# Patent

## Title
Inhibitors for GlyT-1

## Abstract

The present invention relates to compounds of formula I




wherein

    R1, R2,
    R3,
    R4, and
    X are as defined herein or to pharmaceutically acceptable acid addition salts thereof, with the exception of
    4-methoxy-N-[2-oxo-2-(phenylamino)ethyl]-N-phenyl-benzamide,
    4-chloro-N-[2-[(4-methylphenyl)amino]-2-oxoethyl]-N-phenyl-benzamide,
    4-chloro-N-[2-[5-chloro-2-methoxyphenyl)amino]-2-oxoethyl]-N-benzamide,
    4-methyl-N-(2-oxo-2-[(2,4,6-trichlorophenyl)amino]ethyl]-N-benzamide,
    N-[2-[(4-methylphenyl)amino]-2-oxoethyl]-N-phenyl-benzamide,
    4-methyl-N-[2-[(4-methylphenyl)amino]-2-oxoethyl]-N-phenyl-benzamide,
    4-chloro-N-(2-oxo-2-[(2,4,6-trichlorophenyl)amino]ethyl]-N-benzamide and
    N-[2-[(2,4-dimethoxyphenyl)amino]-2-oxoethyl]-N-[(2-fluorophenyl)methyl]-benzeneacetamide. The compounds are useful in the treatment of neurological and neuropsychiatric disorders.

## Background
PRIORITY TO RELATED APPLICATION(S)
This application claims the benefit of European Patent Application No. 06119758.8, filed Aug. 30, 2006, which is hereby incorporated by reference in its entirety.
BACKGROUND OF THE INVENTION
Schizophrenia is a progressive and devastating neurological disease characterized by episodic positive symptoms such as delusions, hallucinations, thought disorders and psychosis and persistent negative symptoms such as flattened affect, impaired attention and social withdrawal, and cognitive impairments (Lewis D A and Lieberman J A, Neuron, 2000, 28:325-33). For decades research has focused on the “dopaminergic hyperactivity” hypothesis which has led to therapeutic interventions involving blockade of the dopaminergic system (Vandenberg R J and Aubrey K R., Exp. Opin. Ther. Targets, 2001, 5 (4): 507-518; Nakazato A and Okuyama S, et al., 2000, Exp. Opin. Ther. Patents, 10 (1): 75-98). This pharmacological approach poorly address negative and cognitive symptoms which are the best predictors of functional outcome (Sharma T., Br. J. Psychiatry, 1999, 174 (suppl. 28): 44-51).
A complementary model of schizophrenia was proposed in the mid-1960' based upon the psychotomimetic action caused by the blockade of the glutamate system by compounds like phencyclidine (PCP) and related agents (ketamine) which are non-competitive NMDA receptor antagonists. Interestingly in healthy volunteers, PCP-induced psychotomimetic action incorporates positive and negative symptoms as well as cognitive dysfunction, thus closely resembling schizophrenia in patients (Javitt D C et al., 1999, Biol. Psychiatry, 45: 668-679 and refs. herein). Furthermore transgenic mice expressing reduced levels of the NMDAR1 subunit displays behavioral abnormalities similar to those observed in pharmacologically induced models of schizophrenia, supporting a model in which reduced NMDA receptor activity results in schizophrenia-like behavior (Mohn A R et al., 1999, Cell, 98: 427-236).
Glutamate neurotransmission, in particular NMDA receptor activity, plays a critical role in synaptic plasticity, learning and memory, such as the NMDA receptors appears to serve as a graded switch for gating the threshold of synaptic plasticity and memory formation (Hebb DO, 1949, The organization of behavior, Wiley, N.Y.; Bliss T V and Collingridge GL, 1993, Nature, 361: 31-39). Transgenic mice overexpressing the NMDA NR2B subunit exhibit enhanced synaptic plasticity and superior ability in learning and memory (Tang J P et al., 1999, Nature: 401-63-69).
Thus, if a glutamate deficit is implicate in the pathophysiology of schizophrenia, enhancing glutamate transmission, in particular via NMDA receptor activation, would be predicted to produce both anti-psychotic and cognitive enhancing effects.
The amino acid glycine is known to have at least two important functions in the CNS. It acts as an inhibitory amino acid, binding to strychnine sensitive glycine receptors, and it also influences excitatory activity, acting as an essential co-agonist with glutamate for N-methyl-D-aspartate (NMDA) receptor function. While glutamate is released in an activity-dependent manner from synaptic terminals, glycine is apparently present at a more constant level and seems to modulate/control the receptor for its response to glutamate.
One of the most effective ways to control synaptic concentrations of neurotransmitter is to influence their re-uptake at the synapses. Neurotransmitter transporters by removing neurotransmitters from the extracellular space, can control their extracellular lifetime and thereby modulate the magnitude of the synaptic transmission (Gainetdinov R R et al, 2002, Trends in Pharm. Sci., 23 (8): 367-373).
Glycine transporters, which form part of the sodium and chloride family of neurotransmitter transporters, play an important role in the termination of post-synaptic glycinergic actions and maintenance of low extracellular glycine concentration by re-uptake of glycine into presynaptic nerve terminals and surrounding fine glial processes.
Two distinct glycine transporter genes have been cloned (GlyT-1 and GlyT-2) from mammalian brain, which give rise to two transporters with  ̃50% amino acid sequence homology. GlyT-1 presents four isoforms arising from alternative splicing and alternative promoter usage (1a, 1b, 1c and 1d). Only two of these isoforms have been found in rodent brain (GlyT-1a and GlyT-1b). GlyT-2 also presents some degree of heterogeneity. Two GlyT-2 isoforms (2a and 2b) have been identified in rodent brains. GlyT-1 is known to be located in CNS and in peripheral tissues, whereas GlyT-2 is specific to the CNS. GlyT-1 has a predominantly glial distribution and is found not only in areas corresponding to strychnine sensitive glycine receptors but also outside these areas, where it has been postulated to be involved in modulation of NMDA receptor function (Lopez-Corcuera B et al., 2001, Mol. Mem. Biol., 18: 13-20). Thus, one strategy to enhance NMDA receptor activity is to elevate the glycine concentration in the local microenvironment of synaptic NMDA receptors by inhibition of GlyT-1 transporter (Bergereon R. Et al., 1998, Proc. Natl. Acad. Sci. USA, 95: 15730-15734; Chen L et al., 2003, J. Neurophysiol., 89 (2): 691-703).
Glycine transporters inhibitors are suitable for the treatment of neurological and neuropsychiatric disorders. The majority of diseases states implicated are psychoses, schizophrenia (Armer R E and Miller D J, 2001, Exp. Opin. Ther. Patents, 11 (4): 563-572), psychotic mood disorders such as severe major depressive disorder, mood disorders associated with psychotic disorders such as acute mania or depression associated with bipolar disorders and mood disorders associated with schizophrenia, (Pralong E T et al., 2002, Prog. Neurobiol., 67: 173-202), autistic disorders (Carlsson M L, 1998, J. Neural Transm. 105: 525-535), cognitive disorders such as dementias, including age related dementia and senile dementia of the Alzheimer type, memory disorders in a mammal, including a human, attention deficit disorders and pain (Armer R E and Miller D J, 2001, Exp. Opin. Ther. Patents, 11 (4): 563-572).
Thus, increasing activation of NMDA receptors via GlyT-1 inhibition may lead to agents that treat psychosis, schizophrenia, dementia and other diseases in which cognitive processes are impaired, such as attention deficit disorders or Alzheimer's disease.
SUMMARY OF THE INVENTION
The present invention provides compounds of formula I




wherein

    R1 is lower alkyl, aryl or heteroaryl, wherein aryl and heteroaryl are optionally substituted by halogen, lower alkyl, lower alkoxy, lower alkyl substituted by halogen, lower alkoxy substituted by halogen, cyano, amino, di-lower alkyl amino or morpholinyl;
    R2 is lower alkyl, —(CH2)n-aryl, —(CH2)n-heteroaryl or —(CH2)n-cycloalkyl, wherein the aryl or heteroaryl groups are optionally substituted by one or more substituents selected from the group consisting of halogen, lower alkyl, cyano, or lower alkoxy;
    R3 is hydrogen or lower alkyl;
    R4 is aryl or heteroaryl, wherein aryl and heteroaryl are optionally substituted by one or more substituents selected from the group consisting of halogen, lower alkyl substituted by halogen, lower alkoxy substituted by halogen, lower alkyl;
    X is a bond or —OCH2—;
    n is 0, 1 or 2;

or pharmaceutically acceptable acid addition salts thereof, with the exception of

    4-methoxy-N-[2-oxo-2-(phenylamino)ethyl]-N-phenyl-benzamide,
    4-chloro-N-[2-[(4-methylphenyl)amino]-2-oxoethyl]-N-phenyl-benzamide,
    4-chloro-N-[2-[5-chloro-2-methoxyphenyl)amino]-2-oxoethyl]-N-phenylmethyl-benzamide,
    4-methyl-N-(2-oxo-2-[(2,4,6-trichlorophenyl)amino]ethyl]-N-phenylmethyl-benzamide,
    N-[2-[(4-methylphenyl)amino]-2-oxoethyl]-N-phenyl-benzamide,
    4-methyl-N-[2-[(4-methylphenyl)amino]-2-oxoethyl]-N-phenyl-benzamide,
    4-chloro-N-(2-oxo-2-[(2,4,6-trichlorophenyl)amino]ethyl]-N-phenylmethyl-benzamide and
    N-[2-[(2, 4-dimethoxyphenyl)amino]-2-oxoethyl]-N-[(2-fluorophenyl)methyl]-benzeneacetamide.


The first excepted compound has been described in Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972), (7), 909-13 in a cyclisation process of α-acylamino-acids. The other excepted compounds have been listed in the CAS registry file.
Furthermore, the invention includes all racemic mixtures, all their corresponding enantiomers and/or optical isomers.
The present invention also provides pharmaceutical compositions containing a compound of formula I or a pharmaceutical salt thereof. The invention also provides methods for the preparation of the compounds and compositions of the invention.
Compounds of general formula I are good inhibitors of the glycine transporter 1 (GlyT-1) and have a good selectivity to glycine transporter 2 (GlyT-2) inhibitors. The invention provides methods for the treatment of diseases related to activation of NMDA receptors via GlyT-1 inhibition, such as psychoses, dysfunction in memory and learning, schizophrenia, dementia and other diseases in which cognitive processes are impaired, such as attention deficit disorders or Alzheimer's disease. The preferred indications of the present invention are schizophrenia, cognitive impairment and Alzheimer's disease.


DETAILED DESCRIPTION OF THE INVENTION
The following definitions of the general terms used in the present description apply irrespective of whether the terms in question appear alone or in combination. It must be noted that, as used in the specification and the appended claims, the singular forms “a”, “an,” and “the” include plural forms unless the context clearly dictates otherwise.
As used herein, the term “lower alkyl” denotes a saturated straight- or branched-chain hydrocarbon group containing from 1 to 7 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, n-butyl, i-butyl, 2-butyl, t-butyl and the like. Preferred alkyl groups are groups with 1-4 carbon atoms.
The term “cycloalkyl” denotes a saturated or partially saturated carbocyclic ring containing from 3 to 7 carbon atoms, for example cyclopropyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl or cycloheptenyl.
The term “halogen” denotes chlorine, iodine, fluorine and bromine.
The term “aryl” denotes a monovalent cyclic aromatic hydrocarbon radical having 6 to 12 ring atoms and consisting of one or more fused rings in which at least one ring is aromatic in nature, for example phenyl or naphthyl.
The term “heteroaryl” denotes a cyclic aromatic hydrocarbon radical, containing one, two or three heteroatoms selected from the group consisting of oxygen, sulphur or nitrogen wherein at least one ring is aromatic in nature, for example pyridyl, quinoxalinyl, dihydrobenzofuranyl, thiophenyl, benzothiophenyl, isoxazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thiazolyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl and isothiazolyl.
The term “lower alkyl substituted by halogen” denotes a lower alkyl group as defined above, wherein at least one hydrogen atom is replaced by a halogen atom, for example the following groups: CF3, CHF2, CH2F, CH2CF3, CH2CHF2, CH2CH2F, CH2CH2CF3, CH2CH2CH2CF3, CH2CH2Cl, CH2CF2CF3, CH2CF2CHF2, CF2CHFCF3, C(CH3)2CF3, CH(CH3)CF3 or CH(CH2F)CH2F.
The term “lower alkoxy” denotes a alkyl group wherein the lower alkyl residue is as defined above and which is attached via an oxygen atom.
The term “lower alkoxy substituted by halogen” denotes an alkoxy group, wherein at least one hydrogen atom is replaced by halogen as defined above.
“Pharmaceutically acceptable,” such as pharmaceutically acceptable carrier, excipient, etc., means pharmacologically acceptable and substantially non-toxic to the subject to which the particular compound is administered.
The term “pharmaceutically acceptable acid addition salts” embraces salts with inorganic and organic acids, such as hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, fumaric acid, maleic acid, acetic acid, succinic acid, tartaric acid, methane-sulfonic acid, p-toluenesulfonic acid and the like.
“Therapeutically effective amount” means an amount that is effective to prevent, alleviate or ameliorate symptoms of disease or prolong the survival of the subject being treated.
The present invention provides compounds of formula I




wherein

    R1 is lower alkyl, aryl or heteroaryl, wherein aryl and heteroaryl are optionally substituted by halogen, lower alkyl, lower alkoxy, lower alkyl substituted by halogen, lower alkoxy substituted by halogen, cyano, amino, di-lower alkyl amino or morpholinyl;
    R2 is lower alkyl, —(CH2)n-aryl, —(CH2)n-heteroaryl or —(CH2)n-cycloalkyl, wherein the aryl or heteroaryl groups are optionally substituted by one or more substituents selected from the group consisting of halogen, lower alkyl, cyano, or lower alkoxy;
    R3 is hydrogen or lower alkyl;
    R4 is aryl or heteroaryl, wherein aryl and heteroaryl are optionally substituted by one or more substituents selected from the group consisting of halogen, lower alkyl substituted by halogen, lower alkoxy substituted by halogen, lower alkyl;
    X is a bond or —OCH2—;
    n is 0, 1 or 2;

or pharmaceutically acceptable acid addition salts thereof, with the exception of

    4-methoxy-N-[2-oxo-2-(phenylamino)ethyl]-N-phenyl-benzamide,
    4-chloro-N-[2-[(4-methylphenyl)amino]-2-oxoethyl]-N-phenyl-benzamide,
    4-chloro-N-[2-[5-chloro-2-methoxyphenyl)amino]-2-oxoethyl]-N-benzamide,
    4-methyl-N-(2-oxo-2-[(2,4,6-trichlorophenyl)amino]ethyl]-N-benzamide,
    N-[2-[(4-methylphenyl)amino]-2-oxoethyl]-N-phenyl-benzamide,
    4-methyl-N-[2-[(4-methylphenyl)amino]-2-oxoethyl]-N-phenyl-benzamide,
    4-chloro-N-(2-oxo-2-[(2,4,6-trichlorophenyl)amino]ethyl]-N-benzamide and
    N-[2-[(2,4-dimethoxyphenyl)amino]-2-oxoethyl]-N-[(2-fluorophenyl)methyl]-benzeneacetamide.


Preferred compounds of formula I are those, wherein X is a bond.
Preferred compounds of formula I of the present invention are further those, wherein R1 and R4 are both monosubstituted aryl, preferably halogen substituted phenyl, for example the following compounds:

    4-Chloro-N-[(3-chloro-phenylcarbamoyl)-methyl]-N-(2,6-difluoro-benzyl)-benzamide,
    4-Chloro-N-[(3-chloro-phenylcarbamoyl)-methyl]-N-(2,3-difluoro-benzyl)-benzamide,
    4-Chloro-N-[(3-chloro-phenylcarbamoyl)-methyl]-N-(2-fluoro-benzyl)-benzamide,
    4-Chloro-N-[(3-chloro-phenylcarbamoyl)-methyl]-N-thiophen-2-ylmethyl-benzamide,
    4-Chloro-N-[(3-chloro-phenylcarbamoyl)-methyl]-N-(2-methoxy-benzyl)-benzamide,
    4-Chloro-N-(3-chloro-benzyl)-N-[(3-chloro-phenylcarbamoyl)-methyl]-benzamide and
    4-Chloro-N-(2-chloro-benzyl)-N-[(3-chloro-phenylcarbamoyl)-methyl]-benzamide.


Further preferred compounds are those, wherein R1 and R4 are both monosubstituted aryl, for R1 preferably methoxy substituted phenyl and for R4 preferably halogen substituted phenyl, for example the following compounds:

    N-[(3-Chloro-phenylcarbamoyl)-methyl]-N-(2,6-difluoro-benzyl)-4-methoxy-benzamide and
    N-(3-Chloro-benzyl)-N-[(3-chloro-phenylcarbamoyl)-methyl]-4-methoxy-benzamide.


Preferred compounds of formula I of the present invention are further those, wherein R1 is heteroaryl, preferably benzothiophenyl, for example the following compounds:

    Benzo[b]thiophene-2-carboxylic acid (2-chloro-benzyl)-[(3-trifluoromethyl-phenylcarbamoyl)-methyl]-amide,
    Benzo[b]thiophene-2-carboxylic acid (2-chloro-benzyl)-[(3-fluoro-phenylcarbamoyl)-methyl]-amide,
    Benzo[b]thiophene-2-carboxylic acid (3,5-difluoro-benzyl)-[(3-fluoro-phenylcarbamoyl)-methyl]-amide,
    Benzo[b]thiophene-2-carboxylic acid [(3-chloro-4-fluoro-phenylcarbamoyl)-methyl]-(2,6-difluoro-benzyl)-amide,
    Benzo[b]thiophene-2-carboxylic acid [(3-chloro-4-fluoro-phenylcarbamoyl)-methyl]-(2,3-difluoro-benzyl)-amide and
    Benzo[b]thiophene-2-carboxylic acid [(3-chloro-4-fluoro-phenylcarbamoyl)-methyl]-(3,5-difluoro-benzyl)-amide.


Preferred compounds of formula I of the present invention are further those, wherein R1 and R4 are monosubstituted aryl, preferably halogen substituted phenyl for R1 and CF3 substituted phenyl for R4, for example the following compound:

    N-(2-Chloro-benzyl)-4-fluoro-N-[(3-trifluoromethyl-phenylcarbamoyl)-methyl]-benzamide.


The present compounds of formula I and their pharmaceutically acceptable salts can be prepared by methods known in the art, for example, by processes described below, which processes comprise
a) reacting a compound of formula




with a compound of formula

R2—NH2  II

and with a compound of formula





in the presence of N-ethyldiisopropylamine

to produce a compound of formula





wherein the substituents are as defined above, or

b) reacting a compound of formula




with a compound of formula





in presence of triethylamine

to produce a compound of formula





wherein the substituents are as defined above or

c) reacting a compound of formula

NHR3R4  IX

with a compound of formula





in the presence of N-ethyldiisopropylamine and HATU [O-(7-Azabenzotriazole-1-yl)-N, N,N′N′-tetramethyluronium hexafluorophosphate],

to produce a compound of formula





wherein the substituents are as defined above, or

d) reacting a compound of formula




with a compound of formula





in the presence of triethylamine,

to produce a compound of formula





wherein the substituents are as defined above

and

if desired, converting the compounds obtained into pharmaceutically acceptable acid addition salts.
The acid addition salts of the basic compounds of formula I can be converted to the corresponding free bases by treatment with at least a stoichiometric equivalent of a suitable base such as sodium or potassium hydroxide, potassium carbonate, sodium bicarbonate, ammonia, and the like.
The compounds of formula I can be prepared in accordance with process variant a) to d), with the following schemes and with working examples 1-128.
The starting material is commercially available or can be prepared in accordance with known methods.
Procedure A
This procedure is used to prepare Example 34 (N-phenyl-N-(p-tolylcarbamoyl-methyl)-6-trifluoromethyl-nicotinamide).




To a compound of formula III, for example 2-bromo-N-(4-methyl-phenyl)-acetamide, in THF is added a compound of formula II, for example aniline and N-ethyldiisopropylamine, and a compound of formula IV, for example 6-trifluoromethyl-nicotynoyl chloride, and the reaction mixture is stirred over night at reflux. Then the reaction is concentrated in vacuo, and the reaction mixture is purified in conventional manner.
Procedure B
This procedure is used to prepare Example 30: N-[(3,4-dichloro-phenylcarbamoyl)-methyl]-N-phenyl-3-trifluoromethyl benzamide.




Step 1: Compound of Formula V

To a compound of formula III, for example 2-bromo-N-(3,4-dichloro-phenyl)-acetamide, in THF is added a compound of formula II, for example aniline and N-ethyldiisopropylamine, and the reaction mixture is stirred over night at reflux. The precipitated salt is then filtered off, and the filtrate was then concentrated in vacuo. The residue was then purified in conventional manner.
Step 2: Compound of Formula I
To a compound of formula V, for example N-(3,4-dichloro-phenyl)-2-phenylamino-acetamide, in THF is added triethylamine and a compound of formula IV, for example 3-trifluoromethylbenzoyl chloride, and the reaction mixture is stirred at room temperature for about 30 minutes. Water is then added to the mixture until precipitation occurred, and the mixture is stirred for 5 minutes. Then the precipitate is isolated by filtration and washed.
Procedure C
This procedure is used to prepare Example 30: 4-chloro-N-[(3-chloro-phenylcarbamoyl)-methyl]-N-(2-fluoro-benzyl)benzamide.




Step 1: Compound of Formula VII

To a compound of formula VI, for example (2,6-dichloro-benzylamino)-acetic acid ethyl ester, in suspension THF is added triethylamine and a compound of formula IV, for example 4-methoxybenzoyl chloride, and the reaction mixture is stirred at room temperature for 10 min. Water is then added to the reaction mixture, and the aqueous phase is extracted with diethylacetate. The combined organic phases are then dried, concentrated in vacuo and purified.
Step 2: Compound of Formula VIII
To a compound of formula VII, for example N-(3,4-dichloro-phenyl)-2-phenylamino-acetamide, in ethanol is added NaOH, and the reaction mixture is stirred at room temperature for about 3 hours. The reaction mixture is then neutralized by addition of HCl, and the ethanol is eliminated by evaporation. Water and ethyl acetate is then added to the residue. The organic phase is separated, and the aqueous phase is extracted with ethylacetate. The combined organic phase is then washed again with water, dried and concentrated in vacuo.
Step 3: Compound of Formula I
To a solution of a compound of formula IX, for example 3-chloroaniline, in DMF is added N-ethyldiiopropylamine, a compound of formula VIII, for example [(2,6-dichloro-benzyl)-(4-methoxy-benzoyl)-amino]-acetic acid, and HATU; and the reaction mixture is stirred at room temperature over night. Then water is added until precipitation occurs, and the precipitate is isolated by filtration and washed with a mixture of water and ethanol to yield the title compound.
Procedure D
This procedure was used to prepare Example 1: 4-chloro-N-[(3-chloro-phenylcarbamoyl)-methyl]-N-(2,6-difluoro-benzyl)-benzamide.




To a compound of formula III-1, for example N-1-(3-chlorophenyl)-2-chloroacetamide, in DMF is added a compound of formula II, for example 2,6-difluorobenzylamine and triethylamine, and a compound of formula IV, such as 4-chlorobenzoyl chloride. The reaction mixture is stirred at room temperature for about 15 min and then purified.
Procedure E
This procedure was used to prepare Example 97: N-[(3,4-dichloro-phenylcarbamoyl)-methyl]-N-isobutyl-4-methoxy-benzamide.




Step 1: Hydrobromide of a Compound of Formula V-1

To a solution of a compound of formula III, for example 2-bromo-N-(3,4-dichloro-phenyl)-acetamide, in dichloromethane at 0° C. is slowly added isobutylamine in dichloromethane. The reaction mixture is allowed to warm up to room temperature and then stirred for another 24 hours. Then the salt is filtered off and the filtrate is concentrated in vacuo. The residue is then purified.
Step 2: Compound of Formula I-1.
To a solution of a compound of formula V-1, such as N-(3,4-dichloro-phenyl)-2-isobutylamino-acetamide hydrobromide, in THF are slowly added a solution of triethylamine in THF and a solution of a compound of formula IV, for example 4-methoxybenzoyl chloride, in THF, and the reaction mixture is stirred at room temperature for about 24 hours. Then water is added to the reaction mixture, and the precipitate is isolated by filtration and then purified.
The compounds of formula I and their pharmaceutically usable addition salts possess valuable pharmacological properties. Specifically, the compounds of the present invention are good inhibitors of the glycine transporter I (GlyT-1).
The compounds were investigated in accordance with the test given hereinafter.
Solutions and Materials
DMEM complete medium: Nutrient mixture F-12 (Gibco Life-technologies), fetal bovine serum (FBS) 5%, (Gibco life technologies), Penicillin/Streptomycin 1% (Gibco life technologies), Hygromycin 0.6 mg/ml (Gibco life technologies), Glutamine 1 mM Gibco life technologies)
Uptake buffer (UB): 150 mM NaCl, 10 mM Hepes-Tris, pH 7.4, 1 mM CaCl2, 2.5 mM KCl, 2.5 mM MgSO4, 10 mM (+) D-glucose.
Flp-inTM-CHO (Invitrogen Cat n° R758-07) cells stably transfected with mGlyT1b cDNA.
Glycine Uptake Inhibition Assay (mGlyT-1b)
On day 1 mammalian cells, (Flp-inTM-CHO), transfected with mGlyT-1b cDNA, were plated at the density of 40,000 cells/well in complete F-12 medium, without hygromycin in 96-well culture plates. On day 2, the medium was aspirated and the cells were washed twice with uptake buffer (UB). The cells were then incubated for 20 min at 22° C. with either (i) no potential competitor, (ii) 10 mM non-radioactive glycine, (iii) a concentration of a potential inhibitor. A range of concentrations of the potential inhibitor was used to generate data for calculating the concentration of inhibitor resulting in 50% of the effect (e.g. IC50, the concentration of the competitor inhibiting glycine uptake of 50%). A solution was then immediately added containing [3H]-glycine 60 nM (11-16 Ci/mmol) and 25 μM non-radioactive glycine. The plates were incubated with gentle shaking and the reaction was stopped by aspiration of the mixture and washing (three times) with ice-cold UB. The cells were lysed with scintillation liquid, shaken 3 hours and the radioactivity in the cells was counted using a scintillation counter.
The compounds described in examples 1-128 have an IC50 data <1.0 μM. The IC50 data (<0.4 μM) for representative compounds 1-128 is be provided in table 2.
The present invention also provides pharmaceutical compositions containing compounds of the invention, for example compounds of formula I and their pharmaceutically suitable acid addition salts, and a pharmaceutically acceptable carrier. Such pharmaceutical compositions can be in the form of tablets, coated tablets, dragées, hard and soft gelatin capsules, solutions, emulsions or suspensions. The pharmaceutical compositions also can be in the form of suppositories or injectable solutions.
The pharmaceutical compounds of the invention, in addition to one or more compounds of the invention, contain a pharmaceutically acceptable carrier. Suitable pharmaceutically acceptable carriers include pharmaceutically inert, inorganic and organic carriers. Lactose, corn starch or derivatives thereof, talc, stearic acids or its salts and the like can be used, for example, as such carriers for tablets, coated tablets, dragées and hard gelatine capsules. Suitable carriers for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like. Depending on the nature of the active substance no carriers are however usually required in the case of soft gelatine capsules. Suitable carriers for the production of solutions and syrups are, for example, water, polyols, glycerol, vegetable oil and the like. Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like.
The pharmaceutical compositions can, moreover, contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances.
The invention also provides a method for preparing compositions of the invention which comprises bringing one or more compounds of formula I and/or pharmaceutically acceptable acid addition salts and, if desired, one or more other therapeutically valuable substances into a galenical administration form together with one or more therapeutically inert carriers.
The most preferred indications in accordance with the present invention are those, which include disorders of the central nervous system, for example the treatment or prevention of schizophrenia, cognitive impairment and Alzheimer's disease. The invention provides a method for the treatment of schizophrenia, which comprises administering to an individual a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof. The invention also provides a method for the treatment of Alzheimer's disease, which comprises administering to an individual a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof. The invention further comprises a method for improving cognition, which comprises administering to an individual a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof.
The dosage at which compounds of the invention can be administered can vary within wide limits and will, of course, have to be adjusted to the individual requirements in each particular case. In the case of oral administration the dosage for adults can vary from about 0.01 mg to about 1000 mg per day of a compound of general formula I or of the corresponding amount of a pharmaceutically acceptable salt thereof. The daily dosage can be administered as single dose or in divided doses and, in addition, the upper limit can also be exceeded when this is found to be indicated.












Tablet Formulation (Wet Granulation)












mg/tablet












Item
Ingredients
5 mg
25 mg
100 mg
500 mg





1.
Compound of formula I
5
25
100
500


2.
Lactose Anhydrous DTG
125
105
30
150


3.
Sta-Rx 1500
6
6
6
30


4.
Microcrystalline Cellulose
30
30
30
150


5.
Magnesium Stearate
1
1
1
1



Total
167
167
167
831










Manufacturing Procedure











1.
Mix items 1, 2, 3 and 4 and granulate with purified water.


2.
Dry the granules at 50° C.


3.
Pass the granules through suitable milling equipment.


4.
Add item 5 and mix for three minutes; compress on a suitable press.










Capsule Formulation












mg/capsule












Item
Ingredients
5 mg
25 mg
100 mg
500 mg





1.
Compound of formula I
5
25
100
500


2.
Hydrous Lactose
159
123
148
—


3.
Corn Starch
25
35
40
70


4.
Talc
10
15
10
25


5.
Magnesium Stearate
1
2
2
5



Total
200
200
300
600










Manufacturing Procedure











1.
Mix items 1, 2 and 3 in a suitable mixer for 30 minutes.


2.
Add items 4 and 5 and mix for 3 minutes.


3.
Fill into a suitable capsule.









The following examples illustrate the present invention without limiting it. All temperatures are given in degree Celsius.
Procedure A
This procedure is used to prepare Example 34
N-Phenyl-N-(p-tolylcarbamoyl-methyl)-6-trifluoromethyl-nicotinamide
To 2-bromo-N-(4-methyl-phenyl)-acetamide (100 mg) in THF (3.0 mL) was added aniline (41 mg) and N-ethyldiisopropylamine and 6-trifluoromethyl-nicotynoyl chloride (110 mg) the reaction mixture was stirred over night at reflux. Then the reaction was concentrated in vacuo and the reaction mixture was purified by column chromatography to yield the title compound as a light brown solid (127 mg, 70%).

Procedure B

This procedure was used to prepare Example 30
N-[(3,4-Dichloro-phenylcarbamoyl)-methyl]-N-phenyl-3-trifluoromethyl benzamide
Step 1: N-(3,4-Dichloro-phenyl)-2-phenylamino-acetamide
To 2-bromo-N-(3,4-dichloro-phenyl)-acetamide (2 g) in THF (80 mL) was added aniline (41 mg) and N-ethyldiisopropylamine and the reaction mixture was stirred over night at reflux. The precipitated salt was then filtered off and the filtrate was then concentrated in vacuo. The residue was then purified by column chromatography to give the title compound as a light brown solid (1.3 g, mp=110-112° C.).
Step 2: N-[(3,4-Dichloro-phenylcarbamoyl)-methyl]-N-phenyl-3-trifluoromethyl benzamide
To N-(3,4-dichloro-phenyl)-2-phenylamino-acetamide (73 mg) in THF (3.1 mL) was added tiethylamine (52 μL) and 3-trifluoromethylbenzoyl chloride (62 mg) and the reaction mixture was stirred at room temperature for 30 minutes. To the mixture was then added water under precipitation occurred and the mixture was stirred for 5 minutes. Then the precipitate was isolated by filtration and washed with a mixture water-ethanol (1:1) to yield the title compound as a white solid (64 mg, mp=130-132° C.).
Procedure C
This procedure was used to prepare Example 30
4-Chloro-N-[(3-chloro-phenylcarbamoyl)-methyl]-N-(2-fluoro-benzyl)benzamide
Step 1: N-(3,4-Dichloro-phenyl)-2-phenylamino-acetamide
To (2,6-dichloro-benzylamino)-acetic acid ethyl ester (100 mg) in suspension THF (5 mL) was added triethylamine (0.08 mL) and 4-methoxybenzoyl chloride (78 mg) and the reaction mixture was stirred at room temperature for 10 min. After such time the water was added to the reaction mixture and the aqueous phase was extracted with diethylacetate. The combined organic phases were then dried over sodium sulfate, concentrated vacuo and purified by column chromatography to yield the title (128 mg). MS (m/e): 396.3 (M+H+)
Step 2: [(2,6-Dichloro-benzyl)-(4-methoxy-benzoyl)-amino]-acetic acid
To N-(3,4-dichloro-phenyl)-2-phenylamino-acetamide in ethanol (10 mL) was added 1N NaOH (0.38 μL) and the reaction mixture was stirred at room temperature for 3 hours. After such time the reaction mixture was neutralized by addition of 3N HCl and the ethanol was eliminated by evaporation. To the residue was added more water and ethyl acetate. The organic phase was separated and the aqueous phase was extracted with ethylacetate. The combined organic phase was then washed again with water, dried over sodium sulfate and concentrated in vacuo to yield the title compound (90 mg). MS (m/e): 366.0 (M−H).
Step 3: 4-Chloro-N-[(3-chloro-phenylcarbamoyl)-methyl]-N-(2-fluoro-benzyl)benzamide
To a solution of 3-chloroaniline (20 mg) in DMF (1.5 mL) was added N-ethyldiiopropylamine (137 μL), [(2,6-Dichloro-benzyl)-(4-methoxy-benzoyl)-amino]-acetic acid (58 mg) and HATU (Across 365312) and the reaction mixture was stirred at room temperature over night. Then water was added until the precipitation occurs and the precipitate was isolated by filtration and washed with a mixture of water and ethanol (2:1) to yield the title compound (35 mg). MS (m/e): 479.2 (M+H+).
Procedure D
This procedure was used to prepare Example 1
4-Chloro-N-[(3-chloro-phenylcarbamoyl)-methyl]-N-(2,6-difluoro-benzyl)-benzamide
To N1-(3-chlorophenyl)-2-chloroacetamide (61 mg) in DMF (1 mL) was added 2,6-difluorobenzylamine (38 mg) and triethylamine (0.1 mL) and 4-chlorobenzoyl chloride (58 mg) the reaction mixture was stirred at room temperature for 15 min and then purified by HPLC preparative to yield the title compound (55 mg). MS (m/e): 447.0 (M−H).

Procedure E

This procedure was used to prepare Example 97
N-[(3,4-Dichloro-phenylcarbamoyl)-methyl]-N-isobutyl-4-methoxy-benzamide
Step 1: N-(3,4-Dichloro-phenyl)-2-isobutylamino-acetamide hydrobromide
To a solution of 2-bromo-N-(3,4-dichloro-phenyl)-acetamide (0.1 g) in dichloromethane (80 mL) at 0° C. was slowly added of isobutylamine (52 mg) in dichloromethane. The reaction mixture was allowed to warm up to room temperature and then stirred for another 24 hours. Then the salt was filtered off and the filtrate was concentrated in vacuo. The residue was then purified by column chromatography to yield the title compound as a white solid (0.1 g). MS (m/e): 357.1 (M+H+).
Step 2: N-[(3,4-Dichloro-phenylcarbamoyl)-methyl]-N-isobutyl-4-methoxy-benzamide
To a solution of N-(3,4-dichloro-phenyl)-2-isobutylamino-acetamide hydrobromide (0.090 g) in THF were slowly added a solution of triethylamine (0.064 mg) in THF (5 mL) and a solution of 4-methoxybenzoyl chloride (47 mg) in THF (5 mL) and the reaction mixture was stirred at room temperature for 24 hours. Then water was added to the reaction mixture and the precipitate was isolated by filtration and then purified by column chromatography to yield the title compound (78 mg). MS (m/e): 409.2 (M−H, 100%).
The following starting materials for preparation of compounds of formula I have been used:











TABLE 1







Amine/
Chloro amide or



Exp
Procedure
Aniline
bromo amide
Acyl chloride



















1
D
2,6-
N1-(3-Chlorophenyl)-
4-Chlorobenzoyl




Difluorobenzylamine
2-chloroacetamide
chloride


2
D
3,4-
N1-(3-Chlorophenyl)-
4-Chlorobenzoyl




Difluorobenzylamine
2-chloroacetamide
chloride


3
D
3,5-
N1-(3-Chlorophenyl)-
4-Chlorobenzoyl




Difluorobenzylamine
2-chloroacetamide
chloride


4
D
2,3-
N1-(3-Chlorophenyl)-
4-Chlorobenzoyl




Difluorobenzylamine
2-chloroacetamide
chloride


5
D
2,4-
N1-(3-Chlorophenyl)-
4-Chlorobenzoyl




Difluorobenzylamine
2-chloroacetamide
chloride


6
D
2,5-
N1-(3-Chlorophenyl)-
4-Chlorobenzoyl




Difluorobenzylamine
2-chloroacetamide
chloride


7
D
4-Fluorobenzylamine
N1-(3-Chlorophenyl)-
4-Chlorobenzoyl





2-chloroacetamide
chloride


8
D
3-Fluorobenzylamine
N1-(3-Chlorophenyl)-
4-Chlorobenzoyl





2-chloroacetamide
chloride


9
D
2-Fluorobenzylamine
N1-(3-Chlorophenyl)-
4-Chlorobenzoyl





2-chloroacetamide
chloride


10
D
Thiophen-3-yl-
N1-(3-Chlorophenyl)-
4-Methoxybenzoyl




methylamine
2-chloroacetamide
chloride


11
D
2,6-
N1-(3-Chlorophenyl)-
4-Methoxybenzoyl




Difluorobenzylamine
2-chloroacetamide
chloride


12
D
3,5-
N1-(3-Chlorophenyl)-
4-Methoxybenzoyl




Dichlorobenzylamine
2-chloroacetamide
chloride


13
D
2,6-
N1-(3-Chlorophenyl)-
4-Methoxybenzoyl




Dichlorobenzylamine
2-chloroacetamide
chloride


14
D
3-Chlorobenzylamine
N1-(3-Chlorophenyl)-
4-Methoxybenzoyl





2-chloroacetamide
chloride


15
D
Benzylamine
N1-(3-Chlorophenyl)-
4-Fluorobenzoyl chloride





2-chloroacetamide


16
D
benzylamine
N1-(3-Chlorophenyl)-
4-Chlorobenzoyl





2-chloroacetamide
chloride


17
D
Thiophen-2-yl-
N1-(3-Chlorophenyl)-
4-Chlorobenzoyl




methylamine
2-chloroacetamide
chloride


18
D
Thiophen-2-yl-
N1-(3-Chlorophenyl)-
4-Methoxybenzoyl




methylamine
2-chloroacetamide
chloride


19
C
(2,6-Dichloro-
3-Chloro aniline
4-Methoxybenzoyl




benzylamino)-acetic

chloride




acid ethyl ester


20
D
3-Fluoroaniline
2-Bromo-N-(3,4-
4-Methoxybenzoyl





dichloro-phenyl)-
chloride





acetamide


21
D
2-Fluoroaniline
2-Bromo-N-(3,4-
4-Methoxybenzoyl





dichloro-phenyl)-
chloride





acetamide


22
B
Aniline
2-Bromo-N-(3,4-
4-Methoxybenzoyl





dichloro-phenyl)-
chloride





acetamide


23
C
Phenylamino-acetic
3-Chloro-2-
4-Methoxybenzoyl




acid ethyl ester
Fluoroaniline
chloride


24
C
Phenylamino-acetic
5-Amino-2,2-difluoro-
4-Methoxybenzoyl




acid ethyl ester
1,3-benzodioxole
chloride


25
C
Phenylamino-acetic
3-
4-Methoxybenzoyl




acid ethyl ester
(Trifluoromethoxy)aniline
chloride


26
C
Phenylamino-acetic
m-Toluidine
4-Methoxybenzoyl




acid ethyl ester

chloride


27
C
Phenylamino-acetic
3-
4-Methoxybenzoyl




acid ethyl ester
Aminobenzotrifluoride
chloride


28
C
Phenylamino-acetic
3-Chloroaniline
4-Methoxybenzoyl




acid ethyl ester

chloride


29
C
Phenylamino-acetic
3-methoxybenzonitrile
4-Methoxybenzoyl




acid ethyl ester

chloride


30
B
Aniline
2-Bromo-N-(3,4-
3-trifluoromethylbenzoyl





dichloro-phenyl)-
chloride





acetamide


31
B
Aniline
2-Bromo-N-(3,4-
3-cyanobenzoyl chloride





dichloro-phenyl)-





acetamide


32
B
Aniline
2-Bromo-N-(3,4-
2-Methoxybenzoyl





dichloro-phenyl)-
chloride





acetamide


33
B
Aniline
2-Bromo-N-(3,4-
3-Methylbenzoyl





dichloro-phenyl)-
chloride





acetamide


34
A
Aniline
2-Bromo-N-(4-methyl-
6-trifluoromethyl-





phenyl)-acetamide
nicotynoyl chloride


35
B
Aniline
2-Bromo-N-(3,4-
3-Chlorobenzoyl





dichloro-phenyl)-
chloride





acetamide


36
A
Aniline
2-Bromo-N-(4-fluoro-
6-trifluoromethyl-





phenyl)-acetamide
nicotynoyl chloride


37
B
Aniline
2-Bromo-N-(3,4-
6-Trifluoromethyl-





dichloro-phenyl)-
nicotinoyl chloride





acetamide


38
B
Aniline
2-Bromo-N-(3,4-
4-cyanobenzoyl chloride





dichloro-phenyl)-





acetamide


39
B
Aniline
2-Bromo-N-(3,4-
2-Fluorobenzoyl chloride





dichloro-phenyl)-





acetamide


40
B
Aniline
2-Bromo-N-(3,4-
3-fluorobenzoyl chloride





dichloro-phenyl)-





acetamide


41
B
Aniline
2-Bromo-N-(3,4-
4-methoxybenzoyl





dichloro-phenyl)-
chloride





acetamide


42
B
Aniline
2-Bromo-N-(3,4-
4-fluorobenzoyl chloride





dichloro-phenyl)-





acetamide


43
D
2-Chloro-benzylamine
2-Chloro-N-(3-
3-Methylbenzoyl





trifluoromethyl-
chloride





phenyl)-acetamide


44
D
2-Chloro-benzylamine
2-Chloro-N-(3-
6-trifluoromethyl-





trifluoromethyl-
nicotynoyl chloride





phenyl)-acetamide


45
D
3,5-difluoro-
2-Chloro-N-(3-
3-Chlorobenzoyl




benzylamine
trifluoromethyl-
chloride





phenyl)-acetamide


46
D
3,5-difluoro-
2-Chloro-N-(3-
6-trifluoromethyl-




benzylamine
trifluoromethyl-
nicotynoyl chloride





phenyl)-acetamide


47
D
3,5-difluoro-
2-Chloro-N-(3-
6-Trifluoromethyl-




benzylamine
trifluoromethyl-
nicotinoyl chloride





phenyl)-acetamide


48
D
3,5-difluoro-
2-Chloro-N-(3-
4-cyanobenzoyl chloride




benzylamine
trifluoromethyl-





phenyl)-acetamide


49
D
3,5-difluoro-
2-Chloro-N-(3-
2-Fluorobenzoyl chloride




benzylamine
trifluoromethyl-





phenyl)-acetamide


50
D
3,5-difluoro-
2-Chloro-N-(3-
4-cyanobenzoyl chloride




benzylamine
trifluoromethyl-





phenyl)-acetamide


51
D
2-Chloro-benzylamine
2-Chloro-N-(3-
Benzo[b]thiophene-2-





trifluoromethyl-
carbonyl chloride





phenyl)-acetamide


52
D
2-Chloro-benzylamine
2-Chloro-N-(3-
3-fluorobenzoyl chloride





trifluoromethyl-





phenyl)-acetamide


53
D
2-Chloro-benzylamine
2-Chloro-N-(3-
4-Chlorobenzoyl





trifluoromethyl-
chloride





phenyl)-acetamide


54
D
2-Chloro-benzylamine
2-Chloro-N-(3-
4-





trifluoromethyl-
trifluoromethoxybenzoyl





phenyl)-acetamide
chloride


55
D
2-Chloro-benzylamine
2-Chloro-N-(3-
4-Fluorobenzoyl chloride





trifluoromethyl-





phenyl)-acetamide


56
D
3,5-difluoro-
2-Chloro-N-(3-
6-trifluoromethyl benzyl




benzylamine
trifluoromethyl-
chloride





phenyl)-acetamide


57
D
2-Chloro-benzylamine
2-Chloro-N-(3-fluoro-
Benzo[b]thiophene-2-





phenyl)-acetamide
carbonyl chloride


58
D
2-Chloro-benzylamine
2-Chloro-N-(3-fluoro-
3-fluorobenzoyl chloride





phenyl)-acetamide


59
D
2-Chloro-benzylamine
2-Chloro-N-(3-fluoro-
3-Methylbenzoyl





phenyl)-acetamide
chloride


60
D
2-Chloro-benzylamine
2-Chloro-N-(3-fluoro-
4-





phenyl)-acetamide
trifluoromethoxybenzoyl






chloride


61
D
2-Chloro-benzylamine
2-Chloro-N-(3-fluoro-
4-Fluorobenzoyl chloride





phenyl)-acetamide


62
D
2-Chloro-benzylamine
2-Chloro-N-(3-fluoro-
4-cyanobenzoyl chloride





phenyl)-acetamide


63
D
3,5-difluoro-
2-Chloro-N-(3-fluoro-
Benzo[b]thiophene-2-




benzylamine
phenyl)-acetamide
carbonyl chloride


64
D
3,5-difluoro-
2-Chloro-N-(3-fluoro-
3-Methylbenzoyl




benzylamine
phenyl)-acetamide
chloride


65
D
3,5-difluoro-
2-Chloro-N-(3-fluoro-
4-




benzylamine
phenyl)-acetamide
trifluoromethoxybenzoyl






chloride


66
D
3,4-difluoro-
2-Chloro-N-(3-fluoro-
Benzo[b]thiophene-2-




benzylamine
phenyl)-acetamide
carbonyl chloride


67
D
3,4-difluoro-
2-Chloro-N-(3-fluoro-
3-Methylbenzoyl




benzylamine
phenyl)-acetamide
chloride


68
D
3,4-difluoro-
2-Chloro-N-(3-fluoro-
4-




benzylamine
phenyl)-acetamide
trifluoromethoxybenzoyl






chloride


69
D
2,6-difluoro-
2-Chloro-N-(3-
Benzo[b]thiophene-2-




benzylamine
Chloro,4-fluoro-
carbonyl chloride





phenyl)-acetamide


70
D
2,6-difluoro-
2-Chloro-N-(3-
3-Methylbenzoyl




benzylamine
Chloro,4-fluoro-
chloride





phenyl)-acetamide


71
D
2,6-difluoro-
2-Chloro-N-(3-
4-




benzylamine
Chloro,4-fluoro-
trifluoromethoxybenzoyl





phenyl)-acetamide
chloride


72
D
2-Chloro-benzylamine
2-Chloro-N-(3-
Benzo[b]thiophene-2-





Chloro,4-fluoro-
carbonyl chloride





phenyl)-acetamide


73
D
2-Chloro-benzylamine
2-Chloro-N-(3-
3-fluorobenzoyl chloride





Chloro,4-fluoro-





phenyl)-acetamide


74
D
2-Chloro-benzylamine
2-Chloro-N-(3-
4-Chlrorobenzoyl





Chloro,4-fluoro-
chloride





phenyl)-acetamide


75
D
2-Chloro-benzylamine
2-Chloro-N-(3-
4-





Chloro,4-fluoro-
trifluoromethoxybenzoyl





phenyl)-acetamide
chloride


76
D
2-Chloro-benzylamine
2-Chloro-N-(3-
4-Fluorobenzoyl chloride





Chloro,4-fluoro-





phenyl)-acetamide


77
D
2-Chloro-benzylamine
2-Chloro-N-(3-
4-cyanobenzoyl chloride





Chloro,4-fluoro-





phenyl)-acetamide


78
D
2,6-difluoro-
2-Chloro-N-(3-
4-Fluorobenzoyl chloride




benzylamine
Chloro,4-fluoro-





phenyl)-acetamide


79
D
2-Chloro-benzylamine
2-Chloro-N-(3-
6-trifluoromethyl benzyl





Chloro,4-fluoro-
chloride





phenyl)-acetamide


80
D
2,3-Difluoro-
2-Chloro-N-(3-
Benzo[b]thiophene-2-




benzylamine
Chloro,4-fluoro-
carbonyl chloride





phenyl)-acetamide


81
D
2,3-Difluoro-
2-Chloro-N-(3-
3-fluorobenzoyl chloride




benzylamine
Chloro,4-fluoro-





phenyl)-acetamide


82
D
2,3-Difluoro-
2-Chloro-N-(3-
4-Chlrorobenzoyl




benzylamine
Chloro,4-fluoro-
chloride





phenyl)-acetamide


83
D
2,3-Difluoro-
2-Chloro-N-(3-
4-




benzylamine
Chloro,4-fluoro-
trifluoromethoxybenzoyl





phenyl)-acetamide
chloride


84
D
2,3-Difluoro-
2-Chloro-N-(3-
4-Fluorobenzoyl chloride




benzylamine
Chloro,4-fluoro-





phenyl)-acetamide


85
D
2,3-Difluoro-
2-Chloro-N-(3-
4-cyanobenzoyl chloride




benzylamine
Chloro,4-fluoro-





phenyl)-acetamide


86
D
2,3-Difluoro-
2-Chloro-N-(3-
6-trifluoromethyl benzyl




benzylamine
Chloro,4-fluoro-
chloride





phenyl)-acetamide


87
D
2,3-Difluoro-
2-Chloro-N-(3-
Benzo[b]thiophene-2-




benzylamine
Chloro,4-fluoro-
carbonyl chloride





phenyl)-acetamide


88
D
2,6-difluoro-
2-Chloro-N-(3-
4-cyanobenzoyl chloride




benzylamine
Chloro,4-fluoro-





phenyl)-acetamide


89
D
2,3-Difluoro-
2-Chloro-N-(3-
3-Methylbenzoyl




benzylamine
Chloro,4-fluoro-
chloride





phenyl)-acetamide


90
D
3,5-difluoro-
2-Chloro-N-(3-
4-




benzylamine
Chloro,4-fluoro-
trifluoromethoxybenzoyl





phenyl)-acetamide
chloride


91
D
3,5-difluoro-
2-Chloro-N-(3-
4-Fluorobenzoyl chloride




benzylamine
Chloro,4-fluoro-





phenyl)-acetamide


92
D
3,5-difluoro-
2-Chloro-N-(3-
4-cyanobenzoyl chloride




benzylamine
Chloro,4-fluoro-





phenyl)-acetamide


93
D
3,5-difluoro-
2-Chloro-N-(3-
6-trifluoromethyl benzyl




benzylamine
Chloro,4-fluoro-
chloride





phenyl)-acetamide


94
D
3,4-Difluoro-
2-Chloro-N-(3-
Benzo[b]thiophene-2-




benzylamine
Chloro,4-fluoro-
carbonyl chloride





phenyl)-acetamide


95
D
2,2-simethyl
2-Chloro-N-(3-Chloro
4-Chlrorobenzoyl




propylamine
phenyl)-acetamide
chloride


96
D
3,3-dimethyl
2-Chloro-N-(3-Chloro
4-Chlrorobenzoyl




butylamine
phenyl)-acetamide
chloride


97
E
iso butylamine
2-Bromo-N-(3,4-
4-Methoxybenzoyl





dichloro phenyl)-
chloride





acetamide


98
E
3-methyl butylamine
2-Bromo-N-(3,4-
4-Methoxybenzoyl





dichloro phenyl)-
chloride





acetamide


99
B
benzylamine
2-Bromo-N-(3,4-
4-Methoxybenzoyl





dichloro phenyl)-
chloride





acetamide


100
D
3-cyano-benzylamine
2-Chloro-N-(3-chloro-
4-Chlorobenzoyl





phenyl)-acetamide
chloride


101
D
3-methoxy-
2-Chloro-N-(3-chloro-
4-Chlorobenzoyl




benzylamine
phenyl)-acetamide
chloride


102
D
2-methoxy-
2-Chloro-N-(3-chloro-
4-Chlorobenzoyl




benzylamine
phenyl)-acetamide
chloride


103
D
3-methyl-benzylamine
2-Chloro-N-(3-chloro-
4-Chlorobenzoyl





phenyl)-acetamide
chloride


104
D
2-methyl-benzylamine
2-Chloro-N-(3-chloro-
4-Chlorobenzoyl





phenyl)-acetamide
chloride


105
D
3-Chloro-benzylamine
2-Chloro-N-(3-chloro-
4-Chlorobenzoyl





phenyl)-acetamide
chloride


106
D
2-Chloro-benzylamine
2-Chloro-N-(3-chloro-
4-Chlorobenzoyl





phenyl)-acetamide
chloride


107
D
C-Furan-2-yl-
2-Chloro-N-(3-chloro-
4-Chlorobenzoyl




methylamine
phenyl)-acetamide
chloride


108
C
Phenylamino-acetic
2-Bromo-N-(3,4-
4-methoxy benzoyl




acid ethyl ester
dichloro phenyl)-
chloride





acetamide


119
B
2-fluoro-benzylamine
3-Chloro aniline
6-Morpholin-4-yl-






nicotinoyl chloride


120
B
2-fluoro-benzylamine
3-Chloro aniline
6-Chloro-nicotinoyl






chloride


121
B
2-Fluoro-benzylamine
3-Chloro aniline
2-Chloro-isonicotinoyl






chloride


122
B
2-Fluoro-benzylamine
3-Chloro aniline
2,6-Dichloro-






isonicotinoyl chloride


123
A
C-Cyclohexyl-
2-Chloro-N-(3-chloro-
4-chlorobenzoyl chloride




methylamine
phenyl)-acetamide


124
A
C-Cyclohexyl-
2-Chloro-N-(3-chloro-
4-Chlorobenzoyl




methylamine
phenyl)-acetamide
chloride


125
A
C-Cyclohexyl-
2-Chloro-N-(3-chloro-
4-Fluorobenzoyl chloride




methylamine
phenyl)-acetamide


126
A
Cyclopentylamine
2,4-Dichloro-N-(3-
4-Methoxybenzoyl





chloro-phenyl)-
chloride





acetamide


127
A
Cyclopropylamine
2,4-Dichloro-N-(3-
4-Methoxybenzoyl





chloro-phenyl)-
chloride





acetamide


128
A
Cyclohexylamine
2,4-Dichloro-N-(3-
4-Methoxybenzoyl





chloro-phenyl)-
chloride





acetamide









The following compounds have been prepared in accordance with table 1:







TABLE 2







I













 














Procedure
R1
R2
R3
R4
X
IC50
Exp

















D








H




bond
0.052
1


 


D








H




bond
0.265
2


 


D








H




bond
0.184
3


 


D








H




bond
0.074
4


 


D








H




bond
0.16
5


 


D








H




bond
0.165
6


 


D








H




bond

7


 


D








H




bond
0.128
8


 


D








H




bond
0.074
9


 


D








H




bond
0.285
10


 


D








H




bond
0.1
11


 


D








H




bond
0.243
12


 


D








H




bond
0.122
13


 


D








H




bond
0.024
14


 


D








H




bond
0.312
15


 


D








H




bond
0.156
16


 


D








H




bond
0.077
17


 


D








H




bond
0.257
18


 


C








H




bond
0.164
19


 


D








H




bond

20


 


D








H




bond
0.315
21


 


B








H




bond

22


 


C








H




bond

23


 


C








H




bond

24


 


C








H




bond

25


 


C








H




bond

26


 


C








H




bond
0.148
27


 


C








H




bond
0.267
28


 


C








H




bond

29


 


B








H




bond

30


 


B








H




bond
0.35
31


 


B








H




bond

32


 


B








H




bond

33


 


A








H




bond

34


 


B








H




bond

35


 


A








H




bond

36


 


B








H




bond
0.154
37


 


B








H




bond

38


 


B








H




bond
0.291
39


 


B








H




bond

40


 


B








H




bond
0.276
41


 


B








H




bond

42


 


D








H




bond
0.339
43


 


D








H




bond

44


 


D








H




bond
0.298
45


 


D








H




bond

46


 


D








H




bond

47


 


D








H




bond

48


 


D








H




bond

49


 


D








H




bond

50


 


D








H




bond
0.06
51


 


D








H




bond
0.153
52


 


D








H




bond
0.241
53


 


D








H




bond
0.196
54


 


D








H




bond
0.097
55


 


D








H




bond

56


 


D








H




bond
0.088
57


 


D








H




bond

58


 


D








H




bond
0.166
59


 


D








H




bond
0.107
60


 


D








H




bond

61


 


D








H




bond
0.357
62


 


D








H




bond
0.07 
63


 


D








H




bond

64


 


D








H




bond
0.278
65


 


D








H




bond
0.167
66


 


D








H




bond

67


 


D








H




bond

68


 


D








H




bond
0.09
69


 


D








H




bond

70


 


D








H




bond
0.107
71


 


D








H




bond
0.205
72


 


D








H




bond

73


 


D








H




bond
0.142
74


 


D








H




bond
0.259
75


 


D








H




bond
0.159
76


 


D








H




bond
0.182
77


 


D








H




bond
0.282
78


 


D








H




bond

79


 


D








H




bond
0.066
80


 


D








H




bond

81


 


D








H




bond
0.108
82


 


D








H




bond
0.078
83


 


D








H




bond
0.178
84


 


D








H




bond
0.123
85


 


D








H




bond

86


 


D








H




bond
0.036
87


 


D








H




bond
0.199
88


 


D








H




bond
0.306
89


 


D








H




bond
0.288
90


 


D








H




bond

91


 


D








H




bond

92


 


D








H




bond

93


 


D








H




bond

94


 


D








H




bond

95


 


D








H




bond
0.359
96


 


E








H




bond

97


 


E








H




bond

98


 


B








H




bond

99


 


D








H




bond
0.192
100


 


D








H




bond

101


 


D








H




bond
0.06
102


 


D








H




bond
0.142
103


 


D








H




bond
0.209
104


 


D








H




bond
0.021
105


 


D








H




bond
0.025
106


 


D








H




bond
0.199
107


 


C








H




bond
0.182
108


 


C








H




bond

109


 


C








H




bond
0.369
110


 


C








H




bond

111


 


C








H




bond

112


 


B








H




bond
0.15
113


 


B








H




bond
0.091
114


 


B








H




bond

115


 


B








H




bond
0.191
116


 


B








H




bond
0.21
117


 


B








H




OCH2
0.259
118


 


B








H




bond
0.355
119


 


B








H




bond
0.182
120


 


B








H




bond

121


 


B








H




bond

122


 


A








CH3




bond

123


 


A








H




bond

124


 


A








H




bond

125


 


A








H




bond
0.357
126


 


A








H




bond

127


 


A








H




bond

128




















TABLE 3







MS
MS



Compound name
MW
result
mode
Example



















4-Chloro-N-[(3-chloro-phenylcarbamoyl)-methyl]-
449.28
447.0
neg
1


N-(2,6-difluoro-benzyl)-benzamide


4-Chloro-N-[(3-chloro-phenylcarbamoyl)-methyl]-
449.28
447.0
neg
2


N-(3,4-difluoro-benzyl)-benzamide


4-Chloro-N-[(3-chloro-phenylcarbamoyl)-methyl]-
449.28
447.0
neg
3


N-(3,5-difluoro-benzyl)-benzamide


4-Chloro-N-[(3-chloro-phenylcarbamoyl)-methyl]-
449.28
449.2
pos
4


N-(2,3-difluoro-benzyl)-benzamide


4-Chloro-N-[(3-chloro-phenylcarbamoyl)-methyl]-
449.28
449.2
pos
5


N-(2,4-difluoro-benzyl)-benzamide


4-Chloro-N-[(3-chloro-phenylcarbamoyl)-methyl]-
449.28
449.2
pos
6


N-(2,5-difluoro-benzyl)-benzamide


4-Chloro-N-[(3-chloro-phenylcarbamoyl)-methyl]-
431.29
431.4
pos
7


N-(4-fluoro-benzyl)-benzamide


4-Chloro-N-[(3-chloro-phenylcarbamoyl)-methyl]-
431.29
431.4
pos
8


N-(3-fluoro-benzyl)-benzamide


4-Chloro-N-[(3-chloro-phenylcarbamoyl)-methyl]-
431.29
431.4
pos
9


N-(2-fluoro-benzyl)-benzamide


N-[(3-Chloro-phenylcarbamoyl)-methyl]-4-
414.9
415.3
pos
10


methoxy-N-thiophen-3-ylmethyl-benzamide


N-[(3-Chloro-phenylcarbamoyl)-methyl]-N-(2,6-
444.9
443.2
neg
11


difluoro-benzyl)-4-methoxy-benzamide


N-[(3-Chloro-phenylcarbamoyl)-methyl]-N-(3,5-
477.8
477.1
pos
12


dichloro-benzyl)-4-methoxy-benzamide


N-[(3-Chloro-phenylcarbamoyl)-methyl]-N-(2,5-
477.8
479.2
pos
13


dichloro-benzyl)-4-methoxy-benzamide


N-(3-Chloro-benzyl)-N-[(3-chloro-
443.3
443.3
pos
14


phenylcarbamoyl)-methyl]-4-methoxy-benzamide


N-Benzyl-N-[(3-chloro-phenylcarbamoyl)-methyl]-
496.8
497.1
pos
15


4-fluoro-benzamide


N-Benzyl-4-chloro-N-[(3-chloro-phenylcarbamoyl)-
413.3
413.2
pos
16


methyl]-benzamide


4-Chloro-N-[(3-chloro-phenylcarbamoyl)-methyl]-
419.3
419.1
pos
17


N-thiophen-2-ylmethyl-benzamide


N-[(3,4-Dichloro-phenylcarbamoyl)-methyl]-4-
449.4
449.1
pos
18


methoxy-N-thiophen-2-ylmethyl-benzamide


N-[(3-Chloro-phenylcarbamoyl)-methyl]-N-(2,6-
477.8
479.2
pos
19


dichloro-benzyl)-4-methoxy-benzamide


N-[(3,4-Dichloro-phenylcarbamoyl)-methyl]-N-(3-
447.3
447.1
pos
20


fluoro-phenyl)-4-methoxy-benzamide


N-[(3,4-Dichloro-phenylcarbamoyl)-methyl]-N-(2-
447.3
447.1
pos
21


fluoro-phenyl)-4-methoxy-benzamide


Pentanoic acid [(3,4-dichloro-phenylcarbamoyl)-
379.3
379.3
pos
22


methyl]-phenyl-amide


N-[(3-Chloro-2-fluoro-phenylcarbamoyl)-methyl]-
412.8
413.4
pos
23


4-methoxy-N-phenyl-benzamide


N-[(2,2-Difluoro-benzo[1,3]dioxol-5-ylcarbamoyl)-
440.4
441.0
pos
24


methyl]-4-methoxy-N-phenyl-benzamide


4-Methoxy-N-phenyl-N-[(3-trifluoromethoxy-
444.4
445.1
pos
25


phenylcarbamoyl)-methyl]-benzamide


4-Methoxy-N-phenyl-N-(m-tolylcarbamoyl-
374.4
375.1
pos
26


methyl)-benzamide


4-Methoxy-N-phenyl-N-[(3-trifluoromethyl-
428.4
429.0
pos
27


phenylcarbamoyl)-methyl]-benzamide


N-[(3-Chloro-phenylcarbamoyl)-methyl]-4-
394.9
395.0
pos
28


methoxy-N-phenyl-benzamide


4-Methoxy-N-[(3-methoxy-phenylcarbamoyl)-
390.4
391.3
pos
29


methyl]-N-phenyl-benzamide


N-[(3,4-Dichloro-phenylcarbamoyl)-methyl]-N-
467.3
467.0
pos
30


phenyl-3-trifluoromethyl-benzamide


3-Cyano-N-[(3,4-dichloro-phenylcarbamoyl)-
424.3
467.0
pos
31


methyl]-N-phenyl-benzamide


N-[(3,4-Dichloro-phenylcarbamoyl)-methyl]-2-
429.3
429.2
pos
32


methoxy-N-phenyl-benzamide


N-[(3,4-Dichloro-phenylcarbamoyl)-methyl]-3-
413.3
413.2
pos
33


methyl-N-phenyl-benzamide


N-Phenyl-N-(p-tolylcarbamoyl-methyl)-6-
413.4
414.4
pos
34


trifluoromethyl-nicotinamide


3-Chloro-N-[(3,4-dichloro-phenylcarbamoyl)-
433.7
433.0
pos
35


methyl]-N-phenyl-benzamide


N-[(4-Fluoro-phenylcarbamoyl)-methyl]-N-phenyl-
417.4
418.0
pos
36


6-trifluoromethyl-nicotinamide


N-[(3,4-Dichloro-phenylcarbamoyl)-methyl]-N-
468.3
468.1
pos
37


phenyl-6-trifluoromethyl-nicotinamide


4-Cyano-N-[(3,4-dichloro-phenylcarbamoyl)-
424.3
424.0
pos
38


methyl]-N-phenyl-benzamide


N-[(3,4-Dichloro-phenylcarbamoyl)-methyl]-2-
417.3
417.3
pos
39


fluoro-N-phenyl-benzamide


N-[(3,4-Dichloro-phenylcarbamoyl)-methyl]-3-
417.3
417.1
pos
40


fluoro-N-phenyl-benzamide


N-[(3,4-Dichloro-phenylcarbamoyl)-methyl]-4-
429.3
429.3
pos
41


methoxy-N-phenyl-benzamide


N-[(3,4-Dichloro-phenylcarbamoyl)-methyl]-4-
417.3
417.1
pos
42


fluoro-N-phenyl-benzamide


N-(2-Chloro-benzyl)-4-cyano-N-[(3-
471.9
472.2
pos
43


trifluoromethyl-phenylcarbamoyl)-methyl]-


benzamide


N-(2-Chloro-benzyl)-3-trifluoromethyl-N-[(3-
514.9
515.2
pos
44


trifluoromethyl-phenylcarbamoyl)-methyl]-


benzamide


Benzo[b]thiophene-2-carboxylic acid (3,5-difluoro-
504.5
506.2
pos
45


benzyl)-[(3-trifluoromethyl-phenylcarbamoyl)-


methyl]-amide


N-(3,5-Difluoro-benzyl)-3-fluoro-N-[(3-
466.4
467.2
pos
46


trifluoromethyl-phenylcarbamoyl)-methyl]-


benzamide


4-Chloro-N-(3,5-difluoro-benzyl)-N-[(3-
482.8
483.4
pos
47


trifluoromethyl-phenylcarbamoyl)-methyl]-


benzamide


N-(3,5-Difluoro-benzyl)-4-trifluoromethoxy-N-[(3-
432.4
433.2
pos
48


trifluoromethyl-phenylcarbamoyl)-methyl]-


benzamide


N-(3,5-Difluoro-benzyl)-4-fluoro-N-[(3-
466.4
467.2
pos
49


trifluoromethyl-phenylcarbamoyl)-methyl]-


benzamide


4-Cyano-N-(3,5-difluoro-benzyl)-N-[(3-
473.4
474.2
pos
50


trifluoromethyl-phenylcarbamoyl)-methyl]-


benzamide


Benzo[b]thiophene-2-carboxylic acid (2-chloro-
502.9
503.1
pos
51


benzyl)-[(3-trifluoromethyl-phenylcarbamoyl)-


methyl]-amide


N-(2-Chloro-benzyl)-3-fluoro-N-[(3-
464.9
465.3
pos
52


trifluoromethyl-phenylcarbamoyl)-methyl]-


benzamide


4-Chloro-N-(2-chloro-benzyl)-N-[(3-
481.3
481.2
pos
53


trifluoromethyl-phenylcarbamoyl)-methyl]-


benzamide


#N!-(2-Chloro-benzyl)-4-trifluoromethoxy-#N!-[(3-
530.9
531.1
pos
54


trifluoromethyl-phenylcarbamoyl)-methyl]-


benzamide


N-(2-Chloro-benzyl)-4-fluoro-N-[(3-
464.9
465.3
pos
55


trifluoromethyl-phenylcarbamoyl)-methyl]-


benzamide


N-(3,5-Difluoro-benzyl)-3-trifluoromethyl-N-[(3-
516.4
517.2
pos
56


trifluoromethyl-phenylcarbamoyl)-methyl]-


benzamide


Benzo[b]thiophene-2-carboxylic acid (2-chloro-
452.9
453.0
pos
57


benzyl)-[(3-fluoro-phenylcarbamoyl)-methyl]-amide


N-(2-Chloro-benzyl)-3-fluoro-N-[(3-fluoro-
414.8
415.3
pos
58


phenylcarbamoyl)-methyl]-benzamide


4-Chloro-N-(2-chloro-benzyl)-N-[(3-fluoro-
431.3
431.1
pos
59


phenylcarbamoyl)-methyl]-benzamide


N-(2-Chloro-benzyl)-N-[(3-fluoro-
480.8
481.1
pos
60


phenylcarbamoyl)-methyl]-4-trifluoromethoxy-


benzamide


N-(2-Chloro-benzyl)-4-fluoro-N-[(3-fluoro-
414.8
415.2
pos
61


phenylcarbamoyl)-methyl]-benzamide


N-(2-Chloro-benzyl)-4-cyano-N-[(3-fluoro-
421.9
422.1
pos
62


phenylcarbamoyl)-methyl]-benzamide


Benzo[b]thiophene-2-carboxylic acid (3,5-difluoro-
454.5
455.2
pos
63


benzyl)-[(3-fluoro-phenylcarbamoyl)-methyl]-amide


4-Chloro-N-(3,5-difluoro-benzyl)-N-[(3-fluoro-
432.8
433.2
pos
64


phenylcarbamoyl)-methyl]-benzamide


N-(3,5-Difluoro-benzyl)-N-[(3-fluoro-
482.4
483.1
pos
65


phenylcarbamoyl)-methyl]-4-trifluoromethoxy-


benzamide


Benzo[b]thiophene-2-carboxylic acid (3,4-difluoro-
454.5
455.2
pos
66


benzyl)-[(3-fluoro-phenylcarbamoyl)-methyl]-amide


4-Chloro-N-(3,4-difluoro-benzyl)-N-[(3-fluoro-
432.8
433.2
pos
67


phenylcarbamoyl)-methyl]-benzamide


N-(3,4-Difluoro-benzyl)-N-[(3-fluoro-
482.4
483.4
pos
68


phenylcarbamoyl)-methyl]-4-trifluoromethoxy-


benzamide


Benzo[b]thiophene-2-carboxylic acid [(3-chloro-4-
488.9
489.1
pos
69


fluoro-phenylcarbamoyl)-methyl]-(2,6-difluoro-


benzyl)-amide


4-Chloro-N-[(3-chloro-4-fluoro-phenylcarbamoyl)-
467.3
467.1
pos
70


methyl]-N-(2,6-difluoro-benzyl)-benzamide


N-[(3-Chloro-4-fluoro-phenylcarbamoyl)-methyl]-
518.8
517.1
pos
71


N-(2,6-difluoro-benzyl)-4-trifluoromethoxy-


benzamide


Benzo[b]thiophene-2-carboxylic acid (2-chloro-
487.4
487.2
pos
72


benzyl)-[(3-chloro-4-fluoro-phenylcarbamoyl)-


methyl]-amide


N!-(2-Chloro-benzyl)-N!-[(3-chloro-4-fluoro-
449.3
449.1
pos
73


phenylcarbamoyl)-methyl]-3-fluoro-benzamide


4-Chloro-N-(2-chloro-benzyl)-N-[(3-chloro-4-
465.7
465.2
pos
74


fluoro-phenylcarbamoyl)-methyl]-benzamide


N-(2-Chloro-benzyl)-N-[(3-chloro-4-fluoro-
515.3
512.3
pos
75


phenylcarbamoyl)-methyl]-4-trifluoromethoxy-


benzamide


N-(2-Chloro-benzyl)-N-[(3-chloro-4-fluoro-
449.3
449.1
pos
76


phenylcarbamoyl)-methyl]-4-fluoro-benzamide


N-(2-Chloro-benzyl)-N-[(3-chloro-4-fluoro-
456.3
456.3
pos
77


phenylcarbamoyl)-methyl]-4-cyano-benzamide


N-[(3-Chloro-4-fluoro-phenylcarbamoyl)-methyl]-
450.8
451.1
pos
78


N-(2,6-difluoro-benzyl)-4-fluoro-benzamide


N-(2-Chloro-benzyl)-N-[(3-chloro-4-fluoro-
499.3
499.2
pos
79


phenylcarbamoyl)-methyl]-3-trifluoromethyl-


benzamide


Benzo[b]thiophene-2-carboxylic acid [(3-chloro-4-
488.9
489.2
pos
80


fluoro-phenylcarbamoyl)-methyl]-(2,3-difluoro-


benzyl)-amide


N-[(3-Chloro-4-fluoro-phenylcarbamoyl)-methyl]-
450.8
451.1
pos
81


N-(2,3-difluoro-benzyl)-3-fluoro-benzamide


4-Chloro-N-[(3-chloro-4-fluoro-phenylcarbamoyl)-
467.3
467.2
pos
82


methyl]-N-(2,3-difluoro-benzyl)-benzamide


N-[(3-Chloro-4-fluoro-phenylcarbamoyl)-methyl]-
516.8
517.1
pos
83


N-(2,3-difluoro-benzyl)-4-trifluoromethoxy-


benzamide


N-[(3-Chloro-4-fluoro-phenylcarbamoyl)-methyl]-
450.8
451.1
pos
84


N-(2,3-difluoro-benzyl)-4-fluoro-benzamide


N-[(3-Chloro-4-fluoro-phenylcarbamoyl)-methyl]-
457.8
458.3
pos
85


4-cyano-N-(2,3-difluoro-benzyl)-benzamide


N-[(3-Chloro-4-fluoro-phenylcarbamoyl)-methyl]-
500.8
501.1
pos
86


N-(2,3-difluoro-benzyl)-3-trifluoromethyl-


benzamide


Benzo[b]thiophene-2-carboxylic acid [(3-chloro-4-
488.9
499.1
pos
87


fluoro-phenylcarbamoyl)-methyl]-(3,5-difluoro-


benzyl)-amide


N-[(3-Chloro-4-fluoro-phenylcarbamoyl)-methyl]-
457.8
458.3
pos
88


4-cyano-N-(2,6-difluoro-benzyl)-benzamide


4-Chloro-N-[(3-chloro-4-fluoro-phenylcarbamoyl)-
467.3
467.4
pos
89


methyl]-N-(3,5-difluoro-benzyl)-benzamide


N-[(3-Chloro-4-fluoro-phenylcarbamoyl)-methyl]-
516.8
517.1
pos
90


N-(3,5-difluoro-benzyl)-4-trifluoromethoxy-


benzamide


N-[(3-Chloro-4-fluoro-phenylcarbamoyl)-methyl]-
450.8
451.1
pos
91


N-(3,5-difluoro-benzyl)-4-fluoro-benzamide


N-[(3-Chloro-4-fluoro-phenylcarbamoyl)-methyl]-
457.8
458.3
pos
92


4-cyano-N-(3,5-difluoro-benzyl)-benzamide


N-[(3-Chloro-4-fluoro-phenylcarbamoyl)-methyl]-
500.8
501.1
pos
93


N-(3,5-difluoro-benzyl)-3-trifluoromethyl-


benzamide


Benzo[b]thiophene-2-carboxylic acid [(3-chloro-4-
488.9
489.1
pos
94


fluoro-phenylcarbamoyl)-methyl]-(3,4-difluoro-


benzyl)-amide


4-Chloro-N-[(3-chloro-phenylcarbamoyl)-methyl]-
393.3
393.1
neg
95


N-(2,2-dimethyl-propyl)-benzamide


4-Chloro-N-[(3-chloro-phenylcarbamoyl)-methyl]-
407.3
408.3
neg
96


N-(3,3-dimethyl-butyl)-benzamide


N-[(3,4-Dichloro-phenylcarbamoyl)-methyl]-N-
409.3
409.2
neg
97


isobutyl-4-methoxy-benzamide


N-[(3,4-Dichloro-phenylcarbamoyl)-methyl]-4-
423.3
421.0
neg
98


methoxy-N-(3-methyl-butyl)-benzamide


N-Benzyl-N-[(3,4-dichloro-phenylcarbamoyl)-
443.3
441.2
neg
99


methyl]-4-methoxy-benzamide


4-Chloro-N-[(3-chloro-phenylcarbamoyl)-methyl]-
438.3
436.0
neg
100


N-(3-cyano-benzyl)-benzamide


4-Chloro-N-[(3-chloro-phenylcarbamoyl)-methyl]-
443.3
440.9
neg
101


N-(3-methoxy-benzyl)-benzamide


4-Chloro-N-[(3-chloro-phenylcarbamoyl)-methyl]-
443.3
440.9
neg
102


N-(2-methoxy-benzyl)-benzamide


4-Chloro-N-[(3-chloro-phenylcarbamoyl)-methyl]-
427.3
446.8
neg
103


N-(3-methyl-benzyl)-benzamide


4-Chloro-N-[(3-chloro-phenylcarbamoyl)-methyl]-
427.3
424.9
neg
104


N-(2-methyl-benzyl)-benzamide


4-Chloro-N-(3-chloro-benzyl)-N-[(3-chloro-
447.8
446.8
neg
105


phenylcarbamoyl)-methyl]-benzamide


4-Chloro-N-(2-chloro-benzyl)-N-[(3-chloro-
447.8
446.8
neg
106


phenylcarbamoyl)-methyl]-benzamide


4-Chloro-N-[(3-chloro-phenylcarbamoyl)-methyl]-
403.3
401.0
neg
107


N-furan-2-ylmethyl-benzamide


N-[(3-Chloro-4-fluoro-phenylcarbamoyl)-methyl]-
412.9
413.0
pos
108


4-methoxy-N-phenyl-benzamide


N-[(5-Chloro-2-methyl-phenylcarbamoyl)-methyl]-
408.9
409.2
pos
109


4-methoxy-N-phenyl-benzamide


N-[(3-Chloro-4-methyl-phenylcarbamoyl)-methyl]-
408.9
409.2
pos
110


4-methoxy-N-phenyl-benzamide


N-[(3,5-Dichloro-phenylcarbamoyl)-methyl]-4-
429.3
429.3
pos
111


methoxy-N-phenyl-benzamide


N-[(4-Bromo-3-chloro-phenylcarbamoyl)-methyl]-
473.8
472.9
pos
112


4-methoxy-N-phenyl-benzamide


Benzo[b]thiophene-2-carboxylic acid [(3,4-dichloro-
455.4
454.9
pos
113


phenylcarbamoyl)-methyl]-phenyl-amide


N-[(3,4-Dichloro-phenylcarbamoyl)-methyl]-N-
483.3
482.9
pos
114


phenyl-4-trifluoromethoxy-benzamide


Isoxazole-5-carboxylic acid [(3,4-dichloro-
390.2
390.0
pos
115


phenylcarbamoyl)-methyl]-phenyl-amide


N-[(3,4-Dichloro-phenylcarbamoyl)-methyl]-4-
442.3
442.0
pos
116


dimethylamino-N-phenyl-benzamide


N-(3-Chloro-phenyl)-N-[(3,4-dichloro-
463.7
462.8
pos
117


phenylcarbamoyl)-methyl]-4-methoxy-benzamide


2-(4-Chloro-phenoxy)-N-[(3,4-dichloro-
463.7
462.8
pos
118


phenylcarbamoyl)-methyl]-N-phenyl-acetamide


N-[(3-Chloro-phenylcarbamoyl)-methyl]-N-(2-
462.9
483.5
pos
119


fluoro-benzyl)-6-morpholin-4-yl-nicotinamide


6-Chloro-N-[(3-chloro-phenylcarbamoyl)-methyl]-
432.3
432.2
pos
120


N-(2-fluoro-benzyl)-nicotinamide


2-Chloro-N-[(3-chloro-phenylcarbamoyl)-methyl]-
432.3
432.1
pos
121


N-(2-fluoro-benzyl)-isonicotinamide


2,6-Dichloro-N-[(3-chloro-phenylcarbamoyl)-
466.7
468.1
pos
122


methyl]-N-(2-fluoro-benzyl)-isonicotinamide


4-Chloro-N-{[(3-chloro-phenyl)-methyl-
445.3
445.4
pos
123


carbamoyl]-methyl}-N-(3-fluoro-benzyl)-benzamide


4-Chloro-N-[(3-chloro-phenylcarbamoyl)-methyl]-
419.4
419.1
pos
124


N-cyclohexylmethyl-benzamide


N-[(3-Chloro-phenylcarbamoyl)-methyl]-N-
402.9
403.3
pos
125


cyclohexylmethyl-4-fluoro-benzamide


N-Cyclopentyl-N-[(3,4-dichloro-phenylcarbamoyl)-
421.3
420.9
pos
126


methyl]-4-methoxy-benzamide


N-Cyclopropyl-N-[(3,4-dichloro-phenylcarbamoyl)-
393.3
393.0
pos
127


methyl]-4-methoxy-benzamide


N-Cyclohexyl-N-[(3,4-dichloro-phenylcarbamoyl)-
435.3
435.1
pos
128


methyl]-4-methoxy-benzamide

## Claims

1. A compound of formula I




wherein
R1 is heteroaryl, which is optionally substituted by halogen, lower alkyl, lower alkoxy, lower alkyl substituted by halogen, lower alkoxy substituted by halogen, cyano, amino, di-lower alkyl amino or morpholinyl;
R2 is —(CH2)n-aryl, or —(CH2)n-heteroaryl wherein the aryl or heteroaryl groups are substituted by one or more substituents selected from the group consisting of halogen, lower alkyl, cyano, and lower alkoxy;
R3 is hydrogen or lower alkyl;
R4 is aryl or heteroaryl, wherein aryl and heteroaryl are optionally substituted by one or more substituents selected from the group consisting of halogen, lower alkyl substituted by halogen, lower alkoxy substituted by halogen, and lower alkyl;
X is a bond or —OCH2—; and
n is 0, 1 or 2;

or a pharmaceutically acceptable acid addition salt thereof.

2. A compound of claim 1, wherein X is a bond.

3. A compound of claim 1, wherein R4 is monosubstituted aryl.

4. A compound of claim 3, wherein the monosubstituted aryl is halogen substituted phenyl.

5. A compound of claim 1, wherein R1 is heteroaryl.

6. A compound of claim 5, wherein R1 is benzothiophenyl.

7. A compound of claim 6, selected from the group consisting of
Benzo[b]thiophene-2-carboxylic acid (2-chloro-benzyl)-[(3-trifluoromethyl-phenylcarbamoyl)-methyl]-amide,
Benzo[b]thiophene-2-carboxylic acid (2-chloro-benzyl)-[(3-fluoro-phenylcarbamoyl)-methyl]-amide,
Benzo[b]thiophene-2-carboxylic acid (3,5-difluoro-benzyl)-[(3-fluoro-phenylcarbamoyl)-methyl]-amide,
Benzo[b]thiophene-2-carboxylic acid [(3-chloro-4-fluoro-phenylcarbamoyl)-methyl]-(2,6-difluoro-benzyl)-amide,
Benzo[b]thiophene-2-carboxylic acid [(3-chloro-4-fluoro-phenylcarbamoyl)-methyl]-(2,3-difluoro-benzyl)-amide and
Benzo[b]thiophene-2-carboxylic acid [(3-chloro-4-fluoro-phenylcarbamoyl)-methyl]-(3,5-difluoro-benzyl)-amide.

8. A pharmaceutical composition comprising a compound of formula I




wherein
R1 is heteroaryl, which is optionally substituted by halogen, lower alkyl, lower alkoxy, lower alkyl substituted by halogen, lower alkoxy substituted by halogen, cyano, amino, di-lower alkyl amino or morpholinyl;
R2 is —(CH2)n-aryl, or —(CH2)n-heteroaryl wherein the aryl or heteroaryl groups are substituted by one or more substituents selected from the group consisting of halogen, lower alkyl, cyano, and lower alkoxy,
R3 is hydrogen or lower alkyl;
R4 is aryl or heteroaryl, wherein aryl and heteroaryl are optionally substituted by one or more substituents selected from the group consisting of halogen, lower alkyl substituted by halogen, lower alkoxy substituted by halogen, and lower alkyl;
X is a bond or —OCH2—; and
n is 0, 1 or 2;

or a pharmaceutically acceptable acid addition salt thereof and a pharmaceutically acceptable carrier.