pipérazinecarbodithioate-l de sodium hydraté, P.F. 310-312C (méthanol), à partir de (méthyl-3 thiadiazol-1,2,4 yl-S)-l pip~razine, P.F. de son dichlorhydrate :
240-245C, et de sulfure de carbone. 12. (3-methyl-thiadiazol-1,2,4 yl-51-4 pipérazinecarbodithioate-l sodium hydrate, PF 310-312C (methanol), from (methyl-3 thiadiazol-1,2,4 yl-S) -l pip ~ razine, PF of its dihydrochloride:
240-245C, and carbon sulfide.
13. (thiadiazol-1,2,4 yl-5)-4 pip~razinecarbodithioate-l de sodium hydrat~, P.F. 275-277C avec décomposition (méthanol), a partir de (thiadiazol-1,2,4 yl-5)-1 pip~razine, P.F. de son dichlorhydrate :
248-250C, et de sulfure de carbone. 13. (thiadiazol-1,2,4 yl-5) -4 pip ~ sodium razinecarbodithioate-l hydrate ~, PF 275-277C with decomposition (methanol), from (thiadiazol-1,2,4 yl-5) -1 pip ~ razine, PF of its dihydrochloride:
248-250C, and carbon sulfide.
14. (4H-triazol-1,2,4 yl-3)-4 pipirazinecarbodithioate-l de sodium hydraté, P.F. 270-280C avec décomposition (méthanol), à partir de (4H-triazol-1,2,4 yl-3)-1 pipérazine, P.F. de son dichlorhydrate :
265-272C, et de sulfure de carbone. 14. (4H-triazol-1,2,4 yl-3) -4 sodium pipirazinecarbodithioate-l hydrated, PF 270-280C with decomposition (methanol), from (4H-triazol-1,2,4 yl-3) -1 piperazine, PF of its dihydrochloride:
265-272C, and carbon sulfide.
15. (méthyl-2 triazol-1,2,4 yl-3)-4 pipérazinecarbodithioate-l de sodium, P.F. 320-330C avec décomposition, à partir de (méthyl-2 triazol-1,2,4 yl-3)-1 pipérazine, P.F. de son dichlorhydrate 270-275C, et de sulfure de carbone. 15. (2-methyl-triazol-1,2,4 yl-3) -4 piperazinecarbodithioate-1 sodium, PF 320-330C with decomposition, from (methyl-2 triazol-1,2,4 yl-3) -1 piperazine, PF of its dihydrochloride 270-275C, and carbon sulfide.
16. (chloro-5 thiazolyl-2)-4 pip~razinecarbodithioate-l de sodium hydraté, P.F. 295-300C avec décomposition (isopropanol), à partir de (chloro-5 thiazolyl-2)-1 pip~razine, P~F~ de son monochlorhydra-te : 243-246C avec décomposition, et de sulfure de carbone. 16. (5-chloro-2-thiazolyl) -4 pip ~ sodium razinecarbodithioate-l hydrated, PF 295-300C with decomposition (isopropanol), from of (5-chloro-thiazolyl-2) -1 pip ~ razine, P ~ F ~ of its monochlorhydra-te: 243-246C with decomposition, and carbon sulfide.
17. (benzyl-4 thiazolyl-2)-4 pipérazinecarbodithioate-1 de sodium hydrate, P.F. 262-267C, à partir de (benzyl-4 thiazolyl-2)-1 pipérazine, P.F. 73-74C, et de sulfure de carbone.
13. (~thyl-4 thiazolyl-2)-4 pipérazinecarbodithioate-l de sodium hydraté, P.F. 300-315C, a partir d'(~thyl-4thiazolyl-2)-1 pipéra-.
zine, Eb./0,07mmHg : 130-140C, et de sulfure de carbone.
1~. (butyl-4 thiazolyl-2)-4 pipérazinecarbodithioate-l de sodium hydraté, P.F. 370C avec décomposition (isopropanol/éther), a partir de (butyl-4 thiazolyl-2)-1 pipérazine, Eb./0,045mmHg :
140-150C et de sulfure de carbone.
.. . . . . . .. 17. (4-benzyl-2-thiazolyl) -4 sodium piperazinecarbodithioate-1 hydrate, PF 262-267C, from (4-benzyl-2-thiazolyl) -1 piperazine, PF 73-74C, and carbon sulfide.
13. (~ 4-thyl-2-thiazolyl) -4 sodium piperazinecarbodithioate-1 hydrated, PF 300-315C, from (~ thyl-4thiazolyl-2) -1 pipera-.
zine, Eb./0.07mmHg: 130-140C, and carbon sulfide.
1 ~. (4-butyl-2-thiazolyl) -4 sodium piperazinecarbodithioate-l hydrated, PF 370C with decomposition (isopropanol / ether), a from (4-butyl-2-thiazolyl) -1 piperazine, Eb./0,045mmHg:
140-150C and carbon sulfide.
... . . . . ..
Claims (18)
EXCLUSIF DE PROPRIETE OU DE PRIVILEGE EST REVENDIQUE SONT
DEFINIES COMME SUIT: THE ACHIEVEMENTS OF THE INVENTION ABOUT WHICH A RIGHT
EXCLUSIVE OF PROPERTY OR PRIVILEGE IS CLAIMED ARE
DEFINED AS FOLLOWS:
dans laquelle:
un des symboles A et B représente un atome d'azote et l'autre représente un atome d'oxygène, de soufre ou un radical ?N - Y dans lequel Y est un atome d'hydrogène ou un radical méthyle, ou B est un atome de soufre et A est un radical ?C - R' dans lequel R' est un atome d'hydrogène, un radical alkyle ayant de 1 à 5 atomes de carbone, un radical phényle ou un radical benzyle, R est un atome d'hydrogène, un atome d'halogène, un groupe alkyle ayant de 1 à 5 atomes de carbone ou un radical phényle, ou lorsque B est soufre et A est ?C - R', R et R' représen-tent ensemble le groupe - CH = CH - CH = CH - qui peut être éven-tuellement substitué par un atome d'halogène ou par un ou plusieurs radicaux alkyle ou alcoxy ayant chacun de 1 à 5 atomes de carbone, afin de former avec le groupe thiazolyle auquel ils sont liés un radical benzothiazolyle éventuellement substitué, et de leurs sels d'addition avec des agents alcalins appropriés, caractérisé en ce que l'on fait réagir les pipérazines N-mono-substituées de formule générale II :
II
dans laquelle A, B et R ont les significations définies précé-demment avec un excès de sulfure de carbone, et si on le désire, on traite les dérivés ainsi obtenus avec des agents alcalins compatibles pour donner les sels d'addition correspondants. 1.- Process for the preparation of new acid derivatives piperazinecarbodithioic of general formula I:
in which:
one of the symbols A and B represents a nitrogen atom and the other represents an oxygen or sulfur atom or a radical ? N - Y in which Y is a hydrogen atom or a radical methyl, where B is a sulfur atom and A is a radical? C - R ' in which R 'is a hydrogen atom, an alkyl radical having from 1 to 5 carbon atoms, a phenyl radical or a radical benzyl, R is a hydrogen atom, a halogen atom, a group alkyl having from 1 to 5 carbon atoms or a phenyl radical, or when B is sulfur and A is? C - R ', R and R' represent together try the group - CH = CH - CH = CH - which can be event-either substituted by a halogen atom or by one or more alkyl or alkoxy radicals each having from 1 to 5 carbon atoms, in order to form with the thiazolyl group to which they are linked a optionally substituted benzothiazolyl radical, and their addition salts with appropriate alkaline agents, characterized in that the N-mono- piperazines are reacted substituted of general formula II:
II
in which A, B and R have the meanings defined above apply with an excess of carbon sulfide, and if desired, the derivatives thus obtained are treated with alkaline agents compatible to give the corresponding addition salts.
I
dans laquelle:
un des symboles A et B représente un atome d'azote et l'autre représente un atome d'oxygène, de soufre ou un radical ?N - Y dans lequel Y est un atome d'hydrogène ou un radical méthyle, ou B est un atome de soufre et A est un radical ?C - R' dans lequel R' est un atome d'hydrogène, un radical alkyle ayant de 1 à 5 atomes de carbone, un radical phényle ou un radical benzyle, R est un atome d'hydrogène, un atome d'halogène, un groupe alkyle ayant de 1 à 5 atomes de carbone ou un radical phényle, ou lorsque B est soufre et A est ?C - R', R et R' repré-sentent ensemble le groupe - CH = CH - CH = CH - qui peut être éventuellement substitué par un atome d'halogène ou par un ou plusieurs radicaux alkyle ou alcoxy ayant chacun de 1 à 5 atomes de carbone, afin de former avec le groupe thiazolyle auquel ils sont liés un radical benzothiazolyle éventuellement substitué
et leurs sels d'addition avec des agents alcalins compatibles, lorsque préparés selon le procédé de la revendication 1 ou par un procédé chimique équivalent. 10.- Derivatives of piperazinecarbodithioic acid of general formula I:
I
in which:
one of the symbols A and B represents a nitrogen atom and the other represents an oxygen or sulfur atom or a radical ? N - Y in which Y is a hydrogen atom or a radical methyl, where B is a sulfur atom and A is a radical? C - R ' in which R 'is a hydrogen atom, an alkyl radical having from 1 to 5 carbon atoms, a phenyl radical or a radical benzyl, R is a hydrogen atom, a halogen atom, a alkyl group having 1 to 5 carbon atoms or a radical phenyl, or when B is sulfur and A is? C - R ', R and R' represent feel together the group - CH = CH - CH = CH - which can be optionally substituted by a halogen atom or by one or several alkyl or alkoxy radicals each having from 1 to 5 atoms carbon, in order to form with the thiazolyl group to which they are linked an optionally substituted benzothiazolyl radical and their addition salts with compatible alkaline agents, when prepared according to the process of claim 1 or by an equivalent chemical process.
razinecarbodithioïque - 1 and its sodium salt, when prepared according to the process of claim 3 or by a chemical process equivalent.
chimique équivalent. 17.- Acid (4H - triazol - 1,2,4, yl - 3) - 4 pipéra-zinecarbodithioic- 1 and its sodium salt, when prepared according to the method of claim 8 or by a method equivalent chemical.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB24,370 | 1977-06-10 | ||
| GB2437077 | 1977-06-10 | ||
| GB30,851 | 1977-07-22 | ||
| GB3085177 | 1977-07-22 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1098524A true CA1098524A (en) | 1981-03-31 |
Family
ID=26257079
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA305,059A Expired CA1098524A (en) | 1977-06-10 | 1978-06-08 | Process for the preparation of new derivatives of piperazincarbodithioic acid |
Country Status (13)
| Country | Link |
|---|---|
| JP (1) | JPS545987A (en) |
| AT (1) | AT360545B (en) |
| AU (1) | AU3692878A (en) |
| CA (1) | CA1098524A (en) |
| DE (1) | DE2825407C3 (en) |
| ES (1) | ES470679A1 (en) |
| FR (1) | FR2393802A1 (en) |
| GR (1) | GR63662B (en) |
| IT (1) | IT1104750B (en) |
| NL (1) | NL7806321A (en) |
| NZ (1) | NZ187474A (en) |
| PT (1) | PT68159A (en) |
| YU (1) | YU135378A (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2961406D1 (en) * | 1978-04-13 | 1982-01-28 | Science Union & Cie | Monosubstituted piperazines, processes for their preparation and pharmaceutical compositions containing them |
| JP2002519346A (en) * | 1998-06-30 | 2002-07-02 | ニューロゲン コーポレイション | 1- (benzothiazol-2-yl) -4- (1-phenylmethyl) piperazine: a dopamine receptor subtype specific ligand |
| ES2388681T3 (en) * | 2006-03-28 | 2012-10-17 | High Point Pharmaceuticals, Llc | Benzothiazoles with histamine H3 receptor activity |
| JP2012505898A (en) * | 2008-10-16 | 2012-03-08 | シェーリング コーポレイション | Pyrrolidine, piperidine and piperazine derivatives and methods for their use |
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| GB1307256A (en) * | 1970-09-15 | 1973-02-14 | Science Union & Cie | Piperazine derivatives and a process for their preparation |
| CH583232A5 (en) * | 1973-02-02 | 1976-12-31 | Wander Ag Dr A | |
| GB1432660A (en) * | 1973-10-30 | 1976-04-22 | Science Union & Cie | Piperazine derivatives processes for their preparation and and pharamacueitcal compositions containing them |
-
1978
- 1978-06-06 NZ NZ187474A patent/NZ187474A/en unknown
- 1978-06-06 YU YU01353/78A patent/YU135378A/en unknown
- 1978-06-08 GR GR56478A patent/GR63662B/en unknown
- 1978-06-08 AU AU36928/78A patent/AU3692878A/en active Pending
- 1978-06-08 IT IT49764/78A patent/IT1104750B/en active
- 1978-06-08 CA CA305,059A patent/CA1098524A/en not_active Expired
- 1978-06-09 AT AT420878A patent/AT360545B/en not_active IP Right Cessation
- 1978-06-09 NL NL7806321A patent/NL7806321A/en not_active Application Discontinuation
- 1978-06-09 FR FR787817256A patent/FR2393802A1/en active Granted
- 1978-06-09 ES ES470679A patent/ES470679A1/en not_active Expired
- 1978-06-09 PT PT68159A patent/PT68159A/en unknown
- 1978-06-09 DE DE2825407A patent/DE2825407C3/en not_active Expired
- 1978-06-09 JP JP6975378A patent/JPS545987A/en active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| IT7849764A0 (en) | 1978-06-08 |
| AT360545B (en) | 1981-01-12 |
| YU135378A (en) | 1982-08-31 |
| DE2825407A1 (en) | 1978-12-14 |
| FR2393802A1 (en) | 1979-01-05 |
| DE2825407C3 (en) | 1981-04-30 |
| PT68159A (en) | 1978-07-01 |
| AU3692878A (en) | 1979-12-13 |
| JPS545987A (en) | 1979-01-17 |
| ATA420878A (en) | 1980-06-15 |
| IT1104750B (en) | 1985-10-28 |
| FR2393802B1 (en) | 1981-04-17 |
| NL7806321A (en) | 1978-12-12 |
| NZ187474A (en) | 1981-03-16 |
| DE2825407B2 (en) | 1980-07-10 |
| ES470679A1 (en) | 1979-03-16 |
| GR63662B (en) | 1979-11-28 |
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