WO2001028991A1 - Derives thiooxamide de n-cycloalkyle - Google Patents

Derives thiooxamide de n-cycloalkyle Download PDF

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Publication number
WO2001028991A1
WO2001028991A1 PCT/JP2000/007245 JP0007245W WO0128991A1 WO 2001028991 A1 WO2001028991 A1 WO 2001028991A1 JP 0007245 W JP0007245 W JP 0007245W WO 0128991 A1 WO0128991 A1 WO 0128991A1
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group
alkyl
alkyl group
alkoxy
compound
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PCT/JP2000/007245
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English (en)
Japanese (ja)
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Masakazu Sato
Yuko Kobayashi
Takuya Hamaguchi
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Taisho Pharmaceutical Co., Ltd
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Priority to AU79484/00A priority Critical patent/AU7948400A/en
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    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/20—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof
    • C07D295/205—Radicals derived from carbonic acid
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    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4453—Non condensed piperidines, e.g. piperocaine only substituted in position 1, e.g. propipocaine, diperodon
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    • A61K31/5375—1,4-Oxazines, e.g. morpholine
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C327/00—Thiocarboxylic acids
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    • C07C327/40—Amides of thiocarboxylic acids having carbon atoms of thiocarboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C327/42—Amides of thiocarboxylic acids having carbon atoms of thiocarboxamide groups bound to hydrogen atoms or to acyclic carbon atoms to hydrogen atoms or to carbon atoms of a saturated carbon skeleton
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three 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
    • C07D277/38—Nitrogen atoms
    • C07D277/44—Acylated amino or imino radicals
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    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C07D295/125—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/13—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
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    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
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    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
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    • C07C2603/74—Adamantanes

Definitions

  • the present invention relates to a compound having a tyrosine phosphatase inhibitory activity. More specifically, the present invention has a tyrosine phosphatase inhibitory activity possessed by the CD45 antigen. It relates to an expected new N-cycloalkyl thioxamide derivative. Background art
  • Reversible phosphorylation of tyrosine residues in proteins plays an important role in signal transduction pathways involved in cell function expression. Molecules involved in signal transduction induce enzymatic activity and change the molecular structure depending on the phosphorylation state of the tyrosine residue. This phosphorylation state is controlled by phosphorylase (kinase) and phosphatase (phosphatase).
  • CD45 a common human leukocyte antigen
  • CD45 antigen a molecule that regulates signal transduction necessary for activation of T cells and mast cells involved in immune and allergic reactions. Therefore, by inhibiting the tyrosine phosphatase activity of the CD45 antigen, immune responses such as T cell-derived type IV allergy, IgE-derived type I allergy, and dermatitis involving both of them are considered. Is considered to be able to be suppressed at an early stage.
  • Sodium vanadate-phenylarsenic oxide has been reported as a tyrosine phosphatase inhibitor, and is known to inhibit IgE-induced mast cell degranulation.
  • the toxicity of these compounds is a problem with heavy metals. Therefore, inhibitors of low molecular organic compounds are desired.
  • An object of the present invention is to provide a drug having a novel mechanism of action, which is related to activation of T cells and mast cells involved in immunity and allergic reactions and inhibits tyrosine phosphatase possessed by CD45 antigen. I do. Disclosure of the invention
  • R 1 is C ⁇ . Alkyl groups; C 2-8 alkenyl group; Ji 3_ 8 cycloalkyl group; C 5 alkyl C 3- 8 cycloalkyl group; C 3 - 8 cycloalkyl C 5 alkyl group; C 3 -8 Shikuroaruke chloride.
  • Alkoxy groups C 2 - 5 alkoxycarbonyl alkylsulfonyl ⁇ i-5 alkyl group, a nitro group, triflate Ruo Russia methyl group, tri Furuorometokishi group, phenyl group, phenoxy groups, C Bok 5 alkyl substituted phenoxy group, a styryl group, d- S-alkoxy-substituted styryl, benzyl and benzyloxy-substituted phenyl; 13-substituted phenyl; naphthyl; tetrahydronaphthyl; naphthyl C! -3 alkyl; pyridyl: phenyl
  • a benzene ring is substituted with 13 selected from a halogen atom, a trifluoromethyl group, a trifluoromethoxy group, a Ci-5 alkyl group, a d-5 alkoxy group and a Ci-3 alkylenedioxy group; phenyl alkyl group; ⁇ Dammann chill methyl; I Ndaniru group; Noruporuniru group; phenylene Ruimidazoriru group; a benzhydryl group; base Nzuhidoriru d-5 alkyl groups; phenylene point pen Gilles methyl group; a thienyl d-5 Al kills group; furyl Alkyl group; 1 _C 2 -5 alkoxycarboyl 4-piperidyl group; or formula
  • R represents a hydrogen atom or a C 2 -alkoxycarbonyl group
  • R ′ represents a d- 5 alkyl group
  • R 2 represents a cyclopropyl group or a cyclobutyl group are shown
  • R 3 is a hydrogen atom; a benzyl group; C 5 alkoxy C> - 5 alkyl group; or R 1 and morpholinyl group with connexion adjacent nitrogen atom such together, pyrrolidyl group, piperazinyl Rijino group
  • 4-C 2 -5 represents a group which forms a 5- alkoxyl-bi-biperazino group or a 4-benzyloxycarborbi-perazino group.
  • the alkyl group means a straight or branched chain alkyl group having a carbon number of 1 5, for example a methyl group, Echiru group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, Tert-butyl group, pentyl group, isopentyl group and the like can be mentioned.
  • the alkyl group means a linear or branched alkyl group having 210 carbon atoms, for example, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, tert-butyl group, pentyl group. Group, isopentyl group, hexyl group, isohexyl group, heptyl group, octyl group, nonyl group, decyl group and the like.
  • An octogen atom is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
  • C 5 The alkoxy group to agree taste a linear or branched alkoxy group having a carbon number of 1 5, such as methoxy group, E Bok alkoxy group, a propoxy group, isopropoxy group, butoxy group, and the like heptoxy Can be mentioned.
  • Examples of the alkoxy group include the above-mentioned hexoxy group and the like.
  • the alkenyl group means a straight or branched chain alkenyl group having a carbon number of 2 8, such as vinyl group, Ariru group, propenyl group, isopropenyl group, a pentenyl group, isopentenyl group And the like.
  • C 3 - 8 means a cycloalkyl group having a carbon number of 3 8 cycloalkyl group, their these are cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group and Shikurookuchiru group cycloheteroalkyl .
  • C alkyl C 3 - 8 cycloalkyl and alkyl group means the cycloalkyl group any position cycloalkyl ring is substituted by C 5 alkyl, such as 4 - methylcyclohexyl hexyl group, 2-Echirushi click port pentyl group, 4-tert-butylcyclohexyl group and the like.
  • the C 3-8 cycloalkyl C! -5 alkyl group means a C alkyl group substituted with the cycloalkyl group, and examples thereof include a cyclohexylmethyl group, a cyclopentylethyl group, and a cyclohexylpropyl group. it can.
  • -5 means an alkyl group, for example, a cyclopentenylethyl group, a cyclohexenylmethyl group, a cyclohexenylethyl group, a cyclohexenylpropyl group, etc.
  • a C 5 alkyl group means a C 5 alkyl group in which a C 5 alkoxy group is substituted at an arbitrary position, for example, a methoxymethyl group, a methoxypropyl group, an ethoxymethyl group, an ethoxyethyl group, a propoxymethyl group.
  • a di (C 5 alkoxy) C 5 alkyl group means a C -5 alkyl group in which two C 5 alkoxy groups are substituted on the same carbon, such as a 22-dimethoxyethyl group, a 22-diethoxyethyl group, Examples thereof include a 2,2-dimethyloxypropyl group.
  • the phenoxy C t- 5 alkyl group means a C 5 alkyl group substituted by a phenoxy group, and examples thereof include a phenoxymethyl group, a phenoxethyl group, and a phenoxypropyl group.
  • the piperidyl C5 alkyl group means a C, -5 alkyl group substituted by a piperidyl group, and examples thereof include piperidyl-1-methyl group and piperidyl-1-propyl group.
  • C 2 - 5 alkoxycarbonyl is a carbonyl group means a straight or branched alkoxy force Lupo two Le group having a carbon number of 2 5, for example, methoxycarbonyl group, Etokishikarupo two group, an ethoxycarbonyl group, Examples include a propoxycarbonyl group and a tert-butoxycarbonyl group.
  • C 2-5 alkoxycarbonyl! -5 alkyl group means a d-5 alkyl group in which the above-mentioned alkoxycarbonyl group is substituted at an arbitrary position, for example, methoxycarbonylmethyl group, ethoxycarbonylmethyl group, ethoxycarbonylethyl group, propoxycarbonyl. Examples thereof include a methyl group and a tert-butoxycarbonylmethyl group.
  • 5-Alkyl group is C-5 alkyl substituted by Benzhydryl group A benzylhydrylmethyl group, a benzhydrylethyl group, a benzhydrylpropyl group, and the like.
  • the quinyl-5 alkyl group means a Ci-5 alkyl group substituted by a phenyl group, and examples thereof include a phenylmethyl group, a phenylethyl group, and a phenylpropyl group.
  • the furyl alkyl group means a Ci-S alkyl group substituted by a furyl group, and examples thereof include a furylmethyl group, a furylethyl group, and a furylpropyl group.
  • the d-3 alkylene dioxy group is a methylene dioxy group, an ethylene dioxy group, or a trimethylene dioxy group.
  • R 1 is Ci. Alkyl group; C 3 - 8 cycloalkyl group; C 3 - 8 consequent opening alkyl C i-5 alkyl group; a halogen atom, C 5 - i.
  • the compound of the present invention can be synthesized by the method shown in the following reaction formula according to the method described in J. Chem. Soc., Page 2969 (1959) (where RR 2 and R 3 are This is the same as described above).
  • Compound (a) is reacted with chloroacetyl chloride in a solvent in the presence of a base to obtain compound (b), and then reacted with sodium thiosulfate in a solvent to give compound (c). Get. This can be reacted with a primary amine without a solvent or in a solvent to obtain the compound of the present invention.
  • the base may be, for example, an alkali such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium hydroxide, dimesyl sodium, sodium hydride, sodium amide, tert-butyl potassium, etc.
  • Metals, amines such as triethylamine, diisopropylethyl, and aminepyridine, sodium acetate, potassium acetate, and the like can be used.
  • a reaction solvent water, methanol, ethanol, isopropyl alcohol, tert-butyl alcohol, and the like can be used.
  • Inert solvents such as alcohols, ethers such as dioxane and tetrahydrofuran, dimethylformamide, dimethylsulfoxide, pyridine, methylene chloride, chloroform, acetone and acetic acid can be used. it can.
  • the compound of the present invention is added with a conventional bulking agent, binder, disintegrant, pH adjuster, solubilizing agent, etc., and tablets, pills, Capsules, granules, powders, solutions, emulsions, suspensions, injections, etc. can be prepared.
  • the compound of the present invention can be administered orally or parenterally to an adult patient at 0.1 to 500 mg / day once or several times a day. This dose can be appropriately adjusted according to the type of disease, age, weight, and symptoms of the patient.
  • Triethylamine (3.35 ml;) was added to a solution of p-heptylaniline (3.83 g) in methylene chloride (40 ml) cooled at 0 ° C (ice bath), and chloroacetyl chloride (1.91 m) was added. 1)) was added dropwise, and the mixture was stirred at room temperature for 1 hour. After the reaction mixture was diluted with black form (16 Om 1), it was washed successively with a 7% aqueous solution of citric acid (70 ml) and water (7 Om 1 ⁇ 2 times). The organic layer is treated with anhydrous magnesium sulfate. After drying with a solvent, the solvent was distilled off. The obtained crude crystals were recrystallized from ethyl acetate / hexane to give p-heptylphenylcarbamoylmethyl chloride (5.04 g) as a colorless powder.
  • Example 1 The same operation as in Example 1 was performed using the corresponding starting materials to obtain the compounds shown in Table 1.
  • Table 1 shows a list of synthesized compounds including Compound 1.
  • the Rf values in the table were measured using a thin layer chromatography (Silicagel 60 F254, manufactured by Merck) and mixed with ethyl acetate: hexane 1: 9 (* is a mixture of ethyl ethyl acetate: toluene 1: 9). Shows the Rf value when expanded with.
  • the terms posi and nega show the measured values of the cation peak (M + H) and the anion peak (M-H) observed in the positive mode or the negative mode when the mass spectrum was measured by ES.
  • Protein tyrosine phosphatase CD45 was prepared from the cell membrane of cultured cell Ball-1. Human leukemia cells Ball-1 expressing a large amount of CD45 were cultured at 37 in RPMI1640 medium containing 10% calf serum, saturated with 5% carbon dioxide and water vapor in an incubator. Cells were prepared in 5 X 1 0 7 or ZML, 2 5 mM Tris-HCl (pH 7. 5), 25 mM Gerhard one sucrose, 0.
  • Table 2 shows the 50% inhibitory activity (IC 5 ) when the compound was added, where the protein phosphatase activity when no drug was added was 100%.
  • the compound of the present invention exhibits an effect of inhibiting the activity of tyrosine phosphatase possessed by the CD45 antigen, and is a disease involving tyrosine phosphatase in humans and animals (including farm animals), for example, immunity, various allergic diseases It is useful as a therapeutic agent for

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Abstract

On décrit des dérivés thiooxamide de N-cycloalkyle représentés par la formule (I) dans laquelle R1 représente alkyle, alcényle, cycloalkyle, alkylcycloalkyle, cycloalkylalkyle, cycloalcénylalkyle, alcoxyalkyle, dialcoxylakyle, phénoxyalkyle, pipéridinylalkyle, phényle substitué, naphtyle, tétrahydronaphtyle, naphtylalkyle, pyridyle, phénylalkyle, phénylalkyle substitué au niveau de l'anneau benzène, et autres. L'invention concerne également des médicaments ayant un nouveau mécanisme de fonctionnement qui participe à l'activation des cellules T et des basophiles/mastocytes lesquels jouent un rôle dans l'immunité et les réactions allergiques et inhibent la tyrosine phosphatase portée par l'antigène CD45.
PCT/JP2000/007245 1999-10-19 2000-10-19 Derives thiooxamide de n-cycloalkyle WO2001028991A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU79484/00A AU7948400A (en) 1999-10-19 2000-10-19 N-cycloalkyl thiooxamide derivatives

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP11/297003 1999-10-19
JP29700399 1999-10-19

Publications (1)

Publication Number Publication Date
WO2001028991A1 true WO2001028991A1 (fr) 2001-04-26

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PCT/JP2000/007245 WO2001028991A1 (fr) 1999-10-19 2000-10-19 Derives thiooxamide de n-cycloalkyle

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Country Link
AU (1) AU7948400A (fr)
WO (1) WO2001028991A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2007262068A (ja) * 2006-03-28 2007-10-11 Epitech Group Srl 免疫系の一般的反応により引き起こされる病態の治療のための医薬組成物

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE1270552C2 (fr) * 1967-04-21 1969-01-16

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE1270552C2 (fr) * 1967-04-21 1969-01-16

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
YAROVENKO V.N. ET AL.: "Reactions of monothiooxamides with N-nucleophiles. Synthesis of 4,5-dihydroimidazole-2-carboxanilides", RUSS. CHEM. BULL., vol. 48, no. 4, 1999, pages 749 - 753, XP002936366 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2007262068A (ja) * 2006-03-28 2007-10-11 Epitech Group Srl 免疫系の一般的反応により引き起こされる病態の治療のための医薬組成物
EP1844784A1 (fr) * 2006-03-28 2007-10-17 Epitech Group S.r.l. Composition pharmaceutique pour le traitement de pathologies causées par une réponse immunitaire

Also Published As

Publication number Publication date
AU7948400A (en) 2001-04-30

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