GB1602110A - Acetamidoxime derivatives - Google Patents
Acetamidoxime derivatives Download PDFInfo
- Publication number
- GB1602110A GB1602110A GB1670377A GB1670377A GB1602110A GB 1602110 A GB1602110 A GB 1602110A GB 1670377 A GB1670377 A GB 1670377A GB 1670377 A GB1670377 A GB 1670377A GB 1602110 A GB1602110 A GB 1602110A
- Authority
- GB
- United Kingdom
- Prior art keywords
- groups
- group
- crl
- alkyl
- phenyl
- 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
- AEXITZJSLGALNH-UHFFFAOYSA-N n'-hydroxyethanimidamide Chemical class CC(N)=NO AEXITZJSLGALNH-UHFFFAOYSA-N 0.000 title claims description 9
- 239000000203 mixture Substances 0.000 claims description 32
- -1 methylenedioxy groups Chemical group 0.000 claims description 31
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 22
- 229910052736 halogen Inorganic materials 0.000 claims description 17
- 150000002367 halogens Chemical group 0.000 claims description 17
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 17
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 16
- 150000003839 salts Chemical class 0.000 claims description 16
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 14
- 239000002253 acid Substances 0.000 claims description 12
- MDFFNEOEWAXZRQ-UHFFFAOYSA-N aminyl Chemical group [NH2] MDFFNEOEWAXZRQ-UHFFFAOYSA-N 0.000 claims description 12
- JCXJVPUVTGWSNB-UHFFFAOYSA-N Nitrogen dioxide Chemical group O=[N]=O JCXJVPUVTGWSNB-UHFFFAOYSA-N 0.000 claims description 11
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 8
- 125000003118 aryl group Chemical group 0.000 claims description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- 150000007513 acids Chemical class 0.000 claims description 3
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims description 3
- 125000004076 pyridyl group Chemical group 0.000 claims description 3
- 230000001225 therapeutic effect Effects 0.000 claims description 3
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 claims description 2
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 claims description 2
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 2
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 2
- 231100000252 nontoxic Toxicity 0.000 claims description 2
- 230000003000 nontoxic effect Effects 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 125000006168 tricyclic group Chemical group 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims 1
- 241000699670 Mus sp. Species 0.000 description 57
- 230000004899 motility Effects 0.000 description 37
- 239000000047 product Substances 0.000 description 36
- 230000000694 effects Effects 0.000 description 35
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 32
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 29
- 241001465754 Metazoa Species 0.000 description 27
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 24
- 239000000243 solution Substances 0.000 description 23
- 230000008018 melting Effects 0.000 description 21
- 238000002844 melting Methods 0.000 description 21
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 19
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 16
- RSDOPYMFZBJHRL-UHFFFAOYSA-N Oxotremorine Chemical compound O=C1CCCN1CC#CCN1CCCC1 RSDOPYMFZBJHRL-UHFFFAOYSA-N 0.000 description 16
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 15
- 206010021143 Hypoxia Diseases 0.000 description 15
- 206010039897 Sedation Diseases 0.000 description 15
- 230000036280 sedation Effects 0.000 description 15
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 14
- 241000700159 Rattus Species 0.000 description 14
- 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 13
- LCQMZZCPPSWADO-UHFFFAOYSA-N Reserpilin Natural products COC(=O)C1COCC2CN3CCc4c([nH]c5cc(OC)c(OC)cc45)C3CC12 LCQMZZCPPSWADO-UHFFFAOYSA-N 0.000 description 13
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- 238000010992 reflux Methods 0.000 description 13
- 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 13
- 229960003147 reserpine Drugs 0.000 description 13
- 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 13
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 12
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- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
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- 230000007246 mechanism Effects 0.000 description 5
- 235000015497 potassium bicarbonate Nutrition 0.000 description 5
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 5
- 239000011736 potassium bicarbonate Substances 0.000 description 5
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 5
- 230000035939 shock Effects 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
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- 206010042008 Stereotypy Diseases 0.000 description 4
- 239000000460 chlorine Substances 0.000 description 4
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- 239000002244 precipitate Substances 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 206010052804 Drug tolerance Diseases 0.000 description 3
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 3
- 208000006550 Mydriasis Diseases 0.000 description 3
- VMWNQDUVQKEIOC-CYBMUJFWSA-N apomorphine Chemical group C([C@H]1N(C)CC2)C3=CC=C(O)C(O)=C3C3=C1C2=CC=C3 VMWNQDUVQKEIOC-CYBMUJFWSA-N 0.000 description 3
- 125000004429 atom Chemical group 0.000 description 3
- 230000006399 behavior Effects 0.000 description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 3
- 229910052794 bromium Inorganic materials 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- 230000026781 habituation Effects 0.000 description 3
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 3
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 3
- 230000006872 improvement Effects 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 230000001665 lethal effect Effects 0.000 description 3
- NNFCIKHAZHQZJG-UHFFFAOYSA-N potassium cyanide Chemical compound [K+].N#[C-] NNFCIKHAZHQZJG-UHFFFAOYSA-N 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- GKQXPTHQTXCXEV-UHFFFAOYSA-N (4-chlorophenyl)methanethiol Chemical compound SCC1=CC=C(Cl)C=C1 GKQXPTHQTXCXEV-UHFFFAOYSA-N 0.000 description 2
- RENMDAKOXSCIGH-UHFFFAOYSA-N Chloroacetonitrile Chemical compound ClCC#N RENMDAKOXSCIGH-UHFFFAOYSA-N 0.000 description 2
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 description 2
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- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
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- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- 230000001430 anti-depressive effect Effects 0.000 description 2
- 239000000935 antidepressant agent Substances 0.000 description 2
- 229940005513 antidepressants Drugs 0.000 description 2
- 239000002249 anxiolytic agent Substances 0.000 description 2
- 229960004046 apomorphine Drugs 0.000 description 2
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- 239000003179 convulsant agent Substances 0.000 description 2
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- ZZVUWRFHKOJYTH-UHFFFAOYSA-N diphenhydramine Chemical group C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 ZZVUWRFHKOJYTH-UHFFFAOYSA-N 0.000 description 2
- 239000012153 distilled water Substances 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 125000005843 halogen group Chemical group 0.000 description 2
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- 125000003396 thiol group Chemical group [H]S* 0.000 description 2
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- GPRLSGONYQIRFK-MNYXATJNSA-N triton Chemical compound [3H+] GPRLSGONYQIRFK-MNYXATJNSA-N 0.000 description 2
- YFDYEHIAUKXEDK-UHFFFAOYSA-N (n-hydroxy-c-methylcarbonimidoyl)azanium;chloride Chemical compound Cl.C\C(N)=N\O YFDYEHIAUKXEDK-UHFFFAOYSA-N 0.000 description 1
- WJFKNYWRSNBZNX-UHFFFAOYSA-N 10H-phenothiazine Chemical compound C1=CC=C2NC3=CC=CC=C3SC2=C1 WJFKNYWRSNBZNX-UHFFFAOYSA-N 0.000 description 1
- JMUXEZCHNRYQJU-UHFFFAOYSA-N 2-[(4-chlorophenyl)methylsulfanyl]acetonitrile Chemical compound ClC1=CC=C(CSCC#N)C=C1 JMUXEZCHNRYQJU-UHFFFAOYSA-N 0.000 description 1
- GRIXINIGTYIHSN-UHFFFAOYSA-N 2-chloro-n,n-diphenylacetamide Chemical compound C=1C=CC=CC=1N(C(=O)CCl)C1=CC=CC=C1 GRIXINIGTYIHSN-UHFFFAOYSA-N 0.000 description 1
- CAXNYFPECZCGFK-UHFFFAOYSA-N 2-phenyl-2-pyridin-2-ylacetonitrile Chemical compound C=1C=CC=NC=1C(C#N)C1=CC=CC=C1 CAXNYFPECZCGFK-UHFFFAOYSA-N 0.000 description 1
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 1
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- 208000019789 abdominal cramp Diseases 0.000 description 1
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- DGJMPUGMZIKDRO-UHFFFAOYSA-N cyanoacetamide Chemical compound NC(=O)CC#N DGJMPUGMZIKDRO-UHFFFAOYSA-N 0.000 description 1
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- MGHPNCMVUAKAIE-UHFFFAOYSA-N diphenylmethanamine Chemical compound C=1C=CC=CC=1C(N)C1=CC=CC=C1 MGHPNCMVUAKAIE-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C255/00—Carboxylic acid nitriles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C259/00—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups
- C07C259/12—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. N-hydroxyamidines
- C07C259/14—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. N-hydroxyamidines having carbon atoms of hydroxamidine groups bound to hydrogen atoms or to acyclic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/58—Amidines
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D233/72—Two oxygen atoms, e.g. hydantoin
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
- C07D279/10—1,4-Thiazines; Hydrogenated 1,4-thiazines
- C07D279/14—1,4-Thiazines; Hydrogenated 1,4-thiazines condensed with carbocyclic rings or ring systems
- C07D279/18—[b, e]-condensed with two six-membered rings
- C07D279/22—[b, e]-condensed with two six-membered rings with carbon atoms directly attached to the ring nitrogen atom
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Description
(54) ACETAMIDOXIME DERIVATIVES
(71) We, SOCIETE ANONYME DITE: LABORATOIRE L. LAFON, a
French Body Corporate of 1, rue Georges Mederic, 94700, Maisons-Alfort,
France, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:- The present invention relates, by way of new industrial products, to acetamidoxime derivatives and to their addition salts. It also relates to a process for the preparation of these products and their application in therapy, especially as agents which act on the central nervous system.
The invention provides acetamidoxime derivatives of the general formula:
in which R2 represents a hydrogen atom, a C1-C6 alkyl group or a pyridyl group,
R3 represents a hydrogen atom or a C1-C6 alkyl group, and R, represents a C1-C6 alkyl group, a N,N-disubstituted carbamoyl group of the formula:
(where Z, and Z2, which may be identical or different,-each represent a C5 or C6 cycloalkyl group, a phenyl group or a phenyl group which is substituted, especially by one or more C1-C4 alkyl groups, C1-C4 alkoxy groups, methylenedioxy groups, halogen, NH2 or CF3 groups), a 3-hydrantoinyl group of the formula:
(where X, is a phenyl group which is optionally substituted, especially by one or more C1-C4 alkyl groups, C1-C4 alkoxy groups, NH2, halogen or CF3 groups, and
X2 is H, a C1-C6 alkyl group or a phenyl group optionally substituted by one or more C1-C4 alkyl groups, C1-C4 alkoxy groups, methylenedioxy groups, halogen,
CF3, NO2 or NH2 groups), a group of the formula:
(where each of the phenyl groups is optionally substituted, especially by one or more C1-C4 alkyl groups, C1-C4 alkoxy groups, halogen, NH2, CF3 or NO2 groups), an arylsulphinyl group of the formula Z3-CH2-SO- (where Z3 is an aryl group, especially an a-naphthyl, ss-naphthyl or phenyl group, each of which is optionally substituted, especially by one or more C1-C4 alkyl groups, C1-C4 alkoxy groups, halogen, NH2, CF3, NO2 or methylenedioxy groups), a group of formula Z4-A- [where Z4 is a phenyl group, an α-naphthyl group, a ss-naphthyl group (each phenyl nucleus of these groups being optionally substituted, especially by one or more
C1-C4 alkyl groups, C1-C4 alkoxy groups, methylenedioxy groups, halogen, CF3,
NH2 or NO2 groups) or an adamantyl group, and -A- represents a simple bond, -CONH-, -CON(C1-C4 alkyl)-, -CON(C5-C6 cycloalkyl)-, -NHCONH-, N(Z4)CONH-, or
where Z4 can represent (an optionally) substituted benzhydryl group if -A- is different from -CONH-], a benzimidazolyl group of the formula:
(where Z5 is an aryl group, especially a phenyl group, the said aryl group and the
nucleus (a) being optionally substituted by one or more C1-C4 alkyl groups, C1- C4 alkoxy groups, methylenedioxy groups, halogen, CF3, NO2 or NH2 groups) or a tricyclic group (T) of the formula:
[where Y, is a simple bond, -CH2-, -CH=CH-, -CH2CH2-, -S-, -O-, -SCH2-, or -OCH2-, Y2 is
and Y3 is a simple bond or a -CH2- or -CO- group, and where each of the phenyl nuclei can be substituted, especially by one or more C1-C4 alkyl groups, C1-C4 alkoxy groups, methylenedioxy groups, halogen, CF3, NO2 or NH2 groups); and their addition salts with acids.
By halogen atom there is here understood an atom of fluorine, chlorine, bromine or iodine. The preferred halogen atoms are the atoms of fluorine, chlorine and bromine, from the pharmacological point of view, and the atoms of chlorine and bromine from the point of view of the synthesis reaction mechanisms.
In general terms, each phenyl nucleus, which is included in the definitions given above, can be substituted, especially (but without implying any limitation, of course) by one or more C1-C4 alkyl groups, C1-C4 alkoxy groups, methylenedioxy groups, halogen, CF3, NO2, or NH2 groups. In the same way, if the
Z4 group represents the benzhydryl group, each of the phenyl nuclei can be substituted by one or more groups mentioned especially above.
If A represents a ureido group, the preferred groups are -NHCONH-, -N(C6H 5)CONH-, and -N(p-ClC6.114)CONH-.
By the generic term "pyridyl", there is here understood the 2-pyridyl, 3pyridyl and 4-pyridyl groups.
A certain number of compounds according to the invention have been listed in
Table I below, without implying any limitation. The melting points which have been shown, are instantaneous melting points measured on the Kofler Bench.
TABLE I
I ps Q U cJ O U O 0 o o o a) O vi \o M o re O Nh -rl tn O IL) C, Ir)v n( viv U 40257 h H Hydrochloride 175-1780c F9 m ccl pm 3: p p p P :n n 1 :1 ash rl ---------- H H :free base 214-2150c (b) o H H free base 215-2160c 2 (a) U S TABLE I (continuation)
R R2 R3 Base or addition ~ 'I Code Number C\lv Q) 5 CRL 40383 H @ HN N h a o o o O O o o 6 CRL 40384 Cc6H5)2Nc0- H H Hydrochloride 20-2150C (a) 7 CRL 40410 Cl H H Hydrochloride 172-740C h CH2-SO- (a) g ne s o to H P2s X U 50 b Notes: (a) : with decomposition (b) : the corresponding hydrochloride melts at 228-230 C (c) : the product obtained according to the methods of operations described in Example 2 is a mixture of the dihydrochloride and the monohydrochloride.
The acetamidoxime derivatives and their addition salts can be prepared in accordance with a method which is in itself known, by application of conventional reaction mechanisms. The method proposed according to the invention consists of reacting a corresponding cyano derivative of the formula II below with hydroxylamine. This reaction is carried out in solution or in suspension in a C1-C4 lower alkanol such as methanol, ethanol, propanol, isopropanol and butanol, the reaction mechanism being shown schematically in the following equation:
where R1, R2, and R3 are defined as above. During this reaction, it is not necessary to remove the iminoalkyl ester which is formed as an intermediate product.
The acid addition salts can be prepared in accordance with a method which is in itself known, for example by reacting the free base with an inorganic or organic acid.
Finally, if R, must contain a sulphinyl group SO, it is possible first to prepare the corresponding acetamidoxime in which R, contains a mercapto group S and then to oxidise the said mercapto group thereafter to the sulphinyl group by means of H2O2. In that case, it is possible to proceed in accordance with the following reaction mechanism:
which is illustrated in Example 6 below.
According to the invention, a therapeutic composition is proposed which contains, in association with a physiologically acceptable excipient, at least one compound of the formula I or one of its non-toxic addition salts with acids, particularly by way of sedatives, anxiolytic agents and/or muscular relaxants, it being possible, in addition, for certain of the compounds of formula I and their salts to exhibit a bradycardia-inducing effect.
Other advantages and characteristics of the invention will be better understood on reading the preparation examples which follow, which are nonlimiting and are given by way of illustration.
EXAMPLE I
p-( 1 0-Phenothiazinyl)propionoamidoxime hydrochloride
Code No.: CRL 40,257.
1) p-(10-Phenothiazinyl)propionitrile 0.3 ml of "Triton" B (40% strength solution in methanol) is added to a solution, which is stirred at 0 C, of 20 g (0.1 mol) of phenothiazine, 30 ml (0.45 mol) of acrylonitrile and 150 ml of benzene; after the initial temperature rise, the mixture is heated under reflux for 1 hour. "Triton" is a Registered Trade Mark. The mixture is cooled, and the product is filtered off and recrystallised from benzene. The stated product is obtained with a yield of 72%. Melting point=153--154"C.
2) CRL 40,257
A stirred mixture of 7 g (0.1 mol) of hydroxylamine hydrochloride, 10 g of potassium bicarbonate in 10 ml of water and 12.6 g (0.05 mol) of P - (10 phenothiazinyl) - propionitrile in 30 ml of butanol is heated for 5 hours under reflux. After leaving overnight, the butanol is evaporated in vacuo, 100 ml of water and 50 ml of benzene are added and the base is filtered off. Melting point=104-- 106"C.
The base, suspended in 30 ml of water, is acidified with 3 N HC1 and the product is filtered off. It is recrystallised from water and CRL 40,257 is obtained with a yield of 60%. It is in the form of small pink crystals which melt with decomposition at 175-1780C. It is soluble in water and in alcohols, and insoluble in ether, in ethyl acetate and in benzene.
EXAMPLE 2 ez-Phenyl--2-pyridylacetamidoxime hydrochloride
n HC1 (n = 1 or 2)
Code No.: CRL 40,345.
0.5 mol (34.7 g) of hydroxylamine hydrochloride is dissolved in methanol and the solution is cooled by an ice bath. Thereafter a solution of 0.5 mol (27 g) of sodium methylate in methanol is added. The mixture is stirred for 10 minutes and the NaCI which has formed is filtered off. A solution of 48.5 g (0.25 mol) of a phenyl - - - 2 - pyridylacetonitrile in methanol is added to the preceding filtrate, which is cooled by an ice bath. The mixture is stirred overnight at ambient temperature. A quantity of water is added which is twice the reaction volume, and the mixture is cooled by an ice bath. The precipitate is filtered off and recrystallised from benzene. The free base (sg - phenyl - a - 2 - pyridylacetamidoxime) is thus obtained. The purity of the base is verified by thin layer chromatography (eluant: CH3OH, Merck silica gel plate and development by U.V.+Draggendorf reagent).
The free base is dissolved in acetone and the hydrochloride is precipitated by bubbling in HCI gas. CRL 40,345 is filtered off and recrystallised from an acetone/ethanol (1:1 v/v) mixture.
Weight=15 g
Yield=20%
Melting point=2000C.
Analysis shows that the product which is thus obtained is a mixture of the monohydrochloride and the dihydrochloride.
EXAMPLE 3
N-B enzhydryl-carbamoyl-acetamidoxime
Code No.: CRL 40,336.
1) N-(Benzhydryl)-a-chloracetamide A suspension of 9.15 g (0.05 mol) of benzhydrylamine and 20 g (0.19 mol) of dry Na2CO3 in 50 ml of anhydrous acetone is stirred very vigorously and 10 g (0.086 mol) of chloroacetyl chloride are added dropwise. The mixture is heated for half an hour under reflux, filtered and evaporated to dryness in vacuo. The residue (melting point=l 18--119"C) is filtered off and washed with a little cold diisopropyl ether.
2) N-(B enzhydryl)carbamoylacetonitrile (alternative nomenclature: N - (benzhydryl) - or a cyanoacetamide).
26 g (0.1 mol) of N - (benzhydryl) - a - chloracetamide and 7.7 g (0.11 mol) of potassium cyanide in 300 ml of ethanol and 100 ml of water are heated under reflux for 2 hours whilst stirring. Thereafter 500 ml of water are added and the product is filtered off, dried and recrystallised from benzene. 17 gof the stated product (yield 68%) are obtained. Melting point=158--160"C.
3) CRL 40,336.
7 g (0.1 mol) of hydroxylamine hydrochloride, 10 g of potassium bicarbonate in 10 ml of water and 16 g (0.064 mol) of N - (benzhydryl)carbamoylacetonitrile in 45 ml of butanol are mixed at 200C. This mixture is heated at 95--1000C for 1 hour, whilst stirring, and is then left to cool, and the product is filtered off and washed with water and with ether. CRL 40,336 is obtained by recrystallisation from ethanol. Yield 52%. Melting point=214-215 C.
The corresponding monohydrochloride is obtained by treatment with HCI.
Melting point=228--230"C.
EXAMPLE 4 N-(4,4'-Dichloro-benzhydryl)carbamoylacetamidoxime
Code No.: CRL 40,415.
1) N-(4,4'-Dichloro-benzhydryl)-a-chloracetamide A mixture of 11.3 g (0.045 mol) of 4,4 - dichlorobenzhydrylamine (boiling point 0.6 mm Hg=162--164"C), 250 ml of benzene and 45 ml of 1 N NaOH is stirred very vigorously and a solution of 3.8 ml (0.045 mol) of chloroacetyl chloride in 50 ml of benzene is added dropwise, the mixture is stirred for a further hour, the mixture is decanted, the product phase is washed with water and dried, and the solvent is evaporated. The residue is taken up in diisopropyl ether, the insoluble matter is filtered off, and 12 g of the stated product (yield 80%) are obtained.
Melting point=142--144"C.
2) N-(4,4'-Dichloro-benzhydryl)carbamoylacetonitrile (alternative nomenclature: N- (4,4' - dichloro - benzhydryl) - acyanoacetamide).
12 g (0.036 mol) of the preceding chloro compouind and 2.5 g (0.036 mol) of potassium cyanide in 90 ml of ethanol and 30 ml of water are heated under reflux for half an hour, 100 ml of water are added, and the product is filtered off and washed with water and with diisopropyl ether. 10.5 g (yield 91%) of the stated product are obtained. Melting point=198--2000C.
3) CRL 40,415
A solution of hydroxylamine is prepared with 5.25 g (0.075 mol) of hydroxylamine hydrochloride, 7.5 g of potassium bicarbonate and 10 ml of water.
16 g (0.05 mol) of the preceding product, suspended in 60 ml of butanol, are added and the mixture is heated for 2 hours under reflux. The mixture is cooled and the product is filtered off, washed with water and with diisopropyl ether and recrystallised from ethanol in order to obtain CRL 40,415. Yield 45%. Melting point=215--2160C (with decomposition).
EXAMPLE 5 3-(5,5-Diphenyl-hydantoinyl)acetamidoxime hydrochloride
Code No.: CRL 40,383.
1) 3.(5,5-Diphenyl-hydantoinyl)acetonitrile A solution of 12.6 g (0.05 mol) of 5,5 - diphenylhydantoin and 4.2 g (0.055 mol) of chloroacetonitrile in 75 ml of ethanol is heated under reflux, whilst stirring, and a solution of 1.15 g (0.05 gram-atom) of sodium in 100 ml of ethanol is added dropwise. The mixture is maintained under reflux for 2 hours and the sodium chloride filtered off. The filtrate is evaporated to dryness in vacuo, 100 ml of ethyl acetate are added, the mixture is washed with water, dried and evaporated to dryness and the residue is taken up in diisopropyl ether and the insoluble matter filtered off. 9 g (yield 60%) of the stated product are obtained. Melting point=198 199"C.
2) CRL 40,383
A mixture of 3.15 g (0.045 mol) of hydroxylamine hydrochloride, 4.5 g of potassium bicarbonate and 8.72 g (0.03 mol) of 3 - (5,5 diphenylhydantoinyl)acetonitrile in 40 ml of butanol and 4.5 ml of water is heated under reflux for 3 hours. The mixture is cooled and the product is filtered off and washed with water and with 10 ml of cold ethanol. The precipitate, dissolved in 200 ml of acetone, is acidified with a solution of hydrogen chloride in ethanol. The product is filtered off and recrystallised from a methanol/ethyl acetate mixture (1:1 v/v), in order to obtain CRL 40,383. Yield 58%. Melting point=178--180"C.
EXAMPLE 6
N,N-Diphenylcarbamoylacetamidoxime hydrochloride
Code No.: CRL 40,384.
1) N,N-Diphenylcarbamoylacetonitrile
A solution of 24.55 g (0.1 mol) of N,N - diphenylchloracetamide (melting point=l17-1l80C) and 7.7 g (0.11 mol) of potassium cyanide in 300 ml of ethanol
and 100 ml of water is heated under reflux for 2 hours. The alcohol is evaporated
off in vacuo, the residue is taken up in water and the mixture is extracted with
methylene chloride. The extract is washed with dilute HCI, with dilute sodium
bicarbonate and with water, dried and evaporated; the residue is taken up in
diisopropyl ether and the insoluble matter is filtered off and recrystallised from
ethanol. 15 g (yield 64%) of the stated product are obtained. Melting point=151 152"C.
2) CRL 40,384
14.15 g (0.06 mol) of N,N - diphenylcarbamoylacetonitrile, dissolved in 40 ml of butanol, are added to a solution of 7 g (0.1 mol) of hydroxylamine hydrochloride and 10 g of potassium bicarbonate in 10 ml of water. The mixture is heated under reflux for 3 hours, whilst stirring, and is cooled, and the product is filtered off, washed with water and dried. The free base (melting point=147-1480C) is thus obtained, and is converted into the hydrochloride with a solution of hydrogen chloride in ethanol. CRL 40,384 is obtained by recrystallisation from ethanol. Yield 51%. Melting point=210--215"C (with decomposition).
EXAMPLE 7
4-Chlorobenzylsulphinylacetamidoxime hydrochloride
Code No.: CRL 40,410 1) 4-Chlorobenzylmercapto-acetonitrile
13 ml (15.9 g; 0.1 mol) of 4-chlorobenzylmercaptan and a solution of 4.2 g (0.105 mol) of NaOH in 50 ml of water are mixed whilst cold. Thereafter the mixture is heated at about 60"C and then 7.5 ml (about 1.2 mols) of chloroacetonitrile are added dropwise at this temperature. At the end of this addition (the temperature is then about 80"C), the mixture is heated under reflux (1000C for 30 to 45 minutes. The mixture is cooled, the oil which forms is extracted with ether and the aqueous phase is removed. The ether solution is washed with dilute NaOH and then with water until the pH of the wash waters is neutral. The ether solution is dried over MgSO4 which Is filtered off before evaporating the ether. 19.7 g of the stated product (yield about 100%, relative to the starting 4- chlorobenzylmercaptan) are collected in the form of an oil.
2) 4 - Chlorobenzylmercapto - acetamidoxime hydrochloride
The preceding product (about 0.1 mol) is taken up with 100 ml of n-butanol and mixed, whilst cold, with an aqueous solution (50 ml) of 0.2 mol (14 g) of hydroxylamine. The whole is heated at the reflux temperature of the n butanoMwater mixture for 2 hours 30 minutes to 3 hours, with vigorous stirring. The butanoMwater mixture is then evaporated and the residue taken up in water. The base (4 chlorobenzylmercapto - acetamidoxime) crystallises, the mixture is allowed to stand for some hours at 5--100C and the product is filtered off and dried. 19.6 g of the said base (instantaneous melting point=76 C; yield 85%) are thus collected. The hydrochloride is prepared by dissolving the base in ether and adding a solution of hydrogen chloride in ethanol. After filtration and drying in vacuo, 21 g of the expected product are collected. Instantaneous melting point=174--176"C (with decomposition). Yield 78.5%.
3) CRL 40,410
21 g (0.078 mol) of the preceding compound are mixed with 100 ml of anhydrous acetic acid and 7.8 ml of H202 of 110 volumes strength (at 200 C) are added. The sulphide dissolves gradually and an increase in the temperature is noted. Thereafter the mixture is heated at 500C for about one hour to obtain complete oxidation (the progress of the reaction is followed by chromatography), the acetic acid is then evaporated and the oil which remains is taken up in acetone; (para-chlorobenzylsulphinyl)acetamidoxime hydrochloride precipitates. The precipitate is filtered off, dried and recrystallised from an acetone/isopropanol (1:1 v/v) mixture. 17 g of CRL 40,410 are thus collected. Melting point=172--174"C (with decomposition). Yield 60%.
The tests which were carried out with the compounds according to the invention are summarised below. In the text which follows, unless otherwise indicated, the products have been administered intraperitoneally, in suspension in a gum solution, in a volume of 20 ml/kg in the case of mice and of 5 ml/kg in the case of rats. Moreover, the doses tested were 2 mglkg, 4 mg/kg, 8 mg/kg, 16 mg/kg, 32 mg/kg, 64 mg/kg, 128 mg/kg, 256 mg/kg, 512 mg/kg and 1,024 mg/kg in the case of mice and 1 mg/kg, 2 mg/kg, 4 mg/kg, 8 mg/kg, 16 mg/kg, 32 mg/kg, 64 mg/kg, 128 mg/kg and 256 mg/kg in the case of rats.
Tests on CRL 40,336 (product of Example 3)
A. Toxicity and observations on animals
The LDo in the case of mice is greater than 1,024 mg/kg.
In the case of mice, sedation for 30 minutes to 60 minutes and hyper-reactivity to touch for 3 hours are observed at the dose of 8 mglkg, at the dose of 32 mg/kg sedation for 2 to 3 hours and hyper-reactivity to touch for 1 hour are observed, at the dose of 128 mg/kg sedation of a duration which is variable depending on the animals (1 to 3 hours) and hyper-reactivity for 2 to 3 hours are observed, and at the dose of 512 mg/kg sedation for 3 hours and moderate hypothermia (2.9"C) are observed.
In the case of rats, at doses of 16 mg/kg, 64 mgXkg and 256 mglkg, CRL 40,336
induces sedation accompanied by a reduction in muscular tonus for 3 hours.
B. Effect on the central nervous system
1) Interaction with amphetamine
Amphetamine (2 mg/kg, given intraperitoneally) is administered to batches of 5 rats 30 minutes after the administration of CRL 40,336. At doses from 16 mg/kg upwards, CRL 40,336 causes a prolongation of the stereotype behaviour induced by amphetamine.
2) Interaction with reserpine
CRL 40,336 is administered to batches of 6 mice which, 4 hours previously, have received an intraperitoneal injection of 2.5 mg/kg of reserpine. With regard to the effect on the temperature, CRL 40,336 causes an aggravation of reserpineinduced hypothermia at doses of 32, 128 and 512 mg/kg. With regard to the action on ptosis, CRL 40,336 does not release the palpebral ptosis produced by reserpine.
3) Effect on the four-plate test, traction and electrical shock
The test is carried out on batches of 20 sensitive mice (Ivic Ceba) 30 minutes after the administration of CRL 40,336. At doses from 0.5 mg/kg upwards, CRL 40,336 appears to induce an increase in the number of incorrect moves. This effect does not increase with the dose, probably due to interference with the spontaneous motility. Moreover, CRL 40,336 does not cause a major motor loss and does not modify the convulsant and lethal effects of the electric shock.
4) Action on the motility
Spontaneous motility
Thirty minutes after the administration of CRL 40,336, the mice (6 per dose, 12 comparison animals) are placed in an actimeter, where their motility is recorded for half an hour. At doses from 32 mg/kg upwards, CRL 40,336 induces hypomotility in mice.
Residual motility
After a stay of 18 hours in the actimeters, the mice receive CRL 40,336 and then, half an hour afterwards, the recording of the motility starts and is continued for 30 minutes. It is noted that CRL 40,336 does not cause resumption of the motor activity in mice accustomed to their cage.
Motor recovery after hypoxia aggression
Thirty minutes after having received CRL 40,336, the mice (10 per dose, 20 comparison animals) are subjected to anoxia, by pressure reduction, and are then placed in an actimeter where their motility is recorded for 10 minutes (8, 32, 128 and 512 mg/kg given intraperitoneally). It is noted that CRL 40,336 does not cause an improvement in the motor recovery of mice suffering from anoxia. At a high dose, the depressant effect on the motility is again found.
5) Action on the interaction group aggressiveness
After a stay of 3 weeks in each of the halves of a cage divided by an opaque partition, batches of 3 mice receive the product to be tested 30 minutes before being brought together by withdrawing the partition. The number of fights which take place in the course of 15 minutes which follow are then counted. At a dose of 32 mg/kg, CRL 40,336 inhibits the intraspecific aggressive behaviour of mice. At lower doses (8 mg/kg), this effect disappears.
It follows from this set of results that CRL 40,336 possesses an anxiolytic activity (revealed by the four-plate test) without a major disabling effect and without a clear reduction in the aggressive behaviour.
Tests on CRL 40,315 (product of Example 4)
A. Toxicity and observation on animals
At high doses (256 and 512 mg/kg), in the case of mice, sedation with trembling movements is observed. The Lid, its greater than 256 mg/kg and less than 512 mg/kg, this being the dose at which the mice die.
At a dose of 128 mg/kg, the mice are under sedation and exhibit some transient extrapyramidal signs. At a dose of 32 mg/kg, sedation for 30 minutes to 3 hours and moderate hypothermia (-2.6"C) are noted. At doses of 8 and 2 mg/kg, the sedation lasts for 30 minutes.
B. Effect on the central nervous system
The results which relate to the action on the motility are given below.
1) Spontaneous motility
Thirty minutes after the mice have received CRL 40,315, a reduction in the spontaneous motility is observed.
2) Residual motility
After a stay of 18 hours in the actimeters, the mice receive CRL 40,315 and then, after half an hour without recording, their motility is noted for 30 minutes (6 animals per dose, 12 comparison animals). At a dose of 32 mg/kg, CRL 40,315 causes a certain resumption of activity in mice accustomed to their cage.
3) Motor recovery after hypoxia aggression
Thirty minutes after having been subjected to hyporbaric anoxia, the mice (10 per dose, 20 comparison animals) receive CRL 40,315 and then their motility is recorded for 10 minutes. CRL 40,315 does not cause an improvement in the motor recovery of mice which have been subjected to hypobaric anoxia.
Tests on CRL 40,383 (product of Example 5)
A. Toxicity and observations on animals
The toxicity varies according to the mouse strain. In the case of mice of the
Fesal strain, CRL 40,383 no mortality whatsoever is caused at doses of 512 mg/kg and 1024 mg/kg. On the other hand, in the case of mice of the Ivic Ceba strain, it causes death at doses from 512 mg/kg upwards, half an hour after administration.
In the case of mice, reduction of the spontaneous motor activity has been found and, in the case of rats, at doses of 16 mg/kg and 64 mg/kg, moderate mydriasis is observed for 1 to 2 hours.
B. Effect on the central nervous system 1) Interaction with amphetamine
Thirty minutes after the administration of CRL 40,383, batches of 6 rats receive an intraperitoneal injection of 2 mg/kg of amphetamine.
A
3) Interaction with oxotremorine
Batches of 6 mice receive an intraperitoneal injection of 0.5 mg/kg of oxotremorine 30 minutes after the adminstration of CRL 40,383.
(a) Effect on the temperature
90 minutes after the injection of oxotremorine, that is to say 2 hours after its administration, CRL 40,383, at a dose of 128 mg/kg, exerts a very partial antagonism towards the lowering of temperature produced by oxotremorine.
(b) Effect on the trembling movements
The trembling movements produced by oxotremorine are not modified by
CRL 40,383.
4) Effect on the motility (a) Spontaneous motility
Thirty minutes after the administration of CRL 40,383, the mice are placed in actimeters where their motility is recorded for half an hour (6 animals per dose, 12 comparison animals). At high doses (32 and 128 mg/kg), CRL 40,383 induces a reduction in spontaneous motor activity.
(b) Motility reduced by habituation to the cage (residual motility)
After a stay of 18 hours in the actimeters, the mice (6 per dose, 12 comparison animals) receive CRL 40,383. They are immediately replaced in their cages after the injection and, after a period of half an hour, their motility is recorded for 30 minutes. It is found that CRL 40,383 does not cause a clear resumption of activity in mice accustomed to their cage.
(c) Motility reduced by hypoxia aggression
Half an hour after having received CRL 40,383, the mice are subjected to hypobaric anoxia (pressure reduction of 600 mm Hg in 90 seconds, return to normal pressure in 45 seconds) and are then placed in an actimeter and their motility is recorded for 10 minutes (10 mice per dose, 20 comparison animals). It is thus found that CRL 40,383 does not improve the motor recovery of mice whose motility has been depressed by hypobaric anoxia, and does not exhibit clear antiaggressive activity.
Together, the results given above make it possible to demonstrate the mechanism of the action of the product in the organism. Thus, CRL 40,383 exhibits, firstly, effects of the antidepressant type: antagonism to reserpine-induced hypothermia, antagonism to hypothermia produced by oxotremorine and potentiation of the amphetamine-induced stereotypies, and, secondly, effects of the sedative type: hypomotility and reduction of aggressiveness.
Tests on CRL 40,384 (product of Example 6)
CRL 40,384 was administered intraperitoneally in solution in distilled water, at a volume of 20 ml/kg in the case of mice and 5 ml/kg in the case of rats.
A. Toxicity and behaviour of the animals
The LDo in the case of mice is greater than 256 mg/kg and less than 512 mg/kg.
In the case of mice, trembling movements and sedation are observed at a dose of 526 mg/kg, at a dose of 128 mg/kg hyper-reactivity to touch (for 30 minutes), trembling movements (for 15 minutes) and hypothermia (-2.9"C for 2 hours) are observed and, at doses of 8 and 32 mg/kg, hyper-reactivity is observed for the second hour.
In the case of rats, hyper-reactivity to the touch, trembling movememnts (for 15 minutes) and mydriasis (for 2 hours) are observed at a dose of 64 mg/kg, and at a dose of 16 mg/kg mydriasis (for 1 hour).
B. Effect on the central nervous system 1) Interaction with amphetamine
Batches of 6 rats receive an intraperitoneal injection of 2 mg/kg of amphetamine 30 minutes after the administration of CRL 40,384. It is found that, at doses of 16 and 64 mg/kg, CRL 40,384 prolongs the duration of the amphetamineinduced stereotypies.
2) Interaction with reserpine
Four hours after the administration of reserpine (2.5 mg/kg given intraperitoneally), batches of 6 mice receive CRL 40,383.
(a) Effect on the temperature
At a high dose, CRL 40,383 aggrevates the hypothermia-inducing effect of reserpine. At a dose of 32 mg/kg, it appears to exert a delayed discrete antagonism towards reserpine-induced hypothermia.
(b) Action on the ptosis
At a high dose (128 mg/kg), CRL 40,384 exerts a very moderate antagonism towards the palpebral ptosis induced by reserpine.
3) Interaction with oxotremorine
Thirty minutes after the administration of CRL 40,384, the mice receive an intraperitoneal injection of 0.5 mg/kg of oxotremorine (12 animals per dose and 12 animals in the comparison batch).
(a) Effect on the temperature
At doses from 2 mg/kg upwards, CRL 40,384 partially antagonises the hypothermia-inducing action of oxotremorine.
(b) Effects on the trembling movements
CRL 40,384, at a high dose, leads to a potentiation of the trembling movements induced by oxotremorine. This effect may be due to the inherent tremorigenic effect of CRL 40,384.
(c) Effect on the peripheral cholinergic symptoms
At doses from 8 mg/kg upwards, CRL 40,384 reduces defaecation and at 128 mg/kg the lacrymation which takes place after the administration of oxotremorine.
4) Effect on the four-plate test, traction and electrical shock
Batches of 10 mice are subjected to the test 30 minutes after having received
CRL 40,384. At a high dose (128 mg/kg), CRL 40,384 reduces the number of incorrect moves. At no dose does it bring about a major motor deficiency and a modification of the convulsivant and lethal effects of the electric shock.
5) Action on the motility (a) Spontaneous motility
Thirty minutes after having received CRL 40,384, the mice are placed in an actimeter where their motility is noted for half an hour (6 animals per dose, 12 comparison animals). At the highest dose (128 mg/kg), CRL 40,384 induces reduction of the spontaneous locomotor activity.
(b) Motility reduced by habituation to the cage
After a stay of 18 hours in the actimeters, the mice (6 per dose, 12 comparison animals) receive CRL 40,384. They are immediately replaced in their cages and, half an hour after the administration of the product, recording of the motltity Is started and is continued for 30 minutes. At all doses, CRL 40,384 appears to induce a resumption of activity in mice accustomed to their cage, but this effect is almost totally due to one or two animals per group.
(c) Motility reduced by hypoxia aggression
Thirty minutes after the administration of CRL 40,384, the mice (10 per dose, 20 comparison animals) are subjected to hypobaric anoxia (pressure reduction of 600 mm Hg in 90 seconds, return to normal pressure in 45 seconds) and are then placed in the actimeters where their motility is recorded for 10 minutes. At no dose does CRL 40,384 cause an improvement in the motor recovery in mice whose activity has been reduced by hypobaric anoxia.
6) Effect on inter-group aggressiveness
After a stay of 3 weeks in each of the halves of a cage divided by an opaque partition, groups of 3 mice receive CRL 40,384 and then, half an hour later, they are brought together by withdrawing the partition. The number of fights which take place during the following 15 minutes is then noted. It is found that CRL 40,384 leads to a moderate reduction in the number of combat episodes.
Tests on CRL 40,410 (product of Example 7)
CRL 40,410 was administered intraperitoneally in solution in distilled water (the pH of this solution was 3), at a volume of 20 ml/kg in the case of mice and 5 ml/kg in the case of rats.
A. Toxicity and behaviour of the animals
In the case of mice, injection of CRL 40,410 at doses of 1024 and 512 mg/kg causes sedation with hyper-reactivity to touch and respiratory depression to appear; death of the animal takes place after 20 minutes and 3 hours respectively; at the non-lethal doses of 256 and 128 mg/kg, sedation with hyper-reactivity to touch and hypothermia are observed, and the mice exhibit abdominal cramp which is very probably connected with the acidity of the solution administered; at doses of 64 mg/kg and 32 mg/kg, and after a brief (10 minutes) phase of excitation, the appearance of sedation accompanied by hyper-reactivity to touch is noted.
In the case of rats, at a dose of 64 mg/kg, sedation for 15 to 30 minutes followed by a period of excitation of 1 hour are observed, at a dose of 16 mg/kg a period of excitation from 15 minutes to 2 hours, with stereotype movements being exhibited, is observed, and at doses of 1 mg/kg and 4 mg/kg a transient period of excitation (duration 30 minutes) is observed.
B. Effect on the central nervous system 1) Interaction with apomorphine
Groups of 12 rats receive an administration of apomorphine (0.5 mg/kg, administered subcutaneously) 30 minutes after the administration of CRL 40,410. It is observed that the stereotypies induced by apomorphine are virtually unmodified by CRL 40,410.
2) Interaction with amphetamine
Thirty minutes after the administration of CRL 40,410, batches of 12 rats receive an intraperitoneal injection of 2 mg/kg of amphetamine. It is noted that
CRL 40,410 causes a moderate potentiation of the amphetamine-induced stereotypies.
3) Interaction with reserpine
Four hours after the administration of reserpine (2.5 mg/kg given intraperitoneally), the mice receive CRL 40,410 (18 animals per dose).
(a) Effect on the temperature
CRL 40,410 does not modify reserpine-induced hypothermia.
(b) Effect on the ptosis
CRL 40,410 does not reduce the palpebral ptosis induced by reserpine.
4) Interaction with oxotremorine
Oxotremorine (0.5 mg/kg) is injected intraperitoneally into batches of 6 mice, 30 minutes after the administration of CRL 40,410.
(a) Effect on the temperature
At a dose of 128 mg/kg, CRL 40,410 partially opposes the hypothermiainducing action of oxotremorine.
(b) Effect on the trembling movements
CRL 40,410 does not combat the trembling movements caused by oxotremorine.
(c) Effect on the peripheral cholinergic symptoms CRL 40,410 appears to increase the salivary and lachrymal hypersecretion as well as the defaecation which take place after the administration of oxotremorine.
5) Action on the four-plate test, traction and electrical shock
Batches of 10 mice are subjected to the test 30 minutes after the administration of CRL 40,410. It is observed that CRL 40,410 does not bring about an increase in the number of incorrect moves, does not induce a major motor deficiency and does not oppose the convulsant effects of electrical shock. At a high dose, it seems to aggrevate the lethal effects of electrical shock.
6) Action on the motility (a) Spontaneous motility
Thirty minutes after the administration of CRL 40,410, the mice (6 per dose, 12 comparison animals) are placed in an actimeter where their motility is recorded for 30 minutes. It is observed that, at a high dose (128 mg/kg), CRL 40,410 induces a very great lowering of the motor activity of the mice.
(b) Motility reduced by habituation to the cage
After a stay of 18 hours in the actimeters, the mice (6 per dose, 12 comparison animals) receive CRL 40,410. Immediately afterwards they are put into their cages and, half an hour later, recording of the motility begins, which is continued for 30 minutes. It is observed that CRL 40,410 does not cause a resumption in the activity of mice habituated to their cage.
(c) Motility reduced by hypoxia aggression
Thirty minutes after having received CRL 40,410, the mice (10 per dose, 20 comparison animals) are subjected to hypobaric anoxia (pressure reduction of 600 mm Hg in 90 seconds, return to normal pressure in 45 seconds) and are then placed in the actimeters where their motility is noted for 10 minutes. It is observed that
CRL 40,410 does not improve the motor recovery of mice suffering from anoxia.
Taken together, the results given above demonstrate that CRL 40,410 reduces spontaneous motility and exhibits a particular pharmacological spectrum, that is to say, sedation in the case of mice and excitation in the case of rats.
Tests on CRL 40,345 (product of Example 2)
The tests which were carried out show that CRL 40,345 acts on the central nervous system and exhibits very valuable bradycardia inducing properties.
The recommended clinical doses for the compounds of formula I and their salts are 50 to 400 mg orally per day. The most interesting product from the therapeutic point of view, CRL 40,383 (Example 5), has given good results in man as an antidepressant, orally administered in the form of gelatin-coated pills each containing 100 mg of the active ingredient at the rate of three pills per day.
Claims (9)
1. Acetamidoxime derivatives of the general formula:
in which R2 represents a hydrogen atom, a C1-C6 alkyl group or a pyridyl group,
R3 represents a hydrogen atom or a C1-C6 alkyl group, and R, represents a C1-C6 alkyl group, a N,N-disubstituted carbamoyl group of the formula:
(where Z, and Z2, which may be identical or different, each represent a C5 or C6 cycloalkyl group, a phenyl group or a phenyl group which is substituted, especially by one or more C,-C4 alkyl groups, methylenedioxy groups, halogen, NH2 or CF3 groups), a 3-hydrantoinyl group of the formula:
(where X is a phenyl group which is optionally substituted, especially by one or more C1-C4 alkyl groups, C1-C4 alkoxy groups, NH2, halogen or CF3 groups, and
X2 is H, a C1-C6 alkyl group or a phenyl group optionally substituted by one or more C1-C4 alkyl groups, C1-C4 alkoxy groups, methylenedioxy groups, halogen,
CF3, NO2 or NH2 groups), a group of the formula:
(where each of the phenyl groups is optionally substituted, especially by one or more C1-C4 alkyl groups, C1-C4 alkoxy groups, halogen, NH2, CF3 or NO2 groups), and arylsulphinyl group of the formula: Z3-CH2-SO- (where Z3 is an aryl group, especially an α-naphthyl, ss-naphthyl or phenyl group, each of which is optionally substituted, especially by one or more C1-C4 alkyl groups, C1-C4 alkoxy groups, halogen, NH2, CF3, NO2 or methylenedioxy groups), a group of formula: Z4-A- [where Z4 is a phenyl group, am α-naphthyl group, a ss-naphthyl group (each phenyl nucleus of these groups being optionally substituted, especially by one or more
C1-C4 alkyl groups, C1-C4 alkoxy groups, methylenedioxy groups, halogen, CF3,
NH2 or NO2 groups) or an adamantyl group, and -A- represents a simple bond, -CONH-, -CON(C1-C4 alkyl)-, -CON(C5-C6 cycloalkyl)-, -NHCONH-, N(Z4)CONH-, or
where Z can represent an optionally substituted benzhydryl group if -A- is different from -CONH-] a benzimidazolyl group of the formula:
(where Z5 is an aryl group, especially a phenyl group, the said aryl group and the nucleus (a) being optionally substituted by one or more C1-C4 alkyl groups, C1- C4 alkoxy groups, methylenedioxy groups, halogen, CF3, NO2 or NH2 groups) or a tricyclic group (T) of the formula:
(where Y, is a simple bond, -CH2-, -CH=CH-, -CH2CH2-, -S-, -O-, -SCM2- or -0CM2-, Y2 is
and Y3 is a simple bond or a -CM2- or -CO- group, and where each of the phenyl nuclei can be substituted, especially by one or more C1-C4 alkyl groups, C1-C4 alkoxy groups, methylenedioxy groups, halogen, CF3, NO2 or NH2 groups); and their addition salts with acids.
2. ss - (10 - Phenothiazinyl) - propionamidoxime and its acid addition salts.
3. cr - Phenyl - - 2 - pyridylactamidoxime and its acid addition salts.
4. (N - Benzhydrylcarbamoyl) - acetamidoxime and its acid addition salts.
5. [N - (4,4' - Dichlorobenzhydryl) - carbamoyli - acetamidoxime and its acid addition salts.
6. 3 - (5,5 - Diphenylhydantoinyl) - acetamidoxime and its acid addition salts.
7. (N,N - Diphenylcarbamoyl) - acetamidoxime and its acid addition salts.
8. 4 - Chlorobenzylsulphinylacetamidoxime and its acid addition salts.
9. A therapeutic composition comprising at least one acetamidoxime derivative according to any one of claims 1 to 8, or a non-toxic acid addition salt thereof, in association with a physiologically acceptable excipient.
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB1670377A GB1602110A (en) | 1977-04-21 | 1977-04-21 | Acetamidoxime derivatives |
FR7810109A FR2392967A1 (en) | 1977-04-21 | 1978-04-05 | NEW ACETAMIDOXIME DERIVATIVES USEFUL PARTICULARLY IN THERAPEUTICS |
BE2056890A BE866163A (en) | 1977-04-21 | 1978-04-20 | NEW ACETAMIDOXIME DERIVATIVES USEFUL PARTICULARLY IN THERAPEUTICS |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB1670377A GB1602110A (en) | 1977-04-21 | 1977-04-21 | Acetamidoxime derivatives |
Publications (1)
Publication Number | Publication Date |
---|---|
GB1602110A true GB1602110A (en) | 1981-11-04 |
Family
ID=10082146
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
GB1670377A Expired GB1602110A (en) | 1977-04-21 | 1977-04-21 | Acetamidoxime derivatives |
Country Status (3)
Country | Link |
---|---|
BE (1) | BE866163A (en) |
FR (1) | FR2392967A1 (en) |
GB (1) | GB1602110A (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2005117847A2 (en) * | 2004-06-02 | 2005-12-15 | Combinatorx, Incorporated | Methods and compounds for the treatment of neoplasms |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2506767A1 (en) * | 1981-05-26 | 1982-12-03 | Synthelabo | HETEROCYCLIC DERIVATIVES OF AMIDOXIMES, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE1770537A1 (en) * | 1967-06-01 | 1972-02-24 | Toraude Lab | New phenothiazine-10-propionamidoximes and processes for their preparation |
-
1977
- 1977-04-21 GB GB1670377A patent/GB1602110A/en not_active Expired
-
1978
- 1978-04-05 FR FR7810109A patent/FR2392967A1/en active Granted
- 1978-04-20 BE BE2056890A patent/BE866163A/en not_active IP Right Cessation
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2005117847A2 (en) * | 2004-06-02 | 2005-12-15 | Combinatorx, Incorporated | Methods and compounds for the treatment of neoplasms |
WO2005117847A3 (en) * | 2004-06-02 | 2006-01-12 | Combinatorx Inc | Methods and compounds for the treatment of neoplasms |
Also Published As
Publication number | Publication date |
---|---|
BE866163A (en) | 1978-10-20 |
FR2392967B1 (en) | 1981-12-11 |
FR2392967A1 (en) | 1978-12-29 |
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Legal Events
Date | Code | Title | Description |
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PS | Patent sealed | ||
PCNP | Patent ceased through non-payment of renewal fee |