[go: up one dir, main page]
More Web Proxy on the site http://driver.im/

WO2003031435A1 - Pyrazole derivatives as glycine transporter inhibitors - Google Patents

Pyrazole derivatives as glycine transporter inhibitors Download PDF

Info

Publication number
WO2003031435A1
WO2003031435A1 PCT/EP2002/010172 EP0210172W WO03031435A1 WO 2003031435 A1 WO2003031435 A1 WO 2003031435A1 EP 0210172 W EP0210172 W EP 0210172W WO 03031435 A1 WO03031435 A1 WO 03031435A1
Authority
WO
WIPO (PCT)
Prior art keywords
pyrazol
fluorophenyl
formula
ylmethyl
compounds
Prior art date
Application number
PCT/EP2002/010172
Other languages
French (fr)
Other versions
WO2003031435A8 (en
Inventor
Kai Schiemann
Michael Arlt
Dirk Finsinger
Karl-August Ackermann
Wilfried Rautenberg
Joachim Leibrock
Hartmut Greiner
Takahiko Tobe
Original Assignee
Merck Patent Gmbh
Yamanouchi Pharmaceutical Co. Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Merck Patent Gmbh, Yamanouchi Pharmaceutical Co. Ltd. filed Critical Merck Patent Gmbh
Priority to AU2002342675A priority Critical patent/AU2002342675A1/en
Publication of WO2003031435A1 publication Critical patent/WO2003031435A1/en
Publication of WO2003031435A8 publication Critical patent/WO2003031435A8/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • 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
    • C07D401/06—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
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
    • 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
    • C07D417/06—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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems

Definitions

  • the invention relates to compounds of the formula I
  • X is CH or N
  • R 1 is H, A, Hal, (CH 2 ) n Het, (CH 2 ) n Ar, cycloalkyl having from 3 to 7 carbon atoms, CF 3 , N0 2l CN, C(NH)NOH or OCF 3l
  • R 2 is (CH ) n Het, (CH 2 ) n Ar, cycloalkyl having from 3 to 7 carbon atoms or CF 3 ,
  • R 5 is H or A
  • A is straight-chain or branched alkyl having from 1 to 10 carbon atoms, alkenyl having from 2 to 10 carbon atoms or alkoxyalkyl having from 2 to 10 carbon atoms,
  • Het is a saturated, unsaturated or aromatic monocyclic or bicyclic heterocyclic radical which is unsubstituted or monosubstituted or polysubstituted by A and/or Hal,
  • Ar is a phenyl radical which is unsubstituted or monosubstituted or polysubstituted by A and/or Hal, OR 5 , OOCR 5 , COOR 5 ,
  • n 0, 1, 2, 3, 4 or 5
  • Hal is F, Cl, Br or I
  • R 1 and R 4 are H, X is CH 2 , R 2 is phenyl or p-chlorophenyl, and R 3 is 1-methyl-4-piperidyloxycarbonyl, 2-(4-phenylpiperazino)ethoxycarbonyl, benzoxazol-2-yl, benzothiazol-2-yl, tetrazol-5-yl or unsubstituted or substituted thiazolidin-2-yl, and salts and solvates thereof, are excluded.
  • the invention had the object of finding novel compounds having valuable properties, in particular those which can be used for the preparation of medicaments.
  • the compounds of the formula I according to the invention are suitable as glycine transporter inhibitors and can be used in human and veterinary medicine for the prophylaxis and treatment of schizophrenia, depression, dementia, Parkinson's disease, Alzheimer's disease, Lewy bodies dementia, Huntington's disease, Tourette's syndrome, anxiety, learning and memory restrictions, neurodegenerative disorders and other cognitive impairments, as well as nicotine dependence and pain.
  • Glycine is known as an excitatory and inhibitory neurotransmitter of the central and peripheral nervous system. These functions are exerted via two different types of receptor, with different types of glycine transporters being involved in each case in regulation of neuronal transmission.
  • the function as inhibitory neurotransmitter acts via the strychnine-sensitive glycine receptor, which occurs predominantly in the spinal cord and in the brain stem.
  • the excitatory function is exerted via the N-methyl-D- aspartic acid (NMDA) receptor, which is a sub-type of the glutamate receptors and is widespread in the brain, in particular in the cerebral cortex and the hippocampus.
  • NMDA N-methyl-D- aspartic acid
  • Glycine acts here as coagonist on the NMDA receptor (Johnson, J.W., Asher, P., Nature, 325, 529-531. (1987)).
  • Neurotransmitter transporters play an important role in control of the concentration of neurotransmitters in the synaptic cleft, with the transmitters being taken up by the cells. It is assumed that neurotransmitter transporters also contribute to recycling of the neurotransmitters in that the neurotransmitters are taken up by the pre-synaptic nerve endings.
  • GLYT glycine transporter
  • GLYT1 has numerous splicing variants (Kim, K.M. et al., Mol. Pharmacol., 45, 608-17, 1994) and is expressed predominantly in the spinal cord, brain stem, cerebellum, diencephalon and in the retina, while it is expressed to a smaller extent in the bulbus olfactorius and the cerebrum halves. It is assumed that GLYT1 is involved in control of the NMDA receptor function (Smith, K.E. et al., Neuron, 8, 927-35; Guastella, J. et al., Proc. Natl. Acad. Sci, 89, 7189-93, 992; Bergeron, R. et al., Proc. Natl. Acad. Sci. USA, 95, 15730-15734, 1998)
  • GDA glycine transporter inhibitor glycyldodecyl- amide
  • GLYT2 The expression of GLYT2 is limited to the spinal cord, the brain stem and the cerebellum (Goebel, D.J., Mol. Brain Res., 40, 139-42, 1996; Zafra, F. et al., J. Neurosci., 15, 3952-69, 1995). It is therefore assumed that GLYT2 is involved in control of the function of the strychnine-sensitive glycine receptor. It is assumed that the inhibition of GLYT2 reduces the trans- mission of pain in the spinal cord through the reinforcing action of the strychnine-sensitive glycine transporter function (Yaksh, T. L, Pain, 37, 111-123, 1989).
  • the reinforcement of the strychnine-sensitive glycine receptor function can be employed in the therapeutic treatment of abnormal muscle contraction, such as, for example, cramps, myoclonia and epilepsy (Truong, D.D. et al.,
  • Cramps are associated with nerve disorders and damage, as occur in epilepsy, disorders of the cerebral blood vessel system, head injuries, multiple sclerosis, damage to the spinal cord and dystonia. It is known that the NMDA receptor is involved in various syndromes. Thus, it is thought that the functional weakening of the NMDA receptor plays a role in schizophrenia (Javitt, D.C., Zukin, S.R., American Journal of Psychiatry, 148, 1301-8, 1991).
  • WO 97/45115 mentions tertiary amines
  • WO 97/45423 mentions pyrimidine derivatives
  • WO 99/34790 mentions amino acid derivatives
  • WO 99/41227 mentions tricyclic compounds
  • WO 99/44596 and WO 99/45011 mention piperidine derivatives
  • WO 00/07978 mentions aminomethylcarboxylic acid derivatives in addition to glycyldo- decylamide (GDA) as glycine transporter inhibitors.
  • GDA glycyldo- decylamide
  • the compounds of the formula I can be employed as medicament active ingredients in human and veterinary medicine. They can furthermore be employed as intermediates for the preparation of further medicament active ingredients.
  • the invention accordingly relates to the compounds of the formula I and to the use thereof in human and animal medicine.
  • the present invention furthermore relates to a process for the preparation of compounds of the formula IA
  • R 1 and X are as defined above, is reacted with a compound of the formula
  • a and R 2 are as defined above,
  • the present invention furthermore relates to a process for the preparation of compounds of the formula IB
  • R 1 and X are as defined above, is reacted with a compound of the formula IV in which
  • a and R 2 are as defined above,
  • the compounds of the formulae IA and IB can be converted into further compounds of the formula I by conventional methods.
  • the compounds of the formulae IA and IB can be converted, using reducing agents, such as, for example, lithium aluminium hydride, into the corresponding alcohols of the formulae IC and ID
  • the compounds of the formulae IE and IF can themselves be aminated by known methods using corresponding nucleophiles, such as, for example, nitrogen bases, in particular hydroxylamine, O-methylhydroxylamine, morpholine, piperidine, piperazine, N-methylpiperazine, 4-methylpiperazin- 1-ylamine, pyrrolidine, pyrazolidine or imidazolidine, if desired in the presence of a reducing agent, such as sodium triacetoxyborohydride, or converted into the corresponding imines.
  • nucleophiles such as, for example, nitrogen bases, in particular hydroxylamine, O-methylhydroxylamine, morpholine, piperidine, piperazine, N-methylpiperazine, 4-methylpiperazin- 1-ylamine, pyrrolidine, pyrazolidine or imidazolidine, if desired in the presence of a reducing agent, such as sodium triacetoxyborohydride, or converted into the corresponding imines.
  • the compounds of the formulae IE and IF can be converted, by Wittig reaction with methoxymethyltriphenylphosphonium salts, into the corresponding enol ethers, which can be converted, by treatment with an acid, into the homologous aldehydes IG and IH
  • the compounds of the formulae IG and IH can be converted into further compounds of the formula I analogously to the compounds of the formulae IE and IF.
  • the invention likewise relates to the novel compounds of the formulae II, III, IV and V.
  • solvates of the compounds of the formula I is taken to mean adductions of inert solvent molecules onto the compounds of the formula I which form owing to their mutual attractive force.
  • Solvates are, for example, mono- or dihydrates or alcoholates.
  • R 1 is preferably A, Hal, (CH 2 ) n Het or (CH 2 ) n Ar, in particular A, (CH 2 ) n Het or (CH 2 ) n Ar.
  • R 1 is very particularly preferably phenyl, 2-, 3- or4-cyanophenyl, 2-, 3- or 4-fluorophenyl, 2-, 3- or 4-methyl-, -ethyl-, -n-propyl- or -n-butyl- phenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4-, 3,5- or 3,6-difluoro-, -dichloro- or
  • R 2 is preferably (CH ) n Het or (CH 2 ) n Ar, in particular (CH 2 ) n Ar.
  • R 2 is very particularly preferably phenyl, 2-, 3- or 4-cyanophenyl, 2-, 3- or 4-fluorophenyl, 2-, 3- or 4-methyl-, -ethyl-, -n-propyl- or -n-butylphenyl, 2,3-, 2,4-, 2,5- or 2,6-difluoro- or -dicyanophenyl, thiophen-2-yl or thiophen-3-yl, 2-, 3- or 4-pyridyl, 2-, 4- or 5-oxazolyl, 2-, 4- or 5-thiazolyl, quinolinyl, isoquino- linyl, 2- or 4-pyridazyl, 2-, 4- or 5-pyrimidyl, or 2- or 3-pyrazinyl.
  • R 4 is particularly preferably H.
  • R 5 is preferably A.
  • A is preferably alkyl, is preferably unbranched and has 1, 2, 3, 4, 5, 6, 7, 8,
  • 9 or 10 carbon atoms preferably 1 , 2, 3, 4, 5 or 6 carbon atoms, and is preferably methyl, ethyl, n-propyl, furthermore preferably isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, but also n-pentyl, neopentyl, isopentyl or n-hexyl.
  • Particular preference is given to methyl, ethyl, n-propyl, isopropyl, n-butyl, n-pentyl, n-hexyl or n-decyl.
  • A is furthermore preferably the (CH 2 ) m OCH3 or (CH 2 )mC 2 H 5 group, in which m is 2, 3, 4, 5 or 6, but in particular 2.
  • A is alkenyl, it is preferably allyl, 2- or 3-butenyl, isobutenyl, sec-butenyl, furthermore preferably 4-pentenyl, isopentenyl or 5-hexenyl.
  • Het is preferably an aromatic or in particular saturated heterocyclic radical which is unsubstituted or substituted by A.
  • Het is preferably 1-piperidyl, 1-piperazyl, 1-(4-methyl)piperazyl, 4-methylpiperazin-1-ylamine, 4-mor- pholinyl, 1-pyrrolidinyl, 1-pyrazolidinyl, 1-(2-methyl)pyrazolidinyl, 1-imidazo- lidinyl or 1-(3-methyl)imidazolidinyl, thiophen-2-yl or thiophen-3-yl, 2-, 3- or 4-pyridyl, which may be unsubstituted or substituted by one or more CN groups, 2-, 4- or 5-oxazolyl, 2-, 4- or 5-thiazolyl, quinolinyl, isoquinolin l, 2- or 4-pyridazyl, 2-, 4- or 5-pyrimidyl, or 2- or 3-pyrazinyl. Het is furthermore preferably a radical from the following table:
  • Het is particularly preferably one of the following radicals:
  • Ar is preferably a phenyl radical which is unsubstituted or substituted by Hal, OH, CN, N0 3 , NH 2 , NHCOCH 3l COOCH 3> CONH 2 or CF 3 .
  • Ar is preferably substituted in the 4- or 3-position.
  • n is preferably 0, 1 or 2, in particular 0 or 1.
  • Cycloalkyl preferably has 3-7 carbon atoms and is preferably cyclopropyl or cyclobutyl, furthermore preferably cyclopentyl or cyclohexyl, furthermore also cycloheptyl, particularly preferably cyclopentyl.
  • Hal is preferably F, Cl or Br, but also
  • the present invention relates to the enantiomers, diastereomers and mixtures thereof.
  • radicals which occur more than once may be identical or different, i.e. are independent of one another.
  • the invention relates, in particular, to the compounds of the formula I in which at least one of the radicals mentioned has one of the preferred meanings indicated above.
  • Some preferred groups of compounds may be expressed by the following sub-formulae 11 to 19, which conform to the formula I and in which the radicals not designated in greater detail are as defined for the formula I, but in which
  • R 1 is (CH 2 ) n Het or (CH 2 ) n Ar;
  • R 1 is (CH 2 ) ⁇ Het or (CH 2 ) n Ar, R 2 is (CH 2 ) n Ar; in 13 R 1 is (CH 2 ) n Ar, R 2 is (CH 2 ) n Ar;
  • R 1 is (CH 2 ) n Het or (CH 2 ) n Ar,
  • R 2 is (CH 2 ) n Ar
  • R 4 is H
  • R 3 is (CH 2 )nC0 2 R 5 , (CH 2 ) n CO-Het, CHO, CH 2 OR 5 , (CH 2 ) n -Het,
  • R 1 is (CH 2 ) ⁇ Het or (CH 2 ) n Ar,
  • R 2 is (CH 2 ) n Ar
  • R 4 is H
  • R 5 is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, n-pentyl, n-hexyl or n-decyl;
  • R 1 is (CH 2 ) n Het or (CH 2 ) n Ar
  • R 2 is (CH 2 ) n Ar
  • R 4 is H
  • R 3 is (CH 2 )nC ⁇ 2R 5 , (CH 2 ) n CO-Het, CHO, CH 2 OR 5 , (CH 2 ) n -Het,
  • R 5 is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, n-pentyl, n-hexyl or n-decyl, n is 0, 1 or 2;
  • R 1 is (CH 2 ) n Het or (CH 2 ) n Ar
  • R 2 is (CH 2 ) ⁇ Ar
  • R 3 is H
  • R 1 is (CH 2 ) n Het or (CH 2 ) n Ar
  • R 2 is (CH 2 ) n Ar
  • R 3 is H
  • R 4 is (CH 2 ) n C0 2 R 5 , (CH 2 ) n CO-Het, CHO, CH 2 OR 5 , (CH 2 ) ⁇ -Het,
  • R 5 is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, n-pentyl, n-hexyl or n-decyl;
  • R 1 is (CH 2 ) n Het or (CH 2 ) n Ar,
  • R 2 is (CH 2 ) n Ar
  • R 3 is H
  • R 5 is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, n-pentyl, n-hexyl or n-decyl, n is O, 1 or 2.
  • the compounds of the formula I and also the starting materials for their preparation are, in addition, prepared by methods known per se, as described in the literature (for example in the standard works, such as Houben-Weyl, Methoden der organischen Chemie [Methods of Organic Chemistry], Georg-Thieme-Verlag, Stuttgart), to be precise under reaction conditions which are known and suitable for the said reactions. Use can also be made here of variants which are known per se, but are not mentioned here in greater detail.
  • the compound of the formula III is preferably obtained by reaction of compounds of the formula V
  • R 2 and A are as defined above, under conditions which are known for reactions of this type.
  • the starting materials can, if desired, also be formed in situ by not isolating them from the reaction mixture, but instead immediately converting them further into the compounds of the formula I. On the other hand, it is possible to carry out the reaction stepwise.
  • the starting materials of the formulae II, HI and IV are generally known. If they are not known, they can be prepared by methods known per se.
  • the reactions of the compounds of the formula II with the compounds of the formula III and the compounds of the formula IV are carried out in the presence or absence of a preferably inert solvent at temperatures between about -20 and about 150°, preferably between 20 and 100°.
  • suitable inert solvents are hydrocarbons, such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons, such as trichloroethylene, 1 ,2-dichioroethane, tetrachloromethane, chloroform or dichloromethane; alcohols, such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; ethers, such as diethyl ether, diiso- propyl ether, tetrahydrofuran (THF) or dioxane; glycol ethers, such as ethylene glycol monomethyl or monoethyl ether or ethylene glycol dimethyl ether (diglyme); ketones, such as acetone or butanone; amides, such as acetamide, dimethylacetamide or dimethylformamide (DMF); nitriles
  • the pH necessary for the reaction can be set in accordance with pH values selected for similar reactions of carbonyl compounds with amino com- pounds.
  • the pH is preferably pre-specified through the use of the particular acid-addition salt, preferably a hydrogen halide addition salt, of the compound of the formula II, i.e. there is no additional addition of a base or acid to the reaction mixture.
  • Preferred acid-addition salts are hydrochlorides or hydrobromides.
  • a base of the formula I can be converted into the associated acid-addition salt using an acid, for example by reaction of equivalent amounts of the base and the acid in an inert solvent, such as ethanol, followed by evaporation.
  • Suitable acids for this reaction are, in particular, those which give physiologically acceptable salts.
  • inorganic acids for example sulfuric acid, nitric acid, hydrohalic acids, such as hydrochloric acid or hydrobromic acid, phosphoric acids, such as orthophosphoric acid, or sulfamic acid, furthermore organic acids, in particular aliphatic, alicyclic, araiiphatic, aromatic or heterocyclic monobasic or polybasic carboxylic, sulfonic or sulfuric acids, for example formic acid, acetic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, methane- or ethanesulfonic acid, ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid,
  • inorganic acids for
  • salts with physiologically unacceptable acids for example picrates, can be used for the isolation and/or purification of the compounds of the formula I.
  • the free bases of the formula I can be liberated from their salts using bases (for example sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate).
  • bases for example sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate.
  • the invention relates in particular to compounds of the formula I and physiologically acceptable salts and solvates thereof as medicaments.
  • the invention also relates to the compounds of the formula I and physiologically acceptable salts and solvates thereof as glycine transporter inhibitors.
  • the invention furthermore relates to the use of the compounds of the formula I and/or physiologically acceptable salts and/or solvates thereof for the preparation of pharmaceutical preparations, in particular by non- chemical methods.
  • they can be converted into a suitable dosage form together with at least one solid, liquid and/or semi-liquid excipient or adjuvant and, if desired, in combination with one or more further active ingredients.
  • the invention furthermore relates to pharmaceutical preparations com- prising at least one compound of the formula I and/or one of its physiologically acceptable salts and/or solvates.
  • Suitable excipients are organic or inorganic substances which are suitable for enteral (for example oral), parenteral or topical administration and do not react with the novel compounds, for example water, vegetable oils, benzyl alcohols, alkylene glycols, polyethylene glycols, glycerol triacetate, gelatine, carbohydrates, such as lactose or starch, magnesium stearate, talc or Vaseline.
  • Suitable for oral administration are, in particular, tablets, pills, coated tablets, capsules, powders, granules, syrups, juices or drops, suitable for rectal administration are suppositories, suitable for parenteral administration are solutions, preferably oil-based or aqueous solutions, furthermore suspensions, emulsions or implants, and suitable for topical application are ointments, creams or powders.
  • the novel com- pounds may also be lyophilised and the resultant lyophilisates used, for example, for the preparation of injection preparations.
  • the preparations indicated may be sterilised and/or comprise assistants, such as lubricants, preservatives, stabilisers and/or wetting agents, emulsifiers, salts for modifying the osmotic pressure, buffer substances, dyes and flavours and/or one or more further active ingredients, for example one or more vitamins.
  • assistants such as lubricants, preservatives, stabilisers and/or wetting agents, emulsifiers, salts for modifying the osmotic pressure, buffer substances, dyes and flavours and/or one or more further active ingredients, for example one or more vitamins.
  • the substances according to the invention are preferably administered in doses of between 1 and 500 mg, in particular between 5 and 100 mg per dosage unit.
  • the daily dose is preferably between about 0.02 and 10 mg/kg of body weight.
  • the specific dose for each patient depends on a wide variety of factors, for example on the efficacy of the specific compound employed, on the age, body weight, general state of health, sex, on the diet, on the time and method of administration, on the excretion rate, medicament combination and severity of the particular illness to which the therapy applies. Oral administration is preferred.
  • the glycine transporter inhibition is determined from the synaptosomal take-up of glycine.
  • a synaptosomal fraction (P 2 fraction) is prepared from the brain of a rat by the method of Whittaker (The synapto- some. In: Lajtha (ed.), Handbook of Neurochemistry, Vol.2. Plenum, London and New York, 1969, 327-364), giving a synaptosome-enriched suspension of 3 mg of protein/ml.
  • the non-specific take-up of glycine is determined in sodium-free Krebs-Ringer buffer solution (252 mmol/l of sucrose, 15.8 mmol/l of tris, 11 mmol/l of glucose, 1.4 mmol/l of magnesium chloride, 4.8 mmol/l of potassium chloride, 0.9 mmol/l of calcium chloride, pH 7.4, 346 mosmol).
  • a solution of 2.090 g of 9 in 25 ml of THF is added dropwise with stirring and ice cooling under a nitrogen atmosphere to a suspension of 1.139 g of lithium aluminium hydride in 25 ml of tetrahydrofuran. After the mixture has been stirred for 1 hour, a further 0.500 g of lithium aluminium hydride is added. After the mixture has been stirred for a further 2 hours, saturated sodium chloride solution is added dropwise with ice cooling, and the mixture is subjected to conventional work-up, giving 10.
  • 0.017 ml of acetic acid is added to a solution of 0.103 g of 11 and 0.040 ml of 12 in 2.00 ml of dichloroethane and 1.00 ml of tetrahydrofuran, and the mixture is stirred for 3 hours. After 0.120 g of sodium triacetoxyborohydride has been added, the mixture is stirred overnight, saturated sodium hydrogencarbonate is subsequently added, and the mixture is subjected to conventional work-up, giving 13.
  • a solution of 0.258 g of potassium tert-butoxide in 5 ml of THF is added dropwise at a maximum of 7°C to a solution of 0.685 g of 17 and 0.789 g of 18 in 10 ml of THF with stirring and ice cooling.
  • the reaction mixture is stirred for 2 days and subsequently subjected to conventional work-up, giving 19.
  • 0.033 ml of acetic acid is added to a solution of 200.00 mg of 17 and 74.66 mg of o-methylhydroxylamine hydrochloride 23 in 8.50 ml of dichloroethane and 4.5 ml of tetrahydrofuran, and the mixture is stirred for 3 hours. 130.287 mg of sodium triacetoxyborohydride are subsequently added. After the mixture has been stirred for 5 hours, it is subjected to conventional work-up, giving 24.
  • a solution of 100 g of an active ingredient of the formula I and 5 g of disodium hydrogenphosphate in 3 I of bidistilled water is adjusted to pH 6.5 using 2N hydrochloric acid, sterile filtered, transferred into injection vials, lyophilised under sterile conditions and sealed under sterile conditions. Each injection vial contains 5 mg of active ingredient.
  • a mixture of 20 g of an active ingredient of the formula I is melted with 100 g of soya lecithin and 1400 g of cocoa butter, poured into moulds and allowed to cool. Each suppository contains 20 mg of active ingredient.
  • a solution is prepared from 1 g of an active ingredient of the formula I, 9.38 g of NaH 2 P0 4 ⁇ 2 H 2 0, 28.48 g of Na 2 HP0 4 ⁇ 12 H 2 0 and 0.1 g of benzalkonium chloride in 940 ml of bidistilled water. The pH is adjusted to 6.8, and the solution is made up to 1 I and sterilised by irradiation. This solution can be used in the form of eye drops.
  • 500 mg of an active ingredient of the formula l are mixed with 99.5 g of Vaseline under aseptic conditions.
  • Example F Coated tablets
  • Tablets are pressed analogously to Example E and subsequently coated in a conventional manner with a coating of sucrose, potato starch, talc, traga- canth and dye.
  • a solution of 1 kg of active ingredient of the formula I in 60 I of bidistilled water is sterile filtered, transferred into ampoules, lyophilised under sterile conditions and sealed under sterile conditions. Each ampoule contains 10 mg of active ingredient.

Landscapes

  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Neurosurgery (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Psychiatry (AREA)
  • Hospice & Palliative Care (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Compounds of the formula (I) and salts and solvates thereof, in which X, R?1, R2, R3, R4 and R5¿ are as defined in Claim 1, are suitable as glycine transporter inhibitors and can be used in human and veterinary medicine for the prophylaxis and treatment of schizophrenia, depression, dementia, Parkinson's disease, Alzheimer's disease, Lewy bodies dementia, Huntington's disease, Tourette's syndrome, anxiety, learning and memory restrictions, neurodegenerative disorders and other cognitive impairments, as well as nicotine dependence and pain.

Description

PYRAZOLE DERIVATIVES AS GLYCINE TRANSPORTE INHIBITORS
The invention relates to compounds of the formula I
Figure imgf000002_0001
in which
X is CH or N,
R1 is H, A, Hal, (CH2)nHet, (CH2)nAr, cycloalkyl having from 3 to 7 carbon atoms, CF3, N02l CN, C(NH)NOH or OCF3l
R2 is (CH )nHet, (CH2)nAr, cycloalkyl having from 3 to 7 carbon atoms or CF3,
R3 and R4 are H, (CH2)nC02R5, (CH2)nCOHet, (CH2)nCOO(CH2)nHet, CHO, (CH2)nOR5, (CH2)nHet, (CH2)nN(R5)2, CH=N-OA, CH2CH=N-OA, (CH2)nNHOA, (CH2)nN(R5)Het, (CH2)nCH=N-Het, (CH2)nOCOR5, (CH2)nN(R5)CH2CH2OR5, (CH2)nN(R5)CH2CH2OCF3, (CH2)nN(R5)C(R5)HCOOR5, (CH2)nN(R5)CH2COHet, (CH2)nN(R5)CH2Het! (CH2)nN(R5)CH2CH2Hetl (CH2)nN(R5)CH2CH2N(R5)CH2COOR5, (CH2)nN(R5)CH2CH2N(R5)2, CH=CHCOOR5, CH=CHCH2NR5Het, CH=CHCH2N(R5)2l CH=CHCH2OR5, (CH2)nN(R5)Ar, (CH2)πN(COOR5)COOR5, (CH2)nN(CONH2)COOR5, (CH2)nN(CONH2)CONH2, (CH2)nN(CH2COOR5)COOR5, (CH2)nN(CH2CONH2)COOR5, (CH2)nN(CH2CONH2)CONH2l (CH2)nCHR5COR5, (CH2)nCHR5COOR5 or (CH2)nCHR5CH2OR5, where in each case one of the radicals R3 or R4 is H,
R5 . is H or A, A is straight-chain or branched alkyl having from 1 to 10 carbon atoms, alkenyl having from 2 to 10 carbon atoms or alkoxyalkyl having from 2 to 10 carbon atoms,
Het is a saturated, unsaturated or aromatic monocyclic or bicyclic heterocyclic radical which is unsubstituted or monosubstituted or polysubstituted by A and/or Hal,
Ar is a phenyl radical which is unsubstituted or monosubstituted or polysubstituted by A and/or Hal, OR5, OOCR5, COOR5,
CON(R5)2, CN, N02, NH2l NHCOR5, CF3 or S02CH3,
n is 0, 1, 2, 3, 4 or 5,
and
Hal is F, Cl, Br or I,
and salts and solvates thereof, in particular physiologically tolerated salts and solvates thereof,
where compounds of the formula I in which R1 and R4 are H, X is CH2, R2 is phenyl or p-chlorophenyl, and R3 is 1-methyl-4-piperidyloxycarbonyl, 2-(4-phenylpiperazino)ethoxycarbonyl, benzoxazol-2-yl, benzothiazol-2-yl, tetrazol-5-yl or unsubstituted or substituted thiazolidin-2-yl, and salts and solvates thereof, are excluded.
The invention had the object of finding novel compounds having valuable properties, in particular those which can be used for the preparation of medicaments.
It has been found that the compounds of the formula I and their salts and solvates have very valuable pharmacological properties and are well tolerated. Similar compounds are disclosed, for example, in DE 2201889, DE 2258033 and DE 2906252.
In particular, the compounds of the formula I according to the invention are suitable as glycine transporter inhibitors and can be used in human and veterinary medicine for the prophylaxis and treatment of schizophrenia, depression, dementia, Parkinson's disease, Alzheimer's disease, Lewy bodies dementia, Huntington's disease, Tourette's syndrome, anxiety, learning and memory restrictions, neurodegenerative disorders and other cognitive impairments, as well as nicotine dependence and pain.
Glycine is known as an excitatory and inhibitory neurotransmitter of the central and peripheral nervous system. These functions are exerted via two different types of receptor, with different types of glycine transporters being involved in each case in regulation of neuronal transmission.
The function as inhibitory neurotransmitter acts via the strychnine-sensitive glycine receptor, which occurs predominantly in the spinal cord and in the brain stem. On the other hand, the excitatory function is exerted via the N-methyl-D- aspartic acid (NMDA) receptor, which is a sub-type of the glutamate receptors and is widespread in the brain, in particular in the cerebral cortex and the hippocampus.
Glycine acts here as coagonist on the NMDA receptor (Johnson, J.W., Asher, P., Nature, 325, 529-531. (1987)).
Neurotransmitter transporters play an important role in control of the concentration of neurotransmitters in the synaptic cleft, with the transmitters being taken up by the cells. It is assumed that neurotransmitter transporters also contribute to recycling of the neurotransmitters in that the neurotransmitters are taken up by the pre-synaptic nerve endings.
Control of the functions of the neurotransmitters can make a significant contribution towards therapeutic treatment of various illnesses caused by dysfunction of the neural functions, where mention should also be made of control of the concentration of the neurotransmitter in the synaptic cleft. The glycine transporter (GLYT) was cloned for the first time in 1992 (Guastella, J. et al., Proc. Natl. Acad. Sci., 89, 7189-93, 1992). Two types of these transporters, GLYT1 and GLYT2, have been identified to date (Liu, Q.R. et al., J. Biol. Chem., 268, 22802-8, 1993).
GLYT1 has numerous splicing variants (Kim, K.M. et al., Mol. Pharmacol., 45, 608-17, 1994) and is expressed predominantly in the spinal cord, brain stem, cerebellum, diencephalon and in the retina, while it is expressed to a smaller extent in the bulbus olfactorius and the cerebrum halves. It is assumed that GLYT1 is involved in control of the NMDA receptor function (Smith, K.E. et al., Neuron, 8, 927-35; Guastella, J. et al., Proc. Natl. Acad. Sci, 89, 7189-93, 992; Bergeron, R. et al., Proc. Natl. Acad. Sci. USA, 95, 15730-15734, 1998)
It is furthermore known that the glycine transporter inhibitor glycyldodecyl- amide (GDA) inhibits hyperactivity in mice caused by the non-competitive NMDA receptor antagonist phencylidine (PCP) (Javitt, D.C. et al., Neuro- psychopharmacology, 17, 202-4, 1997)
The expression of GLYT2 is limited to the spinal cord, the brain stem and the cerebellum (Goebel, D.J., Mol. Brain Res., 40, 139-42, 1996; Zafra, F. et al., J. Neurosci., 15, 3952-69, 1995). It is therefore assumed that GLYT2 is involved in control of the function of the strychnine-sensitive glycine receptor. It is assumed that the inhibition of GLYT2 reduces the trans- mission of pain in the spinal cord through the reinforcing action of the strychnine-sensitive glycine transporter function (Yaksh, T. L, Pain, 37, 111-123, 1989).
The reinforcement of the strychnine-sensitive glycine receptor function can be employed in the therapeutic treatment of abnormal muscle contraction, such as, for example, cramps, myoclonia and epilepsy (Truong, D.D. et al.,
Movement Disorders, 3, 77-87, 1988; Becker, CM. et al., FASEB J. 4,
2767-2774, 1990).
Cramps are associated with nerve disorders and damage, as occur in epilepsy, disorders of the cerebral blood vessel system, head injuries, multiple sclerosis, damage to the spinal cord and dystonia. It is known that the NMDA receptor is involved in various syndromes. Thus, it is thought that the functional weakening of the NMDA receptor plays a role in schizophrenia (Javitt, D.C., Zukin, S.R., American Journal of Psychiatry, 148, 1301-8, 1991).
Furthermore, it is claimed that the negative symptoms in schizophrenia patients can be ameliorated by administration of high doses of glycine (Heresco-Levy, U. et al., Br. J. Psychiatry, 169, 610-7, 1996). Furthermore, activation of the NMDA receptor is involved in the formation of so-called long-term potentiation (LTP) (Collingridge, G.L. , Bliss T.V.,
Trends. Neurosci., 10, 288-93, 1987).
Morris et al. have observed that the administration of an NMDA receptor antagonist induces a memory disorder (Morris, R.G. et al., Nature, 319, 774-6, 1986, Benvenga, M. Theodore, C.S. Pharmacol. Biochem. Behav.,
30, 205-207, 1988). It is thus assumed that the NMDA receptor plays an important role in the memory and learning process.
In patients with Alzheimer's-type dementia, an impairment in the function of the NMDA receptors has been observed (Ninomiya, H. et al., J. Neuro- chem., 54, 526-32, 1990; Tohgi, H. et al. Neurosci. Lett., 141 , 5-8, 1992).
Furthermore, a number of articles have reported that a memory disorder can be countered by administration of a "glycine site" agonist in an animal model (Matsuoka, N., Aigner, T.G., J. Exp. Pharmacol. Ther., 278, 891-7,
1996; Ohno, M. et al. J. Pharmacol., 253, 183-7, 1994; Fishkin, J.J. et al., Behav. Neural. Biol., 59, 150-7, 1993).
These results confirm that active ingredients which inhibit the activity of the glycine transporters and activate the function of the NMDA receptor via the associated increased glycine concentration can be used in human and veterinary medicine, in particular for the prophylaxis and treatment of schizophrenia, depression, dementia, Parkinson's disease, Alzheimer's disease, Lewy bodies dementia, Huntington's disease, Tourette's syndrome, anxiety, learning and memory restrictions, neurodegenerative disorders and other cognitive impairments, as well as nicotine dependence and pain. Various compounds have already been disclosed as glycine transporter inhibitors. Thus, WO 97/45115 mentions tertiary amines, WO 97/45423 mentions pyrimidine derivatives, WO 99/34790 mentions amino acid derivatives, WO 99/41227 mentions tricyclic compounds, WO 99/44596 and WO 99/45011 mention piperidine derivatives and WO 00/07978 mentions aminomethylcarboxylic acid derivatives in addition to glycyldo- decylamide (GDA) as glycine transporter inhibitors.
However, none of the above-mentioned documents describes the compounds of the formula I or the use of the compounds of the formula I according to the invention as glycine transporter inhibitors.
The compounds of the formula I can be employed as medicament active ingredients in human and veterinary medicine. They can furthermore be employed as intermediates for the preparation of further medicament active ingredients.
The invention accordingly relates to the compounds of the formula I and to the use thereof in human and animal medicine.
The present invention furthermore relates to a process for the preparation of compounds of the formula IA
Figure imgf000007_0001
and salts and solvates thereof, which is characterised in that a compound of the formula II
Figure imgf000007_0002
or acid-addition salts thereof in which
R1 and X are as defined above, is reacted with a compound of the formula
Figure imgf000008_0001
in which
A and R2 are as defined above,
and/or in that a basic compound of the formula IA is converted into one of its salts by treatment with an acid.
The present invention furthermore relates to a process for the preparation of compounds of the formula IB
Figure imgf000008_0002
and salts and solvates thereof, which is characterised in that a compound of the formula II
Figure imgf000008_0003
or acid-addition salts thereof in which
R1 and X are as defined above, is reacted with a compound of the formula IV
Figure imgf000009_0001
in which
A and R2 are as defined above,
and/or in that a basic compound of the formula IB is converted into one of its salts by treatment with an acid.
The compounds of the formulae IA and IB can be converted into further compounds of the formula I by conventional methods. In particular, the compounds of the formulae IA and IB can be converted, using reducing agents, such as, for example, lithium aluminium hydride, into the corresponding alcohols of the formulae IC and ID
Figure imgf000009_0002
which can be oxidised, for example using Mnθ2, to give the compounds IE and IF
Figure imgf000009_0003
The compounds of the formulae IE and IF can themselves be aminated by known methods using corresponding nucleophiles, such as, for example, nitrogen bases, in particular hydroxylamine, O-methylhydroxylamine, morpholine, piperidine, piperazine, N-methylpiperazine, 4-methylpiperazin- 1-ylamine, pyrrolidine, pyrazolidine or imidazolidine, if desired in the presence of a reducing agent, such as sodium triacetoxyborohydride, or converted into the corresponding imines. Furthermore, the compounds of the formulae IE and IF can be converted, by Wittig reaction with methoxymethyltriphenylphosphonium salts, into the corresponding enol ethers, which can be converted, by treatment with an acid, into the homologous aldehydes IG and IH
Figure imgf000010_0001
The compounds of the formulae IG and IH can be converted into further compounds of the formula I analogously to the compounds of the formulae IE and IF.
The invention likewise relates to the novel compounds of the formulae II, III, IV and V.
The term solvates of the compounds of the formula I is taken to mean adductions of inert solvent molecules onto the compounds of the formula I which form owing to their mutual attractive force. Solvates are, for example, mono- or dihydrates or alcoholates.
Above and below, the radicals X, A, Ar, Het, n, R1, R2, R3, R4 and R5 are as defined for the formula I, unless expressly stated otherwise.
X is preferably N. R1 is preferably A, Hal, (CH2)nHet or (CH2)nAr, in particular A, (CH2)nHet or (CH2)nAr. R1 is very particularly preferably phenyl, 2-, 3- or4-cyanophenyl, 2-, 3- or 4-fluorophenyl, 2-, 3- or 4-methyl-, -ethyl-, -n-propyl- or -n-butyl- phenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4-, 3,5- or 3,6-difluoro-, -dichloro- or
-dicyanophenyl, 3,4,5-trifluorophenyl, 3,4,5-trimethoxy- or -triethoxyphenyl, thiophen-2-yl or thiophen-3-yl.
R2 is preferably (CH )nHet or (CH2)nAr, in particular (CH2)nAr. R2 is very particularly preferably phenyl, 2-, 3- or 4-cyanophenyl, 2-, 3- or 4-fluorophenyl, 2-, 3- or 4-methyl-, -ethyl-, -n-propyl- or -n-butylphenyl, 2,3-, 2,4-, 2,5- or 2,6-difluoro- or -dicyanophenyl, thiophen-2-yl or thiophen-3-yl, 2-, 3- or 4-pyridyl, 2-, 4- or 5-oxazolyl, 2-, 4- or 5-thiazolyl, quinolinyl, isoquino- linyl, 2- or 4-pyridazyl, 2-, 4- or 5-pyrimidyl, or 2- or 3-pyrazinyl.
If R3 is H, R4 is preferably (CH2)nC02R5, (CH2)nCO-Het, CHO, CH2OR5, (CH2)n-Het, (CH2)nN(R5)2 or CH=N-OA, but in particular (CH2)nCO2R5, (CH2)nCO-Het, CHO, CH=N-OA or (CH2)n-Het. If R4 is H, R3 is preferably (CH2)nC02R5, (CH2)nCO-Het, CHO, CH2OR5, (CH2)n-Het, (CH2)nN(R5)2 or CH=N-OA, but in particular (CH2)nC02R5, (CH2)nCO-Het, CHO, CH=N-OA or (CH2)n-Het. R4 is particularly preferably H.
R5 is preferably A.
A is preferably alkyl, is preferably unbranched and has 1, 2, 3, 4, 5, 6, 7, 8,
9 or 10 carbon atoms, preferably 1 , 2, 3, 4, 5 or 6 carbon atoms, and is preferably methyl, ethyl, n-propyl, furthermore preferably isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, but also n-pentyl, neopentyl, isopentyl or n-hexyl. Particular preference is given to methyl, ethyl, n-propyl, isopropyl, n-butyl, n-pentyl, n-hexyl or n-decyl.
A is furthermore preferably the (CH2)mOCH3 or (CH2)mC2H5 group, in which m is 2, 3, 4, 5 or 6, but in particular 2.
If A is alkenyl, it is preferably allyl, 2- or 3-butenyl, isobutenyl, sec-butenyl, furthermore preferably 4-pentenyl, isopentenyl or 5-hexenyl. Het is preferably an aromatic or in particular saturated heterocyclic radical which is unsubstituted or substituted by A. Het is preferably 1-piperidyl, 1-piperazyl, 1-(4-methyl)piperazyl, 4-methylpiperazin-1-ylamine, 4-mor- pholinyl, 1-pyrrolidinyl, 1-pyrazolidinyl, 1-(2-methyl)pyrazolidinyl, 1-imidazo- lidinyl or 1-(3-methyl)imidazolidinyl, thiophen-2-yl or thiophen-3-yl, 2-, 3- or 4-pyridyl, which may be unsubstituted or substituted by one or more CN groups, 2-, 4- or 5-oxazolyl, 2-, 4- or 5-thiazolyl, quinolinyl, isoquinolin l, 2- or 4-pyridazyl, 2-, 4- or 5-pyrimidyl, or 2- or 3-pyrazinyl. Het is furthermore preferably a radical from the following table:
Figure imgf000012_0001
Figure imgf000013_0001
Figure imgf000014_0001
Figure imgf000015_0001
Figure imgf000016_0001
Figure imgf000017_0001
Figure imgf000018_0001
Het is particularly preferably one of the following radicals:
Figure imgf000018_0002
Figure imgf000019_0001
Ar is preferably a phenyl radical which is unsubstituted or substituted by Hal, OH, CN, N03, NH2, NHCOCH3l COOCH3> CONH2 or CF3. Ar is preferably substituted in the 4- or 3-position.
n is preferably 0, 1 or 2, in particular 0 or 1.
Cycloalkyl preferably has 3-7 carbon atoms and is preferably cyclopropyl or cyclobutyl, furthermore preferably cyclopentyl or cyclohexyl, furthermore also cycloheptyl, particularly preferably cyclopentyl.
Hal is preferably F, Cl or Br, but also
If the compounds of the formula I have one or more chiral carbon atoms, the present invention relates to the enantiomers, diastereomers and mixtures thereof.
Throughout the invention, all radicals which occur more than once may be identical or different, i.e. are independent of one another.
Accordingly, the invention relates, in particular, to the compounds of the formula I in which at least one of the radicals mentioned has one of the preferred meanings indicated above. Some preferred groups of compounds may be expressed by the following sub-formulae 11 to 19, which conform to the formula I and in which the radicals not designated in greater detail are as defined for the formula I, but in which
in 11 R1 is (CH2)nHet or (CH2)nAr;
in 12 R1 is (CH2)πHet or (CH2)nAr, R2 is (CH2)nAr; in 13 R1 is (CH2)nAr, R2 is (CH2)nAr;
in 14 R1 is (CH2)nHet or (CH2)nAr,
R2 is (CH2)nAr,
R4 is H,
R3 is (CH2)nC02R5, (CH2)nCO-Het, CHO, CH2OR5, (CH2)n-Het,
(CH2)nN(R5)2 or CH=N-OA;
in 15 R1 is (CH2)πHet or (CH2)nAr,
R2 is (CH2)nAr,
R4 is H,
R3 is (CH2)nC02R5, (CH2)nCO-Het, CHO, CH2OR5, (CH2)n-Het, (CH2)nN(R5)2 or CH=N-OA,
R5 is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, n-pentyl, n-hexyl or n-decyl;
in 16 R1 is (CH2)nHet or (CH2)nAr, R2 is (CH2)nAr,
R4 is H,
R3 is (CH2)nCθ2R5, (CH2)nCO-Het, CHO, CH2OR5, (CH2)n-Het,
(CH2)πN(R5)2 or CH=N-OA,
R5 is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, n-pentyl, n-hexyl or n-decyl, n is 0, 1 or 2;
in 17 R1 is (CH2)nHet or (CH2)nAr, R2 is (CH2)πAr, R3 is H,
R4 is (CH2)nC02R5, (CH2)nCO-Het, CHO, CH2OR5, (CH2)n-Het, (CH2)nN(R5)2 or CH=N-OA;
in 18 R1 is (CH2)nHet or (CH2)nAr, R2 is (CH2)nAr,
R3 is H, R4 is (CH2)nC02R5, (CH2)nCO-Het, CHO, CH2OR5, (CH2)π-Het,
(CH2)nN(R5)2 or CH=N-OA, R5 is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, n-pentyl, n-hexyl or n-decyl;
in 19 R1 is (CH2)nHet or (CH2)nAr,
R2 is (CH2)nAr,
R3 is H,
R4 is (CH2)nC02R5, (CH2)nCO-Het, CHO, CH2OR5, (CH2)π-Het, (CH2)nN(R5)2 or CH=N-OA,
R5 is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, n-pentyl, n-hexyl or n-decyl, n is O, 1 or 2.
The compounds of the formula I and also the starting materials for their preparation are, in addition, prepared by methods known per se, as described in the literature (for example in the standard works, such as Houben-Weyl, Methoden der organischen Chemie [Methods of Organic Chemistry], Georg-Thieme-Verlag, Stuttgart), to be precise under reaction conditions which are known and suitable for the said reactions. Use can also be made here of variants which are known per se, but are not mentioned here in greater detail. The compound of the formula III is preferably obtained by reaction of compounds of the formula V
Figure imgf000021_0001
in which A is as defined above, with compounds of the formula VI
Figure imgf000021_0002
in which R2 and A are as defined above, under conditions which are known for reactions of this type. The starting materials can, if desired, also be formed in situ by not isolating them from the reaction mixture, but instead immediately converting them further into the compounds of the formula I. On the other hand, it is possible to carry out the reaction stepwise.
The starting materials of the formulae II, HI and IV are generally known. If they are not known, they can be prepared by methods known per se.
Specifically, the reactions of the compounds of the formula II with the compounds of the formula III and the compounds of the formula IV are carried out in the presence or absence of a preferably inert solvent at temperatures between about -20 and about 150°, preferably between 20 and 100°.
Examples of suitable inert solvents are hydrocarbons, such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons, such as trichloroethylene, 1 ,2-dichioroethane, tetrachloromethane, chloroform or dichloromethane; alcohols, such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; ethers, such as diethyl ether, diiso- propyl ether, tetrahydrofuran (THF) or dioxane; glycol ethers, such as ethylene glycol monomethyl or monoethyl ether or ethylene glycol dimethyl ether (diglyme); ketones, such as acetone or butanone; amides, such as acetamide, dimethylacetamide or dimethylformamide (DMF); nitriles, such as acetonitrile; sulfoxides, such as dimethyl sulfoxide (DMSO); nitro com- pounds, such as nitromethane or nitrobenzene; esters, such as ethyl acetate, or mixtures of the said solvents.
The pH necessary for the reaction can be set in accordance with pH values selected for similar reactions of carbonyl compounds with amino com- pounds. The pH is preferably pre-specified through the use of the particular acid-addition salt, preferably a hydrogen halide addition salt, of the compound of the formula II, i.e. there is no additional addition of a base or acid to the reaction mixture. Preferred acid-addition salts are hydrochlorides or hydrobromides. A base of the formula I can be converted into the associated acid-addition salt using an acid, for example by reaction of equivalent amounts of the base and the acid in an inert solvent, such as ethanol, followed by evaporation. Suitable acids for this reaction are, in particular, those which give physiologically acceptable salts. Thus, it is possible to use inorganic acids, for example sulfuric acid, nitric acid, hydrohalic acids, such as hydrochloric acid or hydrobromic acid, phosphoric acids, such as orthophosphoric acid, or sulfamic acid, furthermore organic acids, in particular aliphatic, alicyclic, araiiphatic, aromatic or heterocyclic monobasic or polybasic carboxylic, sulfonic or sulfuric acids, for example formic acid, acetic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, methane- or ethanesulfonic acid, ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenemono- and
-disulfonic acids, or laurylsulfuric acid. Salts with physiologically unacceptable acids, for example picrates, can be used for the isolation and/or purification of the compounds of the formula I.
On the other hand, if desired, the free bases of the formula I can be liberated from their salts using bases (for example sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate).
The invention relates in particular to compounds of the formula I and physiologically acceptable salts and solvates thereof as medicaments.
The invention also relates to the compounds of the formula I and physiologically acceptable salts and solvates thereof as glycine transporter inhibitors.
The invention furthermore relates to the use of the compounds of the formula I and/or physiologically acceptable salts and/or solvates thereof for the preparation of pharmaceutical preparations, in particular by non- chemical methods. In this case, they can be converted into a suitable dosage form together with at least one solid, liquid and/or semi-liquid excipient or adjuvant and, if desired, in combination with one or more further active ingredients.
The invention furthermore relates to pharmaceutical preparations com- prising at least one compound of the formula I and/or one of its physiologically acceptable salts and/or solvates.
These preparations can be used as medicaments in human or veterinary medicine. Suitable excipients are organic or inorganic substances which are suitable for enteral (for example oral), parenteral or topical administration and do not react with the novel compounds, for example water, vegetable oils, benzyl alcohols, alkylene glycols, polyethylene glycols, glycerol triacetate, gelatine, carbohydrates, such as lactose or starch, magnesium stearate, talc or Vaseline. Suitable for oral administration are, in particular, tablets, pills, coated tablets, capsules, powders, granules, syrups, juices or drops, suitable for rectal administration are suppositories, suitable for parenteral administration are solutions, preferably oil-based or aqueous solutions, furthermore suspensions, emulsions or implants, and suitable for topical application are ointments, creams or powders. The novel com- pounds may also be lyophilised and the resultant lyophilisates used, for example, for the preparation of injection preparations. The preparations indicated may be sterilised and/or comprise assistants, such as lubricants, preservatives, stabilisers and/or wetting agents, emulsifiers, salts for modifying the osmotic pressure, buffer substances, dyes and flavours and/or one or more further active ingredients, for example one or more vitamins.
In general, the substances according to the invention are preferably administered in doses of between 1 and 500 mg, in particular between 5 and 100 mg per dosage unit.
The daily dose is preferably between about 0.02 and 10 mg/kg of body weight. However, the specific dose for each patient depends on a wide variety of factors, for example on the efficacy of the specific compound employed, on the age, body weight, general state of health, sex, on the diet, on the time and method of administration, on the excretion rate, medicament combination and severity of the particular illness to which the therapy applies. Oral administration is preferred.
Above and below, all temperatures are indicated in °C. In the following examples, "conventional work-up" means that water is added if necessary, the mixture is extracted with ethyl acetate or dichloromethane, the phases are separated, the organic phase is dried over sodium sulfate and evaporated, and the product is purified by chromatography on silica gel and/or by crystallisation.
The glycine transporter inhibition is determined from the synaptosomal take-up of glycine. For this purpose, a synaptosomal fraction (P2 fraction) is prepared from the brain of a rat by the method of Whittaker (The synapto- some. In: Lajtha (ed.), Handbook of Neurochemistry, Vol.2. Plenum, London and New York, 1969, 327-364), giving a synaptosome-enriched suspension of 3 mg of protein/ml. After pre-incubation of the test compounds and synaptosomes in Krebs-Ringer buffer solution (126 mmol/l of sodium chloride, 1.4 mmol/l of magnesium chloride, 4.8 mmol/l of potassium chloride, 15.8 mmol/l of disodium hydrogenphosphate, 11 mmol/l of glucose, 0.9 mmol/l of calcium chloride, pH 7.4, 346 mosmol) for 10 minutes at 37°C, 3H-glycine is added, and the mixture is incubated at 37°C for a further 30 minutes. The concentration of 3H-gIycine is 1.75 nmol/l in a total assay volume of 575 microlitres. The non-specific take-up of glycine is determined in sodium-free Krebs-Ringer buffer solution (252 mmol/l of sucrose, 15.8 mmol/l of tris, 11 mmol/l of glucose, 1.4 mmol/l of magnesium chloride, 4.8 mmol/l of potassium chloride, 0.9 mmol/l of calcium chloride, pH 7.4, 346 mosmol).
Example 1
Figure imgf000026_0001
2
A solution of 6.218 g of 1 and 1.360 g of tetrakis(triphenylphosphine)- palladium(O) in 200 ml of ethylene glycol dimethyl ether is warmed slightly and, after addition of 5.26 g of 2 and 13.107 g of caesium fluoride, is refluxed for 6 hours. Conventional work-up of the reaction mixture gives 3.
Example 2
Figure imgf000026_0002
3.02 g of 3 are hydrogenated at atmospheric pressure in the presence of
1.50 g of Raney nickel in 160 ml of methanol. Conventional work-up gives 4.
Example 3
Figure imgf000026_0003
Cl
4
2.34 g of 4 are added to 23.3 ml of water, and 43.1 ml of 32% aqueous hydrochloric acid are added dropwise over the course of 15 minutes with stirring at from -5°C to 0°C. A solution of 0.949 g of sodium nitrite in 11.4 ml of water is subsequently added dropwise over the course of 20 minutes, and the mixture is stirred for a further 30 minutes. The resultant mixture is added dropwise at from -5°C to 0°C over the course of 20 minutes to a solution of 15.58 g of tin(ll) chloride dihydrate and 35.3 ml of concentrated hydrochloric acid. The solvent is removed, and the residue is subjected to conventional work-up, giving 5.
Example 4
Figure imgf000027_0001
8
A solution of 41.00 ml of 6 and 61.97 ml of 7 in 820 ml of tetrahydrofuran is stirred for 80 hours and subsequently distilled, giving 8 (b.p.161°C at 0.4 mbar).
Example 5
Figure imgf000027_0002
8
3.95 g of 8, 3.30 g of 4 and 170 ml of ethanol are combined and refluxed for 5 hours. Conventional work-up of the reaction mixture gives 9. Example 6
Figure imgf000028_0001
10
A solution of 2.090 g of 9 in 25 ml of THF is added dropwise with stirring and ice cooling under a nitrogen atmosphere to a suspension of 1.139 g of lithium aluminium hydride in 25 ml of tetrahydrofuran. After the mixture has been stirred for 1 hour, a further 0.500 g of lithium aluminium hydride is added. After the mixture has been stirred for a further 2 hours, saturated sodium chloride solution is added dropwise with ice cooling, and the mixture is subjected to conventional work-up, giving 10.
Example 7
Figure imgf000028_0002
10 11
1.480 g of 10, 2.897 g of manganese(lV) oxide, 9.00 ml of tetrahydrofuran and 3.0 ml of dichloromethane are combined and stirred for 3 days. After filtration, the solvent is removed, and the residue is subjected to conventional work-up, giving 11. Example 8
Figure imgf000029_0001
0.017 ml of acetic acid is added to a solution of 0.103 g of 11 and 0.040 ml of 12 in 2.00 ml of dichloroethane and 1.00 ml of tetrahydrofuran, and the mixture is stirred for 3 hours. After 0.120 g of sodium triacetoxyborohydride has been added, the mixture is stirred overnight, saturated sodium hydrogencarbonate is subsequently added, and the mixture is subjected to conventional work-up, giving 13.
Example 9
Figure imgf000029_0002
14 15 16
1.00 ml of a 2M sodium carbonate solution is added dropwise to a solution of 91.30 mg of 14, 46.00 mg of 15 and 6.500 mg of bisdichloropalladium(ll) in 3.00 ml of dimethoxyethane. The mixture is refluxed overnight. After the batch has been cooled, 5 ml of water are added, and the mixture is subjected to conventional work-up, giving 16. Example 10
Figure imgf000030_0001
17 18 19
A solution of 0.258 g of potassium tert-butoxide in 5 ml of THF is added dropwise at a maximum of 7°C to a solution of 0.685 g of 17 and 0.789 g of 18 in 10 ml of THF with stirring and ice cooling. The reaction mixture is stirred for 2 days and subsequently subjected to conventional work-up, giving 19.
Example 11
Figure imgf000030_0002
20 21
A mixture of 50.00 mg of 20, 3.00 ml of 16% aqueous sulfuric acid and 3.00 ml of toluene is refluxed for 2 hours. The mixture is subsequently stirred at room temperature for 3 days. Conventional work-up gives 21. Example 12
Figure imgf000031_0001
21 12 22
0.010 ml of acetic acid is added to a solution of 61.000 mg of 21 and 22.35 mg of morpholine in 3.000 ml of dichloroethane and 1.5 ml of tetrahydrofuran. The mixture is stirred for 3 hours, and 68.668 mg of sodium triacetoxyborohydride are subsequently added. After the mixture has been stirred for 2 days, it is subjected to conventional work-up, giving the free base of 22. After reaction of the base with one equivalent of a 0.1 M HCl/2-propanol solution, the hydrochloride 22 precipitates out after addition of methyl tert-butyl ether, enabling it to be isolated by filtration.
Figure imgf000032_0001
17 23 24
0.033 ml of acetic acid is added to a solution of 200.00 mg of 17 and 74.66 mg of o-methylhydroxylamine hydrochloride 23 in 8.50 ml of dichloroethane and 4.5 ml of tetrahydrofuran, and the mixture is stirred for 3 hours. 130.287 mg of sodium triacetoxyborohydride are subsequently added. After the mixture has been stirred for 5 hours, it is subjected to conventional work-up, giving 24.
Example 14
Figure imgf000032_0002
17 25 26 27
0.026 ml of acetic acid is added to 0.160 g of 17 and 0.087 ml of 25 in a mixture of 3.00 ml of dichloroethane and 1.50 ml of tetrahydrofuran, and the mixture is stirred for 3 hours. After addition of 0.188 g of 26, stirring is continued overnight, and the mixture is subjected to conventional work-up, giving 28, the free base of 27- By reaction with 1 equivalent of a 0.1 M solution of HCI in 2-propanol, the hydrochloride 27 can be obtained.
Example 15
Figure imgf000033_0001
28 29
80.00 mg of 28 are hydrogenated at atmospheric pressure in the presence of 0.70 g of Raney nickel in 10 ml of ethanol. Conventional work-up and addition of hydrochloric acid gives 29.
Example 16
Figure imgf000033_0002
1.20 g of 6, 2.70 g of 30, 6.0 ml of hydrochloric acid and 40.0 ml of dimethylacetamide are combined and stirred overnight. After 40 ml of water have been added, the mixture is stirred for a further 4 hours and subjected to conventional work-up, giving 31. Example 17
Figure imgf000034_0001
31 32
4.00 ml of an aqueous 2M sodium carbonate solution and 150.00 mg of tetrakis(triphenylphosphine)palladium(0) are added to a solution of 1.00 g of 31 and 630.0 mg of 2 in 15.0 ml of ethylene glycol dimethyl ether. The mixture is refluxed for 3 hours. After cooling, the mixture is subjected to conventional work-up, giving 32.
Example 18
Figure imgf000034_0002
32 33
A solution of 3.6 g of 32 in 30 ml of tetrahydrofuran is added dropwise in a nitrogen atmosphere to a suspension of 450.00 mg of lithium aluminium hydride in 20 ml of tetrahydrofuran. The mixture is stirred for 2 hours. 50 ml of a mixture of water and tetrahydrofuran (1:1 v/v) are slowly added drop- wise with ice cooling, the resultant precipitate is filtered off with suction, and the filtrate is subjected to conventional work-up, giving 33. xample 19
Figure imgf000035_0001
33 34
1.600 g of 33, 4.00 g of manganese(lV) oxide and 50.00 ml of dichloro- methane are combined and stirred at room temperature for 4 hours. After a further 2 g of manganese(IV) oxide have been added, the mixture is stirred for 2 days and subsequently subjected to conventional work-up, giving 34.
Example 20
Figure imgf000035_0002
34 35 36
0.10 ml of acetic acid is added to a solution of 430.00 mg of 34 and 0.210 ml of 35 in 10.0 ml of dichloroethane and 5.0 ml of tetrahydrofuran. The reaction mixture is stirred for 3 hours. 0.50 g of sodium triacetoboro- hydride is subsequently added, and the mixture is stirred for 2 hours and then subjected to conventional work-up, giving the free base of 36, from which 36 is obtained in crystalline form by addition of ethereal HCI (m.p.: 277°C). The following compounds according to the invention are obtained analogously using the corresponding precursors:
Examples 21 - 240:
IC50 [mol/l]
(21 ) Ethyl 1 -biphenyl-4-yl-5-(2-fluorophenyl)-1 H-pyrazole- 4-carbonate
(22) [1 -Biphenyl-4-yl-5-(2-fluorophenyl)-1 H-pyrazol-4-yl]- methanol
(23) 1-Biphenyl-4-yl-5-(2-fluorophenyl)-1 H-pyrazol-4-yl- methyl acetate (24) 1-[1-Biphenyl-4-yl-5-(2-fluorophenyl)-1H-pyrazol-4-yl- 4.10E-7 methyl]piperidine
(25) 1-Benzyl-4-[1-biphenyl-4-yl-5-(2-fluorophenyl)-1H- 4.40E-7 pyrazol-4-ylmethyl]piperazine
(26) 4-{1 -[1 -Biphenyl-4-yl-5-(2-fluorophenyl)-1 H-pyrazol-4- 1.80E-6 ylmethyl]piperidin-4-yl}morpholine
(27) [1 -Biphenyl-4-yl-5-(2-f luorophenyl)-1 H-pyrazol-4-yl- 1.10E-6 methyl]-(3-methoxypropyl)amine
(28) 2-[1-Biphenyl-4-yl-5-(2-fluorophenyl)-1H-pyrazol-4-yl- 1.50E-6 methyl]-1, 3,4,6,7, 11b-hexahydro-2H- pyrazino[2,1-a]isoquinoline
(29) 4-[1-Biphenyl-4-yl-5-(2-fluorophenyl)-1 H-pyrazol-4-yl- 3.20E-7 methyl]morpholine
(30) [1 -Biphenyl-4-yl-5-(2-fluorophenyl)-1 H-pyrazoi-4-yl- methylene]-(4-methylpiperazin-1-yl)amine
(31 ) 1-[1-Biphenyl-4-yl-5-(2-fluorophenyl)-1 H-pyrazol-4-yl- 2.1 OE-7 methyl]-4-methylpiperazine
(32) {[1 -Biphenyl-4-yl-5-(2-fluorophenyl)-1 H-pyrazol-4-yl- methyl]amino}acetic acid
(33) tert-Butyl {[1 -biphenyl-4-yl-5-(2-fluorophenyl)-1 H- pyrazol-4-ylmethyl]amino}acetate
(34) 1-Biphenyl-4-yl-4-(2,5-dihydropyrrol-1-ylmethyl)-5-(2- 2.50E-7 fluorophenyl)-1 H-pyrazole
(36 1 -[1 -Biphenyl-4-yl-5-(2-f luorophenyl)-1 H-pyrazol-4-yl- 9.30E-7 methyl]azepan
(36 Benzyl-[1-biphenyl-4-yl-5-(2-fluorophenyl)-1H-pyrazol- 6.00E-7
4-ylmethyl]ethylamine
(37 [1 -Biphenyl-4-yl-5-(2-fluorophenyl)-1 H-pyrazol-4-yl- 3.30E-7 methyϊjdiethylamine
(38 [1 -Biphenyl-4-yl-5-(2-fluorophenyl)-1 H-pyrazol-4-yl- 1.10E-6 methyljdimethylamine
(39 1-Biphenyl-4-yl-5-(2-fluorophenyl)-4-pyrrolidin-1-yl- 4.70E-7 methyl-1 H-pyrazole
(40 3-[1-Biphenyl-4-yl-5-(2-fluorophenyl)-1 H-pyrazol-4-yl- 1.50E-7 methyljthiazolidine
(41 2-[1-Biphenyl-4-yl-5-(2-fluorophenyl)-1H-pyrazol-4-yl- 5.60E-7 methyl]-1 ,2,3,4-tetrahydroisoquinoline
(42 {1 -[1 -Biphenyl-4-yl-5-(2-fluorophenyl)-1 H-pyrazol-4-yl- 8.20E-7 methyl]piperidin-4-yl}dimethylamine
(43 1 -[1 -Biphenyl-4-yl-5-(2-f luorophenyl)-1 H-pyrazol-4-yl- 2.70E-7 methyl]-1 ,2,3,6-tetrahydropyridine
(44; [1-Biphenyl-4-yl-5-(2-fluorophenyl)-1H-pyrazol-4-yl- 5.90E-7 methyl]methyl-(1-methylpiperidin-4-yl)amine
(45; 4-[1 -Biphenyl-4-yl-5-(2-fluorophenyl)-1 H-pyrazol-4-yl- 3.80E-7 methyl]-2,6-dimethylmorpholine
(46 [1 -BiphenyI-4-yl-5-(2-fluorophenyl)-1 H-pyrazol-4-yl- 4.80E-6 methyl](4-methylpiperazin-1-yl)amine
(47 3-[1 -Biphenyl-4-yl-5-(2-fluorophenyl)-1 H-pyrazol-4-yl]- acrylic acid
(48 1 -[1 -Biphenyl-4-yl-5-(2-fluorqphenyl)-1 H-pyrazoI-4-yl- 3.40E-7 methyl]-4-methylpiperazine
(49; Ethyl 3-[1-biphenyI-4-yl-5-(2-fluorophenyl)-1 H-pyrazol- 5.30E-6
4-yl]acrylate
(50 3-[1 -Biphenyl-4-yl-5-(2-f luorophenyl)-1 H-pyrazol-4-yl]- 6.30E-7 prop-2-en-1-ol
(51 4-{2-[1-Biphenyl-4-yl-5-(2-fluorophenyl)-1H-pyrazoI-4- 5.80E-7 yl]ethyl}morpholine
(52 Ethyl 1 -biphenyl-4-yl-5-(2-fluorophenyl)-1 H-pyrazole- 3-carbonate
(53 [1-Biphenyl-4-yl-5-(2-fluorophenyl)-1H-pyrazol-3-yl]- methanol (54 1-[1-Biphenyl-4-yl-5-(2-fluorophenyl)-1H-pyrazol-3-yl- 1.50E-6 methyl]piperidine (55 4-[1-Biphenyl-4-yl-5-(2-fluorophenyl)-1 H-pyrazol-3-yl- 3.00E-6 methyljmorpholine (56 1-[1-Biphenyl-4-yl-5-(2-fluorophenyl)-1 H-pyrazol-3-yl- 7.70E-7 methyl]-4-methylpiperazine (57. 4-{3-[1-Biphenyl-4-yl-5-(2-fluorophenyl)-1 H-pyrazol-4- 1.60E-6 yl]allyl}morpholine (58 4-{3-[1 -Biphenyl-4-yl-5-(2-f luorophenyl)-1 H-pyrazol-4- 4.40E-7 yl]propyl}morpholine (59; 1 -Biphenyl-4-yl-5-(2-fluorophenyl)-4-(2-methoxy- 8.60E-7 methylpyrrolidin-1 -ylmethyl)-1 H-pyrazole (60 tert-Butyl 1 -[1 -biphenyl-4-yl-5-(2-fluorophenyl)-1 H- pyrazol-4-ylmethyl]pyrrolidine-2-carbonate (61 tert-Butyl 2-{[1-biphenyl-4-yl-5-(2-fluorophenyl)-1 H- pyrazol-4-ylmethyl]amino}propionate (62 1 -[1 -Biρhenyl-4-yl-5-(2-fluorophenyl)-1 H-pyrazol-4-yl- 9.20E-7 methyl]-3-(3-methoxyphenyl)piperidine (63 1 -[1 -Biphenyl-4-yl-5-(2-fluorophenyl)-1 H-pyrazol-4-yl- methyl]-3-cyclohexylmethylpiperidine (64 1 -[1 -Biphenyl-4-yl-5-(2-fluorophenyl)-1 H-pyrazol-4-yl- 4.00E-7 methyl]-4-methylpiperidine (65 8-[1 -Biphenyl-4-yI-5-(2-fluorophenyl)-1 H-pyrazol-4-yl- 8.20E-7 methyl]-1,4-dioxa-8-azaspiro[4.5]decane (66 tert-Butyl 2-{[1 -biphenyl-4-yl-5-(2-fluorophenyl)-1 H- pyrazol-4-ylmethyl]amino}-3-methylbutyrate (67 N-{1 -[1 -Biphenyl-4-yl-5-(2-fluorophenyl)-1 H-pyrazol-4- 5.80E-7 ylmethyl]pyrrolidin-3-yl}acetamide (68 1-[1-Biphenyl-4-yl-5-(2-fluorophenyl)-1 H-pyrazol-4-yI- 9.40E-7 methyl]-2-methylpiperidine (69 {1-[1-Biphenyl-4-yl-5-(2-fluorophenyl)-1H-pyrazol-4-yl- 3.00E-7 methyl]piperidin-2-ylmethyl}diethylamine (70 Ethyl 5-(2-fluorophenyl)-1-(4-nitrophenyl)-1 H-pyrazole- 4-carbonate
(71 Ethyl 1-(4-cyanophenyl)-5-(2-fluorophenyl)-1 H- pyrazole-4-carbonate
(72; Ethyl 5-(2-fluorophenyl)-1-[4-(1 H-tetrazol-5-yl)phenyl]-
1 H-pyrazole-4-carbonate
(73. 1-[1-Biphenyl-4-yl-5-(2-fluorophenyl)-1 H-pyrazol-4-yl- 4.30E-7 methyl]piperidin-4-one
(74 tert-Butyl {[1-biphenyl-4-yl-5-(2-fluorophenyl)-1 H- pyrazol-4-ylmethyl]methylamino}acetate
(75 1 -[1 -Biphenyl-4-yl-5-(2-fluorophenyl)-1 H-pyrazol-4-yl]- 7.60E-7
1 -(4-methylpiperazin-1 -yl)methanone
(76 1-[1-Biphenyl-4-yl-5-(2-fluorophenyl)-1H-pyrazol-4-yl- 7.60E-7 methyl]pyrrolidin-3-ol
(77 Ethyl 5-(2-fiuorophenyl)-1 -[4-(N-hydroxycarbam- imidoyl)phenyl]-1 H-pyrazole-4-carbonate
(78 tert-Butyl 4-[1-biphenyl-4-yl-5-(2-fluorophenyl)-1H- 5.30E-6 pyrazol-4-ylmethyl]piperazine-1-carbonate
(79 1 -[1 -Biphenyl-4-yl-5-(2-fluorophenyl)-1 H-pyrazol-4-yl- 9.20E-7 methyljpiperazine
(80 Ethyl 5-(2-fluorophenyl)-1-[4-(5-methyl-[1 ,2,4]oxa- diazol-3-yl)phenyl]-1H-pyrazole-4-carbonate
(81 1 -Biphenyl-4-yl-5-(2-fluorophenyl)-1 H-pyrazol-4-carb- aldehyde O-methyl oxime
(82; 1-Biphenyl-4-yl-5-(2-fluorophenyl)-1 H-pyrazol-4-carb- 2.80E-7 aldehyde O-allyl oxime
(83 4-[1 -(4'-Fluorobiphenyl-4-yl)-5-(2-fluorophenyl)-1 H- 7.00E-7 pyrazol-4-ylmethyl]morpholine
(84 4-[5-(2-Fluorophenyl)-1 -(3\4\5'-trimethoxybiphenyl-4- 8.70E-6 yl)-1 H-pyrazol-4-ylmethyl]morpholine
(85 4-[5-(2-Fluorophenyl)-1 -(4'-trifiuoromethylbiphenyl-4- 6.30E-7 yl)-1H-pyrazol-4-ylmethyl]morpholine
(86; 4'-[5-(2-Fluorophenyl)-4-morpholin-4-ylmethylpyrazol- 2.20E-6
1 -yl]biphenyl-2-carbonitrile
(87 4-[1 -(2'-Chlorobiphenyl-4-yl)-5-(2-fluorophenyl)-1 H- 8.40E-7 pyrazol-4-ylmethyl]morpholine
(88 4-[1 -(3',5'-Dichlorobiphenyl-4-yl)-5-(2-fluorophenyl)- 5.70E-6 1H-pyrazol-4-ylmethyl]morpholine
(89) 4-[5-(2-Fluorophenyl)-1-(4'-methoxybiphenyl-4-yl)-1 H- 1.90E-6 pyrazol-4-ylmethyl]morpholine
(90) 4-[1-(3',4'-Difluorobiphenyl-4-yl)-5-(2-fluorophenyl)-1 H- 1.10E-6 pyrazol-4-yimethyl]morpholine
(91 ) 4-[5-(2-Fluorophenyl)-1 -(4'-methylbiphenyl-4-yl)-1 H- 1.60E-6 pyrazol-4-ylmethyl]morpholine
(92) 4-[5-(2-Fluorophenyl)-1-(3'-methoxybiphenyl-4-yl)-1 H- 8.40E-6 pyrazol-4-ylmethyl]morpholine (93) 4-[1-(3'-Chlorobiphenyl-4-yl)-5-(2-fluorophenyl)-1H- 5.40E-7 pyrazol-4-ylmethyl]morpholine
(94) 4-[5-(2-Fluorophenyl)-1 -(2 -trif luoromethylbiphenyl-4- 4.40E-6 yl)-1H-pyrazol-4-ylmethyl]morpholine
(95) 4-[5-(2-Fluorophenyl)-1-(2'-methoxybiphenyl-4-yl)-1 H- 2.50E-6 pyrazol-4-ylmethyl]morpholine
(96) 4-[1 -(3'-Ethoxybiphenyl-4-yl)-5-(2-fluorophenyl)-1 H- 2.10E-6 pyrazol-4-ylmethyl]morpholine
(97) 4-[1-(2,-Fluorobiphenyl-4-yl)-5-(2-fluorophenyl)-1 H- 8.90E-7 pyrazol-4-ylmethyl]morpholine (98) 4-[1-[4-(2,3-Dihydrobenzo[1 ,4]dioxin-6-yl)phenyl]-5-(2- 1.50E-7 fluorophenyl)-1 H-pyrazol-4-ylmethyl]morpholine
(99) 4-[5-(2-Fluorophenyl)-1-(4-thiophen-3-ylphenyl)-1H- 1.10E-6 pyrazol-4-ylmethyl]morpholine
(100) 4-[1 -(4-Butylphenyl)-5-(2-fluorophenyl)-1 H-pyrazol-4- 1.30E-6 ylmethyl]morpholine
(101) 4'-[5-(2-Fluorophenyl)-4-morphoIin-4-ylmethylpyrazol- 2.60E-6 1 -yI]biphenyl-4-carbonitrile
(102) 4'-[5-(2-Fluorophenyl)-4-morpholin-4-ylmethylpyrazol- 1.20E-6 1 -yljbiphenyl-3-carbonitrile (103) 4-[1-(3',5'-Difluorobiphenyl-4-yl)-5-(2-fluorophenyl)-1H- 6.80E-6 pyrazol-4-ylmethyl]morpholine
(104) 4-[1-(2',4'-Difluorobiphenyl-4-yl)-5-(2-fluorophenyl)-1 H- 1.10E-6 pyrazol-4-ylmethyl]morpholine
(105) 4-[1 -(2',5'-Difluorobiphenyl-4-yl)-5-(2-fluorophenyl)-1 H- 1.80E-6 pyrazol-4-ylmethyl]morpholine
(106) 4-[5-(2-Fluorophenyl)-1 -(4-thiophen-2-ylphenyl)-1 H- 1.90E-6 pyrazol-4-yImethyl]morpholine
(107) 4-[1 -(4'-Chlorobiphenyl-4-yl)-5-(2-fluorophenyl)-1 H- 7.50E-7 pyrazol-4-ylmethyl]morpholine
(108) 4-[5-(2-Fluorophenyl)-1-(3',4',5,-trifluorobiphenyl-4-yl)- 1.10E-6 1H-pyrazol-4-ylmethyl]morpholine
(109) Ethyl 5-(2-fluorophenyl)-1-(4-trifluoromethylphenyl)- 1 H-pyrazole-4-carbonate
(110) 4-[5-(2-Fluorophenyl)-1-p-tolyl-1 H-pyrazol-4-ylmethyl]- morpholine
(111) {[1 -Biphenyl-4-yl-5-(2-fluorophenyl)-1 H-pyrazol-4-yl- methyl]methylamino}acetic acid
(112) 1 -[1 -Biphenyl-4-yl-5-(2-fluorophenyl)-1 H-pyrazol-4-yl- methyl]pyrrolidine-2-carboxylic acid
(113) 2-{[1-Biphenyl-4-yl-5-(2-fluorophenyl)-1H-pyrazol-4-yl- methyI]amino}-3-methylbutyric acid
(114) 2-{[1 -Biphenyl-4-yl-5-(2-f luorophenyl)-1 H-pyrazol-4-yl- methyl]amino}propionic acid
(115) 1 -[1 -(2'-Fluorobiphenyl-4-yl)-5-(2-fluorophenyl)-1 H- pyrazol-4-ylmethyl]-4-methylpiperazine
(116) 1-[1-(4'-Fluorobiphenyl-4-yl)-5-(2-fluorophenyl)-1 H- pyrazol-4-ylmethyl]-4-methylpiperazine
(117) 1-[1-(2',5'-Difluorobiphenyl-4-yl)-5-(2-fluorophenyl)-1 H- pyrazol-4-ylmethyl]-4-methylpiperazine
(118) 1 -[5-(2-Fluorophenyl)-1 -(4-thiophen-3-ylphenyl)-1 H- pyrazol-4-ylmethyl]-4-methylpiperazine
(119) {[1 -Biphenyl-4-yl-5-(2-fluorophenyl)-1 H-pyrazol-4-yl- methyl]methylamino}morpholin-4-ylethanone
(120) Ethyl 5-(2-fluorophenyl)-1-(4-imidazol-1-ylphenyl)-1H- pyrazole-4-carbonate
(121) [5-(2-Fluorophenyl)-1-(4-imidazol-1-ylphenyl)-1 H- pyrazol-4-yl]methanol
(122) 1-[1-Biphenyl-4-yl-5-(2-fluorophenyl)-1 H-pyrazol-4-yl- methyl]pyrrolidine-2-carboxamide
(123) [5-(2-Fluorophenyl)-1 -(4-trifluoromethylphenyl)-1 H- pyrazol-4-yl]methanol
(124) Ethyl {[1-biphenyl-4-yl-5-(2-fluorophenyl)-1H-pyrazol- 4-ylmethyi]amino}acetate
(125) tert-Butyl (2-{[1-biphenyl-4-yl-5-(2-fluorophenyl)-1H- pyrazol-4-ylmethyl]amino}ethyl)carbamate
(126) tert-Butyl 4-{[1-biphenyl-4-yl-5-(2-fluorophenyl)-1 H- pyrazol-4-ylmethyl]amino}piperidine-1-carbonate
(127) Ethyl 1-[1-biphenyl-4-yl-5-(2-fluorophenyl)-1H-pyrazol- 4-ylmethyl]piperidine-4-carbonate
(128) Ethyl 4-{[1-biphenyl-4-yl-5-(2-fluorophenyl)-1H- pyrazol-4-ylmethyl]amino}piperidine-1-carbonate
(129) 4-[5-(2-Fluorophenyl)-1-(4-imidazol-1-ylphenyl)-1 H- pyrazol-4-ylmethyl]morpholine
(130) 1 -[5-(2-Fluorophenyl)-1 -(4-imidazol-1 -ylphenyl)-1 H- pyrazol-4-ylmethyl]-4-methylpiperazine
(131) Ethyl {[5-(2-fluorophenyl)-1-(4-imidazol-1-ylphenyl)- 1H-pyrazol-4-ylmethyl]amino}acetate
(132) Ethyl {4-[1-biphenyl-4-yl-5-(2-fluorophenyl)-1H- pyrazol-4-ylmethyl]piperazin-1-yl}acetate
(133) 1-[1-Biphenyl-4-yl-5-(2-fluorophenyl)-1 H-pyrazol-4-yl- methyl]piperidine-4-carboxylic acid
(134) [1-Biphenyl-4-yl-5-(2-fluorophenyl)-1 H-pyrazol-4-yl- methyl]piperidin-4-ylamine
(135) {4-[1 -Biphenyl-4-yl-5-(2-fluorophenyl)-1 H-pyrazol-4-yl- methyl]piperazin-1 -yljacetic acid
(136) N1-[1-Biphenyl-4-yl-5-(2-fluorophenyl)-1H-pyrazol-4- ylmethyl]ethane-1 ,2-diamine
(137) {[1 -Biphenyl-4-yl-5-(2-fluorophenyl)-1 H-pyrazol-4-yl- methyl]amino}acetic acid
(138) 2-{[1 -Biphenyl-4-yl-5-(2-fluorophenyl)-1 H-pyrazol-4-yl- methyl]amino}ethanol
(139) [1 -Biphenyl-4-yl-5-(2-fluorophenyl)-1 H-pyrazol-4-yl- methyl](2-methoxyethyl)amine
(140) 2-{4-[1-Biphenyl-4-yl-5-(2-fluorophenyl)-1 H-pyrazol-4- ylmethyl]piperazin-1 -yl}ethanol
(141) 1-[1-Biphenyl-4-yl-5-(2-fluorophenyl)-1H-pyrazol-4-yl- methyl]-4-ethylpiperidin-4-oI
(142) 1-[1-Biphenyl-4-yl-5-(2-fluorophenyl)-1 H-pyrazol-4-yl- methyl]-4-t:fιiophen-3-ylpiperidin-4-ol
(143) 1-[1-Biphenyl-4-yl-5-(2-fluorophenyl)-1H-pyrazol-4-yl- methyl]piperidin-4-ol
(144) 5-[1-Biphenyl-4-yl-5-(2-fluorophenyl)-1H-pyrazol-4-yl- methyl]-2~oxa-5-azabicyclo[2.2.1]heptane
(145) 8-[1 -Biphenyl-4-yl-5-(2-fluorophenyl)-1 H-pyrazol-4-yl- methyl]-8-azabicyclo[3.2.1 ]octan-3-ol
(146) tert-Butyl 4-[5-(2-fluorophenyl)-1-(4-trifluoromethyl- phenyl)-1 H-pyrazol-4-ylmethyl]piperazine-1 -carbonate
(147) 1 -[1 -Biphenyl-4-yl-5-(2-fluorophenyl)-1 H-pyrazol-4-yl- methyl]piperidine-4-carboxamide
(148) 1-[5-(2-Fluorophenyl)-1-(4-trifluoromethylphenyl)-1H- pyrazol-4-ylmethyl]piperazine
(149) 1-[5-(2-Fluorophenyl)-1-(4-trifluoromethylphenyl)-1H- pyrazol-4-ylmethyl]-4-methylpiperazine
(150) [1 -Biphenyl-4-yl-5-(2-fluorophenyl)-1 H-pyrazol-4-yl- methyl](1-ethylpyrrolidin-2-ylmethyl)amine
(151) N-[1 -Biphenyl-4-yl-5-(2-f luorophenyl)-1 H-pyrazol-4-yl- methyl]-N,N N'-trimethylethane-1,2-diamine
(152) [1 -Biphenyl-4-yl-5-(2-fluorophenyl)-1 H-pyrazol-4-yl- methyl]pyridin-3-ylmethylamine
(153) tert-Butyl 5-[1-biphenyl-4-yl-5-(2-fluorophenyl)-1H- pyrazol-4-ylmethyl]-2,5-diazabicyclo[2.2.1]heptane-2- carboxylate
(154) 1 -[1 -Biphenyl-4-yI-5-(2-fluorophenyl)-1 H-pyrazol-4-yl- methyl]-4-ethylpiperazine
(155) 1 -{4-[1 -Biphenyl-4-yl-5-(2-fluorophenyl)-1 H-pyrazol-4- ylmethyl]piperazin-1-yl}-2-pyrrolidin-1-ylethanone
(156) 2-{[1 -Biphenyl-4-yl-5-(2-fluorophenyl)-1 H-pyrazol-4-yl- methyl]methylamino}ethanol
(157) 4-[1 -Biphenyl-4-yl-5-(2-fluorophenyl)-1 H-pyrazol-4-yl- methyl]piperazine-1-carbaldehyde
(158) Ethyl {1-[1-biphenyl-4-yl-5-(2-fluorophenyl)-1H- pyrazol-4-ylmethyl]-3-oxopiperazin-2-yl}acetate
(159) 1 -[1 -Biphenyl-4-yl-5-(2-f luorophenyl)-1 H-pyrazol-4-yl- methyl]-4-methyl[1 ,4]diazepan 160) 4-[1-Biphenyl-4-yl-5-(2-fluorophenyl)-1 H-pyrazol-4-yl- methyl]thiomorpholine
161) 8-[1-Biphenyl-4-yl-5-(2-fluorophenyl)-1 H-pyrazol-4-yl- methyl]-1-phenyl-1 ,3,8-triazaspiro[4.5]decan-4-one
162) 1 -[1 -Biphenyl-4-yl-5-(2-fluorophenyl)-1 H-pyrazoi-4-yl- methyl]-3,5-dimethylpiperazine
163) [1 -Biphenyl-4-yl-5-(2-fluorophenyl)-1 H-pyrazol-4-yl- methyl]pyridin-3-yiamine
164) 1 -[1 -Biphenyl-4-yl-5-(2-f luorophenyI)-1 H-pyrazol-4-yl- methyl]imidazolidin-2-one
165) 1-[5-(2-Fluorophenyl)-1-(4-pyrrol-1-ylphenyl)-1 H- pyrazol-4-ylmethyl]-4-methylpiperazine
166) (1-Azabicyclo[2.2.2]oct-3-yl)-[1-biphenyl-4-yl-5-(2- fluorophenyl)-1H-pyrazol-4-ylmethyl]amine
167) 4-[1 -Biphenyl-4-yl-5-(2-f luorophenyl)-1 H-pyrazol-4-yl- methyl]thiomorphoIine 1 , 1 -dioxide
168) 2-[1 -Biphenyl-4-yl-5-(2-fluorophenyl)-1 H-pyrazol-4-yl- methy!]-5-methyl-2,5-diazabicyclo[2.2.1]heptane
169) 4-[1 -Biphenyl-4-yl-5-(2-fluorophenyl)-1 H-pyrazol-4-yl- methyljthiomorpholine 1 -oxide
170) Ethyl 4-{[1 -biphenyl-4-yl-5-(2-fluorophenyl)-1 H- pyrazol-4-ylmethyl]methylamino}piperidine-1- carboxylate
171) Dimethyl 2-{[1-biphenyl-4-yl-5-(2-fluorophenyl)-1 H- pyrazol-4-ylmethyl]amino}succinate
172) 2-{4-[1 -Biphenyl-4-yl-5-(2-fluorophenyl)-1 H-pyrazol-4- ylmethyl]piperazin-1-yl}acetamide
173) 4-[1 -(2',6'-Difluorobiphenyl-4-yl)-5-(2-fluorophenyl)-1 H- pyrazol-4-ylmethyl]morpholine
174) 2-{[1 -Biphenyl-4-yl-5-(2-fluorophenyl)-1 H-pyrazol-4-yl- methyl]amino}malonamide
175) Ethyl [1-biphenyl-4-yl-5-(2-fluorophenyl)-1 H-pyrazol-4- ylmethyljcarbamoylmethylcarbamate
176) Methyl 3-{[1-biphenyl-4-yl-5-(2-fluorophenyl)-1H- pyrazol-4-ylmethyl]amino}propionate
177) 4-[1 -Biphenyl-4-yl-5-(2-f luorophenyl)-1 H-pyrazol-4-yl- methyl]morpholine-3,5-dione
(178 1 -[1 -Biphenyl-4-yl-5-(2-fluorophenyl)-1 H-pyrazol-4-yl- methyl]piperidin-4-one O-methyl oxime
(179 1-[5-(2-Fluorophenyl)-1-(4-isopropylphenyl)-1H- pyrazol-4-ylmethyl]-4-methylpiperazine
(180 4-[5-(2-Fluorophenyl)-1 -(4-isopropylphenyl)-1 H- pyrazol-4-ylmethyl]morpholine
(181 Ethyl {[5-(2-fluorophenyl)-1-(4-isopropylphenyl)-1 H- pyrazol-4-ylmethyl]amino}acetate
(182 1-[5-(2-Fluorophenyl)-1-(4-trifluoromethoxyphenyl)-1H- pyrazol-4-ylmethyl]-4-methylpiperazine
(183 4-[5-(2-Fluorophenyl)-1-(4-trifluoromethoxyphenyl)-1H- pyrazol-4-ylmethyl]morpholine
(184; Ethyl {[5-(2-fluorophenyl)-1 -(4-trifluoromethoxyphenyl)-
1 H-pyrazol-4-ylmethyl]amino}acetate
(185 Ethyl 5-(2-fluorophenyl)-1-(6-phenylpyridin-3-yi)-1H- 2.50E-6 pyrazole-4-carboxylate
(186 [5-(2-Fluorophenyl)-1 -(6-phenylpyridin-3-yl)-1 H- 2.30E-6 pyrazol-4-yl]methanol
(187 4-[5-(2-Fluorophenyl)-1 -(6-phenylpyridin-3-yi)-1 H- 1.20E-6 pyrazol-4-ylmethyl]morpholine
(188 tert-Butyl {[5-(2-fluorophenyl)-1 -(6-phenylpyridin-3-yl)-
1 H-pyrazol-4-ylmethyl]amino}acetate
(189 {[5-(2-Fluorophenyl)-1 -(6-phenylpyridin-3-yl)-1 H- pyrazol-4-ylmethyl]amino}acetic acid
(190 1 -[5-(2-Fluorophenyl)-1 -(6-phenylpyridin-3-yl)-1 H- pyrazol-4-ylmethyl]piperazine
(191 1 -[5-(2-Fluorophenyl)- 1 -(6-phenylpyridin-3-yl)- 1 H- pyrazol-4-ylmethyl]-4-methylpiperazine
(192 tert-Butyl 4-[5-(2-fluorophenyl)-1-(6-phenylpyridin-3- yl)-1 H-pyrazol-4-ylmethyl]piperazine-1 -carboxylate
(193 Ethyl 1-[5-(2-fluorophenyl)-1-(6-phenylpyridin-3-yl)-1 H- pyrazol-4-ylmethyl]piperidine-4-carboxylate
(194 2-{4-[5-(2-Fluorophenyl)-1 -(6-phenylpyrid in-3-yl)- 1 H- pyrazol-4-ylmethyl]piperazin-1-yl}nicotinonitrile
(195 tert-Butyl (2-{[5-(2-fluorophenyl)-1 -(6-phenylpyridin-3- yl)-1 H-pyrazol-4-ylmethyl]amino}ethyl)carbamate (196) tert-Butyl 4-{[5-(2-fluorophenyl)-1-(6-phenylpyridin-3- yl)-1 H-pyrazol-4-ylmethyl]amino}piperidine-1 -carboxylate (197) Methyl 5-{[5-(2-fluorophenyl)-1-(6-phenylpyridin-3-yl)-
1H-pyrazol-4-ylmethyl]amino}furan-2-carboxyIate
(198) Ethyl 4-{[5-(2-fluorophenyl)-1-(6-phenylpyridin-3-yl)- 1H-pyrazol-4-ylmethyl]amino}piperidine-1-carboxylate
(199) N 1 -[5-(2-Fluorophenyl)-1 -(6-phenylpyridin-3-yi)-1 H- pyrazol-4-ylmethyl]ethane-1 ,2-diamine
(200) [5-(2-Fluorophenyl)-1-(6-phenylpyridin-3-yl)-1 H- pyrazol-4-ylmethyl]piperidin-4-ylamine
(201 ) 1 -[5-(2-Fluorophenyl)-1 -(6-phenylpyridin-3-yl)-1 H- pyrazol-4-ylmethyl]piperidine-4-carboxylic acid (202) 4-Ethyl-1-[5-(2-fluorophenyl)-1-(6-phenylpyridin-3-yl)-
1H-pyrazol-4-ylmethyl]piperidin-4-ol
(203) 5-[5-(2-Fluorophenyl)-1-(6-phenylpyridin-3-yl)-1H- pyrazol-4-ylmethyl]-2-oxa-5-azabicyclo[2.2.1 ]heptane
(204) Ethyl {4-[5-(2-fluorophenyl)-1-(6-phenylpyridin-3-yl)- 1 H-pyrazol-4-ylmethyl]piperazin-1 -yljacetate
(205) {4-[5-(2-Fluorophenyl)-1-(6-phenylpyridin-3-yl)-1H- pyrazol-4-ylmethyl]piperazin-1 -yljacetic acid
(206) 5-[5-(2-Fluorophenyl)-4-piperidin-1 -ylmethylpyrazol-1 - yl]-2-phenylpyridine (207) 1-{5-(2-Fluorophenyl)-1-[6-(4-fluorophenyl)pyridin-3- yl]-1 H-pyrazol-4-ylmethyl}-4-methylpiperazine
(208) 4-{5-(2-Fluorophenyl)-1 -[6-(4-fluorophenyl)pyridin-3- yl]-1 H-pyrazol-4-ylmethyl}morpholine
(209) Ethyl ({5-(2-fluorophenyl)-1-[6-(4-fluorophenyl)pyridin- 3-yl]-1 H-pyrazol-4-ylmethyl}amino)acetate
(210) {[1-Biphenyl-4-yl-5-(2-fluorophenyl)-1 H-pyrazol-4-yl- methyl]amino}acetic acid
(211) tert-Butyl {[1 -biphenyl-4-yl-5-(2-fluorophenyl)-1 H- pyrazol-4-ylmethyl]amino}acetate (212) tert-Butyl {[5-(2-fluorophenyl)-1-(6-phenylpyridin-3-yi)-
1 H-pyrazol-4-ylmethyl3amino}acetate (213 {[5-(2-Fluorophenyl)-1 -(6-phenylpyridin-3-yl)-1 H- pyrazol-4-ylmethyl]amino}acetic acid
(214 tert-Butyl [(1-biphenyl-4-yl-5-phenyl-1 H-pyrazol-4-yl- methyl)amino]acetate
(215 tert-Butyl {[biphenyl-4-yl-(bistrifluoromethylphenyl)-1 H- pyrazol-4-ylmethyl]amino}acetate
(216 tert-Butyl 1-[1-biphenyl-4-yl-5-(2-fluorophenyl)-1 H- pyrazol-4-ylmethyl]pyrrolidine-2-carboxylate
(217 tert-Butyl 2-{[1-biphenyl-4-yl-5-(2-fluorophenyl)-1 H- pyrazol-4-ylmethyl]amino}propionate
(218 tert-Butyl 2-{[1-biphenyl-4-yl-5-(2-fluorophenyl)-1 H- pyrazol-4-ylmethyl]amino}-3-methylbutyrate
(219 {[Biphenyl-4-yl-(bistrifluoromethylphenyl)-1H-pyrazoI-4- ylmethyl]amino}acetic acid
(220 [(1 -Biphenyl-4-yl-5-phenyl-1 H-pyrazol-4-ylmethyl)- amino]acetic acid
(221 tert-Butyl {[1-biphenyl-4-yl-5-(2-fluorophenyl)-1 H- pyrazol-4-ylmethyl]methylamino}acetate
(222 {[1 -Biphenyl-4-yl-5-(2-fluorophenyl)-1 H-pyrazoI-4-yl- methyl]methylamino}acetic acid
(223 1 -[1 -Biphenyl-4-yl-5-(2-fluorophenyl)-1 H-pyrazol-4-yl- methyl]pyrrolidine-2-carboxylic acid
(224 2-{[1 -BiphenyI-4-yl-5-(2-fluorophenyl)-1 H-pyrazol-4-yl- methyl]amino}-3-methylbutanoic acid
(225 2-{[1 -Biphenyl-4-yl-5-(2-fluorophenyl)-1 H-pyrazol-4-yl- methyl]amino}propionic acid
(226 {[1 -Biphenyl-4-yl-5-(2-fluorophenyl)-1 H-pyrazol-4-yl- methyl]methylamino}morpholin-4-ylethanone
(227 1-[1-Biphenyl-4-yl-5-(2-fluorophenyl)-1H-pyrazol-4-yl- methyl]pyrrolidine-2-carboxamide
(228 Ethyl {[1 -biphenyl-4-yl-5-(2-fluorophenyl)-1 H-pyrazol-4- ylmethyl]amino}acetate
(229 Ethyl {[5-(2-fluorophenyl)-1-(4-imidazol-1-ylphenyl)-1 H- pyrazol-4-ylmethyl]amino}acetate
(230 {[1 -Biphenyl-4-yl-5-(2-f luorophenyl)-1 H-pyrazol-4-yl- methyl]amino}acetic acid (231) Ethyl {1-[1-biphenyl-4-yl-5-(2-fluoroρhenyl)-1H-pyrazol- 4-ylmethyl]-3-oxopiperazin-2-yl}acetate
(232) Dimethyl 2-{[1 -biphenyl-4-yl-5-(2-fluorophenyl)-1 H- pyrazol-4-ylmethyl]amino}succinate (233) 2-{[1-Biphenyl-4-yl-5-(2-fluorophenyl)-1H-pyrazol-4-yl- methyl]amino}malonamide
(234) Ethyl [1-biphenyl-4-yl-5-(2-fluorophenyl)-1 H-pyrazol-4- ylmethyl]carbamoylmethylcarbamate
(235) Ethyl {[5-(2-fluorophenyl)-1-(4-isopropylphenyl)-1H- pyrazol-4-ylmethyl]amino}acetate
(236) Ethyl {[5-(2-fluorophenyl)-1-(4-trifluoromethoxyphenyl)- 1H-pyrazol-4-ylmethyl]amino}acetate
(237) Ethyl ({5-(2-fluorophenyl)-1-[6-(4-fluorophenyl)pyridin- 3-yl]-1H-pyrazo!-4-ylmethyl}amino)acetate (238) Ethyl [(1-biphenyl-4-yl-5-pyridin-3-yl-1H-pyrazol-4-yl- methyl)amino]acetate
(239) 2-{[1 -Biphenyl-4-yl-5-(2-fluorophenyl)-1 H-pyrazol-4-yl- methyl]amino}acetamide
(240) 4-(1 -Biphenyl-4-yl-5-pyridin-2-yl-1 H-pyrazol-4-yl- methyl)morpholine
Examples 241 - 290:
Figure imgf000048_0001
R1 R2 X
(241) CH
\ ~~ i_ ~
(242) F_ ~ CH
\ ~~
(243) CH
Q~ -I (244) Nc~ ~~ CH _ ~
(245) CH _ ~
Figure imgf000049_0001
(252) CH
F~~ ~~ CF3
(253) CH
Q" CF3
Figure imgf000049_0002
(256) CH
(__ ~
(257) F~ ~ 58) ø~ CH
(2 CH
Q- Q~
(259) CH
NC~0~ Q~
Figure imgf000050_0001
(261) " - Cp3 CH
(262) c /^λ CF3 CH
(263) /"^X CF3 CH
Figure imgf000050_0002
(265) CF3 CH
N -N ^
(266) N
\JT \_ ~
(267) F- -- N _ ~~
(268) N
Q~~ _~~
Figure imgf000050_0003
(272) P_/=aV_ " - N
\
CN
Figure imgf000050_0004
Figure imgf000051_0001
(282) B _ T =\ N
F~ _ ~ W /
(283) /=\_ /=\
N__ - \ \i_ rN-
Figure imgf000051_0002
(286) /=\ CF3 N
(287) F^T ~ CF3 N
(288) =V CF3 N
Figure imgf000051_0003
Examples 291 - 340:
Figure imgf000052_0001
R1 R2 X
(291) CH
^ // XJ
Figure imgf000052_0002
Figure imgf000053_0001
(305) CH
N-
CF3
(306)
\j^~~ G- CH
(307)
F- ~~ CH
Q-~
(308) CH
Q~ Q~~
(309)
NC~ ~~ ø~ CH
Figure imgf000053_0002
(311) CF3 CH _
(312)
F- ~ CF3 CH
(313) CF3 CH
Q~
(314) Nc- ~- CF3 CH
(315) ~ CF3 CH
(316) N
\ ~~ __ ~
(317) N
F" ~ _ "~
(318) N
Q~ Y_ ~~
(319) N
NC- ~~ Y_ ~
(320) N
^N^"" γ_#
Figure imgf000054_0001
(323) N
N—J '
CN
Figure imgf000054_0002
(330) r _ N
^ \
CF3
(331) _ \— N '/ V N M
Figure imgf000054_0003
(335) \ =\ N
N ' ^—
Figure imgf000054_0004
(337) CF3 N
W // (338) CF3 N
N- ' (339) NC- CF3 N //
Figure imgf000055_0001
Examples 341 -390:
Figure imgf000055_0002
R1 R2 X
(341) CH
\_ ~ \j~
(342) F_0~ CH
\j~
(343) CH ~
(344) CH
NC~0~~ ~
(345) CH
N^N ~
Figure imgf000055_0003
Figure imgf000056_0001
(356) /^X ^ - CH
Figure imgf000056_0002
(358) ^V ==\_ CH
Figure imgf000056_0003
(360) rV_ /""X CH
(361) C - CF3 CH
(362) e /=\ CF3 CH F~ _ ~
(363) /^Y CF3 CH
Figure imgf000056_0004
(365) I — CF3 CH
(366) ~ N
Y_ ~~
(367) F~~ ~~ N
V_ ~
Figure imgf000057_0001
(369) NC — v. J) N _ ~~
Figure imgf000057_0002
(374) N
NC~ ~
CN
Figure imgf000057_0003
(376) N _
CF-
Figure imgf000057_0004
(379) N
NC- ~~
CF3
Figure imgf000057_0005
Figure imgf000058_0001
(382) N // x -N (383) N
N ' λ -N (384) NC- N
Λ // -N ft (385) N-N- N
^— N (386) CF3 N
\ // (387) CF3 ~x // N
(388) CF3 N
\ * (389) NC- CF3 N
~Λ // (390) CF3 N
N r_
~N
Examples 391 - 440:
Figure imgf000058_0002
R1 R2
Figure imgf000058_0003
(392) F~ ~ ~ CH
(393) CH
Q~ \JT (394) CH
NC- ~~ _#
Figure imgf000059_0001
(405) CH --N
CFS
Figure imgf000059_0002
(407) p~o~ Q~ CH
(408) CH
Q" Q~
(409) CH
NC~ " Q~ (410)
N-N ~ CH
(411) CF3 CH
V_
(412) CF3
F~ " CH
(413) CFs CH
Q~~
(414)
NC — / CF3 CH
Figure imgf000060_0001
(416) N
\_
(417) F~ ~" N
\_)~~
(418)
9) o- N _ ~
(41 HC-^^ N __"
(420) o~ N
Figure imgf000060_0002
(426) N
Y_ ~~
CF,
Figure imgf000061_0001
(431) N
\_ Q~~
(432)
F~~ ~~ Q~ N
(433) Q~ Q^ N
(434) NC — N
Q~~
(435) rv N
Q^~
(436) CF3 N
\-
(437) CF3 N
Ψ _
(438) CF3 N
Q~
(439) CF3 N
NC~O~
(440) CF3 N
1 /) — Examples 441 - 490:
Figure imgf000062_0001
R1 Rz X
(441) CH > V
Figure imgf000062_0002
(443) CH
\ *
Figure imgf000062_0003
Figure imgf000063_0001
(457) c /^\- Λ— CH F~ // v "
(458) Λ___ S— CH
(459) I^ /^λ /==V_ CH
^— ' ^-
Figure imgf000063_0002
(461) — CFS CH
(462) e _ = __ CF3 CH
Figure imgf000063_0003
(464) «-o-
(465) «rV_ CF3 CH
N-~N
(466) /== _ ==\_ N
(467) c /==\__ ==\_ N F~ __ ~ \ ~~
(468) ^ - ^ - N
(469) NC-4 /""Λ λ— / i"" }X— N (470) It /> N
N-N _ ~~
Figure imgf000064_0001
(478) N
Q~~ CF3
Figure imgf000064_0002
(482) N
F- ~ (483) N
(484) N
NC~ ~" Q~
(485) N u > — N-rf Q~
Figure imgf000065_0001
(487) CF3 N
F~\\ // (488) CF3 N
N ' (489) NC- CF3 N
W // (490) CF3 N
/>
Examples 491 - 540:
Figure imgf000065_0002
R1 R2 X
(491) CH //
Figure imgf000065_0003
Figure imgf000066_0001
(506) ==\_ ^ . CH
Figure imgf000066_0002
(508) /^λ . ^ CH N-^ ^-
(509) κv._ == _ /==V_ CH
(510) tr _ /==\_ CH N~-N ^ (511) /" — CF3 CH
(512) c /==V_ CF3 CH
(513) ^ - CF3 CH
\\ N 7 (514) CF3 CH
Nc~ ~~
(515) II > — CF3 CH
Figure imgf000067_0001
(517) N
F~ ~ {_
(518) Q~ N _ ~~
(519) N
NC~ ~ _ —
(520) N
N~~N \JT
Figure imgf000067_0002
(523) o~ N
CN
Figure imgf000067_0003
Figure imgf000068_0001
(531) N // -N (532) N f~\ // -N (533) N
\ * -N (534)
NC- N A x -N
Figure imgf000068_0002
(536) CF3 N
XJf (537) CF3 N // (538) CF3 N
^ N A ' (539) NC CF3 N
~ (540) -N. CF3 N
Examples 541 - 590:
Figure imgf000068_0003
R1 R2 X
(541) CH (542)
F~^0~ CH _ ~
(543) CH
Q~~ \_J
(544) CH
NC~^Q~ γ_ ~
(545) I? )) — CH _#
Figure imgf000069_0001
(551) CH
Y_ ~
CF3
Figure imgf000069_0002
(557) CH
F" ~ Q~~ (558) CH
N-^ \JΓ
(559) CH
Nc- ~ Q~
Figure imgf000070_0001
(561) CF3 CH
\JT
(562) CF3 CH
F~ "
(563) CF3 CH
Q~
(564) CF3 CH
NC~ ~
(565) CF3 CH -N
Figure imgf000070_0002
Figure imgf000071_0001
(577) F~ " N
CF3
Figure imgf000071_0002
(581) N _ ~~ Q~
(582) N
F _ Q~
Figure imgf000071_0003
(584) NC — (\ } Q~ N
Figure imgf000071_0004
(586) CF3 N
\_ ~~
(587) F~ ~ CF3 N
(588) o~ CF3 N
Figure imgf000071_0005
(590) ϊi > — CF3 N N-N^ -71-
Examples 591 - 640:
Figure imgf000072_0001
R R2 X
(591) CH
\J
Figure imgf000072_0002
Figure imgf000073_0001
(606) — ΓX~- CH
N
Figure imgf000073_0002
(611) ~- CFS CH
(612) ._/= __ CF3 CH
(613) /^ ... CF3 CH
(614) κ N,„C- /=\ CF3 CH A
Figure imgf000073_0003
(616) /^X . ^X
W ~ _# (617) c /==\_ /^X
Figure imgf000073_0004
(620) r N
-N //
Figure imgf000074_0001
(633) ""V " — N — ' — N
(634) ^X /^W. N
(635) r _ ==\_ N κ- W (636) CF3 N ~
(637) CF3 N
F~ ~~
(638) o~ CF3 N
(639) CF3 N
NC~ ~
Figure imgf000075_0001
Examples 641 -690:
Figure imgf000075_0002
R1 R2 X
(641) CH
WT~ (_
(642) CH
F→G^~ _ ~
(643) CH
Q~ J~~
(644) CH
NC~ ~ \JT
Figure imgf000075_0003
Figure imgf000076_0001
(657)
F~ ~ CH
Q~~
(658) CH
Q~ Q~
(659)
NC~ ~ CH
Q™
(660) rV CH
Q~
Figure imgf000076_0002
(662)
F~ ~ CF3 CH
(663) CF3 CH
Q~ (664) CF3 CH
NC~ ~~
Figure imgf000077_0001
(666) N
WT~ WT
(667) F~ ~ N
V/~~
(668) N
Q~ _ ~
(669) N
NC- ~ _y
(670) N
JC — _ ~
Figure imgf000077_0002
(674) N n°-ζ -
CN
Figure imgf000077_0003
(677) N
?-~0~
CF3
Figure imgf000077_0004
Figure imgf000078_0001
(681)
(_)~~ ' o~ N
(682) F~0~ Q~ N
(683) 0~ Q~ N
(684)
NC~ ~ Q~ N
(685)
II / — Q~ N
(686) CF3 N _
(687) CF3 N
F γ_)~~
(688)
Q~ CF3 N
Figure imgf000078_0002
(690) NΛ_ CF3 N
Examples 691 - 740:
Figure imgf000078_0003
R1 Rz
(691) CH
Figure imgf000079_0001
(693) - CH
\_ ~~
Figure imgf000079_0002
(700) CH
N-N^^
CN
Figure imgf000079_0003
(706) CH
(_)~ Q~
(707) ~o- CH
Q~ (708) o~ CH
Q~
(709) CH
NC~ ~ Q~
(710) N-N\ _
N-N ^_N\— CH
Figure imgf000080_0001
(712) C_T=\ _ CF3 CH F~ _ ~
(713) /=\_ CF3 CH
N— J
(714) ' ^ NC_ —T ^ _ CF3 CH
(715) jr\ CF3 CH
Figure imgf000080_0002
(717) N w // W //
(718) N
\\ // w //
Figure imgf000080_0003
Figure imgf000081_0001
(731) N
\j~~ Q"
(732) F~ ~ 0~ N
(733)
Q~~ Q~ N
(734) NC_^ __ N
Q~~
(735) N l- ~ Q-~
(736) CF3 N
WT"
(737) F~ ~ CF3 N
(738) CF3 N
Q~
(739) CF3 N
NC~ ~~
(740) π Λ> — CF3 N N-N^ The examples below relate to pharmaceutical preparations:
Example A: Injection vials
A solution of 100 g of an active ingredient of the formula I and 5 g of disodium hydrogenphosphate in 3 I of bidistilled water is adjusted to pH 6.5 using 2N hydrochloric acid, sterile filtered, transferred into injection vials, lyophilised under sterile conditions and sealed under sterile conditions. Each injection vial contains 5 mg of active ingredient.
Example B: Suppositories
A mixture of 20 g of an active ingredient of the formula I is melted with 100 g of soya lecithin and 1400 g of cocoa butter, poured into moulds and allowed to cool. Each suppository contains 20 mg of active ingredient.
Example C: Solution
A solution is prepared from 1 g of an active ingredient of the formula I, 9.38 g of NaH2P04 ■ 2 H20, 28.48 g of Na2HP04 ■ 12 H20 and 0.1 g of benzalkonium chloride in 940 ml of bidistilled water. The pH is adjusted to 6.8, and the solution is made up to 1 I and sterilised by irradiation. This solution can be used in the form of eye drops.
Example D: Ointment
500 mg of an active ingredient of the formula l are mixed with 99.5 g of Vaseline under aseptic conditions.
Example E: Tablets
A mixture of 1 kg of active ingredient of the formula I, 4 kg of lactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate is pressed in a conventional manner to give tablets in such a way that each tablet contains 10 mg of active ingredient. Example F: Coated tablets
Tablets are pressed analogously to Example E and subsequently coated in a conventional manner with a coating of sucrose, potato starch, talc, traga- canth and dye.
Example G: Capsules
2 kg of active ingredient of the formula I are introduced in a conventional manner into hard gelatine capsules in such a way that each capsule contains 20 mg of the active ingredient.
Example H: Ampoules
A solution of 1 kg of active ingredient of the formula I in 60 I of bidistilled water is sterile filtered, transferred into ampoules, lyophilised under sterile conditions and sealed under sterile conditions. Each ampoule contains 10 mg of active ingredient.
Example I: Inhalation spray
14 g of active ingredient of the formula I are dissolved in 10 I of isotonic NaCI solution, and the solution is transferred into commercially available spray containers with pump mechanism. The solution can be sprayed into the mouth or nose. One spray shot (about 0.1 ml) corresponds to a dose of about 0.14 mg.

Claims

Patent Claims
1. Compounds of the formula I
Figure imgf000084_0001
in which
X is CH or N,
R1 is H, A, Hal, (CH2)nHet, (CH2)nAr, cycloalkyl having from 3 to 7 carbon atoms, CF3, N0 , CN, C(NH)NOH or OCF3)
R2 is (CH2)nHet, (CH2)nAr, cycloalkyl having from 3 to 7 carbon atoms or CF3,
R3 and R4 are H, (CH2)nC02R5, (CH2)πCOHet, (CH2)nCOO(CH2)nHet, CHO, (CH2)nOR5, (CH2)nHet, (CH2)nN(R5)2, CH=N-OA, CH2CH=N-OA, (CH2)nNHOA, (CH2)nN(R5)Het, (CH2)nCH=N-Het, (CH2)nOCOR5, (CH2)nN(R5)CH2CH2θR5, (CH2)nN(R5)CH2CH2OCF3, (CH2)nN(R5)C(R5)HCOOR5, (CH2)nN(R5)CH2COHet, (CH2)nN(R5)CH2Het, (CH2)nN(R5)CH2CH2Het, (CH2)πN(R5)CH2CH2N(R5)CH2COOR5, (CH2)nN(R5)CH2CH2N(R5)2l CH=CHCOOR5, CH=CHCH2NR5Het, CH=CHCH2N(R5)2, CH=CHCH2OR5, (CH2)nN(R5)Ar, (CH2)nN(COOR5)COOR5, (CH2)nN(CONH2)COOR5 > (CH2)nN(CONH2)CONH2, (CH2)nN(CH2COOR5)COOR5, (CH2)nN(CH2CONH2)COOR5, (CH2)nN(CH2CONH2)CONH2, (CH2)nCHR5COR5, (CH2)nCHR5COOR5 or (CH2)nCHR5CH2OR5, where in each case one of the radicals R3 or R4 is H, R5 is H or A,
A is straight-chain or branched alkyl having from 1 to 10 carbon atoms, alkenyl having from 2 to 10 carbon atoms or alkoxyalkyl having from 2 to 10 carbon atoms,
Het is a saturated, unsaturated or aromatic monocyclic or bicyclic heterocyclic radical which is unsubstituted or monosubstituted or polysubstituted by A and/or Hal,
Ar is a phenyl radical which is unsubstituted or monosubstituted or [polysubstituted by A and/or Hal, OR5, OOCR5, COOR5, CON(R5)2, CN, N02, NH2, CF3 or S02CH3,
n is 0, 1 , 2, 3, 4 or 5,
and
Hal is F. CI, Br or l,
and salts and solvates thereof,
where compounds of the formula I in which R1 and R4 are H, X is CH2, R2 is phenyl or p-chlorophenyl, and R3 is 1-methyl-4-piperidyl- oxycarbonyl, 2-(4-phenylpiperazino)ethoxycarbonyl, benzoxazol-2-yl, benzothiazol-2-yl, tetrazol-5-yl or unsubstituted or substituted thiazolidin-2-yl, and salts and solvates thereof, are excluded.
2. Compounds of the formula I according to Claim 1 , in which R1 is phenyl, 2-, 3- or 4-cyanophenyl, 2-, 3- or 4-fluorophenyl, 2-, 3- or 4- methyl-, -ethyl-, -n-propyl- or -n-butylphenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4-, 3,5- or 3,6-difluoro-, -dichloro- or -dicyanophenyl, 3,4,5-trifluoro- phenyl, 3,4,5-trimethoxy- or -triethoxyphenyl, thiophen-2-yl or thio- phen-3-yl.
3. Compounds of the formula I according to one or more of the preceding claims, in which R3 is H.
4. Compounds of the formula I according to one or more of the preceding claims, in which R4 is H.
5. Compounds of the formula I according to one or more of the preceding claims, in which R2 is phenyl, 2-, 3- or 4-cyanophenyl, 2-, 3- or 4-fluorophenyl, 2-, 3- or 4-methyl-, -ethyl-, -n-propyl- or -n- butylphenyl, 2,3-, 2,4-, 2,5- or 2,6-difluoro- or -dicyanophenyl, thiophen-2-yl or thiophen-3-yl, 2-, 3- or 4-pyridyl, 2-, 4- or 5-oxazolyl, 2-, 4- or 5-thiazolyl, quinolinyl, isoquinolinyl, 2- or 4-pyridazyl, 2-, 4- or 5-pyrimidyl, or 2- or 3-pyrazinyl.
6. Compounds of the formula I according to one or more of the preceding claims, in which X is CH.
7. Compounds of the formulae (a) to (j) according to Claim 1 :
(a) 1 -biphenyl-4-yl-4-(2,5-dihydropyrrol-1 -ylmethyl)-5-(2- fluorophenyl)-1 H-pyrazole
(b) 1-[1-biphenyl-4-yl-5-(2-fluorophenyl)-1H-pyrazol-4-ylmethyl]- 1 ,2,3,6-tetrahydropyridine
(c) 1 -[1 -biphenyl-4-yl-5-(2-fluorophenyl)-1 H-pyrazol-4-yimethyl]-4- methylpiperazine (d) 1-[5-(2-fluorophenyl)-1-(6-phenylpyridin-3-yl)-1 H-pyrazol-4-yl- methyl]-4-methylpiperazine
(e) {5-(2-Fluoro-phenyl)-1 -[6-(4-fluoro-phenyl)-pyridin-3-yl]-1 H- pyrazol-4-ylmethyl}-isoxazol-3-yi-amine (f) [5-(2-Fluoro-phenyl)-1 -(6-phenyl-pyridin-3-yl)-1 H-pyrazol-4- ylmethyl]-pyridin-3-yl-amine
(g) [5-(2-Fluoro-phenyi)-1 -(6-phenyl-pyridin-3-yl)-1 H-pyrazoI-4- ylmethyl]-isoxazol-3-yl-amine
(h) {5-(2-Fluoro-phenyl)-1 - 6-(4-fluoro-phenyl)-pyridin-3-yl]-1 H- pyrazol-4-ylmethyl}-pyridin-3-yl-amine (i) [5-(2-Fluoro-phenyl)-1 -(6-phenyl-pyridin-3-yl)-1 H-pyrazol-4- ylmethyl]-pyrazin-2-yl-amine
(j) {5-(2-Fluoro-phenyl)-1 -[6-(4-fluoro-phenyl)-pyridin-3-yl]-1 H- pyrazol-4-ylmethyl}-pyrazin-2-yl-amine and salts and solvates thereof.
8. Compounds of the formulae IA, IB, IC, ID, IE and IF:
Figure imgf000087_0001
in which R1, R 2 and X are as defined in Claim 1.
9. Process for the preparation of compounds of the formula IA
Figure imgf000088_0001
in which R1, R2, R3, R4, X and A are as defined in Claim 1, and salts and solvates thereof, which is characterised in that a compound of the formula II
Figure imgf000088_0002
or acid-addition salts thereof in which
R1 and X are as defined in Claim 1 , is reacted with a compound of the formula III
Figure imgf000088_0003
in which
A and R2 are as defined in Claim 1 , and/or in that a basic compound of the formula IA is converted into one of its salts by treatment with an acid.
10. Process for the preparation of compounds of the formula IB
Figure imgf000089_0001
in which R1, R2, R3, R4, X and A are as defined in Claim 1, and salts and solvates thereof, which is characterised in that a compound of the formula II
Figure imgf000089_0002
or acid-addition salts thereof in which
R1 and X are as defined in Claim 1 , is reacted with a compound of the formula IV
Figure imgf000089_0003
in which
A and R2 are as defined in Claim 1, and/or in that a basic compound of the formula IB is converted into one of its salts by treatment with an acid.
11. Compounds of the formula I according to Claim 1 and physiologically acceptable salts and solvates thereof as medicaments.
12. Compounds of the formula I according to Claim 1 and physiologically acceptable salts and solvates thereof as glycine transporter inhibitors.
13. Pharmaceutical preparation, characterised by a content of at least one compound of the formula I according to Claim 1 and/or one of its physiologically acceptable salts and/or one of its solvates.
14. Process for the preparation of pharmaceutical preparations, characterised in that a compound of the formula I according to Claim 1 and/or one of its physiologically acceptable salts and/or one of its solvates is converted into a suitable dosage form together with at least one solid, liquid or semi-liquid excipient or adjuvant.
15. Use of compounds of the formula I according to Claim 1 and/or physiologically acceptable salts or solvates thereof for the preparation of a medicament for the prophylaxis and/or treatment of schizophrenia, depression, dementia, Parkinson's disease, Alzheimer's disease, Lewy bodies dementia, Huntington's disease, Tourette's syndrome, anxiety, learning and memory restrictions, neurodegenerative disorders and other cognitive impairments, as well as nicotine dependence and pain.
16. Compounds of the formula I in which Het is one of the following radicals:
Figure imgf000090_0001
PCT/EP2002/010172 2001-10-06 2002-09-11 Pyrazole derivatives as glycine transporter inhibitors WO2003031435A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2002342675A AU2002342675A1 (en) 2001-10-06 2002-09-11 Pyrazole derivatives as glycine transporter inhibitors

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE10149370.3 2001-10-06
DE10149370A DE10149370A1 (en) 2001-10-06 2001-10-06 New 1-(phenyl or pyridinyl)-1H-pyrazole derivatives, are glycine transporter inhibitors useful e.g. for treating schizophrenia, depression, dementia, neurodegenerative diseases or pain

Publications (2)

Publication Number Publication Date
WO2003031435A1 true WO2003031435A1 (en) 2003-04-17
WO2003031435A8 WO2003031435A8 (en) 2003-05-15

Family

ID=7701652

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2002/010172 WO2003031435A1 (en) 2001-10-06 2002-09-11 Pyrazole derivatives as glycine transporter inhibitors

Country Status (3)

Country Link
AU (1) AU2002342675A1 (en)
DE (1) DE10149370A1 (en)
WO (1) WO2003031435A1 (en)

Cited By (48)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004037793A1 (en) * 2002-10-24 2004-05-06 Wakamoto Pharmaceutical Co., Ltd. Pyrazole-4-alkanoate derivatives inhibiting cyclooxygenase and 5-lipoxygenase
WO2004089931A1 (en) * 2003-04-05 2004-10-21 Merck Patent Gmbh Substituted pyrazoles
WO2006075011A3 (en) * 2005-01-14 2006-11-23 Organon Nv Glycine reuptake inhibitors for treating drug and alcohol dependence
WO2007039317A2 (en) 2005-10-05 2007-04-12 Bayer Cropscience Ag Plants having an increased content of amino sugars
WO2007052615A1 (en) 2005-10-31 2007-05-10 Eisai R & D Management Co., Ltd. Pyridine derivative substituted by heterocycle and fungicide containing the same
WO2008136279A1 (en) 2007-04-27 2008-11-13 Eisai R & D Management Co., Ltd. Salt of heterocycle-substituted pyridine derivative or crystal thereof
WO2008136324A1 (en) 2007-04-27 2008-11-13 Eisai R & D Management Co., Ltd. Pyridine derivative substituted with heterocycle and phosphonoamino and antifungal agent containing the same
US7566709B2 (en) 2003-04-05 2009-07-28 Merck Patent Gmbh 1,3,4-Substituted pyrazoles as 5-HT receptor antagonists for the treatment of psychoses and neurological disorders
US7622471B2 (en) 2003-02-07 2009-11-24 Daiichi Pharmaceutical Co., Ltd. Pyrazole derivatives having a pyridazine and pyridine functionality
JP2009542661A (en) * 2006-06-28 2009-12-03 アムジエン・インコーポレーテツド Glycine transporter-1 inhibitor
US7691882B2 (en) 2005-10-31 2010-04-06 Eisai R&D Management Co., Ltd. Heterocycles substituted pyridine derivatives and antifungal agent containing thereof
AU2004228119B2 (en) * 2003-04-05 2010-09-02 Merck Patent Gmbh Pyrazole compounds
US7842695B2 (en) 2003-04-05 2010-11-30 Merck Patent Gmbh Substituted pyrazole compounds
US7910592B2 (en) * 2005-12-30 2011-03-22 Merck Sharp & Dohme Corp. CETP inhibitors
WO2012008528A1 (en) 2010-07-15 2012-01-19 大日本住友製薬株式会社 Pyrazole compound
US8420670B2 (en) 2007-08-22 2013-04-16 Abbott Laboratories 4-benzylaminoquinolines, pharmaceutical compositions containing them, and their use in therapy
US8455638B2 (en) 2007-09-06 2013-06-04 Merck Sharp & Dohme Corp. Soluble guanylate cyclase activators
US8507512B2 (en) 2009-02-26 2013-08-13 Merck Sharp & Dohme Corp. Soluble guanylate cyclase activators
US8513287B2 (en) 2007-12-27 2013-08-20 Eisai R&D Management Co., Ltd. Heterocyclic ring and phosphonoxymethyl group substituted pyridine derivatives and antifungal agent containing same
US8563617B2 (en) 2009-02-16 2013-10-22 AbbVie Deutschland GmbH & Co. KG Aminotetraline derivatives, pharmaceutical compositions containing them, and their use in therapy
US8642587B2 (en) 2009-02-16 2014-02-04 AbbVie Deutschland GmbH & Co. KG Heterocyclic compounds, pharmaceutical compositions containing them, and their use in therapy
US8653100B2 (en) 2008-04-01 2014-02-18 Abbvie Inc. Tetrahydroisoquinolines, pharmaceutical compositions containing them, and their use in therapy
US8846743B2 (en) 2010-08-13 2014-09-30 Abbott Laboratories Aminoindane derivatives, pharmaceutical compositions containing them, and their use in therapy
US8846741B2 (en) 2011-11-18 2014-09-30 Abbvie Inc. N-substituted aminobenzocycloheptene, aminotetraline, aminoindane and phenalkylamine derivatives, pharmaceutical compositions containing them, and their use in therapy
US8853196B2 (en) 2011-08-05 2014-10-07 AbbVie Deutschland GmbH & Co. KG Aminochromane, aminothiochromane and amino-1,2,3,4-tetrahydroquinoline derivatives, pharmaceutical compositions containing them, and their use in therapy
US8877794B2 (en) 2010-08-13 2014-11-04 Abbott Laboratories Phenalkylamine derivatives, pharmaceutical compositions containing them, and their use in therapy
US8883839B2 (en) 2010-08-13 2014-11-11 Abbott Laboratories Tetraline and indane derivatives, pharmaceutical compositions containing them, and their use in therapy
US8952026B2 (en) 2013-03-14 2015-02-10 Epizyme, Inc. PRMT1 inhibitors and uses thereof
US9023883B2 (en) 2013-03-14 2015-05-05 Epizyme, Inc. PRMT1 inhibitors and uses thereof
US9045455B2 (en) 2013-03-14 2015-06-02 Epizyme, Inc. Arginine methyltransferase inhibitors and uses thereof
US9045459B2 (en) 2010-08-13 2015-06-02 AbbVie Deutschland GmbH & Co. KG Phenalkylamine derivatives, pharmaceutical compositions containing them, and their use in therapy
US9051280B2 (en) 2010-08-13 2015-06-09 AbbVie Deutschland GmbH & Co. KG Tetraline and indane derivatives, pharmaceutical compositions containing them, and their use in therapy
US9120757B2 (en) 2013-03-14 2015-09-01 Epizyme, Inc. Arginine methyltransferase inhibitors and uses thereof
US9133189B2 (en) 2013-03-14 2015-09-15 Epizyme, Inc. Arginine methyltransferase inhibitors and uses thereof
US9309200B2 (en) 2011-05-12 2016-04-12 AbbVie Deutschland GmbH & Co. KG Benzazepine derivatives, pharmaceutical compositions containing them, and their use in therapy
US9346761B2 (en) 2013-03-14 2016-05-24 Epizyme, Inc. Arginine methyltransferase inhibitors and uses thereof
US9365527B2 (en) 2013-03-14 2016-06-14 Epizyme, Inc. Arginine methyltransferase inhibitors and uses thereof
US9365512B2 (en) 2012-02-13 2016-06-14 AbbVie Deutschland GmbH & Co. KG Isoindoline derivatives, pharmaceutical compositions containing them, and their use in therapy
US9394258B2 (en) 2013-03-14 2016-07-19 Epizyme, Inc. Arginine methyltransferase inhibitors and uses thereof
US9447079B2 (en) 2013-03-14 2016-09-20 Epizyme, Inc. PRMT1 inhibitors and uses thereof
US9550754B2 (en) 2014-09-11 2017-01-24 AbbVie Deutschland GmbH & Co. KG 4,5-dihydropyrazole derivatives, pharmaceutical compositions containing them, and their use in therapy
US9586942B2 (en) 2013-10-17 2017-03-07 AbbVie Deutschland GmbH & Co. KG Aminotetraline and aminoindane derivatives, pharmaceutical compositions containing them, and their use in therapy
US9598374B2 (en) 2013-03-14 2017-03-21 Epizyme, Inc. Arginine methyltransferase inhibitors and uses thereof
US9650334B2 (en) 2013-03-15 2017-05-16 Abbvie Inc. Pyrrolidine derivatives, pharmaceutical compositions containing them, and their use in therapy
US9656955B2 (en) 2013-03-15 2017-05-23 Abbvie Inc. Pyrrolidine derivatives, pharmaceutical compositions containing them, and their use in therapy
WO2017142091A1 (en) * 2016-02-19 2017-08-24 国立大学法人鳥取大学 Therapeutic or prophylactic drug for dementia
ITUA20164199A1 (en) * 2016-06-08 2017-12-08 Univ Degli Studi Del Piemonte Orientale Amedeo Avogadro MODULATORS OF SOCE COMPISATIONS AND RELATED USES
US11034669B2 (en) 2018-11-30 2021-06-15 Nuvation Bio Inc. Pyrrole and pyrazole compounds and methods of use thereof

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20080090834A1 (en) * 2006-07-06 2008-04-17 Pfizer Inc Selective azole pde10a inhibitor compounds
US7977358B2 (en) 2007-07-26 2011-07-12 Hoffmann-La Roche Inc. Pyrazol derivatives
AU2014336153A1 (en) 2013-10-17 2016-04-28 AbbVie Deutschland GmbH & Co. KG Aminochromane, aminothiochromane and amino-1,2,3,4-tetrahydroquinoline derivatives, pharmaceutical compositions containing them, and their use in therapy

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0014847A1 (en) * 1979-02-19 1980-09-03 MERCK PATENT GmbH Pyrazole derivatives, pharmaceutical preparations containing them and process for their production
US6001854A (en) * 1996-05-31 1999-12-14 Allelix Neuroscience Inc. Pharmaceutical for treating of neurological and neuropsychiatric disorders
WO2000027394A1 (en) * 1998-11-05 2000-05-18 University College London Activators of soluble guanylate cyclase
WO2001057024A1 (en) * 2000-02-04 2001-08-09 University College London Blockade of voltage dependent sodium channels
WO2001087855A1 (en) * 2000-05-19 2001-11-22 Yamanouchi Pharmaceutical Co., Ltd. Triazole derivatives

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0014847A1 (en) * 1979-02-19 1980-09-03 MERCK PATENT GmbH Pyrazole derivatives, pharmaceutical preparations containing them and process for their production
US6001854A (en) * 1996-05-31 1999-12-14 Allelix Neuroscience Inc. Pharmaceutical for treating of neurological and neuropsychiatric disorders
WO2000027394A1 (en) * 1998-11-05 2000-05-18 University College London Activators of soluble guanylate cyclase
WO2001057024A1 (en) * 2000-02-04 2001-08-09 University College London Blockade of voltage dependent sodium channels
WO2001087855A1 (en) * 2000-05-19 2001-11-22 Yamanouchi Pharmaceutical Co., Ltd. Triazole derivatives

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
CANNON G W ET AL: "ACYLATION STUDIES. I. METHYL CYCLOPROPYL KETONE", JOURNAL OF ORGANIC CHEMISTRY, AMERICAN CHEMICAL SOCIETY. EASTON, US, vol. 17, no. 5, 1 May 1952 (1952-05-01), pages 685 - 692, XP000573850, ISSN: 0022-3263 *
F. CORELLI ET AL.: "Heterocyclic systems. VIII. Synthesis of 1H,4H-Pyrazolo[4,3-f]pyrrolo[1,2-a]azepine derivatives", J. HETEROCYCLIC CHEM., vol. 24, 1987, pages 1445 - 7, XP002226577 *
G. MENOZZI ET AL.: "Reaction of 2-dimethylaminomethylene-1,3-diones with dinucleophiles", J. HETEROCYCLIC CHEM., vol. 24, 1987, pages 1669 - 75, XP002226576 *
G. MENOZZI ET AL.: "Synthesis of 5-substituted 1-aryl-1H-pyrazole-4-acetonitriles, 4-methyl-1-phenyl-1H-pyrazole-3-carbonitriles and pharmacologically acive 1-aryl1H-pyrazole-4-acetic acids", J. HETEROCYCLIC CHEM., vol. 30, 1993, pages 997 - 1002, XP002226575 *
J. BECK; F. WRIGHT: "Synthesis of 1-aryl5-(trifluoromethyl)-1H-prazole-4-carboxylic acids and esters", J. HETEROCYCLIC CHEM., vol. 24, 1987, pages 739 - 740, XP002226574 *
KUDO N ET AL: "SYNTHESIS AND HERBICIDAL ACTIVITY OF 1,5-DIARYLPYRAZOLE DERIVATIVES", CHEMICAL AND PHARMACEUTICAL BULLETIN, PHARMACEUTICAL SOCIETY OF JAPAN. TOKYO, JP, vol. 47, no. 6, 1999, pages 857 - 868, XP001026111, ISSN: 0009-2363 *

Cited By (85)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004037793A1 (en) * 2002-10-24 2004-05-06 Wakamoto Pharmaceutical Co., Ltd. Pyrazole-4-alkanoate derivatives inhibiting cyclooxygenase and 5-lipoxygenase
US7622471B2 (en) 2003-02-07 2009-11-24 Daiichi Pharmaceutical Co., Ltd. Pyrazole derivatives having a pyridazine and pyridine functionality
AU2004228119B2 (en) * 2003-04-05 2010-09-02 Merck Patent Gmbh Pyrazole compounds
US7960413B2 (en) 2003-04-05 2011-06-14 Merck Patent Gmbh Pyrazole compounds
AU2004228120B2 (en) * 2003-04-05 2010-12-02 Merck Patent Gmbh Substituted pyrazoles
US7566709B2 (en) 2003-04-05 2009-07-28 Merck Patent Gmbh 1,3,4-Substituted pyrazoles as 5-HT receptor antagonists for the treatment of psychoses and neurological disorders
US7842695B2 (en) 2003-04-05 2010-11-30 Merck Patent Gmbh Substituted pyrazole compounds
WO2004089931A1 (en) * 2003-04-05 2004-10-21 Merck Patent Gmbh Substituted pyrazoles
AU2006205796B2 (en) * 2005-01-14 2010-09-02 Merck Sharp & Dohme B.V. Glycine reuptake inhibitors for treating drug and alcohol dependence
WO2006075011A3 (en) * 2005-01-14 2006-11-23 Organon Nv Glycine reuptake inhibitors for treating drug and alcohol dependence
WO2007039317A2 (en) 2005-10-05 2007-04-12 Bayer Cropscience Ag Plants having an increased content of amino sugars
EP2628738A1 (en) 2005-10-31 2013-08-21 Eisai R&D Management Co., Ltd. Heterocyclic substituted pyridine derivatives and antifungal agent containing same
US7691882B2 (en) 2005-10-31 2010-04-06 Eisai R&D Management Co., Ltd. Heterocycles substituted pyridine derivatives and antifungal agent containing thereof
US8841327B2 (en) 2005-10-31 2014-09-23 Eisai R&D Management Co., Ltd. Heterocycles substituted pyridine derivatives and antifungal agent containing thereof
WO2007052615A1 (en) 2005-10-31 2007-05-10 Eisai R & D Management Co., Ltd. Pyridine derivative substituted by heterocycle and fungicide containing the same
US7910592B2 (en) * 2005-12-30 2011-03-22 Merck Sharp & Dohme Corp. CETP inhibitors
JP2009542661A (en) * 2006-06-28 2009-12-03 アムジエン・インコーポレーテツド Glycine transporter-1 inhibitor
WO2008136324A1 (en) 2007-04-27 2008-11-13 Eisai R & D Management Co., Ltd. Pyridine derivative substituted with heterocycle and phosphonoamino and antifungal agent containing the same
US8507530B2 (en) 2007-04-27 2013-08-13 Eisai R&D Management Co., Ltd. Pyridine derivatives substituted by heterocyclic ring and phosphonoamino group, and anti-fungal agent containing same
WO2008136279A1 (en) 2007-04-27 2008-11-13 Eisai R & D Management Co., Ltd. Salt of heterocycle-substituted pyridine derivative or crystal thereof
US8420670B2 (en) 2007-08-22 2013-04-16 Abbott Laboratories 4-benzylaminoquinolines, pharmaceutical compositions containing them, and their use in therapy
US8455638B2 (en) 2007-09-06 2013-06-04 Merck Sharp & Dohme Corp. Soluble guanylate cyclase activators
US8513287B2 (en) 2007-12-27 2013-08-20 Eisai R&D Management Co., Ltd. Heterocyclic ring and phosphonoxymethyl group substituted pyridine derivatives and antifungal agent containing same
US8957089B2 (en) 2008-04-01 2015-02-17 AbbVie Deutschland GmbH & Co. KG Tetrahydroisoquinolines, pharmaceutical compositions containing them, and their use in therapy
US8653100B2 (en) 2008-04-01 2014-02-18 Abbvie Inc. Tetrahydroisoquinolines, pharmaceutical compositions containing them, and their use in therapy
US9096619B2 (en) 2009-02-16 2015-08-04 AbbVie Deutschland GmbH & Co. KG Aminotetraline derivatives, pharmaceutical compositions containing them, and their use in therapy
US8563617B2 (en) 2009-02-16 2013-10-22 AbbVie Deutschland GmbH & Co. KG Aminotetraline derivatives, pharmaceutical compositions containing them, and their use in therapy
US8642587B2 (en) 2009-02-16 2014-02-04 AbbVie Deutschland GmbH & Co. KG Heterocyclic compounds, pharmaceutical compositions containing them, and their use in therapy
US9067871B2 (en) 2009-02-16 2015-06-30 AbbVie Deutschland GmbH & Co. KG Aminotetraline derivatives, pharmaceutical compositions containing them, and their use in therapy
US8507512B2 (en) 2009-02-26 2013-08-13 Merck Sharp & Dohme Corp. Soluble guanylate cyclase activators
WO2012008528A1 (en) 2010-07-15 2012-01-19 大日本住友製薬株式会社 Pyrazole compound
US10087146B2 (en) 2010-07-15 2018-10-02 Sumitomo Dainippon Pharma Co., Ltd. Pyrazole compound
US8569353B2 (en) 2010-07-15 2013-10-29 Dainippon Sumitomo Pharma Co., Ltd. Pyrazole compound
US9663472B2 (en) 2010-07-15 2017-05-30 Sumitomo Dainippon Pharma Co., Ltd. Pyrazole compound
US10183913B2 (en) 2010-07-15 2019-01-22 Sumitomo Dainippon Pharma Co., Ltd. Pyrazole compound
US11312688B2 (en) 2010-07-15 2022-04-26 Sumitomo Dainippon Pharma Co., Ltd. Pyrazole compound
US8809383B2 (en) 2010-07-15 2014-08-19 Dainippon Sumitomo Pharma Co., Ltd. Pyrazole compound
US10723703B2 (en) 2010-07-15 2020-07-28 Sumitomo Dainippon Pharma Co., Ltd. Pyrazole compound
US9051280B2 (en) 2010-08-13 2015-06-09 AbbVie Deutschland GmbH & Co. KG Tetraline and indane derivatives, pharmaceutical compositions containing them, and their use in therapy
US8877794B2 (en) 2010-08-13 2014-11-04 Abbott Laboratories Phenalkylamine derivatives, pharmaceutical compositions containing them, and their use in therapy
US8846743B2 (en) 2010-08-13 2014-09-30 Abbott Laboratories Aminoindane derivatives, pharmaceutical compositions containing them, and their use in therapy
US8883839B2 (en) 2010-08-13 2014-11-11 Abbott Laboratories Tetraline and indane derivatives, pharmaceutical compositions containing them, and their use in therapy
US9045459B2 (en) 2010-08-13 2015-06-02 AbbVie Deutschland GmbH & Co. KG Phenalkylamine derivatives, pharmaceutical compositions containing them, and their use in therapy
US9227930B2 (en) 2010-08-13 2016-01-05 Abbvie Inc. Aminoindane derivatives, pharmaceutical compositions containing them, and their use in therapy
US9238619B2 (en) 2010-08-13 2016-01-19 AbbVie Deutschland GmbH & Co. KG Phenalkylamine derivatives, pharmaceutical compositions containing them, and their use in therapy
US9309200B2 (en) 2011-05-12 2016-04-12 AbbVie Deutschland GmbH & Co. KG Benzazepine derivatives, pharmaceutical compositions containing them, and their use in therapy
US8853196B2 (en) 2011-08-05 2014-10-07 AbbVie Deutschland GmbH & Co. KG Aminochromane, aminothiochromane and amino-1,2,3,4-tetrahydroquinoline derivatives, pharmaceutical compositions containing them, and their use in therapy
US8846741B2 (en) 2011-11-18 2014-09-30 Abbvie Inc. N-substituted aminobenzocycloheptene, aminotetraline, aminoindane and phenalkylamine derivatives, pharmaceutical compositions containing them, and their use in therapy
US9365512B2 (en) 2012-02-13 2016-06-14 AbbVie Deutschland GmbH & Co. KG Isoindoline derivatives, pharmaceutical compositions containing them, and their use in therapy
US9475776B2 (en) 2013-03-14 2016-10-25 Epizyme, Inc. PRMT1 inhibitors and uses thereof
US9776972B2 (en) 2013-03-14 2017-10-03 Epizyme Inc. Pyrazole derivatives as arginine methyltransferase inhibitors and uses thereof
US9394258B2 (en) 2013-03-14 2016-07-19 Epizyme, Inc. Arginine methyltransferase inhibitors and uses thereof
US9440950B2 (en) 2013-03-14 2016-09-13 Epizyme, Inc. Arginine methyltransferase inhibitors and uses thereof
US9447079B2 (en) 2013-03-14 2016-09-20 Epizyme, Inc. PRMT1 inhibitors and uses thereof
US9346761B2 (en) 2013-03-14 2016-05-24 Epizyme, Inc. Arginine methyltransferase inhibitors and uses thereof
US11512053B2 (en) 2013-03-14 2022-11-29 Epizyme, Inc. Arginine methyltransferase inhibitors and uses thereof
US8952026B2 (en) 2013-03-14 2015-02-10 Epizyme, Inc. PRMT1 inhibitors and uses thereof
US9598374B2 (en) 2013-03-14 2017-03-21 Epizyme, Inc. Arginine methyltransferase inhibitors and uses thereof
US9630961B2 (en) 2013-03-14 2017-04-25 Epizyme, Inc. Arginine methyltransferase inhibitors and uses thereof
US11185531B2 (en) 2013-03-14 2021-11-30 Epizyme, Inc. Arginine methyltransferase inhibitors and uses thereof
US10800743B2 (en) 2013-03-14 2020-10-13 Epizyme, Inc. Arginine methyltransferase inhibitors and uses thereof
US9133189B2 (en) 2013-03-14 2015-09-15 Epizyme, Inc. Arginine methyltransferase inhibitors and uses thereof
US9724332B2 (en) 2013-03-14 2017-08-08 Epizyme, Inc. Arginine methyltransferase inhibitors and uses thereof
US9732041B2 (en) 2013-03-14 2017-08-15 Epizyme, Inc. Arginine methyltransferase inhibitors and uses thereof
US9023883B2 (en) 2013-03-14 2015-05-05 Epizyme, Inc. PRMT1 inhibitors and uses thereof
US9765035B2 (en) 2013-03-14 2017-09-19 Epizyme, Inc. Arginine methyltransferase inhibitors and uses thereof
US9365527B2 (en) 2013-03-14 2016-06-14 Epizyme, Inc. Arginine methyltransferase inhibitors and uses thereof
US10632103B2 (en) 2013-03-14 2020-04-28 Epizyme, Inc. Arginine methyltransferase inhibitors and uses thereof
US10227307B2 (en) 2013-03-14 2019-03-12 Epizyme, Inc. PRMT1 inhibitors and uses thereof
US9868703B2 (en) 2013-03-14 2018-01-16 Epizyme, Inc. PRMT1 inhibitors and uses thereof
US9943504B2 (en) 2013-03-14 2018-04-17 Epizyme, Inc. Arginine methyltransferase inhibitors and uses thereof
US10039748B2 (en) 2013-03-14 2018-08-07 Epizyme, Inc. PRMT1 inhibitors and uses thereof
US10081603B2 (en) 2013-03-14 2018-09-25 Epizyme Inc. Arginine methyltransferase inhibitors and uses thereof
US9120757B2 (en) 2013-03-14 2015-09-01 Epizyme, Inc. Arginine methyltransferase inhibitors and uses thereof
US9045455B2 (en) 2013-03-14 2015-06-02 Epizyme, Inc. Arginine methyltransferase inhibitors and uses thereof
US9656955B2 (en) 2013-03-15 2017-05-23 Abbvie Inc. Pyrrolidine derivatives, pharmaceutical compositions containing them, and their use in therapy
US9650334B2 (en) 2013-03-15 2017-05-16 Abbvie Inc. Pyrrolidine derivatives, pharmaceutical compositions containing them, and their use in therapy
US9586942B2 (en) 2013-10-17 2017-03-07 AbbVie Deutschland GmbH & Co. KG Aminotetraline and aminoindane derivatives, pharmaceutical compositions containing them, and their use in therapy
US9550754B2 (en) 2014-09-11 2017-01-24 AbbVie Deutschland GmbH & Co. KG 4,5-dihydropyrazole derivatives, pharmaceutical compositions containing them, and their use in therapy
WO2017142091A1 (en) * 2016-02-19 2017-08-24 国立大学法人鳥取大学 Therapeutic or prophylactic drug for dementia
US11344539B2 (en) 2016-02-19 2022-05-31 National University Corporation Tottori University Therapeutic or prophylactic drug for dementia
WO2017212414A1 (en) * 2016-06-08 2017-12-14 Università Degli Studi Del Piemonte Orientale "Amedeo Avogadro" Modulators of soce, compositions, and uses thereof
US10519138B2 (en) 2016-06-08 2019-12-31 Universita Degli Studi Del Piemonte Orientale Modulators of SOCE, compositions, and uses thereof
ITUA20164199A1 (en) * 2016-06-08 2017-12-08 Univ Degli Studi Del Piemonte Orientale Amedeo Avogadro MODULATORS OF SOCE COMPISATIONS AND RELATED USES
US11034669B2 (en) 2018-11-30 2021-06-15 Nuvation Bio Inc. Pyrrole and pyrazole compounds and methods of use thereof

Also Published As

Publication number Publication date
WO2003031435A8 (en) 2003-05-15
AU2002342675A1 (en) 2003-04-22
DE10149370A1 (en) 2003-04-10

Similar Documents

Publication Publication Date Title
WO2003031435A1 (en) Pyrazole derivatives as glycine transporter inhibitors
AU2004228120B2 (en) Substituted pyrazoles
US11512066B2 (en) Sulfonyl piperidine derivatives and their use for treating prokineticin mediated diseases
US10183025B2 (en) Autotaxin inhibitors
JP2009544626A (en) Compounds and compositions as ITPKB inhibitors
JP2008525408A (en) 1,6-Substituted (3R, 6R) -3- (2,3-dihydro-1H-inden-2-yl) -2 as an oxytocin receptor antagonist for the treatment of preterm birth, dysmenorrhea and endometriosis , 5-Piperazinedione derivatives
CA2644068A1 (en) Therapeutic compounds
US20240254101A1 (en) Gpr52 modulator compounds
US20130184460A1 (en) Glycine transporter inhibiting substances
DE10315570A1 (en) New 1-aryl-1,2,3-triazole derivatives useful for treating e.g. schizophrenia, depression, dementia, Parkinson's disease or Alzheimer's disease, are glycine transporter inhibitors
JP7510358B2 (en) 4-Substituted phenyl-1,3,5-triazine derivatives as TRK receptor modulators - Patents.com
US7842695B2 (en) Substituted pyrazole compounds
US8618303B2 (en) Pyrrolidine derivatives
WO2007043581A1 (en) Thienopyridine-2-carboxamide derivative

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BY BZ CA CH CN CO CR CU CZ DE DM DZ EC EE ES FI GB GD GE GH HR HU ID IL IN IS JP KE KG KP KR LC LK LR LS LT LU LV MA MD MG MN MW MX MZ NO NZ OM PH PL PT RU SD SE SG SI SK SL TJ TM TN TR TZ UA UG US UZ VC VN YU ZA ZM

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW MZ SD SL SZ UG ZM ZW AM AZ BY KG KZ RU TJ TM AT BE BG CH CY CZ DK EE ES FI FR GB GR IE IT LU MC PT SE SK TR BF BJ CF CG CI GA GN GQ GW ML MR NE SN TD TG

CFP Corrected version of a pamphlet front page

Free format text: UNDER (54) PUBLISHED TITLE REPLACED BY CORRECT TITLE

121 Ep: the epo has been informed by wipo that ep was designated in this application
DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase

Ref country code: JP

WWW Wipo information: withdrawn in national office

Country of ref document: JP