US20100197715A1 - Piperidine derivatives - Google Patents

Piperidine derivatives Download PDF

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Publication number
US20100197715A1
US20100197715A1 US12/690,128 US69012810A US2010197715A1 US 20100197715 A1 US20100197715 A1 US 20100197715A1 US 69012810 A US69012810 A US 69012810A US 2010197715 A1 US2010197715 A1 US 2010197715A1
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Prior art keywords
phenyl
trifluoromethyl
piperidin
methyl
benzamide
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Inventor
Sabine Kolczewski
Emmanuel Pinard
Henri Stalder
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Hoffmann La Roche Inc
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Hoffmann La Roche Inc
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Assigned to HOFFMANN-LA ROCHE, INC. reassignment HOFFMANN-LA ROCHE, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: F. HOFFMANN-LA ROCHE AG
Assigned to F. HOFFMANN-LA ROCHE AG reassignment F. HOFFMANN-LA ROCHE AG ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: KOLCZEWSKI, SABINE, PINARD, EMMANUEL, STADLER, HENRI
Publication of US20100197715A1 publication Critical patent/US20100197715A1/en
Priority to US13/766,840 priority Critical patent/US9067911B2/en
Abandoned legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/451—Non condensed piperidines, e.g. piperocaine having a carbocyclic group directly attached to the heterocyclic ring, e.g. glutethimide, meperidine, loperamide, phencyclidine, piminodine
    • 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
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • 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
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • 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
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no 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
    • C07D211/56—Nitrogen 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
    • C07D213/56—Amides
    • C—CHEMISTRY; METALLURGY
    • 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
    • C07D221/20—Spiro-condensed ring systems
    • 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
    • C07D401/04—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 directly linked by a ring-member-to-ring-member bond
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/10—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 aromatic rings

Definitions

  • Schizophrenia is a progressive and devastating neurological disease characterized by episodic positive symptoms such as delusions, hallucinations, thought disorders and psychosis and persistent negative symptoms such as flattened affect, impaired attention and social withdrawal, and cognitive impairments (Lewis D A and Lieberman J A, Neuron, 2000, 28:325-33).
  • episodic positive symptoms such as delusions, hallucinations, thought disorders and psychosis
  • persistent negative symptoms such as flattened affect, impaired attention and social withdrawal, and cognitive impairments
  • For decades research has focused on the “dopaminergic hyperactivity” hypothesis which has led to therapeutic interventions involving blockade of the dopaminergic system (Vandenberg R J and Aubrey K R., Exp. Opin. Ther. Targets, 2001, 5(4): 507-518; Nakazato A and Okuyama S, et al., 2000 , Exp. Opin. Ther. Patents, 10(1): 75-98).
  • This pharmacological approach poorly address negative and cognitive symptoms
  • PCP phencyclidine
  • ketamine non-competitive NMDA receptor antagonists
  • transgenic mice expressing reduced levels of the NMDAR1 subunit displays behavioral abnormalities similar to those observed in pharmacologically induced models of schizophrenia, supporting a model in which reduced NMDA receptor activity results in schizophrenia-like behavior (Mohn A R et al., 1999 , Cell, 98: 427-236).
  • Glutamate neurotransmission in particular NMDA receptor activity, plays a critical role in synaptic plasticity, learning and memory, such as the NMDA receptors appears to serve as a graded switch for gating the threshold of synaptic plasticity and memory formation (Hebb D O, 1949 , The organization of behavior , Wiley, NY; Bliss T V and Collingridge G L, 1993 , Nature, 361: 31-39).
  • Transgenic mice overexpressing the NMDA NR2B subunit exhibit enhanced synaptic plasticity and superior ability in learning and memory (Tang J P et al., 1999 , Nature: 401-63-69).
  • the amino acid glycine is known to have at least two important functions in the CNS. It acts as an inhibitory amino acid, binding to strychnine sensitive glycine receptors, and it also influences excitatory activity, acting as an essential co-agonist with glutamate for N-methyl-D-aspartate (NMDA) receptor function. While glutamate is released in an activity-dependent manner from synaptic terminals, glycine is apparently present at a more constant level and seems to modulate/control the receptor for its response to glutamate.
  • NMDA N-methyl-D-aspartate
  • One of the most effective ways to control synaptic concentrations of neurotransmitter is to influence their re-uptake at the synapses.
  • Neurotransmitter transporters by removing neurotransmitters from the extracellular space, can control their extracellular lifetime and thereby modulate the magnitude of the synaptic transmission (Gainetdinov R R et al, 2002, Trends in Pharm. Sci., 23(8): 367-373).
  • Glycine transporters which form part of the sodium and chloride family of neurotransmitter transporters, play an important role in the termination of post-synaptic glycinergic actions and maintenance of low extracellular glycine concentration by re-uptake of glycine into presynaptic nerve terminals and surrounding fine glial processes.
  • GlyT-1 and GlyT-2 Two distinct glycine transporter genes have been cloned (GlyT-1 and GlyT-2) from mammalian brain, which give rise to two transporters with ⁇ 50% amino acid sequence homology.
  • GlyT-1 presents four isoforms arising from alternative splicing and alternative promoter usage (1a, 1b, 1c and 1d). Only two of these isoforms have been found in rodent brain (GlyT-1a and GlyT-1b).
  • GlyT-2 also presents some degree of heterogeneity.
  • Two GlyT-2 isoforms (2a and 2b) have been identified in rodent brains.
  • GlyT-1 is known to be located in CNS and in peripheral tissues, whereas GlyT-2 is specific to the CNS.
  • GlyT-1 has a predominantly glial distribution and is found not only in areas corresponding to strychnine sensitive glycine receptors but also outside these areas, where it has been postulated to be involved in modulation of NMDA receptor function (Lopez-Corcuera B et al., 2001 , Mol. Mem. Biol., 18: 13-20).
  • one strategy to enhance NMDA receptor activity is to elevate the glycine concentration in the local microenvironment of synaptic NMDA receptors by inhibition of GlyT-1 transporter (Bergereon R. Et al., 1998 , Proc. Natl. Acad. Sci. USA, 95: 15730-15734; Chen L et al., 2003 , J. Neurophysiol., 89 (2): 691-703).
  • Glycine transporters inhibitors are suitable for the treatment of neuroligical and neuropsychiatric disorders.
  • the majority of diseases states implicated are psychoses, schizophrenia (Armer R E and Miller D J, 2001 , Exp. Opin. Ther. Patents, 11 (4): 563-572), psychotic mood disorders such as severe major depressive disorder, mood disorders associated with psychotic disorders such as acute mania or depression associated with bipolar disorders and mood disorders associated with schizophrenia, (Pralong E T et al., 2002 , Prog. Neurobiol., 67: 173-202), autistic disorders (Carlsson M L, 1998 , J. Neural Transm.
  • cognitive disorders such as dementias, including age related dementia and senile dementia of the Alzheimer type, memory disorders in a mammal, including a human, attention deficit disorders and pain (Armer R E and Miller D J, 2001 , Exp. Opin. Ther. Patents, 11 (4): 563-572).
  • NMDA receptors via GlyT-1 inhibition may lead to agents that treat psychosis, schizophrenia, dementia and other diseases in which cognitive processes are impaired, such as attention deficit disorders or Alzheimer's disease.
  • the present invention provides a compound of formula I
  • the invention includes all racemic mixtures, all their corresponding enantiomers and/or optical isomers.
  • the present invention provides pharmaceutical compositions containing the compounds of formula I or pharmaceutically acceptable acid addition salts thereof.
  • the invention also provides methods for the manufacture of the compounds and compositions of the invention.
  • Compounds of formula I are good inhibitors of the glycine transporter 1 (GlyT-1) and have a good selectivity to glycine transporter 2 (GlyT-2) inhibitors.
  • the compounds of the invention are useful for the treatment of diseases related to activation of NMDA receptors via Glyt-1 inhibition.
  • the invention provides methods for the treatment of neurological and neuropsychiatric disorders, for example psychoses, dysfunction in memory and learning, schizophrenia, dementia and other diseases in which cognitive processes are impaired, such as attention deficit disorders or Alzheimer's disease.
  • the preferred indications using the compounds of the present invention are schizophrenia, cognitive impairment and Alzheimer's disease.
  • lower alkyl denotes a saturated straight- or branched-chain hydrocarbon group containing from 1 to 7 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, n-butyl, i-butyl, 2-butyl, t-butyl and the like.
  • Preferred alkyl groups are groups with 1-4 carbon atoms.
  • lower alkoxy denotes a lower alkyl group as defined above, which is linked through an O atom.
  • cycloalkyl denotes a saturated or partially saturated ring containing from 3 to 7 carbon atoms, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl or cycloheptenyl.
  • Preferred cycloalkyl rings are cyclopropyl and cyclopentyl.
  • heterocycloalkyl denotes a saturated or partially saturated ring containing from 3 to 6 ring atoms, wherein at least one ring atom is a heteroatom selected from N, S and O, with the rest of the ring atoms being carbon, for example piperazinyl, pyrrolidinyl, oxetanyl, morpholinyl piperidinyl, or tetrahydropyranyl.
  • halogen denotes chlorine, iodine, fluorine and bromine.
  • aryl denotes a monovalent cyclic aromatic hydrocarbon radical consisting of one or more fused rings in which at least one ring is aromatic in nature, for example phenyl or naphthyl.
  • lower alkyl substituted by halogen denotes a lower alkyl group as defined above, wherein at least one hydrogen atom is replaced by a halogen atom, for example the following groups: CF 3 , CHF 2 , CH 2 F, CH 2 CF 3 , CH 2 CHF 2 , CH 2 CH 2 F, CH 2 CH 2 CF 3 , CH 2 CH 2 CH 2 CF 3 , CH 2 CH 2 Cl, CH 2 CF 2 CF 3 , CH 2 CF 2 CHF 2 , CF 2 CHFCF 3 , C(CH 3 ) 2 CF 3 , CH(CH 3 )CF 3 or CH(CH 2 F)CH 2 F.
  • lower alkoxy substituted by halogen denotes an alkoxy group as defined above, wherein at least one hydrogen atom is replaced by halogen as defined above.
  • heteroaryl denotes a cyclic aromatic radical consisting of one or more fused rings containing 5-14 ring atoms, preferably containing 5-10 ring atoms, in which at least one ring is aromatic in nature, and which contains at least one heteroatom, selected from N, O and S, for example quinoxalinyl, dihydroisoquinolinyl, pyrazinyl, pyridazinyl, pyrazolyl, pyridinyl, pyridyl, pyrimidinyl, oxadiazolyl, triazolyl, tetrazolyl, thiazolyl, thiadiazolyl, thienyl, furyl, imidazolyl, benzofuranyl, dihydrobenzofuranyl and benzo[1,3]dioxole.
  • Preferred heteroaryl group is pyridinyl.
  • “Pharmaceutically acceptable,” such as pharmaceutically acceptable carrier, excipient, etc., means pharmacologically acceptable and substantially non-toxic to the subject to which the particular compound is administered.
  • pharmaceutically acceptable acid addition salts embraces salts with inorganic and organic acids, such as hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, fumaric acid, maleic acid, acetic acid, succinic acid, tartaric acid, methane-sulfonic acid, p-toluenesulfonic acid and the like.
  • “Therapeutically effective amount” means an amount that is effective to prevent, alleviate or ameliorate symptoms of disease or prolong the survival of the subject being treated.
  • Preferred compounds of formula I are those, wherein R 1 is lower alkyl and Ar and R are phenyl.
  • phenyl group for Ar is substituted by at least two CF 3 groups, for example the following compounds:
  • Preferred compounds of formula I are those, wherein R 1 is cycloalkyl or heterocycloalkyl and Ar and R are phenyl, for example
  • Preferred compounds of formula I are those, wherein R 1 is lower alkyl, Ar is phenyl and R is heteroaryl, for example
  • Preferred compounds of formula I are those, wherein R 1 is hydrogen and Ar and R are phenyl, for example, rac-2-cyclopropyl-N-(3-phenyl-piperidin-3-yl)-4-trifluoromethyl-benzamide.
  • Preferred compounds of formula I are those, wherein R 2 is hydroxy, for example
  • Preferred compounds of formula I are those, wherein R 2 is halogen, for example rac-N-(5-fluoro-1-methyl-3-phenyl-piperidin-3-yl)-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide.
  • Preferred compounds of formula I are those, wherein R 1 is CD 3 , for example the following compound [2H-methyl]-2-methoxy-N—(R) or (S)-1-methyl-3-phenyl-piperidin-3-yl)-6-methylsulfanyl-4-trifluoromethyl-benzamide hydrochloride.
  • R 4 and R 5 are lower alkyl or form together with the carbon atom to which they are attached a cycloalkyl or heterocycloalkyl group, and if desired, converting the compounds obtained into pharmaceutically acceptable acid addition salts.
  • the compounds of formula I can be prepared in accordance with process variant a) or b) or c) and with the following schemes 1-12.
  • the starting material is commercially available or can be prepared in accordance with known methods.
  • Piperidine derivatives of formula II can be prepared by reacting piperidine derivatives of formula II with acid of formula III in the presence of an activating agent like HATU (o-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate) or thionyl chloride.
  • Piperidine derivatives of formula II can be prepared by reacting piperidone derivative VI with an organometallic reagent like a Grignard to provide alcohol VII followed by a treatment with sodium azide in the presence of an acid like TFA to provide azide derivative VIII which is transformed into II in the presence of a reducing agent like lithium aluminium hydride.
  • piperidine derivatives of formula II in which R 2 is hydrogen can be prepared from nitro-piperidone derivatives XII after reduction of the nitro group with reducing agent like Raney Nickel under an atmosphere of hydrogen or like Zinc in the presence of acid like hydrochloride acid to provide amino-piperidone derivatives XIII which can be reduced to II in the presence of reducing agent like lithium aluminium hydride.
  • Nitro-piperidone derivatives XII can be prepared from nitro derivatives XI according to an intramolecular Mannich type reaction performed in the presence of an amine: R 1 NH 2 and an aldehyde like formaldehyde.
  • XI can be prepared by Michael addition of nitro-methyl-aryl derivatives IX onto methyl acrylate in the presence of base like Amberlyst A21 or Triton B or by reacting aryl halide derivatives X with methyl 4-nitrobutyrate in the presence of Palladium catalyst like Pd 2 dba 3 , ligand like 2-(di-t-butylphosphino)-2′-methybiphenyl and base like cesium carbonate as described by Buchwald et al. in J. Org. Chem. 2002, 106.
  • piperidine derivatives of formula II in which R is an alkyl group can be prepared from acid XVI after a Curtius rearrangement in the presence of a reagent like DPPA (diphenylphosphoryl azide) to provide isocyanate XVII which is then hydrolyzed in presence of base like sodium hydroxide to lead to protected piperidine XVIII that is reduced in II in a presence of a reducing agent like lithium aluminiumhydride.
  • Acid XVI can be prepared from ester XIV after treatment with a base like lithium diisopropylamide and an alkylating agent R—X to provide intermediate ester XV which is then saponified to XVI in the presence of base like lithium hydroxide.
  • R 4 and R 5 are lower alkyl or form together with the carbon atom to which they are attached a cycloalkyl or heterocycloalkyl group.
  • compounds of general formula I can be prepared by reaction of piperidine derivative IV with either an alkylating agent R 1 X in the presence of base like N-ethyldiisopropylamine or with a carbonyl reagent V in the presence of a reducing agent like sodium cyanoborohydride.
  • Piperidine derivative IV can be prepared after reduction of azide VIII with reagent like sodium borohydride to provide amine derivative XIX which can be then coupled with acid III in the presence of an activating agent like HATU or thionyl chloride to yield amide derivative XX which is then transformed into IV after cleavage of the N-protective group.
  • piperidine derivatives of formula II in which R 2 is fluorine can be prepared from fluorinated nitro piperidone XXI after two consecutive reductions.
  • the first reduction uses an agent like Raney Nickel, and the second reduction uss an agent like lithium aluminiumhydride.
  • XXI can be prepared by reaction of nitro piperidine XII with a base like lithium diisopropylamine followed by treatment with an electrophilic fluorinating agent like N-fluorobenzenesulphonimide.
  • piperidine derivatives of formula II in which R 2 is alkyl can be prepared from alkylated nitro piperidone XXIII after two consecutive reductions.
  • the first reduction uses an agent like Raney Nickel
  • the second reduction uses an agent like lithium aluminiumhydride.
  • XXIII can be prepared by reaction of nitro piperidine XII with a base like lithium diisopropylamine followed by treatment with an electrophilic alkylating agent like R 2 X where X is an halogen.
  • piperidine derivatives of formula II which contains two geminal alkyl group R 2 can be prepared from bis-alkylated nitro piperidone XXV after two consecutive reductions.
  • the first reduction uses an agent like Raney Nickel
  • the second reduction uses an agent like lithium aluminiumhydride.
  • XXV can be prepared by reaction of mono-alkylated nitro piperidine XXIII with a base like lithium diisopropylamine in the presence of TMEDA (tetramethylethylenediamine) followed by treatment with an electrophilic alkylating agent like R 2 X where X is an halogen.
  • TMEDA tetramethylethylenediamine
  • the first reduction uses an agent like Raney Nickel
  • the second reduction uses an agent like lithium aluminiumhydride.
  • XXVIII can be prepared from XXVII by reaction with a base like sodium hydride and an electrophilic alkylating agent like R 6 X where X is an halogen.
  • XXVII can be prepared by reaction of nitro piperidine XII with a base like lithium diisopropylamine followed by treatment with an electrophilic hydroxylating agent like (oxodiperoxy(pyridine) (1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidone)molybdenum(IV)) or bis(trimethylsilyl)peroxide.
  • a base like lithium diisopropylamine
  • an electrophilic hydroxylating agent like (oxodiperoxy(pyridine) (1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidone)molybdenum(IV)) or bis(trimethylsilyl)peroxide.
  • piperidine derivatives of formula II in which R is an heteroaryl group like pyridine can be prepared from nitro piperidine thione XXX after two consecutive reductions
  • the first reduction uses an agent like sodium borohydride, and the second reduction uses an agent like Raney Nickel.
  • XXX can be prepared from nitro piperidinone XXII by reaction with Lawesson's reagent.
  • piperidine derivatives of formula II which contains two geminal methyl groups can be prepared from Boc-protected amino piperidinone XXXII after reaction with methylmagnesium bromide and Zirconium (IV) chloride followed by cleavage of the Boc group under acidic condition.
  • XXXII can be prepared after reaction of amino piperidone XIII with di-tert-butyl dicarbonate.
  • piperidine derivatives of formula II which contains a cyclopropyl unit can be prepared from Boc-protected amino piperidinone XXXII after reaction with ethyl magnesium bromide and titanium isopropoxide followed by cleavage of the Boc group under acidic condition.
  • piperidine derivatives of formula II in which R 2 is an alkyl group can be prepared from nitro derivative XXXIX following an intramolecular Mannich reaction performed in the presence of an aldehyde like formaldehyde to provide nitro piperidine XXXX which is then treated with a reducing agent like Raney Nickel.
  • XXXIX can be obtained by deprotection of Boc-protected nitro derivative XXXVIII which can be prepared by reaction of nitro derivative XXXI with halogenated compound XXXVII in the presence of a base like n-butyl lithium.
  • XXXVII can be obtained after protection and halogenation of amino alcohol XXXV.
  • Racemic mixtures of chiral compound I can be separated using chiral HPLC.
  • the acid addition salts of the basic compounds of formula I can be converted to the corresponding free bases by treatment with at least a stoichiometric equivalent of a suitable base such as sodium or potassium hydroxide, potassium carbonate, sodium bicarbonate, ammonia, and the like.
  • a suitable base such as sodium or potassium hydroxide, potassium carbonate, sodium bicarbonate, ammonia, and the like.
  • step 1 rac-3-Hydroxy-3-phenyl-piperidine-1-carboxylic acid benzyl ester
  • step 2 rac-3-Azido-3-phenyl-piperidine-1-carboxylic acid benzyl ester
  • step 3 rac-1-Methyl-3-phenyl-piperidin-3-ylamine
  • step 1-3 the title compound was prepared from 3-oxo-piperidine-1-carboxylic acid benzyl ester (commercial) and 4-fluoro-phenylmagnesium bromide. MS (m/e): 209.2 (M+H + ).
  • step 1-3 the title compound was prepared from 3-oxo-piperidine-1-carboxylic acid benzyl ester (commercial) and 4-chloro-phenylmagnesium bromide. MS (m/e): 225.3 (M+H + ).
  • step 1-3 the title compound was prepared from 3-oxo-piperidine-1-carboxylic acid benzyl ester (commercial) and 4-methyl-phenylmagnesium bromide. MS (m/e): 205.3 (M+H + ).
  • step 1 3-Hydroxy-2-methyl-piperidine-1-carboxylic acid benzyl ester
  • step 2 rac-2-Methyl-3-oxo-piperidine-1-carboxylic acid benzyl ester
  • step 3 rac-1,2-Dimethyl-3-phenyl-piperidin-3-ylamine
  • step 1-3 the title compound was prepared from rac-2-methyl-3-oxo-piperidine-1-carboxylic acid benzyl ester and phenylmagnesium bromide. MS (m/e): 205.2 (M+H + ).
  • step 1 rac-4-(3-Chloro-phenyl)-4-nitro-butyric acid methyl ester
  • step 2 rac-5-(3-Chloro-phenyl)-1-methyl-5-nitro-piperidin-2-one
  • step 3 rac-5-Amino-5-(3-chloro-phenyl)-1-methyl-piperidin-2-one
  • step 4 rac-3-(3-Chloro-phenyl)-1-methyl-piperidin-3-ylamine
  • step 1 rac-4-(4-Methoxy-phenyl)-4-nitro-butyric acid methyl ester
  • the mixture was stirred vigorously for 1 minute at room temperature and the flask was placed in a preheated oil bath at 50° C. and stirred at this temperature overnight.
  • the reaction mixture was cooled to room temperature, and a saturated NH 4 Cl solution and ethyl acetate were added.
  • Aqueous phase was extracted 3 times with ethyl acetate and combined organic phases were washed with brine, and concentrated in vacuo.
  • the crude product was purified with flash column chromatography on silica gel (Eluent: heptane/ethyl acetate 0 to 20%) to provide 897 mg (90%) of the title compound as a orange oil.
  • step 2 rac-3-(4-Methoxy-phenyl)-1-methyl-piperidin-3-ylamine
  • step 1 rac-1-Methyl-5-nitro-5-phenyl-piperidin-2-one
  • step 2 rac-3-Fluoro-1-methyl-5-nitro-5-phenyl-piperidin-2-one
  • step 3 rac-5-Amino-3-fluoro-1-methyl-5-phenyl-piperidin-2-one
  • step 4 rac-5-Fluoro-1-methyl-3-phenyl-piperidin-3-ylamine
  • step 1 rac-3-Hydroxy-1-methyl-5-nitro-5-phenyl-piperidin-2-one
  • step 2 rac-3-Methoxymethoxy-1-methyl-5-nitro-5-phenyl-piperidin-2-one
  • step 3 rac-5-Amino-3-methoxymethoxy-1-methyl-5-phenyl-piperidin-2-one
  • step 4 rac-5-Methoxymethoxy-1-methyl-3-phenyl-piperidin-3-ylamine
  • step 1 rac-4-Cyclohexyl-4-nitro-butyric acid methyl ester
  • step 2 rac-5-Cyclohexyl-1-methyl-5-nitro-piperidin-2-one
  • step 3 rac-5-Amino-5-cyclohexyl-1-methyl-piperidin-2-one
  • step 4 rac-3-Cyclohexyl-1-methyl-piperidin-3-yl-amine
  • step 2 rac-1-Methyl-3-(tetrahydro-pyran-4-yl)-piperidin-3-ylamine
  • step 1 rac-3-Isocyanato-3-methyl-piperidine-1-carboxylic acid tert-butyl ester
  • step 2 rac-3-Amino-3-methyl-piperidine-1-carboxylic acid tert-butyl ester
  • step 3 rac-1,3-Dimethyl-piperidin-3-ylamine dihydrochloride
  • step 1 rac-1-Methyl-3-nitro-2,3,4,5-tetrahydro-1H-[3,4′]bipyridinyl-6-one
  • step 2 rac-1-Methyl-3-nitro-2,3,4,5-tetrahydro-1H-[3,4′]bipyridinyl-6-thione
  • step 3 rac-1-Methyl-3-nitro-1,2,3,4,5,6-hexahydro-[3,4′]bipyridinyl
  • step 4 rac-1-Methyl-1,4,5,6-tetrahydro-2H-[3,4′]bipyridinyl-3-ylamine
  • step 1 rac-1-Methyl-3-nitro-2,3,4,5-tetrahydro-1H-[3,3′]bipyridinyl-6-one
  • step 2 rac-1-Methyl-1,4,5,6-tetrahydro-2H-[3,3′]bipyridinyl-1-3-ylamine
  • step 1 (3SR,5RS)-3-Methoxy-1-methyl-5-nitro-5-phenyl-piperidin-2-one
  • step 2 (3SR,5RS)-5-Amino-3-methoxy-1-methyl-5-phenyl-piperidin-2-one
  • step 3 (3RS,5SR)-5-Methoxy-1-methyl-3-phenyl-piperidin-3-ylamine
  • step 1 (3SR,5RS)-1,3-Dimethyl-5-nitro-5-phenyl-piperidin-2-one
  • step 2 (3SR,5RS)-5-Amino-1,3-dimethyl-5-phenyl-piperidin-2-one
  • step 4 the title compound was prepared from (3SR,5RS)-1,3-Dimethyl-5-nitro-5-phenyl-piperidin-2-one. MS (m/e): 202.2 (M ⁇ NH 2 )
  • step 3 (3RS,5SR)-1,5-Dimethyl-3-phenyl-piperidin-3-ylamine
  • step 2 rac-1,5,5-Trimethyl-3-phenyl-piperidin-3-ylamine
  • step 2 (1-Methyl-6-oxo-3-phenyl-piperidin-3-yl)-carbamic acid tert-butyl ester
  • step 3 (1,6,6-Trimethyl-3-phenyl-piperidin-3-yl)-carbamic acid tert-butyl ester
  • step 4 rac-1,6,6-Trimethyl-3-phenyl-piperidin-3-ylamine
  • step 1 rac-3-(3-Bromo-phenyl)-1-methyl-3-nitro-piperidine
  • step 1-3 the title compound was prepared from 1-Bromo-3-nitromethyl-benzene (CAS:854634-33-6). MS (m/e): 300.3 (M+H).
  • step 2 rac-3-(3-Bromo-phenyl)-1-methyl-piperidin-3-ylamine
  • step 3 the title compound was prepared from rac-3-(3-Bromo-phenyl)-1-methyl-3-nitro-piperidine. MS (m/e): 269.2 (M+H).
  • step 1 rac-4-Nitro-4-phenyl-butyric acid methyl ester
  • step 1 the title compound was prepared from Nitromethyl-benzene (CAS: 622-42-4).
  • step 2 rac-5-Nitro-5-phenyl-piperidin-2-one
  • step 3 rac-5-Amino-5-phenyl-piperidin-2-one
  • step 4 the title compound was prepared from rac-5-Nitro-5-phenyl-piperidin-2-one. MS (m/e): 191.4 (M+H).
  • step 4 rac-3-Phenyl-piperidin-3-ylamine
  • step 4 the title compound was prepared from rac-5-Amino-5-phenyl-piperidin-2-one. MS (m/e): 177.7 (M+H).
  • step 5 rac-2-(3-Amino-3-phenyl-piperidin-1-yl)-2-methyl-propionitrile
  • step 6 rac-1-tert-Butyl-3-phenyl-piperidin-3-ylamine
  • step 1 rac-(4-Methyl-6-phenyl-4-aza-spiro[2.5]oct-6-yl)-carbamic acid tert-butyl ester
  • step 2 rac-4-Methyl-6-phenyl-4-aza-spiro[2.5]oct-6-ylamine hydrochloride
  • step 4 the title compound was prepared from rac-(4-Methyl-6-phenyl-4-aza-spiro[2.5]oct-6-yl)-carbamic acid tert-butyl ester. MS (m/e): 217.4 (M+H).
  • step 1 2-Bromo-4-trifluoromethyl-benzoic acid methyl ester
  • step 2 2-Cyclopropyl-4-trifluoromethyl-benzoic acid methyl ester
  • step 1 2-Ethyl-4,6-bis-trifluoromethyl-benzoic acid
  • step 1 2-Difluoromethoxy-4-trifluoromethyl-benzoic acid methyl ester
  • step 2 2-Difluoromethoxy-4-trifluoromethyl-benzoic acid
  • step 3 the title compound was prepared from 2-difluoromethoxy-4-trifluoromethyl-benzoic acid methyl ester. MS (m/e): 254.9 (M ⁇ H)
  • step 1 2-Pyrrolidin-1-yl-4-trifluoromethyl-benzoic acid methyl ester
  • step 2 2-Pyrrolidin-1-yl-4-trifluoromethyl-benzoic acid
  • step 3 the title compound was prepared from 2-pyrrolidin-1-yl-4-trifluoromethyl-benzoic acid methyl ester. MS (m/e): 258.0 (M ⁇ H).
  • step 1 2-Iodo-4-trifluoromethyl-benzoic acid methyl ester
  • step 1 the title compound was prepared from 2-iodo-4-trifluoromethyl-benzoic acid (CAS: 54507-44-7).
  • step 2 2-Cyclohexyl-4-trifluoromethyl-benzoic acid methyl ester
  • step 3 2-Cyclohexyl-4-trifluoromethyl-benzoic acid
  • step 3 the title compound was prepared from 2-cyclohexyl-4-trifluoromethyl-benzoic acid methyl ester. MS (m/e): 271.2 (M ⁇ H).
  • step 2 2-Methoxy-6-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-benzonitrile
  • step 3 2-Methoxy-6-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-benzoic acid
  • step 1 2-(2-Methoxy-4-trifluoromethyl-phenyl)-4,4-dimethyl-4,5-dihydro-oxazole
  • step 2 2-(2-Methoxy-3-methyl-4-trifluoromethyl-phenyl)-4,4-dimethyl-4,5-dihydro-oxazole
  • step 3 2-(2-Ethyl-3-methyl-4-trifluoromethyl-phenyl)-4,4-dimethyl-4,5-dihydro-oxazole
  • step 4 2-(2-Ethyl-3-methyl-4-trifluoromethyl-phenyl)-3,4,4-trimethyl-4,5-dihydro-oxazol-3-ium iodide
  • step 1 (3-Hydroxy-1-methyl-propyl)-methyl-carbamic acid tert-butyl ester
  • step 2 (3-Bromo-1-methyl-propyl)-methyl-carbamic acid tert-butyl ester
  • step 3 Methyl-(1-methyl-4-nitro-4-phenyl-butyl)-carbamic acid tert-butyl ester
  • step 4 the title compound was prepared from Methyl-(1-methyl-4-nitro-4-phenyl-butyl)-carbamic acid tert-butyl ester. MS (m/e): 223.3 (M+H).
  • step 7 N-(1,6-Dimethyl-3-phenyl-piperidin-3-yl)-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide
  • step 1 rac-3-Amino-3-phenyl-piperidine-1-carboxylic acid benzyl ester
  • step 2 rac-3-(2-Methoxy-4,6-bis-trifluoromethyl-benzoylamino)-3-phenyl-piperidine-1-carboxylic acid benzyl ester
  • step 3 rac-2-Methoxy-N-(3-phenyl-piperidin-3-yl)-4,6-bis-trifluoromethyl-benzamide
  • step 1 rac-3-(2-Methoxy-6-methylsulfanyl-4-trifluoromethyl-benzoylamino)-3-phenyl-piperidine-1-carboxylic acid benzyl ester
  • step 2 rac-2-Methoxy-6-methylsulfanyl-N-(3-phenyl-piperidin-3-yl)-4-trifluoromethyl-benzamide hydrochloride
  • step 1 rac-2-Methoxy-N-(5-methoxymethoxy-1-methyl-3-phenyl-piperidin-3-yl)-6-methylsulfanyl-4-trifluoromethyl-benzamide
  • step 2 rac-N-(5-Hydroxy-1-methyl-3-phenyl-piperidin-3-yl)-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide
  • the examples 56-57 have been prepared by separation of the racemic material by chiral HPLC followed by formation of the hydrochloride salt with HCl/Methanol:
  • the examples 61-62 have been prepared by separation of the racemic material by chiral HPLC:
  • step 1 rac-2-Methoxy-N-(1-methyl-5-oxo-3-phenyl-piperidin-3-yl)-6-methylsulfanyl-4-trifluoromethyl-benzamide
  • step 2 N-((3RS,5RS)-5-Hydroxy-1-methyl-3-phenyl-piperidin-3-yl)-2-methoxy-6 methylsulfanyl-4-trifluoromethyl-benzamide
  • the examples 106-128 have been prepared by separation of the racemic material by chiral HPLC:
  • the compounds of formula I and their pharmaceutically usable addition salts possess valuable pharmacological properties.
  • compounds of the present invention are good inhibitors of the glycine transporter I (GlyT-1).
  • the compounds were investigated in accordance with the test given hereinafter.
  • DMEM complete medium Nutrient mixture F-12 (Gibco Life-technologies), fetal bovine serum (FBS) 5%, (Gibco life technologies), Penicillin/Streptomycin 1% (Gibco life technologies), Hygromycin 0.6 mg/ml (Gibco life technologies), Glutamine 1 mM Gibco life technologies)
  • Uptake buffer 150 mM NaCl, 10 mM Hepes-Tris, pH 7.4, 1 mM CaCl 2 , 2.5 mM KCl, 2.5 mM MgSO 4 , 10 mM (+) D -glucose.
  • Flp-inTM-CHO (Invitrogen Cat n o R758-07) cells stably transfected with mGlyTlb cDNA.
  • mammalian cells (Flp-inTM-CHO), transfected with mGlyT-1b cDNA, were plated at the density of 40,000 cells/well in complete F-12 medium, without hygromycin in 96-well culture plates.
  • the medium was aspirated and the cells were washed twice with uptake buffer (UB).
  • the cells were then incubated for 20 min at 22° C. with either (i) no potential competitor, (ii) 10 mM non-radioactive glycine, (iii) a concentration of a potential inhibitor.
  • a range of concentrations of the potential inhibitor was used to generate data for calculating the concentration of inhibitor resulting in 50% of the effect (e.g.
  • IC 50 the concentration of the competitor inhibiting glycine uptake of 50%.
  • a solution was then immediately added containing [ 3 H]-glycine 60 nM (11-16 Ci/mmol) and 25 ⁇ M non-radioactive glycine.
  • the plates were incubated with gentle shaking and the reaction was stopped by aspiration of the mixture and washing (three times) with ice-cold UB.
  • the cells were lysed with scintillation liquid, shaken 3 hours and the radioactivity in the cells was counted using a scintillation counter.
  • IC 50 data ⁇ 1.0 ⁇ M.
  • IC 50 data ( ⁇ 0.2 ⁇ M) for compounds 1-128 is provided in table 1.
  • Example IC 50 data ( ⁇ M) 4 0.0264 5 0.1074 7 0.0854 11 0.0202 13 0.013 16 0.1379 18 0.0244 19 0.0672 25 0.1256 26 0.0593 27 0.0262 28 0.0277 36 0.0839 37 0.1817 38 0.0101 39 0.1843 45 0.0245 46 0.1693 47 0.1811 48 0.1973 51 0.0582 55 0.0777 56 0.1617 57 0.0227 58 0.1561 63 0.0100 66 0.243 67 0.1289 68 0.1746 69 0.1175 70 0.1973 71 0.0559 72 0.0369 73 0.0544 74 0.1226 75 0.0538 76 0.0929 77 0.0881 80 0.1759 82 0.0253 83 0.03 84 0.0173 85 0.0313 86 0.0715 87 0.0396 88 0.1457 89 0.107 91 0.1132 93 0.0479 94 0.0596 95 0.0515 96 0.0682 97 0.1851 98 0.0622 99 0.0366
  • the present invention also provides pharmaceutical compositions containing compounds of the invention, for example, compounds of formula I or pharmaceutically acceptable acid addition salts thereof and a pharmaceutically acceptable carrier.
  • Such pharmaceutical compositions can be in the form of tablets, coated tablets, dragées, hard and soft gelatin capsules, solutions, emulsions or suspensions.
  • the pharmaceutical compositions also can be in the form of suppositories or injectable solutions.
  • compositions of the invention in addition to one or more compounds of the invention, contain a pharmaceutically acceptable carrier.
  • suitable pharmaceutically acceptable carriers include pharmaceutically inert, inorganic or organic carriers. Lactose, corn starch or derivatives thereof, talc, stearic acids or its salts and the like can be used, for example, as such carriers for tablets, coated tablets, dragées and hard gelatin capsules.
  • Suitable carriers for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like. Depending on the nature of the active substance no carriers are however usually required in the case of soft gelatin capsules.
  • Suitable carriers for the production of solutions and syrups are, for example, water, polyols, glycerol, vegetable oil and the like.
  • Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like.
  • compositions can, moreover, contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances.
  • the present invention also provides a method for the manufacture of pharmaceutical compositions. Such process comprises bringing one or more compounds of formula I and/or pharmaceutically acceptable acid addition salts thereof and, if desired, one or more other therapeutically valuable substances into a galenical administration form together with one or more therapeutically inert carriers.
  • the most preferred indications in accordance with the present invention are those, which include disorders of the central nervous system, for example the treatment or prevention of schizophrenia, cognitive impairment and Alzheimer's disease.
  • the dosage at which compounds of the invention can be administered can vary within wide limits and will, of course, have to be adjusted to the individual requirements in each particular case.
  • the dosage for adults can vary from about 0.01 mg to about 1000 mg per day of a compound of general formula I or of the corresponding amount of a pharmaceutically acceptable salt thereof.
  • the daily dosage can be administered as single dose or in divided doses and, in addition, the upper limit can also be exceeded when this is found to be indicated.
  • Tablet Formulation mg/tablet Item Ingredients 5 mg 25 mg 100 mg 500 mg 1. Compound of formula I 5 25 100 500 2. Lactose Anhydrous DTG 125 105 30 150 3. Sta-Rx 1500 6 6 6 30 4. Microcrystalline Cellulose 30 30 30 150 5. Magnesium Stearate 1 1 1 1 Total 167 167 167 831
  • Capsule Formulation mg/capsule Item Ingredients 5 mg 25 mg 100 mg 500 mg 1. Compound of formula I 5 25 100 500 2. Hydrous Lactose 159 123 148 — 3. Corn Starch 25 35 40 70 4. Talc 10 15 10 25 5. Magnesium Stearate 1 2 2 5 Total 200 200 300 600

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KR20120109292A (ko) * 2009-06-24 2012-10-08 다이닛본 스미토모 세이야꾸 가부시끼가이샤 Ｎ-치환-시클릭 아미노 유도체
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EP2736329A4 (en) * 2011-07-29 2015-03-25 Tempero Pharmaceuticals Inc COMPOUNDS AND METHODS

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NZ593279A (en) 2013-03-28
CO6341621A2 (es) 2011-11-21
SG173116A1 (en) 2011-08-29
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BRPI1007410A2 (pt) 2016-02-16
AR075160A1 (es) 2011-03-16
EP2391603B1 (en) 2014-01-08
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AU2010209816A1 (en) 2011-08-11
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