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WO1996005185A1 - Nouveaux derives alkylamino utilises comme ligands selectifs sigma 2 - Google Patents

Nouveaux derives alkylamino utilises comme ligands selectifs sigma 2 Download PDF

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Publication number
WO1996005185A1
WO1996005185A1 PCT/JP1995/001600 JP9501600W WO9605185A1 WO 1996005185 A1 WO1996005185 A1 WO 1996005185A1 JP 9501600 W JP9501600 W JP 9501600W WO 9605185 A1 WO9605185 A1 WO 9605185A1
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adamantyl
alkyl
ylmethyl
piperidin
group
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PCT/JP1995/001600
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English (en)
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Jean-Philippe Rocher
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Mitsubishi Chemical Corporation
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Priority to EP95928013A priority Critical patent/EP0777660A1/fr
Priority to JP8507194A priority patent/JPH10508826A/ja
Priority to KR1019970701035A priority patent/KR970705550A/ko
Publication of WO1996005185A1 publication Critical patent/WO1996005185A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D275/00—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings
    • C07D275/04—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D275/06—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings condensed with carbocyclic rings or ring systems with hetero atoms directly attached to the ring sulfur atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/26—Psychostimulants, e.g. nicotine, cocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
    • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
    • C07D221/04—Ortho- or peri-condensed ring systems
    • C07D221/06—Ring systems of three rings
    • C07D221/10—Aza-phenanthrenes
    • C07D221/12—Phenanthridines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D267/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D267/02—Seven-membered rings
    • C07D267/08—Seven-membered rings having the hetero atoms in positions 1 and 4
    • C07D267/12—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
    • C07D267/16—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems condensed with two six-membered rings
    • C07D267/20—[b, f]-condensed
    • 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
    • C07D279/02—1,2-Thiazines; Hydrogenated 1,2-thiazines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D281/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one sulfur atom as the only ring hetero atoms
    • C07D281/02—Seven-membered rings
    • C07D281/04—Seven-membered rings having the hetero atoms in positions 1 and 4
    • C07D281/08—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
    • C07D281/12—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems condensed with two six-membered rings
    • C07D281/16—[b, f]-condensed
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    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • 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
    • C07D417/06—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 linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • the present invention relates to novel alkylamino derivatives, pharmaceutical compositions comprising such compounds and the use of such compounds in the treatment of central nervous system disorders as well as several other disorders.
  • the pharmaceutically active compounds of this invention are highly selective and high affinity sigma 2 ligands.
  • the recently identified brain sigma receptors/binding sites are potential targets for development of antjpsychotic drugs that lack the adverse effects associated with currently available dopaminergic D2 antipsychotic agents
  • receptor refers to membrane-bound receptors and to other binding sites.
  • the existence of at least two sigma receptor subtypes, sigma 1 and sigma 2 has been confirmed and a classification of sigma binding sites has been proposed [R. Quirion, W.D. Bowen, Y. Itzhak, J.L. Junien, J.M. Musacchio,
  • Sigma 1 binding sites are characterized by high affinity for haloperidol, Di-o- Tolyl Guanidine (DTG) and (+) benzomorphans such as (+) pentazocine.
  • Sigma 2 binding sites are characterized by high affinity for haloperidol and DTG but low affinity for the (+) benzomorphans.
  • Sigma 1 ligands have shown gastro-intestinal effects ; moreover, sigma 1 sites appear to mediate the inhibition by sigma ligands of the muscarinic acetylcholine receptor phosphoinositide response. Sigma 1 binding sites are not only present in the brain but also on splenocytes. Such sigma ligands may inadvertently suppress the immune system [H.H. Garza, S.
  • sigma 2 binding sites are present in hypothalamus, cerebellum and pons medulla. In rat brain, they are more abundant than sigma 1 sites in hippocampus, frontal and posterior cortex [D. J. Mc Cann, A. D. Weissmann and T.P. Su, Soc. Neurosci abstr. 1992, 18, 22, abstract 16.5].
  • Guinea pig hippocampus membranes possess also sigma 2 binding sites which are selectively labelled by pH] BIMU [D.W. Bonhaus, D.N. Loury, L.B. Jakeman, Z. To, A. DeSouza, R.M. Eglen and E.H.F. Wong, J. Pharmacol. Exp.
  • WO 93/00313 relates to sigma receptor ligands and their sigma 1/ sigma 2 selectivity; three compounds present an interesting sigma 2 selectivity, they belong to the phenyl piperazine class and are also high affinity 5-HT1 A serotonin ligands [R.A. Glennon, N.A. Naiman, R.A. Lyon and M. Boater, J. Med. Chem., 1988, 31 , 1968-1971]. Sub-nanomolar affinity sigma binding sites ligands have been presented as sigma 2 ligands [J. Perregaard, E.K. Moltzen, E. Meier, C. Sanchez and J. Hyttel, Soc. Neurosci.
  • EP 546388 discloses heteroaryl methyl piperidino derivatives of chromanes, without examples of naphtosultam compounds. Alkylamino naphtosultam derivatives are described with examples in EP 352613, these compounds are claimed as 5-HT1 A ligands.
  • EP 350403, EP 429341 and WO 91/16323 disclose series of naphtosultam derivatives as 5- HT2 antagonists and 5-HT reuptake inhibitors.
  • the present invention relates to a substituted (preferentially adamantyl, cycloalkyl)hydroxy-amino and diamino derivatives.
  • Numerous phenyl ethanolamino derivatives exhibit important pharmaceuticals properties [Pharmaceutical Chemistry Vol. 1 : drug synthesis, H.J. Roth, A. Kleemann and T. Beisswenger, Ellis Horwood limited, Chichester England, 37-69].
  • benzyl-piperidino derivatives like Ifenprodil and its derivatives belong to this class and are known to interact with sigma, adrenergic and glutamatergic receptors [B.L. Chenard, I.A. Shalaby, B.K. Koe, R.T.
  • EP 518 216 discloses certain N-[arylethyl]-N-alkyl-2-(1 -pyrrolidinyl)ethylamine compounds for CNS disorders.
  • WO 93/22279 discloses 3-phenyl-1 ,2- propanediamine derivatives having selective affinity for sigma receptors. These compounds are potent preferentially sigma 1 ligands; no heteroaromatic derivatives are described and they are not substituted in a position by a cycloalkyl group.
  • WO 93/10073 relates to ethylenediamine derivatives as substance P receptor antagonists; the general formula refers to secondary amino compounds.
  • US 5,039,706 describes benzylamine derivatives having phospholipase A2 inhibiting properties, some examples of phenyl-propane diamino compounds are given.
  • the present invention resides in the discovery of a group of selective and high affinity sigma 2 binding site ligands.
  • the inhibition constant Ki for sigma 2 binding site is of at least 50 nM and these new ligands have at least a 5 fold greater affinity for sigma 2 than sigma 1 binding sites and dopaminergic (D1 , D2), serotoninergic (5-HT1 A, 5-HT2, 5-HT3), adrenergic (alpha and beta) and phencyclidine (PCP) receptors.
  • D1 , D2 dopaminergic
  • 5-HT1 A serotoninergic
  • 5-HT2 adrenergic
  • PCP phencyclidine
  • Novel alkylamino derivatives of the invention which conform to the formula :
  • Y represents hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, adamantyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl; wherein each of said aryl and heteroaryl groups may optionally be substituted with one or more substituents, each of the said substituents being independently selected from halo, nitro, cydoalkyl, alkenyl, alkyl optionally substituted with one to three fluorine atoms, hydroxy, alkoxy opfonally substituted with one to three fluorine atoms, phenyl, amino, alkylamino, carbamoyl, sulfamoyl, carboxyalkyl, cyano oralkynyl.
  • Y represents hydrogen, alkyl, alkenyl or cycloalkyl.
  • A represents the group -O-R 9 in which R 9 represents hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, aryl, arylalkyl, hydroxyalkyl, carboxyalkyl or carboxyaryl; or A represents the group
  • R 10 and R 11 represent independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, hydroxyalkyl, carboxyalkyl, haloalkyl, haloalkoxyalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl; each of the said aryl and heteroaryl groups may optionally be substituted with one or more substituents, each of the said substituents being independently selected from halo, nitro, cycloalkyl, alkenyl, alkyl optionally substituted with from one to three fluorine atoms, hydroxy, alkoxy optionally substituted with one to three fluorine atoms, phenyl, amino, alkylamino, carboxy, carbamoyl, sulfamoyl, carboxyalkyl, cyano or alkynyl.
  • R 10 and R 11 taken together may form a ring corresponding to the formula :
  • D represents a single bond, oxygen, sulfur or a nitrogen atom substituted by hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkylalkyl, aryl or arylalkyl; m is a number selected from 1 to 3; R 10 and R 11 taken together with the nitrogen atom may form a 3-10 atom unsaturated heterocyclic ring which optionally contains 1 to 4 further heteroatom selected from oxygen, nitrogen and sulfur; such heterocyclic group may optionally be substituted with one or more substituents, each of the said substituents being independently selected from halo, nitro, cycloalkyl, alkenyl, alkyl optionally substituted with one to three fluorine atoms, hydroxy, alkoxy optionally substituted with one to three fluorine atoms, phenyl, amino, alkylamino, carbamoyl, sulfamoyl,
  • R 1 and R 2 which may be the same or different, are hydrogen, alkyl, cycloalkyl, hydroxyalkyl or alkenyl.
  • R 3 represents alkyl, cycloalkyl, hydroxyalkyl or alkenyl;
  • R 4 represents the group -(CH 2 ) p -B where p is a number selected from 3 to 8;
  • R 3 and R 4 together with the intervening nitrogen atom represent a piperidine ring which is substituted as depicted in formula (II) :
  • R 5 and R 6 represent independently hydrogen or alkyl; or R 5 and R 6 together with the intervening atom represent a 5 to 7 heterocyclic ring.
  • B is a heteroaryl group of formula
  • R 7 and R 8 are independently selected from hydrogen, halo, nitro, cycloalkyl, alkenyl, alkyl optionally substituted with one to three fluorine atoms, hydroxy, alkoxy optionally substituted with one to three fluorine atoms, phenyl, amino, alkylamino, carbamoyl, sulfamoyl, carboxyalkyl, cyano or alkynyl.
  • R 12 is selected from hydrogen or alkyl.
  • W and W' represent independently a benzene ring or heteroaryl group of 5 to 7 atoms which contains one oxygen atom , one sulfer atom or one or two nitrogen atoms, provided that at least one of W and W is heteroaryl group.
  • R 13 represents hydrogen or alkyl.
  • alkyl includes C 1 -C 6 alkyl group such as methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group, isopentyl group, neopentyl group, tert-pentyl group, hexyl group or the like.
  • Cycloalkyl includes C 3 -C 6 cycloalkyl group such as cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group or the like.
  • Cycloalkyalkyl includes C 3 -C 6 cycloalkyl-C 1 -C 3 alkyl group such as cyclopropyl methyl group, cyclopropylethyl group, cyclopropylpropyl group, cyclobutylmethyl group, cyclobutylethyl group, cyclopentylmethyl group, cyclohexylmethyl group or the like.
  • Alkenyl includes C 3 -C 6 alkenyl group such as 1 -propenyl group, allyl group, isopropenyl group, 1-butenyl group, 3-butenyl group, 1-pentenyl group, 2-pentenyl group, 3-pentenyl group, 4-pentenyl group, 1 -hexenyl group, 2-hexenyl group or the like.
  • Alkynyl includes C 3 -C 6 alkynyl group such as 2-propynyl group, 3- butynyl group, 4-pentynyl group, 5-hexynyl group or the like.
  • Alkoxy includes C 1 -C 6 alkoxy group such as methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, isobutoxy group, tert- butoxy group, pentyloxy group, hexyloxy group or the like.
  • Halo includes atoms such as fluorine atom, chlorine atom, bromine atom, iodine atom or the like.
  • Alkylamino includes C 1 -C 6 alkylamino group such as methylamino group, ethylamino group, propylamino group, butylamino group, pentylamino group, hexylamino group, dimethylamino group, methylethylamino group, diethylamino group, dipropylamino group or the like.
  • Carboxyalkyl includes carboxy- C 1 -C 6 alkyl group such as carboxymethyl group, 2-carboxyethyl group, 3-carboxypropyl group, 4- carboxybutyl group, 5-carboxypentyl group, 6-carboxyhexyl group or the like.
  • “Hydroxyalkyl” includes hydroxy-C 2 -C 6 alkyl group such as 2- hydroxyethyl group, 3-hydroxypropyl group, 4-hydroxybutyl group, 5- hydroxypentyl group, 6-hydroxyhexyl group or the like.
  • Haloalkyl includes halogenated-C 1 -C 3 alkyl group such as chloromethyl group, dichloromethyl group, trichloromethyl group, fluoromethyl group, difluoromethyl group, trifluoromethyl group, bromomethyl group, 1 -chloroethyl group, 1 ,1 -dichloroethyl group, 2-chloroethyl group, 2,2- dichloroethyl group, 2,2,2-trichloroethyl group, 1 -fluoroethyl group, 1 ,1 - difluoroethyl group, 2-fluoroethyl group, 2,2-difluoroethyl group, 2,2,2- trifluoroethyl group, 2-bromoethyl group, 3-chloropropyl group, 3-fluoropropyl group, 3-bromopropyl group or the like.
  • Haloalkoxyalkyl includes halogenated-C 1 -C 3 alkoxy-C 1 -C 3 alkyl group such as chloromethoxymethyl group, chloromethoxyethyl group, chloromethoxypropyl group, fluoromethoxymethyl group, fluoromethoxyethyl group, trifluoromethoxymethyl group, trifluoromethoxyetiyl group, trifluoromethoxypropyl group, bromomelhoxymethyl group, bromomefioxyethyl group, bromometioxypropyl group, 1 -chloroethoxymethyl group, 2- chbroelhoxymethyl group, 2-chloroethoxyethyl group, 2-chloroethoxypropyl group, 2-1uoroethoxymethyl group, 2-fluoroethoxyethyl group, 2- fluoroetioxypropyl group, 2,2,2-trifluoroethoxymethyl group, 3- chbropropoxymethyl group
  • Aryl includes C 6 -C 10 aryl group such as phenyl group, 1 -naphtyl group, 2-naphtyl group or the like.
  • Arylalkyl includes C 6 -C 10 aryl-C 1 -C 3 alkyl group such as benzyl group, 1 -phenylethyl group, 2-phenylethyl group, 1 -phenylpropyl group, 2- phenylpropyl group, 3-phenylpropyl group, 1 -naphtylmethyl group, 2- naphtylmethyl group or the like.
  • Carboxyaryl includes carboxy-C 6 -C 10 aryl group such as 2- carboxyphenyl group, 3-carboxyphenyl group, 4-carboxyphenyl group, 2,6- dicarboxyphenyl group, 2,4,6-tricarboxyphenyl group, 2-carboxy-1 -naphthyl group, 3-carboxy-1 -naphthyl group, 4-carboxy-1 -naphthyl group, 1 -carboxy- 2-naphthyl group, 3-carboxy-2-naphthyl group, 4-carboxy-2-naphthyl group, 1 ,5-dicarboxy-2-naphthyl group or the like.
  • HeteroaryrJn cludes 5-10 membered heterocyclic group containing 1 to 4 hetero atoms selected from oxygen atom, sulfur atom and nitrogen atom to form a ring such as furyl group (furan ring), benzofuranyl group (benzofuran ring), isobenzofuranyl group (isobenzofuran ring), thienyl group (thiophene ring), benzothiophenyl group (benzothiophene ring), pyrrolyl group (pyrrole ring), imidazolyl group (irridazole ring), pyrazolyl group (pyrazole ring), thiazolyl group (thiazole ring), isothiazolyl group (isothiazole ring), triazolyl group (triazole ring), tefrazolyl group (tetrazde ring), pyridyl group (pyridine ring), pylazynyl group (pyrazine ring), pyrimidin
  • Heteroarylalkyl includes heteroaryl-C 1 -C 3 alkyl group, wherein examples of heteroaryl are the same as those illustrated in the above definition, such as 2-furylmethyl group, 3-furylmethyl group, 2-thienylmethyl group, 3-thienylmethyl group, 1 -imidazolylmethyl group, 2-imidazolylmethyl group, 2-thiazolylmethyl group, 1 -pyridylmethyl group, 2-pyridylmethyl group, 3-pyridylmethyl group, 4-pyridylmethyl group, 1 -quinolylmethyl group, 2- quinolylmethyl group or the like.
  • Preferred compounds of the present invention are compounds of formula (I) wherein :
  • Y represents hydrogen, C 1 -C 6 alkyl, C 3 -C 6 alkenyl, C 3 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkyl-C 1 -C 3 -alkyl, adamantyl, aryl selected from phenyl and naphthyl, aryl-C 1 -C 3 -alkyl; wherein each of said aryl group may optionally be substituted with one to three substituents, each of the said substituents being independently selected from halo, nitro, C 3 -C 6 cycloalkyl, C 3 -C 6 alkenyl, C 1 -C 6 alkyl optionally substituted with one to three fluorine atoms, hydroxy, C 1 -C 6 alkoxy optionally substitute
  • Y represents hydrogen, C 1 -C 6 alkyl, C 3 -C 6 alkenyl or C 3 -C 6 cycloalkyl.
  • A represents the group -O-R 9 in which R 9 represents hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 3 -C 6 cydoalkyl-C 1 -C 3 -alkyl, C 3 -C 6 alkenyl, phenyl, phenyl-C 1 -C 3 -alkyl, hydroxy-C 2 -C 6 -alkyl, carboxy-C 1 -C 3 -alkyl or carboxyphenyl; or A represents the group R 10 and R 11 represent independently hydrogen, C 1 -C 6 alkyl, C 3 -C 6 alkenyl, C 3 -C 6 alkynyl, C 3 -C 6 cycloalkyl, pheny
  • R 10 and R 11 taken together may form a ring corresponding to the formula : -(CH 2 ) m -D-(CH 2 ) m -
  • D represents a single bond, oxygen, sulfur or a nitrogen atom substituted by hydrogen or C 1 -C 6 alkyl
  • m is a number selected from 1 to 3; or Y and A taken together may form oxo or hydroxyimino.
  • R 1 and R 2 which may be the same or different, are hydrogen, C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, hydroxy-C 2 -C 3 alkyl or C 3 -C 6 alkenyl.
  • R 3 represents C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, hydroxy-C 2 -C 3 -alkyl or C 3 - C 6 -alkenyl;
  • R 4 represents the group -(CH 2 ) p -B where p is a number selected from 3 to 6; or R 3 and R 4 together with the intervening nitrogen atom represent a piperidine ring which is substituted as depicted in formula (II) :
  • R 5 and R 6 represent independently hydrogen or C 1 -C 3 alkyl
  • B is a heteroaryl group of formula
  • R 7 and R 8 are independently selected from hydrogen, halo, nitro, C 1 -C 6 alkyl optionally substituted with one to three fluorine atoms, hydroxy or C 1 -C 6 alkoxy optionally substituted with one to three fluorine atoms.
  • R 12 is selected from hydrogen or C 1 -C 6 alkyl.
  • W and W' represent independently a benzene ring or heteroaryl group of 5 to 7 atoms which contains one oxygen atom , one sulfer atom or one or two nitrogen atoms, provided that at least one of W and W' is heteroaryl group.
  • R 13 represents hydrogen or C 1 -C 6 alkyl.
  • Particularly preferred compounds of the present invention are those compounds of formula (I) wherein :
  • X represents C 3 -C 6 cycloalkyl-C 1 -C 3 -alkyl, adamantyl or C 3 -C 6 cycloalkyl
  • Y represents hydrogen, C 1 -C 6 alkyl, C 3 -C 6 alkenyl or C 3 -C 6 cycloalkyl.
  • A represents the group -O-R 9 in which R 9 represents hydrogen, C 1 -C 4 alkyl, C 3 -C 6 alkenyl or hydroxy-C 2 -C 4 -alkyl; or A represents amino, C 1 -C 3 alkylamino, phenyl-C 1 -C 3 -alkylamino, C 3 -C 6 alkenylamino, C 2 -C 6 dialkylamino,
  • C 4 -C 5 cydoalkylamino, C 4 -C 7 alkylalkenylamino, piperidino, piperazino, C 1 -C 3 alkylpiperazino ormorpholino; or Y and A taken together may form oxo or hydroxyimino.
  • R 1 and R 2 which may be the same or different, are hydrogen or C 1 -C 3 alkyl.
  • R 3 represents C 1 -C 3 alkyl;
  • R 4 represents the group -(CH 2 ) p -B where p is a number selected from 3 to 6;
  • R 3 and R 4 together with the intervening nitrogen atom represent a piperidine ring which is substituted as depicted in formula (II) :
  • R 5 and R 6 represent hydrogen
  • B is a heteroaryl group of formula
  • R 7 and R 8 are independently selected from hydrogen, halo, nitro, C 1 -C 6 alkyl optionally substituted with one to three fluorine atoms, hydroxy or C 1 -C 6 alkoxy optionally substituted with one to three fluorine atoms;
  • R 12 is selected from hydrogen or C 1 -C 6 alkyl
  • R 13 represents hydrogen or C 1 -C 6 alkyl.
  • R 7 and R 8 are independently selected from hydrogen, halo, nitro, C 1 -C 6 alkyl optionally substituted with one to three fluorine atoms, hydroxy or C 1 -C 6 alkoxy optionally substituted with one to three fluorine atoms;
  • R 13 represents hydrogen or C 1 -C 6 alkyl.
  • Specifically preferred compounds are :
  • Compounds of the present invention can exist as optical isomers and both the racemic mixture of the isomers as well as the individual optical isomers are within the scope of this invention.
  • the racemic mixtures can be separated into their individual isomers by techniques well known to those skilled in the art.
  • the present invention also relates to the pharmaceutically acceptable acid addition salts of compounds of the formula (I) or pharmaceutically acceptable carriers or diluents.
  • the present invention relates to a method of treating or preventing a condition in a mammal, including a human, the treatment or prevention of which is affected or facilitated by the neuromodulatory effect of sigma 2 ligands.
  • the present invention relates to a method of treating or preventing a condition selected from the group consisting of anxiety, depression or dysthymic disorders, psychosis, pain, dyskinesia, ischaemia induced brain disorders, convulsions, stroke, epilepsy, dementia, parkinsonism, neuropathological disorders and memory impairment, hypertension, arrhythmia and angina.
  • a condition selected from the group consisting of anxiety, depression or dysthymic disorders, psychosis, pain, dyskinesia, ischaemia induced brain disorders, convulsions, stroke, epilepsy, dementia, parkinsonism, neuropathological disorders and memory impairment, hypertension, arrhythmia and angina.
  • the present invention relates to pharmaceutical compositions which provide from about 0.01 to 100 mg of the active ingredient per unit dose.
  • the compositions may be administered by any suitable route. For example orally in the form of tablets or capsules, etc., parenterally in the form of solutions for injection, topically in the form of onguents or lotions, ocularly in the form of eye-lotion.
  • methods well known in the art may be used; the nature of the pharmaceutical composition employed will depend on the desired route of administration.
  • the total daily dose usually ranges from about 0.05 - 500 mg.
  • the compounds of Formula (I) may be prepared by general route of synthesis as disclosed in the following methods.
  • Scheme A1 illustrates the preparation of compounds of the formula (I).
  • the reaction is typically carried out in the presence of a base such as triethylamine or potassium carbonate in a polar solvent like dimethylformamide, acetonitrile.
  • the reduction is generally accomplished by using sodium borohydride in ethanol, methanol or tetrahydrofuran at room temperature.
  • the oxime of the keto derivative V is prepared according to oximation method as described in Organic Functional Group Preparation Vol. Ill [S.R. Sandlerand W. Karo, Academic Press, London, 1989, 430-481].
  • the conversion by standard methods of the hydroxy group to a leaving group like Q (e.g. halide, mesylate) and subsequent substitution by an amino group to give an amino derivative is also a general method of synthesis.
  • the reaction of substitution may be carried out with sodium azide to give an azide.
  • the azido derivative may be reduced to give primary amine [Comprehensive organic transformations, R.C. Larock, VCH Publishers, New York, 1989, 409-410].
  • the oximino derivative prepared as described above can also be reduced to give the free amino derivative by standard reduction process like catalytic hydrogenation over platinum oxide or palladium on carbon or chemical reduction with lithium aluminum hydride.
  • the target amino derivative VIII has been chosen in the piperidino series, however, acyclic amino derivatives may be obtained according to the same process.
  • the P substituent in the compounds of formula VI and VIII represents a protective group like those described in Protective Groups in Organic
  • the N-alkylation reaction is preferably conducted in dimethylformamide in the presence of sodium hydride as base and at a temperature above 50 °C.
  • the reaction can also be conducted under phase transfer process using toluene as solvent, sodium or potassium hydroxide as base, in the presence of catalytic amount of tetrabutylammonium hydrogen sulfate or other suitable salt.
  • This route of synthesis can be extended to other heteroaryl rings of formula B as depicted in the description of invention.
  • the heteroaryl ring of formula B may be purchased from commercial sources or they may be prepared via known methods.
  • the synthesis of ring substituted 6H-dibenzo[c,e][1 ,2]thiazine S,S-dioxide may be accomplished by employing the method described by F. Ullmann and C. Grob in Chem. Ber. 1910, 43,2694 for unsubstituted sultam.
  • Q' is generally another electrophilic group which could be interconverted to Q and reacted with the N-protected amino derivative XI to give XII.
  • the removal of the protective group from the amino precursors VIlI and XII is accomplished by standard process and gives the resulting amine IV.
  • the e poxy derivative XIII may be obtained according to different usual methods : oxidation of an alkenyl derivative, dehydrohalogenation of a halohydrin, synthesis starting from a carboxaldehyde.
  • the relevant starting material in the above-mentioned processes may be in racemic form or in the desired optically active form to give racemic or optically active compounds.
  • the desired optically active enantiomer may also be obtained by resolution according to conventional techniques.
  • the compounds of the formula (I) which are basic in nature can form a wide variety of different pharmaceutically acceptable salts with various inorganic and organic acids. These salts are readily prepared by treating the base compound with a substancially equivalent amount of the chosen mineral or organic acid in a suitable organic solvent such as methanol, ethanol or isopropanol. Best Mode for Carrying Out the Invention
  • melting points (m.p.) are uncorrected and (dec) indicates decomposition; (iv) solvent ratios are given in volume:volume terms;
  • Di-tert-Butyl dicarbonate (101.1 g, 464 mmol) was added dropwise to a stirred solution of isonipecotic acid (60 g, 464 mmol) and sodium hyd roxide (37.6 g, 940 mmol) in a mixture of water (86 ml) and tert- butanol (176 ml). After the addition was completed, tert-butanol (100 ml) was added and the mixture was sti rred for 3 hours at room temperature. The solution was diluted with water (200 ml) and extracted two times with pentane (150 ml).
  • N-Boc derivative 2(c) (36.0 g, 83.1 mmol) in ethyl acetate (400 ml) was treated with 4N hydrochloride solution in dioxane (83 ml) at room temperature overnight. Resulted white precipitate of 2(d) hydrochloride was filtered off and washed carefully with ethyl acetate. Quantitative yield, m.p. > 280 °C.
  • the aminoketone 2(e) was synthesized from piperidine 2(d) (1 1.2 g, 37 mmol) and 1 -(bromoacetyl)adamantane (10.28 g, 40 mmol) folbwing the procedure described in example 1 (c).
  • the crude product was isolated as an oil which crystallized on storing at room temp. Resulted orange powder was washed with ethanol and collected by filtration to give pure aminoketone 2(e) (13.6 g, 75%), m.p.: 168-170°C.
  • TLC: Rf 0.4 (ethyl acetate/ methylene chloride 1 :1 ).
  • This compound was prepared from 4-(N-methylamino)butyric acid hydrochloride (23 g, 150 mmol) and di-tert-butyl dicarbonate (32.7 g, 150 mmol) according to the method described in Example 2(a).
  • the product 10(a) (31 g, 95%) was obtained as an oil.
  • N- tert-Butoxycarbonyl-N-methyl-4-hydroxybutylamine was obtained as an oil.
  • Ketone 10(d) (3.2 g, 7.0 mmol) was reduced with sodium borohydride in ethanol, folbwing the procedure described in Example 1 (d), yielding the free aminoalcohol 10(e) (3.0 g, 94%) as an oil.
  • TLC: Rf 0.3 (methanol / methylene chloride 1 :9).
  • the title tartrate salt 12 was crystallized in a usual way (exp. 1 (d) and 6(c)) from ethanol in 40% yield as a white powder, m.p.: 189-190°C.
  • the fumarate salt was prepared in ethanol, according to the usual procedure, in 68% yield as a slightly brown powder, m.p.: 194-196°C.
  • the dihydrochloride salt was prepared in 61% yield, according to the procedure 2(e), as a white hygroscopic solid, m.p.: 182-184°C.
  • the hydrochloride salt was prepared in 48 % yield, according to the procedure 2(e), as a white solid, m.p.: 213.5-214.3°C.
  • the hydrochloride salt was prepared according to the procedure 2(e) as a white solid, m.p.: 198-205 °C.
  • the hydrochloride salt was prepared according to the procedure 2(e) as a white hygroscopic foam.
  • [a] D 20 + 13.2° (c 1 , CHCl 3 ).
  • the hydrochbride salt was prepared according to the procedure 2 (e) as a white hygroscopic foam.
  • the fumarate salt 24 was crystallized in a usual way, from ethanol in 64% yield as a white solid, m.p.: 206.7-207.4°C.
  • Methyl lithium (1.4 M in ether, 6.0 ml, 8.4 mmol) was slowly added dropwise at 0°C to a stirred suspension of aminoketone 2(e) (4.0 g, 8.4 mmol) in tetrahydrofuran (80 ml). The suspension gradually changed to a pink solution.
  • the hydrochloride salt was prepared, according to the general procedure 2(e), as a white solid, mp : 271.2-272 °C.
  • hydrochbride salt was prepared according to the usual procedure 2(e) as a white solid, m.p.: 262.7-264 °C. Anal.Cab'd for C 24 H 32 N 2 O 3 S + 1.75 HCl:
  • Hydrochloride 28(b) (3.19 g, 8.69 mmol) and l -(bromoacetyl) adamantane (2.38g, 9.25 mmol) were reacted in boiling acetonitrile (35 ml) in the presence of anhydrous potassium carbonate (1.25 g, 9.04 mmol) folbwing the method descrbed in Example 1 (c).
  • the aminoketone 27(c) (3.4 g, 77 %) was obtained as a cream colored solid, m.p.: 178-181 °C.
  • Fumarate salt 30(d) contained ca. 5 % of ethanol (basis on 1 H-NMR). The salt decomposed slowly when exposed to light.
  • Compound 31(a) was prepared from 5H -dibenz[b,f]azepine (4.25 g, 22 mmol) and N-tert-butoxycarbonyl-4-(methanesulfonyloxymethyl) piperidine (6.54 g, 22 mmol) according to the method described in Example 2(c). The crude product was chromatographed (silicagel, methylene chbride / hexane 7:3) to give 31 (a) (3.9 g, 45 %) as a viscous oil. b) 4-[5-(5H-Dibenz[b,f]azepinyl)methylJpiperidine.
  • Rf 0.5 (methylene chloride / methanol 9:1 ).
  • the hydrochloride salt 34 was prepared in 90 % yield according to the usual procedure 2(e).
  • White powder, m.p.: 195-197 °C. [a] D 20 + 14.2 ° (c 1 ,
  • the hydrochbride salt 35 was prepared in 90 % yield according to the usual method 2(e).
  • White powder, m p : 269-271 °C. [a] D 20 - 18.5 ° (c 1 , CHCl 3 ).
  • the hemitartrate salt 36(d) was crystallized, in a usual way, from ethanol in 69% yield as a white solid, m.p.: 221.1-223.4°C. MS: 321 (M-165). Anal. Calc'd for C 33 H 41 N 2 O 6 + 1.25 H 2 O: C,67.78; H.7.45; N,4.81. Found: 0,67.70; H,7.29; N,4.81.
  • Compound 37(a) was prepared from 10,11 - dihydrodibenzo[b,e][1 ,4]diazepin-11 -one (4.6 g, 22 mmol) and N-tert- Butoxycarbonyl-4-(methanesulfonyloxymethyl)piperidine (6.0 g, 20 mmol) according to the method described in Example 2(c).
  • the crude product was chromatographed (silicagel, ethyl acetate / methylene chbride 1 :9) yielding 37(a) (3.2 g, 39 %) as an oil.
  • TLC: Rf 0.4 (diethyl ether / methylene chbride 2:8).
  • the free amine 37(b) was obtained in a usual way, in quantitative yield as a foam.
  • the hydrochloride salt 37(c) was prepared, following general procedure 2(e), in 69% yield as a white solid, m.p.: 196-198°C. MS: 320 (M-165). Anal. Calc'd for C 31 H 39 N 3 O 2 + HCl + 0.5 H 2 O: C,70.06; H,7.72; N,7.90;CI,6.68. Found : 0,70.07; H,7.94; N,7.76;CI,6.77.
  • the fumarate salt 38(c) was crystallized from ethanol, folbwing usual procedure, in 72 % yield as a white solid, m.p.: 207-209°C. MS: 337 (M-165). Anal. Calc'd for C 35 H 42 N 2 O 6 S : 0,67.94; H.6.84; N.4.53. Found: 0,67.73; H.6.85; N.4.43.
  • the maleate salt 39(d) was crystallized from ethanol / diethyl ether, in a usual way, in 81% yield as a white solid, m.p.: 224.5-225.5°C. MS: 333 (M-165). Anal.
  • fumarate salt 40(d) was crystallized from ethanol in
  • Compound 41(a) was prepared from 6-(6H-dibenzo[c,e] [1 ,2]thiazine 5,5-dioxide (4.62 g, 20 mmol) and N-tert-Butoxycarbonyl-4- (methanesulfonybxymethyl)piperidine (6.0 g, 20 mmol) according to the method described in Example 2(c).
  • 6-(6H-Dibenzo[c,e][1 ,2]thiazine 5,5-dioxide was prepared according to Ullmann F., Grob C, Chem. Ber., 1910, 43, 2694. b) 4-[6-(6H-Dibenzo[c,e][1 ,2]thiazin)methyl]piperidine S,S-dioxide.
  • Residual solid was purified by filtration through a silica pad (hexane / ethyl acetate 1 :2) and recrystallized from ethanol / hexane yielding fluoro-sultam 46(a) (1.74 g, 18%) as an orange crystalline solid, m.p.: 205.8-206.8 °C.
  • TLC: Rf 0.43 (hexane / ethyl acetate 1 :1).
  • the fumarate salt 46(c) was crystallized from ethanol / diethyl ether, according to the usual procedure, as a white hygroscopic solid, m.p.: 138.7-140.2 °C. MS: 359 (M-165). Anal. Calc'd for C 34 H 41 FN 2 O 7 S + 1/2 H 2 O: 0,62.77; H,6.46;
  • the title fluoro-sultam 47(a) was synthesized from 4-fluoroaniline folbwing the sequence of reactbns described in Example 46(a). Reaction with 2-nitrobenzenesulfonyl chbride gave 2-nitrobenzenesulfon-4'-fluoroanilide in 66% yield as a solid, m.p.: 104.7-105.9°C. Next, reduction of the nitro group provided crude 2-aminobenzenesulfon-4'-fluoroanilide in 88% yield.
  • hydrochloride salt 48(c) was prepared according to the procedure described in Example 2(e) as a white solid, m.p.: 228.2-230.1°C. MS: 359 (M- 165). Anal. Calc'd for C 30 H 38 CIFN 2 O 3 S: C,64.21 ; H,6.83; N.4.99; C,.6.32.
  • the hydrochloride salt 49(c) was prepared according to the procedure described in Example 2(d), as a white solid, m.p.: 176-177°C. MS: 375 (M-165). Anal. Calc'd for C 30 H 38 CI 2 N 2 O 3 S + 2/3 H 2 O: C,61.01 ; H.6.66; N.4.74; 01,12.03. Found: C,61.03; H.6.98; N.4.62; 01,12.16.
  • the title methoxy-sultam 50(a) was prepared from 3-methoxy aniline folbwing the sequence of reactbns described in Example 46(a). Reaction with 2-nitrobenzenesulfonyl chbride gave 2-nitrobenzenesulfon-3'- methoxyanilide in 75% yield as a yellow powder, m.p. 105.5-106.6°C. Next, reduction of the nitro group produced crude 2-aminobenzenesulfon-3'- methoxyanilide in 97% yield.
  • the hydrochloride salt 50(c) was prepared folbwing the usual procedure described in Example 2(d), as a white solid, m.p.: 216-219°C. MS: 371 (M-165). Anal. Calc'd for C 31 H 41 CIN 2 O 4 S + 2/3 H 2 O: C,63.58; H,7.23; N,4.79; Cl,6.07.
  • the hydrochloride salt was prepared according to the procedure described in Example 2(d), as a white hygroscopic foam.
  • the hydrochloride salt 52(c) was prepared according to Example 2(e), but in methylene chloride / diethyl ether, as a white hygroscopic foam.
  • the hydrochloride salt was prepared according to the procedure described in Example 2(e), but in methylene chbride / diethyl ether, as a white hygroscopic foam.
  • the title hydrochloride 55 was prepared according to the usual procedure described in Example 2(e), as a hygroscopic foam.
  • Membrane fractions (0.4 ml) were allowed to incubate 150 min at 37 °C in the presence of various concentrations of the reference compound (Haloperidol 10 -1 0 to 10 -6 M) or of the test ligand (10 -10 to 10 -5 M) and the radioligand, in a final volume of 0.5 ml of 50 mM Tris-HCl, pH 7.4. Assays were terminated by rapid filtration through Whatman GF/B filters. Prior to use, filters were soaked in 0.5 % pdyethyleneimine for 1 hour. After filtration using a Brandell cell harvester, filters were washed four times with ice cold incubation buffer.
  • Non specific binding was determined using Haloperidol 1 ⁇ M.
  • the radioactivity on the filters was determined by scintillation spectrometry using Formula 989 (New England Nuclear, Dupont de Nemours) as scintillator liquid and a counter LS 6000 TA (Becmann).
  • Competition curves were analyzed with the curve fitting program Ligand (G.A. Mc Pherson, Computer Programs in Biomedicine, 1983, 17, 107). Ki and IC 50 values were calculated.
  • Kd value for [ 3 H]-(+) pentazocine was 3nM. Values are averages ⁇ SEM of three experiments, each carried out in duplicate.
  • Tolyl-Guanidine (1 nM final, 37 Ci/mmd, New England Nuclear, Dupont de Nemours) as the radioligand.
  • Crude P2 membrane fraction was prepared from the livers of male Sprague-Dawley rats according to the method described by X. He, W.D. Bowen, K.S. Lee, W. Williams, D.R. Weinberger and B.R. de Costa (J. Med. Chem. 1993, 36, 566-571 ).
  • Membrane fractions (0.4 ml) were allowed to incubate 2 hours at 25 °C in the presence of 500 nM of pentazocine and of various concentrations of the reference compound (Haloperidol 10 -1 0 to 10 -6 M) or of the test ligand (10 -1 0 to 10 -5 M) and the radioligand, in a final volume of 0.5 ml of 50 mM Tris-HCl, pH 7.4. Assays were terminated by rapid filtration through Whatman GF/B filters. Prior to use, filters were soaked in 0.5 % polyethyleneimine for 1 hour. After filtration using a Brandell cell harvester, filters were washed four times with ice cold incubation buffer. Non specific binding was determined using Haloperidol 1 ⁇ M. Scintillation counting and curve analysis were determined as previously described. Kd value for [ 3 H]- DTG was predetermined and equal to 6.9 nM.
  • binding data presented in the above table show that the molecules of the present invention are moderatly to highly potent sigma 2 ligands and that they show a high selectivity for this site.
  • X D1 , D2, 5-HT1 , 5-HT1A, 5-HT2, 5-HT3, alphal adrenergic, beta 1 and 2 adrenergic and phencyclidine receptors.
  • the psychotropic properties of the compounds have been determined by some standard tests exploring dopaminergic, serotonergic and glutamatergic mechanisms, which are all involved in schizophrenic pathogenia.
  • mice This is a modification of the method of Cook L., Tarn S.W. and Rohrbach K.W. [J. Pharmacol. Exp. Ther. 1992, 263, 1 159-1166].
  • compounds (10 animals /dose) were administered per os 60 min before 10 mg/kg i.p. of Mescaline. 10 minutes after the challenge, mice were observed during a 10 min period and the number of scratching were counted.
  • the ED50 was defined as the dose of the test compound that protected 50 % of the scratching number.
  • Table VII shows that compounds of the inventbn strongly antagonize the scratching behavior in mice. In this tests, these compounds had excellent oral psychotropic activity.
  • mice The study of the toxicity of the products of the invention was determined on mice by oral administration by the approximate determination of their LD 50. It has been observed that the products of the invention generally had an acute toxicity or LD 50 greater than 1 000 mg/Kg. No cataleptic effect was observed with these compounds.
  • the pharmaceutical formulations of the invention may be prepared by conventional methods in the art.
  • the compound 2 can be replaced by the same amount of any of the described examples 1 to 55. 2) Suspension :
  • An aqueous suspension is prepared for oral administration so that each 1 milliliter contains 1 to 5 mg of one of the described example, 50 mg of sodium carboxymethyl cellubse, 1 mg of sodium benzoate , 500 mg of sorbitol and water ad 1 ml.
  • a parenteral composition is prepared by stirring 1.5 % by weight of active ingredient in 10 % by volume propylene glycol and water.
  • the compound 2 can be replaced by the same amount of any of the described examples 1 to 55.
  • the compounds of the present invention exhibit a high selectivity and high affinity for sigma 2 receptor and therefore are useful in the treatment of central nervous system disorders as well as other disorders modulated by this receptor.

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Abstract

L'invention porte sur de nouveaux dérivés alkylamino de formule (I). Ces composés manifestent une sélectivité élevée et une forte affinité pour le récepteur sigma 2; ils se révèlent ainsi utiles pour le traitement de perturbations du système nerveux central ainsi que d'autres perturbations modulées par ce récepteur.
PCT/JP1995/001600 1994-08-16 1995-08-10 Nouveaux derives alkylamino utilises comme ligands selectifs sigma 2 WO1996005185A1 (fr)

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EP95928013A EP0777660A1 (fr) 1994-08-16 1995-08-10 Nouveaux derives alkylamino utilises comme ligands selectifs sigma 2
JP8507194A JPH10508826A (ja) 1994-08-16 1995-08-10 シグマ２選択性リガンドである新規アルキルアミノ誘導体
KR1019970701035A KR970705550A (ko) 1994-08-16 1995-08-10 시그마 2 선택적 리간드인 신규한 알킬아미노 유도체들

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GB9416571A GB9416571D0 (en) 1994-08-16 1994-08-16 Novel alkylamino derivatives as sigma 2 selective ligands
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EP0881220A1 (fr) * 1996-02-15 1998-12-02 Mitsubishi Chemical Corporation Derives du diarylsultame
EP1043319A1 (fr) * 1997-11-05 2000-10-11 Mitsubishi Chemical Corporation Nouveaux derives alkylamino
WO2002002488A3 (fr) * 2000-06-30 2002-04-18 Univ California Procedes et composes pour moduler la fixation de coactivateurs a des recepteurs nucleaires
WO2003053927A1 (fr) * 2001-12-21 2003-07-03 Taisho Pharmaceutical Co.,Ltd. Dérivé de piperazine
EP1635805A2 (fr) * 2003-06-12 2006-03-22 Agy Therapeutics, Inc. Ligands des recepteurs sigma pour regeneration neuronale et retablissement fonctionnel
US7417040B2 (en) 2004-03-01 2008-08-26 Bristol-Myers Squibb Company Fused tricyclic compounds as inhibitors of 17β-hydroxysteroid dehydrogenase 3
US9504692B2 (en) 2011-08-02 2016-11-29 Helmholtz Zentrum Munchen, Deutsches Forschungszentrum Fur Gesundheit Und Umwelt (Gmbh) Selective inhibition of MALT1 protease by phenothiazine derivatives
WO2021236879A1 (fr) 2020-05-20 2021-11-25 The Board Of Trustees Of The University Of Illinois Méthode de traitement de maladies lysosomales à l'aide de peptides d'histatine
IT202100013244A1 (it) 2021-05-21 2022-11-21 Fond Telethon MODULATORI DI PrPC E LORO USI

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EP0350403A1 (fr) * 1988-07-07 1990-01-10 Rhone-Poulenc Sante Dérivés de (aza)naphtalènesultame, leurs procédés de préparation et les médicaments les contenant
WO1991006297A1 (fr) * 1989-10-27 1991-05-16 The Du Pont Merck Pharmaceutical Company (n-phthalimidoalkyle)piperidines
EP0429341A2 (fr) * 1989-11-20 1991-05-29 Rhone-Poulenc Sante Dérivés hétérocycliques, leur préparation et les médicaments les contenant
EP0433149A2 (fr) * 1989-12-13 1991-06-19 Rhone-Poulenc Sante Antagonistes de la sérotonine, leur préparation et les médicaments les contenant
FR2675801A1 (fr) * 1991-04-24 1992-10-30 Rhone Poulenc Rorer Sa Piperidines, leur preparation et les medicaments les contenant.
WO1993000313A2 (fr) * 1991-06-27 1993-01-07 Virginia Commonwealth University Ligands de recepteurs sigma et leur utilisation

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Publication number Priority date Publication date Assignee Title
EP0350403A1 (fr) * 1988-07-07 1990-01-10 Rhone-Poulenc Sante Dérivés de (aza)naphtalènesultame, leurs procédés de préparation et les médicaments les contenant
WO1991006297A1 (fr) * 1989-10-27 1991-05-16 The Du Pont Merck Pharmaceutical Company (n-phthalimidoalkyle)piperidines
EP0429341A2 (fr) * 1989-11-20 1991-05-29 Rhone-Poulenc Sante Dérivés hétérocycliques, leur préparation et les médicaments les contenant
EP0433149A2 (fr) * 1989-12-13 1991-06-19 Rhone-Poulenc Sante Antagonistes de la sérotonine, leur préparation et les médicaments les contenant
FR2675801A1 (fr) * 1991-04-24 1992-10-30 Rhone Poulenc Rorer Sa Piperidines, leur preparation et les medicaments les contenant.
WO1993000313A2 (fr) * 1991-06-27 1993-01-07 Virginia Commonwealth University Ligands de recepteurs sigma et leur utilisation

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0881220A1 (fr) * 1996-02-15 1998-12-02 Mitsubishi Chemical Corporation Derives du diarylsultame
EP0881220A4 (fr) * 1996-02-15 1999-04-21 Mitsubishi Chem Corp Derives du diarylsultame
EP1043319A1 (fr) * 1997-11-05 2000-10-11 Mitsubishi Chemical Corporation Nouveaux derives alkylamino
EP1043319A4 (fr) * 1997-11-05 2002-07-17 Mitsubishi Chem Corp Nouveaux derives alkylamino
WO2002002488A3 (fr) * 2000-06-30 2002-04-18 Univ California Procedes et composes pour moduler la fixation de coactivateurs a des recepteurs nucleaires
WO2003053927A1 (fr) * 2001-12-21 2003-07-03 Taisho Pharmaceutical Co.,Ltd. Dérivé de piperazine
EP1635805A2 (fr) * 2003-06-12 2006-03-22 Agy Therapeutics, Inc. Ligands des recepteurs sigma pour regeneration neuronale et retablissement fonctionnel
EP1635805A4 (fr) * 2003-06-12 2007-08-08 Ms Science Corp Ligands des recepteurs sigma pour regeneration neuronale et retablissement fonctionnel
US7863272B2 (en) 2003-06-12 2011-01-04 M's Science Corporation Sigma ligands for neuronal regeneration and functional recovery
US7417040B2 (en) 2004-03-01 2008-08-26 Bristol-Myers Squibb Company Fused tricyclic compounds as inhibitors of 17β-hydroxysteroid dehydrogenase 3
US9504692B2 (en) 2011-08-02 2016-11-29 Helmholtz Zentrum Munchen, Deutsches Forschungszentrum Fur Gesundheit Und Umwelt (Gmbh) Selective inhibition of MALT1 protease by phenothiazine derivatives
WO2021236879A1 (fr) 2020-05-20 2021-11-25 The Board Of Trustees Of The University Of Illinois Méthode de traitement de maladies lysosomales à l'aide de peptides d'histatine
IT202100013244A1 (it) 2021-05-21 2022-11-21 Fond Telethon MODULATORI DI PrPC E LORO USI
WO2022243549A1 (fr) 2021-05-21 2022-11-24 Fondazione Telethon Modulateur de prpc et utilisations associées

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JPH10508826A (ja) 1998-09-02
CN1164856A (zh) 1997-11-12

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