HK1158631B - Derivatives of (bridged piperazinyl)-1-alkanone and use thereof as p75 inhibitors - Google Patents

Description

(bridged piperazinyl) -1-alkanone derivatives and their use as p75 inhibitors

Technical Field

The present invention relates to ((phenyl) -3, 6-dihydropyridin-1-yl) (bridged piperazinyl) -1-one derivatives and ((phenyl) -2, 5-dihydropyrrol-1-yl) (bridged piperazinyl) -1-one derivatives, processes for their preparation and their therapeutic use. Compound pair of the invention p75^NTRNeurotrophin receptor (p 75)^NTRneurotrophin receptor) has affinity.

Background

Neurotrophins belong to a family of proteins whose biological role is in particular in cell survival and differentiation.

p75^NTRThe receptor (i.e., the receptor for all neurotrophins) is a transmembrane glycoprotein in the Tumor Necrosis Factor (TNF) receptor family (w.j.friedman and l.a.greene, exp.cell.res., 1999, 253, 131-. p75^NTRThe receptor is expressed in several cell types and several biological functions are attributed to p75^NTRReceptor: first, the affinity of neurotrophins for receptor tyrosine kinases (trk) is modulated; second, signals for apoptosis-induced cell death were induced in the absence of trk. In addition, neurotrophin precursors (i.e., prepreurotrophic proteins) can bind p75 with high affinity^NTRCombined and believed to be p75 in neurons and certain cell lines^NTRPotent inducers of dependent apoptosis.

In the central nervous system, several studies have shown that apoptosis is involved in several pathologies, such as amyotrophic lateral sclerosis, multiple sclerosis, alzheimer's disease, parkinson's disease, huntington's disease, and prion disease. P75 is also known^NTROver-expressed in a variety of neurodegenerative diseases such as Alzheimer's disease and Amyotrophic Lateral Sclerosis (ALS) (Longo F.M.et. al., curr. Alzheimer Res.2007; 4: 503-506 and Lowry K.S.et. al., Amyotrop. Laterai.Scler. other. Motor. neuron. D.2001; 2: 127-34).

Some research results suggest p75^NTRMay play a dominant role in the mechanisms leading to apoptotic neuronal death following ischemia (p.p.roux et al., j.neurosci., 1999, 19, 6887-.

Some findings (V.Della-Bianca et al, J.biol.chem., 2001, 276: 38929-33 and S.Rabizadeh et al, Proc.Natl.Acad.Sci.USA, 1994, 91, 10703-: p75^NTRInduced by infectious prion proteinPlays an important role in neuronal death (transmissible spongiform encephalopathy) or β -amyloid-induced neuronal death (alzheimer's disease).

p75^NTRThe receptor is also associated with Nogo receptors and is involved in the signaling of the inhibitory effect of this myelin protein on axonal growth. Thus, p75^NTRReceptors play a major role in neuronal plasticity regulation and neuronal-glial interactions and therefore represent alternative therapeutic targets for promoting nerve regeneration.

In addition to neurological and neurodegenerative diseases, p75 has also been implicated^NTRMay play a role in cardiovascular diseases such as atherosclerosis and myocardial ischemia (M.L. Bockaton-Pialat et al, am.J. Pathol., 1995, 146, 1-6 and H.Perlman, Circulation, 1997, 95, 981-. Recent studies have shown that p75^NTRAnd neurotrophin expression and extensive apoptosis are increased in atherosclerotic lesions.

Several studies also suggested p75^NTRAre mediators of inflammation (Rihl M.et al., Ann. Rheum.Dis.2005: 64 (11): 1542-9, Raychaudhuri S.P.et al., prog.brain. Res.2004; 146: 433-7 and Tokuoka S.et al., Br.J.Pharmacol.2001, 134: 1580-.

p75^NTRBut also plays an important role in tumor biology.

A variety of compounds are known to react with trkA/NGF/p75^NTRSystemic interactions or NGF (nerve growth factor) -type activity. Thus, patent application WO 00/59893 describes substituted pyrimidine derivatives which show NGF-type activity and/or increase NGF activity on PC12 cells.

Patent application WO 03/104225 describes the treatment of p75^NTRA compound whose receptor exhibits affinity. These compounds are highly metabolized and show a high percentage inhibition of the hERG Gene (human Ether a go-go Related Gene).

hERG gene encoding K in potassium channel_v11.1. A protein. This protein is known to have an effect on the electrical activity of the heart. When the ability of the channel to conduct current through the cell membrane is inhibited by the action of drugs, it can lead to a potentially fatal condition known as QT syndrome. Certain drugs may inhibit the protein, which causes the risk of sudden death complications as an undesirable side effect. This has made hERG inhibition an important issue in drug management and drug development (Sanguinetti MC, Tristani-Firouzi M (March 2006). "hERG loci channels and cardiac arrhythmia". Nature 440 (7083): 463-9).

Disclosure of Invention

Subject of the invention is p75^NTRNovel compounds with affinity for the receptor that do not have the drawbacks of the existing compounds, i.e., high metabolism and strong hERG inhibition. Therefore, it shows an advantage for the development of new drugs.

The subject of the invention is a compound having formula (I):

wherein

m represents 0 or 1;

a representsAnd B represents a hydrogen atom; or

A represents a hydrogen atom and B represents

-W-is a nitrogen-containing heterocycle selected from:

1-3 represents 1,2 or 3;

n represents 1 or 2;

r1 represents a halogen atom, or (C)₁-C₄) Alkyl, trifluoromethyl, (C)₁-C₄) Alkoxy or trifluoromethoxy;

r2 represents a hydrogen atom, a halogen atom, or (C)₁-C₄) Alkyl, trifluoromethyl, (C)₁-C₄) Alkoxy, trifluoromethoxy, -COOR or-CONH₂；

R5 represents the following group:

wherein R3 and R4 at any available position independently represent a hydrogen atom, a halogen atom, a (C)₁-C₄) Alkyl, (C)₁-C₄) Alkoxy, trifluoromethyl, trifluoromethoxy, cyano, -COOH, -COOalkyl, -CONH₂-CONR6R7 or-NHCOR;

r, R6 and R7 represent C₁-C₆An alkyl group.

The compounds of formula (I) may contain one or more asymmetric carbon atoms. Thus, they may exist as enantiomers or diastereomers. These enantiomers and diastereomers and mixtures thereof (including racemic mixtures) are part of the present invention.

The compounds of formula (I) may exist in the form of base or acid addition salts. Such addition salts are part of the present invention.

These salts may be prepared with pharmaceutically acceptable acids, but salts of other acids useful, for example, in the purification or isolation of compounds of formula (I) are also part of the invention.

In the context of the present invention:

the term "halogen atom" means fluorine, chlorine, bromine or iodine;

the term "alkyl" means a straight-chain or branched saturated aliphatic radical, such as C₁-C₄Alkyl may represent methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl;

the term "fluoroalkyl" means an alkyl group in which one or more hydrogen atoms have been replaced by fluorine atoms;

the term "perfluoroalkyl" means an alkyl group in which all the hydrogen atoms have been replaced by fluorine atoms, such as trifluoromethyl;

the term "alkoxy" means an-O-alkyl group, wherein the alkyl group is as defined above.

In the compounds of formula (I) which are the subject of the present invention, a further group of compounds consists of the compounds of formula (I) below, in the form of the base or of the acid addition salt, wherein

m represents 0 or 1;

a representsAnd B represents a hydrogen atom; or

A represents a hydrogen atom and B represents

-W-is the following group:

n is 1 or 2; or n is 1;

r1 is a halogen atom or trifluoromethyl;

r2 is a hydrogen atom, trifluoromethyl, -COOR or-CONH₂；

R5 represents the following group:

r3 or R4 independently represent a hydrogen atom, halogen, trifluoromethyl, -CONH₂-COOH or-NHCOCH₃(ii) a Or

R3 represents a hydrogen atom, halogen, trifluoromethyl, -CONH₂-COOH or-NHCOCH₃And R4 represents a hydrogen atom.

In the compounds of formula (I) which are the subject of the present invention, a further group of compounds consists of the compounds of formula (I) below, in the form of the base or of the acid addition salt, wherein

m represents 1;

a representsAnd B represents a hydrogen atom;

-W-is a nitrogen-containing heterocycle selected from:

1-3 represents 1,2 or 3;

n represents 1 or 2;

r1 represents a halogen atom, or (C)₁-C₄) Alkyl, trifluoromethyl, (C)₁-C₄) Alkoxy or trifluoromethoxy;

r2 represents a hydrogen atom, a halogen atom, or (C)₁-C₄) Alkyl, trifluoromethyl, (C)₁-C₄) Alkoxy or trifluoromethoxy;

r5 represents the following group:

wherein R3 and R4 at any available position independently represent a hydrogen atom, a halogen atom, a (C)₁-C₄) Alkyl, (C)₁-C₄) Alkoxy, trifluoromethyl, trifluoromethoxy, cyano, -COOH or-COOalkyl.

In the compounds of formula (I) which are the subject of the present invention, a further group of compounds consists of the compounds of formula (I) below, in the form of the base or of the acid addition salt, wherein

m represents 1;

a representsAnd B represents a hydrogen atom;

-W-is the following group:

n is 1 or 2; or n is 1;

r1 is a halogen atom or trifluoromethyl;

r2 is a hydrogen atom or a trifluoromethyl group;

r5 represents the following group:

r3 or R4 independently represent a hydrogen atom, halogen or trifluoromethyl; or

R3 represents a hydrogen atom, halogen or trifluoromethyl and R4 represents a hydrogen atom.

Among the compounds of formula (I) which are the subject of the present invention, mention may be made in particular of the following compounds, in base form or in acid addition salt form:

-compound 1: 1- [4- (3-trifluoromethylphenyl) -3, 6-dihydro-2H-pyridin-1-yl]-2- [8- (5-trifluoromethylpyridin-2-yl) -3, 8-diazabicyclo [3.2.1]Oct-3-yl]An ethanone;

-compound 2: 1- [4- (4-chlorophenyl) -3, 6-dihydro-2H-pyridin-1-yl]-2- (8- (pyrimidin-2-yl) -3, 8-diazabicyclo [3.2.1]Oct-3-yl) ethanone;

-compound 3: 2- (3- (pyrazin-2-yl) -3, 8-diazabicyclo [3.2.1]Oct-8-yl) -1- [4- (3-trifluoromethylphenyl) -3, 6-dihydro-2H-pyridin-1-yl]An ethanone;

-compound 4: 2- (8- (pyrimidin-2-yl) -3, 8-diazabicyclo [3.2.1]Oct-3-yl) -1- [4- (3-trifluoromethylphenyl) -3, 6-dihydro-2H-pyridin-1-yl]An ethanone;

-compound 5: 1- [4- (3-trifluoromethylphenyl) -3, 6-dihydro-2H-pyridin-1-yl]-2- [3- (5-trifluoromethylpyridin-2-yl) -3, 8-diazabicyclo [3.2.1]Oct-8-yl]An ethanone;

-chemical combinationObject 6: 2- (8- (pyridin-2-yl) -3, 8-diazabicyclo [3.2.1]Oct-3-yl) -1- [4- (3-trifluoromethylphenyl) -3, 6-dihydro-2H-pyridin-1-yl]An ethanone;

-compound 7: 1- [4- (4-chlorophenyl) -3, 6-dihydro-2H-pyridin-1-yl]-2- [8- (5-trifluoromethylpyridin-2-yl) -3, 8-diazabicyclo [3.2.1]Oct-3-yl]An ethanone;

-compound 8: 1- [4- (4-chloro-3-trifluoromethylphenyl) -3, 6-dihydro-2H-pyridin-1-yl]-2- [8- (5-trifluoromethylpyridin-2-yl) -3, 8-diazabicyclo [3.2.1]Oct-3-yl]An ethanone;

-compound 9: 2- (8- (quinolin-2-yl) -3, 8-diazabicyclo [3.2.1]Oct-3-yl) -1- [4- (3-trifluoromethylphenyl) -3, 6-dihydro-2H-pyridin-1-yl]An ethanone;

-compound 10: 1- [4- (4-chlorophenyl) -3, 6-dihydro-2H-pyridin-1-yl]-2- [3- (5-trifluoromethylpyridin-2-yl) -3, 8-diazabicyclo [3.2.1]Oct-8-yl]An ethanone;

-compound 11: 1- [4- (4-chloro-3-trifluoromethylphenyl) -3, 6-dihydro-2H-pyridin-1-yl]-2- [8- (5-fluoropyrimidin-2-yl) -3, 8-diazabicyclo [3.2.1]Oct-3-yl]An ethanone;

-compound 12: 2- [8- (5-Bromopyrimidin-2-yl) -3, 8-diazabicyclo [3.2.1]Oct-3-yl]-1- [4- (4-chloro-3-trifluoromethylphenyl) -3, 6-dihydro-2H-pyridin-1-yl]An ethanone;

-compound 13: 1- [4- (3-trifluoromethylphenyl) -3, 6-dihydro-2H-pyridin-1-yl]-2- [5- (5-trifluoromethylpyridin-2-yl) -2, 5-diazabicyclo [2.2.1]Hept-2-yl]An ethanone;

-compound 14: 1- [4- (4-chlorophenyl) -3, 6-dihydro-2H-pyridin-1-yl]-2- [5- (5-trifluoromethylpyridin-2-yl) -2, 5-diazabicyclo [2.2.1]Hept-2-yl]An ethanone;

-compound 15: 1- [4- (4-chloro-3-trifluoromethylphenyl) -3, 6-dihydro-2H-pyridin-1-yl]-2- [5- (5-trifluoromethylpyridin-2-yl) -2, 5-diazaBicyclo [2.2.1]Hept-2-yl]An ethanone;

-compound 16: 1- [4- (4-chloro-3-trifluoromethylphenyl) -3, 6-dihydro-2H-pyridin-1-yl]-2- (5- (pyridin-2-yl) -2, 5-diazabicyclo [2.2.1]Hept-2-yl) ethanone;

-compound 17: 1- [4- (4-chloro-3-trifluoromethylphenyl) -3, 6-dihydro-2H-pyridin-1-yl]-2- [5- (5-fluoropyrimidin-2-yl) -2, 5-diazabicyclo [2.2.1]Hept-2-yl]An ethanone;

-compound 18: 1- [4- (4-chloro-3-trifluoromethylphenyl) -3, 6-dihydro-2H-pyridin-1-yl]-2- [9- (5-trifluoromethylpyridin-2-yl) -3, 9-diazabicyclo [3.3.1]Non-3-yl]An ethanone;

-compound 19: 2- [8- (5-Fluoropyrimidin-2-yl) -3, 8-diazabicyclo [3.2.1]Oct-3-yl]-1- [4- (4-trifluoromethylphenyl) -3, 6-dihydro-2H-pyridin-1-yl]An ethanone;

-compound 20: 1- [4- (3-chlorophenyl) -3, 6-dihydro-2H-pyridin-1-yl]-2- [8- (5-fluoropyrimidin-2-yl) -3, 8-diazabicyclo [3.2.1]Oct-3-yl]An ethanone;

-compound 21: 2- [8- (5-Fluoropyrimidin-2-yl) -3, 8-diazabicyclo [3.2.1]Oct-3-yl]-1- [4- (3-trifluoromethylphenyl) -3, 6-dihydro-2H-pyridin-1-yl]An ethanone;

-compound 22: 1- [4- (4-chlorophenyl) -3, 6-dihydro-2H-pyridin-1-yl]-2- [8- (5-fluoropyrimidin-2-yl) -3, 8-diazabicyclo [3.2.1]Oct-3-yl]An ethanone;

-compound 23: 1- [4- (3, 5-bis (trifluoromethyl) phenyl) -3, 6-dihydro-2H-pyridin-1-yl]-2- [8- (5-fluoropyrimidin-2-yl) -3, 8-diazabicyclo [3.2.1]Oct-3-yl]An ethanone;

-compound 24: 2- [8- (5-Fluoropyrimidin-2-yl) -3, 8-diazabicyclo [3.2.1]Oct-3-yl]-1- (4-m-tolyl-3, 6-dihydro-2H-pyridin-1-yl) ethanone;

-compound 25: 1- [4- (4-chloro-3-trifluoromethylphenyl)-3, 6-dihydro-2H-pyridin-1-yl]-2- [8- (pyrimidin-2-yl) -3, 8-diazabicyclo [3.2.1]Oct-3-yl]An ethanone;

-compound 26: 1- [4- (4-chloro-3-trifluoromethylphenyl) -3, 6-dihydro-2H-pyridin-1-yl]-2- [3- (5-Fluoropyrimidin-2-yl) -3, 8-diazabicyclo [3.2.1]Oct-8-yl]An ethanone;

-compound 27: 1- [4- (4-chloro-3-trifluoromethylphenyl) -3, 6-dihydro-2H-pyridin-1-yl]-2- (8- (pyridin-3-yl) -3, 8-diazabicyclo [3.2.1]Oct-3-yl) ethanone;

-compound 28: 6- (3- {2- [4- (4-chloro-3-trifluoromethylphenyl) -3, 6-dihydro-2H-pyridin-1-yl]-2-oxoethyl } -3, 8-diazabicyclo [3.2.1]Oct-8-yl) pyridine-3-carboxylic acid methyl ester;

-compound 29: 6- (3- {2- [4- (4-chloro-3-trifluoromethylphenyl) -3, 6-dihydro-2H-pyridin-1-yl]-2-oxoethyl } -3, 8-diazabicyclo [3.2.1]Oct-8-yl) pyridine-3-carboxylic acid;

-compound 30: 1- [4- (4-chloro-3-trifluoromethylphenyl) -3, 6-dihydro-2H-pyridin-1-yl]-2- [8- (6-trifluoromethylpyridin-3-yl) -3, 8-diazabicyclo [3.2.1]Oct-3-yl]An ethanone;

-compound 31: 2- [8- (5-Chloropyridin-2-yl) -3, 8-diazabicyclo [3.2.1]Oct-3-yl]-1- [4- (4-chloro-3-trifluoromethylphenyl) -3, 6-dihydro-2H-pyridin-1-yl]An ethanone;

-compound 32: 1- [4- (4-chloro-3-trifluoromethylphenyl) -3, 6-dihydro-2H-pyridin-1-yl]-2- (8- (quinolin-2-yl) -3, 8-diazabicyclo [3.2.1]Oct-3-yl) ethanone;

-compound 33: 1- [4- (4-chloro-3-trifluoromethylphenyl) -3, 6-dihydro-2H-pyridin-1-yl]-2- [8- (5-Fluoropyridin-2-yl) -3, 8-diazabicyclo [3.2.1]Oct-3-yl]An ethanone;

-compound 34: 2- [8- (6-Chloropyridin-3-yl) -3, 8-diazabicyclo [3.2.1]Oct-3-yl]-1- [4- (4-chloro-3-trifluoromethylphenyl) -3, 6-dihydro-2H-pyri-dinePyridin-1-yl]An ethanone;

-compound 35: 1- [4- (3-trifluoromethylphenyl) -3, 6-dihydro-2H-pyridin-1-yl]-2- [8- (3-trifluoromethylpyridin-2-yl) -3, 8-diazabicyclo [3.2.1]Oct-3-yl]An ethanone;

-compound 36: 6- (3- {2- [4- (4-chloro-3-trifluoromethylphenyl) -3, 6-dihydro-2H-pyridin-1-yl]-2-oxoethyl } -3, 8-diazabicyclo [3.2.1]Oct-8-yl) pyridine-3-carboxylic acid ethyl ester;

-compound 37: 2- (8- (pyrazin-2-yl) -3, 8-diazabicyclo [3.2.1]Oct-3-yl) -1- [4- (3-trifluoromethylphenyl) -3, 6-dihydro-2H-pyridin-1-yl]An ethanone;

-compound 38: 2- (8- (pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1]Oct-3-yl) -1- [4- (3-trifluoromethylphenyl) -3, 6-dihydro-2H-pyridin-1-yl]An ethanone;

-compound 39: 1- [4- (4-chloro-3-trifluoromethylphenyl) -3, 6-dihydro-2H-pyridin-1-yl]-2- (8- (pyrazin-2-yl) -3, 8-diazabicyclo [3.2.1]Oct-3-yl) ethanone;

-compound 40: 2- (8- (pyrazin-2-yl) -3, 8-diazabicyclo [3.2.1]Oct-3-yl) -1- (4-m-tolyl-3, 6-dihydro-2H-pyridin-1-yl) ethanone;

-compound 41: 2- (3- {2- [4- (4-chloro-3-trifluoromethylphenyl) -3, 6-dihydro-2H-pyridin-1-yl]-2-oxoethyl } -3, 8-diazabicyclo [3.2.1]Oct-8-yl) pyrimidine-5-carboxylic acid methyl ester;

-compound 42: 2- (3- {2- [4- (4-chloro-3-trifluoromethylphenyl) -3, 6-dihydro-2H-pyridin-1-yl]-2-oxoethyl } -3, 8-diazabicyclo [3.2.1]Oct-8-yl) pyrimidine-5-carboxylic acid;

-compound 43: 1- [4- (4-chloro-3-trifluoromethylphenyl) -3, 6-dihydro-2H-pyridin-1-yl]-3- [8- (5-fluoropyrimidin-2-yl) -3, 8-diazabicyclo [3.2.1]Oct-3-yl]Propan-1-one;

-compound 44：1-[4-(4-chloro-3-trifluoromethylphenyl) -3, 6-dihydro-2H-pyridin-1-yl]-2- [5- (5-fluoropyrimidin-2-yl) -2, 5-diazabicyclo [2.2.2]Oct-2-yl]An ethanone;

-compound 45: 2- [8- (5-Fluoropyrimidin-2-yl) -3, 8-diazabicyclo [3.2.1]Oct-3-yl]-1- [4- (3-methoxyphenyl) -3, 6-dihydro-2H-pyridin-1-yl]An ethanone;

-compound 46: 1- [4- (4-chloro-3-trifluoromethylphenyl) -3, 6-dihydro-2H-pyridin-1-yl]-2- [5- (6-trifluoromethylpyridazin-3-yl) -2, 5-diazabicyclo [2.2.1]Hept-2-yl]An ethanone;

-compound 47: 2- [8- (5-Fluoropyrimidin-2-yl) -3, 8-diazabicyclo [3.2.1]Oct-3-yl]-1- [3- (3-trifluoromethyl-4-chlorophenyl) -2, 5-dihydropyrrol-1-yl]An ethanone;

-compound 48: 6- (3- {2- [4- (4-chloro-3-trifluoromethylphenyl) -3, 6-dihydro-2H-pyridin-1-yl]-2-oxoethyl } -3, 8-diazabicyclo [3.2.1]Oct-8-yl) pyridine-3-carboxamide;

-compound 49: 2- [8- (5-Fluoropyrimidin-2-yl) -3, 8-diazabicyclo [3.2.1]Oct-3-yl]-1- [4- (2, 3-dichlorophenyl) -3, 6-dihydro-2H-pyridin-1-yl]An ethanone;

-compound 50: 1- [4- (4-chloro-3-trifluoromethylphenyl) -3, 6-dihydro-2H-pyridin-1-yl]-2- [8- (6-Fluoropyridin-3-yl) -3, 8-diazabicyclo [3.2.1]Oct-3-yl]An ethanone;

-compound 51: 2- [8- (5-Fluoropyrimidin-2-yl) -3, 8-diazabicyclo [3.2.1]Oct-3-yl]-1- [5- (3-trifluoromethylphenyl) -3, 6-dihydro-2H-pyridin-1-yl]An ethanone;

-compound 52: 2- [8- (5-Fluoropyrimidin-2-yl) -3, 8-diazabicyclo [3.2.1]Oct-3-yl]-1- [3- (3-trifluoromethylphenyl) -2, 5-dihydropyrrol-1-yl]An ethanone;

-compound 53: 3- (1- {2- [8- (5-Fluoropyrimidin-2-yl) -3, 8-diazabicyclo [3.2.1]Oct-3-yl]Acetyl } -1,2,5, 6-tetrahydropyridin-3-yl) benzylAcid methyl ester;

-compound 54: 2- [8- (5-Fluoropyrimidin-2-yl) -3, 8-diazabicyclo [3.2.1]Oct-3-yl]-1- [5- (2-trifluoromethylphenyl) -3, 6-dihydro-2H-pyridin-1-yl]An ethanone;

-compound 55: 1- [4- (4-chloro-3-trifluoromethylphenyl) -3, 6-dihydro-2H-pyridin-1-yl]-2- (8- (pyrimidin-5-yl) -3, 8-diazabicyclo [3.2.1]Oct-3-yl) ethanone;

-compound 56: 2- [8- (5-Fluoropyrimidin-2-yl) -3, 8-diazabicyclo [3.2.1]Oct-3-yl]-1- [4- (3-trifluoromethoxyphenyl) -3, 6-dihydro-2H-pyridin-1-yl]An ethanone;

-compound 57: 1- [4- (4-chloro-3-trifluoromethylphenyl) -3, 6-dihydro-2H-pyridin-1-yl]-2- [5- (6-trifluoromethylpyridazin-3-yl) -2, 5-diazabicyclo [2.2.2]Oct-2-yl]An ethanone;

-compound 58: n- [6- (3- {2- [4- (4-chloro-3-trifluoromethylphenyl) -3, 6-dihydro-2H-pyridin-1-yl]-2-oxoethyl } -3, 8-diazabicyclo [3.2.1]Oct-8-yl) pyridin-3-yl]An acetamide;

-compound 59: 2- (8- (quinolin-3-yl) -3, 8-diazabicyclo [3.2.1]Oct-3-yl) -1- [4- (3-trifluoromethyl-4-chlorophenyl) -3, 6-dihydro-2H-pyridin-1-yl]An ethanone.

In the following, the term "protecting group Pg" means a group which on the one hand can protect a reactive functional group, such as a hydroxyl or amino group, during synthesis and on the other hand can regenerate the said reactive functional group intact at the end of synthesis. Examples of protecting Groups and methods of protection and deprotection are found in Protective Groups in Organic Synthesis, Green et al, 2nd edition (John Wiley & Sons, Inc., New York).

According to the invention, the compounds of general formula (I) can be prepared according to the following process.

Scheme 1

More specifically, the process for the preparation of compounds of formula (I) wherein A, B, m, n, W and R5 are as defined above comprises reacting a compound of formula (II) with a compound of formula (III) according to methods known to those skilled in the art, for example in the presence of a base in a solvent (see WO 03/104225),

the compounds of formula (II) are:

wherein A, B, m and n are as defined in formula (I) and Hal represents a halogen atom such as chlorine,

the compounds of the general formula (III) are:

H-W-R5(III)

wherein W and R5 are as defined in formula (I). Thus, mention may be made of organic bases such as triethylamine, N-diisopropylamine, Diisopropylethylamine (DPEA) or N-methylmorpholine or alkali metal carbonates or bicarbonates such as potassium carbonate, sodium carbonate or sodium bicarbonate, in the presence or absence of alkali metal iodides such as potassium iodide or sodium iodide. The reaction is carried out in a solvent such as acetonitrile, N-Dimethylformamide (DMF), N-methylpyrrolidone, toluene or propan-2-ol and at ambient to solvent reflux temperature. The term "ambient temperature" means a temperature of 5 to 25 ℃. For example, the reaction may be carried out in the presence of sodium bicarbonate and sodium iodide in a solvent such as DMF.

In the product of general formula (I) thus obtained, R, R1, R2, R3, R4, R6 and R7 can be modified by the treatment methods customary to the person skilled in the art, for example by hydrolysis of the ester groups to give carboxyl groups.

In general, acid addition salts of compounds of formula (I) can be obtained by addition with an appropriate acid, such as hydrochloric, hydrobromic or oxalic acid.

The compounds of formula (III), optionally in salt form, may be prepared from the corresponding compounds of formula (VII):

Pg-W-R5(VII)

wherein W and R5 are as defined for formula (I) and Pg represents a protecting group for the nitrogen atom in W. Preferably, Pg is benzyl and deprotection is carried out according to conventional methods well known to those skilled in the art, such as Pd/C catalytic hydrogenation or treatment with chloroformate followed by hydrolysis in acidic medium.

The compound of formula (VII) may be prepared from a compound of formula (VIII) and a compound of formula (IX):

Pg-W-H(VIII)

Hal-R5(IX)

wherein Pg, W and R5 are as defined above and Hal denotes a halogen atom, preferably chlorine. This reaction is generally carried out under the same conditions as the reaction for preparing the compound of formula (I) from the compounds of formulae (II) and (III).

Alternatively, the compound of formula (III) may be prepared by the Buchwald coupling method under the following conditions: in the presence of a suitably selected palladium catalyst and a suitably selected phosphine, an inert solvent such as toluene or xylene is used as solvent at ambient temperature to 110 ℃.

Examples of such reactions are described in the experimental section.

The compounds of formula (II) can be obtained as follows: reacting the corresponding compound of formula (IV), optionally in the form of an acid addition salt, with a compound of formula (V),

the compound of formula (IV) is:

wherein A, B and m are as defined in formula (I),

the compounds of formula (V) are:

wherein Hal and n are as defined in formula (II) and Hal' represents a halogen atom which may be the same as or different from Hal. Preferably, Hal' represents a chlorine atom.

The reaction is generally carried out under the following conditions: in the presence of a base (e.g. triethylamine, N-diisopropylethylamine or N-methylmorpholine) in a solvent (e.g. dichloromethane, chloroform, tetrahydrofuran, dioxane or mixtures of these solvents) at from 0 ℃ to ambient temperature. The compounds of formula (V) are generally commercially available.

The compounds of formula (IV), optionally in the form of acid addition salts, can be obtained from compounds of formula (VIa) or (VIb) by dehydration:

wherein R1, R2 and m are as defined above.

The dehydration was carried out under the following conditions: in an acidic medium (using, for example, concentrated hydrochloric acid, an acetic acid/hydrochloric acid mixture or an acetic acid/sulfuric acid mixture), at ambient temperature to 140 ℃. The reaction can also be carried out under the following conditions: p-toluenesulfonic acid is used in a solvent such as toluene at ambient to reflux temperature.

Alternatively, a compound of formula (IV) (wherein m ═ 1) can be prepared from a compound of formula (X):

wherein A and B are as defined above, said preparation being carried out as follows: benzylplum ammonium salts are formed and then reduced with sodium borohydride in solvents such as methanol or dioxane at temperatures from 0 ℃ to ambient temperature and debenzylation is carried out according to conventional methods known to the person skilled in the art, for example by Pd/C-catalyzed hydrogenation or by treatment with chloroformates and then hydrolysis in acidic medium.

Examples of such reactions are described in the experimental section.

Optionally, the process of the invention comprises a subsequent step of isolating the desired product obtained.

If no methods for preparing the products and reactants of formulae (VI), (V), (VIII), (IX) and (X) are described, they are commercially available or described in the literature or can be prepared according to the methods described herein or known to those skilled in the art.

According to another aspect of the invention, the subject of the invention is also the compounds of formula (II), in base form or in acid addition salt form:

wherein A, B, m, n and Hal are as defined above. These compounds are useful as synthetic intermediates for compounds of formula (I).

The following examples describe the preparation of some of the compounds of the present invention. These examples are non-limiting and are only intended to illustrate the invention. The numbering of the compounds of the examples refers to those given in the table below which shows the chemical structure and physical properties of some of the compounds of the invention.

The physicochemical measurements were performed as follows:

melting points were measured with a Buchi B540 instrument.

Proton nuclear magnetic resonance (¹H NMR) spectra were recorded under the following conditions:

a)500MHz, Bruker instrument, equipped with an Avance III console;

b)400MHz, Bruker instrument, equipped with an Avance I console.

Chemical shifts are given in ppm relative to TMS frequency.

All spectra were recorded at 40 ℃.

Abbreviations used to characterize the signals are as follows: s is singlet, bs is broad singlet, m is multiplet, bm is broad multiplet, d is doublet, bd is broad doublet, t is triplet, q is quartet.

Not integratable due to interference from water broad peaks.

Not integratable due to interference from NMR solvent peaks.

2 xm-two sets of partially overlapping multiplets.

HPLC was performed by a ThermoElectron LCQ Deca XP Max system equipped with an ion trap mass spectrometer detector and a diode array detector.

Conditions for the liquid chromatography-mass spectrometry (LC/UV/MS) analysis were as follows:

and (3) a chromatographic system A:

-eluent a ═ H₂O+0.01％TFA

-eluent B ═ CH₃CN

-a gradient: 98% A was run for 10 min to 95% B, then eluted with 95% B for 5 min.

-a flow rate of 0.5 ml/min; the temperature is 40 DEG C

Injection of 2. mu.l of a solution of 0.1mg/ml in CH₃CN∶H₂Solution in a 9: 1 mixture of OLiquid chromatography system B:

-eluent a ═ H₂O+0.05％TFA

-eluent B ═ CH₃CN+0.035％TFA

-a gradient: 98% A was run for 12 min to 95% B and then eluted with 95% B for 3 min.

-a flow rate of 0.7 ml/min; the temperature is 40 DEG C

Injection of 2. mu.l of a solution of 0.1mg/ml in CH₃CN∶H₂Solution chromatography system C in a 9: 1 mixture:

-eluent a ═ 5mM ammonium acetate buffer (pH 6.5)

-eluent B ═ CH₃CN

-a gradient: 98% A was run for 10 min to 95% B, then eluted with 95% B for 5 min.

-a flow rate of 0.5 ml/min; the temperature is 40 DEG C

Injection of 2. mu.l of a solution of 0.1mg/ml in CH₃CN∶H₂Solution chromatography system D in 9: 1 mixture:

-eluent a ═ H₂O+0.005％TFA

-eluent B ═ CH₃CN

-a gradient: 95% A was 17 minutes to 90% B and then eluted with 90% B for 5 minutes.

-a flow rate of 0.3 ml/min; the temperature is 30 DEG C

Injection of 2. mu.l of a solution of 0.1mg/ml in CH₃CN∶H₂Solution chromatography system E in 9: 1 mixture:

-eluent a ═ 5mM ammonium acetate buffer (pH 6.5)

-eluent B ═ CH₃CN

-a gradient: 95% A was 17 minutes to 90% B and then eluted with 90% B for 5 minutes.

-a flow rate of 0.3 ml/min; the temperature is 30 DEG C

Injection of 2. mu.l of a solution of 0.1mg/ml in CH₃CN∶H₂Solution chromatography system F in a 9: 1 mixture:

-eluent a ═ H₂O+0.005％TFA

-eluent B ═ CH₃CN

-a gradient: 95% A was run for 22 min to 90% B and then eluted with 90% B for 7 min.

-a flow rate of 0.3 ml/min; the temperature is 40 DEG C

Injection of 2. mu.l of a solution of 0.1mg/ml in CH₃CN∶H₂Solution chromatography system in 9: 1 mixture O:

-eluent a ═ H₂O+0.01％TFA

-eluent B ═ CH₃CN

-a gradient: 80% A was 15 minutes to 60% B, then 60% A was 5 minutes to 100% B, followed by elution with 100% B for 5 minutes.

-a flow rate of 0.4 ml/min; the temperature is 40 DEG C

Injection of 2. mu.l of a solution of 0.1mg/ml in CH₃CN∶H₂Solution chromatography system H in 9: 1 mixture:

-eluent a ═ H₂O+0.01％TFA

-eluent B ═ CH₃CN

-a gradient: 80% A was run for 19 min to 95% B and then eluted with 95% B for 3 min.

-a flow rate of 0.5 ml/min; the temperature is 40 DEG C

-injection2 μ l in CH with a concentration of 0.1mg/ml₃CN∶H₂The product of the solution in the 9: 1 mixture was detected by UV (220 nm).

The chromatographic column used is a C18 column (particle size 2-4 μm and preferably 3.5 μm).

For the mass spectrometry section:

-ionization mode: positive electric spray (ESI +)

-scan range: 100 to 1200 uma.

Thin layer chromatography was performed on Merck silica gel 60TLC plates. Silica gel for flash column chromatography was purchased from Biotage.

All solvents used were "reagent grade" pure or "HPLC grade" pure.

Preparation 1

2- [8- (5-trifluoromethylpyridin-2-yl) -3, 8-diazabicyclo [3.2.1] octane hydrochloride

0.9g of 2-chloro-5- (trifluoromethyl) pyridine (IX), 1g of 1-benzyl-3, 8-diazabicyclo [3.2.1]Octane, 0.75g potassium carbonate and 0.33g NaI were added to 8ml DMF. In thatThe reaction was allowed to proceed at 160 ℃ for 30 minutes in a microwave reactor. The resulting product was then poured into saturated aqueous sodium chloride solution, and the mixture was extracted with ethyl acetate. Na for organic phase₂SO₄Drying, filtering and vacuum evaporating. 1.5g of oil are isolated by flash chromatography onPurify on column eluting with 98/2 cyclohexane/ethyl acetate. 440mg of light oil are isolated. 0.44g of the compound obtained in the preceding stage is hydrogenated in 20ml of ethanol and 2ml of isopropanol/HCl in the presence of 0.14g of 10% Pd/C at 45 ℃ for 4 hours at atmospheric pressure. The product was filtered, evaporated in vacuo and isolated to 350mg of the title productSubstance in the form of a white solid.

Preparation 2

2- [8- (5-Fluoropyrimidin-2-yl) -3, 8-diazabicyclo [3.2.1] octane hydrochloride

1.44g of 2-chloro-5-fluoropyrimidine, 2.2g of 1-benzyl-3, 8-diazabicyclo [3.2.1]Octane, 1.7g potassium carbonate and 0.73g NaI were added to 27ml N-methylpyrrolidone. The mixture was heated at 110 ℃ for 5 hours. Then, it was poured into a saturated aqueous sodium chloride solution, and the resulting mixture was extracted with ethyl acetate. Na for organic phase₂SO₄Drying, filtering and vacuum evaporating. 3.2g of oil are isolated by flash chromatography onPurify on column eluting with 95/5 cyclohexane/ethyl acetate. 1.4g of a white solid was isolated and dissolved in 35ml of 1, 2-dichloroethane. 0.72ml of 1-chloroethyl chloroformate was added at 0 ℃ and the mixture was stirred at 0 ℃ for 10 minutes under a stream of nitrogen and then at 85 ℃ for 3 hours. The solvent was distilled off, and 35ml of methanol was added. The resulting mixture was heated at reflux temperature for 30 minutes. The solvent was evaporated off and the residue was treated with isopropanol. A white solid was obtained, filtered off and isolated as 900mg of the title product. M.p.236-239 ℃.

Preparation 3

2- [8- (3-pyridin-2-yl) -3, 8-diazabicyclo [3.2.1] octane hydrochloride

0.39g of 3-bromopyridine and 1g of 1-benzyl-3, 8-diazabicyclo [3.2.1]Octane, 0.07g of palladium acetate, 0.34g of sodium tert-butoxide and 0.06g of tri-tert-butylphosphine were added to 8ml of o-xylene. The mixture was heated at 120 ℃ for 6 hours. The product obtained is filtered through celite and the solvent is distilled off. 1.3g of oil are isolated by flash chromatographyPurify on column eluting with 6/4 cyclohexane/ethyl acetate. Is divided into700mg of light oil was isolated. The product obtained in the preceding stage was hydrogenated in 29ml of ethanol and 2ml of isopropanol/HCl in the presence of 0.35g of 10% Pd/C at 40 ℃ for 4 hours at atmospheric pressure. The resulting product was filtered, evaporated in vacuo and isolated to 500mg of the title product as a white solid.

Preparation 4

3, 8-diazabicyclo [3.2.1] oct-8-ylpyridine-3-carboxylic acid methyl ester hydrochloride

0.42g of methyl 6-chloropyridine-3-carboxylate (IX), 0.5g of 1-benzyl-3, 8-diazabicyclo [3.2.1]Octane, 0.4g potassium carbonate and 0.17g NaI were added to 7ml N-methylpyrrolidone. The mixture was heated at 110 ℃ for 7 hours. Then, it was poured into a saturated aqueous sodium chloride solution, and the resulting mixture was extracted with ethyl acetate. Na for organic phase₂SO₄Drying, filtering and vacuum evaporating. 1.1g of oil is isolated by flash chromatography onPurify on column eluting with 8/2 cyclohexane/ethyl acetate. 520mg of light oil are isolated. The product obtained in the preceding stage was hydrogenated in 20ml ethanol and 2ml isopropanol/HCl in the presence of 0.22g 10% Pd/C at 40 ℃ for 2 hours at atmospheric pressure. The resulting product was filtered, evaporated in vacuo and isolated to 440mg of the title product as a white solid.

Preparation 5

4- (3-trifluoromethylphenyl) -1,2, 3, 6-tetrahydropyridine hydrochloride

To 377ml of water and 514ml of concentrated hydrochloric acid, 50g of 4- (3-trifluoromethylphenyl) piperidin-4-ol are added in a round bottom flask equipped with a mechanical stirrer. The mixture was refluxed for 5 hours and then cooled to ambient temperature. A white solid precipitated. It was filtered off with a buchner funnel and oven dried. 37g of a white solid are isolated. M.p.203-204 ℃.

Preparation 6

4- (3-trifluoromethyl-4-chlorophenyl) -1,2, 3, 6-tetrahydropyridine hydrochloride

Using the procedure described in preparation 5, but using 4- (3-trifluoromethyl-4-chlorophenyl) piperidin-4-ol instead of 4- (3-trifluoromethylphenyl) piperidin-4-ol, the title compound was obtained. M.p.263-265 ℃.

Preparation 7

3- (1, 2,5, 6-tetrahydropyridin-3-yl) benzoic acid methyl ester hydrochloride

10.9g of methyl 3- (pyridin-3-yl) benzoate, 90ml of toluene and 8.72g of benzyl bromide were added and the mixture was heated at reflux temperature for 8 hours. The resulting product was evaporated and treated with diisopropyl ether. 19.65g of a solid are obtained, which is dissolved in 540ml of methanol. 3.7g of sodium borohydride were added slowly at 0 ℃ and the mixture was stirred for 30 minutes at ambient temperature.

The solvent was evaporated off, the residue was taken up in water and the product was extracted with ethyl acetate. Na for organic phase₂SO₄Drying, filtering and vacuum evaporating. 18g of oil were isolated and purified by flash chromatography eluting with 8/2 cyclohexane/ethyl acetate. 10g of oil were isolated. The product obtained in the preceding stage was hydrogenated in 200ml of methanol and 5ml of isopropanol/HCl in the presence of 1.2g of 10% Pd/C at 40 ℃ for 2 hours at atmospheric pressure. The resulting product was filtered, evaporated in vacuo and isolated to 440mg of the title product as a white solid. M.p.160-162 ℃.

Preparation 8

2-chloro-1- [4- (3-trifluoromethylphenyl) -3, 6-dihydro-2H-pyridin-1-yl ] ethanone

3.44g of preparation 5 compound were suspended in 33.5ml of dichloromethane in a round-bottom flask equipped with a mechanical stirrer. 3.8ml of triethylamine were added and the mixture was brought to 0 ℃. 1.01ml of chloroacetyl chloride (i.e. the compound of formula (V) wherein Hal ═ Hal' ═ Cl and n ═ 1) are added dropwise at 0 ℃. The mixture was allowed to react for 1.5 hours and poured into water. The resulting mixtureThe mixture was extracted with dichloromethane. Na for organic phase₂SO₄Drying, filtering and vacuum evaporating. 4.1g of dark oil was separated, ground, and then cooled and left to stand. The product was isolated by settling and the supernatant evaporated in vacuo. 420mg of light oil are isolated.

Preparation 9

2-chloro-1- [4- (3-trifluoromethyl-4-chlorophenyl) -3, 6-dihydro-2H-pyridin-1-yl ] ethanone

Using the procedure described in preparation 8, but using the compound of preparation 6 instead of the compound of preparation 5, the crude product was purified by flash chromatography to give the title compound as a white solid.

Preparation 10

2- (chloroacetyl) -1,2,5, 6-tetrahydropyridine-3-carboxylic acid methyl ester

Using the procedure described in preparation 9, but using the compound of preparation 7 instead of the compound of preparation 6, the title compound was obtained as a white solid.

Example 1

Compound 1: 1- [4- (3-trifluoromethylphenyl) -3, 6-dihydro-2H-pyridin-1-yl ] -2- [8- (5-trifluoromethylpyridin-2-yl) -3, 8-diazabicyclo [3.2.1] oct-3-yl ] ethanone and oxalate salts thereof

0.19g of the compound obtained in preparation 1, 0.18g of the compound obtained in preparation 8, 0.18g of potassium carbonate and 0.04g of NaI are reacted in 4.5ml of DMF. In thatThe reaction was allowed to proceed at 180 ℃ for 30 minutes in a microwave reactor. The resulting product was poured into water, and the resulting mixture was extracted with ethyl acetate. Na for organic phase₂SO₄Drying, filtering and vacuum evaporating. 250mg of oil were isolated. It is purified by flash column chromatography, usingThe column was eluted with 8/2 mixture cyclohexane/ethyl acetate. 100mg of oil was isolated. Salination with oxalic acid gave 80mg of a white solid.

NMR (instrument b), δ (ppm, dmso-d 6): 1.80-2.05(m, 4H), 2.41-2.6(m,. times.), 2.59-2.84(m, 3H), 3.5(bs, 1H), 3.31(bs, 1H), 3.69(m, 1H), 3.76(m, 1H), 4.12(s, 1H), 4.33(s, 1H), 4.66(bs, 2H), 6.36(m, 1H), 6.87(m, 1H), 7.57-7.67(m, 2H), 7.70-7.82(m, 3H), 8.40(bs, 1H).

Example 2

Compound 11: 1- [4- (3-trifluoromethyl-4-chlorophenyl) -3, 6-dihydro-2H-pyridin-1-yl ] -2- [8- (5-fluoropyrimidin-2-yl) -3, 8-diazabicyclo [3.2.1] oct-3-yl ] ethanone

40.1g of the compound obtained in preparation 9, 26.6g of the compound obtained in preparation 2, 30ml of diisopropylethylamine and 1500ml of DMF were reacted together. The mixture was heated at 100 ℃ for 3 hours. The resulting product was poured into water, and the resulting mixture was extracted with ethyl acetate. Na for organic phase₂SO₄Drying, filtering and vacuum evaporating. 69g of oil were isolated. It was purified by flash column chromatography eluting with an 7/3 mixture of hexane/ethyl acetate. 42.14g of the title product are isolated. The product was treated with diethyl ether and the resulting product was filtered to yield 33.45g of a white solid.

NMR (instrument a), δ (ppm, dmso-d 6): 1.72-1.98(m, 4H), 2.38(m, 2H), 2.45-2.54(m, ×), 2.56-2.74(m, 3H), 3.14(s, 1H), 3.18(s, 1H), 3.68(m, 1H), 3.78(m, 1H), 4.12(bs, 1H), 4.36(bs, 1H), 4.59(m, 2H), 6.38+6.41(2 × m, 1H), 7.70(d, J ═ 8.5Hz, 1H), 7.75(bd, J ═ 8.5Hz, 1H), 7.82(bd, J ═ 2Hz, 1H), 8.42(bs, 2H).

Example 3

Compound 27: 1- [4- (3-trifluoromethyl-4-chlorophenyl) -3, 6-dihydro-2H-pyridin-1-yl ] -2- [8- (-3-pyridin-2-yl) -3, 8-diazabicyclo [3.2.1] oct-3-yl ] ethanone

Using the procedure described in example 2, but using the compound of preparation 3 instead of the compound of preparation 2, the title compound was obtained as the free base.

NMR (instrument a), δ (ppm, dmso-d 6): 1.77-1.98(m, 4H), 2.40-2.67(m, x), 3.09(s, 1H), 3.13(s, 1H), 3.68(m, 1H), 3.77(m, 1H), 4.11(bs, 1H), 4.26-4.40(m, 3H), 6.38(m, 0.5H), 6.42(m, 0.5H), 7.11-7.22(m, 2H), 7.71(d, J ═ 8.5Hz, 1H), 7.76(bd, J ═ 8.5Hz, 1H), 7.82(bd, J ═ 2Hz, 1H), 7.86(bs, 1H), 8.19(m, 1H).

Example 4

Compound 28: 6- (3- {2- [4- (4-chloro-3-trifluoromethylphenyl) -3, 6-dihydro-2H-pyridin-1-yl ] -2-oxoethyl } -3, 8-diazabicyclo [3.2.1] oct-8-yl) pyridine-3-carboxylic acid methyl ester and hydrochloride thereof

Using the procedure described in example 2, but using the compound of preparation 4 instead of the compound of preparation 2, the title compound was obtained as the free base. This was dissolved in ether and a solution of isopropanol saturated with HCl was added to give the hydrochloride salt as a glassy solid.

NMR (instrument a), δ (ppm, dmso-d 6): 2.12(m, 2H), 2.24(m, 2H), 2.46-2.55(m, x), 2.60(bs, 1H), 3.27(m, 2H), 3.46-3.64(m, 3H), 3.72(m, 1H), 3.83(s, 3H), 4.05(bs, 1H), 4.17(bs, 4.20-4.36(m, x), 4.89(bs, 2H), 6.37(m, 1H), 6.97(d, J ═ 9.0Hz, 1H), 7.69-7.78(m, 2H), 7.80(m, 1H), 8.07(m, 1H), 8.71(m, 1H), 9.4-10.1(bs, 1H).

Example 5

Compound 29: 6- (3- {2- [4- (4-chloro-3-trifluoromethylphenyl) -3, 6-dihydro-2H-pyridin-1-yl ] -2-oxoethyl } -3, 8-diazabicyclo [3.2.1] oct-8-yl) pyridine-3-carboxylic acid and fumarate salts thereof

0.35g of the compound of example 4 is dissolved in 3ml of 35% aqueous HCl. The resulting solution was heated at reflux temperature for 1 hour and washed with ether. The pH was adjusted to 5 with NaOH solution and extracted with ethyl acetate. After drying and evaporation of the organic phase, 220mg of a glassy solid are obtained. The solid was dissolved in isopropanol and a solution of fumaric acid in isopropanol was added. The fumarate salt precipitated and was filtered off. 70mg of the title product are isolated as a white solid.

NMR (instrument a), δ (ppm, dmso-d 6): 1.74-2.07(m, 4H), 2.31-2.55(m, x), 2.58-2.76(m, 3H), 3.09-3.36(m, x), 3.68(m, 1H), 3.78(m, 1H), 4.12(bs, 1H), 4.35(bs, 1H), 4.64(bs, 2H), 6.40(m, 1H), 6.64(s, 2H), 6.76(m, 1H), 7.71(d, J ═ 8.5Hz, 1H), 7.76(m, 1H), 7.82(bs, 1H), 7.91(m, 1H), 8.62(bs, 1H), 12.1-13.4(m, 2H).

Example 6

Compound 53: 3- (1- {2- [8- (5-Fluoropyrimidin-2-yl) -3, 8-diazabicyclo [3.2.1] oct-3-yl ] acetyl } -1,2,5, 6-tetrahydropyridin-3-yl) benzoic acid methyl ester

Using the procedure described in example 2, but using the compound of preparation 10 instead of the compound of preparation 9, the title compound was obtained as the free base.

NMR (instrument a), δ (ppm, dmso-d 6): 1.66(m, 2H), 1.78-1.99(m, 2H), 2.23-2.35(m, 2H), 2.35-2.46(m, 2H), 2.57-2.75(m, 2H), 3.19(s, 2H), 3.61(m, 1H), 3.70(m, 1H), 3.88(s, 3H), 4.34(s, 1H), 4.50-4.72(m, 3H), 6.41(m, 0.5H), 6.46(m, 0, 5H), 7.54(m, 1H), 7.76(m, 1H), 7.89(m, 1H), 7.96(bs, 0.5H), 8.02(bs, 0.5H), 8.43(m, 2H).

The following table describes examples obtained by using and/or adapting the process using the appropriate reactants and starting materials:

biochemical studies have been conducted on the compounds of the present invention.

Cell culture

Strain SH-SY-5Y (human neuroblastoma) was routinely cultured in collagen-coated culture flasks (Becton Dickinson, France) in DMEM Medium (Dulbecco's Modified Eagle's Medium, Gibco BRL, France) containing FCS (5%) (fetal calf serum) (Boehringer Mannheim, Germany), sodium pyruvate (1mM) and glutamine (4 mM).

Conventional culture of parent SK-N-BE (human neuroblastoma) and Stable expression of human p75^NTRClone Bep75 (SK-N-BE Bep 75) in which the medium is RPMI medium containing the receptor in its intact formThere was FCS (5%), sodium pyruvate (1mM) and glutamine (4 mM). For SK-N-BE Bep75 cells, hygromycin (200. mu.l/20 ml medium) was added as a selection agent.

To pair¹²⁵I NGF and p75^NTRBinding of receptor

NGF binding studies (iodine-125 radiolabelled nerve growth factor, Amersham, 2000Ci/mmol) were performed on cell suspensions of the SK-N-BE Bep75 strain according to the method described by Weskamp (Neuron, 1991, 6, 649-663). Non-specific binding was determined as follows: total binding was measured after preincubation with cells in the presence of non-radiolabeled NGF (1. mu.M) for 1 hour at 37 ℃. Specific binding was calculated by summing the difference between the binding and non-specific binding measurements. Using NGF iodide (at a concentration of 0.3 nM)¹²⁵I NGF) was performed. The compound of the invention is¹²⁵I NGF and p75^NTR50% Inhibitory Concentration (IC) of receptor binding₅₀) Is low and ranges from 10^-6To 10^-11M。

The compound of formula (I) showed activity in this assay, its IC₅₀Value of 10^-6To 10^-11And M. For example, compounds 1,2, 7 and 11 showed IC's of 1.35nM, 0.18nM, 0.29nM and 0.98nM, respectively₅₀。

For p75^NTRReceptor dimerization independently of its ligand

Cell suspension pair p75 of SK-N-BE Bep75 strain^NTRReceptor dimerization was studied. Cells were plated in each well of a 96-well plate (2.5X 10)⁴Individual cells/well) and maintained for 24 hours, then pre-incubated for 1 hour at 37 ℃ in the presence or absence of a compound of the invention. Then, the supernatant (final concentration of 10nM) obtained by culturing kidney-derived HEK293 human cells expressing and secreting soluble p75 conjugated to alkaline phosphatase 48 hours after transfection was added^NTRReceptor (the extracellular portion of the receptor). Soluble p75^NTRReceptor and receptor binding in SK-N-BEBeSpecific binding of receptors on p75 cells was quantified as follows: the cells were cultured at 37 ℃ for 1 hour in the presence of the supernatant, and then the enzyme activity of alkaline phosphatase was measured. The filters were filtered and transferred to 24-well plates, and alkaline phosphatase activity was determined by adding CDP-Star chemiluminescent substrate (Ready, Roche). Compound pair of the invention p75^NTR50% Inhibitory Concentration (IC) for receptor dimerization₅₀) Is low and in the range of 10^-6To 10^-11M。

The compound of formula (I) showed activity in this assay, its IC₅₀Value of 10^-6To 10^-11And M. For example, compounds 1, 3,8, 11, 27, 28, 29 and 53 showed IC's of 23.4nM, 0.05nM, 0.68nM, 0.2nM, 0.23nM, 9.84nM, 0.14nM and 2.08nM, respectively₅₀。

Measurement of apoptosis

Cells (human neuroblastoma strains SH-SY-5Y and SK-N-BE Bep 75) were plated in 35mm diameter petri dishes (Biocoat collagen I) (10)⁵Individual cells/well) and maintained for 24 hours, wherein the medium is an appropriate medium containing 5% FCS. The medium was then removed and the cells were rinsed with PBS (Dulbecco's phosphate buffered saline) followed by addition of fresh medium containing 5% FCS or medium containing NGF (10 ng/ml concentration) or beta-amyloid peptide (Abeta 1-40) (10. mu.M concentration) in the presence or absence of the compound of the invention. The extent of apoptosis was measured by quantifying cytoplasmic histones associated with DNA fragments 48 hours after the SH-SY-5Y strain treatment and 24 hours after the SK-N-BE Bep75 strain treatment (cell death assay, Boehringer Mannheim, Germany). Expression of the extent of apoptosis as the amount of oligonucleosomes/10⁵And (4) cells. Each value corresponds to the average of 9 experimental points distributed over three independent experiments.

The compounds of formula (I) have inhibitory activity on NGF-induced apoptosis, IC thereof₅₀Value of 10^-6To 10^-11And M. For example, compounds 1, 3,8, 11, 27 and 29 showed 1.33nM, 0.067nM, 2.24n, respectivelyIC of M, 0.21nM, 0.088nM and 0.22nM₅₀。

Thus, the compounds of the invention are reacted with p75^NTRThe binding of the receptor is manifested on the one hand by inhibition, at the biochemical level, of receptor dimerization induced by neurotrophins or independently of the ligand and, on the other hand, by inhibition, at the cellular level, of p75^NTRReceptor-mediated pro-apoptotic effects.

Thus, according to one subject of the invention, the compound of formula (I) is p75^NTRDimerization of the receptor independently of its ligand shows a very advantageous inhibitory activity.

Thus, the compounds of the invention are useful for the preparation of medicaments, in particular for the prophylaxis or treatment of diseases in which p75 is involved^NTRDrugs of any pathology of the receptor, more particularly those described below.

The compounds of the invention may also be useful in the prevention or treatment of diseases involving p75^NTRAny pathology of the receptor (more particularly those described below).

Thus, according to another aspect of the invention, the subject of the invention is a medicament comprising a compound of formula (I) or an addition salt thereof with a pharmaceutically acceptable acid.

Thus, the compounds of the present invention may be used in humans or animals for the treatment or prevention of various p75^NTRDependence disorders, such as central and peripheral neurodegenerative diseases such as senile dementia, epilepsy, Alzheimer's disease, Parkinson's disease, Huntington's chorea, Down's syndrome, prion diseases, amnesia, schizophrenia, depression, bipolar disorders; amyotrophic lateral sclerosis, multiple sclerosis; cardiovascular disorders, such as post-ischemic heart injury, cardiomyopathy, myocardial infarction, heart failure, cardiac ischemia, cerebral infarction; peripheral neuropathy (diabetic, traumatic or iatrogenic); ocular nerve damage and retinal damage (retinitis pigmentosa, glaucoma); retinal ischemia; macular degeneration; spinal cord trauma and craniocerebral trauma; atherosclerosis; stenosis; a healing disorder; alopecia is caused.

The compounds of the invention are also useful in the treatment of cancers such as lung, thyroid, pancreatic, prostate, small intestine, colon, breast, and in the treatment of tumors, metastases and leukemias.

The compounds of the present invention are also useful in the treatment of respiratory disorders such as pneumonia, allergy, asthma or chronic obstructive pulmonary disease.

The compounds of the invention are also useful in the treatment of skin pain (cutaneous pain, pain in the subcutaneous tissues and pain in the associated organs), somatic pain, visceral pain (circulatory, respiratory, gastrointestinal or genitourinary systems) and neuropathic pain.

The compounds of the invention are also useful in the treatment of chronic neuropathic and inflammatory pain, and in the treatment of autoimmune diseases such as rheumatoid arthritis.

The compounds of the invention are also useful in the treatment of diseases such as ankylosing spondylitis, psoriatic arthritis or plaque psoriasis.

The compounds of the invention may also be useful in the treatment of bone fractures, or may be useful in the treatment or prevention of bone disorders such as osteoporosis.

According to another aspect of the invention, the invention relates to a pharmaceutical composition comprising as active ingredient a compound of the invention. These pharmaceutical compositions contain an effective dose of at least one compound of the invention or a pharmaceutically acceptable salt of said compound and at least one pharmaceutically acceptable excipient.

The excipients are selected from the conventional excipients known to the person skilled in the art, according to the pharmaceutical form and the desired method of administration.

In the pharmaceutical compositions of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, intratracheal, intranasal, transdermal or rectal administration, the active ingredient of formula (I) above or a salt thereof may be administered in unit dosage form (in admixture with conventional pharmaceutical excipients) to animals and humans for the prophylaxis or treatment of the above-mentioned conditions or diseases.

Suitable unit administration forms include oral administration forms (e.g. tablets, soft or hard capsules, powders, granules and oral solutions or suspensions), sublingual administration forms, buccal administration forms, intratracheal administration forms, intraocular administration forms, intranasal administration forms, inhalation administration forms, topical administration forms, parenteral administration forms (e.g. transdermal administration forms, subcutaneous administration forms, intramuscular administration forms or intravenous administration forms), rectal administration forms and implants. For topical administration, the compounds of the present invention may be used in creams, gels, ointments or lotions.

For example, a unit dosage form of a compound of the invention in tablet form may comprise the following components:

compound of the invention 50.0mg

Mannitol 223.75mg

Croscarmellose sodium 6.0mg

Corn starch 15.0mg

Hydroxypropyl methylcellulose 2.25mg

Magnesium stearate 3.0mg

The daily dose of the active ingredient may be from 0.01 to 100mg/kg (taken 1 or more times), preferably from 0.02 to 50 mg/kg. In general, the daily dosage of a compound of the invention should be the lowest effective dose of the compound that will produce a therapeutic effect.

Higher or lower doses may be appropriate for the particular situation; such dosages are within the scope of the present invention. According to conventional practice, the dosage suitable for each patient is determined by a physician according to the method of administration and the weight and response of said patient.

According to another aspect of the invention, the invention also relates to a method of treating the pathologies described above, which comprises administering to a patient an effective dose of a compound according to the invention, or of a pharmaceutically acceptable salt thereof.

Claims (13)

1. A compound of formula (I) in base form or in acid addition salt form:

wherein

m represents 1;

a representsAnd B represents a hydrogen atom; or

A represents a hydrogen atom and B represents

-W-is a nitrogen-containing heterocycle selected from:

1-3 represents 2;

n represents 1;

r1 represents a halogen atom or a trifluoromethyl group;

r2 represents a hydrogen atom, a halogen atom, a trifluoromethyl group or-COOR;

r5 represents the following group:

wherein R3 and R4 at any available position independently represent a hydrogen atom, a halogen atom, a trifluoromethyl group, -COOH or-COO alkyl group, wherein the alkyl group represents C₁-C₄An alkyl group;

r represents C₁-C₆An alkyl group.

2. A compound of formula (I) according to claim 1, selected from the following compounds:

-compound 1: 1- [4- (3-trifluoromethylphenyl) -3, 6-dihydro-2H-pyridin-1-yl]-2- [8- (5-trifluoromethylpyridin-2-yl) -3, 8-diazabicyclo [3.2.1]Oct-3-yl]An ethanone;

-compound 2: 1- [4- (4-chlorophenyl) -3, 6-dihydro-2H-pyridin-1-yl]-2- (8- (pyrimidin-2-yl) -3, 8-diazabicyclo [3.2.1]Oct-3-yl) ethanone;

-compound 3: 2- (3- (pyrazin-2-yl) -3, 8-diazabicyclo [3.2.1]Oct-8-yl) -1- [4- (3-trifluoromethylphenyl) -3, 6-dihydro-2H-pyridin-1-yl]An ethanone;

-compound 7: 1- [4- (4-chlorophenyl) -3, 6-dihydro-2H-pyridin-1-yl]-2- [8- (5-trifluoromethylpyridin-2-yl) -3, 8-diazabicyclo [3.2.1]Oct-3-yl]An ethanone;

-compound 8: 1- [4- (4-chloro-3-trifluoromethylphenyl) -3, 6-dihydro-2H-pyridin-1-yl]-2- [8- (5-trifluoromethylpyridin-2-yl) -3, 8-diazabicyclo [3.2.1]Oct-3-yl]An ethanone;

-compound 11: 1- [4- (4-chloro-3-trifluoromethylphenyl) -3, 6-dihydro-2H-pyridin-1-yl]-2- [8- (5-fluoropyrimidin-2-yl) -3, 8-diazabicyclo [3.2.1]Oct-3-yl]An ethanone;

-compound 27: 1- [4- (4-chloro-3-trifluoromethylphenyl) -3, 6-dihydro-2H-pyridin-1-yl]-2- (8- (pyridin-3-yl) -3, 8-diazabicyclo [3.2.1]Oct-3-yl) ethanone;

-compound 28: 6- (3- {2- [4- (4-chloro-3-trifluoromethylphenyl) -3, 6-dihydro-2H-pyridin-1-yl]-2-oxoethyl } -3, 8-diazabicyclo [3.2.1]Oct-8-yl) pyridine-3-carboxylic acid methyl ester;

-compound 29: 6- (3- {2- [4- (4-chloro-3-trifluoromethylphenyl) -3, 6-dihydro-2H-pyridin-1-yl]-2-oxoethyl } -3, 8-diazabicyclo [3.2.1]Oct-8-yl) pyridine-3-carboxylic acid;

-compound 53: 3- (1- {2- [8- (5-Fluoropyrimidin-2-yl) -3, 8-diazabicyclo [3.2.1]Oct-3-yl]Acetyl } -1,2,5, 6-tetrahydropyridin-3-yl) benzoic acid methyl ester.

3. A process for the preparation of a compound of the formula (I) according to claim 1, characterized in that a compound of the formula (II) is reacted with a compound of the general formula (III),

the compounds of formula (II) are:

wherein A, B, m and n are as defined in claim 1 and Hal represents a halogen atom,

the compounds of the general formula (III) are:

H-W-R5(III)

wherein W and R5 are as defined in claim 1.

4. A compound of formula (II) in base form or in acid addition salt form:

wherein A, B, m and n are as defined in claim 1 and Hal represents a halogen atom; but excluding 2-chloro-1- [4- (4-bromophenyl) -3, 6-dihydro-2H-pyridin-1-yl ] ethanone.

5. Pharmaceutical, characterized in that it comprises a compound of formula (I) according to claim 1 or an addition salt of this compound with a pharmaceutically acceptable acid.

6. Pharmaceutical composition, characterized in that it comprises a compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient.

7. Use of a compound of claim 1 for the manufacture of a medicament for the prevention or treatment of: central and peripheral neurodegenerative diseases, cardiovascular disorders, ocular and retinal injuries, respiratory disorders, autoimmune diseases and bone diseases.

8. The use of claim 7, wherein the compound of claim 1 has the effect of inhibiting p75^NTRThe receptor is independent of the ability of its ligand to dimerize.

9. Use of a compound of claim 1 for the manufacture of a medicament for the prevention or treatment of: senile dementia, epilepsy, parkinson's disease, huntington's chorea, down's syndrome, prion diseases, amnesia, schizophrenia, depression, bipolar disorder, amyotrophic lateral sclerosis, multiple sclerosis, post-ischemic heart injury, cardiomyopathy, cerebral infarction, peripheral neuropathy, retinitis pigmentosa, glaucoma, retinal ischemia, macular degeneration, spinal cord trauma, craniocerebral trauma, atherosclerosis, stenosis, healing disorders, hair loss, cancer, tumor, leukemia, allergy, asthma, chronic obstructive pulmonary disease, skin pain, somatic pain, visceral pain, neuropathic pain, inflammatory pain, plaque psoriasis, bone fracture and osteoporosis.

10. The use of claim 9, wherein the compound of claim 1 has the effect of inhibiting p75^NTRThe receptor is independent of the ability of its ligand to dimerize.

11. Use of a compound of claim 1 for the manufacture of a medicament for the prevention or treatment of: alzheimer's disease.

12. The use of claim 11, wherein the compound of claim 1 has the effect of inhibiting p75^NTRThe receptor is independent of the ability of its ligand to dimerize.

13. Use of a compound of claim 1 for the manufacture of a medicament for the prevention or treatment of: myocardial infarction, heart failure, cardiac ischemia, pneumonia, chronic neuropathic pain, rheumatoid arthritis, ankylosing spondylitis and psoriatic arthritis.