Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/24—Antidepressants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings

Definitions

• the present invention relates to 1-amino-isoquinoline derivatives, to their preparation and to their therapeutic application.
• MCH MCHi receptor 1
• MCH 1 receptor previously called the SLC-1 or GPR24 receptor (Chambers et al., Nature 1999; 400: 261-265), and the MCH 2 receptor previously called SLT (Mori et al. Biochem Biophys Res Commun 2001; 283: 1013-1018).
• Ri represents an aryl or a heteroaryl; the aryl and heteroaryl groups being optionally substituted by one or more radicals Z which are identical to or different from each other;
• R 2 represents a hydrogen atom, a C 1-5 -alkyl or C 1-3 -fluoroalkyl group
• R 4 represents a hydrogen atom or a Ci -5 alkyl group, C 1-3 fluoroalkyl, C 3-6 - cycloalkyl, C 1-3 -alkylene-C 3-6 -cycloalkyl, C 3. - alkylene-OC 1-3 -alkyl, C 1-3 -alkylene- (OH) Ci -3 -alkylene-OC 4-6 -cycloalkyl, C 1-3 -alkylene-XC 1-3 alkyl wherein X is S , SO or SO 2 ,
• R 4 represents a C 1-3 -alkylene-NR a R b, aryl, C 1-3 -alkylene-aryl, Ci -3 -alkylene-O-aryl, C 1-3 -alkylene-OC 1- 3 -alkylene-aryl, heteroaryl or Ci -3 -alkylene-heteroaryl; aryl, Ci -3 -alkylene-aryl, C 1-3 -alkylene-O-aryl, C 1-3 -alkylene-O-C 1-3 -alkylene-aryl, heteroaryl and C 1-3 -alkylene- heteroaryl being optionally substituted with one or more radicals Z which are identical to or different from one another,
• R 4 represents a heterocycle group; said heterocycle being optionally substituted by C 1-3 -alkyl, -C (O) -C -5 -alkyl, -C (O) -C 1-5 - fluoroalkyl, C 1-3 -alkylene-C 3. 6- cycloalkyl, C 1-3 -alkylene-aryl, C 1-3 -alkylene-heteroaryl; the C 1-3 -alkylene-aryl and C 1-3 -alkylene-heteroaryl groups being optionally substituted by one or more Z radicals that are identical or different from each other;
• R 7 represents a hydrogen or halogen atom or a C 1-5 -alkyl, C 1-3 -fluoroalkyl, C 1-5 -alkoxy, C 1-3 -fluoroalkoxy, C 1-3 -alkylene group; - (OH), -CN, -COOH, -C (O) OC 1-3 -alkyl, -NO 2 , -XC 1-3 -alkyl where X is S, SO or SO 2 ,
• R 7 represents a group -NR 3 Rb, C 1-3 -alkylene-NR a Rb, -C (O) -NR a R b , -C (O) -C 1-3 -alkyl, aryl, O-aryl or heteroaryl; the aryl, -O-aryl and heteroaryl groups being optionally substituted by one or more radicals Z which are identical to or different from each other;
• R p and R ' p represent, independently of one another, a hydrogen atom or a C 1-5 -alkyl group; or R p and R ' p together form a single bond or a C 1-4 alkylene group;
• Z represents a halogen atom or a C 1-5 -alkyl, C 1-3 -fluoroalkyl, C 3-6 -cycloalkyl, C 1-3 -alkylene-C 3-6 -cycloalkyl, C- ⁇ -group; 5 -alkoxy, Ci -3 -fluoroalkoxy, C 1-3 -alkylene-O-C 1-3 -alkyl, C 1-3 -alkylene- (OH), NO 2, -CN, -SO 2 NR a R b , -XC 1 . 3 -alkyl, C. 3 -alkylene-X-Ci -3 - alkyl in which X represents S, SO or SO 2,
• . or Z is optionally substituted by a halogen atom phenyl, C 1-5 -alkyl, Ci. 5 -alkoxy or Ci -3 fluoroalkyl,
• or Z represents an alkynyl radical of the type -C ⁇ CR C , in which R 0 represents a hydrogen atom, a C 1-3 -alkyl, C 1-6 -alkylene-OR d or C 1-6 group ; alkylene-NR a R b ,
• or Z represents a tetrazole group substituted with a C 1-3 -alkyl group, or Z is -NR 3 Rb, C 1-3 -alkylene-NR a R b , -C (O) -NR 3 Rb, -C (O) -C 1-3 -alkyl, -C (O) OC 1-4 -alkyl or -C (O) -C 3 . 6 -cycloalkyl, or Z represents an oxo radical, or Z represents a group -OC 1 . 5 -alkylene-NR a R b , or Z represents a -C 4-6 -alkylene-NR a R b group .
• Z is -OC 0- 3-alkylene-heterocycle, optionally substituted by one or more groups Ci -3 alkyl, oxo or -C (O) -C 1-3 -alkyl. or Z represents a group -O-C 1-5 -alkylene-OR d ,
• or Z represents a group -OC 0 - 3 -alkylene-C 5 . 7 -cycloalkyl optionally substituted with a group -OR d ,
• or Z represents a group -NR e -C 0-3 -alkylene-heterocycle optionally substituted with one or more C 1-3 -alkyl, oxo or -C (O) -C 1-3 -alkyl groups. or Z represents a group -NR e -C 2 -5-alkylene-OR d ,. or Z represents a group -O-C 1-3 -alkylene-nveniroaryle optionally substituted by one or more C 1-3 -alkyl groups,
• or Z represents a group -OC 1-3 -alkylene-C (O) -NR a R b ,. or Z represents a fused bicyclic or fused bicyclic heterocyclic ring, or two adjacent Z radicals together form a C 1-3 - alkylenedioxy group;
• R 3 and R b each independently of one another represent a hydrogen atom or a C 1-3 -alkyl or -C (O) -C 1-3 -alkyl group,
• R 3 and R b together with the nitrogen atom which carries them, a heterocycle optionally substituted with one or more groups Ci -3 alkyl, oxo, -NR a R b, hydroxy, C 1-3 -alkoxy, C 1-3 -alkylene- (OH) or -C (O) -C 1-3 -alkyl; • R d represents a hydrogen atom or a C 1-3 -alkyl group; • R e represents a hydrogen atom or a C 1-3 -alkyl group.
• the compounds of formula (I) may comprise one or more asymmetric carbon atoms. They can therefore exist as enantiomers or diastereoisomers. These enantiomers, diastereoisomers, as well as their mixtures, including the racemic mixtures, form part of the invention.
• the compounds of formula (I) may comprise one or more rings. They can therefore exist in the form of axial / equatorial isomers, or endo / exo, or cis / trans. These isomers and their mixtures are part of the invention.
• the compounds of formula (I) may exist in the form of bases or addition salts with acids. Such addition salts are part of the invention.
• salts are advantageously prepared with pharmaceutically acceptable acids, but the salts of other acids that are useful, for example, for the purification or the isolation of the compounds of formula (I) are also part of the invention.
• the compounds of formula (I) can also exist in the form of hydrates and / or solvates, namely in the form of combinations or combinations with water and / or solvent. Such hydrates and solvates are also part of the invention.
• C tZ where t and z can take the values from 0 to 6, a chain or carbon ring possibly containing from t to z carbon atoms, for example C 0-3 can characterize a single bond or a carbon chain having from 1 at 3 carbon atoms; a halogen atom: a fluorine, a chlorine, a bromine or an iodine; an alkyl group: a saturated monovalent aliphatic group, linear or branched.
• alkylene group a divalent saturated, linear or branched aliphatic group.
• a C 1-3 -alkylene group represents a divalent carbon chain of 1 to 3 carbon atoms, linear or branched, such as a methylenyl (-CH 2 -), an ethylenyl (-CH 2 CH 2 - ), a 1-methylethylenyl (-CH (CH 3 ) CH 2 -), a propylenyl (-CH 2 CH 2 CH 2 -), etc .; a cycloalkyl group: a saturated cyclic aliphatic group.
• cyclopropyl methylcyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl groups, and the like
• an alkoxy group an O-alkyl radical where the alkyl group is as previously defined
• an alkylenedioxy group a -O-alkylene-O- group, where the alkylene group is as previously defined.
• a fluoroalkyl group an alkyl group of which one or more hydrogen atoms have been substituted by a fluorine atom.
• the groups -CF 3 , -CH 2 CF 3 a fluoroalkoxy group: an alkoxy group of which one or more hydrogen atoms have been substituted by a fluorine atom.
• a fluoroalkoxy group an alkoxy group of which one or more hydrogen atoms have been substituted by a fluorine atom.
• a heterocycle group may represent a bridged heterocycle group comprising from 6 to 10 members, wherein at least 2 atoms of the bicyclic structure are joined by a single bond or a chain which may have from 1 to 4 members;
• an aryl group monocyclic or polycyclic aromatic system comprising from 6 to 14 carbon atoms, preferably from 6 to 10 carbon atoms.
• the system is polycyclic, at least one of the rings is aromatic.
• a heteroaryl group monocyclic or polycyclic aromatic system comprising from 5 to 14 members, preferably from 5 to 10 members and comprising one to more heteroatoms such as nitrogen, oxygen or sulfur atoms.
• the system is polycyclic, at least one of the rings is aromatic. Nitrogen atoms can be in the form of N-oxides.
• monocyclic heteroaryl groups mention may be made of thiazolyl, thiadiazolyl, thienyl, imidazolyl, triazolyl, tetrazolyl, pyridyl, furanyl, oxazolyl, isoxazolyl, oxadiazolyl, pyrrolyl, pyrazolyl, pyrimidinyl and pyridazinyl groups.
• bicyclic heteroaryl groups mention may be made of the indolyl, benzofuranyl, chromen-2-on-yl, benzimidazolyl, benzothienyl, benzotriazolyl, benzothiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, indazolyl, indolizinyl, quinazolinyl, phthalazinyl and quinoxalinyl groups. , naphthyridinyl, 2,3-dihydro-1H-indolyl, 2,3-dihydro-benzofuranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl.
• R p and R p > each represent, independently of one another, an atom hydrogen; • R represents a hydrogen atom, Ci -5 alkyl group such as methyl or ethyl, or -C (O) C 1-3 alkyl such as -C (O) -methyl;
• R 1 represents aryl such as phenyl or naphthyl, or R 1 represents a heteroaryl group such as benzo-1,3-dioxolyl or pyrrolyl; the aryl and heteroaryl groups being optionally substituted by one or more radicals Z which are identical to or different from each other;
• R 2 represents a hydrogen atom
• R 4 represents:
• a heterocycle group such as a piperidinyl or tetrahydropyranyl group; said heterocycle group being optionally substituted by a C 1-3 -alkylene-aryl group such as -methylene-phenyl, or R 4 represents an aryl group such as a phenyl group; said aryl group being optionally substituted with one or more radicals Z which are identical to or different from each other;
• R 7 represents a halogen atom such as a chlorine or a bromine or a C 1-5 alkoxy group such as a methoxy group
• Z represents a halogen atom such as a fluorine or a chlorine, a C 1-5 alkoxy group such as a methoxy, or a phenyl optionally substituted with a C 1-3 -fluoroalkyl group such as a trifluoromethyl group
• R c represents a hydrogen atom, Ci -6 -alkylene-OR d or C 1-6 -alkylene-NR a R b in which groups C 1-6 -alkylene are such as isopropylene or methylene,
• or Z represents a -C 4-6 -alkylene-OR d group in which the C 4-6 -alkylene group is such as butylene,
• Z represents a tetrazole group substituted with a C 1-3 -alkyl group such as a methyl group, or Z represents a group -NR a R b ,
• or Z represents a -C 4 group. 6 -alkylene-NR a R b in which the C 4-6 -alkylene group is such as butylene,
• or Z is -OC 1-5 -alkylene-NR to Rb in which the C 1-5 -alkylene group is such as ethylene or propylene, or Z represents a group -OC 0 . 3 -alkylene-heterocycle in which the alkylene group is absent or is such that a methylene, ethylene group, and the heterocycle is such that azepanyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, 1-azabicyclo [2.2.2] octyl or 8-azabicyclo [3.2.1] octyl, the said group -OC 0 . 3 -alkylene-heterocycle being optionally substituted by one or more C 1-3 -alkyl groups such a methyl or an oxo group,
• or Z is -O-C 1 -C 3 -alkylene-heteroaryl in which the C 1-3 -alkylene group is such as a methylene or ethylene group and the heteroaryl group is such that an imidazolyl or pyridinyl group,
• or Z represents a -CONH-C 1-5 -alkylene-NR a R b group in which the C 1-5 -alkylene group is such that an ethylene group,
• . or Z represents a group -OC 1 . 3 -alkylene-C (O) -NR a R b wherein C 1-3 - alkylene is such that methylene,
• . or Z represents a fused or spiric bicyclic diamino heterocycle chosen from:
• R 3 and R b each represent independently of the other a C 1-3 -alkyl group such as methyl,
• R a and R b together with the nitrogen atom to which they are attached form a heterocycle such as a morpholinyl, piperidinyl or pyrrolidinyl group, optionally substituted with one or more oxo groups, -NR 3 R b or hydroxy;
• R d represents a hydrogen atom or a C 1-3 -alkyl group such as methyl
• R e represents a C 1-3 -alkyl group such as methyl
• R p and R p ' represents, independently of one another, a hydrogen atom;
• R represents a hydrogen atom;
• R 1 represents a phenyl, naphthyl or benzo-1,3-dioxolyl group; said phenyl, naphthyl and benzo-1,3-dioxolyl groups being optionally substituted by one or more radicals Z which are identical to or different from each other;
• R 2 represents a hydrogen atom;
• R 4 represents:
• a phenyl group said phenyl group being optionally substituted with one or more radicals Z which are identical to or different from each other;
• R 7 represents a chlorine atom, bromine or a methoxy group
• Z represents a fluorine or chlorine atom
• or Z represents a group -NR 3 R b ,. or Z represents a -O-propylene-NR a Rb group. or Z represents a -O-azepanyl group, said -O-azepanyl group being optionally substituted by one or more methyl groups, or Z represents a -O-propylene-OR d group ;
• R 3 and R b each represent, independently of each other, a methyl group, or R a and R b together with the nitrogen atom to which they are attached form a pyrrolidinyl or piperidinyl group;
• R d represents a hydrogen atom
• R represents a hydrogen atom or a C 1-5 -alkyl, C 1-3 -fluoroalkyl, C 3-6 -cycloalkyl, C 1-3 -alkylene-C 3-6 -cycloalkyl group;
• Ri represents an aryl or a heteroaryl; the aryl and heteroaryl groups being optionally substituted by one or more radicals Z which are identical to or different from each other;
• R 2 represents a hydrogen atom or a C 1-3 -alkyl group
• R 4 represents a hydrogen atom or a C 1-5 -alkyl, C 1-3 -fluoroalkyl, C 3-6 -cycloalkyl, C 1-3 -alkylene-C 3 group . 6 -cycloalkyl, C 1-3 -alkylene-OC 1-3 -alkyl, Ci -3 -alkylene- (OH)
• R 4 represents C -3 -alkylene-NR a R b, aryl, C 1-3 -alkylene-aryl, C 1-3 -alkylene-O-aryl, C 1-3 -alkylene-O-Ci -3 -alkylene-aryl, heteroaryl or Ci -3 -alkylene-heteroaryl; aryl, C 1-3 -alkylene-aryl, C 1-3 -alkylene-O-aryl, C 1-3 -alkylene-O-
• R 4 represents a heterocycle group; said heterocycle being optionally substituted by C 1-3 -alkyl, -C (O) -C -5 -alkyl, -C (O) -C 1-5 - fluoroalkyl, C 1-3 -alkylene-C 3. 6 -cycloalkyl, C 1-3 -alkylene-aryl, the C 1-3 -alkylene-aryl group being optionally substituted by one or more radicals Z which are identical to or different from each other;
• R 7 represents a halogen atom or a C- ⁇ -5 -alkyl group and especially a methyl, C 1-3 -fluoroalkyl and in particular trifluoromethyl, d. 5- alkoxy and in particular methoxy, -CN, -COOH, -NO 2 ;
• Rp and R ' p represent, independently of one another, a hydrogen atom or a C 1-5 alkyl group and in particular a methyl, or R p and R ' p together form a C 1-4 -alkylene group;
• Z represents a halogen atom or a C 1-5 -alkyl, C 1-3 -fluoroalkyl, C 3-6 -cycloalkyl, C 1-3 -alkylene-C 3-6 -cycloalkyl, a phenyl, C 1-5 -alkoxy, Ci -3 -fluoroalkoxy, C 1-3 - alkylene-OC 1-3 -alkyl, C 1-3 -alkylene- (OH), NO 2, -CN, -SO 2 NR a R b , -XC 1-3 -alkyl, C 1-3 - alkylene-XC 1-3 -alkyl wherein X is S, SO or SO 2 , or Z is -NR 3 Rb, C 1-3 -alkylene-NR a Rb, -C (O) -NR 3 Rb,
• or Z represents a group -O-C 1-5 -alkylene-NR a Rb,
• R 3 and R b each independently of one another represent a hydrogen atom or a C 1-3 -alkyl or -C (O) -C 1-3 -alkyl group,
• R a and R b together with the nitrogen atom carrying them, form a heterocycle optionally substituted with one or more C 1-3 -alkyl or oxo groups.
• R represents a hydrogen atom or a C 1-5 alkyl group and in particular an ethyl, C 1-3 -alkylene-C 3-6 -cycloalkyl;
• R 1 represents aryl or heteroaryl; the aryl and heteroaryl groups being optionally substituted by one or more radicals Z which are identical to or different from each other;
• R 2 represents a hydrogen atom or a C 1-5 alkyl and in particular a methyl group
• R 4 represents a hydrogen atom or a C 1-5 -alkyl, C 1-3 -fluoroalkyl group and in particular a trifluoromethyl, C 1-3 -alkylene-OC 1-3 -alkyl group and in particular a methylene- O-methyl,
• R 4 represents a C 1-3 -alkylene-NR a R b , aryl and in particular a phenyl, C 1-3 -alkylene-aryl and in particular a C 1-3 -alkylene-phenyl, Ci- 3 -alkylene-O-aryl and in particular a C 1-3 -alkylene-O-phenyl, heteroaryl and in particular a pyridinyl; the aryl, C 1-3 -alkylene-aryl, C 1-3 -alkylene-O-aryl and heteroaryl groups being optionally substituted with one or more Z radicals that are identical to or different from each other,
• R 4 represents a heterocycle group; said heterocycle being optionally substituted with C 1-3 -alkyl, -C (O) -C 1-5 -alkyl, -C (O) -C 1-5 -fluoroalkyl, C 1-3 -alkylene-C 3 . 6- cycloalkyl, C 1-3 -alkylene-aryl and especially methylene-phenyl; the -3 -alkylene-aryl group being optionally substituted by one or more radicals Z which are identical or different from one another; R 7 represents a halogen atom, a methyl, a methoxy, a trifluoromethyl, -CN or -NO 2 ;
• R p and R ' p independently of one another represent a hydrogen atom or a methyl
• R p and R ' p together form a C 1-4 alkylene group; • Z represents a halogen atom or a Ci -5 alkyl group, Ci -3 fluoroalkyl, especially trifluoromethyl, phenyl, Ci -5 alkoxy and in particular methoxy, -CN, -SO 2 NR 3 R b , -XC 1-3 -alkyl, C 1-3 -alkylene-XC 1-3 -alkyl wherein X is S, SO or SO 2 ,
• Z represents a group -NR 3 Rb or -C (O) -NR 3 Rb, -C (O) -C 1-3 -alkyl, -C (O) OC 1-4 -alkyl, -C (O) -C 3-6 -cycloalkyl, or else Z represents an oxo radical,
• or Z represents a group -O-C 1-5 -alkylene-NR a Rb,
• R a and R b each independently represent a hydrogen atom or a C 1-3 -alkyl or -C (O) -C 1-3 -alkyl group,
• R 3 and R b together with the nitrogen atom carrying them, form a heterocycle optionally substituted with one or more C 1-3 -alkyl or oxo groups.
• R represents a hydrogen atom or an ethyl group
• R 1 represents aryl or heteroaryl; the aryl and heteroaryl groups being optionally substituted by one or more radicals Z which are identical to or different from each other;
• R 2 represents a hydrogen atom or a methyl group;
• R 4 represents a hydrogen atom or a C 1-5 alkyl group, a trifluoromethyl, a methylene-O-methyl,
• R 4 represents phenyl, pyridinyl; the phenyl and pyridinyl groups being optionally substituted by one or more radicals Z which are identical to or different from each other;
• R 7 represents a halogen atom, a methyl, a methoxy, -CN or -NO 2 ;
• R p and R ' p represent independently of one another a hydrogen atom or a methyl
• Z represents a halogen atom or a C 1-5 alkyl, trifluoromethyl or phenyl group; a methoxy, -CN, -SO 2 NR a R b ,
• Z represents an oxo radical, or Z represents a group -O-C 1-5 -alkylene-NR a R b ,
• R 3 and R b each independently represent a hydrogen atom or a C 1 -C 3 -alkyl or -C (O) -C 1 -C 3 -alkyl group,
• R a and R b together with the nitrogen atom carrying them, form a heterocycle optionally substituted with one or more C 1-3 -alkyl or oxo groups.
• the starting compounds and reagents when their method of preparation is not described, are commercially available or described in the literature, or they can be prepared according to methods described therein or which are known to man of career. According to the invention, the compounds of general formula (I) can be prepared according to the process illustrated by the following scheme 1.
• the compound of general formula (I) is prepared from a compound of formula (III), in which R 4 and R 7 are as defined in general formula (I), according to route A by nucleophilic substitution of chlorine with the amine of the compound of formula (II), wherein R 1 , R 2 , R p , R ' p and R are as defined in general formula (I).
• This reaction can be carried out by heating the compounds of formulas (II) and (III) in an alcohol such as n-butanol or n-pentanol or can be catalyzed by a transition metal such as palladium for example under tris (dibenzylidene-acetone) dipalladium form in the presence of a ligand such as BINAP (2,2'-bis (diphenylphosphino) -1,1'-binaphthyl) and a base such as Fe / Fe-butylate; sodium according to the method described by Wolfe et al (J. Am Chem Soc 1996, 118, 7215-7216).
• a transition metal such as palladium for example under tris (dibenzylidene-acetone) dipalladium form
• a ligand such as BINAP (2,2'-bis (diphenylphosphino) -1,1'-binaphthyl) and a base such as Fe
• the compound of general formula (I) in which R is different from the hydrogen atom can also be prepared according to route B from the compound of general formula (I 1 ) in which R is a hydrogen atom by alkylation with an alkyl halide (RX) in the presence of a base such as, for example, sodium hydride in a solvent such as dimethylformamide, tetrahydrofuran or N-methylpyrrolidinone.
• a base such as, for example, sodium hydride in a solvent such as dimethylformamide, tetrahydrofuran or N-methylpyrrolidinone.
• the compound of general formula (I 1 ) can also be acylated by an anhydride or an acid chloride of the type R 1 C (O) Y to form an amide of general formula (I ")
• This amide can be reduced by lithium aluminum hydride (LiAlH 4 ) or by the complex borane-tetrahydrofuran (BH 3 -TI-IF) to obtain the compound of general formula (I) in which R represents an alkyl.
• the compound of formula (I '), wherein R is a hydrogen atom is prepared from of the compound of formula (III), wherein R 4 and R 7 are as defined in general formula (I) and the amino compound of formula (H 1 ) by the methods mentioned above for the preparation of the compound of general formula ( I),
• Amines of formula (U ') or (II) in which R represents a hydrogen atom, when they are not commercial can be prepared by analogy to the methods described in the literature (Mach et al., J. Med. 1993, 36, 3707-3720, Dostert et al, Eur J. Chem Chem Ther 1984, 19 (2), 105-110, Moragues et al Farmaco, Ed. ScL 1980, 35 (11), 951. -964 and Shum et al Nucleosides Nucleotides 2001, (4-7), 1067-1078).
• the amine of formula (II) for which R represents a methyl may be prepared by reduction with lithium aluminum hydride (LiAlH 4 ) of the tert-butoxycarbonyl group previously introduced on the primary amine according to the reduction method used by Gibson. et al (Tetrahedron Asymmetry 1995, 6, 1553-1556).
• the amine of formula (II) for which R represents an alkyl other than methyl may be prepared by reduction of an amide (previously introduced on the primary amine) with lithium aluminum hydride (LiAlH 4 ) or by borane-tetrahydrofuran complex (BH 3 -THF).
• LiAlH 4 lithium aluminum hydride
• BH 3 -THF borane-tetrahydrofuran complex
• the compound of general formula (I) can be prepared from a compound of formula (Ib), in which R 4 , R 7 , R p , R ' p and R are as defined in US Pat. general formula (I), and in which the nitrogen of the nitrogenous ring is not substituted, in particular by a reductive amination reaction with an aldehyde or a ketone of general formula RrC (O) R 2 , in which R 1 and R 2 are as defined in the general formula (I).
• This reaction may be carried out, for example, in the presence of sodium triacetoxy borohydride in a solvent such as dichloromethane or 1,2-dichloroethane, according to one of the methods described in Abdel-Magid et al (J. Org Chem 1996, 61, 3849-3862).
• the compound of general formula (Ib) is obtained by deprotection of the compound of general formula (la) which has on the nitrogen of the nitrogen ring a protective group PG.
• This protective group can be for example benzyl, ethoxycarbonyl or tert-butoxycarbonyl and deprotection can be accomplished by methods cited in Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons, New York, 1999.
• the compound of general formula (la) is synthesized by reacting a compound of general formula (III) wherein R 4 and R 7 are as defined in general formula (I), with a compound of general formula (N ”) according to the methods already described previously for the compound (I).
• the compound of general formula (III) when it is not commercial, can be prepared from a compound of formula (IV) 1 derived N-oxide of isoquinoline in which R 4 and R 7 are as defined in the general formula (I), by heating in the presence of phosphoryl chloride in a solvent such as chloroform.
• the compound of general formula (III) can also be obtained from the 2/7-isoquinolin-1-one derivative of formula (IV) in which R 4 and R 7 are as defined in the general formula (I) by heating in phosphoryl chloride, for example.
• the 2H-isoquinolin-1-one derivative of formula (IV) can be obtained by treatment of the 1f / -isochromen-1-one derivative of formula (V) with, for example, ammonium carbonate in acetic acid.
• the 1H-isochromen-1-one derivative of formula (V) can be synthesized from an ester of formula (VI) by cyclization with ylide (VII) in dimethylformamide, according to the method described by Clough et al ( Tetrahedron Lett., 1984, 25, 3025-3028).
• the ester of formula (VI) may be prepared from the 2-acyl-benzoic acid of formula (VIII) by esterification reaction for example with methyl iodide in the presence of potassium carbonate in dimethylformamide.
• the 2-acyl-benzoic acid of formula (VIII) can be synthesized from a 2-bromo-benzoic acid of formula (IX) by halogen-metal exchange and then reaction with an acid chloride of formula (X) or with a Weinreb amide, of the ⁇ / -methoxy- ⁇ / -methylamine type of formula (X '): N-Me MeO
• the compounds of formula (I) are very affine and selective with respect to the Melanin-Concentrating Hormone Receptor (MCH) 1 , MCH 1 .
• MCH is an important regulator of food intake
• small nonpeptide molecules able to antagonize its stimulating action of the MCH 1 receptor are a therapy of choice for treating metabolic problems related to obesity but also to bulimia nervosa.
• an MCH 1 receptor antagonist such as the
• SNAP-7941 (described by Synaptic Laboratories) confirms the important role of MCH in regulating energy balance and the development of obesity (Katsuura et al., Curr Med Chem 2003; 3: 217-227).
• the compounds according to the invention therefore represent a therapy of choice for the treatment of diseases presenting disorders of the regulation of the energy balance as well as for the treatment of the development of obesity.
• MCH is a functional antagonist of the melanocortin system, counteracting its effects on food intake and on the hypothalamic-pituitary-adrenal axis (Ludwig et al., Am J Physiol 1998; 274: E627-E633). It is also involved in regulation of the hypothalamic-pituitary-adrenal axis and in stress response via hypothalamic CRF release (Kennedy et al., J Neuroendocrinol 2003; 15 (3): 268-272). The use of an MCH-1 receptor antagonist has recently confirmed the anxiogenic effect of MCH.
• SNAP-7941 has an anxiolytic and / or antidepressant profile in different animal models such as social conflict and forced swimming in rats as well as maternal separation in guinea pigs (Katsuura et al, Curr Med Chem 2003; : 217-227). MCH 1 receptor antagonist molecules have therefore a therapeutic interest in depression and / or anxiety.
• the MCH seems to be involved with other regulatory systems.
• testicular location (Hervieu et al., Biology of Reproduction 1996; 5: 1161-1172) and hypothalamic (dependent estrogen, Viale et al., Peptides 1999; 20: 553-559) and .
• hypothalamic dependent estrogen, Viale et al., Peptides 1999; 20: 553-559
• stimulating effects of male rat sexual activity (Gonzales et al., Peptides 1996; 17: 171-177)
• luteinizing hormone secretion Chocchio et al., Biology of Reproduction 2001; 64: 1466-1472)
• the MCH seems to play a role in reproductive functions.
• MCH is implicated in cognitive function-related behaviors by increasing the extinction of passive avoidance in rats, suggesting that an MCHi receptor antagonist may be useful in memory disorders (MacBride et al. al, Peptides 1994; 15 (4): 757-759).
• the compounds according to the invention may constitute a therapy of choice for the treatment of memory disorders.
• MCH plays a role in urinary disorders and in particular urinary incontinence (US2004 / 0038855A1).
• the compounds of the invention find use in therapy, especially in the treatment of obesity, cellulitis, urinary incontinence, metabolic disorders and their associated pathologies such as diabetes, cardiovascular disorders, Syndrome X, in the treatment of stress-related pathologies such as anxiety and depression, as well as in the treatment of any other diseases involving MCH 1 receptor-related dysfunction at both central and / or peripheral level.
• the subject of the invention is medicaments which comprise a compound of formula (I), or an addition salt thereof to a pharmaceutically acceptable acid, or a hydrate or a solvate.
• the present invention relates to pharmaceutical compositions comprising, as active ingredient, at least one compound according to the invention.
• These pharmaceutical compositions comprise an effective dose of at least one compound according to the invention, or a pharmaceutically acceptable salt, a hydrate or solvate of said compound, as well as at least one pharmaceutically acceptable excipient.
• Said excipients are chosen according to the pharmaceutical form and the desired mode of administration, from the usual excipients which are known to those skilled in the art.
• compositions of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, local, intratracheal, intranasal, transdermal or rectal administration the active ingredient of formula (I) above, or its salt, solvate or hydrate, 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 disorders or diseases.
• Suitable unit dosage forms include oral forms such as tablets, soft or hard capsules, powders, granules and oral solutions or suspensions, sublingual, oral, intratracheal, intraocular, intranasal forms of administration. by inhalation, topical, transdermal, subcutaneous, intramuscular or intravenous administration forms, rectal administration forms and implants.
• the compounds according to the invention can be used in creams, gels, ointments or lotions.
• a unitary form of administration of a compound according to the invention in tablet form may comprise the following components: Compound according to the invention 50.0 mg
• Said unit forms are dosed to allow daily administration of 0.5 mg to 800 mg of active ingredient per individual, more particularly from 0.5 mg to 200 mg, depending on the dosage form.
• the dosage appropriate to each patient is determined by the physician according to the mode of administration, the weight and the response of said patient.
• the present invention also relates to a method of treatment of the pathologies indicated above which comprises the administration, to a patient, an effective dose of a compound according to the invention, or a pharmaceutically acceptable salt thereof or hydrates or solvates.
• PF Melting points
• Eluent B CH 3 CN + 0.005% TFA.
• Ionization mode positive electrospray (API-ES polarity +)
• the analytical characteristics of LC / MS of the products are the ratio m / z of the ion MH + and MNa + ion and retention time (tR) of the corresponding peak observed in UV and expressed in minutes.
• Some pluriazote products can be eluted on the HPLC column in two forms, a very large majority, depending on the degree of salification; in this case, the two retention times are noted.
• Quantification salts and solvates is determined using elemental analysis, the determination of water content by the Karl-Fischer and the integration of the signals characteristic of Solvent 1 H NMR
• the mixture is hydrolyzed with 100 ml of water and then extracted with dichloromethane.
• the organic phase is washed with 100 ml of 1N HCl, 150 ml of 1N NaOH and then with water and salt water. It is dried over anhydrous sodium sulphate, filtered and evaporated to dryness. 31.2 g of oil are obtained.
• a solution of 18.5 g (80 mmol) of 2-bromo-5-methoxybenzoic acid in 150 mL of THF is stirred under nitrogen at -78 ° C.
• 100 ml (160 mmol) of a 1.6M solution of n-butyllithium in hexane are added dropwise for about 2 hours, ensuring that the temperature does not exceed -70 ° C.
• the mixture is stirred at -78 ° C for 1 hour and then a solution of 16 g (80 mmol) of 4-chloro / V- Methoxy- ⁇ -methylbenzamide in 20 ml of THF is added dropwise.
• the reaction medium is stirred at -78 ° C.
• the aqueous phase containing the carboxylate is acidified with a solution of 5N HCl and extracted with dichloromethane.
• the dichloromethane phase is washed with salt water, dried over anhydrous sodium sulphate, filtered and concentrated.
• the product is crystallized in isopropyl ether; after filtration and drying 12.7 g of product are obtained.
• the resulting mixture is stirred while allowing the temperature to rise progressively to room temperature, then it is heated between 50 and 60 ° C. for 2 hours 30 minutes.
• the cooled reaction medium is poured into 500 ml of water and extracted twice with ethyl acetate.
• the combined organic phases are washed with water and with saturated sodium chloride solution, then dried over anhydrous sodium sulphate and evaporated under reduced pressure.
• the residue is dissolved in dichloromethane and then added with isopropyl ether. By partial evaporation of the dichloromethane a precipitate is formed which is filtered and then recrystallized from isopropyl ether. 1.28 g of product are obtained in powder form.
• the mixture is stirred at 80 ° C. for 24 hours. After returning to ambient temperature, the reaction medium is hydrolyzed with sodium hydrogen carbonate solution and then extracted with ethyl acetate. The organic phase is dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure. The residue obtained is purified by chromatography on a column of silica gel (eluent: dichloromethane / methanol from 100/0 to 80/20 (v / v)). 258 mg of product are obtained.
• the dihydrochloride salt is obtained by treatment of the product dissolved in dichloromethane with a solution of 2M hydrochloric acid in diethyl ether. Trituration and addition of diethyl ether gives a suspension which is filtered. The powder obtained is dried at 40 ° C. under reduced pressure in the presence of diphosphorus pentoxide.
• the dihydrochloride is obtained by the treatment described in 1.7.
• the mixture is heated under reflux for 18 hours and then 140 mg (2.62 mmol) of ammonium chloride are added and heating is continued for 24 hours.
• the reaction medium is cooled to room temperature, hydrolyzed with 20 ml of a 1N sodium hydroxide solution and then extracted with dichloromethane. The organic phase is washed with a saturated sodium chloride solution and then dried over anhydrous magnesium sulfate. After filtration, it is evaporated under reduced pressure. The residue obtained is purified by column chromatography on silica gel (eluent: dichloromethane / methanol 100/0 to 90/10 (v / v)). 138 mg of product are obtained.
• the residue obtained is purified on a column of silica (eluent: cyclohexane / ethyl acetate 9/1 (v / v)).
• the first product eluted is the expected 1-chloro-7-methoxyisoquinoline (320 mg).
• the other two products eluted are 3-chloro-7-methoxyisoquinoline (91 mg) and 4-chloro-7-methoxyisoquinoline (86 mg), respectively.
• Mp 73 ° C (M)
• the dihydrochloride is obtained by the treatment described in 1.7.
• Example 7 N- (1- ⁇ 4- [3- (Dimethylamino) propoxy] -3-fluorobenzyl ⁇ -piperidin-4-yl) -7-methoxyisoquinolin-1-amine trihydrochloride (Compound No. 7)
• the manipulation is carried out under an inert atmosphere (nitrogen).
• a tricolor of 100 ml are introduced 0.2 g of 10% palladium on charcoal and 16 ml of water.
• To this stirred mixture at 85 ° C is added dropwise a previously prepared solution of 1.35 g of N- (1-benzylpiperidin-4-yl) -7-methoxyisoquinolin-1-amine in 8 mL of ethanol and 0.56 g mL (14.6 mmol) of formic acid.
• the reaction mixture is stirred at reflux for 2 hours. After returning to ambient temperature and filtration, the ethanol is evaporated under reduced pressure.
• the mixture is then basified with 2N sodium hydroxide and is then extracted with dichloromethane.
• the trihydrochloride is obtained by the treatment described in 1.7. .
• the residue obtained is dissolved in 250 ml of N hydrochloric acid and the solution is washed with 2 times 100 ml of ethyl acetate and then basified with 30 ml of 35% sodium hydroxide.
• This alkaline aqueous phase is extracted with dichloromethane and the organic phase obtained is washed with water and then with saturated water of sodium chloride, dried over anhydrous sodium sulphate and then evaporated under reduced pressure.
• the residue is purified on a column of alumina (eluent: dichloromethane / methanol 100/0 to 90/10 (y N)).
• This compound in the base form is obtained by reductive amination according to the procedure described in 7.3. by reaction of 7-chloro- ⁇ - (piperidin-4-yl) isoquinolin-1-amine with 4- (3-dimethylaminopropoxy) -3-fluoro-benzaldehyde (preparation in 7.2.)
• the trihydrochloride is obtained by the treatment described in 1.7. .
• the second compound eluted is 4 - [(1-methylazepan-4-yl) oxy] benzaldehyde:
• This compound in the base form is obtained by reductive amination according to the procedure described in 7.3. by reaction of 7-chloro- ⁇ - (piperidin-4-yl) isoquinolin-1-amine (preparation in 8.2) with 4 - [(1-methylazepan-4-yl) oxy] benzaldehyde.
• the trihydrochloride is obtained by the treatment described in 1.7. .
• This compound in the base form is obtained by reductive amination according to the procedure described in 7.3. by reaction of 7-chloro- ⁇ - (piperidin-4-yl) isoquinolin-1-amine (preparation in 8.2) with 4- (4-pyrrolidin-1-ylpiperidin-1-yl) benzaldehyde.
• the organic phase is treated with 50 ml of 1N hydrochloric acid and the mixture is vigorously stirred for 1 hour.
• the acidic aqueous phase is separated and then alkalinized with a 2N sodium hydroxide solution and extracted with dichloromethane.
• the organic phase is washed with water saturated with sodium chloride, dried over anhydrous sodium sulphate and then evaporated under reduced pressure. 350 mg of white solid product is obtained.
• the compounds according to the invention have been the subject of pharmacological tests. Their affinity towards the Melanin-Concentrating Hormone (MCH) receptor 1, MCH 1 , was thus determined. Attempts were to measure the in vitro activity of the compounds of the invention on MCH 1 MCH receptors.
• MCH Melanin-Concentrating Hormone
• the measurement of the affinity of the compounds of the invention for the MCH receptors was carried out by studying the displacement of the binding of a radio-labeled derivative of the MCH to the MCH 1 receptors. This study is carried out on membrane preparations of rat and / or mouse brain according to the protocol described below.
• the brains were diluted in 25 mM HEPES buffer (pH 7.4) containing MgCl 2 5 mM of CaCl 2 1 mM, homogenized using a
• Polytron 3 times 20 seconds (speed 25), then undergo ultracentrifugation for 22 minutes at 22,000 RPM at + 4 ° C.
• the pellet is taken up by the same buffer and the membranes are aliquoted and stored frozen at -80 ° C. until they are used.
• the membranes are brought back to ambient temperature and are then incubated in the presence of the test compounds, and 50 ⁇ M of a radiolabelled molecule derived from the MCH, the
• Nonspecific binding is determined in the presence of 1 ⁇ M of non-radiolabelled S36057. Specific binding is obtained by difference between total binding and non-specific binding.
• the inhibitory activity of the compounds of the invention is expressed by the concentration which inhibits 50% of the specific binding (Cl 50 ).
• the Cl 50 of the compounds are generally less than
• the compounds of formula (I) advantageously have Cl 50 less than 1 ⁇ M, more advantageously less than or equal to 10 ⁇ M and even more advantageously less than or equal to 10 ⁇ M.
• the compound according to Example 3 has a Cl 50 of 9 nM in the rat and 5 nM in the mouse.
• an MCH receptor 1 antagonist can be pharmacologically controlled using a rat test (young rats weighing 80 to 80
• This test consists in inducing a food intake behavior by an i.c.v injection. (intra-cerebroventricular) MCH performed manually.
• the injection i.c.v. peptide solubilization buffer (without the MCH) in a first control group makes it possible to quantify the importance of the effect due to the MCH.
• a compound according to the invention is administered orally 1 or 2 hours before treatment i.c.v.
• the effect of a compound according to the invention is measured by the reduction it can cause on food intake, previously induced by i.c.v injection. from MCH.
• the specificity of action of the product can be evaluated using another orexigenic peptide such as NPY, also injected by i.c.v.
• NPY another orexigenic peptide
• a specific product of the MCH1 receptor will have no effect on food intake induced by another orexigenic peptide such as NPY.
• the compounds according to the invention can be used for the preparation of medicaments, in particular antagonists of the MCHi receptor of the MCH.

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