WO2003031435A1

WO2003031435A1 - Pyrazole derivatives as glycine transporter inhibitors

Info

Publication number: WO2003031435A1
Application number: PCT/EP2002/010172
Authority: WO
Inventors: 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
Current assignee: Merck Patent GmbH; Yamanouchi Pharmaceutical Co Ltd
Priority date: 2001-10-06
Filing date: 2002-09-11
Publication date: 2003-04-17
Anticipated expiration: 2004-04-06
Also published as: DE10149370A1; WO2003031435A8; AU2002342675A1

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

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_2l CN, C(NH)NOH or OCF_3l

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)CH₂CH₂Het_l (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)CONH_2l (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, NH_2l 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

and salts and solvates thereof, which is characterised in that a compound of the formula II

or acid-addition salts thereof in which

R¹ and X are as defined above, is reacted with a compound of the formula

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

or acid-addition salts thereof in which

R¹ and X are as defined above, is reacted with a compound of the formula IV

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

which can be oxidised, for example using Mnθ₂, to give the compounds IE and IF

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

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:

Het is particularly preferably one of the following radicals:

Ar is preferably a phenyl radical which is unsubstituted or substituted by Hal, OH, CN, N0₃, NH₂, NHCOCH_3l COOCH_3> 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

in which A is as defined above, with compounds of the formula VI

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

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

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

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

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

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

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

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

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

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

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

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

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.

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

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

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

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

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

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

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

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:

R¹ R² X

(241) CH

\ ^~~ i_ ^~

(242) ^{F_ ~} CH

\ ^~~

(243) CH

Q^~ -I (244) ^{Nc~ ~~} CH _ ^~

(245) CH _ ^~

(252) CH

^{F~~ ~~} CF₃

(253) CH

Q^" CF₃

(256) CH

(__ ^~

(257) ^{F~ ~} 58) ø^~ CH

(2 CH

Q- Q^~

(259) CH

^NC~0^~ Q^~

(261) " - ^{Cp3 CH}

(262) _c /^λ CF₃ CH

(263) /"^X CF₃ CH

(265) CF₃ CH

N -N ^

(266) N

\JT \_ ^~

(267) ^F- -- N _ ^~~

(268) N

Q^~~ _^~~

(272) _P_/^=aV_ " - ^N

\

CN

(282) _B _ T =\ N

^F~ _ ^~ W ^/

(283) /=\_ /=\

_N__ - \ \i_ r_N-

(286) /=\ CF₃ N

(287) _F^T _~ CF₃ N

(288) =V CF₃ N

Examples 291 - 340:

R¹ R² X

(291) CH

^ // XJ

(305) CH

^N-

CF₃

(306)

\j^^~~ G- CH

(307)

^F- ^~~ CH

Q-^~

(308) CH

Q^~ Q^~~

(309)

^{NC~ ~~} ø^~ CH

(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_#

(323) N

_N—J '

CN

(330) _r _ N

^ \

CF₃

(331) _ \— ^N '/ V N M

(335) \ =\ N

N ' ^—

(337) CF₃ N

W // (338) CF₃ N

N- ' (339) NC- CF₃ N //

Examples 341 -390:

R¹ R² X

(341) CH

\_ ^~ \j^~

(342) ^F_0^~ CH

\j^~

(343) CH ^~

(344) CH

^NC~0^{~~ ~}

(345) CH

^N^N ^~

(356) /^{^}X ^{^} - ^CH

(358) ^{^}V ⁼⁼\_ ^CH

(360) rV_ /""X ^CH

(361) C - ^{CF3 CH}

(362) _e /=\ CF₃ CH ^F~ _ ~

(363) /^{^}Y ^CF3 ^CH

(365) I — CF₃ CH

(366) ~ N

Y_ ^~~

(367) ^{F~~ ~~} N

V_ ^~

(369) NC — v. J) N _ ^~~

(374) N

^{NC~ ~}

CN

(376) N _

CF-

(379) N

^NC- ^~~

CF₃

(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:

R¹ R²

(392) ^{F~ ~ ~} CH

(393) CH

Q^~ \JT (394) CH

^NC- ^~~ _#

(405) CH --_N

CF_S

(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

(416) N

\_

(417) ^{F~ ~"} N

\_)^~~

(418)

9) o- N _ ^~

(41 HC-^^ N __^"

(420) o^~ N

(426) N

Y_ ^~~

CF,

(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:

R¹ R^z X

(441) CH ^> V

(443) CH

\ *

(457) _c /^{^}\- Λ— ^CH ^F~ // v ^"

(458) Λ___ S— ^CH

(459) _I^ /^{^}λ /⁼⁼V_ CH

^— ' ^-

(461) — ^{CFS CH}

(462) _e _ = __ CF₃ CH

⁽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 _ ^~~

(478) N

Q^~~ CF₃

(482) N

^F- ^~ (483) N

(484) N

^{NC~ ~"} Q^~

(485) N u > — ^N-rf Q^~

(487) CF₃ N

^F~\\ // (488) CF₃ N

N ' (489) NC- CF₃ N

W // (490) CF₃ N

/>

Examples 491 - 540:

R¹ R² X

(491) CH //

(506) ⁼⁼\_ ^{^} . ^CH

(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

(517) N

^{F~ ~} {_

(518) Q^~ N _ ^~~

(519) N

^{NC~ ~} _ —

(520) N

^N~~N \JT

(523) o^~ N

CN

(531) N // -N (532) N ^f~\ // -N (533) N

\ * -N (534)

NC- N A ^x -N

(536) CF₃ N

XJf (537) CF₃ N // (538) CF₃ N

^ N A ' (539) NC CF₃ N

^~ (540) -N. CF₃ N

Examples 541 - 590:

R¹ R² X

(541) CH (542)

^F~^0^~ CH _ ^~

(543) CH

Q^~~ \_J

(544) CH

^{NC~^}Q^~ γ_ ^~

(545) I? )) — CH _#

(551) CH

Y_ ^~

CF₃

(557) CH

^{F" ~} Q^~~ (558) CH

N-^ \JΓ

(559) CH

^Nc- ^~ Q^~

(561) CF₃ CH

\JT

(562) CF₃ CH

^{F~ "}

(563) CF₃ CH

Q^~

(564) CF₃ CH

^{NC~ ~}

(565) CF₃ CH -N

(577) ^{F~ "} N

CF₃

(581) N _ ^~~ Q^~

(582) N

^F _ Q^~

(584) NC — (\ } Q^~ N

(586) CF₃ N

\_ ^~~

(587) ^{F~ ~} CF₃ N

(588) o^~ CF₃ N

(590) ϊi > — CF₃ N ^N-N^ -71-

Examples 591 - 640:

R R² X

(591) CH

\J

(606) — ΓX~- ^CH

N

(611) ~- ^{CFS CH}

(612) ._/⁼ __ CF₃ CH

(613) /^{^} _... CF₃ CH

(614) _κ N,„C- /=\ CF₃ CH A

(616) /^{^}X _. ^{^}X

W ^~ _# (617) _c /⁼⁼\_ /^{^}X

(620) r N

-N //

(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~ ~}

Examples 641 -690:

R¹ R² X

(641) CH

WT^~ (_

(642) CH

^F→G^^~ _ ^~

(643) CH

Q^~ J^~~

(644) CH

^{NC~ ~} \JT

(657)

^{F~ ~} CH

Q^~~

(658) CH

Q^~ Q^~

(659)

^{NC~ ~} CH

Q^™

(660) rV CH

Q^~

(662)

^{F~ ~} CF₃ CH

(663) CF₃ CH

Q^~ (664) CF₃ CH

^{NC~ ~~}

(666) N

WT^~ WT

(667) ^{F~ ~} N

V/^~~

(668) N

Q^~ _ ^~

(669) N

^NC- ^~ _y

(670) N

JC — _ ^~

(674) N ⁿ°-ζ -

CN

(677) N

^?-^~0^~

CF₃

(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

(690) NΛ_ CF₃ N

Examples 691 - 740:

R¹ R^z

(691) CH

(693) - CH

\_ ^~~

(700) CH

^N-N^^{^}

CN

(706) CH

(_)~ Q^~

(707) ~o- CH

Q^~ (708) o^~ CH

Q^~

(709) CH

^{NC~ ~} Q^~

(710) N-^N\ _

N-_N ^__N\— CH

(712) _C_T⁼\ _ CF₃ CH ^F~ _ ~

(713) /=\_ CF₃ CH

N— ^J

(714) ' _^ NC_ —T ^ _ CF₃ CH

(715) jr\ CF₃ CH

(717) N w // W //

(718) N

\\ // w //

(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

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,

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:

in which R¹, R ² and X are as defined in Claim 1.

9. Process for the preparation of compounds of the formula IA

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

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

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

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

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: