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Title:
DI-AROMATIC SUBSTITUTED AMIDES AS INHIBITORS FOR GLYT1
Document Type and Number:
WIPO Patent Application WO/2008/022938
Kind Code:
A1
Abstract:
The present invention relates to compounds of the general Formula (I) wherein (A) is a 5 or 6-membered aromatic or heteroaromatic ring; R1 is cycloalkyl or is aryl or heteroaryl, wherein at least one ring is aromatic in nature, unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of halogen, lower alkyl, lower alkyl substituted by halogen, lower alkoxy, lower alkoxy substituted by halogen, -C(O) -lower alkyl, -S(O)2-lower alkyl, nitro or cyano; R2 is hydrogen or lower alkyl; R3 is hydrogen or lower alkyl; R4 is halogen, lower alkyl, lower alkyl substituted by halogen, lower alkoxy, lower alkoxy substituted by halogen or nitro; R5 is hydrogen, halogen, lower alkyl or lower alkyl substituted by halogen; X is a bond, -(CH2)m-, -CH2O- or -CH2NH-; The dotted line denotes a bond or not; n is 1 or 2; m is 1, 2 or 3; and pharmaceutically acceptable acid addition salts thereof and their use in the treatment of neurological and neuropsychiatric disorders.

Inventors:
JOLIDON SYNESE (CH)
NARQUIZIAN ROBERT (FR)
PINARD EMMANUEL (FR)
Application Number:
EP2007/058350
Publication Date:
February 28, 2008
Filing Date:
August 13, 2007
Export Citation:
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Assignee:
HOFFMANN LA ROCHE (CH)
JOLIDON SYNESE (CH)
NARQUIZIAN ROBERT (FR)
PINARD EMMANUEL (FR)
International Classes:
C07C237/22; A61K31/16; C07C255/57; C07C271/22; C07C275/24; C07D213/40; C07D213/81; C07D261/18; C07D275/02; C07D279/02; C07D307/79; C07D333/20; C07D333/38; C07D333/44; C07D335/18
Domestic Patent References:
WO1998022433A11998-05-28
WO1996033161A11996-10-24
WO2006080477A12006-08-03
WO1999034790A11999-07-15
Foreign References:
US6506782B12003-01-14
EP0838471A11998-04-29
Other References:
SAKAKIBARA, SHUMPEI ET AL: "Use of anhydrous hydrogen fluoride in peptide synthesis. I. Behavior of various protective groups in anhydrous hydrogen fluoride", BULLETIN OF THE CHEMICAL SOCIETY OF JAPAN, vol. 40, no. 9, 1967, pages 2164 - 2167, XP009092024
DATABASE CAPLUS [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; STEGLICH, WOLFGANG ET AL: "Steric effects in the reaction of (5)-oxazolones and (5)-pseudooxazolones with the esters of amino acids", XP002458221, retrieved from STN Database accession no. 1968:87532
OOI, TAKASHI ET AL.: "Highly Enantioselective Phase-Transfer-Catalyzed Alkylation of Protected .alpha.-Amino Acid Amides toward Practical Asymmetric Synthesis of Vicinal Diamines, .alpha.-Amino Ketones, and .alpha.-Amino Alcohols", J. AM. CHEM. SOC., vol. 127, no. 14, 2005, pages 5073 - 5083, XP002458218
J. D. CONLEY; H. KOHN: "Functionalized DL-Amino Acid Derivatives. Potent New Agents for the treatment of Epilepsy", J. MED. CHEM., vol. 30, no. 3, 1987, pages 567 - 574, XP002458219
RAJIC, ZRINKA ET AL.: "Hydantoin Derivatives of L- and D-amino acids: Synthesis and Evaluation of Their Antiviral and Antitumoral Activity", MOLECULES, vol. 11, no. 11, 1 November 2006 (2006-11-01), pages 837 - 848, XP009092029
DATABASE CHEMCATS Chemical Abstract Service, Columbus, Ohio, US, retrieved from STN; 2007, XP002458222
BARUAH ET AL., SYNLETT, 1999, pages 409
LAURENT ET AL., SYNTHESIS, 2000, pages 667
DEJAEGHER ET AL., SYNLETT, 2002, pages 113
Attorney, Agent or Firm:
POPPE, Regina (Basel, CH)
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Claims:

Claims

1. Compounds of the general formula

wherein

is a 5 or 6-membered aromatic or heteroaromatic ring; R is cycloalkyl or is aryl or heteroaryl, wherein at least one ring is aromatic in nature, unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of halogen, lower alkyl, lower alkyl substituted by halogen, lower alkoxy, lower alkoxy substituted by halogen, -C(O) -lower alkyl, -S(O) 2 -lower alkyl, nitro or cyano; R 2 is hydrogen or lower alkyl;

R 3 is hydrogen or lower alkyl; R 4 is halogen, lower alkyl, lower alkyl substituted by halogen, lower alkoxy, lower alkoxy substituted by halogen or nitro;

R 5 is hydrogen, halogen, lower alkyl or lower alkyl substituted by halogen;

X is a bond, -(CH 2 ) m -, -CH 2 O- or -CH 2 NH-;

The dotted line denotes a bond or not; n is 1 or 2; m is 1, 2 or 3; and pharmaceutically acceptable acid addition salts thereof.

2. Compounds of formula I according to claim 1, wherein X is a bond and the other definitions are as described in claim 1.

3. Compounds of formula I according to claim 2,

wherein is phenyl, monosubstitued by halogen, lower alkyl substituted by halogen or by lower alkyl, R 3 and R 4 are hydrogen, and R 1 is an aryl group, unsubstituted or substituted by fluoro, cyano or nitro.

4. Compounds of formula I according to claim 3, which compounds are

rac-N-({ [(4-chloro-phenyl)-phenyl-methyl]-carbamoyl}-methyl)-4-fluoro-benzamide rac-N-({ [phenyl-(3-trifluoromethyl-phenyl) -methyl] -carbamoyl} -methyl) -benzamide rac-4-fluoro-N-({ [phenyl-(3-trifluoromethyl-phenyl) -methyl] -carbamoyl} -methyl) - benzamide rac-4-cyano-N-({ [phenyl-(3-trifluoromethyl-phenyl)-methyl]-carbamoyl}-methyl)- benzamide

N- [ (benzhydryl-carbamoyl) -methyl] -4-fluoro-benzamide rac-N-({ [(3-chloro-phenyl)-phenyl-methyl]-carbamoyl}-methyl)-4-fluoro-benzamide rac-4-fluoro-N-{ [(phenyl-m-tolyl-methyl) -carbamoyl] -methyl} -benzamide rac-4-fluoro-N-({ [(4-fluoro-phenyl)-phenyl-methyl]-carbamoyl}-methyl) -benzamide

N-({ [bis-(3-fluoro-phenyl) -methyl] -carbamoyl} -methyl) -4-fluoro-benzamide rac-N-({ [(3,5-difluoro-phenyl)-phenyl-methyl]-carbamoyl}-methyl)-4-fluoro- benzamide rac-N-({ [(4-chloro-phenyl)-(3-trifluoromethyl-phenyl)-methyl] -carbamoyl} -methyl) -4- fluoro-benzamide rac-4-fluoro-N-({ [(4-fluoro-phenyl)-(3-trifluoromethyl-phenyl)-methyl]-carbamoyl}- methyl) -benzamide rac-4-fluoro-N-({ [(3-fluoro-phenyl)-(3-trifluoromethyl-phenyl) -methyl] -carbamoyl}- methyl) -benzamide rac-4-fluoro-N-({ [p-tolyl-(3-trifluoromethyl-phenyl)-methyl]-carbamoyl}-methyl)- benzamide

5-methyl-thiophene-2-carboxylic acid ({ [bis-(3-fluoro-phenyl)-methyl]-carbamoyl}- methyl) -amide or N-({ [bis-(3-fluoro-phenyl) -methyl] -carbamoyl} -methyl) -4-nitro-benzamide.

5. Compounds of formula I according to claim 2,

wherein is phenyl, monosubstitued by halogen, R 3 and R 4 are hydrogen, X is a bond and R 1 is heteroaryl, unsubstituted or substituted by nitro.

6. Compounds of formula I according to claim 5, which compounds are

rac-5-nitro-thiophene-2-carboxylic acid ({ [(4-chloro-phenyl)-phenyl-methyl]- carbamoyl} -methyl) -amide rac-thiophene-3-carboxylic acid ({ [(4-chloro-phenyl)-phenyl-methyl] -carbamoyl}- methyl) -amide

5-nitro-thiophene-2-carboxylic acid ({ [bis-(3-fluoro-phenyl)-methyl]-carbamoyl}- methyl) -amide or thiophene-3-carboxylic acid ({ [bis-(3-fluoro-phenyl)-methyl]-carbamoyl}-methyl)- amide.

7. Compounds of formula I according to claim 1, wherein X is -(CH 2 ) m - and the other definitions are as described in claim 1.

8. Compounds of formula I according to claim 1, wherein X is -CH 2 O- and the other definitions are as described in claim 1.

9. Compounds of formula I according to claim 1, wherein X is -CH 2 NH- and the other definitions are as described in claim 1.

10. Processes for preparation of compounds of formula I and their pharmaceutically acceptable salts, which processes comprise

a) reacting a compound of formula II

with a compound of formula

in the presence of an activating agent to a compound of formula

wherein the substituents are as defined in claim 1, or

b) reacting a compound of formula

R Y O XV for X = -(CH 2 ) n - with a compound of formula

in presence of a coupling reagent or with an acid halide to a compound of formula

wherein the substituents are as defined in claim 1 and Y is halogen or hydroxy, or

c) reacting a compound of formula

R N VI for X = -CH 2 NH- with a compound of formula

to a compound of formula

wherein the substituents are as defined in claim 1,

and if desired, converting the compounds obtained into pharmaceutically acceptable acid addition salts.

11. A compound according to claim 1, whenever prepared by a process as claimed in claim 10 or by an equivalent method.

12. A medicament containing one or more compounds as claimed in claim 1 and pharmaceutically acceptable excipients.

13. A medicament according to claim 12 for the treatment of illnesses based on the glycine uptake inhibitor.

14. A medicament according to claim 13, wherein the illnesses are psychoses, pain, disfunction in memory and learning, attention deficit, schizophrenia, dementia disorders or Alzheimer's disease.

15. The use of a compound as claimed in claim 1 for the manufacture of medicaments for the treatment of psychoses, pain, disfunction in memory and learning, attention deficit, schizophrenia, dementia disorders or Alzheimer's disease.

> 16. The invention as herein before described.

Description:

DI-AROMATIC SUBSTITUTED AMIDES AS INHIBITORS FOR GLYTl

The present invention relates to compounds of the general formula I

wherein

is a 5 or 6-membered aromatic or heteroaromatic ring; R is cycloalkyl or is aryl or heteroaryl, wherein at least one ring is aromatic in nature, unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of halogen, lower alkyl, lower alkyl substituted by halogen, lower alkoxy, lower alkoxy substituted by halogen, -C(O) -lower alkyl, -S(O) 2 -lower alkyl, nitro or cyano;

R 2 is hydrogen or lower alkyl;

R 3 is hydrogen or lower alkyl;

R 4 is halogen, lower alkyl, lower alkyl substituted by halogen, lower alkoxy, lower alkoxy substituted by halogen or nitro; R 5 is hydrogen, halogen, lower alkyl or lower alkyl substituted by halogen;

X is a bond, -(CH 2 ) m -, -CH 2 O- or -CH 2 NH-;

The dotted line denotes a bond or not; n is 1 or 2; m is 1, 2 or 3; and pharmaceutically acceptable acid addition salts thereof.

The present invention relates to compounds of general formula I, to pharmaceutical compositions containing them and their use in the treatment of neurological and neuropsychiatric disorders.

It has surprisingly been found that the compounds of general formula I are good inhibitors of the glycine transporter 1 (GIyT-I), and that they have a good selectivity to glycine transporter 2 (GlyT-2) inhibitors.

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 DA and Lieberman JA, 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 RJ and Aubrey KR., 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., BrJ. 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 noncompetitive 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 DC et al., 1999, Biol. Psychiatry, 45: 668-679 and refs. herein). Furthermore transgenic mice expressing reduced levels of the NMDARl sub unit 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 AR 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, NY; Bliss TV 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 JP 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 RR 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 reuptake of glycine into presynaptic nerve terminals and surrounding fine glial processes.

Two distinct glycine transporter genes have been cloned (GIyT-I and GlyT-2) from mammalian brain, which give rise to two transporters with -50 % amino acid sequence homology. GIyT- 1 presents four isoforms arising from alternative splicing and alternative promoter usage ( Ia, Ib, Ic and Id). Only two of these isoforms have been found in rodent brain (GIyT-Ia and GIyT-Ib). GlyT-2 also presents some degree of heterogeneity. Two GlyT-2 isoforms (2a and 2b) have been identified in rodent brains. GIyT-I is known to be located in CNS and in peripheral tissues, whereas GlyT-2 is specific to the CNS. GIyT- 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, MoI. 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 GIyT- 1 transporter (Bergereon R. Et al., 1998, Proc. Natl. Acad. Sd. USA, 95: 15730-15734; Chen L et al., 2003, /. NeurophysioL, 89 (2): 691-703).

- A -

Glycine transporters inhibitors are suitable for the treatment of neuroligical and neuropsychiatric disorders.The majority of diseases states implicated are psychoses, schizophrenia (Armer RE and Miller DJ, 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 ET et al., 2002, Prog. NeurobioL, 67: 173-202), autistic disorders (Carlsson ML, 1998, /. 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 RE and Miller DJ, 2001, Exp. Opin. Ther. Patents, 11 (4): 563-572).

Thus, increasing activation of NMDA receptors via GIyT-I 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.

Objects of the present invention are the compounds of formula I per se, the use of compounds of formula I and their pharmaceutically acceptable salts for the manufacture of medicaments for the treatment of diseases related to activation of NMDA receptors via Glyt- 1 inhibition, their manufacture, medicaments based on a compound in accordance with the invention and their production as well as the use of compounds of formula I in the control or prevention of illnesses such as psychoses, disfunction in memory and learning, schizophrenia, dementia and other diseases in which cognitive processes are impaired, such as attention deficit disorders or Alzheimer's disease.

The preferred indications using the compounds of the present invention are schizophrenia, cognitive impairment and Alzheimer's disease.

Furthermore, the invention includes all racemic mixtures, all their corresponding enantiomers and/or optical isomers.

As used herein, the term "lower alkyl" denotes a saturated straight- or branched- chain 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 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 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, wherein at least one ring is aromatic in nature" denotes a cyclic aromatic hydrocarbon radical, containing one, two or three heteroatoms, selected from the group consisting of oxygen, sulphur or nitrogen, for example pyridyl, quinoxalinyl, dihydrobenzofuranyl, thiophenyl, isoxazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thiazolyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl or isothiazolyl.

The term is a 5 or 6 membered aromatic or heteroaromatic ring, which denotes a cyclic aromatic hydrocarbon radical, optionally containing one, two or three heteroatoms, selected from the group consisting of oxygen, sulphur or nitrogen, for example phenyl, thiophenyl, isothiazolyl, pyridyl or pyridazinyl.

The term "lower alkyl substituted by halogen" denotes an lower alkyl group as defined above, wherein at least one hydrogen atom is replaced by a halogen atom, for example the following groups: CF 3 , CHF 2 , CH 2 F, CH 2 CF 3 , CH 2 CHF 2 , CH 2 CH 2 F,

CH 2 CH 2 CF 3 , CH 2 CH 2 CH 2 CF 3 , CH 2 CH 2 Cl, CH 2 CF 2 CF 3 , CH 2 CF 2 CHF 2 , CF 2 CHFCF 3 , C(CH 3 ) 2 CF 3 , CH(CH 3 )CF 3 or CH(CH 2 F)CH 2 F.

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.

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.

Preferred compounds of formula I of the present invention are those, wherein

is a 6-membered aromatic group, preferentially phenyl, monosubstitued by halogen, lower alkyl substituted by halogen or by lower alkyl, R 3 and R 4 are preferentially hydrogen, X is preferentially a bond and R 1 is preferentially an aryl group, unsubstituted or substituted by fluoro, cyano or nitro. Such compounds are for example

rac-N-({ [(4-chloro-phenyl)-phenyl-methyl]-carbamoyl}-methyl)-4-fluor o-benzamide rac-N-({ [phenyl-(3-trifluoromethyl-phenyl) -methyl] -carbamoyl} -methyl) -benzamide rac-4-fluoro-N-({ [phenyl-(3-trifluoromethyl-phenyl)-methyl] -carbamoyl} -methyl) - benzamide rac-4-cyano-N-({ [phenyl-(3-trifluoromethyl-phenyl) -methyl] -carbamoyl} -methyl) - benzamide

N- [ (benzhydryl-carbamoyl) -methyl] -4-fluoro-benzamide rac-N-({ [(3-chloro-phenyl)-phenyl-methyl] -carbamoyl} -methyl) -4-fluoro-benzamide rac-4-fluoro-N-{ [(phenyl-m-tolyl-methyl) -carbamoyl] -methyl} -benzamide rac-4-fluoro-N-({ [(4-fluoro-phenyl)-phenyl-methyl]-carbamoyl}-methyl) -benzamide

N-({ [bis-(3-fluoro-phenyl) -methyl] -carbamoyl} -methyl) -4-fluoro-benzamide rac-N-({ [(3,5-difluoro-phenyl)-phenyl-methyl]-carbamoyl}-methyl)-4-f luoro- benzamide rac-N-({ [(4-chloro-phenyl)-(3-trifluoromethyl-phenyl) -methyl] -carbamoyl} -methyl) -A- fluoro-benzamide rac-4-fluoro-N-({ [(4-fluoro-phenyl)-(3-trifluoromethyl-phenyl)-methyl]-carbam oyl}- methyl) -benzamide rac-4-fluoro-N-({ [(3-fluoro-phenyl)-(3-trifluoromethyl-phenyl)-methyl] -carbamoyl}- methyl) -benzamide rac-4-fluoro-N-({ [p-tolyl-(3-trifluoromethyl-phenyl)-methyl]-carbamoyl}-methy l)- benzamide

5-methyl-thiophene-2-carboxylic acid ({ [bis-(3-fluoro-phenyl)-methyl]-carbamoyl}- methyl) -amide or

N-({ [bis-(3-fluoro-phenyl)-methyl]-carbamoyl}-methyl)-4-nitro-be nzamide.

Preferred compounds of formula I of the present invention are further those,

wherein is a 6-membered aromatic group, preferentially phenyl, monosubstitued by halogen, R 3 and R 4 are preferentially hydrogen, X is preferentially a bond and R 1 is preferentially heteroaryl, unsubstituted or substituted by nitro. Such compounds are for example

rac-5-nitro-thiophene-2-carboxylic acid ({ [(4-chloro-phenyl)-phenyl-methyl]- carbamoyl} -methyl) -amide rac-thiophene-3-carboxylic acid ({ [(4-chloro-phenyl)-phenyl-methyl] -carbamoyl}- methyl) -amide

5-nitro-thiophene-2-carboxylic acid ({ [bis-(3-fluoro-phenyl)-methyl]-carbamoyl}- methyl) -amide or thiophene-3-carboxylic acid ({ [bis-(3-fluoro-phenyl)-methyl]-carbamoyl}-methyl)- amide.

A further embodiment of the invention are compounds of formula I, wherein

X is -(CH 2 ) m - or -CH 2 O- or -CH 2 NH- and the other definitions are as described above.

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 process comprises

a) reacting a compound of formula II

with a compound of formula

in the presence of an activating agent such as TBTU (2-(lH-benzotriazole-l-yl)-l,l,3,3- tetramethyluroniumtetrafluoroborate), DCC N,N'-dicyclohexylcarbodiimide or EDCI 1- (3-dimethylaminopropyl)-3-ethylcarbodiimide

to a compound of formula

wherein the substituents are as defined above, or b) reacting a compound of formula

R Y O XV for X = -(CH 2 ) n - with a compound of formula

in presence of a coupling reagent like TBTU, DCC or EDCI or with an acid halide to a compound of formula

wherein the substituents are as defined above and Y is halogen or hydroxy, or c) reacting a compound of formula

-.0

*C

R N VI for X = -CH 2 NH- with a compound of formula

to 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 maybe 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 may be prepared in accordance with process variant a) to c), with the following schemes 1 to 7, and with working examples 1.1 - 1.98.

The starting material is commercially available or may be prepared in accordance with known methods.

The following abbreviations have been used in the schemes and examples:

TBTU = (2-(lH-benzotriazole-l-yl)-l,l,3,3-tetramethyluroniumtetrafl uoroborate) DCC = N^N'-dicyclohexylcarbodiimide EDCI = l-(3-dimethylaminopropyl)-3-ethylcarbodiimide DIPEA = ethyl-diisopropyl-amine

Scheme 1 shows the preparation of compounds of formula I by reacting a compound of formula II with a compound of formula III, which reaction may be carried out in the presence of an activating agent such as TBTU, DCC or EDCI.

Scheme 1

Compounds of the formula II are either commercially available, their preparation is described in the chemical literature or they can be prepared by methods known in the art, for example by coupling glycine or serine with an organic acid in presence of an activating agent like TBTU, DCC or EDCI (when X = -(CH 2 ) m -) or by coupling glycine or serine with an isocyanate (when X = -CH 2 NH-).

Scheme 2

Compounds of the formula III are either commercially available, their preparation is described in the chemical literature or they can be prepared by methods known in the art. These methods include: * Reducing of ketimines or oximes, as described for example by Baruah et al., Synlett 1999, 409.

Scheme 3

* Reacting a secondary alcohol with phenylcarbamate and deprotecting the intermediate carbamate, as described by Laurent et al., Synthesis 2000, 667.

Scheme 4

* Adding a Grignard- reagent to a nitrile and reducing the intermediate imine with sodium borohydride, as described by Dejaegher et al, Synlett 2002, 113.

Scheme 5

Alternatively, compounds of formula I can be prepared by reacting a compound of the type XIV with either an organic acid in presence of a coupling reagent like TBTU, DCC or EDCI or with an acid halide (when X is -(CH 2 ) n -) or reacting compound XIV with an isocyanate (when X = -CH 2 NH-)

Scheme 6

Compounds XIV can be prepared by reacting an N-protected glycine or serine-derivative with a compound of the type III. The protecting group, which is for example BOC (N- tert.butyloxycarbonyl) is then removed by known procedures.

Scheme 7

The compounds of formula I and their pharmaceutically usable addition salts possess valuable pharmacological properties. Specifically, it has been found that the compounds of the present invention are good inhibitors of the glycine transporter I (GIyT-I).

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 CaCl 2 , 2.5 mM

KCl, 2.5 mM MgSO 4 , 10 mM (+) D-glucose.

Flp-in™-CHO (Invitrogen Cat n° R758-07)cells stably transfected with mGlyTlb cDNA.

Glycine uptake inhibition assay (mGlyT-lb)

On day 1 mammalian cells, (Flp-in™-CHO), transfected with mGlyT-lb 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 [ 3 H] -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 following IC50 data (<0.1 μM) for preferred compounds may be provided:

The compounds of formula I and the pharmaceutically acceptable salts of the compounds of formula I can be used as medicaments, e.g. in the form of pharmaceutical preparations. The pharmaceutical preparations can be administered orally, e.g. in the form of tablets, coated tablets, dragees, hard and soft gelatine capsules, solutions, emulsions or suspensions. The administration can, however, also be effected rectally, e.g. in the form of suppositories, parenterally, e.g. in the form of injection solutions.

The compounds of formula I can be processed with pharmaceutically inert, inorganic or organic carriers for the production of pharmaceutical preparations. 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, dragees 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 preparations 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.

Medicaments containing a compound of formula I or a pharmaceutically acceptable salt thereof and a therapeutically inert carrier are also an object of the present invention, as is a process for their production, 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 dosage 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 may 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)

Item Ingredients mg/ tablet

5 mg 25 mg 100 mg 500

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 0 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

Item Ingredients mg/capsule

5 mg 25 mg 100 mg 500

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.

Example 1.1 Preparation of N-[(Benzhydryl-methyl-carbamoyl)-methyl]-3-phenyl-propionami de

A solution of 2.0 mmol N-(diphenylmethyl)methylamine, 2.0 mmol (3-phenyl- propionylamino) -acetic acid (CA [56613-60-6]) and 6.0 mmol DIPEA in 10 ml of acetonitrile was treated with 2.2 mmol of TBTU. After 2 hours at room temperature, the reaction mixture was concentrated, diluted with water and extracted 3 times with ethyl acetate. The organic phase was dried and the residue purified by chromatography (SiC^; dichloromethane / methanol) to give the title compound as a slightly yellowish solid. Yield = 46%. MS (m/e): 385.2 (MH " , 100%).

Example 1.2

Preparation of rac-N-[(2-Chloro-9H-thioxanthen-9-ylcarbamoyl)-methyl]-3-phe nyl- propionamide

Prepared in analogy to example 1.1 from rac-2-chloro-9H-thioxanthen-9-ylamine (CA [51065-24-8]) and (3-phenyl-propionylamino)-acetic acid (CA [56613-60-6]). MS (m/e): 435.2 (MH " , 100%).

Example 1.3

Preparation of rac-N-({[(4-Chloro-phenyl)-phenyl-methyl]-carbamoyl}-methyl) - benzamide

Prepared in analogy to example 1.1 from rac-4-chlorobenzhydrylamine hydrochloride and hippuric acid acid. MS (m/e): 377.3 (MH " , 100%).

Example 1.4 Preparation of rac-({[(4-Chloro-phenyl)-phenyl-methyl]-carbamoyl}-methyl)-c arbamic acid benzyl ester

Prepared in analogy to example 1.1 from rac-4-chlorobenzhydrylamine hydrochloride and benzyloxycarbonylamino-acetic acid (CA [1138-80-3]). MS (m/e) : 409.3 (M+H + ; 45%) .

Example 1.5

Preparation of rac-(N-({[(4-Chloro-phenyl)-phenyl-methyl]-methyl-carbamoyl} - methyl)-3-phenyl-propionamide

Prepared in analogy to example 1.1 from rac-[(4-chloro-phenyl)-phenyl-methyl] -methyl - amine (CA [118762-04-2]) and (3-phenyl-propionylamino)-acetic acid

(CA [56613-60-6]).

MS (m/e): 419.3 (MH " , 100%).

Example 1.6 Preparation of rac-N-({[(4-Chloro-phenyl)-phenyl-methyl]-carbamoyl}-methyl) -2- phenyl- acetamide

Prepared in analogy to example 1.1 from rac-4-chlorobenzhydrylamine hydrochloride and phenylacetylamino- acetic acid (CA [500-98-1]). MS (m/e): 391.2 (MH " , 100%).

Example 1.7

Preparation of rac-3-(4-Chloro-phenyl)-N-({[(4-chloro-phenyl)-phenyl-methyl ]- carbamoyl} -methyl) -propionamide

Prepared in analogy to example 1.1 from rac-4-chlorobenzhydrylamine hydrochloride and [3-(4-chloro-phenyl)-propionylamino] -acetic acid (Example 2.1). MS (m/e): 439.3 (MH " , 100%).

Example 1.8

Preparation of rac-N-({[(4-Chloro-phenyl)-phenyl-methyl]-carbamoyl}-methyl) -3-(4- methoxy-phenyl) -propionamide

Prepared in analogy to example 1.1 from rac-4-chlorobenzhydrylamine hydrochloride and [3-(4-methoxy-phenyl)-propionylamino] -acetic acid (Example 2.2). MS (m/e): 435.2 (MH " , 100%).

Example 1.9

Preparation of N-({[Bis-(4-chloro-phenyl)-methyl]-carbamoyl}-methyl)-3-phen yl- propionamide

Prepared in analogy to example 1.1 from C,C-bis-(4-chloro-phenyl)-methylamine (CA [14212-38-5]) and (3-phenyl-propionylamino)-acetic acid (CA [56613-60-6]). MS (m/e): 439.2 (MH " , 100%).

Example 1.10 Preparation of rac-2-(3-Benzyl-ureido)-N-[(4-chloro-phenyl)-phenyl-methyl]- acetamide

A solution of 0.2 mmol rac-2-amino-N-[(4-chloro-phenyl)-phenyl-methyl]-acetamide hydrochloride (Example 3.1) and 0.28 mmol of DIPEA in 2 ml of dioxane was treated with 0.2 mmol of benzylisocyanate. The mixture was stirred at room temperature for 48 hours, concentrated and diluted with diethyl ether. The solid was filtered off, dissolved in dichloromethane and extracted 2 times with a diluted solution of citric acid. The organic phase was dried and concentrated. The residue was triturated with diethyl ether to give the title compound as a colorless solid. Yield = 93%. MS (m/e): 406.4 (MH " , 100%).

Example 1.11

Preparation of rac-3-Phenyl- N- ({[phenyl- (4-trifluoromethyl-phenyl)-methyl]- carbamoyl} -methyl) -propionamide

Prepared in analogy to example 1.1 from rac-C-phenyl-C-(4-trifluoromethyl-phenyl)- methylamine (CA [154238-38-2]) and (3-phenyl-propionylamino) -acetic acid

(CA [56613-60-6]).

MS (m/e): 439.2 (MH " , 100%).

Example 1.12

> Preparation of rac-N-({[(4-Chloro-phenyl)-phenyl-methyl]-carbamoyl}-methyl) -4- phenyl-butyramide

A suspension of 0.32 mmol rac-2-amino-N-[(4-chloro-phenyl)-phenyl-methyl]- acetamide hydrochloride (Example 3.1) in 5 ml acetonitrile was treated successively with 0.32 mmol 4-phenylbutyric acid, 1.61 mmol DIPEA and 0.35 mmol TBTU. The reaction mixture was stirred for 1 hour at room temperature and concentrated. Chromatography (SiO 2 ; dichloromethane / methanol) gave the title compound as a colorless solid. Yield = 71%. MS (m/e): 419.3 (MH " , 100%).

Example 1.13

Preparation of rac-3-Chloro-N-({[(4-chloro-phenyl)-phenyl-methyl]-carbamoyl }- methyl) -benzamide

A suspension of 0.32 mmol rac-2-amino-N- [ (4-chloro-phenyl) -phenyl-methyl] - acetamide hydrochloride (Example 3.1) in 5 ml of dichloromethane was treatet with 1.61 mmol of triethylamine. The resulting slurry was cooled to 0° C and 0.35 mmol of 3- chlorobenzoyl chloride was added. The mixture was stirred for 1 hour at room temperature, concentrated and hydrolysed. The organic phase was dried over magnesium sulfate and concentrated. The resiudue was triturated with diethyl ether to give the title compound as a colorless solid. Yield = 97%. MS (m/e): 411.1 (MH " , 100%).

Example 1.14 Preparation of rac-4-Chloro-N-({[(4-chloro-phenyl)-phenyl-methyl]-carbamoyl }- methyl) -benzamide

Prepared in analogy to example 1.13 from rac-2-amino-N-[(4-chloro-phenyl) -phenyl - methyl] -acetamide hydrochloride (Example 3.1) and 4-chlorobenzoyl chloride. MS (m/e): 411.0 (MH " , 100%).

Example 1.15

Preparation of rac-N-({[(4-Chloro-phenyl)-phenyl-methyl]-carbamoyl}-methyl) -4- methoxy-benzamide

Prepared in analogy to example 1.13 from rac-2-amino-N- [(4-chloro-phenyl) -phenyl - methyl] -acetamide hydrochloride (Example 3.1) and 4-methoxybenzoyl chloride. MS (m/e): 407.4 (MH " , 100%).

Example 1.16 Preparation of rac-3-Phenyl-N-{[(phenyl-p-tolyl-methyl)-carbamoyl]-methyl}- propionamide

Prepared in analogy to example 1.1 from (3-phenyl-propionylamino) -acetic acid (CA [56613-60-6]) and rac-C-phenyl-C-p-tolyl-methylamine (CA [55095-21-1]).

MS (m/e): 385.2 (MH " , 100%).

Example 1.17

Preparation of rac-N-({[(2-Chloro-5-trifluoromethyl-phenyl)-phenyl-methyl]- carbamoyl}-methyl)-3-phenyl-propionamide

Prepared in analogy to example 1.1 from (3-phenyl-propionylamino) -acetic acid (CA [56613-60-6]) and rac-C-(2-Chloro-5-trifluoromethyl-phenyl)-C-phenyl-methylami ne hydrochloride (CA [13954-13-7]). MS (m/e): 473.1 (MH " , 100%).

Example 1.18

Preparation of (-)-4-Chloro-N-({[(R)-(4-chloro-phenyl)-phenyl-methyl]-carba moyl}- methyl) -benzamide

This compound was obtained by separation of the enantiomers from example 1.14 using preparative HPLC (column = Chiralcel OD; solvent = heptane / ethanol 85:15). Specific rotation : -19.4° (c=l; methanol).

Example 1.19 Preparation of (+)-4-Chloro-N-({[(R)-(4-chloro-phenyl)-phenyl-methyl]-carba moyl}- methyl) -benzamide

This compound was obtained by separation of the enantiomers from example 1.14 using preparative HPLC (column = Chiralcel OD; solvent = heptane / ethanol 85:15). Specific rotation : +17.6° (c=l; methanol).

Example 1.20

Preparation of rac-N-({[(4-Chloro-phenyl)-phenyl-methyl]-carbamoyl}-methyl) -4- trifluoromethyl-benzamide

Prepared in analogy to example 1.12 from rac-2-amino-N-[(4-chloro-phenyl)-phenyl- methyl] -acetamide hydrochloride (Example 3.1) and 4-(trifluoromethyl)benzoic acid. MS (m/e): 445.1 (MH " , 100%).

Example 1.21

Preparation of rac-N-({[(4-Chloro-phenyl)-phenyl-methyl]-carbamoyl}-methyl) -4- isopropyl-benzamide

Prepared in analogy to example 1.12 from rac-2-amino-N-[(4-chloro-phenyl) -phenyl - methyl] -acetamide hydrochloride (Example 3.1) and 4-isopropylbenzoic acid. MS (m/e): 419.3 (MH " , 100%).

Example 1.22

Preparation of rac-4-Acetyl-N-({[(4-chloro-phenyl)-phenyl-methyl]-carbamoyl }- methyl) -benzamide

Prepared in analogy to example 1.12 from rac-2-amino-N- [(4-chloro-phenyl) -phenyl - methyl] -acetamide hydrochloride (Example 3.1) and 4-acetylbenzoic acid. MS (m/e): 419.3 (MH " , 100%).

Example 1.23

Preparation of rac-3-Phenyl- N- ({[phenyl- (3-trifluoromethyl-phenyl)-methyl]- carbamoyl} -methyl) -propionamide

Prepared in analogy to example 1.1 from (3-phenyl-propionylamino) -acetic acid (CA [56613-60-6] ) and rac-C-phenyl-C-(3-trifluoromethyl-phenyl)-methylamine (CA [70428-92-1]). MS (m/e): 441.5 (M+H, 80%).

Example 1.24

Preparation of rac-N-({[(4-Chloro-phenyl)-phenyl-methyl]-carbamoyl}-methyl) -4- methanesulfonyl-benzamide

Prepared in analogy to example 1.12 from rac-2-amino-N-[(4-chloro-phenyl) -phenyl - methyl] -acetamide hydrochloride (Example 3.1) and 4-methylsulphonylbenzoic acid. MS (m/e): 455.2 (MH " , 100%).

Example 1.25 Preparation of rac-N-({[(4-Chloro-phenyl)-phenyl-methyl]-carbamoyl}-methyl) -4- nitro-benzamide

Prepared in analogy to example 1.12 from rac-2-amino-N-[(4-chloro-phenyl) -phenyl - methyl] -acetamide hydrochloride (Example 3.1) and 4-nitrobenzoic acid. MS (m/e): 422.1 (MH " , 100%).

Example 1.26

Preparation of rac-N-({[(4-Chloro-phenyl)-phenyl-methyl]-carbamoyl}-methyl) -4- cyano-benzamide

Prepared in analogy to example 1.12 from rac-2-amino-N- [(4-chloro-phenyl) -phenyl - methyl] -acetamide hydrochloride (Example 3.1) and 4-cyanobenzoic acid. MS (m/e): 402.3 (MH " , 100%).

Example 1.27

Preparation of rac-3-Phenyl-N-( {[phenyl- (2-trifluoromethyl-phenyl)-methyl]- carbamoyl} -methyl) -propionamide

Prepared in analogy to example 1.1 from mmol (3-phenyl-propionylamino) -acetic acid (CA [56613-60-6]) and rac-C-phenyl-C-(2-trifluoromethyl-phenyl)-methylamine hydrochloride (CA [49703-62-0]). MS (m/e): 441.5 (M+H + ).

Example 1.28

Preparation of rac-N-({[(4-Chloro-phenyl)-phenyl-methyl]-carbamoyl}-methyl) - isonicotinamide

Prepared in analogy to example 1.12 from rac-2-amino-N-[(4-chloro-phenyl) -phenyl - methyl] -acetamide hydrochloride (Example 3.1) and isonicotinic acid. MS (m/e): 378.3 (MH " , 100%).

Example 1.29

Preparation of rac-N-({[(4-Chloro-phenyl)-phenyl-methyl]-carbamoyl}-methyl) -4- fluoro-benzamide

Prepared in analogy to example 1.12 from rac-2-amino-N-[(4-chloro-phenyl)-phenyl- methyl] -acetamide hydrochloride (Example 3.1) and 4-fluorobenzoic acid. MS (m/e): 395.1 (MH " , 100%).

Example 1.30

Preparation of rac-N-({[Phenyl-(3-trifluoromethyl-phenyl)-methyl]-carbamoyl }- methyl) -benzamide

Prepared in analogy to example 1.1 from rac-C-phenyl-C-(3-trifluoromethyl-phenyl)- methylamine (CA [70428-92-1]) and hippuric acid acid. MS (m/e): 411.2 (MH " , 100%).

Example 1.31

Preparation of N-({[Bis-(4-trifluoromethyl-phenyl)-methyl]-carbamoyl}-methy l)- benzamide

Prepared in analogy to example 1.1 from C,C-bis-(4-trifluoromethyl-phenyl)- methylamine (example 4.1) and hippuric acid acid. MS (m/e): 481.4 (M+H, 100%).

Example 1.32

Preparation of rac-5-Nitro-thiophene-2-carboxylic acid ({[(4-chloro-phenyl)-phenyl- methyl] -carbamoyl}-methyl)-amide

Prepared in analogy to example 1.12 from rac-2-amino-N-[(4-chloro-phenyl) -phenyl - methyl] -acetamide hydrochloride (Example 3.1) and 5-nitrothiophene-2-carboxylic acid. MS (m/e): 428.3 (MH " , 100%).

Example 1.33

Preparation of rac-Thiophene-2-carboxylic acid ({[(4-chloro-phenyl)-phenyl-methyl]- carbamoyl} -methyl) - amide

Prepared in analogy to example 1.12 from rac-2-amino-N-[(4-chloro-phenyl)-phenyl- methyl] -acetamide hydrochloride (Example 3.1) and 2-thiophenecarboxylic acid. MS (m/e): 383.1 (MH " , 100%).

Example 1.34

Preparation of rac-Thiophene-S-carboxylic acid ({[(4-chloro-phenyl)-phenyl-methyl]- carbamoyl} -methyl) - amide

Prepared in analogy to example 1.12 from rac-2-amino-N-[(4-chloro-phenyl) -phenyl - methyl] -acetamide hydrochloride (Example 3.1) and 3-thiophenecarboxylic acid. MS (m/e): 383.1 (MH " , 100%).

Example 1.35

Preparation of rac-N-({[(4-Chloro-phenyl)-phenyl-methyl]-carbamoyl}-methyl) -4- methyl-benzamide

Prepared in analogy to example 1.12 from rac-2-amino-N- [(4-chloro-phenyl)-phenyl- methyl] -acetamide hydrochloride (Example 3.1) and p-toluic acid. MS (m/e): 391.2 (MH " , 100%).

Example 1.36

Preparation of rac-Isoxazole-5-carboxylic acid ({[(4-chloro-phenyl)-phenyl-methyl]- carbamoyl}-methyl)-amide

Prepared in analogy to example 1.12 from rac-2-amino-N- [(4-chloro-phenyl)-phenyl- methyl] -acetamide hydrochloride (Example 3.1) and isoxazole-5-carboxylic acid. MS (m/e): 368.1 (MH " , 100%).

Example 1.37

Preparation of rac-5-Methyl-isoxazole-3-carboxylic acid ({[(4-chloro-phenyl)-phenyl- methyl] - carbamoyl} -methyl) - amide

Prepared in analogy to example 1.12 from rac-2-amino-N- [(4-chloro-phenyl) -phenyl - methyl] -acetamide hydrochloride (Example 3.1) and 5-methylisoxazole-3-carboxylic acid. MS (m/e): 382.0 (MH " , 100%).

Example 1.38

Preparation of rac-4-Chloro-N-( {[phenyl- (4-trifluoromethyl-phenyl)-methyl]- carbamoyl} -methyl) -benzamide

Prepared in analogy to example 1.12 from rac-2-amino-N- [phenyl- (4-trifluoromethyl- phenyl) -methyl] -acetamide hydrochloride (example 3.2) and 4-chlorobenzoic acid. MS (m/e): 445.1 (MH " , 100%).

Example 1.39 Preparation of rac-N- ( { [ (2,4-Dichloro-phenyl) -phenyl-methyl] -carbamoyl} -methyl) - benzamide

Prepared in analogy to example 1.1 from rac-C-(2,4-dichloro-phenyl)-C-phenyl- methylamine (example 4.2) and hippuric acid acid. MS (m/e): 411.1 (M+H, 100%).

Example 1.40

Preparation of rac-5-Chloro-thiophene-2-carboxylic acid ({[(4-chloro-phenyl)-phenyl- methyl] - carbamoyl} -methyl) - amide

Prepared in analogy to example 1.12 from rac-2-amino-N-[(4-chloro-phenyl) -phenyl - methyl] -acetamide hydrochloride (Example 3.1) and 5-chloro-2-thiophenecarboxylic acid.

MS (m/e): 417.1 (MH " , 100%).

Example 1.41

Preparation of rac-4-Fluoro-N-{[(phenyl-p-tolyl-methyl)-carbamoyl]-methyl}- benzamide

Prepared in analogy to example 1.12 from rac-2-amino-N-(phenyl-p-tolyl-methyl)- acetamide (Example 3.3) and 4-fluorobenzoic acid. MS (m/e): 375.3 (M+H, 100%).

Example 1.42 Preparation of rac-4-Chloro-N-{[(phenyl-p-tolyl-methyl)-carbamoyl]-methyl}- benzamide

Prepared in analogy to example 1.12 from rac-2-amino-N-(phenyl-p-tolyl-methyl)- acetamide (Example 3.3) and 4-chlorobenzoic acid. MS (m/e) : 391.2 (MH " , 53%) .

Example 1.43

Preparation of rac-4-Fluoro-N-( {[phenyl- (3-trifluoromethyl-phenyl)-methyl]- carbamoyl} -methyl) -benzamide

Prepared in analogy to example 1.1 from (4-fluoro-benzoylamino) -acetic acid (CA [366-

79-0]) and rac-C-phenyl-C-(3-trifluoromethyl-phenyl)-methylamine (CA [70428-92- I]). MS (m/e): 429.4 (MH " , 100%).

Example 1.44

Preparation of rac-4-Cyano-N-({ [phenyl- (3-trifluoromethyl-phenyl)-methyl]- carbamoyl} -methyl) -benzamide

Prepared in analogy to example 1.1 from (4-cyano-benzoylamino) -acetic acid (CA [90290-83-8]) and rac-C-phenyl-C-(3-trifluoromethyl-phenyl)-methylamine (CA [70428-92-1]). MS (m/e): 436.1 (MH " , 100%).

Example 1.45

Preparation of rac-N-({[(4-Chloro-phenyl)-phenyl-methyl]-carbamoyl}-methyl) -3- fluoro-benzamide

Prepared in analogy to example 1.12 from rac-2-amino-N-[(4-chloro-phenyl) -phenyl - methyl] -acetamide hydrochloride (Example 3.1) and 3-fluorobenzoic acid. MS (m/e): 398.2 (7%) & 396.2 (22%), (M+H).

Example 1.46

Preparation of rac-N-({[(4-Chloro-phenyl)-phenyl-methyl]-carbamoyl}-methyl) -2- trifluoromethyl-benzamide

Prepared in analogy to example 1.12 from rac-2-amino-N-[(4-chloro-phenyl) -phenyl - methyl] -acetamide hydrochloride (Example 3.1) and 2-trifluoromethylbenzoic acid. MS (m/e): 448.2 (6%) & 446.1 (24%), (M+H).

Example 1.47 Preparation of N-[(Benzhydryl-carbamoyl)-methyl]-4-fluoro-benzamide

Prepared in analogy to example 1.1 from p-fluoro-hippuric acid (CA [366-79-0]) and C,C-diphenylmethylamine . MS (m/e): 363.3 (M+H). Example 1.48

Preparation of rac-N-({[(4-Chloro-phenyl)-phenyl-methyl]-carbamoyl}-methyl) -4- methoxy- 3 -methyl-benzamide

Prepared in analogy to example 1.12 from rac-2-amino-N-[(4-chloro-phenyl) -phenyl - methyl] -acetamide hydrochloride (Example 3.1) and 4-methoxy-3-methylbenzoic acid. MS (m/e): 420.8 (MH " , 100%).

Example 1.49

Preparation of rac-N-({ [(4-Chloro-phenyl)-phenyl-methyl]-carbamoyl}-methyl)-3- fluoro-4-methoxy-benzamide

Prepared in analogy to example 1.12 from rac-2-amino-N-[(4-chloro-phenyl)-phenyl- methyl] -acetamide hydrochloride (Example 3.1) and 3-fluoro-4-methoxybenzoic acid. MS (m/e): 424.9 (MH " , 100%).

Example 1.50 Preparation of rac-N-({[(4-Chloro-phenyl)-phenyl-methyl]-carbamoyl}-methyl) -3,4- difluoro-benzamide

Prepared in analogy to example 1.12 from rac-2-amino-N-[(4-chloro-phenyl)-phenyl- methyl] -acetamide hydrochloride (Example 3.1) and 3,4-difluorobenzoic acid. MS (m/e): 412.9 (MH " , 100%).

Example 1.51

Preparation of rac-N-({[(4-Chloro-phenyl)-phenyl-methyl]-carbamoyl}-methyl) -4- fluoro-3-methyl-benzamide

Prepared in analogy to example 1.12 from rac-2-amino-N-[(4-chloro-phenyl) -phenyl - methyl] -acetamide hydrochloride (Example 3.1) and 4-fluoro-3-methylbenzoic acid. MS (m/e): 409.0 (MH " , 100%).

Example 1.52 Preparation of rac-N-({[(4-Chloro-phenyl)-phenyl-methyl]-carbamoyl}-methyl) -3,5- difluoro-benzamide

Prepared in analogy to example 1.12 from rac-2-amino-N-[(4-chloro-phenyl)-phenyl- methyl] -acetamide hydrochloride (Example 3.1) and 3,5-difluorobenzoic acid. MS (m/e): 412.9 (MH " , 100%).

Example 1.53

Preparation of rac-4-Chloro-N-({[(4-chloro-phenyl)-phenyl-methyl]-carbamoyl }- methyl) - 3 -methyl-benzamide

Prepared in analogy to example 1.12 from rac-2-amino-N-[(4-chloro-phenyl)-phenyl- methyl] -acetamide hydrochloride (Example 3.1) and 4-chloro-3-methylbenzoic acid. MS (m/e): 425.0 (MH " , 100%).

Example 1.54

Preparation of rac-N-({[(4-Chloro-phenyl)-phenyl-methyl]-carbamoyl}-methyl) -4- methoxy-2-methyl-benzamide

Prepared in analogy to example 1.12 from rac-2-amino-N-[(4-chloro-phenyl) -phenyl - methyl] -acetamide hydrochloride (Example 3.1) and 4-methoxy-2-methylbenzoic acid. MS (m/e): 421.0 (MH " , 100%).

Example 1.55

Preparation of rac-N-({[(4-Chloro-phenyl)-phenyl-methyl]-carbamoyl}-methyl) -4- difluoromethoxy-benzamide

Prepared in analogy to example 1.12 from rac-2-amino-N-[(4-chloro-phenyl) -phenyl - methyl] -acetamide hydrochloride (Example 3.1) and 4-difluoromethoxybenzoic acid. MS (m/e): 443.2 (MH " , 100%).

Example 1.56 Preparation of rac-N-({[(4-Chloro-phenyl)-phenyl-methyl]-carbamoyl}-methyl) -4- methoxy-3,5-dimethyl-benzamide

Prepared in analogy to example 1.12 from rac-2-amino-N-[(4-chloro-phenyl) -phenyl - methyl] -acetamide hydrochloride (Example 3.1) and 3,5-dimethyl-4-methoxybenzoic acid. MS (m/e): 435.2 (MH " , 100%).

Example 1.57

Preparation of rac-N-({[(4-Chloro-phenyl)-phenyl-methyl]-carbamoyl}-methyl) -4- trifluoromethoxy-benzamide

Prepared in analogy to example 1.12 from rac-2-amino-N-[(4-chloro-phenyl)-phenyl- methyl] -acetamide hydrochloride (Example 3.1) and 4-(trifluoromethoxy)benzoic acid. MS (m/e): 461.1 (MH " , 100%).

Example 1.58

Preparation of rac-2,3-Dihydro-benzofuran-5-carboxylic acid ({[(4-chloro-phenyl)- phenyl-methyl]-carbamoyl}-methyl)-amide

Prepared in analogy to example 1.12 from rac-2-amino-N- [(4-chloro-phenyl) -phenyl - methyl] -acetamide hydrochloride (Example 3.1) and 2,3-dihydrobenzo(B)furan-5- carboxylic acid. MS (m/e): 419.1 (MH " , 100%).

Example 1.59

Preparation of rac-4-Chloro-N-({[(4-chloro-phenyl)-phenyl-methyl]-carbamoyl }- methyl)-2-nitro-benzamide

Prepared in analogy to example 1.12 from rac-2-amino-N- [(4-chloro-phenyl) -phenyl - methyl] -acetamide hydrochloride (Example 3.1) and 4-chloro-2-nitrobenzoic acid. MS (m/e): 456.2 (MH " , 100%).

Example 1.60

Preparation of rac-Quinoxaline-ό-carboxylic acid ({[(4-chloro-phenyl)-phenyl-methyl]- carbamoyl} -methyl) - amide

Prepared in analogy to example 1.12 from rac-2-amino-N- [(4-chloro-phenyl) -phenyl - methyl] -acetamide hydrochloride (Example 3.1) and quinoxaline-6-carboxylic acid. MS (m/e): 429.2 (MH " , 100%).

Example 1.61 Preparation of rac-N-({[(4-Chloro-phenyl)-phenyl-methyl]-carbamoyl}-methyl) -2,4- difluoro-benzamide

Prepared in analogy to example 1.12 from rac-2-amino-N-[(4-chloro-phenyl) -phenyl - methyl] -acetamide hydrochloride (Example 3.1) and 2,4-difluorobenzoic acid. MS (m/e): 413.1 (MH " , 100%).

Example 1.62

Preparation of rac-N-({[(4-Chloro-phenyl)-phenyl-methyl]-carbamoyl}-methyl) -2,4,5- trifluoro-benzamide

Prepared in analogy to example 1.12 from rac-2-amino-N-[(4-chloro-phenyl) -phenyl - methyl] -acetamide hydrochloride (Example 3.1) and 2,4,5 -trifluorobenzoic acid. MS (m/e): 431.2 (MH " , 100%).

Example 1.63

Preparation of rac-N-({[(3-Chloro-phenyl)-phenyl-methyl]-carbamoyl}-methyl) -4- fluoro-benzamide

Prepared in analogy to example 1.1 from 4-fluoro-hippuric acid (CA [366-79-0]) and rac-C-(3-chloro-phenyl)-C-phenyl-methylamine (CA [55095-14-2]) . MS (m/e): 397.3 (M+H, 100%).

Example 1.64

Preparation of rac-2,4-Dichloro-N-({[(4-chloro-phenyl)-phenyl-methyl]-carba moyl}- methyl) -benzamide

Prepared in analogy to example 1.12 from rac-2-amino-N-[(4-chloro-phenyl)-phenyl- methyl] -acetamide hydrochloride (Example 3.1) and 2,4-dichlorobenzoic acid. MS (m/e): 445.1 (MH " , 100%).

Example 1.65

Preparation of rac-2-Chloro-N-({[(4-chloro-phenyl)-phenyl-methyl]-carbamoyl }- methyl) -4-fluoro-benzamide

Prepared in analogy to example 1.12 from rac-2-amino-N- [(4-chloro-phenyl) -phenyl - methyl] -acetamide hydrochloride (Example 3.1) and 2-chloro-4-fluorobenzoic acid. MS (m/e): 429.2 (MH " , 100%).

Example 1.66

Preparation of rac-4-Chloro-N-({[(4-chloro-phenyl)-phenyl-methyl]-carbamoyl }- methyl)-2-methyl-benzamide

Prepared in analogy to example 1.12 from rac-2-amino-N- [(4-chloro-phenyl) -phenyl - methyl] -acetamide hydrochloride (Example 3.1) and 4-chloro-2-methylbenzoic acid. MS (m/e): 425.1 (MH " , 100%).

Example 1.67

Preparation of rac-4-Fluoro-N-{[(phenyl-m-tolyl-methyl)-carbamoyl]-methyl}- benzamide

Prepared in analogy to example 1.1 from 4-fluoro-hippuric acid (CA [366-79-0]) and rac-C-phenyl-C-m-tolyl-methylamine (CA [55095-20-0]) . MS (m/e): 377.4 (M+H, 19%).

Example 1.68

Preparation of rac-4-Fluoro-N-((S)-l-{[phenyl-(3-trifluoromethyl-phenyl)-me thyl]- carbamoyl} - ethyl) -benzamide

Prepared in analogy to example 1.1 from (S)-2-(4-fluoro-benzoylamino)-propionic acid

(CA [214629-12-6]) and rac-C-phenyl-C-(3-trifluoromethyl-phenyl)-methylamine (CA

[70428-92-1]).

MS (m/e): 445.4 (M+H, 71%).

Example 1.69

Preparation of rac-4-Fluoro-N-({[(4-fluoro-phenyl)-phenyl-methyl]-carbamoyl }- methyl) -benzamide

Prepared in analogy to example 1.1 from 4-fluoro-hippuric acid (CA [366-79-0]) and rac-C-(4-fluoro-phenyl)-C-phenyl-methylamine (CA [55095-26-6]) . MS (m/e): 381.3 (M+H, 10%).

Example 1.70 Preparation of N-({[Bis-(3-fluoro-phenyl)-methyl]-carbamoyl}-methyl)-4-fluo ro- benzamide

Prepared in analogy to example 1.1 from 4-fluoro-hippuric acid (CA [366-79-0]) and C,C-bis-(3-fluoro-phenyl)-methylamine (CA [261925-16-0]) . MS (m/e): 399.1 (M+H).

Example 1.71

Preparation of rac-4-Fluoro-N-({[(4-methoxy-phenyl)-phenyl-methyl]-carbamoy l}- methyl) -benzamide

Prepared in analogy to example 1.1 from 4-fluoro-hippuric acid (CA [366-79-0]) and rac-C-(4-methoxy-phenyl)-C-phenyl-methylamine (CA [2538-34-3]) . MS (m/e): 392.9 (M+H).

Example 1.72

Preparation of rac-N-({[(3,5-Difluoro-phenyl)-phenyl-methyl]-carbamoyl}-met hyl)-4- fluoro-benzamide

Prepared in analogy to example 1.1 from 4-fluoro-hippuric acid (CA [366-79-0]) and rac-C-(3,5-difluoro-phenyl)-C-phenyl-methylamine (example 4.3) . MS (m/e): 399.3 (M+H).

Example 1.73

Preparation of rac-N-({[(2-Chloro-5-nitro-phenyl)-phenyl-methyl]-carbamoyl} - methyl) -4-fluoro-benzamide

Prepared in analogy to example 1.1 from 4-fluoro-hippuric acid (CA [366-79-0]) and rac-C-(2-chloro-5-nitro-phenyl)-C-phenyl-methylamine (example 4.4) . MS (m/e): 442.3 (M+H).

Example 1.74

Preparation of rac-N-({[(2-Chloro-5-trifluoromethyl-phenyl)-phenyl-methyl]- carbamoyl} -methyl) -4-fluoro-benzamide

Prepared in analogy to example 1.1 from 4-fluoro-hippuric acid (CA [366-79-0]) and rac-C-(2-chloro-5-trifluoromethyl-phenyl)-C-phenyl-methylami ne hydrochloride

(CA [ 13954-13-7]). MS (m/e): 465.3 (M+H).

Example 1.75

Preparation of rac-4-Fluoro-N-({[(2-fluoro-phenyl)-phenyl-methyl]-carbamoyl }- methyl) -benzamide

Prepared in analogy to example 1.1 from 4-fluoro-hippuric acid (CA [366-79-0]) and rac-C-(2-fluoro-phenyl)-C-phenyl-methylamine (CA [55095-24-4]). MS (m/e): 381.4 (M+H, 16%).

Example 1.76

Preparation of rac-N-({[(4-Chloro-phenyl)-(3-trifluoromethyl-phenyl)-methyl ]- carbamoyl} -methyl) -4-fluoro-benzamide

Prepared in analogy to example 1.1 from 4-fluoro-hippuric acid (CA [366-79-0]) and rac-C-(4-chloro-phenyl)-C-(3-trifluoromethyl-phenyl)-methyla mine hydrochloride (CA [49703-70-0]). MS (m/e): 463.1 (MH " , 100%).

Example 1.77

Preparation of rac-4-Fluoro-N-({[(4-fluoro-phenyl)-(3-trifluoromethyl-pheny l)- methyl]-carbamoyl}-methyl)-benzamide

Prepared in analogy to example 1.1 from 4-fluoro-hippuric acid (CA [366-79-0]) and rac-C-(4-fluoro-phenyl)-C-(3-trifluoromethyl-phenyl)-methyla mine (example 4.5). MS (m/e): 447.1 (MH " , 100%).

Example 1.78

Preparation of rac-4-Fluoro-N-({ [p-tolyl-(3-trifluoromethyl-phenyl)-methyl]- carbamoyl} -methyl) -benzamide

Prepared in analogy to example 1.1 from 4-fluoro-hippuric acid (CA [366-79-0]) and rac-C-p-tolyl-C-(3-trifluoromethyl-phenyl)-methylamine (example 4.6). MS (m/e): 443.3 (MH " , 100%).

Example 1.79

Preparation of rac-4-Fluoro-N-({[(4-methoxy-phenyl)-(3-trifluoromethyl-phen yl)- methyl]-carbamoyl}-methyl)-benzamide

Prepared in analogy to example 1.1 from 4-fluoro-hippuric acid (CA [366-79-0]) and rac-C-(4-methoxy-phenyl)-C-(3-trifluoromethyl-phenyl)-methyl amine (example 4.7). MS (m/e): 459.2 (MH " , 100%).

Example 1.80

Preparation of rac-4-Fluoro-N-({[(4-trifluoromethoxy-phenyl)-(3-trifluorome thyl- phenyl) -methyl] -carbamoyl} -methyl) -benzamide

Prepared in analogy to example 1.1 from 4-fluoro-hippuric acid (CA [366-79-0]) and rac-C-(4-trifluoromethoxy-phenyl)-C-(3-trifluoromethyl-pheny l)-methylamine (example 4.8). MS (m/e): 515.2 (M+H, 3%).

Example 1.81

Preparation of rac-4-Fluoro-N-{[(phenyl-thiophen-2-yl-methyl)-carbamoyl]-me thyl}- benzamide

Prepared in analogy to example 1.1 from 4-fluoro-hippuric acid (CA [366-79-0]) and rac-C-phenyl-C-thiophen-2-yl-methylamine (CA [5693-42-5]). MS (m/e): 367.1 (MH " , 100%).

Example 1.82

Preparation of rac-4-Fluoro-N-{[(phenyl-o-tolyl-methyl)-carbamoyl]-methyl}- benzamide

Prepared in analogy to example 1.1 from 4-fluoro-hippuric acid (CA [366-79-0]) and rac-C-phenyl-C-o-tolyl-methylamine (CA [2936-62-1] ). MS (m/e): 377.4 (M+H).

Example 1.83 Preparation of rac-4-Fluoro-N-{[(isothiazol-5-yl-phenyl-methyl)-carbamoyl]- methyl}- benzamide

Prepared in analogy to example 1.1 from 4-fluoro-hippuric acid (CA [366-79-0]) and rac-C-isothiazol-5-yl-C-phenyl-methylamine hydrochloride (example 4.9). MS (m/e): 368.1 (MH " , 100%).

Example 1.84

Preparation of rac-4-Fluoro-N-{[(phenyl-pyridin-4-yl-methyl)-carbamoyl]-met hyl}- benzamide

Prepared in analogy to example 1.1 from 4-fluoro-hippuric acid (CA [366-79-0]) and rac-C-phenyl-C-pyridin-4-yl-methylamine (CA [58088-57-6] ). MS (m/e): 364.1 (MH " , 100%).

Example 1.85

Preparation of rac-4-Fluoro-N-({[(3-fluoro-phenyl)-(3-trifluoromethyl-pheny l)- methyl]-carbamoyl}-methyl)-benzamide

Prepared in analogy to example 1.1 from 4-fluoro-hippuric acid (CA [366-79-0]) and rac-C-(3-fluoro-phenyl)-C-(3-trifluoromethyl-phenyl)-methyla mine hydrochloride(example 4.10). MS (m/e): 447.1 (MH " , 100%).

Example 1.86

Preparation of 5-Methyl-thiophene-2-carboxylic acid ({[bis-(3-fluoro-phenyl)-methyl]- carbamoyl} -methyl) - amide

Prepared in analogy to example 1.12 from 2-amino-N-[bis-(3-fluoro-phenyl)-methyl]- acetamide (example 3.4) and 5-methyl-thiophene-2-carboxylic acid . MS (m/e): 399.1 (MH " , 78%).

Example 1.87

Preparation of 3-Methyl-thiophene-2-carboxylic acid ({[bis-(3-fluoro-phenyl)-methyl]- carbamoyl} -methyl) - amide

Prepared in analogy to example 1.12 from 2-amino-N-[bis-(3-fluoro-phenyl)-methyl]- acetamide (example 3.4) and 3-methyl-thiophene-2-carboxylic acid. MS (m/e): 399.1 (MH " , 100%).

Example 1.88

Preparation of Cyclohexanecarboxylic acid ({[bis-(3-fluoro-phenyl)-methyl]- carbamoyl}-methyl)-amide

Prepared in analogy to example 1.12 from 2-amino-N-[bis-(3-fluoro-phenyl)-methyl]- acetamide (example 3.4) and cyclohexane-carboxylic acid. MS (m/e): 385.2 (MH " , 100%).

Example 1.89

Preparation of rac-4-Fluoro-N-{[(phenyl-pyridazin-3-yl-methyl)-carbamoyl]-m ethyl}- benzamide

Prepared in analogy to example 1.1 from 4-fluoro-hippuric acid (CA [366-79-0]) and rac-C-phenyl-C-pyridazin-S-yl-methylamine (example 4.11). MS (m/e): 363.3 (MH " , 100%).

Example 1.90

Preparation of N-({[Bis-(3-fluoro-phenyl)-methyl]-carbamoyl}-methyl)-2-chlo ro-3- trifluoromethyl-benzamide

Prepared in analogy to example 1.12 from 2-amino-N-[bis-(3-fluoro-phenyl)-methyl]- acetamide (example 3.4) and 2-chloro-3-trifluoromethyl-benzoic acid. MS (m/e): 481.1 (MH " , 100%).

Example 1.91

Preparation of rac-4-Fluoro-N-({[(3-fluoro-phenyl)-phenyl-methyl]-carbamoyl }- methyl) -benzamide

To rac-C-(3-fluoro-phenyl)-C-phenyl-methyl amine chloride (55095-25-5], 0.1 g) in DMF (2.0 mL) was added 4- (fluoro-benzoylamino) -acetic acid ([366-79-0], 0.075g), Hϋnig's base (0.53 mL) and TBTU (0.123 g) and the reaction mixture was stirred overnight at room temperature. After such time water was added to the reaction mixture and the precipitate was isolated by filtration and washed with water yielding the title

compound (0.1 Ig, 69%) as a white solid. MS (m/e): 379.2 (MH " , 100%).

Example 1.92 Preparation of N-({[Bis-(3-fluoro-phenyl)-methyl]-carbamoyl}-methyl)-benzam ide

Prepared in analogy to example 1.12 from 2-amino-N-[bis-(3-fluoro-phenyl)-methyl]- acetamide (example 3.4) and benzoic acid. MS (m/e): 379.2 (MH " , 100%).

Example 1.93

Preparation of N-({[Bis-(3-fluoro-phenyl)-methyl]-carbamoyl}-methyl)-3-fluo ro- benzamide

Prepared in analogy to example 1.12 from 2-amino-N- [bis-(3-fluoro-phenyl)-methyl] - acetamide (example 3.4) and 3-fluorobenzoic acid. MS (m/e): 397.1 (MH " , 100%).

Example 1.94

Preparation of N-({[Bis-(3-fluoro-phenyl)-methyl]-carbamoyl}-methyl)-4-nitr o- benzamide

Prepared in analogy to example 1.12 from 2-amino-N-[bis-(3-fluoro-phenyl)-methyl]- acetamide (example 3.4) and 4-nitrobenzoic acid. MS (m/e): 424.1 (MH " , 100%).

Example 1.95

Preparation of N-({[Bis-(3-fluoro-phenyl)-methyl]-carbamoyl}-methyl)- isonicotinamide

Prepared in analogy to example 1.12 from 2-amino-N-[bis-(3-fluoro-phenyl)-methyl]- acetamide (example 3.4) and isonicotinic acid. MS (m/e): 380.2 (MH , 100%).

Example 1.96

Preparation of Thiophene-2-carboxylic acid ({[bis-(3-fluoro-phenyl)-methyl]- carbamoyl} -methyl) - amide

Prepared in analogy to example 1.12 from 2-amino-N-[bis-(3-fluoro-phenyl)-methyl]- acetamide (example 3.4) and thiophene-2-carboxylic acid. MS (m/e): 385.1 (MH , 100%).

Example 1.97 Preparation of 5-Nitro-thiophene-2-carboxylic acid ({[bis-(3-fluoro-phenyl)-methyl]- carbamoyl} -methyl) - amide

Prepared in analogy to example 1.12 from 2-amino-N-[bis-(3-fluoro-phenyl)-methyl]- acetamide (example 3.4) and 5-nitro-thiophene-2-carboxylic acid. MS (m/e): 430.2 (MH , 100%).

Example 1.98

Preparation of Thiophene-3-carboxylic acid ({[bis-(3-fluoro-phenyl)-methyl]- carbamoyl} -methyl) - amide

Prepared in analogy to example 1.12 from 2-amino-N-[bis-(3-fluoro-phenyl)-methyl]- acetamide (example 3.4) and thiophene-3-carboxylic acid. MS (m/e): 385.1 (MH " , 100%).

Intermediates for compounds of formula II

Example 2.1 Preparation of [3- (4-Chloro-phenyl)-propionylamino] -acetic acid

To a solution of 26 mmol sodium hydroxide in 7 ml water 8.7 mmol of glycine were added. The mixture was cooled in an ice-bath and a solution of 8.7 mmol 3-(4-chloro- phenyl)-propionyl chloride (CA [52085-96-8]) in 10 ml dioxane was slowly added over a period of 20 minutes. After stirring overnight at room temperature, the mixture was extracted with diethyl ether. The aqueous phase was acidified by addition of diluted hydrochloric acid and filtered. Trituration of the solid in diethyl ether yielded the title compound as a colorless solid. Yield = 42%. MS (m/e): 240.1 (MH " , 100%).

Example 2.2

Preparation of [3-(4-Methoxy-phenyl)-propionylamino]-acetic acid

Prepared in analogy to example 2.1 from glycine and 3-(4-methoxy-phenyl)-propionyl chloride (CA [15893-42-2]). MS (m/e): 236.1 (MH " , 100%).

Intermediates for compounds of formula XIV

Example 3.1

Preparation of 2-Amino-N-[(4-chloro-phenyl)-phenyl-methyl]-acetamide hydrochloride

a) ({ [(4-Chloro-phenyl)-phenyl-methyl1 -carbamoyl} -methyl) -carbamic acid tert-butyl ester

A suspension of 7.9 mmol C-(4-chloro-phenyl)-C-phenyl-methylamine hydrochloride (CA [5267-39-0]) in 100 ml acetonitrile was treated successively with 7.9 mmol N- tert.butyloxycarbonyl glycine, 39 mmol DIPEA and 8.7 mmol TBTU. After stirring for 1 hour at room temperature, the mixture was concentrated. Chromatography (SiO 2 ; ethyl acetate / cyclohexane) yielded the title compound as a colorless solid. Yield = 84%.

b) 2-Amino-N- [(4-chloro-phenyl)-phenyl-methyll -acetamide hydrochloride

6.6 mmol ({ [(4-Chloro-phenyl)-phenyl-methyl]-carbamoyl}-methyl)-carbami c acid tert-butyl ester were treated with 30 ml of a saturated solution of hydrogen chloride in diethyl ether. The mixture was stirred at room temperature for 1 hour. Removal of the diethyl ether in the rotatory evaporator yields the title compound as a colorless solid. Yield = 100%. MS (m/e): 273.0 (MH " , 100%).

Example 3.2

Preparation of 2-Amino-N- [phenyl- (4-trifluoromethyl-phenyl) -methyl] -acetamide hydrochloride

Prepared in analogy to example 3.1, starting from N-tert.butyloxycarbonyl glycine and

C-phenyl-C- (4-trifluoromethyl-phenyl) -methylamine hydrochloride (CA [49703-60-8]). MS (m/e): 307.3 (MH " , 100%).

Example 3.3

Preparation of 2-Amino-N-(phenyl-p-tolyl-methyl)-acetamide hydrochloride

Prepared in analogy to example 3.1, starting from N-tert.butyloxycarbonyl glycine and

C-phenyl-C-p-tolyl-methylamine (CA [164362-05-4]).

MS (m/e): 255.2 (M+H, 100%).

Example 3.4

Preparation of 2-Amino-N-[bis-(3-fluoro-phenyl)-methyl]-acetamide hydrochloride

Prepared in analogy to example 3.1, starting from N-tert.butyloxycarbonyl glycine and C,C-bis-(3-fluoro-phenyl)-methylamine (CA [261925-16-0]). MS (m/e): 311.2 (M+H, 100%).

Intermediates for compounds of formula HI Example 4.1 Preparation of C,C-Bis-(4-trifluoromethyl-phenyl)-methylamine

A suspension of 5 mmol magnesium-turnings in 10 ml diethyl ether was treated with 5 mmol 4-bromobenzotrifluoride to form the corresponding Grignard- reagent. This reagent was slowly added to a cooled solution of 5 mmol 4-(trifluoromethyl) benzonitrile in 10 ml of tetrahydrofuran at -70° C. After 1 hour at -70° C, the reaction mixture was stirred additional 2 hours at room temperature and then refluxed overnight. The resulting mixture was cooled again to 0 0 C and diluted with 10 ml of methanol and 10 mmol sodium borohydride were added. After stirring for 2 hours at room temperature, the mixture was poured into 100ml of 0.5 M aqueous hydrochloric acid and extracted with diethyl ether. The aqueous phase was adjusted to pH = 10 by addition of diluted aqueous sodium hydroxide and extracted 3 times with dichloromethane. Chromatography (SiC^; dichloromethane / methanol) yielded the title compound as a slightly brown foam.

Yield = 2%.

MS (m/e): 320.3 (M+H, 100%).

Example 4.2 ) Preparation of C-(2,4-Dichloro-phenyl)-C-phenyl-methylamine

Prepared in analogy to example 4.1, starting from phenylmagnesium bromide and 2,4- dichloro benzonitrile. Yield = 56%. MS (m/e): 235.0 (M+NH3, 100%)

Example 4.3

Preparation of C-(3,5-Difluoro-phenyl)-C-phenyl-methylamine hydrochloride

Cl

Step 1 : (3,5-Difluoro-phenyl)-phenyl-methanone oxime To 3,5-difluorobenzophenone (2.5 g) in ethanol (30 mL) was added hydroxylamine hydrochloride (3eq) and sodiumcarbonate (3 eq). The reaction mixture was stirred at reflux for 4 hours and then allowed to cool down to room temperature. The precipitate was then isolated by filtration and washed with water to yield the title compound as a white solid (m.p. = 91-93°C, Yield = 89%), reflux, 4h MS(m/e): 234.3 (M+H),

Step 2 : C-O^-Difluoro-phenyD-C-phenyl-methylamine hydrochloride To (3,5-difluoro-phenyl)-phenyl-methanone oxime (1.0 g) in methanol (40 mL) was added Palladium-C (Degussa ElOlN, 5%) and the reaction mixture was starred under a hydrogen atmosphere at room temperature for 2 hours. After such time, the catalyst was removed and the filtrate concentrated in vacuo. The residue was dissolved in 10 mL of diethylether and the corresponding salt was formed by addition of a 1OM HCl solution in diethyl ether. After allowing to stir for an extra 5 minutes, the fine precipitate was isolated by filtration to yield the title compound as a white powder (0.944 g, 86.1%, m.p. : 290-295 0 C, (EI): 219.1 (M)

Example 4.4

Preparation of C-(2-Chloro-5-nitro-phenyl)-C-phenyl-methylamine

This compound was prepared by the method of Dejaegher et al., Synlett 2002, 113 (see Scheme 4).

Example 4.5

Preparation of C-(4-Fluoro-phenyl)-C-(3-trifluoromethyl-phenyl)-methylamine hydrochloride

Under an Argon atmosphere, 3-trifluoromethylbenzyl magnesium bromide (20.3 mL) was added dropwise to a 4-fluoro-benzonitrile (2.Og) solution in diethylether. The reaction mixture was then refluxed for 2 hours and allowed to cool before adding the lithium aluminium hydride solution (IM, 10.8 mL) in a dropwise manner. The reaction was then refluxed overnight and then allowed to cool to room temperature. 3ml of ethyl acetate was added, followed by 4 ml of water. The reaction mixture was then filtered and the product was precipitated from the filtrate with the addition of concentrated hydrochloric acid in ether. The title compound was isolated by filtration, and dried under vacuum to yield the title compound as a white solid ( 1.47g, 30%).

MS (m/e) 255.2 (2%), 254.2 (11), 235.1 (100%)

IH NMR (CDC13, 300 MHz) 9.41 (3H, s, NH), 8.03 (IH, s), 7.89-7.87, (IH, d, J = 7.6 Hz), 7.76-7.70 ( IH, t, J = 7.8 Hz), 7.70-7.64 ( IH, t, J = 9.5 Hz), 7.67-7.63 (H, t, J = 8.5

Hz), 7.32-7.26 (2H, t, J = 8.9 Hz) .

Example 4.6

Preparation of C-p-Tolyl-C-(3-trifluoromethyl-phenyl)-methylamine hydrochloride

Prepared in analogy to example 4.5, starting from 3-trifluoromethylphenylmagnesium bromide and 4-methyl benzonitrile. MS (m/e): 250.1 (2%), 249.1 (100%)

Example 4.7

Preparation of C-(4-Methoxy-phenyl)-C-(3-trifluoromethyl-phenyl)-methylamin e hydrochloride

Prepared in analogy to example 4.5, starting from 3-trifluoromethylphenylmagnesium bromide and 4-methoxybenzonitrile. MS (m/e): 250.1 (2%), 249.1 (100%)

Example 4.8 Preparation of C-(4-Trifluoromethoxy-phenyl)-C-(3-trifluoromethyl-phenyl)- methylamine; hydrochloride

Prepared in analogy to example 4.5, starting from 3-trifluoromethylphenylmagnesium bromide and 4-trifluoromethoxybenzonitrile.

MS (m/e): 267.2 (2%), 266.2 (24), 265.2 (100%)

Example 4.9

Preparation of C-Isothiazol-5-yl-C-phenyl-methylamine hydrochloride

Cl

Step 1: Phenyl-thiazol-2-yl-methanone

This compound was prepared in analogy to the method described by AJ. Layton et al., J. Chem. Soc. (C), 1968, 611.

Step 2: Phenyl-thiazol-2-yl-methanone oxime

To Phenyl-thiazol-2-yl-methanone (0.5g) in ethanol (6 mL) was added hydroxylamine hydrochloride (3eq) and sodiumcarbonate (3 eq). The reaction mixture was stirred at reflux overnight and then allowed to cool down to room temperature. The precipitate

was then isolated by filtration and washed with water to yield the title compound as a light grey solid. MS(m/e): 207.1 (5), 206.1 (10), 205.1 (100% M+H+)

Step 3: C-Isothiazol-S-yl-C-phenyl-methylamine hydrochloride To a solution of Phenyl-thiazol-2-yl-methanone oxime (O.lg) in 1,2-dimethoxyethane (1.0 inL), was added NaBH4 (0.078g). TiCl4 (1.03 mL) was then slowly added under nitrogen atmosphere at 0 0 C. The mixture was warmed up to room temperature and stirred for 24 hours. Then 10 mL of ice cold water was added, the solution was alkalised with ammonium hydroxide solution, and extracted with ethyl acetate. The organic layer was washed with a saturated solution of NaCl, dried over Na2SO4, and evaporated under reduced pressure. The product was disolved in diethylether and filtered. The product was crashed out from the filtrate by addition of HCl/ diethylether. The product was dried under high vacuum at 40 0 C to yield the title compound (0.041 g, 37%). MS (m/e): 176.2 (5%), 175.3 (10), 174.2 (100%)

Example 4.10

Preparation of C-(3-Fluoro-phenyl)-C-(3-trifluoromethyl-phenyl)-methylamine hydrochloride

Prepared in analogy to example 4.5, starting from 3-trifluoromethylphenylmagnesium bromide and 3-fluoro-benzonitrile.

MS (m/e): 254.2 (11%), 253.1 (100%)

Example 4.11 Preparation of C-Phenyl-C-pyridazin-3-yl-methylamine hydrochloride

Cl

Step 1: Phenyl-pyridazin-3-yl-methanone oxime

Phenyl-pyridazin-3-yl-methanone oxime was formed from Phenyl-pyridazin-3-yl- methanone [60906-52-7] in a similar way as phenyl-thiazol-2-yl-methanone oxime

(Example 4.9) was.

MS (EI) 201.2 (15%), 200.1 (98 M+H+), 183.1 (12), 182.1 (100%)

Step 2: C-Phenyl-C-pyridazin-S-yl-methylamine hydrochloride Bis-(3-fluoro-phenyl)-methanone oxime (0.2g) was disolved in methanol (8 mL). Palladium-C (0.043 g) was added to form a suspension and the air within the flask was evacuated. Hydrogen gas was added via a balloon for 4 hours until the reaction was complete by tic. The catalyst was filtered off and the filtrate was concentrated under reduced pressure. The product formed was disolved in diethylether filtered and crashed out of the filtrate with the addition of HCl in diethylether. The solid product was filtered of and dried under high vacuum at 40 0 C for 5 hours to yield the title compound (0.134 g, 60%). MS (m/e): 173.2 (9%), 171.2 (3), 170.2, (14%), 169.1 (100%)




 
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