WO2003031435A1 - Derives pyrazole inhibiteurs de transport de glycine - Google Patents

Derives pyrazole inhibiteurs de transport de glycine Download PDF

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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
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Prior art keywords
pyrazol
fluorophenyl
formula
ylmethyl
compounds
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PCT/EP2002/010172
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English (en)
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WO2003031435A8 (fr
Inventor
Kai Schiemann
Michael Arlt
Dirk Finsinger
Karl-August Ackermann
Wilfried Rautenberg
Joachim Leibrock
Hartmut Greiner
Takahiko Tobe
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Merck Patent Gmbh
Yamanouchi Pharmaceutical Co. Ltd.
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Priority to AU2002342675A priority Critical patent/AU2002342675A1/en
Publication of WO2003031435A1 publication Critical patent/WO2003031435A1/fr
Publication of WO2003031435A8 publication Critical patent/WO2003031435A8/fr

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    • 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.

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Abstract

L'invention concerne des composés de formule (I), ainsi que des sels et des solvates de ces composés, dans laquelle X, R?1, R2, R3, R4 et R5¿ sont tels que définis dans la revendication 1. Ces composés sont des inhibiteurs du transport de la glycine et peuvent être utilisés en médecine humaine et vétérinaire pour la prophylaxie et le traitement dans les cas de schizophrénie, dépression, démence, maladie de Parkinson, maladie d'Alzheimer, démence du corps de Lewy, maladie de Huntington, syndrome de Tourette, anxiété, restrictions d'apprentissage et de mémoire, maladies neurodégénératives et d'autres troubles cognitifs, ainsi que dans les cas de douleurs et de dépendance à la nicotine.
PCT/EP2002/010172 2001-10-06 2002-09-11 Derives pyrazole inhibiteurs de transport de glycine WO2003031435A1 (fr)

Priority Applications (1)

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AU2002342675A AU2002342675A1 (en) 2001-10-06 2002-09-11 Pyrazole derivatives as glycine transporter inhibitors

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DE10149370A DE10149370A1 (de) 2001-10-06 2001-10-06 Pyrazolderivate
DE10149370.3 2001-10-06

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US7842695B2 (en) 2003-04-05 2010-11-30 Merck Patent Gmbh Substituted pyrazole compounds
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AU2006205796B2 (en) * 2005-01-14 2010-09-02 Merck Sharp & Dohme B.V. Glycine reuptake inhibitors for treating drug and alcohol dependence
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WO2007039317A2 (fr) 2005-10-05 2007-04-12 Bayer Cropscience Ag Vegetaux possedant un contenu accru de sucres amino
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