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  • 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
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  • 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
  • C07D401/14—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 three or more hetero rings
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  • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
  • C07D487/10—Spiro-condensed systems

Definitions

• the present invention relates to 1-amino-phthalazine derivatives, their preparation and their therapeutic application.
• the search for MCH receptor 1 antagonists (Melanin-Concentrating
• MCH is one of these neuropeptides.
• SLC-1 or GPR24 receptor the MCH 1 receptor previously called the SLC-1 or GPR24 receptor (Chambers et al., Nature 1999; 400: 261-265)
• SLT the MCH 2 receptor previously called SLT
• WO2005 / 103033 discloses 1-amino-phthalazine derivatives capable of modulating
• A represents a C 1-4 -alkylene group optionally substituted with one or more R 9 groups which are identical to or different from each other;
• B represents a C 1-4 -alkylene group optionally substituted with one or more groups R 10 which are identical to or different from one another;
• R 9 and R 10 are each, independently of one another, a hydrogen atom or a Ci -5 alkyl group,. or R 9 and R 10 together form a single bond or a C 1-4 alkylene group;
• R represents a hydrogen atom or a C 5 alkyl group, C 1-3 fluoroalkyl, C 3-6 -.
• Cycloalkyl, -C (O) C 1-3 -alkyl, C 1-3 -alkylene- C 3-6 -cycloalkyl, -CH 2 -C CH, C 2-3 -alkylene-NR 3 R b , C 1-3 -alkylene-X-C 1-3 -alkyl wherein X is O or SO 2 ;
• 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 and R 3 independently of one another, a hydrogen atom or a C 1-3 -alkyl or Ci. 3 fluoroalkyl,
• R 4 represents:
• 6-cycloalkyl a C 1-3 -alkylene- (OH), C 1-3 -alkylene-X-C 1-3 -alkyl group where X is S, SO or SO 2 ,
• a heterocycle group comprising: said heterocycle group being optionally substituted with a C 1-3 -alkyl, -C (O) C 1-3 -alkyl, -C (O) C 1-3 -fluoroalkyl, C 1-3 -alkylene-C 3 group . 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 radicals
• R 4 represents a C 1-3 -alkylene-NRaRb, aryl, C 1-3 -alkylene-aryl group,
• R 5 represents a hydrogen or halogen atom or a group CI_ 5 -alkyl, C 1-3 -. Fluoroalkyl, C 1-5 alkoxy, C 3 -fluoroalkoxy, Ci.s-alkylene- ⁇ OH) -CN, -XC 1-3 -alkyl where X represents S, SO or SO 2 ,
• R 5 is -NR a R b , C 1-3 -alkylene-NR a R b , aryl, C 1-3 - alkylene-aryl, -O-aryl or heteroaryl; the aryl, C 1-3 -alkylene-aryl, -O-aryl and heteroaryl groups being optionally substituted with one or more Z radicals which are identical to 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, -COOH, -C (O) OC 1-3 group ; alkyl, C 1-3 -fluoroalkoxy, C 1-3 -alkylene- (OH), -CN, -XC 1-3 -alkyl wherein X is S, SO or SO 2 ,
• R 7 represents a group -NR 3 R b , C 1-3 -alkylene-NR a R b , -C (O) -NR 3 Rb, -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; • Z represents a halogen atom or a Ci -5 alkyl group, C 1-3 fluoroalkyl, C 3-6 - cycloalkyl, C 1-3 -alkylene-C 3-6 -cycloalkyl, Ci -5 alkoxy , C 1-3 -fluoroalkoxy, C 1-3 -alkylene-O-C 1-3 -alkyl, C 1-3 -alkylene- (OH), NO 2 , -CN, -SO 2 NRaRb, -XC
• . or Z is optionally substituted by a halogen atom phenyl, C 1-5 -alkyl, CI_ 5 -alkoxy or C 1-3 fluoroalkyl,
• Z represents a -C 4-6 -alkylene-ORd group, 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 Rb, -C (O) -NR 3 Rb, -C (O) -C 1-3 -alkyl, -CO 2 -C 1-4 -alkyl, -C (O) -C 3 . 6 -cycloalkyl,
• Z represents a -C 4 group. 6 -alkylene-NR a R b , or Z represents an oxo radical, or else Z represents a group
• or Z represents a -OC 0-3 -alkylene-heterocycle group, optionally substituted by one or more C 1-3 -alkyl, oxo or -C (O) -C 1-3 -alkyl groups, or Z is -O-C 1-5 -alkylene-O-Rd,
• 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 by 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 -O-C1-3-alkylene-heteroaryl group optionally substituted with one or more C 1-3 -alkyl groups,
• Z represents a group . 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 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 a and R b together with the nitrogen atom to which they are attached form a heterocycle optionally substituted with one or more C 1-3 -alkyl, oxo, -NR a R b , hydroxy, C 1 groups; -3- alkoxy, 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;
• R 4 represents a heterocycle group, said heterocycle being optionally substituted by a C 1-3 alkyl group , -C (O) C 1-3 -alkyl, -C (O) Cl.
• - Z represents phenyl substituted by a halogen atom, a group C 1-5 - alkyl, Ci -5 alkoxy or C 1-3 fluoroalkyl, or
• Z represents a -C 4-6 -alkylene-OR d group
• Z represents a tetrazole group substituted with a C 1-3 -alkyl group
• Z represents a group -C 4 . 6 -alkylene-NR a R b , or else
• Z represents a group -SO 2 -NR 3 R b
• -Z represents a group -O-C 1 -C 5 -alkylene-NR a R b
• Z represents a group -OC 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 -OC 1-5 -alkylene-O-Rci, or
• - Z represents a group -0-C 0-3 -alkylene-C 5. 7 -cycloalkyl optionally substituted with a group -OR d , or
• Z represents -NR e -C 0-3 -alkylene-heterocycle optionally substituted by one or more C 1-3 alkyl, oxo or -C (O) -C 1. 3- alkyl, or
• Z represents a group -NR e -C 2- 5 -alkylene-OR d , or
• Z represents a group -OC- ⁇ -3 -alkylene-heteroaryl optionally substituted with one or more C 1-3 -alkyl groups, or
• Z represents a -CONH-C 1-5 -alkylene-NR a R b group
• -Z represents a -CONH-C 1-5 -alkylene-OR d group
• Z represents a group -OC 1-3 -alkylene-C (O) -NR a R b , in the groups Z mentioned above, the groups R a , R b , R d and R e are as defined previously , to know :
• 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 a and R b together with the nitrogen atom to which they are attached form a heterocycle optionally substituted with one or more C 1-3 -alkyl, oxo, -NR 3 R b , hydroxy, C 1 groups; -3- alkoxy, C 1-3 -alkylene- (OH) or -C (O) -C- ⁇ - 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
• - or Z represents a fused bicyclic or fused bicyclic heterocycle
• - or Z represents a group -NR 3 R b in which R a and R b together with the nitrogen atom to which they are attached form a heterocycle substituted with one or more -NR a R b , hydroxy groups, C 1-3 -alkoxy, C 1-3 -alkylene- (OH) or -C (O) -C 1-3 -alkyl.
• 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 comprise one or more olefinic functions.
• ZIE ZIE isomers. 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 t-2 where t and z can take the values from 0 to 6, a carbon chain or ring which can have from t to z carbon atoms, for example C 0-3 can characterize a single bond or a carbon chain having from 1 to 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.
• the groups -OCF 3 , -OCHF 2 a heterocycle group: a 5- to 7-membered saturated cyclic group having one to several heteroatoms such as nitrogen, oxygen or sulfur atoms.
• 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 connected 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.
• the cycle can be, for example, azetidinyl, pyrrolidinyl, piperidinyl, azepanyl, 8-azabicyclo [3.2.1] octyl, 8-azabicyclo [3.3.1] nonanyl, decahydroisoquinolinyl, 3-azabicyclo [3.1.0] hexanyl.
• A represents a C 1 -C 4 alkylene group, such as the ethylene group, optionally substituted with one or more R 9 groups identical to or different from each other;
• B represents a C 1-4 -alkylene group, such as the ethylene group, optionally substituted by one or more groups R 10 which are identical to or different from each other;
• R 9 and R 10 each independently represent a hydrogen atom
• R represents a hydrogen atom, a C 1-5 -alkyl group such as methyl or ethyl, or a -C (O) C 1-3 -alkyl group 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 and R 3 represent independently of each other a hydrogen atom;
• R 4 represents:
• 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 5 represents a hydrogen atom, C 1-5 alkoxy such as a methoxy group
• R 7 represents a halogen atom such as a chlorine or a C 1-5 alkoxy group such as a methoxy group
• Z represents a hydrogen atom, a halogen atom such as a fluorine, a C 1-5 alkoxy group such as a methoxy or a phenyl optionally substituted by a C 1-3 -fluoroalkyl group such as trifluoromethyl,
• . or Z represents a tetrazole group substituted by a C 1-3 -alkyl group such as a methyl group,
• or Z represents a -C 4-6 -alkylene-NR a Rb group in which the C 4-6 -alkylene group is such as butylene,
• or Z represents a -OC 1-5 -alkylene-NR a R b group 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 an azepanyl, pyrrolidinyl, piperidinyl group, tetrahydrofuranyl, the 1-azabicyclo [2.2.2] octyl group or the 8-azabicyclo [3.2.1] octyl group, the said -O-C 0-3 -alkylene-heterocycle group being optionally substituted by one or more C 1 groups -3 - alkyl such as methyl or an oxo group,
• or Z represents a -O-C 1-5 -alkylene-O-Rd group in which the C 1-5 -alkylene group is such that an ethylene or propylene group,
• or Z represents a -OC 1-3 -alkylene-heteroaryl group 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,
• Z is -OC 1-3 -alkylene-C (O) -NR a R b wherein C 1-3 - alkylene is such as methylene,
• . or Z represents a fused or spiric bicyclic diamino heterocycle chosen from: in which the dotted lines represent the point of attachment to the remainder of the molecule of formula (I) and the solid lines represent a methyl substituent;
• R a and R b each independently represent a C 1-3 -alkyl group such as methyl
• R 3 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 4 represents a heterocycle group such as a piperidinyl or tetrahydropyranyl group, said heterocycle being optionally substituted by a C 1-3 -alkylene-aryl group such as methylene-phenyl, or
• Z represents a phenyl group substituted with a C 1-3 -fluoroalkyl group such as a trifluoromethyl, or Z represents an alkynyl radical of the type -C ⁇ CR C in which R 0 represents a hydrogen atom, C 1 -6 -alkylene-O-Rci or -6 -alkylene-NR a R b wherein Ci -6 -alkylene is such as isopropyl or methyl, or
• Z represents a -C 4-6 -alkylene-OR d group in which C 4 . 6 -alkylene is such that a butylene or -Z represents a C 1-3 -alkyl-substituted tetrazole group such as methyl, or else
• Z represents a -C 4-6 -alkylene-NR a R b group in which C 4-6 -alkylene is such that a butylene group, or
• Z represents a group -OC 1-5 -alkylene-NR a Rb, in which C ⁇ -alkylene is such as propylene or ethylene, or
• Z represents a group -OC 0 . 3 -alkylene-heterocycle in which the alkylene group is absent or is such that a methylene, ethylene or propylene group and in wherein the heterocycle is such that azepanyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, the 1-azabicyclo [2.2.2] octyl group or the 8-azabicyclo [3.2.1] octyl group, the group -OC 0 - 3 -alkylene-heterocycle being optionally substituted by one or more C 1-3 -alkyl groups such as methyl or an oxo group, or
• Z represents a group -OC 1-5 -alkylene-OR d in which C 1-5 -alkylene is such that an ethylene or propylene group, or
• - Z is -NR 8 -C 2-5 -alkylene-OR d wherein C 2 .5-alkylene is such that ethylene, or - Z represents a group -OC 1-3 -alkylene-heteroaryl wherein C 1-3 -alkylene is such as methylene or ethylene and wherein the heteroaryl group is such that an imidazolyl, pyridinyl group, or
• Z represents a group -CONH-C- ⁇ -5 -alkylene-NR a R b in which C 1-5 -alkylene is such that an ethylene group, or -Z represents a -OCi group.
• R a and R b each independently represent 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 piperidinyl, morpholinyl or pyrrolidinyl group, said heterocycle group being optionally substituted by one or more oxo groups, - NR Rb 3 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
• Z represents a fused bicyclic or spiroic diamino heterocycle chosen from:
• Z represents a group -NR 3 R b in which R a and R b together with the nitrogen atom to which they are attached form a heterocycle such as a pyrrolidinyl or piperidinyl group substituted with one or more groups; -NR 3 R b or hydroxy.
• A represents an ethylene group
• R represents a hydrogen atom, a methyl group, ethyl group or a -C (O) -methyl group
• R 1 represents a phenyl, naphthyl, benzo-1,3-dioxolyl or pyrrolyl group; said phenyl, naphthyl, benzo-1,3-dioxolyl and pyrrolyl groups being optionally substituted with one or more Z radicals which are identical to or different from each other;
• R 2 and R 3 represent, independently of one another a hydrogen atom
• R 4 represents:
• R 7 represents a chlorine atom or a methoxy group
• Z represents a hydrogen atom or a fluorine atom, a methoxy group or a phenyl group optionally substituted by a trifluoromethyl group
• NR 3 Rb, . or Z represents -O-heterocycle, -O-methylene-heterocycle, -O-ethylene-heterocycle, wherein heterocycle is such that azepanyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, 1-azabicyclo [ 2.2.2] octyl or the 8-azabicyclo [3.2.1] octyl group, said -O-heterocycle, -O-methylene-heterocycle, -O-ethylene-heterocycle groups being optionally substituted by one or more methyl groups or a group oxo,
• Z is -O-ethylene-OR d or -O-propylene-OR d,. or Z represents a group -NR e -ethylene-OR d ,
• . or Z represents a -O-methylene-heteroaryl, -O-ethylene-heteroaryl group in which the heteroaryl group is such that an imidazolyl, pyridinyl group,
• Z is -CONH-ethylene-NR a R b , or Z is -O-methylene-C (O) -NR a Rb,. or Z represents a fused or spiric bicyclic diamino heterocycle chosen from:
• 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 morpholinyl, piperidinyl or pyrrolidinyl group, optionally substituted with one or more oxo groups, -NR a R b or hydroxy;
• R d represents a hydrogen atom or a methyl group
• R ⁇ represents a methyl group
• R 4 represents a piperidinyl or tetrahydropyranyl group, said piperidinyl or tetrahydropyranyl groups being optionally substituted with a methylene-phenyl group, or
• Z represents a phenyl group substituted with a trifluoromethyl group
• Z represents a butylene-OR group d , or
• Z represents a tetrazole group substituted with a methyl group
• Z represents a butylene-NR a Rb group, or -Z represents a -O-propylene-NR a R b group , or
• Z represents -O-heterocycle, -O-methylene-heterocycle, -O-ethylene-heterocycle, wherein heterocycle is such that azepanyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, 1-azabicyclo [2.2. 2] octyl or the 8-azabicyclo [3.2.1] octyl group, said -OC 0-3 -alkylene-heterocycle group being optionally substituted with one or more methyl groups or an oxo group, or
• Z represents a group -O-ethylene-OR d or -O-propylene-OR d , or
• Z represents a group -NR e -ethylene-OR d , or
• Z represents a group -O-methylene-heteroaryl, -O-ethylene-heteroaryl wherein the heteroaryl group is such that an imidazolyl, pyridinyl group, or -Z represents a -CONH-ethylene-NR a Rb group, or good
• Z represents a group -OC 1-3 -methylene-C (O) -NR a Rb, in the groups Z mentioned above, the groups R 3 , R b , R d and R e are as defined previously, to know :
• 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 piperidinyl, morphonlinyl or pyrrolidinyl group, said piperidinyl, morpholinyl and pyrrolidinyl groups being optionally substituted with one or more oxo groups, -NR a R b or hydroxy;
• R d represents a hydrogen atom or a methyl group
• R e represents a methyl
• Z represents a fused bicyclic or spiroic diamino heterocycle chosen from:
• Z represents a group -NR 3 R b in which R a and R b together with the nitrogen atom to which they are attached form a piperidinyl or pyrrolidinyl group optionally substituted with one or more -NR 3 R groups; b or hydroxy.
• R a and R b together with the nitrogen atom to which they are attached form a piperidinyl or pyrrolidinyl group optionally substituted with one or more -NR 3 R groups; b or hydroxy.
• A represents a C 1-4 -alkylenic group optionally substituted with one or more groups R 9 which are identical to or different from one another;
• B represents a C 1-4 -alkylene group optionally substituted with one or more groups R 10 which are identical to or different from one another;
• R 9 and R 10 each independently represent a hydrogen atom or a C 1-5 -alkyl group; or R 9 and R 10 together form a single bond or a C 1-4 alkylene group;
• R represents a hydrogen atom or a Ci -5 alkyl group, C 1-3 fluoroalkyl, C 3-6 - cycloalkyl, -C (O) C 1-3 -alkyl, C 1-3 -alkylene- C 3-6 -cycloalkyl, -CH 2 -C ⁇ CH, C 2-4 -alkylene-NR a R b , C 1-3 -alkylene-XC 1-3 -alkyl wherein X is O or SO 2 ;
• 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 and R 3 independently of one another, a hydrogen atom or a C 1-3 alkyl or C 1-3 fluoroalkyl
• R 4 represents:
• a heterocycle group comprising: said heterocycle group being optionally substituted by a C 1-3 -alkyl, -C (O) C 1-3 -alkyl, -C (O) C 1-3 -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 with one or more Z radicals that are identical to or different from one another,
• R 4 is C 1-3 -alkylene-NR a R b , aryl, C 1-3 -alkylene-aryl, -O-aryl, C 1-3 -alkylene-O-aryl, C 1-3 -alkylene-OC 1-3 -alkylene-aryl, heteroaryl or C 1-3 - alkylene heteroaryl; aryl, C 1-3 -alkylene-aryl, -O-aryl, C-1. 3 -alkylene-O- aryl, Ci.
• R 5 represents a hydrogen or halogen atom or a Ci -5 alkyl group, C 1-3 - fluoroalkyl, C ⁇ -alkoxy, C 1-3 -fluoroalkoxy, C 1-3 -alkylene- (OH ), -CN, -XC 1-3 -alkyl where X is S, SO or SO 2 ,
• R 5 is -NR a R b, Cii 3 -alkylene-NR a R b, aryl, C 1-3 - alkylene-aryl, -O-aryl or heteroaryl; the aryl, C 1-3 -alkylene-aryl, -O-aryl and heteroaryl groups being optionally substituted with one or more Z radicals which are identical to or different from each other;
• R 7 represents a hydrogen or halogen atom or a Ci -5 alkyl group, C 1-3 - fluoroalkyl, C 1-5 alkoxy, -COOH, -C (O) OC, 3 -alkyl, C 1-3 -fluoroalkoxy, C 1-3 -alkylene- (OH), -CN, -XC 1-3 -alkyl wherein X is S, SO or SO 2 , or R 7 represents a group -NR 3 Rb, C 1-3 -alkylene-NR a R b , -C (O) -NR a R b ,
• Z represents a halogen atom or a Ci -5 alkyl group, C 1-3 fluoroalkyl, C 3. 6 - cycloalkyl, C 1-3 -alkylene-C 3 . 6 cycloalkyl, phenyl, Ci, 5 -alkoxy, C 1-3 -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 where X is S, SO or SO 2 ,
• Z is -NR a R b, C 1-3 -alkylene-NR a R b, -C (O) -NR a R b, -C (O) -C. 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 R b ,
• R a and R b each independently represent a hydrogen atom or a C- ⁇ -3 -alkyl or -C (O) -C 1-3 -alkyl group,
• R 4 represents a heterocycle group; said heterocycle being optionally substituted, - Z represents a group -SO 2 -NR a R b or a group -O-C 1-5 -alkylene-NR a R b .
• R 4 represents a heterocycle group; said heterocycle being optionally substituted, - Z represents a group -SO 2 -NR a R b or a group -O-C 1-5 -alkylene-NR a R b .
• A represents a C 1-4 alkylene group optionally substituted with one or more groups R 9 which are identical to or different from one another;
• B represents a C- ⁇ -4 -alkylene group optionally substituted by one or more identical or Rio groups different from each other;
• R 9 and R 10 are each independently of one another, a hydrogen atom or a C ⁇ -alkyl group and in particular methyl,
• R represents a hydrogen atom or a C 1-5 -alkyl, C 1-3 fluoroalkyl, C 3-6 - cycloalkyl, Ci -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 and R 3 independently of one another represent a hydrogen atom or a C 1-3 -alkyl group
• R 4 represents:
• a heterocycle group comprising: said heterocycle group being optionally substituted with a C 1-3 -alkyl, -C (O) C 1-3 -alkyl, -C (O) C 1 -C 3 -fluoroalkyl, C 1-3 -alkylene- C 3 . 6 - cycloalkyl, C 1-3 -alkylene-aryl; the group C 1-3 -alkylene-aryl optionally substituted by one or more identical radicals Z or different from each other,
• R 4 is C 1-3 -alkylene-NR a R b , aryl, C 1-3 -alkylene-aryl, C 1-3 -alkylene-O-aryl, C 1-3 -alkylene-OC 1 -3 -alkylene-aryl, heteroaryl or C- ⁇ -3 -alkylene-heteroaryl; aryl, C 1-3 -alkylene-aryl, C 1-3 -alkylene-O-aryl, C 1-3 -alkylene-O-
• R 5 represents a hydrogen atom or a C 1-5 alkyl, C 1-5 alkoxy or aryl group; the 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 or a C 1-5 -alkyl group and in particular a methyl, C 1-5 -alkoxy and in particular a methoxy, CN, COOH or -C (O) OC 1-3 - alkyl;
• Z represents a halogen atom or a Ci -5 alkyl group, C 1-3 fluoroalkyl, C 3-6 - cycloalkyl, C 1-3 -alkylene-C 3-6 -cycloalkyl, phenyl, C 1 -5 -alkoxy, C 1-3 -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 where X is S, SO or SO 2 ,
• Z represents a group -NR 3 Rb, C 1-3 -alkylene-NR a R b , -C (O) -NR 3 Rb, -CCCO-C- ⁇ s-alkyl, -C (O) OC 1- 4 -alkyl, -C (O) -C 3 . 6 -cycloalkyl, or else Z represents an oxo radical,
• 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; it being understood that at least one of the conditions previously stated is respected.
• A represents a C 1-4 -alkylene group and in particular an ethylene, optionally substituted with one or more R 9 groups;
• B represents a C 1-4 -alkylene group and in particular an ethylene, optionally substituted with one or more R 10 groups;
• Rg and Rio each represent, independently of one another, a hydrogen atom or a methyl
• R 9 and R 10 together form a C 1-4 -alkylene group
• 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 and R 3 represent, independently of each other, a hydrogen atom or a C 1-3 -alkyl group and in particular a methyl;
• R 4 represents:
• a heterocycle group optionally substituted by a C 1-3 alkyl-C (O) C 1 group . 3 -alkyl, -C (O) C 1 . 3 fluoroalkyl, Ci. 3 -alkylene-C 3. 6 -cycloalkyl, C 1-3 -alkylene-aryl and in particular methylene-phenyl; the C 1-3 -alkylene-aryl group being optionally substituted by one or more radicals Z that are identical to or different from each other,
• 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, C 1- 3 -alkylene-O-aryl and in particular a C 1-3 -alkylene-O-phenyl, C 1-3 -alkylene-OC 1-3 -alkylene-aryl and in particular a C 1-3 -alkylene-OC 1 -3- alkylene-phenyl, heteroaryl and especially thienyl or pyridinyl; aryl, C 1-3 -alkylene-aryl, C 1-3 -alkylene-O-aryl, C 1 groups .
• R 5 represents a hydrogen atom
• R 7 represents a halogen atom, a methyl, a methoxy, CN, COOH or -C (O) O-C 1-3 -alkyl;
• Z represents a halogen atom or a C 1-5 alkyl group, a phenyl, C 1-5 alkoxy and in particular methoxy, C 1 .
• or Z represents a group -NR 3 Rb, C 1-3 -alkylene-NR a Rb, -C (O) -NR 3 Rb, -C (O) -C 1-3 -alkyl,
• Z represents an oxo radical, or Z represents a group -OC 1-5 -alkylene-NR a R b ,
• 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; or 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; it being understood that at least one of the conditions previously stated is respected.
• A represents an ethylene, optionally substituted with one or more groups R 9 ;
• B represents an ethylene, optionally substituted with one or more R 10 groups
• R 8 and R 10 each independently represent a hydrogen atom or a methyl; L represents a single bond;
• R represents a hydrogen atom, an ethyl group or 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 and R 3 represent, independently of one another, a hydrogen atom or a methyl group
• R 4 represents:
• a C 1-3 -alkylene- (OH) group a heterocycle group optionally substituted with a C 1-3 -alkyl group,
• R 4 represents a C 1-3 -alkylene-NR a Rb group, a phenyl, a C 1-3 -alkylene-phenyl, a C 1-3 -alkylene-O-phenyl, a C 1-3 -alkylene- OC 1-3 -alkylene-phenyl, thienyl or pyridinyl; the phenyl, C 1-3 -alkylene-phenyl, C 1-3 -alkylene-O-phenyl, C 1-3 -alkylene-OC 1-3 -alkylene-phenyl, thienyl and pyridinyl groups being optionally substituted by one or more radicals Z identical to or different from each other; R 5 represents a hydrogen atom;
• R 7 represents a halogen atom, a methyl, a methoxy, CN
• Z represents a halogen atom or a Ci -5 alkyl group, phenyl, methoxy, C 1-3 -alkylene-OC 1-3 -alkyl, C 1-3 -alkylene- (OH) -CN , -SO 2 NR a R b , -XC 1-3 -alkyl, C 1-3 - alkylene-XC 1-3 -alkyl where X is S, SO or SO 2 ,. or Z is -NR a R b , C 1-3 -alkylene-NR a R b , -C (O) -NR a R b ,
• or Z represents a group -OC 1-5 -alkylene-NR a R b ,
• 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 a and R b together with the nitrogen atom carrying them, form a heterocycle optionally substituted with one or more C 1 -C 3 -alkyl or oxo groups; it being understood that at least one of the conditions previously stated is respected.
• the compounds of general formula (I) can be prepared according to the process illustrated by the following scheme 1.
• the starting compounds and the reagents when their method of preparation is not described, are commercially available or described in the literature, or they can be prepared according to the methods described therein or are known to those skilled in the art.
• the compound of general formula (I) is prepared from a compound of general formula (III), wherein R4, R5 and R7 are as defined in general formula (I), according to the A, by nucleophilic substitution of chlorine with the amine of the compound of general formula (II), wherein R, R 1, R 2, R 3, L, A and B are as defined in general formula (I).
• This reaction can be carried out by heating the compounds of general formulas (II) and (III) in an alcohol such as n-butanol or n-pentanol in the presence of ammonium chloride according to the method described by Contreras et al (J.
• Chem., 2001, 44, 2707-2718 may also be catalyzed by a transition metal such as palladium for example in the form tris (dibenzylidene-acetone) -palladium in the presence of a ligand such as BINAP (2,2'-bis (diphenylphosphino) -1,1'-binaphthyl) and a base such as sodium or potassium tert-butylate using toluene or dimethoxyethane as the solvent.
• a transition metal such as palladium for example in the form tris (dibenzylidene-acetone) -palladium in the presence of a ligand such as BINAP (2,2'-bis (diphenylphosphino) -1,1'-binaphthyl) and a base such as sodium or potassium tert-butylate using toluene or dimethoxyethane as the solvent.
• the compound of general formula (I) may also be prepared, according to route B, from the compound of general formula (Ib), in which A, B, R, R 4 , R 5 and R 7 are as defined in the 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 R 1 -L-C (O) R 2 , wherein L, R 1 and R 2 are as defined in general formula (I).
• This reaction may for example be carried out 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 protecting group can be, for example, benzyl, ethoxycarbonyl or tert-butoxycarbonyl and deprotection can be carried out according to the methods cited in Protective Groups in Organic Synthesis 3 rd edition John Wiley & Sons, New York 1999.
• the compound of general formula (Ia) is synthesized by reacting a compound of general formula (III) as defined above with a compound of general formula (IIa) according to the methods already described above for compound (I).
• the amines of formula (II) or (IIa) 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. employed by Gibson et al (Tetrahedron Asymmetry 1995, 6, 1553-1556).
• the amines of formula (II) or (IIa) for which R represents an alkyl other than methyl can be prepared by reducing an amide (previously introduced on the primary amine) with lithium aluminum hydride (LiAlH 4 ). or borane-tetrahydrofuran complex (BH 3 -THF).
• BH 3 -THF borane-tetrahydrofuran complex
• the 1-chlorophthalazine of general formula (III) can be obtained by heating 2H-phthalazin-1-one of general formula (IV) in phosphoryl chloride, for example.
• 2 / - / - phthalazin-1-one of general formula (IV) may be prepared from a 2-acyl-benzoic acid of general formula (V) by heating in an alcohol such as ethanol, in presence of hydrazine hydrate for example.
• the 2-acyl-benzoic acid of general formula (V) can be synthesized from a 2-bromo-benzoic acid of general formula (VII) by halogen-metal exchange and then reaction with a chloride of acid of general formula (VI) or with a Weinreb amide, of type / -methoxy- ⁇ / -methylamide type of formula (Vl 1 ):
• the 2-acyl-benzoic acid of general formula (V) can also be obtained by other reactions such as, for example, the Friedel-Crafts reaction on a compound of general formula (VIII) in the presence of a compound of general formula (VI). This reaction is carried out in the presence of aluminum chloride in a solvent such as dichloromethane.
• the compound of general formula (I) in which R is different from the hydrogen atom can also be prepared from the compound of general formula (Ic) in which R is a hydrogen atom, by alkylation with an alkyl halide (RX) in the presence of a base, for example sodium hydride in a solvent such as tetrahydrofuran.
• RX alkyl halide
• the compound of general formula (Ic) can also be acylated with an anhydride or an acid chloride of R 1 C (O) Y type to form an amide of general formula (Id).
• This amide can be reduced by lithium aluminum hydride (LiAlH 4 ) or by the borane-tetrahydrofuran complex (BH 3 -THF) to obtain a compound of general formula (I) in which R represents an alkyl /
• 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 SNAP-7941 (described by Synaptic Laboratories) confirms the important role of MCH in the regulation of 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).
• MHC 1 receptor antagonist molecules are therefore of therapeutic interest in depression and / or anxiety.
• the MCH seems to be involved with other regulatory systems.
• MCH receptor antagonist may be useful when one memory disorders.
• 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 dysfunction related to the MCHi receptor either centrally and / or peripherally.
• 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:
• 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 of an effective dose of a compound according to the invention, or of one of its pharmaceutically acceptable salts or hydrates or solvates.
• the following examples describe the preparation of compounds according to the invention. These examples are not limiting and only illustrate the present invention.
• the numbers of the exemplified compounds refer to those given in Table I.
• PF Melting points
• Eluent B CH 3 CN + 0.005% TFA.
• Eluent B 90% CH 3 CN + 10% H 2 O TFA + 0.1% HFBA.
• 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
• a suspension of 370 mg (1 mmol) of 4- (1-benzylpiperidin-4-yl) -1-chloro-7-methoxy- phthalazine, in 5 ml of n-butanol is added 234 mg (1 mmol) of 1- (1,3-benzodioxol-5-ylmethyl) piperidin-4-yl-amine and 53 ml (1 mmol) of sodium chloride. 'ammonium.
• the mixture is heated at 140 ° C. for 18 hours.
• the reaction medium is cooled to ambient temperature, hydrolysed with water and then basified to pH 10 with 1N sodium hydroxide.
• the mixture is then extracted with ethyl acetate.
• the trihydrochloride is obtained after treatment of the product dissolved in dichloromethane with a solution of hydrochloric acid in diethyl ether. After concentration and addition of diisopropyl ether, a suspension is obtained which is filtered. The powder obtained is dried at 50 ° C. under reduced pressure.
• 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 1 hour, making sure that the temperature does not exceed -70 ° C.
• the mixture is stirred at -78 ° C for 1 hour and then a solution of 15.9 g (80 mmol) of ⁇ , 4-dimethoxy- ⁇ -methylbenzamide in 20 mL of THF is added dropwise.
• the reaction medium is stirred at -78 ° C. for 1 hour and then at room temperature for 18 hours.
• the dichloromethane phase is washed with salt water, dried over anhydrous sodium sulphate, filtered and evaporated.
• the product is crystallized in isopropyl ether; after filtration and drying, 14.6 g of white crystals are obtained.
• Mp 170 ° C (M)
• reaction medium is cooled to ambient temperature and then poured slowly into
• a suspension of 830 mg (2.96 mmol) of 1-chloro-7-methoxy-4- (4-methoxyphenyl) phthalazine in 5 ml of 1-butanol is added with 700 mg (2.75 mmol) of ⁇ -methyl- ⁇ - [1- (2-naphthylmethyl) piperidin-4-yl] -amine and 147 mg (2.8 mmol) of ammonium chloride.
• the mixture is heated under reflux (oil bath at 140 ° C.) for 27 hours.
• the reaction mixture is hydrolyzed and then basified with a 1N sodium hydroxide solution and then extracted with dichloromethane.
• the combined organic phases are washed with salt water, dried over anhydrous sodium sulphate and then evaporated under reduced pressure.
• the residue obtained is purified by chromatography on a column of silica gel (eluent: dichloromethane / methanol from 100/0 to 90/10 (Wv)).
• the dihydrochloride is obtained after treatment of the product dissolved in ethanol with a solution of hydrochloric acid in diethyl ether. After concentration and addition of ethyl acetate, a suspension is obtained which is filtered.
• the powder obtained is dried at 40 ° C. under reduced pressure in the presence of diphosphorus pentoxide.
• the manipulation is carried out under an inert atmosphere (nitrogen).
• an inert atmosphere nitrogen
• 500 ml are introduced 1 g of 10% palladium on carbon and 100 ml of water.
• the reaction mixture is stirred at reflux for 2 hours. After return to temperature Ethanol is evaporated under reduced pressure.
• the mixture is then basified to pH 12 with 2N sodium hydroxide and then extracted with dichloromethane.
• This compound in the base form is obtained according to the procedure described in 3.3. by reaction of 7-methoxy-4- (4-methoxyphenyl) -N- (piperidin-4-yl) phthalazin-1-amine with 4- (2-piperidin-1-ylethoxy) benzaldehyde.
• This compound is synthesized according to the method described in 2.4. by reacting 2-bromo-5-methoxybenzoic acid previously treated with n-butyl lithium with N-methoxy-N-methyl-propionamide. It is used raw in the next reaction.
• This compound in the base form is obtained according to the procedure described in 1.9. by reaction of 1-chloro-4-ethyl-7-methoxy-phthalazine with 1- (1,3-benzodioxol-5-ylmethyl) -N-methylpiperidin-4-amine.
• the dihydrochloride is obtained after treatment of the product dissolved in dichloromethane with a solution of hydrochloric acid in diethyl ether. After concentration and addition of diisopropyl ether, a suspension is obtained which is filtered. The powder obtained is dried at 40 ° C. under reduced pressure in the presence of diphosphorus pentoxide.
• This compound is synthesized according to the method described in 2.4. by reacting 2-bromo-5-methoxybenzoic acid previously treated with n-butyllithium with 2, N-dimethoxy- ⁇ -methyl-acetamide. It is used raw in the next reaction.
• This compound is obtained according to the procedure described in 2.5. by reaction of unpurified 5-methoxy-2- (methoxyacetyl) benzoic acid with hydrazine hydrate.
• This compound in the base form is obtained according to the procedure described in 1.9. by reaction of 1-chloro-7-methoxy-4-methoxymethyl phthalazine with 1- (1,3-benzodioxol-5-ylmethyl) -4-methylamino-piperidine.
• the dihydrochloride salt is obtained by treatment of the product dissolved in dichloromethane with a solution of 2M hydrochloric acid in diethyl ether. After concentration and addition of ethyl ether, a suspension is obtained which is filtered. The powder obtained is dried at 40 ° C. under reduced pressure in the presence of diphosphorus pentoxide.
• Ge compound is obtained according to the procedure described in 4.2. by reaction of N, N-dimethyl-3-chloropropylamine with 3-fluoro-4-hydroxybenzaldehyde.
• This compound in the base form is obtained according to the procedure described in 3.3. by reaction of 7-methoxy-4- (4-methoxyphenyl) - ⁇ - (piperidin-4-yl) phthalazin-1-amine with 4- (2-pyrrolidin-1-ylethoxy) -benzaldehyde.
• This compound in the base form is obtained according to the procedure described in 3.3. by reaction of 7-methoxy-4- (4-methoxyphenyl) - ⁇ - (piperidin-4-yl) phthalazin-1-amine with the
• This compound is obtained according to the procedure described in 5.1. by reaction of ⁇ - (3-chloropropyl) piperidine hydrochloride with 4-hydroxybenzaldehyde.
• This compound in the base form is obtained according to the procedure described in 3.3. by reaction of 7-methoxy-4- (4-methoxyphenyl) -N- (piperidin-4-yl) phthalazin-1-amine with 4- (2-piperidin-1-ylpropoxy) -benzaldehyde.
• the organic extract is washed with salt water, dried over anhydrous sodium sulphate and then evaporated under reduced pressure.
• the residue obtained is purified on a column of neutral alumina (eluent: 100/0 to 98/2 (v / v) dichloromethane / methanol) and then on silica gel column (solvent: dichloromethane / methanol 100/0 to 85/15 (v / v)).
• the residue obtained is purified on a column of neutral alumina (eluent: dichloromethane / methanol 100/0 to 95/5 (Wv)) and then on a column of basic alumina under the same conditions. 130 mg of yellow gummy product is obtained.
• This compound in the base form is obtained according to the procedure described in 3.3. by reaction of 7-methoxy-4- (4-methoxyphenyl) -N- (piperidin-4-yl) phthalazin-1-amine with 4 - [(1-methylazepan-3-yl) oxy] benzaldehyde.
• This compound in the base form is obtained according to the procedure described in 3.3. by reaction of 7-methoxy-4- (4-methoxyphenyl) -N- (piperidin-4-yl) phthalazin-1-amine with 4 - [(1-methylpiperidin-2-yl) methoxy] benzaldehyde.
• This compound in the base form is obtained according to the procedure described in 3.3. by reaction of 7-methoxy-4- (4-methoxyphenyl) -N- (piperidin-4-yl) phthalazin-1-amine with 4 - [(1-methylpiperidin-4-yl) oxy] benzaldehyde.
• the trihydrochloride is obtained by treatment of the product dissolved in ethanol with a 2M solution of hydrochloric acid in diethyl ether. After concentration and addition of ethyl ether, a suspension is obtained which is filtered. The powder obtained is dried at 40 ° C. under reduced pressure in the presence of diphosphorus pentoxide.
• This compound in the base form is obtained according to the procedure described in 3.3. by reaction of 7-methoxy-4- (4-methoxyphenyl) - ⁇ - (piperidin-4-yl) phthalazin-1-amine with 4- (1-Aza-bicyclo [2,2,2] octahydrophosphoric acid 3yloxy) benzaldehyde.
• the hydrochloride is obtained by the treatment described in 7.4.
• This compound is obtained according to the procedure described in 2.4. by reaction of 2-bromo-5-methoxybenzoic acid pretreated with n-butyllithium with N-methoxy-N-methyltetrahydro-2H-pyran-4-carboxamide. It is used raw in the next reaction.
• This compound is obtained according to the procedure described in 2.6. by reaction of 7-methoxy-4- (tetrahydro-2H-pyran-4-yl) phthalazin-1 (2H) -one with phosphoryl chloride.
• This compound in the base form is obtained according to the procedure described in 3.3. by reaction of 7-methoxy-4- (4-methoxyphenyl) -N- (piperidin-4-yl) phthalazin-1-amine with 4- (3-methoxypropoxy) benzaldehyde.
• the dihydrochloride salt is obtained by the treatment described in 4.3.
• This compound is obtained according to the procedure described in 3.1. by reaction of 1-chloro-7-methoxy-4-methoxymethyl phthalazine (synthesis described in 7.3) with 4-amino-1-benzylpiperidine.
• This compound in the base form is obtained according to the procedure described in 8.2. by reaction of 7-methoxy-4-methoxymethyl- ⁇ - (piperidin-4-yl) -phthalazin-1-amine with 4- (3-dimethylaminopropoxy) -3-fluoro-benzaldehyde prepared in 8.1.
• the trihydrochloride is obtained by the treatment described in 7.4.
• This compound is obtained according to the procedure described in 4.2. by reaction of ⁇ - (3-chloropropyl) pyrrolidine with 3-fluoro-4-hydroxybenzaldehyde.
• This compound in the base form is obtained according to the procedure described in 3.3. by reaction of 7-methoxy-4- (4-methoxyphenyl) - ⁇ - (piperidin-4-yl) phthalazin-1-amine with the
• the trihydrochloride is obtained by the treatment described in 6.5.
• This compound is obtained according to the procedure described in 5.1. by reaction of 2-chloro- ⁇ , ⁇ -dimethyl-ethylamine hydrochloride with 4-hydroxybenzaldehyde.
• the two compounds are separated by chromatography on silica gel (eluent toluene / methanol 50/50 (v / v)).
• the first compound eluted is 4- [2- (1-methylpyrrolidin-2-yl) ethoxy] benzaldehyde:
• the second compound eluted is 4 - [(1-methylazepan-4-yl) oxy] benzaldehyde:
• the organic phase is extracted with 40 ml of N hydrochloric acid.
• the acidic aqueous phase obtained is basified with 2N sodium hydroxide and then extracted with dichloromethane.
• the organic extract is washed with water saturated with sodium chloride, dried over anhydrous sodium sulphate and then evaporated under reduced pressure.
• the residue is purified on a basic alumina column (eluent: dichloromethane / methanol 100/0 to 98/2 (v / v)).
• the trihydrochloride is obtained by the treatment described in 4.3.
• This compound in the base form is obtained according to the procedure described in 26.2. by reaction of 7-methoxy-4- (4-methoxyphenyl) -N- (piperidin-4-yl) phthalazin-1-amine with 4 - [(1-methylazepan-4-yl) oxy] benzaldehyde.
• the trihydrochloride is obtained by the treatment described in 4.3.
• the resin is washed with methanol and then suspended in 4 mL of methanol and 3.5 mL of 7N ammonia methanol. The mixture is stirred for at least 4 hours and then filtered. The filtrate is evaporated under reduced pressure. The product obtained is sufficiently pure.
• the dihydrochloride is obtained by the treatment described in 6.5.
• a mixture consisting of 1 g (5.4 mmol) of 4-bromobenzaldehyde, 1 g (6.5 mmol) of A- (i-pyrrolidinyl) piperidine in 10 mL of anhydrous toluene is stirred at room temperature under an argon atmosphere and 2.46 (7.56 mmol) cesium carbonate, 50 mg tris (dibenzylideneacetone) dipalladium (0) and 50 mg 2,2'-bis (diphenylphosphino) -1,1'-binaphthyl (racemic).
• the mixture is stirred at 80 ° C. for 40 hours, then, after cooling, is filtered on celite.
• This compound in the base form is obtained according to the procedure described in 26.2. by reaction of 4-ethyl-7-methoxy-N- (piperidin-4-yl) -phthalazin-1-amine with 4- (4-pyrrolidin-1-ylpiperidin-1-yl) benzaldehyde.
• the trihydrochloride is obtained by treatment of the product dissolved in ethyl acetate with a solution of 2N hydrochloric acid in diethyl ether. A suspension is formed which is filtered. The powder obtained is dried at 40 ° C. under reduced pressure.
• This compound in the base form is obtained according to the procedure described in 8.2. by reaction of 7-methoxy-4-methoxymethyl- ⁇ - (piperidin-4-yl) -phthalazin-1-amine (prepared in 22.2.) with 4- (3-dimethylaminopropoxy) -benzaldehyde.
• the trihydrochloride is obtained by the treatment described in 7.4.
• This compound is obtained according to the procedure described in 31.1 by reaction of 4-bromobenzaldehyde with (3R) -3- (dimethylamino) pyrrolidine.
• This compound in the base form is obtained according to the procedure described in 26.2 by reaction of 7-methoxy-4-methoxymethyl- (V- (piperidin-4-yl) -phthalazin-1-amine (preparation in 22.2) with the 4 - [(3f?) - 3- (dimethylamino) pyrrolidin-1-yl] benzaldehyde.
• the trihydrochloride is obtained by the treatment described in 6.5 ..
• This compound in the base form is obtained according to the procedure described in 26.2 by reaction of 7-methoxy-4-methoxymethyl- ⁇ - (piperidin-4-yl) -phthalazin-1-amine (preparation in 22.2) with the 4 - [(3S) -3- (dimethylamino) pyrrolidin-1-yl] benzaldehyde.
• the trihydrochloride is obtained by the treatment described in 6.5 ..
• This compound is synthesized according to the method described in 2.4. by reacting 2-bromo-5-methoxybenzoic acid previously treated with n-butyl lithium with N-methoxy- ⁇ -methyl-4- (2-methyl-2H-tetrazol-5-yl) benzamide . It is used raw in the next reaction.
• This compound in the base form is obtained according to the procedure described in 1.9. by reaction of 4-chloro-6-methoxy-1- [4- (2-methyl-2H-tetrazol-5-yl) phenyl] phthalazine with 1 - (1,3-benzodioxol-5-ylmethyl) ) piperidin-4-yl-amine.
• the dihydrochloride is obtained by the treatment described in 4.3.
• This compound in the base form is obtained according to the procedure described in 26.2 by reaction of 7-methoxy-4-methoxymethyl- ⁇ - (piperidin-4-yl) -phthalazin-1-amine (preparation in 22.2) with the 4 - [(1-methylpyrrolidin-3-yl) methoxy] benzaldehyde.
• This compound in the base form is obtained according to the procedure described in 26.2 by reaction of 7-methoxy-4-methoxymethyl- ⁇ - (piperidin-4-yl) -phthalazin-1-amine (preparation in 22.2) with the 4 - [(8-methyl-8-azabicyclo [3.2.1] oct-3-yl) oxy] benzaldehyde (beta-anomer).
• the trihydrochloride is obtained by the treatment described in 4.3.
• This compound in the base form is obtained according to the procedure described in 26.2 by reaction of 7-methoxy-4-methoxymethyl- ⁇ - (piperidin-4-yl) -phthalazin-1-amine (preparation in 22.2) with the ⁇ / -methyl-N- (2-hydroxyethyl) -4-aminobenzaldehyde.
• the trihydrochloride is obtained by the treatment described in 4.3.
• EDCl dimethylaminopropyl
• DMAP dimethylaminopyridine
• This compound in the base form is obtained according to the procedure described in 26.2 by reaction of 7-methoxy-4-methoxymethyl- ⁇ - (piperidin-4-yl) -phthalazin-1-amine (preparation in 22.2) with the 4- (2-Oxo-2-pyrrolidin-1-yl-ethoxy) benzaldehyde.
• the dihydrochloride salt is obtained by the treatment described in 4.3.
• This compound in the base form is obtained according to the procedure described in 30.2 by reaction of 7-methoxy-4-methoxymethyl- ⁇ - (piperidin-4-yl) -phthalazin-1-amine (preparation in 22.2) with the 4- [3- (tetrahydro-2H-pyran-2-yloxy) propoxy] benzaldehyde (preparation in 30.1)
• the dihydrochloride salt is obtained by the treatment described in 4.3.
• This compound in the base form is obtained according to the procedure described in 26.2 by reaction of 7-methoxy-4-methoxymethyl- ⁇ - (piperidin-4-yl) -phthalazin-1-amine (preparation in 22.2) with the 4 - [(1-Methylazepan-4-yl) oxy] benzaldehyde (Preparation see 26.1.) -
• the trihydrochloride is obtained by the treatment described in 4.3.
• This compound in the base form is obtained according to the procedure described in 26.2 by reaction of 7-methoxy-4-methoxymethyl- ⁇ - (piperidin-4-yl) -phthalazin-1-amine (preparation in 22.2) with the 4- [2- (1-methylpiperidin-2-yl) ethoxy] benzaldehyde
• the trihydrochloride is obtained by the treatment described in 4.3.
• This compound is synthesized according to the method described in 2.4. by reacting 2-bromo-5-methoxybenzoic acid previously treated with n-butyllithium with N-methoxy-N-methylacetamide. It is used raw in the next reaction.
• the dihydrochloride salt is obtained by the treatment described in 4.3.
• This compound is synthesized according to the method described in 2.4. by reacting 2-bromo-5-chlorobenzoic acid previously treated with n-butyllithium with N-methoxy-N-methylacetamide. It is used raw in the next reaction.
• a suspension of 2.7 g (12.6 mmol) of 1,7-dichloro-4-methyl-phthalazine in 18 ml of n-butanol is admixed with 2.62 g (15.2 mmol) of 4-amino-piperidin-1-yl-carboxylate. ethyl and 0.68 g (12.7 mmol) of ammonium chloride.
• the mixture is heated at 140 ° C. for 8 hours.
• the reaction medium is cooled to ambient temperature, saturated aqueous sodium hydrogencarbonate solution is added and the mixture is extracted with ethyl acetate.
• the organic phase is washed with salt water, dried over anhydrous sodium sulphate and then evaporated under reduced pressure.
• This compound in the base form is obtained according to the procedure described in 26.2 by reaction of 7-chloro-4-methyl- ⁇ - (piperidin-4-yl) -phthalazin-1-amine with 4 - [(1 - methylazepan-4-yl) oxy] benzaldehyde (preparation in 26.1)
• the trihydrochloride is obtained by the treatment described in 4.3.
• This compound in the base form is obtained according to the procedure described in 30.2 by reaction of 7-chloro-4-methyl- ⁇ - (piperidin-4-yl) -phthalazin-1-amine (preparation in 47.4) with the 4- [3- (tetrahydro-2H-pyran-2-yloxy) propoxy] benzaldehyde (synthesis see 30.1.)
• the dihydrochloride salt is obtained by the treatment described in 4.3.
• This compound is obtained according to the procedure described in 8.2. by reaction of 7-methoxy-4-methoxymethyl- ⁇ - (piperidin-4-yl) -phthalazin-1-amine (preparation in 22.2) with 4- (3-hydroxyprop-1-yn-1-yl) benzaldehyde. It was purified on a silica column (eluent: dichloromethane / methanol from 100/0 to 90/10 (v / v)) and is concretized in isopropyl ether.
• This compound is obtained according to the procedure described in 8.2. by reaction of 7-methoxy-4-methoxymethyl- ⁇ - (piperidin-4-yl) -phthalazin-1-amine (preparation in 22.2) with 4- (3-Hydroxy-3-methylbut-1-yn) 1-yl) benzaldehyde. It was purified on a silica column (eluent: 100/0 to 90/10 (v / v) dichloromethane / methanol) and is concretized in isopropyl ether.
• This compound is obtained according to the procedure described in 26.2. by reaction of 7-methoxy-4-methoxymethyl- ⁇ - (piperidin-4-yl) -phthalazin-1-amine (preparation in 22.2) with 4- (4-pyrrolidin-1-ylbutyl) benzaldehyde.
• Trioxalate is obtained by treatment of the product dissolved in acetone with 3 equivalents of oxalic acid. A precipitate is formed which is filtered. The powder obtained is dried at 40 ° C. under reduced pressure in the presence of diphosphorus pentoxide.

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