EP1786809A2 - Aminopiperidine derivatives, preparation thereof and use thereof as melanocortin receptor agonists - Google Patents

Aminopiperidine derivatives, preparation thereof and use thereof as melanocortin receptor agonists

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Publication number
EP1786809A2
EP1786809A2 EP05790800A EP05790800A EP1786809A2 EP 1786809 A2 EP1786809 A2 EP 1786809A2 EP 05790800 A EP05790800 A EP 05790800A EP 05790800 A EP05790800 A EP 05790800A EP 1786809 A2 EP1786809 A2 EP 1786809A2
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EP
European Patent Office
Prior art keywords
cyclohexyl
piperidin
chloro
phenylalanyl
amino
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP05790800A
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German (de)
French (fr)
Inventor
Alain Braun
Bruno Cornet
Gilles Courtemanche
Olivier Crespin
Eykmar Fett
Cécile PASCAL
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Sanofi SA
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Sanofi Aventis France
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Publication of EP1786809A2 publication Critical patent/EP1786809A2/en
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/56—Nitrogen atoms
    • C07D211/58—Nitrogen atoms attached in position 4
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • A61P3/04—Anorexiants; Antiobesity agents
    • 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
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • 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
    • 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
    • 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
    • C07D401/14—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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
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    • 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
    • C07D405/02—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 two hetero rings
    • C07D405/12—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 two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
    • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
    • C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
    • C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems

Definitions

  • the present invention relates to melanocortin receptor agonist compounds, their preparation and their therapeutic application.
  • MC-Rs Melanocortin receptors
  • MC-Rs belong to the G-protein coupled receptor super-family with seven transmembrane domains. Their transduction pathway involves the production of cAMP (Cone, R. D., Recent Prog Horm Res., 1996, 51, 287).
  • Five subtypes of MC-Rs are currently described, MC1-R, MC2-R, MC3-R, MC4-R and MC5-R, and are expressed in different tissues such as the brain (MC3, 4, 5-R) , the exocrine glands (MC5-R), the adrenal glands (MC2-R) and the skin (MC1-R) for the main ones.
  • the natural ligands of the MC-Rs are, for the agonists, ACTH, a, ⁇ and ⁇ -MSH, and for the agonists, the agouti protein and Pagouti-related protein. None of the natural ligands is highly selective for any of the subtypes, except for ⁇ -MSH, which has some selectivity for MC3-R.
  • the melanocortin system is involved in many physiological processes, including pigmentation, inflammation, eating and sexual behavior (including erectile function), energy balance (body weight regulation and lipid storage), exocrine function, protection and neuronal regeneration, immunomodulation, analgesia, etc.
  • MC4-R has been shown to be involved in sexual behavior (Van der Ploeg, LH, Proc Natl Acad ScL USA, 2002, 99, 11381, Martin, WJ, Eur J. Pharmacol. 2002, 454, 71). It has also been demonstrated, through mouse models specifically lacking in some MC-Rs (knockout mice), that central MC-Rs (MC3 and 4-R) were involved in eating behavior, obesity, metabolism and energy balance (Huszar, D., IECI, 1997, 88 (1), '131; Chen AS, Nat Genet, 2000, 26 (1), 97;. Butler, AA, Trends Genet 2001 17, S50-S54). Thus, MC4-R knockout mice are hyperphagic and obese. At the same time, MC3 and / or 4R antagonists favor food intake, whereas stimulation of MC4-R by an endogenous agonist, such as ⁇ -MSH, produces a satiety signal.
  • an endogenous agonist such as ⁇ -MS
  • R a and R 3 - identical to or different from each other, represent a hydrogen atom or an alkyl or cycloalkyl group
  • R 1 represents a hydrogen atom or an alkyl, cycloalkyl, heterocycloalkyl or aryl group
  • R 2 represents a group of formula - (CH 2 ) x - (CO) y -Y or - (CO) y - (CH 2 ) x -Y, in which:
  • X O, 1, 2, 3 or 4,
  • R 1 and R 12 which are identical to or different from each other, represent a hydrogen atom or an alkyl, cycloalkyl, alkoxy or -NR 1 R 14 group , or R 1 and R 12 together form, with nitrogen atom to which they are attached, a mono- or bicyclic structure comprising from 4 to 10 members and optionally comprising 1 to 3 additional heteroatoms and / or 1 to 3 ethylenic or acetylenic unsaturations, this ring being optionally substituted in any positions by 1 to 3 groups selected from halogen atoms and hydroxyl, alkyl, cycloalkyl and alkoxy groups.
  • pyrrolidinyl, morpholinyl, pyrrolinyl and isoindolinyl groups etc.
  • R- 1 3 and Ru identical or different from each other, represent an atom of hydrogen or an alkyl, cycloalkyl or alkoxy group, or else R 13 and Ri 4 together with the nitrogen atom to which they are attached form a mono- or bicyclic structure as defined above,
  • R 3 represents 1 to 3 groups, identical or different from each other, located in any positions of the nucleus to which they are attached and selected from halogen atoms and alkyl, cycloalkyl groups, -OR, -NRR ', - CO-NRR ', -NR-CO-R', -NR-CO-NRR ', -NR-COOR', -NO 2 , -CN and -COOR, where R and R 'are as defined below,
  • R 5 represents a hydrogen atom or an alkyl group
  • R 4 is selected from the groups of formulas (a), (b) and (c), optionally substituted by an oxo group or mono or polysubstituted by an aryl or heteroaryl group below, (each of these cyclic structures (a) (b), (c) being directly bonded to the nitrogen atom of the formula (I) which carries it):
  • a cycloalkyl or heterocycloalkyl group fused with an aryl or heteroaryl group, a cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, alkylheteroaryl, -CO-alkyl, -CO-cycloalkyl, -CO-heterocycloalkyl, -CO-aryl group, -CO-heteroaryl, -CO-alkylaryl, -CO-alkylheteraryl, -CS-alkyl, -CS-cycloalkyl, -CS-heterocycloalkyl, -CS-aryl, -CS-heteroaryl, -CS-alkylaryl, -CS-alkylheteroaryl, -CS-NR 8 R 9, -C ( NH) -NR 8 R 9> -aIkyle -SO 2, -S0 2 -cycloalkyl,
  • R 8 and R 8 are chosen independently of one another from a hydrogen atom and the alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, alkylheteroaryl, -CO-alkyl, -CO-cycloalkyl, -CO- groups; heterocycloalkyls, -CO-aryls, -CO-heteroaryls, -CO-alkylaryls, -CO-alkylheteroaryls, -SO 2 -alkyls,
  • R and R 'independently of one another represent a hydrogen atom or an alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl or alkylheteroaryl group, or may together form a cycloalkyl or a heterocycloalkyl.
  • R 6 is chosen from:
  • alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, alkylheteroaryl, -CO-alkyl, -CO-cycloalkyl, -CO-heterocycloalkyl, -CO-aryl, -CO-heteroaryl, -CO-alkylaryl or -CO-alkylheteroaryl , -CS-alkyl, -CS-cycloalkyl, -CS-heterocycloalkyl, -CS-aryl, -CS-heteroaryl, -CS-alkylaryl, -CS-alkylheteroaryl, -CS-NR 8 R 9 , -C ( NH) -NR 8 R 9 ,
  • the alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl groups being optionally substituted with one or more groups chosen from the groups R, R ', -OR, -NRR', -CO-NRR ', -NR-CO-R 1 , -NR-CO-NRR ', -NO 2 , -CN and -COOR, OCOR, COR, OCONRR', NRCOOR '; the cycloalkyl or heterocycloalkyl groups being optionally fused with an aryl or heteroaryl group,
  • R 7 is selected from hydrogen and halogen and alkyl, cycloalkyl, aryl, heteroaryl, alkylaryl, alkylheteroaryl, -OR, -O-aryl, -O-heteroaryl, -O-alkylaryl, -O- alkylheteroaryls, -NRR ', -CO-NRR', -NR-CO-R ', -NR-CO-NRR'; -NR-COOR ', -NO 2 , -CN and -COOR,
  • R and R 'independently of one another represent a hydrogen atom or an alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl or alkylheteroaryl group, or may together form a cycloalkyl or a heterocycloalkyl.
  • Re and R 7 do not represent at the same time a hydrogen atom.
  • R 4 is chosen from the groups of formulas (a), (b) and (c), optionally mono or polysubstituted by an aryl group, or more preferably heteroaryl wherein X represents a - C (R 6 ) (R 7 ) - linkage, wherein R 6 is selected from:
  • a cycloalkyl or heterocycloalkyl group located in a spiro position on the ring of formula (a) to which it is attached,
  • R 7 is selected from hydrogen and halogen and alkyl, cycloalkyl, aryl, heteroaryl, alkylaryl, alkylheteroaryl, -OR, -O-aryl, -O-heteroaryl, -O-alkylaryl, -O- alkylheteroaryls, -NRR ', -CO-NRR', -NR-CO-R ', -NR-CO-NRR', -NR-COOR ', -NO 2 , -CN and -COOR,
  • R 8 and R 9 are chosen independently of one another from a hydrogen atom and alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, alkylheteroaryl, -CO-alkyl, -CO-cycloalkyl, -CO groups; heterocycloalkyls, -CO-aryls, -CO-heteroaryls, -CO-alkylaryls, -CO-alkylheteroaryls, -SO 2 -alkyls,
  • R and R ' represent, independently of one another, a hydrogen atom or an alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl or alkylheteroaryl group,
  • R 4 is chosen from the groups of formulas (a), (b) and (c) in which X represents a -C (R 6 ) (R 7 ) -, in which R 6 is chosen from a halogen atom or a cycloalkyl or heterocycloalkyl group fused or not located in a spiro position on the ring of formula (a) to which it is attached
  • R 4 is chosen from the groups of formulas (a), (b) and (c) in which X represents a -C (R 6 ) (R 7 ) -, wherein R 6 is selected from -CS-alkyl, -CS : cycloalkyl, -CS-heterocycloalkyl, -CS-aryl, -CS-heteroaryl, -CS-alkylaryl, -CS-alky
  • R 4 is chosen from the groups of formulas (a), (b) and (c) in which X represents a -C (R 6 ) (R 7 ) -, wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl groups are optionally substituted with 1 or more groups selected from R, R ', OCOR 1 COR, OCONRR 1 , NRCOOR'.
  • R 4 is chosen from the groups of formulas (a), (b) and (c) in which X represents a -C (R 6 ) (R 7 ) -, wherein the cycloalkyl or heterocycloalkyl groups are optionally fused with an aryl or heteroaryl group.
  • R 4 is chosen from the groups of formulas (a), (b) and (c) in which X represents a -C (R 6 ) (R 7 ) -, wherein R 8 and R 9 independently selected from each other represent alkyl and aryl groups being optionally substituted with one or more groups selected from R, R ', OCOR, COR, OCONRR 1 or NRCOOR '.
  • R 4 is chosen from the groups of formulas (a), (b) and (c) in which X represents a -C (R 6 ) (R 7 ) -, wherein R and R 'may together form cycloalkyl or heterocycloalkyl.
  • R 7 is hydrogen
  • R 4 is chosen from among the groups of formulas (a), (b) and (c), optionally mono- or polysubstituted with an aryl or heteroaryl group, where X represents a -N (Ri 0 ) - in which
  • a cycloalkyl or heterocycloalkyl group fused with an aryl or heteroaryl group, a cycloalkyl, heterocycloalkyl, aryl, heteroaryl group, alkylaryl, alkylheteroaryl, -CO-cycloalkyl, -CO-heterocycloalkyl, -CO-heteroaryl, -CO-alkylaryl, -CO-alkylheteroaryl, -CS-alkyl, -CS-cycloalkyl, -CS-heterocycloalkyl, -CS-aryl , -CS-heteroaryl, -C-alkylaryl, -CS-alkylheteroaryl, -CS-NR 8 R 9 , -C ( NH) -NR 8 R 9 , -SO 2 -cycloalkyl, -SO 2 -heterocycloalkyl, -S0 2
  • R 8 and R 9 are chosen independently of one another from a hydrogen atom and alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, alkylheteroaryl, -CO-alkyl, -CO-cycloalkyl, -CO groups; heterocycloalkyls, -CO-aryls, -CO-heteroaryls, -CO-alkylaryls, -CO-alkylheteroaryls, -SO 2 -alkyls,
  • R and R ' represent, independently of one another, a hydrogen atom or an alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl or alkylheteroaryl group,
  • R 4 is selected from the group of formulas (a), (b) and (c) optionally substituted with an oxo group where X is -N (R 10 ).
  • R 4 is chosen from the groups of formulas (a), (b) and (c) where X represents a -N (Ri 0 ) - in which R 8 and R 9 together form cycloalkyl or heterocycloalkyl.
  • R 4 is chosen from the groups of formulas (a), (b) and (c) where X represents a -N (R 10 ) - group in which R 10 is, - (CH 2 ) ⁇ are furthermore preferred.
  • R 4 is selected from the groups of formulas (a), (b) and (c) where X is -N (R 10 ) - in which the alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl groups are optionally substituted with 1 or more groups selected from R, R ', OCOR, COR, OCONRR' or NRCOOR '.
  • R 4 is selected from the groups of formulas (a), (b) and (c) wherein X represents a -N (R 10 ) - linkage in which the cycloalkyl or heterocycloalkyl groups are optionally fused with a aryl or heteroaryl group.
  • the compounds of formula (I) comprise at least one asymmetric carbon atom. 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) according to the invention may also exist in the form of mixtures of conformers, which are also part of the invention. They can additionally exist in the form of cis or trans isomers, or in the form of endo or exo isomers. These isomers and their mixture 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 (1) also form part of the invention.
  • the compounds of formula (I) may also exist in the form of hydrates or solvates, namely in the form of associations or combinations with one or more water molecules or with a solvent. Such hydrates and solvates are also part of the invention.
  • halogen atom a fluorine, a chlorine, a bromine or an iodine
  • alkyl group a saturated or unsaturated aliphatic group (that is to say comprising between 1 and 3 ethylenic or acetylenic type unsaturations), comprising from 1 to 6 carbon atoms, linear, cyclic or branched.
  • alkyl group a saturated or unsaturated aliphatic group (that is to say comprising between 1 and 3 ethylenic or acetylenic type unsaturations), comprising from 1 to 6 carbon atoms, linear, cyclic or branched.
  • Such an alkyl group may be substituted with 1 or more groups (for example with 1 to 6 groups) chosen from halogen atoms (resulting for example from a group - CF 3 ) and the groups R, R ', -OR, -NRR ', -CO-NRR', -NR-CO-R ', -NR-CO-NRR', -NO 2 , -CN and -COOR, OCOR, COR, OCONRR ', NRCOOR'; where R and R 'independently of one another represent a hydrogen atom or an alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl or alkylheteroaryl group, or may together form a cycloalkyl or a heterocycloalkyl;
  • a cycloalkyl group a cyclic alkyl group comprising between 3 and 8 carbon atoms, all the carbon atoms being involved in the cyclic structure. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc. Such a cycloalkyl group may be substituted with R, R 'and as described above for the alkyl group;
  • a heterocycloalkyl group a cycloalkyl group as defined above, further comprising between 1 and 4 heteroatoms, such as nitrogen, oxygen and / or sulfur.
  • a heterocycloalkyl group may be substituted as described above for the cycloalkyl group and may include one or more, for example 1 or 2, ethylenic or acetylenic unsaturations.
  • heterocycloalkyl groups mention may be made of the piperidinyl and tetrahydropyran groups;
  • alkoxy group an -O-alkyl radical, where the alkyl group is as previously defined;
  • an aryl group a cyclic aromatic group comprising between 5 and 10 members, for example a phenyl group.
  • Such an aryl group may be substituted with 1 or more groups (for example with 1 to 6 groups) chosen from halogen atoms (resulting for example in a group -CF 3 ) the groups R, R ', -OR, - NRR ', -CO-NRR', -NR-CO-R ', -NR-CO-NRR', -NO 2 , -CN and -COOR, OCOR, COR, OCONRR ', NRCOOR'; where R and R 'independently of one another represent a hydrogen atom or an alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl or alkylheteroaryl group, or may together form a cycloalkyl or a heterocycloalkyl; an alkylaryl group: an alkyl group
  • a heteroaryl group a cyclic aromatic group comprising between 5 and 10 members and comprising between 1 and 6 heteroatoms, such as nitrogen, oxygen and / or sulfur.
  • heteroaryl group may be substituted as described above for the aryl group;
  • an alkylheteroaryl group an alkyl group as defined above, itself substituted by a heteroaryl group as defined above.
  • R a , R a , R 2 , R 3 , R 4 and R 5 are as defined above and R 1 represents a group alkyl, cycloalkyl or heterocycloalkyl.
  • R 1 represents a cycloalkyl group, such as a cyclohexyl or cycloheptyl group.
  • R a , R a >, R 1 , R 3 , R 4 and R 5 are as defined above and R 2 is selected from the following groups: -CO-R 15 , -CO-NR 16 R 17 , -CO-NR 15 -NR 16 R 7 , -CO-aryl, -CO-heteroaryl, -CO- (CH 2 ) ⁇ " NR 16 R 17 , - (CH 2 ) ⁇ -NR 16 R 17) - (CH 2 ) X -OH, - (CH 2 ) x -aryl, - (CH 2 ) x -heteroaryl, - (CH 2 ) ⁇ -CO-R 15 and - (CH 2 ) ⁇ -CO-NR 16 R 17 , wherein:
  • R 5 represents a hydrogen atom or an alkyl, cycloalkyl or alkoxy group
  • R 16 and R 17 which are identical to or different from each other, represent a hydrogen atom or an alkyl, cycloalkyl or alkoxy group, or R 6 and R 17 form together with the nitrogen atom to which they are attached, a mono- or bicyclic structure comprising from 4 to 10 members and optionally comprising 1 to 3 additional heteroatoms and / or 1 to 3 ethylenic or acetylenic unsaturations, this ring being optionally substituted in any position by 1 to 3 groups selected among the halogen atoms and the hydroxyl, alkyl, cycloalkyl and alkoxy groups.
  • R 2 is chosen from the following groups: -CO-R 15 , -CO-NR 1 R 17 , -CO-NR 15 -NR 16 R 17 , -CO- (CH 2) 2 ) x -NR 6 R 7 , - (CH 2 ) x -NR 16 R 7 , - (CH 2 ) X -OH, - (CH 2 ) x -aryl, - (CH 2 ) x -heteroaryl, - (CH 2 ) ⁇ -CO-R 15 and - (CH 2 ) X -CO-N R 16 R 17 , in which x, x ', Ri 5 , Ri 6 and Ri 7 are as defined above.
  • R 2 represents a group -CO-NR 1 R 6 7 , in which R 6 and R 17 represent alkyl or alkoxy groups.
  • R a , R a >, R 1 , R 2 , R 4 and R 5 are as defined above and R 3 represents 1 to 3 groups, identical or different from each other, chosen from halogen atoms.
  • R 3 represents a single group, preferably a chlorine atom.
  • R a , R a , R 1 , R 2 , R 3 and R 4 are as defined above and R 5 .
  • R 5 represents a hydrogen atom or an alkyl group comprising from 1 to 4 carbon atoms carbon.
  • R 5 preferably represents a hydrogen atom.
  • R 1 , R 2 , R 3, R 4 and R 5 are as defined above and R a and R a > represent hydrogen atoms or alkyl groups having 1 to 4 carbon atoms.
  • R 3 and R 3 independently of one another represent hydrogen atoms or methyl groups.
  • R 6 represents a hydrogen atom or a group -OR 8 , -NR 8 R 8 or -NR 8 -CO-R 8 , in which R 8 and R 8 represent a hydrogen atom or an alkyl group.
  • R 7 represents a hydrogen or halogen atom or an alkyl or hydroxyl group (corresponding to a group -OR, where R represents a hydrogen atom) or alkoxy (corresponding to a group -OR, where R represents an alkyl group).
  • R 7 advantageously represents a hydrogen atom.
  • R 8 and R 8 represent a hydrogen atom or an alkyl group.
  • R 10 represents a hydrogen atom or an alkyl or -CO-aryl group (such as -CO-phenyl), or else R 10 forms with nitrogen atom to which it is attached and a carbon atom located at any position of the cyclic structure which carries it (such as the structure of formula (a) or (a-3)), but not adjacent to said atom of nitrogen, a bridge comprising from 3 to 5 members.
  • R and R ' defined above, there may be mentioned those in which R and R' represent a hydrogen atom or a hydrogen atom. alkyl group.
  • the invention relates to the preferred compounds whose names follow: .
  • the figures in front of the product nomenclatures correspond to the example numbers of the compounds of the table
  • the invention relates to a medicinal product characterized in that it comprises a compound of formula (I) as described above or a salt of addition of this compound to a pharmaceutically acceptable acid, or a hydrate or a solvate of the compound of formula (I).
  • the invention relates to a pharmaceutical composition, characterized in that it comprises a compound of formula (I) as described above, or a pharmaceutically acceptable salt, a hydrate or a solvate of this compound, as well as at least one pharmaceutically acceptable excipient.
  • the invention relates to the use of a compound of formula (I) for the preparation of a medicament for the treatment and prevention of obesity, diabetes and sexual dysfunction which may affect both sexes in particular erectile dysfunction, the treatment of cardiovascular diseases as well as in anti-inflammatory applications or in the treatment of alcohol dependence.
  • the invention relates to a process for the preparation of a compound of formula (I) as described above characterized in that a reductive amination of a compound of formula (V) is carried out:
  • a protective group is understood to mean a group which makes it possible, on the one hand, to protect a reactive function such as a hydroxyl or an amine during a synthesis and, on the other hand, to regenerate the function reactive intact at the end of synthesis.
  • Examples of protective and methods of protecting and deprotecting groups are given in "Protective Groups in Organic Synthesis", W. Green et al., 1999, 3 rd Edition (John Wiley & Sons, Inc., New York).
  • leaving group (Lg) is meant, in what follows, a group that can be easily cleaved from a molecule by breaking a heterolytic bond, with the departure of an electronic pair. This group can thus be easily replaced by another group during a substitution reaction, for example.
  • Such leaving groups are, for example, halogens or an activated hydroxy group such as mesyl, tosyl, triflate, acetyl, etc. Examples of leaving groups as well as references for their preparation are given in "March's Advanced Organic Chemistry", J. March et al, 5 th Edition, 2001, -. EMInter Ed.
  • Boc group is meant a t-butoxycarbonyl group, Bn a benzyl group, CBz a benzyloxycarbonyl group, Fmoc a 9-fluorenylmethyl-carbamate group, and h the hours.
  • the invention relates to the compounds of formulas (VI) 1 (XVIII) and (XIX), in which R 1, R 2 , R 3, R 4 , R 5, R a and R a are as defined above. high in the text and Pg represents a protecting group:
  • the compounds of general formula (I) can be prepared according to the process shown in Scheme 1.
  • the compounds of formula (IV) may be prepared by coupling between the intermediates of formula (II) and an amino acid of formula (III), the amino function of which is protected by a protective group Pg (for example a Boc group) , CBz or Fmoc), under conventional peptide coupling conditions, using for example as coupling agent dicyclocarbodiimide, the hydrochloride of the 1- (3-Dimethylaminopropyl) -3-ethylcarbodiimide or bromo-tris-pyrrolidino-phosphonium hexafluorophosphate, in the presence or absence of hydroxybenzo-triazole, and as base triethylamine or diisopropylethylamine in a solvent such as dioxane, dichloromethane or acetonitrile.
  • a protective group Pg for example a Boc group
  • amino acids of general formula (III) are commercially available or can be prepared by methods described in the literature (Williams, R. M., Synthesis of Optically Active ⁇ -Aminoacids, Pergamon Press, Oxford, 1989).
  • the compounds of formula (V) are obtained by deprotection of the amine function of the compounds of formula (IV), by methods chosen from those known to those skilled in the art. They include inter alia the use of trifluoroacetic acid or hydrochloric acid in dichloromethane, dioxane, tetrahydrofuran or diethyl ether in the case of protection by a Boc group, hydrogenation with the appropriate metal in methanol or ethanol in the case of a CBz, and piperidine for a Fmoc group, at temperatures ranging from -1O 0 C to 100 0 C.
  • the compounds of formula (I) are obtained by reductive amination, carried out by bringing the compounds of formula (V) in the presence of a ketone-type derivative R 4 , using a reducing agent such as borohydride sodium, sodium triacetoxyborohydride or sodium cyanoborohydride, in the presence or absence of a Bronsted acid (such as hydrochloric acid) or Lewis acid (such as titanium tetraisopropoxide) in a solvent such as dichloroethane, dichloromethane, acetic acid or methanol at temperatures between -10 ° C. and 30 ° C.
  • a Bronsted acid such as hydrochloric acid
  • Lewis acid such as titanium tetraisopropoxide
  • the R 4 ketone group derivatives may be commercial or obtained by methods known to those skilled in the art, for example by acylation of the amine or free hydroxyl function of the ketone derivative.
  • the compounds of general formula (I) may also be prepared according to the process shown in Scheme 2.
  • the compounds of formula (VIII) can be obtained by reductive amination, as described above, carried out from the amino acids of formula (VII).
  • R 5 represents an alkyl group
  • the amino acids of formula (VII) can be prepared by alkylation of the protected commercial amino acid on the amine function, according to the alkylation methods known to those skilled in the art.
  • the compounds of formula (IX) may be synthesized by saponification of the esters of formula (VIII), for example in the presence of sodium hydroxide or of lithium hydroxide in a solvent such as methanol, tetrahydrofuran or water, or a mixture of these solvents.
  • the compounds of general formula (VI) may be prepared by peptide coupling between the intermediates of formula (II) and the amino acid of formula (IX), under peptide coupling conditions as described in scheme 1.
  • the compounds of formula (II) may be prepared from the compound of formula (X) (where Pg is an amine protecting group, as defined in scheme 1), after deprotection of the amine function by methods selected from those known to those skilled in the art, as described above.
  • the compound of formula (X) is prepared according to the methods described in the literature or known to those skilled in the art, adapted according to the nature of the groups R 1 and R 2 .
  • Diagrams 5 to 9 below show examples of the preparation of compounds of formula (X) according to different types of group R 2 .
  • R 2 represents a group -CO-R 15 , where R 15 is as defined above
  • the preparation of the corresponding compound (Xa) can be carried out according to scheme 5.
  • the compounds of formula (XI) can be obtained by reductive anionization, under the conditions described above, of the piperidone whose amine function is protected (for example commercial Boc-piperidone).
  • the compounds of formula (Xa) are then obtained by reacting the compounds of formula (XI) with an acid chloride of formula R 15 COCI, in the presence of an organic base such as triethylamine or pyridine, in a solvent such as than dichloromethane or tetrahydrofuran.
  • Scheme 6 shows a route of preparation of the compounds of formula (Xb) and (Xc), which respectively correspond to the compounds of formula (X) in which R 2 represents a group -CO-NRi 6 Ri 7 and -CO-NR 15 -NR 16 Ri 7 , where Ri 5 , Ri 6 and Ri 7 are as defined above.
  • the compounds of formula (XII) may be prepared from the compounds of formula (XI) by reaction with phosgene, triphosgene or trichloromethyl chloroformate in dichloromethane or toluene in the presence of triethylamine or pyridine and an amine at temperatures ranging from -10 ° C. to 80 ° C.
  • the reaction of the compounds of formula (XII) with an amine of formula HN (R 16 ) (R 17 ) or a hydrazine of formula HN (Ri 5 ) (NR 16 R 17 ) results respectively in the compounds of formulas (Xb) and (Xc).
  • the compounds of formula (XIII) can be obtained by reductive amination carried out on the compounds of formula (Xl) in the presence of an aldehyde of formula Q-CO- (CH 2 ) ⁇ - 2 -CHO, where Q is -O-alkyl or -N (O-alkyl) (alkyl), using a reductant as described above in connection with Scheme 1.
  • the compounds of formula (Xd) can then be prepared by amination reducing agent prepared in the presence of an amine of formula R 17 R 16 NH, using a reducing agent as described above.
  • the compounds of formulas (Xe) in which R 2 represents a - (CH 2 ) x -heteroaryl group can be obtained by reductive amination from compounds of formula (Xl) i, carried out in the presence of an aldehyde of formula: heteroaryl- (CH 2 ) x-1 -CHO, using a reducing agent as described above in connection with scheme 1.
  • Scheme 9 details an alternative for the synthesis of compounds of formula (Xe) in which R 2 represents a - (CH 2 ) x -heteroaryl group, where x is 2 or 3.
  • the compounds of formula (XIII), in which Q represents a -O-alkyl group can be reduced to the corresponding alcohols by using a reducing agent such as lithium aluminum hydride in a solvent such as diethyl ether or tetrahydrofuran, at temperatures ranging from -60 ° C. to 20 ° C.
  • a reducing agent such as lithium aluminum hydride in a solvent such as diethyl ether or tetrahydrofuran
  • the hydroxyl group of the compounds of formula (XV) is then converted into a leaving group (Lg), such as chloride or mesylate, for example by the action of tetrabromomethane and triphenylphosphine in a solvent such as dichloromethane or by the action of sodium chloride.
  • a leaving group such as chloride or mesylate
  • methanesulfonyl in the presence of an organic base such as triethylamine at temperatures ranging from -20 ° C. to room temperature, to yield compounds of formula (XVI).
  • the compounds of formula (Xe) are then synthesized by a nucleophilic substitution reaction between the compounds of formula (XVI) and the anion of a heteroaryl ("Het" group).
  • the compounds of formula (XVIII) can be obtained by reductive amination between the compound of formula (XVII) and the compounds of formula (V) under conditions as described in Scheme 1.
  • R 8 is different from a hydrogen atom
  • functionalization of the compounds of formula (If) is carried out, for example alkylation in the presence of a base such as sodium hydride and a group R derivative. 8 having a leaving group Lg, which leads to the compounds of formula (Ig).
  • Example 1 ⁇ / - [1- (4-chloro- ⁇ / -piperidin-4-yl-D-phenylalanyI) piperidin-4-yl] - ⁇ / - cyclohexyI- ⁇ f, ⁇ / I -d ⁇ ethylurea (Compound No. 1)
  • the crude product is chromatographed on silica gel, eluting with a mixture of 98/2 / 0.2, 95/5 / 0.5 and then 9/1 / 0.1 and 5/5 0.5 g of dichloromethane, methanol and ammonia to give 11.2 g of ⁇ -cyclohexyl-diethyl-AA-piperidin-4-ylurea.
  • Example 2 [1- [1- [1-Azabicyclo [2.2.2] oct-3-yl-4-chloro-D-phenylalanyl) piperidin-4-yl] -N-cyclohexyl-hydrochloride / 1 > ⁇ T-diethylurea (Compound No. 5) 2.1: ⁇ - [1- ( ⁇ / -1-azabicyclo [2.2.2] oct-3-yl-4-chloro-D-phenylalanyl) piperidin-4-yl] - ⁇ -cyclohexyl- ⁇ . ⁇ / '- diethylurea
  • 0.18 g of ⁇ -cyclohexyl- ⁇ - ⁇ 2- [methoxy (methyl) amino] ethyl ⁇ piperidin-4-amine, obtained in step 3.5, are solubilized in 6.8 ml of dichloromethane in the presence of 0.26 g ⁇ / - [1- (tert-butoxycarbonyl) piperidin-4-yl] ⁇ 4-chloro-D-phenylalanine (obtained in step 3.7), 0.092 g of hydroxybenzotriazole, 0.13 g 1- (3-dimethylaminopropyl) -3-ethyl-carbodiimide hydrochloride and 0.12 ml of diisopropylethylamine.
  • the organic phase is washed with a saturated solution of sodium hydrogencarbonate, with water and then with a saturated aqueous solution of sodium chloride. After drying over MgSO 4 and concentration to dryness, 2 ml of isopropanol and 2.43 ml of 0.1 N hydrochloric acid in isopropanol are added. After concentrating to dryness, the mixture is taken up in diethyl ether and the solid is triturated. The crystals obtained are drained and rinsed with diethyl ether.
  • ⁇ -cyclohexyl-2-ethyl- ⁇ -piperidin-4-ylbutanamide are solubilized in 9 ml of dichloromethane in the presence of 0.36 g of 4-chloro- ⁇ - (1-Boc-piperidin).
  • 4-yl) -D-phenylalanine obtained in step 3.7
  • 0.128 g of hydroxybenzotriazole 0.182 g of 1- (3-dimethylaminopropyl) -3-ethyl-carbodiimide hydrochloride and 0.49 mL of diisopropylethylamine.
  • the mixture is stirred 16h at room temperature.
  • the mixture is extracted with ethyl acetate until the aqueous phase is exhausted.
  • the organic phase is washed with water and then with a saturated solution of sodium chloride.
  • the crude product is chromatographed on silica gel, eluting with a gradient of methanol in dichloromethane ranging from 0% to 5% to yield 0.23 g of 4-f-ferf-butyl.
  • reaction medium is stirred for 16 hours at room temperature. After evaporation to dryness, 1 N sodium hydroxide solution is added until pH 10 and the mixture is extracted with ethyl acetate until the aqueous phase is exhausted. The organic phase is washed with a saturated solution of sodium chloride. After drying over MgSO 4 and evaporation to dryness, the crude is chromatographed on silica gel * eluting with a gradient of methanol / ammonia in dichloromethane ranging from 0% to 5 / 0.5 / 95.
  • 0.46 g of ⁇ - [1- (4-chloro-D-phenylalanyl) piperidin-4-yl] -NH -cyclohexyl- ⁇ -diethylurea, obtained in step 1.5 above, are solubilized. in 10 ml of dichloromethane in the presence of 0.034 g of Boc-nortopinone and 0.42 g of sodium triacetoxyborohydride under N 2 . Stirring is maintained for 18h at room temperature. 0.10 g of Boc-nortropinone and 0.10 g of sodium triacetoxyborohydride are added. The agitation is maintained 24h. After hydrolysis, the mixture is extracted with dichloromethane until the aqueous phase is exhausted.
  • Example 8 ⁇ - ⁇ 1- [4-Chloro- ⁇ - (1-isobutylpiperidin-4-yl) -D-phenylalanyl] piperidin-4-yl ⁇ -N-cyclohexyl- ⁇ -diethylurea hydrochloride (compound 6)
  • Example 9 1 - [(2 R) -3- (4-Chlorophenyl) -1-methylene-2- (piperidin-4-ylamino) propyl] -NH-cyclohexyl-N - (4-methoxyphenyl) piperidine Hydrochloride -4-amine
  • 0.29 g of ⁇ -cyclohexyl- ⁇ - (4-methoxyphenyl) piperidin-4-amine obtained in step 9.3 are solubilized in 10 ml of dichloromethane in the presence of 0.38 g of ⁇ - [1- (tert-butoxycarbonyl) piperidin-4-yl] -4-chloro-D-phenylalanine obtained in step 3.7, 0.14 g of hydroxybenzotriazole, 0.19 g of 1- (3-dimethylaminopropyl) hydrochloride 3-ethylcarbodiimide and 0.17 ml of diisopropylethylamine. The mixture is stirred 16h at room temperature.
  • the crude product obtained is chromatographed eluting with a gradient of a mixture of methanol and ammonia in dichloromethane ranging from 95/5 / 0.5 to 9/1 / 0.1. 0.176 g of 1 - [(2R) -3- (4-chlorophenyl) -2- (piperidin-4-ylamino) propanoyl] -NH-cyclohexyl- ⁇ - (4-methoxyphenyl) piperidin-4-amine are obtained. .
  • Example 10 1 - [(2 R) -3- (4-Chlorophenyl) -2- (piperidin-4-ylamino) propanoyl] -N-cyclohexyl-N- [2- (1H-imidazol-1) hydrochloride yl) ethyl] piperidin-4-amine
  • tert-butyl 4- [cyclohexyl (2-ethoxy-2-oxoethyl) amino] piperidine-1-carboxylate 4.64 g of tert-butyl 4- (cyclohexylamino) piperidine-1-carboxylate, obtained at room temperature, are solubilized. step 1.1 in 164 mL of dichloromethane, and 9.77 mL of ethyl oxoacetate are added. 13.93 g of sodium triacetoxyborohydride are slowly added. Stirring is maintained for 18h at room temperature. 3.25 ml of glyoxilic acid ethyl ester and 3.48 g of sodium triacetoxyborohydride are added again.
  • tert-butyl 4- [cyclohexyl (2-hydroxyethyl) amino] piperidine-1-carboxylate 6.44 g of tert-butyl 4- [cyclohexyl (2-ethoxy-2-oxoethyl) amino] piperidine-1-carboxylate are placed in 175 ml of diethyl ether at 0 ° C. under N 2 . 29.71 mL of 1N lithium aluminum hydride in diethyl ether is slowly added. After stirring for 1 h at 0 ° C., saturated aqueous potassium sulphate solution is added until pH 5-6.
  • 0.05 g of ⁇ -cyclohexyl- ⁇ - [2- (1H-imidazol-1-yl) ethyl] piperidin-4-amine, obtained in step 10.5, are solubilized in 13 ml of dichloromethane in the presence of 0.51 g of N- [1- (tert-butoxycarbonyl) piperidin-4-yl] -4-chloro-D-phenylalanine obtained in step 3.7, 0.18 g of hydroxybenzotriazole, 0.25 g of 1- (3-dimethylaminopropyl) -3-ethyl-carbodiimide hydrochloride and 0.92 ml of diisopropylethylamine.
  • Example 11 ⁇ - ⁇ 1- [ ⁇ - ( ⁇ -4-aminocyclohexyl) -4-chloro-D-phenylalanyl] piperidin-4-yl ⁇ -N-cyclohexyl-2,2-dimethylhydrazinecarboxamide hydrochloride
  • 0.43 ml of diphosgene are placed in 18 ml of dichloromethane at 0 ° C. under N 2 .
  • a solution of 1.0 g of tert-butyl 4- (cyclohexylamino) piperidine-1-carboxylate and 2.47 mL of triethylamine is added dropwise. The solution is stirred for 2 hours at room temperature.
  • the reaction medium is again placed at 0 ° C. and 0.43 ml of diphosgene are again added. After stirring for 2h at room temperature, 5.39 mL of dimethylhydrazine is added. The mixture is stirred at ambient temperature for 18 hours. 30 ml of 0.5N hydrochloric acid are added.
  • the white precipitate thus obtained is filtered cold and rinsed with cold water. After drying over P 2 O 5 , 3.8 g of ⁇ - ⁇ c / s-4 - [(tert-butoxycarbonyl) amino] cyclohexyl ⁇ -4-chloro-D-phenylalanine are obtained.
  • 0.22 g of ⁇ -cyclohexyl-2,2-dimethyl- ⁇ -piperidin-4-yl-hydrazinecarboxamide obtained in step 11.2 are solubilized in 10 ml of dichloromethane in the presence of 0.28 g of ⁇ / - ⁇ c / s-4 - [(tert-butoxycarbonyl) amino] cyclohexyl ⁇ -4-chloro-D-phenylalanine obtained in step 11.4, 0.11 g of hydroxybenzotriazole, 0.24 g of hydrochloride 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide and 0.5 mL of diisopropylethylamine and 0.82 mL of hydrochloric acid in dioxane.
  • Example 12 W- ⁇ 1- [ ⁇ - ( ⁇ -4-aminocyclohexyl) -4-chloro-D-phenylalanyl] piperidin-4-yl ⁇ - ⁇ -cycloheptyl- ⁇ P, ⁇ T-diethylurea hydrochloride ( compound no. 33)
  • 0.24 g of ⁇ -cycloheptyl- ⁇ / 1 are solubilized .
  • ⁇ / 1- diethyl- ⁇ -piperidin-4-ylurea obtained in step 12.3 in 10 ml of dichloromethane in the presence of 0.28 g of N- ⁇ cis-4 - [(tert-butoxycarbonyl) amino] cyclohexyl ⁇ 4-chloro-D-phenylalanine obtained in step 11.4, 0.11 g of hydroxybenzotriazole, 0.23 g of 1- (3-dimethylaminopropyl) -3-ethyl-carbodiimide hydrochloride and 0.5 mL of diisopropylethylamine and then 0.81 mL of 2N hydrochloric acid in dioxane.
  • Example 13 N- (c / s-4 - ⁇ [(1 H) -1- (4-Chlorobenzyl) -2- (trans-4- ⁇ cyclohexyl [(dimethylamino) carbonyl] amino ⁇ -3-methylpiperidine Hydrochloride 1-yl) -2-oxoethyl] amino ⁇ cyclohexyl) acetamide (Compound No. 105)
  • the organic phase is washed with H 2 O, then with a saturated aqueous solution of sodium chloride, dried over MgSO 4 and concentrated to dryness.
  • the crude obtained is solubilized in 8 mL of acetonitrile.
  • 0.71 g of dimethylamine hydrochloride and 1.21 g of potassium carbonate are added. Stirring is maintained 40h at room temperature. It is hydrolyzed and extracted with ethyl acetate until the aqueous phase is exhausted.
  • the organic phase is washed with water, then with a 1N aqueous solution of hydrochloric acid and finally with a saturated aqueous solution of sodium chloride. It is dried over MgSO 4 and concentrated to dryness.
  • 0.6 g of tert-butyl trans-4- ⁇ cyclohexyl [(dimethylamino) carbonyl] amino ⁇ -3-methylpiperidine-1-carboxylate are obtained.
  • tert-butyl trans-4- ⁇ cyclohexyl [(dimethylamino) carbonyl] amino ⁇ -3-methylpiperidine-1-carboxylate are placed in 2 ml of dioxane and then 6.12 ml of acid is added. 4N hydrochloric acid in dioxane and the mixture is stirred for 4 hours at room temperature. After concentration to dryness, the residue is taken up in 1N aqueous sodium hydroxide solution and extracted with ethyl acetate until the aqueous phase is exhausted. The organic phase is washed with an aqueous solution of 1N sodium hydroxide, then with H 2 O and finally with a saturated aqueous solution of sodium chloride.
  • Example 15 ⁇ - (trans-1- ⁇ 4-chloro- ⁇ [4- [2-oxo-1,3-oxazolidin-3-yl] cyclohexyl] -D-phenylalanyl ⁇ hydrochloride methylpiperidin-4-yl) -NH-cyclohexyl-N-dimethylurea (Compound No. 118)
  • hydrochloride thus obtained is dried over P 2 Os under reduced pressure. 0.18 g of hydrochloride is obtained ⁇ - (trans-1 - ⁇ 4-chloro- ⁇ - [4- (2-oxo-1,3-oxazolidin-3-yl) cyclohexyl] -D-phenylalanyl ⁇ -3-methylpiperidin-4-yl ) - ⁇ / -cyclohexyl- ⁇ / ⁇ ⁇ / '- dimethylurea.
  • Example 16 N- (trans-1- [4-Chloro-N- (1-isonicotinoylpiperidin-4-yl) -D-phenylalanyl] -3-methylpiperidin-4-yl ⁇ - ⁇ -cyclohexyl) hydrochloride ⁇ f. ⁇ T-dimethylurea (Compound No. 119)
  • PF represents the melting point of the compound
  • Me, Et and iPr respectively represent methyl, ethyl and isopropyl groups.
  • the compounds according to the invention have been the subject of pharmacological tests for determining their agonist effect of melanocortin receptors, in particular their agonist effect of the MC3 and / or MC4 receptor.
  • This affinity test is carried out by measuring the binding of [ 125 I] - [Nle 4 -D-Phe 7 ] - ⁇ -MSH to cell membranes: the displacement of this radioligand is used to identify inhibitors. specific binding to melanocortin recombinant receptors.
  • membranes prepared from CHO-K1 cells expressing the high density human MC4 receptor (Euroscreen) or purchased membranes (Perkin Elmer Life Sciences, Receptor Biology) of HEK-293 cells expressing hMC3 receptors are used.
  • the CHO-K1 cells transfected with the hMC4 receptor gene (Euroscreen) are seeded in the DMEM / Nutrient Mix F12 culture medium containing 10% calf serum (Biowhittaker), 1% sodium pyruvate, 1% L-glutamine, 1 % non-essential amino acids, 0.4 mg / ml geneticin (G418) and 0.5% PenStrep, these products being supplied by Gibco / BRI, except calf serum.
  • the cells are scraped at 80% confluency and the cell pellets are frozen at -80 ° C.
  • a tube of cells (approximately 70 x 10 6 cells) is thawed on ice and resuspended in 10 ml of binding buffer [25 mM HEPES, pH 7.0, 1 mM MgCl 2 , 1.5 mM CaCl 2 , 100 mM NaCl, 1 mM 1 , 10-phenanthroline and 1 tablet of Complete TM (Roche protease inhibitor) in 50 ml buffer] by 20 sec. The suspension is centrifuged for 20 minutes at 19500 rpm at 4 ° C.
  • the supernatant is discarded and the pellet is resuspended in 5 ml of binding buffer.
  • the amount of protein present in the sample is measured and the concentration is adjusted to 3 ⁇ g / 25 ⁇ l by dilution in binding buffer.
  • [ 125 I] - [NIe 4 , D-Phe 7 ] - ⁇ -MSH is diluted in binding buffer + 0.2% BSA.
  • SPA beads wheatgerm agglutinin polyvinyltoluene, Amersham Pharmacia Biotech
  • the products to be tested are distributed in a white-filled 96-well plate (CORNING 3604 Polystyrene Non-Binding Surface).
  • the nonspecific binding is defined by NDP- ⁇ MSH 10 "7 M.
  • the total binding is measured by the number of cpm in the presence of the radioligand alone.
  • the distribution of the membranes-beads suspension (50 .mu.l / well ) is followed by the distribution of the solution of [ 125 I] - [NIe 4 , D-Phe 7 ] - ⁇ -MSH, 40 ⁇ l / well (100 ⁇ M final concentration), for a final volume of 100 ⁇ l / well. After incubation for 6 h at room temperature, the count is made in a Microbeta TriLux scintillation counter.
  • the IC 50 value of the compounds corresponds to the concentration which displaces the specific binding of the radioligand by 50%.
  • the compounds according to the invention have an affinity for the MC3 and / or MC4 receptors.
  • Their IC 5 O to the MC3 and MC4 receptors are less than 10 microM, mostly between 1 nM and 1 microM.
  • Compound No. 2 of the table has an IC 50 of 300 ' nM towards the MC4 receptor.
  • a functional test is used to discriminate the agonist activity of the antagonist activity.
  • the adenosine-cyclic mono-phosphate (cAMP) formation generated by the activation of the MC3 receptor or of the MC4 receptor is measured.
  • Euroscreen are inoculated in DMEM / Nutrient Mix F12 culture medium (Gibco / BRI) containing 10% calf serum, 0.5% sodium pyruvate, 1% L-glutamine, 1% non-essential amino acids, 200 mg / l hygromycin B and 0.5% PenStrep, these products being supplied by Gibco / BRI, except calf serum (Biowhittaker) and hygromycin B (Sigma).
  • the CHO cells (dhfr-) expressing the human MC3 receptor are inoculated into the Eagle MEM culture medium (Sigma) containing 10% dialyzed calf serum, 1% L-glutamine, 1% sodium pyruvate, 20 mg / 500 ml. -proline, 0.3 mg / ml Geneticin and 0.5% PenStrep, these products being supplied by Gibco / BRI, except dialysis calf serum (Cambrex) and L-proline (Sigma).
  • the intrinsic activity of the compounds is calculated by comparing the cAMP stimulation by these compounds to the stimulation induced by 30 nM NDPaMSH (100% maximum). The EC 50 value of the compounds corresponds to the concentration which produces 50% of the maximal stimulation obtained with this compound.
  • the compounds according to the invention are agonists of the MC3 and / or MC4 receptors. They have EC 50 towards the MC3 and MC4 receptors of less than 10 ⁇ M, mostly between 1 nM and 1 ⁇ M.
  • the compounds No. 1 and 2 of the table respectively have EC 50 of 590 nM and 370 nM to the MC3 receptor, and 80 nM and 30 nM to the MC4 receptor.
  • 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 of compound of formula (I).
  • these drugs find their use in therapeutics, in the pathologies in which the melanocortin receptors, in particular the MG3 and / or MC4 receptors, are involved: these include the treatment and prevention of obesity, diabetes and sexual dysfunction that can affect both sexes, such as erectile dysfunction, cardiovascular diseases such as myocardial infarction or hypertension, as well as anti-inflammatory applications or in the treatment of alcohol dependence.
  • the present invention relates to pharmaceutical compositions comprising, as active principle, a compound according to the invention.
  • These pharmaceutical compositions contain 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 disorders or disorders. diseases above.
  • 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, forms topical, transdermal, subcutaneous, intramuscular or intravenous administration, rectal administration forms and implants.
  • the compounds according to the invention can be used in creams, gels, ointments or lotions.
  • a preferred form of administration is the oral route.
  • a unitary form of administration of a compound according to the invention in tablet form may comprise the following components:
  • 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 one of its pharmaceutically acceptable salts or hydrates or solvates.

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Abstract

The invention concerns aminopiperidine derivatives of general formula (I) wherein: R<sub

Description

DÉRIVÉS D'AMINO-PIPERIDINE, LEUR PRÉPARATION ET LEUR APPLICATION EN THÉRAPEUTIQUE AMINO-PIPERIDINE DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION
La présente invention se rapporte à des composés agonistes des récepteurs aux mélanocortines, à leur préparation et à leur application en thérapeutique.The present invention relates to melanocortin receptor agonist compounds, their preparation and their therapeutic application.
Les récepteurs aux mélanocortines (MC-Rs) appartiennent à la super-famille des récepteurs couplés aux protéines G présentant sept domaines transmembranaires. Leur voie de transduction passe par la production d'AMPc (Cône, R. D., Récent Prog. Horm. Res., 1996, 51, 287). Cinq sous types de MC-Rs sont actuellement décrits, MC1-R, MC2-R, MC3-R, MC4-R et MC5-R, et sont exprimés dans différents tissus tels que le cerveau (MC3, 4, 5-R), les glandes exocrines (MC5-R), les surrénales (MC2-R) et la peau (MC1-R) pour les principaux. Les ligands naturels des MC-Rs sont, pour les agonistes, l'ACTH, l'a, β et γ-MSH, et pour les antagonistes, l'agouti protéine et Pagouti- related protéine. Aucun des ligands naturels n'est très sélectif pour l'un des sous-types, à -l'exception du γ-MSH, qui possède une certaine sélectivité pour le MC3-R.Melanocortin receptors (MC-Rs) belong to the G-protein coupled receptor super-family with seven transmembrane domains. Their transduction pathway involves the production of cAMP (Cone, R. D., Recent Prog Horm Res., 1996, 51, 287). Five subtypes of MC-Rs are currently described, MC1-R, MC2-R, MC3-R, MC4-R and MC5-R, and are expressed in different tissues such as the brain (MC3, 4, 5-R) , the exocrine glands (MC5-R), the adrenal glands (MC2-R) and the skin (MC1-R) for the main ones. The natural ligands of the MC-Rs are, for the agonists, ACTH, a, β and γ-MSH, and for the agonists, the agouti protein and Pagouti-related protein. None of the natural ligands is highly selective for any of the subtypes, except for γ-MSH, which has some selectivity for MC3-R.
Le système mélanocortine est impliqué dans de nombreux processus physiologiques, incluant la pigmentation, l'inflammation, le comportement alimentaire et sexuel (notamment la fonction érectile), la balance énergétique (régulation du poids corporel et stockage lipidique), les fonctions exocrines, la protection et régénération neuronale, Pimmunomodulation, l'analgésie, etc ...The melanocortin system is involved in many physiological processes, including pigmentation, inflammation, eating and sexual behavior (including erectile function), energy balance (body weight regulation and lipid storage), exocrine function, protection and neuronal regeneration, immunomodulation, analgesia, etc.
Notamment, il a été démontré que le MC4-R est impliqué dans le comportement sexuel (Van der Ploeg, L H., Proc. Natl. Acad. ScL USA, 2002, 99, 11381 ; Martin, W. J., Eur. J. Pharmacol., 2002, 454, 71). Il a également été démontré, par l'intermédiaire de modèles de souris spécifiquement dépourvues en certains MC-Rs (souris knockout), que les MC-Rs centraux (MC3 et 4-R) étaient impliqués dans le comportement alimentaire, l'obésité, le métabolisme et la balance énergétique (Huszar, D., CeII, 1997, 88(1), ' 131 ; Chen, A. S., Nat. Genêt, 2000, 26(1), 97; Butler, A.A., Trends Genêt, 2001, 17, S50- S54). Ainsi, les souris knockout MC4-R sont hyperphagiques et obèses. Parallèlement, les antagonistes aux MC3 et/ou 4R favorisent la prise de nourriture, tandis que la stimulation des MC4-R par un agoniste endogène, tel que l'α-MSH, produit un signal de satiété.Notably, MC4-R has been shown to be involved in sexual behavior (Van der Ploeg, LH, Proc Natl Acad ScL USA, 2002, 99, 11381, Martin, WJ, Eur J. Pharmacol. 2002, 454, 71). It has also been demonstrated, through mouse models specifically lacking in some MC-Rs (knockout mice), that central MC-Rs (MC3 and 4-R) were involved in eating behavior, obesity, metabolism and energy balance (Huszar, D., IECI, 1997, 88 (1), '131; Chen AS, Nat Genet, 2000, 26 (1), 97;. Butler, AA, Trends Genet 2001 17, S50-S54). Thus, MC4-R knockout mice are hyperphagic and obese. At the same time, MC3 and / or 4R antagonists favor food intake, whereas stimulation of MC4-R by an endogenous agonist, such as α-MSH, produces a satiety signal.
Ces observations laissent penser que la stimulation du MC3-R et/ou du MC4-R central, en réduisant la prise de nourriture et le poids corporel, est une approche prometteuse pour traiter l'obésité, risque aggravant de, nombreuses autres pathologies (hypertension, diabète, ...)- Ainsi, les recherches ont permis d'identifier dans un premier temps des peptides, pseudo-peptides ou peptides cycliques, capables d'interagir avec les MC-Rs et de moduler ainsi la prise de nourriture.These observations suggest that stimulation of central MC3-R and / or MC4-R, by reducing food intake and body weight, is an important approach. promising to treat obesity, aggravating risk of, many other pathologies (hypertension, diabetes, ...) - Thus, the research made it possible to identify initially peptides, pseudo-peptides or cyclic peptides, capable of interact with MC-Rs and thus modulate food intake.
Afin de maintenir sur le long terme une perte de poids efficace et limiter ainsi les co-morbidités, un traitement quotidien à long terme doit être envisagé. Ceci implique qu'un médicament, pour cette indication thérapeutique, doit pouvoir être administré par une voie simple pour le patient. La voie orale doit donc être privilégiée. Or, les composés peptidiques ne sont généralement pas les plus appropriés pour répondre à cette obligation. C'est pourquoi il est important de développer des petites molécules non peptidiques.In order to maintain effective weight loss in the long term and thus reduce co-morbidities, a long-term daily treatment should be considered. This implies that a drug for this therapeutic indication must be able to be administered by a simple route for the patient. The oral route must therefore be preferred. However, peptide compounds are generally not the most appropriate to meet this obligation. This is why it is important to develop small nonpeptide molecules.
Dans cette optique, les demandes internationales PCT publiées sous les numéros WO 02/059095, WO 02/059108, WO 03/009850 et WO 03/061660 décrivent des dérivés de type pipérazine. D'autres demandes décrivent des dérivés de type pipéridine, telles que les WO 03/092690 et WO 03/093234. Les demandes WO 99/64002 et WO 01/70337 décrivent des dérivés de type spiro-pipéridine. La demande WO 01/91752 décrit des dérivés comportant un motif pipéridine fusionné avec un noyau pyrazolyle. La demande WO 02/059107 décrit des dérivés de type pipéridine et pipérazine substitués par une structure bicyclique. Les demandes WO 02/059117, WO 02/068388 et WO 03/009847 décrivent des dérivés de type pipéridine et/ou pipérazine substitués par un noyau phényle. Quant à la demande WO 03/094918, elle décrit des dérivés de type pipérazine substitués par un noyau phényle ou pyridinyle. On peut également citer les demandes WO 00/74679, WO 01/70708, WO 02/15909, WO 02/079146, WO 03/007949 et WO 04/024720, qui décrivent des dérivés de type pipéridine substituée, ou encore la demande WO 04/037797 ; les composés décrits dans ces demandes de brevets comportent toujours une fonction amide, mimant les structures peptidiques antérieurement connues.In this regard, PCT international applications published under the numbers WO 02/059095, WO 02/059108, WO 03/009850 and WO 03/061660 describe derivatives of the piperazine type. Other applications describe piperidine derivatives, such as WO 03/092690 and WO 03/093234. Applications WO 99/64002 and WO 01/70337 disclose spiro-piperidine derivatives. WO 01/91752 discloses derivatives having a piperidine unit fused with a pyrazolyl ring. WO 02/059107 discloses piperidine and piperazine derivatives substituted with a bicyclic structure. Applications WO 02/059117, WO 02/068388 and WO 03/009847 disclose piperidine and / or piperazine derivatives substituted with a phenyl ring. As for the application WO 03/094918, it describes derivatives of piperazine type substituted by a phenyl or pyridinyl ring. It is also possible to cite WO 00/74679, WO 01/70708, WO 02/15909, WO 02/079146, WO 03/007949 and WO 04/024720, which describe substituted piperidine derivatives, or the WO application. 04/037797; the compounds described in these patent applications always include an amide function, mimicking the previously known peptide structures.
On peut citer aussi WO2005/047251 qui décrit composés agonistes des récepteurs aux mélanocortines de formule générale :We can also cite WO2005 / 047251 which describes melanocortin receptor agonist compounds of general formula:
(D Face au besoin constant d'améliorer les thérapies existantes pour les pathologies évoquées précédemment, les Inventeurs se sont donnés pour but de pourvoir à dé nouveaux composés agonistes des récepteurs aux méianocortines. ; (D In view of the constant need to improve the existing therapies for the pathologies mentioned above, the inventors have set themselves the goal of providing new compounds for meianocortin receptor agonists. ;
La présente invention a pour objet des composés répondant à la formule (I)The subject of the present invention is compounds corresponding to formula (I)
dans laquelle : in which :
Ra et R3-, identiques ou différents l'un de l'autre, représentent un atome d'hydrogène ou un groupe alkyle ou cycloalkyle,R a and R 3 -, identical to or different from each other, represent a hydrogen atom or an alkyl or cycloalkyl group,
R1 représente un atome d'hydrogène ou un groupe alkyle, cycloalkyle, hétérocycloalkyle ou aryle,R 1 represents a hydrogen atom or an alkyl, cycloalkyl, heterocycloalkyl or aryl group,
R2 représente un groupe de formule -(CH2)x-(CO)y-Y ou -(CO)y-(CH2)x-Y, dans laquelle :R 2 represents a group of formula - (CH 2 ) x - (CO) y -Y or - (CO) y - (CH 2 ) x -Y, in which:
. X = O, 1 , 2, 3 ou 4,. X = O, 1, 2, 3 or 4,
. y = O ou 1 ,. y = 0 or 1,
. Y représente un atome d'hydrogène ou un groupe hydroxyle, alkyle, cycloalkyle, alcoxy, aryle, hétéroaryle ou -NR1-IR12, Y étant différent d'un atome d'hydrogène lorsque x = y = 0,. Y represents a hydrogen atom or a hydroxyl, alkyl, cycloalkyl, alkoxy, aryl, heteroaryl or -NR 1 - I R 12 group , Y being different from a hydrogen atom when x = y = 0,
. Ri1 et R12, identiques ou différents l'un de l'autre, représentent un atome d'hydrogène ou un groupe alkyle, cycloalkyle, alcoxy ou -NRi3R14, ou bien Ri1 et R12 forment ensemble, avec l'atome d'azote auquel ils sont rattachés, une structure mono- ou bicyclique comportant de 4 à 10 chaînons et comprenant éventuellement 1 à 3 hétéroatomes supplémentaires et/ou 1 à 3 insaturations éthyléniques ou acétyléniques, ce cycle étant éventuellement substitué en des positions quelconques par 1 à 3 groupes choisis parmi les atomes d'halogène et les groupes hydroxyles, alkyles, cycloalkyles et alcoxy. A titre d'exemples de telles structures cycliques, on peut citer les groupes pyrrolidinyle, morpholinyle, pyrrolinyle, isoindolinyle, etc ...,. R 1 and R 12 , which are identical to or different from each other, represent a hydrogen atom or an alkyl, cycloalkyl, alkoxy or -NR 1 R 14 group , or R 1 and R 12 together form, with nitrogen atom to which they are attached, a mono- or bicyclic structure comprising from 4 to 10 members and optionally comprising 1 to 3 additional heteroatoms and / or 1 to 3 ethylenic or acetylenic unsaturations, this ring being optionally substituted in any positions by 1 to 3 groups selected from halogen atoms and hydroxyl, alkyl, cycloalkyl and alkoxy groups. By way of examples of such cyclic structures, mention may be made of pyrrolidinyl, morpholinyl, pyrrolinyl and isoindolinyl groups, etc.
. R-13 et Ru, identiques ou différents l'un de l'autre, représentent un atome d'hydrogène ou un groupe alkyle, cycloalkyle ou alcoxy, ou bien R13 et Ri4 forment ensemble, avec l'atome d'azote auquel ils sont rattachés, une structure mono- ou bicyclique telle que définie ci-dessus,. R- 1 3 and Ru, identical or different from each other, represent an atom of hydrogen or an alkyl, cycloalkyl or alkoxy group, or else R 13 and Ri 4 together with the nitrogen atom to which they are attached form a mono- or bicyclic structure as defined above,
R3 représente 1 à 3 groupes, identiques ou différents les uns des autres, situés en des positions quelconques du noyau auquel ils sont rattachés et choisis parmi les atomes d'halogène et les groupes alkyles, cycloalkyles, -OR, -NRR', -CO-NRR', -NR-CO-R', -NR-CO-NRR', -NR-COOR', -NO2, -CN et -COOR, où R et R' sont tels que définis ci-dessous,R 3 represents 1 to 3 groups, identical or different from each other, located in any positions of the nucleus to which they are attached and selected from halogen atoms and alkyl, cycloalkyl groups, -OR, -NRR ', - CO-NRR ', -NR-CO-R', -NR-CO-NRR ', -NR-COOR', -NO 2 , -CN and -COOR, where R and R 'are as defined below,
R5 représente un atome d'hydrogène ou un groupe alkyle,R 5 represents a hydrogen atom or an alkyl group,
R4 est choisi parmi les groupes de formules (a), (b) et (c), éventuellement substitués par un groupe oxo ou mono ou polysubstitué par un groupe aryle ou hétéroaryle ci-dessous, (chacune de ces structures cycliques (a), (b), (c) étant directement liée à l'atome d'azote de la formule (I) qui la porte) :R 4 is selected from the groups of formulas (a), (b) and (c), optionally substituted by an oxo group or mono or polysubstituted by an aryl or heteroaryl group below, (each of these cyclic structures (a) (b), (c) being directly bonded to the nitrogen atom of the formula (I) which carries it):
(a) (b) (c)(a) (b) (c)
dans lesquelles:in which:
P = O, 1 , 2 ou 3, m = O, 1 ou 2, et soit a) X représente un chaînon -N(R10)-, oùP = 0, 1, 2 or 3, m = 0, 1 or 2, and either a) X represents a -N (R 10 ) - link, where
R10 est choisi parmi : un groupe -(CH2)X-OR8, -(CH2)X-COOR8, -(CH2)X-NR8R9, -(CH2)X-CO-NR8R9 ou -(CH2)X-NR8-COR9, -(CH2)χ-COR8 dans lesquels x = 1 , 2, 3 ou 4,R 1 0 is chosen from: a group - (CH 2 ) X -OR 8 , - (CH 2 ) X -COOR 8 , - (CH 2 ) X -NR 8 R 9 , - (CH 2 ) X -CO- NR 8 R 9 or - (CH 2 ) X -NR 8 -COR 9 , - (CH 2 ) χ-COR 8 in which x = 1, 2, 3 or 4,
. un groupe cycloalkyle ou hétérocycloalkyle fusionné avec un groupe aryle ou hétéroaryle, un groupe cycloalkyle, hétérocycloalkyle, aryle, hétéroaryle, alkylaryle, alkylhétéroaryle, -CO-alkyle, -CO-cycloalkyle, -CO-hétérocycloalkyle, -CO-aryle, -CO-hétéroaryle, -CO-alkylaryle, -CO-alkylhétérqaryle, -CS-alkyle, -CS-cycloalkyle, -CS-hétérocycloalkyle, -CS-aryle, -CS-hétéroaryle, -CS-alkylaryle, -CS-alkylhétéroaryle, -CS-NR8R9, -C(=NH)-NR8R9> -SO2-aIkyle, -S02-cycloalkyle, -S02-hétérocycloalkyle, -SO2-aryle, -SO2-hétéroaryIe, -SO2-alkylaryle, -SO2-alkylhétéroaryle ou -SO2-NR8R9, les groupes alkyles, cycloalkyles, hétérocycloalkyles, aryles ou hétéroaryles étant éventuellement substitués par 1 ou plusieurs groupes choisis parmi les groupes R, R', - OR, -NRR', -CO-NRR', -NR-CO-R', -NR-CO-NRR', -NO2, -CN et -COOR, OCOR, COR, OCONRR', NRCOOR' les groupes cycloalkyles ou hétérocycloalkyles étant éventuellement fusionnés avec un groupe aryle ou hétéroaryie, ou bien R10 forme, avec l'atome d'azote auquel il est rattaché et un atome de carbone situé en une position quelconque de la structure cyclique de la formule (a), mais non adjacent audit atome d'azote, un pont comprenant de 3 à 5 chaînons,. a cycloalkyl or heterocycloalkyl group fused with an aryl or heteroaryl group, a cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, alkylheteroaryl, -CO-alkyl, -CO-cycloalkyl, -CO-heterocycloalkyl, -CO-aryl group, -CO-heteroaryl, -CO-alkylaryl, -CO-alkylheteraryl, -CS-alkyl, -CS-cycloalkyl, -CS-heterocycloalkyl, -CS-aryl, -CS-heteroaryl, -CS-alkylaryl, -CS-alkylheteroaryl, -CS-NR 8 R 9, -C (= NH) -NR 8 R 9> -aIkyle -SO 2, -S0 2 -cycloalkyl, -S0 2 -heterocycloalkyl, -SO 2 -aryl, -SO 2 -hétéroaryIe, -SO 2 -alkylaryl, -SO 2 -alkylheteroaryl or -SO 2 -NR 8 R 9 , the alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl groups being optionally substituted with one or more groups selected from R, R ', - OR, -NRR ', -CO-NRR', -NR-CO-R ', -NR-CO-NRR', -NO 2 , -CN and -COOR, OCOR, COR, OCONRR ', NRCOOR' cycloalkyl groups or heterocycloalkyls optionally fused with an aryl or heteroaryl group, or R 10 together with the nitrogen atom to which it is attached and a carbon atom at any position in the ring structure of formula (a), but not adjacent to said nitrogen atom, a bridge comprising from 3 to 5 links,
R8 et Rg sont choisis indépendamment l'un de l'autre parmi un atome d'hydrogène et les groupes alkyles, cycloalkyles, hétérocycloalkyles, aryles, hétéroaryles, alkylaryles, alkylhétéroaryles, -CO-alkyles, -CO-cycloalkyles, -CO-hétérocycloalkyles, -CO-aryles, -CO-hétéroaryles, -CO-alkylaryles, -CO-alkylhétéroaryles, -SO2-alkyles,R 8 and R 8 are chosen independently of one another from a hydrogen atom and the alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, alkylheteroaryl, -CO-alkyl, -CO-cycloalkyl, -CO- groups; heterocycloalkyls, -CO-aryls, -CO-heteroaryls, -CO-alkylaryls, -CO-alkylheteroaryls, -SO 2 -alkyls,
-SO2-cycloalkyles, -SO2-hétérocycloalkyles, -SO2-aryles, -SO2-hétéroaryles, -SO2-alkylaryles, -S02-alkylhétéroaryles, -C(=NH)-NRR\ -COOR, -CO-NRR', -CS-NRR' et -(CH2)X-OR, où x = O, 1 , 2, 3 ou 4, ou bien R8 et R9 forment ensemble un cycloalkyle ou un hétérocycloalkyle-Cycloalkyles -SO 2, -SO 2 -hétérocycloalkyles, -SO 2 -aryles, -SO 2 -hétéroaryles, -SO 2 -alkylaryles, -S0 2 -alkylhétéroaryles, -C (= NH) -NRR \ -COOR, -CO -NRR ', -CS-NRR' and - (CH 2 ) X -OR, where x = O, 1, 2, 3 or 4, or R 8 and R 9 together form a cycloalkyl or a heterocycloalkyl
R et R' représentent indépendamment l'un de l'autre un atome d'hydrogène ou un groupe alkyle, cycloalkyle, hétérocycloalkyle, aryle, hétéroaryie, alkyiaryle ou alkylhétéroaryle, ou peuvent former ensemble un cycloalkyle ou un hétérocycloalkyle.R and R 'independently of one another represent a hydrogen atom or an alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl or alkylheteroaryl group, or may together form a cycloalkyl or a heterocycloalkyl.
Soit, b) X représente un chaînon -C(R6)(R7)- oùLet b) X represent a chain -C (R 6 ) (R 7 ) - where
R6 est choisi parmi :R 6 is chosen from:
. un atome d'hydrogène, un atome d'halogène,. a hydrogen atom, a halogen atom,
. un groupe -(CH2)X-OR8, -(CH2)X-COOR8, -(CH2)X-NR8R9, -(CH2)X-CO-NR8R9 ou -(CH2)X-NR8-COR9, dans lesquels x = O, 1 , 2, 3 ou 4,. a group - (CH 2 ) X -OR 8 , - (CH 2 ) X -COOR 8 , - (CH 2 ) X -NR 8 R 9 , - (CH 2 ) X -CO-NR 8 R 9 or - ( CH 2 ) X -NR 8 -COR 9 , in which x = O, 1, 2, 3 or 4,
. un groupe alkyle, cycloalkyle, hétérocycloalkyle, aryle, hétéroaryie, alkyiaryle, alkyihétéroaryle, -CO-alkyle, -CO-cycloalkyle, -CO-hétérocycloalkyle, -CO-aryle, -CO-hétéroaryle, -CO-alkylaryle ou -CO-alkylhétéroaryle, -CS-alkyle, -CS-cycloalkyle, -CS-hétérocycloalkyle, -CS-aryle, -CS-hétéroaryle, -CS-alkylaryle, -CS-alkylhétéroaryle, -CS-NR8R9, -C(=NH)-NR8R9,. alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, alkylheteroaryl, -CO-alkyl, -CO-cycloalkyl, -CO-heterocycloalkyl, -CO-aryl, -CO-heteroaryl, -CO-alkylaryl or -CO-alkylheteroaryl , -CS-alkyl, -CS-cycloalkyl, -CS-heterocycloalkyl, -CS-aryl, -CS-heteroaryl, -CS-alkylaryl, -CS-alkylheteroaryl, -CS-NR 8 R 9 , -C (= NH) -NR 8 R 9 ,
. un groupe cycloalkyle ou hétérocycloalkyle fusionné ou non situé en position spiro sur le cycle de formule (a) auquel il est rattaché,. a cycloalkyl or heterocycloalkyl group fused or not located in the spiro position on the ring of formula (a) to which it is attached,
. un groupe cycloalkyle ou hétérocycloalkyle fusionné avec un groupe aryle ou hétéroaryle,. a cycloalkyl or heterocycloalkyl group fused with an aryl or heteroaryl group,
- les groupe alkyles, cycloalkyles, hétérocycloalkyles, aryles ou hétéroaryles étant éventuellement substitués par 1 ou plusieurs groupes choisis parmi les groupes R, R', -OR, -NRR', -CO-NRR', -NR-CO-R1, -NR-CO-NRR', -NO2, -CN et -COOR, OCOR, COR, OCONRR', NRCOOR' ; les groupes cycloalkyles ou hétérocycloalkyles étant éventuellement fusionnés avec un groupe aryle ou hétéroaryle,the alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl groups being optionally substituted with one or more groups chosen from the groups R, R ', -OR, -NRR', -CO-NRR ', -NR-CO-R 1 , -NR-CO-NRR ', -NO 2 , -CN and -COOR, OCOR, COR, OCONRR', NRCOOR '; the cycloalkyl or heterocycloalkyl groups being optionally fused with an aryl or heteroaryl group,
R7 est choisi parmi les atomes d'hydrogène et d'halogène et les groupes alkyles, cycloalkyles, aryles, hétéroaryles, alkylaryles, alkylhétéroaryles, -OR, -O-aryles, -O-hétéroaryles, -O-alkylaryles, -O-alkylhétéroaryles, -NRR', -CO-NRR', -NR-CO-R', -NR-CO-NRR'; -NR-COOR', -NO2, -CN et -COOR,R 7 is selected from hydrogen and halogen and alkyl, cycloalkyl, aryl, heteroaryl, alkylaryl, alkylheteroaryl, -OR, -O-aryl, -O-heteroaryl, -O-alkylaryl, -O- alkylheteroaryls, -NRR ', -CO-NRR', -NR-CO-R ', -NR-CO-NRR'; -NR-COOR ', -NO 2 , -CN and -COOR,
- R8 et R9 sont choisis indépendamment l'un de l'autre parmi un atome d'hydrogène et les groupes alkyles, cycloalkyles, hétérocycloalkyles, aryles, hétéroaryles, alkylaryles, alkylhétéroaryles, -CO-alkyles, -CO-cycloalkyles, -CO-hétérocycloalkyles, - CO-aryles, -CO-hétéroaryles, -CO-alkylaryles, -CO-alkylhétéroaryles, -SO2-alkyles, -S02-cycioalkyles, -S02-hétérocycloalkyles, -SO2-aryles, -SO2-hétéroaryles, -SO2-alkylaryles, -SO2-alkylhétéroaryles, -C(=NH)-NRR", -COOR, -CO-NRR', -CS-NRR' et -(CH2)X-OR, où x = O, 1 , 2, 3 ou 4, les groupes alkyles et aryles étant éventuellement substitués par un ou plusieurs groupes choisis parmi les groupes R, R', -OR, -NRR', -CO- NRR', -NR-CO-R1, -NR-CO-NRR', -NO2, -CN et -COOR, OCOR, COR, OCONRR', NRCOOR' ou bien Rs et R9 forment ensemble un cycloalkyle ou un hétérocycloalkyle- R 8 and R 9 are chosen independently of one another from a hydrogen atom and alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, alkylheteroaryl, -CO-alkyl, -CO-cycloalkyl, - CO-heterocycloalkyl, - CO-aryl, -CO-heteroaryl, -CO-alkylaryl, -CO-alkylhétéroaryles, -SO 2 -alkyl, -S0 2 -cycioalkyles, -S0 2 -hétérocycloalkyles, -SO 2 -aryles, -SO 2- heteroaryls, -SO 2 -alkylaryls, -SO 2 -alkylheteroaryls, -C (= NH) -NRR ", -COOR, -CO-NRR ', -CS-NRR' and - (CH 2 ) X -OR, where x = O, 1, 2, 3 or 4, the alkyl and aryl groups being optionally substituted by one or more groups chosen from the groups R, R ', -OR, -NRR', -CO-NRR ', -NR -CO-R 1 , -NR-CO-NRR ', -NO 2 , -CN and -COOR, OCOR, COR, OCONRR', NRCOOR 'or Rs and R 9 together form a cycloalkyl or a heterocycloalkyl
- R et R' représentent indépendamment l'un de l'autre un atome d'hydrogène ou un groupe alkyle, cycloalkyle, hétérocycloalkyle, aryle, hétéroaryle, alkylaryle ou alkylhétéroaryle, ou peuvent former ensemble un cycloalkyle ou un hétérocycloalkyle.- R and R 'independently of one another represent a hydrogen atom or an alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl or alkylheteroaryl group, or may together form a cycloalkyl or a heterocycloalkyl.
à l'état de base ou de sel d'addition à un acide, ainsi qu'à l'état d'hydrate ou de solvat.in the form of a base or an addition salt with an acid, as well as with the hydrate or solvate state.
De préférence lorsque X représente un chaînon -C(R6)(R7) dans les composés de formule (I), Re et R7 ne représentent pas en même temps un atome d'hydrogène. Parmi les composés de formule (I) objets de l'invention, on préfère encore ceux dans lesquels R4 est choisi parmi les groupes de formules (a), (b) et (c), éventuellement mono ou polysubstitué par un groupe aryle ou hétéroaryle où X représente un chaînon - C(R6)(R7)-, dans lequel R6 est choisi parmi :Preferably, when X represents a -C (R 6 ) (R 7 ) - chain in the compounds of formula (I), Re and R 7 do not represent at the same time a hydrogen atom. Among the compounds of formula (I) that are subjects of the invention, those in which R 4 is chosen from the groups of formulas (a), (b) and (c), optionally mono or polysubstituted by an aryl group, or more preferably heteroaryl wherein X represents a - C (R 6 ) (R 7 ) - linkage, wherein R 6 is selected from:
. un atome d'hydrogène,. a hydrogen atom,
. un groupe -(CH2)χ-OR8, -(CH2)X-COOR8, -(CH2)X-NR8R9, -(CH2)X-CO-NR8R9 ou -(CH2)X-NR8-COR9, dans lesquels x = 0, 1, 2, 3 ou 4,. a group - (CH 2 ) χ-OR 8 , - (CH 2 ) X -COOR 8 , - (CH 2 ) X -NR 8 R 9 , - (CH 2 ) X -CO-NR 8 R 9 or - ( CH 2 ) X -NR 8 -COR 9 , in which x = 0, 1, 2, 3 or 4,
. un groupe alkyle, cycloalkyle, hétérocycloalkyle, aryle, hétéroaryle, alkylaryle, alkylhétéroaryle, -CO-alkyle, -CO-cycloalkyle, -CO-hétérocycloalkyle, -CO-aryle, -CO-hétéroaryle, -CO-alkylaryle ou -CO-alkylhétéroaryle,. alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, alkylheteroaryl, -CO-alkyl, -CO-cycloalkyl, -CO-heterocycloalkyl, -CO-aryl, -CO-heteroaryl, -CO-alkylaryl or -CO-alkylheteroaryl ,
. un groupe cycloalkyle ou hétérocycloalkyle situé en position spiro sur le cycle de formule (a) auquel il est rattaché,. a cycloalkyl or heterocycloalkyl group located in a spiro position on the ring of formula (a) to which it is attached,
. un groupe cycloalkyle ou hétérocycloalkyle fusionné avec un groupe aryle ou hétéroaryle,. a cycloalkyl or heterocycloalkyl group fused with an aryl or heteroaryl group,
R7 est choisi parmi les atomes d'hydrogène et d'halogène et les groupes alkyles, cycloalkyles, aryles, hétéroaryles, alkylaryles, alkylhétéroaryles, -OR, -O-aryles, -O-hétéroaryles, -O-alkylaryles, -O-alkylhétéroaryles, -NRR', -CO-NRR', -NR-CO-R', -NR-CO-NRR', -NR-COOR', -NO2, -CN et -COOR,R 7 is selected from hydrogen and halogen and alkyl, cycloalkyl, aryl, heteroaryl, alkylaryl, alkylheteroaryl, -OR, -O-aryl, -O-heteroaryl, -O-alkylaryl, -O- alkylheteroaryls, -NRR ', -CO-NRR', -NR-CO-R ', -NR-CO-NRR', -NR-COOR ', -NO 2 , -CN and -COOR,
R8 et R9 sont choisis indépendamment l'un de l'autre parmi un atome d'hydrogène et les groupes alkyles, cycloalkyles, hétérocycloalkyles, aryles, hétéroaryles, alkylaryles, alkylhétéroaryles, -CO-alkyles, -CO-cycloalkyles, -CO-hétérocycloalkyles, -CO-aryles, -CO-hétéroaryles, -CO-alkylaryles, -CO-alkylhétéroaryles, -SO2-alkyles,R 8 and R 9 are chosen independently of one another from a hydrogen atom and alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, alkylheteroaryl, -CO-alkyl, -CO-cycloalkyl, -CO groups; heterocycloalkyls, -CO-aryls, -CO-heteroaryls, -CO-alkylaryls, -CO-alkylheteroaryls, -SO 2 -alkyls,
-SO2-cycloalkyles, -SO2-hétérocycloalkyles, -SO2-aryles, -SO2-hétéroaryles, -SO2-alkylaryles, -SO2-alkylhétéroaryles, -C(=NH)-NRR', -COOR, -CO-NRR', -CS-NRR' et -(CH2)X-OR, où x = O, 1 , 2, 3 ou 4,-SO 2 -cycloalkyls, -SO 2 -heterocycloalkyls, -SO 2 -aryls, -SO 2 -heteroaryls, -SO 2 -alkylaryls, -SO 2 -alkylheteroaryls, -C (= NH) -NRR ', -COOR, - CO-NRR ', -CS-NRR' and - (CH 2 ) X -OR, where x = O, 1, 2, 3 or 4,
R et R' représentent indépendamment l'un de l'autre un atome d'hydrogène ou un groupe alkyle, cycloalkyle, hétérocycloalkyle, aryle, hétéroaryle, alkylaryle ou alkylhétéroaryle,R and R 'represent, independently of one another, a hydrogen atom or an alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl or alkylheteroaryl group,
Parmi les composés de formule (I) objets de l'invention, on préfère encore ceux dans lesquels R4 est choisi parmi les groupes de formules (a), (b) et (c) où X représente un chaînon -C(R6)(R7)-, dans lequel R6 est choisi parmi un atome d'halogène ou un groupe cycloalkyle ou hétérocycloalkyle fusionné ou non situé en position spiro sur le cycle de formule (a) auquel il est rattaché, Parmi les composés de formule (I) objets de l'invention, on préfère encore ceux dans lesquels R4 est choisi parmi les groupes de formules (a), (b) et (c) où X représente un chaînon -C(R6)(R7)-, dans lequel R6 est choisi parmi -CS-alkyle, -CS:cycIoalkyle, -CS-hétérocycloalkyle, -CS-aryle, -CS-hétéroaryle, -CS-alkylaryle, -CS-alkylhétéroaryle, -CS-NR8R9, -C(=NH)-NR8R9.Among the compounds of formula (I) that are subjects of the invention, those in which R 4 is chosen from the groups of formulas (a), (b) and (c) in which X represents a -C (R 6 ) (R 7 ) -, in which R 6 is chosen from a halogen atom or a cycloalkyl or heterocycloalkyl group fused or not located in a spiro position on the ring of formula (a) to which it is attached, Among the compounds of formula (I) that are subjects of the invention, those in which R 4 is chosen from the groups of formulas (a), (b) and (c) in which X represents a -C (R 6 ) (R 7 ) -, wherein R 6 is selected from -CS-alkyl, -CS : cycloalkyl, -CS-heterocycloalkyl, -CS-aryl, -CS-heteroaryl, -CS-alkylaryl, -CS-alkylheteroaryl, -CS -NR 8 R 9 , -C (= NH) -NR 8 R 9 .
Parmi les composés de formule (I) objets de l'invention, on préfère encore ceux dans lesquels R4 est choisi parmi les groupes de formules (a), (b) et (c) où X représente un chaînon -C(R6)(R7)-, dans lequel les groupe alkyles, cycloalkyles, hétérocycloalkyles, aryles ou hétéroaryles sont éventuellement substitués par 1 ou plusieurs groupes choisis parmi R, R', OCOR1 COR, OCONRR1, NRCOOR' .Among the compounds of formula (I) that are subjects of the invention, those in which R 4 is chosen from the groups of formulas (a), (b) and (c) in which X represents a -C (R 6 ) (R 7 ) -, wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl groups are optionally substituted with 1 or more groups selected from R, R ', OCOR 1 COR, OCONRR 1 , NRCOOR'.
Parmi les composés de formule (I) objets de l'invention, on préfère encore ceux dans lesquels R4 est choisi parmi les groupes de formules (a), (b) et (c) où X représente un chaînon -C(R6)(R7)-, dans lequel les groupes cycloaikyles ou hétérocycloalkyles sont éventuellement fusionnés avec un groupe aryle ou hétéroaryle.Among the compounds of formula (I) that are subjects of the invention, those in which R 4 is chosen from the groups of formulas (a), (b) and (c) in which X represents a -C (R 6 ) (R 7 ) -, wherein the cycloalkyl or heterocycloalkyl groups are optionally fused with an aryl or heteroaryl group.
Parmi les composés de formule (I) objets de l'invention, on préfère encore ceux dans lesquels R4 est choisi parmi les groupes de formules (a), (b) et (c) où X représente un chaînon -C(R6)(R7)-, dans lequel R8 et R9 choisis indépendamment l'un de l'autre représentent des groupes alkyles et aryles étant éventuellement substitués par un ou plusieurs groupes choisis parmi les groupes R, R', OCOR, COR, OCONRR1 ou NRCOOR' .Among the compounds of formula (I) that are subjects of the invention, those in which R 4 is chosen from the groups of formulas (a), (b) and (c) in which X represents a -C (R 6 ) (R 7 ) -, wherein R 8 and R 9 independently selected from each other represent alkyl and aryl groups being optionally substituted with one or more groups selected from R, R ', OCOR, COR, OCONRR 1 or NRCOOR '.
Parmi les composés de formule (I) objets de l'invention, on préfère encore ceux dans lesquels R4 est choisi parmi les groupes de formules (a), (b) et (c) où X représente un chaînon -C(R6)(R7)-, dans lequel R et R' peuvent former ensemble un cycloalkyle ou un hétérocycloalkyle.Among the compounds of formula (I) that are subjects of the invention, those in which R 4 is chosen from the groups of formulas (a), (b) and (c) in which X represents a -C (R 6 ) (R 7 ) -, wherein R and R 'may together form cycloalkyl or heterocycloalkyl.
De préférence, dans les composés de formule (I), R7 est l'hydrogène.Preferably, in the compounds of formula (I), R 7 is hydrogen.
On préfère encore ceux dans lesquels R4 représente le groupe de formule a) où p=2 tel que défini ci-dessous :Those in which R 4 represents the group of formula a) where p = 2 as defined below:
On préfère encore ceux dans lesquels R4 est choisi parmi les groupes de formules (a), (b) et (c), éventuellement mono ou polysubstitué par un groupe aryle ou hétéroaryle, où X représente un chaînon -N(Ri0)- dans lequel Those in which R 4 is chosen from among the groups of formulas (a), (b) and (c), optionally mono- or polysubstituted with an aryl or heteroaryl group, where X represents a -N (Ri 0 ) - in which
Rio est choisi parmi : un groupe -CO-NR8Rg , -COOR8 un groupe -(CH2)x-OR8l -(CH2)χ-COOR8, -(CH2)X-NR8R9, -(CH2)X-CO-NR8R9 ou -(CH2)X-NR8-COR9, dans lesquels x = 1 , 2, 3 ou 4,Rio is selected from: -CO-NR 8 R, -COOR 8, a group - (CH 2) x -OR 8 l - (CH 2) χ-COOR 8, - (CH 2) x -NR 8 R 9, - (CH 2 ) X -CO-NR 8 R 9 or - (CH 2 ) X -NR 8 -COR 9 , in which x = 1, 2, 3 or 4,
. un groupe cycloalkyle ou hétérocycloalkyle fusionné avec un groupe aryle ou hétéroaryle, un groupe cycloalkyle, hétérocycloalkyle, aryle, hétéroaryle, . alkylaryle, alkylhétéroaryle, , -CO-cycloalkyle, -CO-hétérocycloalkyle, , -CO-hétéroaryle, -CO- alkylaryle, -CO-alkylhétéroaryle, -CS-alkyle, -CS-cycloalkyle, -CS-hétérocycloalkyle, -CS- aryle, -CS-hétéroaryle, -CS-alkylaryle, -CS-alkylhétéroaryle, -CS-NR8R9, -C(=NH)-NR8R9, , -SO2-cycloalkyle, -SO2-hétérocycloalkyle, , -S02-hétéroaryle, -S02-alkylaryle, -SO2- alkylhétéroaryle ou -SO2-NR8Rg ; ou bien Ri0 forme, avec l'atome d'azote auquel il est rattaché et un atome de carbone situé en une position quelconque de la structure cyclique de la formule (a), mais non adjacent audit atome d'azote, un pont comprenant de 3 à 5 chaînons.. a cycloalkyl or heterocycloalkyl group fused with an aryl or heteroaryl group, a cycloalkyl, heterocycloalkyl, aryl, heteroaryl group, alkylaryl, alkylheteroaryl, -CO-cycloalkyl, -CO-heterocycloalkyl, -CO-heteroaryl, -CO-alkylaryl, -CO-alkylheteroaryl, -CS-alkyl, -CS-cycloalkyl, -CS-heterocycloalkyl, -CS-aryl , -CS-heteroaryl, -C-alkylaryl, -CS-alkylheteroaryl, -CS-NR 8 R 9 , -C (= NH) -NR 8 R 9 , -SO 2 -cycloalkyl, -SO 2 -heterocycloalkyl,, -S0 2 -heteroaryl, -S0 2 -alkylaryl, -SO 2 - alkylheteroaryl or -SO 2 -NR 8 R; or Ri 0 forms, with the nitrogen atom to which it is attached and a carbon atom at any position in the ring structure of formula (a), but not adjacent to said nitrogen atom, a bridge comprising from 3 to 5 links.
R8 et R9 sont choisis indépendamment l'un de l'autre parmi un atome d'hydrogène et les groupes alkyles, cycloalkyles, hétérocycloalkyles, aryles, hétéroaryles, alkylaryles, alkylhétéroaryles, -CO-alkyles, -CO-cycloalkyles, -CO-hétérocycloalkyles, -CO-aryles, -CO-hétéroaryles, -CO-alkylaryles, -CO-alkylhétéroaryles, -SO2-alkyles,R 8 and R 9 are chosen independently of one another from a hydrogen atom and alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, alkylheteroaryl, -CO-alkyl, -CO-cycloalkyl, -CO groups; heterocycloalkyls, -CO-aryls, -CO-heteroaryls, -CO-alkylaryls, -CO-alkylheteroaryls, -SO 2 -alkyls,
-S02-cycloalkyles, -S02-hétérocycloalkyles, -SO2-aryles, -SO2~hétéroaryles, -SO2-alkylaryles, -SO2-alkylhétéroaryles, -C(=NH)-NRR', -COOR, -CO-NRR', -CS-NRR' et -(CH2)X-OR, où x = O, 1 , 2, 3 ou 4,-S0 2 -cycloalkyles, -S0 2 -hétérocycloalkyles, -SO 2 -aryles, -SO 2 ~ heteroaryl, -SO 2 -alkylaryles, -SO 2 -alkylhétéroaryles, -C (= NH) -NRR ', -COOR, - CO-NRR ', -CS-NRR' and - (CH 2 ) X -OR, where x = O, 1, 2, 3 or 4,
R et R' représentent indépendamment l'un de l'autre un atome d'hydrogène ou un groupe alkyle, cycloalkyle, hétérocycloalkyle, aryle, hétéroaryle, alkylaryle ou alkylhétéroaryle,R and R 'represent, independently of one another, a hydrogen atom or an alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl or alkylheteroaryl group,
On préfère encore ceux da.ns lesquels R4 est choisi parmi les groupes de formules (a), (b) et (c) éventuellement substitué par un groupe oxo où X représente un chaînon -N(R10).We still prefer those da . wherein R 4 is selected from the group of formulas (a), (b) and (c) optionally substituted with an oxo group where X is -N (R 10 ).
Parmi les composés de formule (I) objets de l'invention, on préfère encore, ceux dans lesquels R4 est choisi parmi les groupes de formules (a), (b) et (c) où X représente un chaînon -N(Ri0)- dans lequel R8 et R9 forment ensemble un cycloalkyle ou un hétérocycloalkyle.Among the compounds of formula (I) that are the subject of the invention, those in which R 4 is chosen from the groups of formulas (a), (b) and (c) where X represents a -N (Ri 0 ) - in which R 8 and R 9 together form cycloalkyl or heterocycloalkyl.
On préféré encore ceux dans lesquels R4 est choisi parmi les groupes de formules (a), (b) et (c) où X représente un chaînon -N(R10)- dans lequel R10 est, -(CH2)χ-COR8 dans lequel x = 1 , 2, 3 ou 4 .Those in which R 4 is chosen from the groups of formulas (a), (b) and (c) where X represents a -N (R 10 ) - group in which R 10 is, - (CH 2 ) χ are furthermore preferred. -COR 8 in which x = 1, 2, 3 or 4.
On . préféré encore ceux dans lesquels R4 est choisi parmi les groupes de formules (a), (b) et (c) où X représente un chaînon -N(R10)- dans lequel les groupes alkyles, cycloalkyles, hétérocycloalkyles, aryles ou hétéroaryles sont éventuellement substitués par 1 ou plusieurs groupes choisis parmi R, R', OCOR, COR, OCONRR' ou NRCOOR' .We . further preferred are those wherein R 4 is selected from the groups of formulas (a), (b) and (c) where X is -N (R 10 ) - in which the alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl groups are optionally substituted with 1 or more groups selected from R, R ', OCOR, COR, OCONRR' or NRCOOR '.
On préféré encore ceux dans lesquels R4 est choisi parmi les groupes de formules (a), (b) et (c) où X représente un chaînon -N(R10)- dans lequel les groupes cycloalkyles ou hétérocycloalkyles sont éventuellement fusionnés avec un groupe aryle ou hétéroaryle.Still more preferred are those wherein R 4 is selected from the groups of formulas (a), (b) and (c) wherein X represents a -N (R 10 ) - linkage in which the cycloalkyl or heterocycloalkyl groups are optionally fused with a aryl or heteroaryl group.
On préféré encore ceux dans lesquels R4 représente le groupe de formule a) où p=2 tel que défini ci-dessous :Those in which R 4 represents the group of formula a) where p = 2 as defined below:
Les composés de formule (I) comportent au moins un atome de carbone asymétrique. Ils peuvent donc exister sous forme d'énantiomères ou de diastéréoisomères. Ces énantiomères, diastéréoisomères, ainsi que leurs mélanges, y compris les mélanges racémiques, font partie de l'invention.The compounds of formula (I) comprise at least one asymmetric carbon atom. 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.
Parmi les composés de formule (I) objets de l'invention, on préfère ceux dans lesquels l'atome de carbone, identifié par l'astérisque * dans la formule suivante, présente une configuration (R) : Among the compounds of formula (I) which are subjects of the invention, those in which the carbon atom, identified by the asterisk * in the following formula, has a configuration (R) are preferred:
Les composés de formule (I) selon l'invention peuvent également exister sous forme de mélanges de conformères, qui font également partie de l'invention. Ils peuvent en outre exister sous forme d'isomères cis ou trans, ou sous forme d'isomères endo ou exo. Ces isomères ainsi que leur mélange, font partie de l'invention.The compounds of formula (I) according to the invention may also exist in the form of mixtures of conformers, which are also part of the invention. They can additionally exist in the form of cis or trans isomers, or in the form of endo or exo isomers. These isomers and their mixture are part of the invention.
Les composés de formule (I) peuvent exister à l'état de bases ou de sels d'addition à des acides. De tels sels d'addition font partie de l'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.
Ces sels sont avantageusement préparés avec des acides pharmaceutiquement acceptables, mais les sels d'autres acides utiles, par exemple, pour la purification ou l'isolement des composés de formule (1) font également partie de l'invention.These 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 (1) also form part of the invention.
Les composés de formule (I) peuvent également exister sous forme d'hydrates ou de solvats, à savoir sous forme d'associations ou de combinaisons avec une ou plusieurs molécules d'eau ou avec un solvant. De tels hydrates et solvats font également partie de l'invention.The compounds of formula (I) may also exist in the form of hydrates or solvates, namely in the form of associations or combinations with one or more water molecules or with a solvent. Such hydrates and solvates are also part of the invention.
Dans le cadre de la présente invention, et sauf mention différente dans le texte, on entend par :In the context of the present invention, and unless otherwise stated in the text, the following terms mean:
- un atome d'halogène : un fluor, un chlore, un brome ou un iode ; un groupe alkyle : un groupe aliphatique saturé ou insaturé (c'est-à-dire comprenant entre 1 et 3 insaturations de type éthylénique ou acétylénique), comprenant de 1 à 6 atomes de carbone, linéaire, cyclique ou ramifié. A titre d'exemples, on peut citer les groupes méthyle, éthyle, propyle, isopropyle, butyle, isobutyle, tertbutyle, pentyle, neo-pentyle, etc.. et les groupes cycloalkyles définis ci-après, ainsi que les groupes alkyles cyclisés seulement en partie, tel que le groupe méthyl-cyclopropyle. Un tel groupe alkyle peut être substitué par 1 ou plusieurs groupes (par exemple par 1 à 6 groupes) choisis parmi les atomes d'halogène (résultant par exemple en un groupe - CF3) et les groupes R, R', -OR, -NRR', -CO-NRR', -NR-CO-R', -NR-CO-NRR', -NO2, -CN et -COOR, OCOR, COR, OCONRR', NRCOOR' ; où R et R' représentent indépendemment l'un de l'autre un atome d'hydrogène ou un groupe alkyle, cycloalkyle, hétérocycloalkyle, aryle, hétéroaryle, alkylaryle ou alkylhétéroaryle, ou peuvent former ensemble un cycloalkyle ou un hétérocycloalkyle;a halogen atom: a fluorine, a chlorine, a bromine or an iodine; an alkyl group: a saturated or unsaturated aliphatic group (that is to say comprising between 1 and 3 ethylenic or acetylenic type unsaturations), comprising from 1 to 6 carbon atoms, linear, cyclic or branched. By way of examples, mention may be made of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, neo-pentyl, etc. groups and the cycloalkyl groups defined below, as well as cyclized alkyl groups only. in part, such as the methyl-cyclopropyl group. Such an alkyl group may be substituted with 1 or more groups (for example with 1 to 6 groups) chosen from halogen atoms (resulting for example from a group - CF 3 ) and the groups R, R ', -OR, -NRR ', -CO-NRR', -NR-CO-R ', -NR-CO-NRR', -NO 2 , -CN and -COOR, OCOR, COR, OCONRR ', NRCOOR'; where R and R 'independently of one another represent a hydrogen atom or an alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl or alkylheteroaryl group, or may together form a cycloalkyl or a heterocycloalkyl;
- un groupe cycloalkyle : un groupe alkyle cyclique comprenant entre 3 et 8 atomes, de carbone, tous les atomes de carbone étant engagés dans la structure cyclique. A titre d'exemples, on peut citer les groupes cyclopropyle, cyclobutyle, cyclopentyle, cyclohexyle, etc ... Un tel groupe cycloalkyle peut être substitué par R, R' et comme décrit ci-dessus pour le groupe alkyle ;a cycloalkyl group: a cyclic alkyl group comprising between 3 and 8 carbon atoms, all the carbon atoms being involved in the cyclic structure. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc. Such a cycloalkyl group may be substituted with R, R 'and as described above for the alkyl group;
- un groupe hétérocycloalkyle : un groupe cycloalkyle tel que défini ci-dessus, comprenant en outre entre 1 et 4 hétéroatomes, tels que l'azote, l'oxygène et/ou le soufre. Un tel groupe hétérocycloalkyle peut-être substitué comme décrit ci-dessus pour le groupe cycloalkyle et peut comprendre une ou plusieurs, par exemple 1 ou 2, insaturations éthyléniques ou acétyléniques. A titre d'exemples de groupes hétérocycloalkyles, on peut citer les groupes, pipéridinyle et tétrahydropyrane ;a heterocycloalkyl group: a cycloalkyl group as defined above, further comprising between 1 and 4 heteroatoms, such as nitrogen, oxygen and / or sulfur. Such a heterocycloalkyl group may be substituted as described above for the cycloalkyl group and may include one or more, for example 1 or 2, ethylenic or acetylenic unsaturations. As examples of heterocycloalkyl groups, mention may be made of the piperidinyl and tetrahydropyran groups;
- un groupe alcoxy : un radical -O-alkyle, où le groupe alkyle est tel que précédemment défini ;an alkoxy group: an -O-alkyl radical, where the alkyl group is as previously defined;
- un groupe aryle : un groupe aromatique cyclique comprenant entre 5 et 10 chaînons, par exemple un groupe phényle. Un tel groupe aryle peut être substitué par 1 ou plusieurs groupes (par exemple par 1 à 6 groupes) choisis parmi les atomes d'halogène (résultant par exemple en un groupe -CF3) les groupes R, R', -OR, -NRR', -CO-NRR', -NR-CO-R', -NR-CO-NRR', -NO2, -CN et -COOR, OCOR, COR, OCONRR', NRCOOR' ; où R et R' représentent indépendemment l'un de l'autre un atome d'hydrogène ou un groupe alkyle, cycloalkyle, hétérocycloalkyle, aryle, hétéroaryle, alkylaryle ou alkylhétéroaryle, ou peuvent former ensemble un cycloalkyle ou un hétérocycloalkyle; un groupe alkylaryle : un groupe alkyle tel que défini ci-dessus, lui-même substitué par un groupe aryle tel que défini ci-dessus. Un tel groupe alkylaryle est par exemple un groupe benzyle ;an aryl group: a cyclic aromatic group comprising between 5 and 10 members, for example a phenyl group. Such an aryl group may be substituted with 1 or more groups (for example with 1 to 6 groups) chosen from halogen atoms (resulting for example in a group -CF 3 ) the groups R, R ', -OR, - NRR ', -CO-NRR', -NR-CO-R ', -NR-CO-NRR', -NO 2 , -CN and -COOR, OCOR, COR, OCONRR ', NRCOOR'; where R and R 'independently of one another represent a hydrogen atom or an alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl or alkylheteroaryl group, or may together form a cycloalkyl or a heterocycloalkyl; an alkylaryl group: an alkyl group as defined above, itself substituted with an aryl group as defined above. Such an alkylaryl group is, for example, a benzyl group;
- un groupe hétéroaryle : un groupe aromatique cyclique comprenant entre 5 et 10 chaînons et comprenant entre 1 et 6 hétéroatomes, tels que l'azote, l'oxygène et/ou le soufre. A titre d'exemple on peut citer le groupe pyridinyle. Un tel groupe hétéroaryle peut-être substitué comme décrit ci-dessus pour le groupe aryle ;a heteroaryl group: a cyclic aromatic group comprising between 5 and 10 members and comprising between 1 and 6 heteroatoms, such as nitrogen, oxygen and / or sulfur. By way of example, mention may be made of the pyridinyl group. Such a heteroaryl group may be substituted as described above for the aryl group;
- un groupe alkylhétéroaryle : un groupe alkyle tel que défini ci-dessus, lui-même substitué par un groupe hétéroaryle tel que défini ci-dessus.an alkylheteroaryl group: an alkyl group as defined above, itself substituted by a heteroaryl group as defined above.
Parmi les composés de formule (I) objets de l'invention, on peut citer ceux dans lesquels Ra, Ra., R2, R3, R4 et R5 sont tels que définis ci-dessus et Ri représente un groupe alkyle, cycloalkyle ou hétérocycloalkyle. De façon avantageuse, Ri représente un groupe cycloalkyle, tel qu'un groupe cyclohexyle ou cycloheptyle. Parmi les composés de formule (I) objets de l'invention, on peut également citer ceux dans lesquels Ra, Ra>, R1, R3, R4 et R5 sont tels que définis ci-dessus et R2 est choisi parmi les groupes suivants : -CO-R15, -CO-NR16R17, -CO-NR15-NR16Ri7, -CO-aryle, -CO-hétéroaryle, -CO-(CH2)χ"NR16R17, -(CH2)χ-NR16R17) -(CH2)X-OH, -(CH2)x-aryle, -(CH2)x-hétéroaryle, -(CH2)χ-CO-R15 et -(CH2)χ-CO-NR16Ri7, dans lesquels :Among the compounds of formula (I) which are subjects of the invention, mention may be made of those in which R a , R a , R 2 , R 3 , R 4 and R 5 are as defined above and R 1 represents a group alkyl, cycloalkyl or heterocycloalkyl. Advantageously, R 1 represents a cycloalkyl group, such as a cyclohexyl or cycloheptyl group. Among the compounds of formula (I) which are subjects of the invention, mention may also be made of those in which R a , R a >, R 1 , R 3 , R 4 and R 5 are as defined above and R 2 is selected from the following groups: -CO-R 15 , -CO-NR 16 R 17 , -CO-NR 15 -NR 16 R 7 , -CO-aryl, -CO-heteroaryl, -CO- (CH 2 ) χ " NR 16 R 17 , - (CH 2 ) χ-NR 16 R 17) - (CH 2 ) X -OH, - (CH 2 ) x -aryl, - (CH 2 ) x -heteroaryl, - (CH 2 ) χ -CO-R 15 and - (CH 2 ) χ-CO-NR 16 R 17 , wherein:
. X = O, 1 , 2, 3 ou 4 et x' = 1 , 2, 3 ou 4,. X = 0, 1, 2, 3 or 4 and x '= 1, 2, 3 or 4,
. Ri5 représente un atome d'hydrogène ou un groupe alkyle, cycloalkyle ou alcoxy, et. R 5 represents a hydrogen atom or an alkyl, cycloalkyl or alkoxy group, and
. R16 et R17, identiques ou différents l'un de l'autre, représentent un atome d'hydrogène ou un groupe alkyle, cycloalkyle ou alcoxy, ou bien Ri6 et R17 forment ensemble, avec l'atome d'azote auquel ils sont rattachés, une structure mono- ou bicyclique comportant de 4 à 10 chaînons et comprenant éventuellement 1 à 3 hétéroatomes supplémentaires et/ou 1 à 3 insaturations éthyléniques ou acétyléniques, ce cycle étant éventuellement substitué en des positions quelconques par 1 à 3 groupes choisis parmi les atomes d'halogène et les groupes hydroxyles, alkyles, cycloalkyles et alcoxy.. R 16 and R 17 , which are identical to or different from each other, represent a hydrogen atom or an alkyl, cycloalkyl or alkoxy group, or R 6 and R 17 form together with the nitrogen atom to which they are attached, a mono- or bicyclic structure comprising from 4 to 10 members and optionally comprising 1 to 3 additional heteroatoms and / or 1 to 3 ethylenic or acetylenic unsaturations, this ring being optionally substituted in any position by 1 to 3 groups selected among the halogen atoms and the hydroxyl, alkyl, cycloalkyl and alkoxy groups.
Parmi ces composés, on peut notamment citer ceux dans lesquels R2 est choisi parmi les groupes suivants : -CO-R15, -CO-NRi6R17, -CO-NR15-NR16R17, -CO-(CH2)x.-NRi6Ri7, -(CH2)x-NR16Ri7, -(CH2)X-OH, -(CH2)x-aryle, -(CH2)x-hétéroaryle, -(CH2)χ-CO-R15 et -(CH2)X-CO-N R16Ri7, dans lesquels x, x', Ri5, Ri6 et Ri7 sont tels que définis ci-dessus.Among these compounds, mention may especially be made of those in which R 2 is chosen from the following groups: -CO-R 15 , -CO-NR 1 R 17 , -CO-NR 15 -NR 16 R 17 , -CO- (CH 2) 2 ) x -NR 6 R 7 , - (CH 2 ) x -NR 16 R 7 , - (CH 2 ) X -OH, - (CH 2 ) x -aryl, - (CH 2 ) x -heteroaryl, - (CH 2 ) χ-CO-R 15 and - (CH 2 ) X -CO-N R 16 R 17 , in which x, x ', Ri 5 , Ri 6 and Ri 7 are as defined above.
Parmi les composés de formule (1) objets de l'invention, on peut plus particulièrement citer ceux dans lesquels R2 représente un groupe -CO-NRi6Ri7, où Ri6 et R17 représentent des groupes alkyles ou alcoxy.Among the compounds of formula (1) that are the subject of the invention, mention may be made more particularly of those in which R 2 represents a group -CO-NR 1 R 6 7 , in which R 6 and R 17 represent alkyl or alkoxy groups.
Parmi les composés de formule (I) objets de l'invention, on peut également citer ceux dans lesquels Ra, Ra>, R1, R2, R4 et R5 sont tels que définis ci-dessus et R3 représente 1 à 3 groupes, identiques ou différents les uns des autres, choisis parmi les atomes d'halogène. Avantageusement, R3 représente un seul groupe, de préférence un atome de chlore.Among the compounds of formula (I) that are subjects of the invention, mention may also be made of those in which R a , R a >, R 1 , R 2 , R 4 and R 5 are as defined above and R 3 represents 1 to 3 groups, identical or different from each other, chosen from halogen atoms. Advantageously, R 3 represents a single group, preferably a chlorine atom.
Parmi les composés de formule (I) objets de l'invention, on peut également citer ceux dans lesquels Ra, Ra., R1, R2, R3 et R4 sont tels que définis ci-dessus et R5. représente un atome d'hydrogène ou un groupe alkyle comprenant de 1 à 4 atomes de carbone. R5 représente de préférence un atome d'hydrogène.Among the compounds of formula (I) which are subjects of the invention, mention may also be made of those in which R a , R a , R 1 , R 2 , R 3 and R 4 are as defined above and R 5 . represents a hydrogen atom or an alkyl group comprising from 1 to 4 carbon atoms carbon. R 5 preferably represents a hydrogen atom.
Parmi les composés de formule (I) objets de l'invention, on peut également citer ceux dans lesquels R1, R2, R3, R4 et R5 sont tels que définis ci-dessus et Ra et Ra> représentent des atomes d'hydrogène ou des groupes alkyles comprenant de 1 à 4 atomes de carbone. Avantageusement, R3 et R3; représentent indépendamment l'un de l'autre des atomes d'hydrogène ou des groupes méthyles.Among the compounds of formula (I) which are subjects of the invention, mention may also be made of those in which R 1 , R 2 , R 3, R 4 and R 5 are as defined above and R a and R a > represent hydrogen atoms or alkyl groups having 1 to 4 carbon atoms. Advantageously, R 3 and R 3 ; independently of one another represent hydrogen atoms or methyl groups.
Parmi les groupes R6 définis précédemment, on peut notamment citer ceux dans lesquels R6 représente un atome d'hydrogène ou un groupe -OR8, -NR8Rg ou -NR8-CO-Rg, dans lesquels R8 et Rg représentent un atome d'hydrogène ou un groupe alkyle.Among the groups R 6 defined above, mention may especially be made of those in which R 6 represents a hydrogen atom or a group -OR 8 , -NR 8 R 8 or -NR 8 -CO-R 8 , in which R 8 and R 8 represent a hydrogen atom or an alkyl group.
Parmi les groupes R7 définis précédemment, on peut notamment citer ceux dans lesquels R7 représente un atome d'hydrogène ou d'halogène ou un groupe alkyle, hydroxyle (correspondant à un groupe -OR, où R représente un atome d'hydrogène) ou alcoxy (correspondant à un groupe -OR, où R représente un groupe alkyle). R7 représente avantageusement un atome d'hydrogène.Among the groups R 7 defined above, there may be mentioned those in which R 7 represents a hydrogen or halogen atom or an alkyl or hydroxyl group (corresponding to a group -OR, where R represents a hydrogen atom) or alkoxy (corresponding to a group -OR, where R represents an alkyl group). R 7 advantageously represents a hydrogen atom.
Parmi les groupes R8 et Rg définis précédemment, on peut notamment citer ceux dans lesquels R8 et Rg représentent un atome d'hydrogène ou un groupe alkyle.Among the groups R 8 and R 8 defined above, there may be mentioned those in which R 8 and R 8 represent a hydrogen atom or an alkyl group.
Parmi les groupes Ri0 définis précédemment, on peut notamment citer ceux dans lesquels R10 représente un atome d'hydrogène ou un groupe alkyle ou -CO-aryle (tel que -CO-phényle), ou bien R10 forme, avec l'atome d'azote auquel il est rattaché et un atome de carbone situé en une position quelconque de la structure cyclique qui le porte (telle que la structure de formule (a) ou (a-3)), mais non adjacent audit atome d'azote, un pont comprenant de 3 à 5 chaînons.Among the groups R 1 defined above, there may be mentioned those in which R 10 represents a hydrogen atom or an alkyl or -CO-aryl group (such as -CO-phenyl), or else R 10 forms with nitrogen atom to which it is attached and a carbon atom located at any position of the cyclic structure which carries it (such as the structure of formula (a) or (a-3)), but not adjacent to said atom of nitrogen, a bridge comprising from 3 to 5 members.
Parmi les groupes R et R' définis précédemment, on peut notamment citer ceux dans lesquels R et R' représentent un atome d'hydrogène ou un. groupe alkyle.Among the groups R and R 'defined above, there may be mentioned those in which R and R' represent a hydrogen atom or a hydrogen atom. alkyl group.
Chacune des définitions données ci-avant pour les groupes Ra, Ra>, R1, R2, R3, R4, R5, Rβ> R7> Rs, Rg, Rio. R et R' peuvent se combiner les unes avec les autres de façon à obtenir différents sous-groupes de composés de formule (I) selon la présente invention.Each of the definitions given above for the groups R a , R a >, R 1 , R 2 , R 3 , R 4 , R 5 , R β > R 7> R 5 , R 6 , R 10 . R and R 'can combine with each other so as to obtain different subgroups of compounds of formula (I) according to the present invention.
Selon un autre objet l'invention se rapporte aux composés préférés dont les noms suivent : . Dans les listes qui suivent les chiffres devant les nomenclatures des produits correpondent aux n° d'exemple des composés du tableauAccording to another object the invention relates to the preferred compounds whose names follow: . In the lists that follow the figures in front of the product nomenclatures correspond to the example numbers of the compounds of the table
2 : A/-{1 -[Λ/-(4-aminocyclohexyl)-4-chloro-D-phenylalanyl]piperidin-4-yl}-Λ/- cyclohexyl-ΛΛΛ/'-diethylurea2: N - {1 - [Λ] - (4-aminocyclohexyl) -4-chloro-D-phenylalanyl] piperidin-4-yl} -α-cyclohexyl-β-diethylurea
8 : Λ/-{1 -[Λ/-(c/s-4-aminocyclohexyl)-4-chloro-D-phenylalanyl]piperidin-4-yl}-/V- cyclohexyl-1 ,3-dihydro-2/-/-isoindole-2-carboxamide8: Λ- {1 - [Λ- (α-4-aminocyclohexyl) -4-chloro-D-phenylalanyl] piperidin-4-yl} - β-cyclohexyl-1,3-dihydro-2 - / - isoindole-2-carboxamide
9 : Λ/-{1 -[Λ/-(c/s-4-aminocyclohexyl)-4-chloro-D-phenylalanyl]piperidin-4-yl}-Λ/- cyclohexyl-2,5-dimethylpyrrolidine-1-carboxamide9: Λ- {1 - [Λ- (α-4-aminocyclohexyl) -4-chloro-D-phenylalanyl] piperidin-4-yl} Λ-cyclohexyl-2,5-dimethylpyrrolidine-1 carboxamide
12 : Λ/-{1-[Λ/-(c/s-4-aminocyclohexyl)-4-chloro-D-phenylalanyl]piperidin-4-yl}-Λ/- cyclohexyl-Λ/'.Λ/'-dimethylurea12: Λ- {1- [Λ- (α-4-aminocyclohexyl) -4-chloro-D-phenylalanyl] piperidin-4-yl} -Λ-cyclohexyl-β-allyl; dimethylurea
14 : Λ/-{1 -[Λ/-(c/s-4-aminocyclohexyl)-4-chloro-D-phenylalanyl]piperidin-4-yl}-Λ/- cyclohexyl-Λ/'-methoxy-Λ/'-methylurea14: Λ- {1 - [Λ- (α-4-aminocyclohexyl) -4-chloro-D-phenylalanyl] piperidin-4-yl} -β-cyclohexyl-β-methoxy-β / '-methylurea
23 : Λ/-{1-[Λ/-(c/s-4-aminocyclohexyl)-4-chloro-D-phenylalanyl]piperidin-4-yl}-Λ/- cyclohexyl-2,5-dimethyl-2,5-dihydro-1 H-pyrrole-1 -carboxamide23: Λ- {1- [Λ- (α-4-aminocyclohexyl) -4-chloro-D-phenylalanyl] piperidin-4-yl} Λ-cyclohexyl-2,5-dimethyl-2, 5-Dihydro-1H-pyrrole-1-carboxamide
33 : Λ/-{1-[Λ/-(c/s-4-aminocyclohexyl)-4-chloro-D-phenylalanyl]piperidin-4-yl}-Λ/- cycloheptyl-Λ/';A/I-diethylurea33: Λ- {1- [Λ- (α-4-aminocyclohexyl) -4-chloro-D-phenylalanyl] piperidin-4-yl} -Λ-cycloheptyl-Λ / A / I - diethylurea
35 : Λ/-{1-[Λ/-(c/s-4-aminocyclohexyl)-4-chloro-D-phenylalanyl]piperidin-4-yl}-Λ/- cyclooctyl-Λ/\Λ/'-diethylurea35: Λ- {1- [Λ- (α-4-aminocyclohexyl) -4-chloro-D-phenylalanyl] piperidin-4-yl} Λ-cyclooctyl-β-diethylurea
38 : Λ/-{1 -[A/-(c/s-4-aminocyclohexyl)-4-chloro-D-phenylalanyl]piperidin-4-yl}-Λ/- cyclohexyl-Λ/'-(212,2-trifluoroethyl)urea38: Λ- {1- [N- (α-4-aminocyclohexyl) -4-chloro-D-phenylalanyl] piperidin-4-yl} -Λ-cyclohexyl-Λ '- (2 1 2 , 2-trifluoroethyl) urea
48 : Λ/-{1-[Λ/-(c/s-4-aminocyclohexyl)-4-chloro-D-phenylalanyl]-3-methylpiperidin-4- yl}-Λ/-cyclohexyl-Λ/1 , W-d iethyl u rea (trans)48: Λ- {1- [Λ- (cs-4-aminocyclohexyl) -4-chloro-D-phenylalanyl] -3-methylpiperidin-4-yl} -Λ / -cyclohexyl-Λ / 1 , Wd iethyl u rea (trans)
50 : A/-{1 -[Λ/-(frans-4-aminocyclohexyl)-4-chloro-D-phenylalanyl]-3- methylpiperidin-4-yl}-Λ/-cyclohexyl-A/1,Λ/1-diethylurea (trans)50: A / - {1 - [Λ / - (4-amino-4-aminocyclohexyl) -4-chloro-D-phenylalanyl] -3-methylpiperidin-4-yl} -Λ / -cyclohexyl-A / 1 , Λ / 1 -diethylurea (trans)
67 : A/-{1-[Λ/-(c/s-4-anninocyclohexyl)-4-chloro-D-phenylalanyl]piperidin-4-yl}-A/- cyclohexyl-W-ethyl-Λ/'-isopropylurea67: N- {1- [N- (c-S-4-anninocyclohexyl) -4-chloro-D-phenylalanyl] piperidin-4-yl} -N-cyclohexyl-W-ethyl-β- isopropylurea
74 : Λ/-(c/s-4-{[(1R)-1-(4-chlorobenzyl)-2-(4- {cyclohexyl[(diethylamino)carbonyl]amino}piperidin-1-yl)-2-oxoethyl]amino}cyclohexyl)- 2,2,2-trifluoroacetamide74: Λ- (c / s-4 - {[(1R) -1- (4-chlorobenzyl) -2- (4- {cyclohexyl [(diethylamino) carbonyl] amino} piperidin-1-yl} -2- oxoethyl] amino} cyclohexyl) 2,2,2-trifluoroacetamide
Λ/-(trans-4-{[(1 R)-1 -(4-chlorobenzyl)-2-(4-Λ / - (trans-4 - {[(1 R) -1 - (4-chlorobenzyl) -2- (4-
{cyclohexyl[(diethylamino)carbonyl]amino}piperidin-1-yl)-2-oxoethyl]amino}cyclohexyl)- 2,2,2-trifluoroacetamide{cyclohexyl [(diethylamino) carbonyl] amino} piperidin-1-yl) -2-oxoethyl] amino} cyclohexyl) 2,2,2-trifluoroacetamide
75 : Λ/-{1-[Λ/-(1-benzoylpiperidin-4-yl)-4-chloro-D-phenylalanyl]piperidin-4-yl}-Λ/- cyclohexyl-A/'.Λ/'-diethylurea75: Λ- {1- [Λ- (1-benzoylpiperidin-4-yl) -4-chloro-D-phenylalanyl] piperidin-4-yl} -ocyclohexyl-N-allyl; diethylurea
76 : Λ/-{1-[Λ/-(frans-4-aminocyclohexyl)-4-chloro-D-phenylalanyl]piperidin-4-yl}-A/- cyclohexyl-Λ/',Λ/'-bis(2-fluoroethyl)urea76: Λ- {1- [Λ / - (4-amino-4-aminocyclohexyl) -4-chloro-D-phenylalanyl] piperidin-4-yl} -N-cyclohexyl-Λ, N-bis ( 2-fluoroethyl) urea
81 : (2R,5S)-Λ/-{1 -[Λ/-(c/s-4-aminocyclohexy|)-4-chloro-D-phenylalanyl]piperidin-4- yl}-A/-cyclohexyl-2,5-dimethylpyrrolidine-1-carboxamide81: (2R, 5S) -Λ- {1 - [Λ] - (c-4-aminocyclohexyl) -4-chloro-D-phenylalanyl] piperidin-4- -yl} -A / -cyclohexyl-2,5-dimethylpyrrolidine-1-carboxamide
82 : (2R,5S)-/V-(1-{4-chloro-Λ/-[c/s-4-(dimethylamino)cyclohexyl]-D- phenylalanyl}piperidin-4-yl)-Λ/-cyclohexyl-2,5-dimethylpyrrolidine-1-carboxamide82: (2R, 5S) - N - (1- {4-chloro-Λ [- / c- [4- (dimethylamino) cyclohexyl] -D-phenylalanyl} piperidin-4-yl] -Λ-cyclohexyl -2,5-dimethylpyrrolidine-1-carboxamide
83 : 4-{[(1f?)-1-(4-chlorobenzyl)-2-(4-83: 4 - {[(1f?) - 1- (4-chlorobenzyl) -2- (4-
{cyclohexyl^dimethylamino^arbonyOaminoJpiperidin-i-yO^-oxoethyllaminoJ-Λ/.Λ/- dimethylpiperidine-1-carboxamideCyclohexyl-dimethylamino-arbony-amino-piperidin-1-yl-oxoethyllamino-N-dimethylpiperidine-1-carboxamide
84 : 4-{[(1R)-1-(4-chlorobenzyl)-2-(4-84: 4 - {[(1R) -1- (4-chlorobenzyl) -2- (4-
{cyclohexyI[(dimethylamino)carbonyl]amino}piperidin-1-yl)-2-oxoethyl]amino}-A/,Λ/- diethylpiperidine-1-carboxamide{Cyclohexyl [(dimethylamino) carbonyl] amino} piperidin-1-yl) -2-oxoethyl] amino} -N, N-diethylpiperidine-1-carboxamide
85 : Λ/-(1 -{4-chloro-A/-[1 -(pyrrolidin-1 -ylcarbonyl)piperidin-4-yl]-D- phenylalanyl}piperidin-4-y!)-Λ/-cyclohexyI-Λ/I,Λ/'-diπnethylurea85: Λ- (1- {4-chloro-N- [1- (pyrrolidin-1-ylcarbonyl) piperidin-4-yl] -D-phenylalanyl} piperidin-4-yl) -cyclohexyl Λ / I , Λ / '- diπnethylurea
86 : Λ/-(1-{4-chloro-Λ/-[1-(piperidin-1-ylcarbonyl)piperidin-4-yl]-D- phenylalanyl}piperidin-4-yl)-Λ/-cyclohexyl-Λ/',Λ/1-dimethylurea86: Λ- (1- {4-chloro-Λ- [1- (piperidin-1-ylcarbonyl) piperidin-4-yl] -D-phenylalanyl} piperidin-4-yl) -Λ-cyclohexyl-Λ / ', Λ / 1- dimethylurea
87 : Λ/-(1-{4-chloro-Λ/-[1-(morpholin-4-ylcarbonyl)piperidin-4-yl]-D- phenylalanyl}piperidin-4-yl)-Λ/-cyclohexyl-Λ/',A/t-dimethylurea87: Λ- (1- {4-chloro-Λ- [1- (morpholin-4-ylcarbonyl) piperidin-4-yl] -D-phenylalanyl} piperidin-4-yl) -Λ-cyclohexyl-Λ / ', A / t- dimethylurea
88 : 4-{[(1ft)-1-(4~chlorobenzyï)-2-(4-88: 4 - {[(1ft) -1- (4-chlorobenzyl) -2- (4-
{cyclohexyl[(dimethylamino)carbonyl]amino}piperidin-1-yl)-2-oxoethyl]amino}-A/- . phenylpiperidine-1 -carboxamide{cyclohexyl [(dimethylamino) carbonyl] amino} piperidin-1-yl) -2-oxoethyl] amino} -A / -. phenylpiperidine-1-carboxamide
89 : . 4-{[(1/R)-1-(4-chlorobenzyl)-2-(4-89:. 4 - {[(1 / R) -1- (4-chlorobenzyl) -2- (4-
{cyclohexyl[(dimethylamino)carbonyl]amino}piperidin-1-yl)-2-oxoethyl]amino}-Λ/-methyl-Λ/- phenylpiperidine-1 -carboxamide{cyclohexyl [(dimethylamino) carbonyl] amino} piperidin-1-yl) -2-oxoethyl] amino} -α-methyl-β-phenylpiperidine-1-carboxamide
90 : Λ/-benzyl-4-{[(1R)-1-(4-chlorobenzyl)-2-(4- {cyclohexyl[(dimethylamino)carbonyl]amino}piperidin-1-yl)-2-oxoethyl]amino}-Λ/- methylpiperidine-1 -carboxamide90: N -benzyl-4 - {[(1R) -1- (4-chlorobenzyl) -2- (4- {cyclohexyl [(dimethylamino) carbonyl] amino} piperidin-1-yl) -2-oxoethyl] amino } -Λ / - methylpiperidine-1-carboxamide
91 : Λ/-(1-{4-chloro-/V-[1-(trifluoroacetyl)piperidin-4-yl]-D-phenylalanyl}piperidin-4- yO-ΛA-cyclohexyl-Λ/', /V-dimethylurea91: Λ- (1- {4-chloro-N- [1- (trifluoroacetyl) piperidin-4-yl] -D-phenylalanyl} piperidin-4-yl-Λ-cyclohexyl-Λ; dimethylurea
92 : Λ/-{1-[Λ/-(1-acetylpiperidin-4-yl)-4-chloro-D-phenylalanyl]piperidin-4-yl}-Λ/- cyclohexyl-N,Λ/'-dimethylurea92: Λ- {1- [Λ- (1-acetylpiperidin-4-yl) -4-chloro-D-phenylalanyl] piperidin-4-yl} -α-cyclohexyl-N, Λ-dimethylurea
93 : /V-{1 -[4-chloro-Λ/-(c/s-4-hydroxy-4-phenylcyclohexyl)-D-phenylalanyl]piperidin- 4-yI}-Λ/-cyclohexyl-/V,Λ/1-dimethylurea93: N- {1 - [4-chloro-Λ- (c-s-4-hydroxy-4-phenylcyclohexyl) -D-phenylalanyl] piperidin-4-yl} -Λ-cyclohexyl- / V, Λ / 1- dimethylurea
Λ/-{1-[4-chloro-Λ/-(fraA7s-4-hydroxy-4-phenylcyclohexyl)-D- phenyIalanyl]piperidin-4-yl}-Λ/-cyclohexyl-A/',A/1-dimethylureaΛ / - {1- [4-chloro-Λ- (FrA7s-4-hydroxy-4-phenylcyclohexyl) -D-phenylalanyl] piperidin-4-yl} Λ -cyclohexyl-A ', A / 1 - dimethylurea
94 : . Λ/-(c/s-4-{[(1f?)-1-(4-chlorobenzyl)-2-(4-94:. Λ / - (c / s-4 - {[(1f?) - 1- (4-chlorobenzyl) -2- (4-
{cyclohexyl[(dimethylamino)carbonyl]amino}piperidin-1-yl)-2-oxoethyl]amino}cyclohexyl)- 2,2,2-trifluoroacetamide{cyclohexyl [(dimethylamino) carbonyl] amino} piperidin-1-yl) -2-oxoethyl] amino} cyclohexyl) 2,2,2-trifluoroacetamide
Λ/-(frans-4-{[(1 R)-1 -(4-chlorobenzyl)-2-(4- {cyclohexyl[(dimethylamino)carbonyI]amino}piperidin-1-yl)-2-oxoethyl]amino}cyclohexyl)- 2,2,2-trifluoroacetamideΛ / - (4-Frans - {[(1 R) -1- (4-chlorobenzyl) -2- (4- {cyclohexyl [(dimethylamino) carbonyl] amino} piperidin-1-yl) -2-oxoethyl] amino } cyclohexyl) - 2,2,2-trifluoroacetamide
95 : Λ/-[1 -(4-chloro-Λ/-{c/s-4-[(4-fluorophenyl)amino]cyclohexyl}-D- phenylalanyl)piperidin-4-yl]-Λ/-cyclohexyl-Λ/',/\/'-dimethylurea95: Λ- [1- (4-Chloro-Λ) - {cs-4 - [(4-fluorophenyl) amino] cyclohexyl} -D-phenylalanyl) piperidin-4-yl] -Λ-cyclohexyl- Λ / '/ \ /' - dimethylurea
Λ/-[1-(4-chloro-Λ/-{fraπs-4-[(4-fluorophenyl)amino]cyclohexyl}-D- phenylalanyl)piperidin-4-yl]-A/-cyclohexyl-Λ/1,A/'-dimethylureaΛ- [1- (4-chloro-Λ) - -Fri-4 - [(4-fluorophenyl) amino] cyclohexyl} -D-phenylalanyl) piperidin-4-yl] -N-cyclohexyl-Λ / 1 A / '- dimethylurea
98 : - Λ/-[1-(4-chloro-Λ/-{c/s-4-[(2-hydroxyphenyl)amino]cyclohexyl}-D- phenylalanyl)piperidin-4-yl]-Λ/-cyclohexyl-Λ/',Λ/τ-dimethylurea98: - Λ- [1- (4-Chloro-Λ) - [α] -4 - [(2-hydroxyphenyl) amino] cyclohexyl} -D-phenylalanyl) piperidin-4-yl] -Λ-cyclohexyl -Λ / ', Λ / τ -dimethylurea
Λ/-[1-(4-chloro-Λ/-{frans-4-[(2-hydroxyphenyl)amino]cyclohexyl}-D- phenylalanyl)piperidin-4-yl]-Λ/-cyclohexyl-Λ/',Λ/'-dimethylureaΛ- [1- (4-chloro-Λ) - {frans-4 - [(2-hydroxyphenyl) amino] cyclohexyl} -D-phenylalanyl) piperidin-4-yl] -α-cyclohexyl-Λ, Λ / '- dimethylurea
102 : Λ/-{1 -[4-chloro-Λ/-(4-methoxycyclohexyl)-D-phenyla!anyl]-3-methylpiperidin-4- yl}-/V-cyclohexyl-Λ/\Λ/'-dimethylurea (trans)102: Λ- {1- [4-chloro-Λ] - (4-methoxycyclohexyl) -D-phenyl] anyl] -3-methylpiperidin-4-yl} -N-cyclohexyl-Λ / dimethylurea (trans)
103 : Λ/-{1-[4-chloro-Λ/-(4-phenylcyclohexyl)-D-phenylalanyl]-3-methylpiperidin-4- yl}-Λ/-cyclohexyl-Λ/'JA/'-dinnethylurea (trans)103: Λ / - {1- [4-chloro-Λ / - (4-phenylcyclohexyl) -D-phenylalanyl] -3-methylpiperidin-4-yl} -Λ / -cyclohexyl-Λ / 'J A /' - dinnethylurea (trans)
104 : Λ/-{1-[Λ/-(1-acetylpiperidin-4-yl)-4-chloro-D-phenylalanyl]-3-methylpiperidin-4- yl}-Λ/-cyclohexyl-Λ/'1Λ/1-dinπethylurea (trans)104: Λ- {1- [Λ- (1-acetylpiperidin-4-yl) -4-chloro-D-phenylalanyl] -3-methylpiperidin-4-yl} -β-cyclohexyl- 1 / 1 -dinπethylurea (trans)
105 : Λ/-(4-{[(1R)-1-(4-chlorobenzyl)-2-(4-105: Λ / - (4 - {[(1R) -1- (4-chlorobenzyl) -2- (4-
{cyclohexyl[(dimethylamino)carbonyl]amino}-3-methylpiperidin-1-yl)-2- oxoethyl]amino}cyclohexyl)acetamide (trans){cyclohexyl [(dimethylamino) carbonyl] amino} -3-methylpiperidin-1-yl) -2-oxoethyl] amino} cyclohexyl) acetamide (trans)
106 : Λ/-(1-{4-chloro-Λ/-[1-(trifluoroacetyl)piperidin-4-yl]-D-phenylalanyl}-3- methylpiperidin-4-yl)-A/-cyclohexyl-A/',/\/1-dimethylurea (trans)106: Λ- (1- {4-chloro-Λ- [1- (trifluoroacetyl) piperidin-4-yl] -D-phenylalanyl} -3-methylpiperidin-4-yl) -N-cyclohexyl-A / ', / \ / 1- dimethylurea (trans)
107 : ' Λ/-(4-{[(1/R)-1-(4-chIorobenzyl)-2-(4-107: ' Λ / - (4 - {[(1 / R) -1- (4-chlorobenzyl) -2- (4-
{cyclohexyl[(dimethylamino)carbonyl]amino}-3-methylpiperidin-1-yl)-2- oxoethyl]amino}cyclohexyl)-2,2,2-trifluoroacetamide (trans){cyclohexyl [(dimethylamino) carbonyl] amino} -3-methylpiperidin-1-yl) -2-oxoethyl] amino} cyclohexyl) -2,2,2-trifluoroacetamide (trans)
108 : Λ/-{1-[Λ/-(1-benzoylpiperidin-4-yl)-4-chloro-D-phenylalanyl]-3-methylpiperidin- 4-yl}-Λ/-cyclohexyl-Λ/',Λ/'-dimethylurea108: Λ- {1- [Λ- (1-benzoylpiperidin-4-yl) -4-chloro-D-phenylalanyl] -3-methylpiperidin-4-yl} -α-cyclohexyl-Λ, Λ / '- dimethylurea
109 : Λ/-(1 -{4-chloro-Λ/-[1 -(methylsulfonyl)piperidin-4-yl]-D-phenylalanyl}-3- methylpiperidin-4-yl)-Λ/-cyclohexyl-Λ/',Λ/'-dimethylurea (trans)109: Λ- (1 - {4-chloro-Λ / - [1 - (methylsulfonyl) piperidin-4-yl] -D-phenylalanyl} -3-methylpiperidin-4-yl) -β-cyclohexyl-β / ', Λ /' - dimethylurea (trans)
110 : Λ/-{1-[4-chloro-A/-(4-hydroxy-4-phenylcyclohexyl)-D-phenylalanyl]-3- methylpiperidin-4-yl}-Λ/-cyclohexyl-Λ/'>/\/1-dimethylurea (trans)110: Λ / - {1- [4-chloro-A / - (4-hydroxy-4-phenylcyclohexyl) D-phenylalanyl] -3-methylpiperidin-4-yl} -Λ / -cyclohexyl-Λ / '> / \ / 1- dimethylurea (trans)
11 1 : Λ/-[1-(4-chloro-Λ/-{4-[(4-fluorophenyl)amino]cyclohexyl}-D-phenylalanyl)-3- methylpiperidin-4-yl]-Λ/-cyclohexyl-Λ/1,Λ/'-dimethylurea1: Λ- [1- (4-Chloro-Λ) - {4 - [(4-fluorophenyl) amino] cyclohexyl} -D-phenylalanyl) -3-methylpiperidin-4-yl] -α-cyclohexyl Λ / 1 , Λ / '- dimethylurea
113 : Λ/-{1 -[Λ/-(c/s-4-aminocyclohexyl)-4-chloro-D-phenylalanyl]-3-methylpiperidin- 4-yl}-Λ/-cyclohexyl-ΛΛ /V-dimethylurea (trans)113: Λ- {1 - [Λ- (α-4-aminocyclohexyl) -4-chloro-D-phenylalanyl] -3-methylpiperidin-4-yl} Λ -cyclohexyl-ΛΛ / V-dimethylurea (trans)
115 : Λ/-[1 -(4-chloro-A/-{c/s-4-[(2-methoxyphenyl)amino3cyclohexyl}-D- phenylalanyl)piperidin-4-yI]-/\/-cyclohexyl-A/'!Λ/'-dimethylurea115: Λ- [1- (4-Chloro-N- [α] -4 - [(2-methoxyphenyl) amino] cyclohexyl} -D-phenylalanyl) piperidin-4-yl] -cyclohexyl-A / ' ! Λ / '- dimethylurea
A/-[1-(4-chloro-Λ/-{/raA7s-4-[(2-methoxyphenyl)amino]cyclohexyl}-D- phenylalanyl)piperidin-4-yl]-Λ/-cycIohexyl-Λ/1,Λ/'-dimethyIurea 116 : A/-(c/s-4-{[(1 R)-I -(4-chlorobenzyl)-2-(4-N - [1- (4-chloro-Λ] - [N '] s - 4 - [(2-methoxyphenyl) amino] cyclohexyl] -D-phenylalanyl) piperidin-4-yl] -alkylhexyl- 1 , Λ / '- dimethyIurea 116: A / - (c / s-4 - {[(1 R) -1 - (4-chlorobenzyl) -2- (4-
{cyclohexyl[(dimethylamino)carbonyl]amino}piperidin-1-yl)-2- oxoethyl]amino}cyclohexyl)acetamide Λ/-(frans-4-{[(1 R)-1-(4-chlorobenzyl)-2-(4-{cyclohexyl [(dimethylamino) carbonyl] amino} piperidin-1-yl) -2-oxoethyl] amino} cyclohexyl) acetamide Λ / - (frans-4 - {[(1R) -1- (4-chlorobenzyl) -2} - (4-
{cyclohexyl[(dimethylamino)carbonyl]amino}piperidin-1-yl)-2- oxoethyl]amino}cyclohexyl)acetamide{cyclohexyl [(dimethylamino) carbonyl] amino} piperidin-1-yl) -2-oxoethyl] amino} cyclohexyl) acetamide
117 : Λ/-(1-{4-chloro-/V-[c/s-4-(4-hydroxyphenyl)cyclohexyl]-D-phenylalanyl}-3- methylpiperidin-4-yl)-Λ/-cyclohexyl-Λ/'1A/'-dimethylurea117: Λ- (1- {4-chloro-N- [α] -4- (4-hydroxyphenyl) cyclohexyl] -D-phenylalanyl} -3-methylpiperidin-4-yl) Λ -cyclohexyl- Λ / ' 1 A /' - dimethylurea
Λ/-(1-{4-chloro-Λ/-[/rans-4-(4-hydroxyphenyl)cyclohexyl]-D-phenylalanyl}-3- methylpiperidin-4-yl)-Λ/-cyclohexyl-Λ/\Λf-dimethylureaΛ- (1- {4-chloro-Λ- [/ trans-4- (4-hydroxyphenyl) cyclohexyl] -D-phenylalanyl} -3-methylpiperidin-4-yl} -Λ-cyclohexyl-Λ Λf-dimethylurea
118 : Λ/-(1-{4-chloro-Λ/-[4-(2-oxo-1 ,3-oxazolidin-3-yl)cyclohexyl]-D-phenylalanyl}-3- methylpiperidin-4-yl)-Λ/-cyclohexyl-Λ/\Λ/'-dimethylurea (trans)118: Λ- (1- {4-chloro-Λ- [4- (2-oxo-1,3-oxazolidin-3-yl) cyclohexyl] -D-phenylalanyl} -3-methylpiperidin-4-yl) -Cyclohexyl-β / dimethylurea (trans)
119 : Λ/-{1-[4-chloro-Λ/-(1-isonicotinoylpiperidin-4-yl)-D-phenylalanyl]-3- methylpiperidin-4-yl}-Λ/-cyclohexyl-A/',Λ/l-dimethylurea (trans)119: Λ- {1- [4-chloro-Λ] - (1-isonicotinoylpiperidin-4-yl) -D-phenylalanyl] -3-methylpiperidin-4-yl} -Λ-cyclohexyl-A] - / l- dimethylurea (trans)
120 : Λ/-(1-{4-chloro-Λ/-[c/s-4-(1 ,3-dihydro-2H-isoindol-2-yl)cyclohexyl]-D- phenylalanyl}-3-methylpiperidin-4-yl)-/V-cyclohexyl-Λ/',Λ/'-dimethylurea (trans)120: Λ- (1- {4-chloro-Λ- [α] -4- (1,3-dihydro-2H-isoindol-2-yl) cyclohexyl] -D-phenylalanyl} -3-methylpiperidin 4-yl) -N-cyclohexyl-N, N-dimethylurea (trans)
121 : Λ/-{1 -[4-chloro-Λ/-(2-phenylpiperidin-4-yl)-D-phenylalanyi]-3-methylpiperidin- 4-yl}-Λ/-cyclohexyl-Λ/1 1Λ/'-dimethylurea (trans)121: Λ- {1 - [4-chloro-Λ] - (2-phenylpiperidin-4-yl) -D-phenylalanyl] -3-methylpiperidin-4-yl} -Λ-cyclohexyl-Λ / 1 1 / '- dimethylurea (trans)
122 : Λ/-(1 -{4-chloro-Λ/-[4-(3-oxopiperazin-1 -yl)cyclohexyl]-D-phenylalanyl}-3- methylpiperidin-4-yl)-Λ/-cyclohexyl-Λ/',/\/'-dimethylurea (trans)122: Λ- (1- {4-chloro-Λ- [4- (3-oxopiperazin-1-yl) cyclohexyl] -D-phenylalanyl} -3-methylpiperidin-4-yl) -cyclohexyl} Λ / ', / \ /' - dimethylurea (trans)
Parmi les composés préférés de formule I dans laquelle X est CR6R7, on peut citer ceux dont les noms suiventAmong the preferred compounds of formula I in which X is CR 6 R 7 , mention may be made of those whose names follow
2 : Λ/-{1-[A/-(4-aminocyclohexyl)-4-chloro-D-phenylalanyl]pipeπdin-4-yl}-Λ/- cydohexyl-A/'.Λ/'-diethylurea2: Λ- {1- [N- (4-aminocyclohexyl) -4-chloro-D-phenylalanyl] piperidin-4-yl} -ocyclohexyl-N-diethylurea
8 : Λ/-{1-[Λ/-(c/s-4-aminocyclohexyl)-4-chloro-D-phenylalanyl]piperidin-4-yl}-Λ/- cyclohexyl-1 ,3-dihydro-2/-/-isoindole-2-carboxamide8: Λ- {1- [Λ- (α-4-aminocyclohexyl) -4-chloro-D-phenylalanyl] piperidin-4-yl} Λ-cyclohexyl-1,3-dihydro-2 - / - isoindole-2-carboxamide
9 : A/-{1 -[A/-(c/s-4-aminocyclohexyl)-4-chloro-D-phenylalanyl]piperidin-4-yl}-/\/- cyclohexyl-2,5-dimethy!pyrrolidine-1-carboxamide9: N- {1 - [N- (c-S-4-aminocyclohexyl) -4-chloro-D-phenylalanyl] piperidin-4-yl} -1H-cyclohexyl-2,5-dimethyl pyrrolidine -1-carboxamide
12 : Λ/-{1 -[Λ/-(c/s-4-aminocyclohexyl)-4-chloro-D-phenylalanyl]piperidin-4-yl}-Λ/- cyclohexyl-Λ/',Λ/'-dimethylurea12: Λ- {1 - [Λ- (α-4-aminocyclohexyl) -4-chloro-D-phenylalanyl] piperidin-4-yl} -Λ-cyclohexyl-β, Λ- dimethylurea
14 : Λ/-{1 -[Λ/-(c/s-4-aminocyclohexyl)-4-chloro-D-phenylalanyl]piperidin-4-yl}-A/- cyclohexyl-Λ/1-methoxy-Λ/1-methylurea14: Λ- {1 - [Λ- ( α-4-aminocyclohexyl) -4-chloro-D-phenylalanyl] piperidin-4-yl} -N-cyclohexyl-Λ- 1- methoxy-Λ / 1- methylurea
23 : Λ/-{1 -[Λ/-(c/s-4-aminocyclohexyl)-4-chloro-D-phenyla!anyl]piperidin-4-yl}-Λ/- cyclohexyl-2,5-dimethyl-2,5-dihydro-1 H-pyrrole-1 -carboxamide23: Λ- {1 - [Λ- (α-4-aminocyclohexyl) -4-chloro-D-phenylanyl] piperidin-4-yl} -α-cyclohexyl-2,5-dimethyl- 2,5-Dihydro-1H-pyrrole-1-carboxamide
29 : A/-{1 -[Λ/-(c/s-4-aminocyclohexyl)-4-chloro-D-phenylalanyl]piperidin-4-yl}-Λ/- cyciobutyl-A/'.Λ/'-diethyiurea29: N- {1- [N- (c-s-4-aminocyclohexyl) -4-chloro-D-phenylalanyl] piperidin-4-yl} -alkylbutyl-N diethyiurea
32 : Λ/-{1 -[Λ/-(c/s-4-aminocycIohexyI)-4-chloro-D-phenylalanyl]piperidin-4-yl}-Λ/- cyclopentyl-Λ/'.Λ/'-diethylurea 33 : /\/-{1-[Λ/-(c/s-4-anninocycIohexyl)-4-chloro-D-phenylalanyl]piperidin-4-yl}-Λ/- cycloheptyl-Λ/'.Λ/'-diethylurea32: Λ- {1 - [Λ- (α-4-aminocyclohexyl) -4-chloro-D-phenylalanyl] piperidin-4-yl} -Λ-cyclopentyl-β '- diethylurea 33: N- (1- [N- (c-s-4-anninocyclohexyl) -4-chloro-D-phenylalanyl] piperidin-4-yl} -alkylcycloheptyl-β- -diethylurea
35 : Λ/-{1 -[Λ/-(c/s-4-aminocyclohexyl)-4-chloro-D-phenylalanyl]piperidin-4-yI}-A/- cyclooctyl-ΛΛ/V-diethylurea35: Λ- {1 - [Λ- (α-4-aminocyclohexyl) -4-chloro-D-phenylalanyl] piperidin-4-yl} -N-cyclooctyl-ΛΛ / V-diethylurea
37 : Λ/-{1 -[Λ/-(c/s-4-aminocyclohexyl)-4-chloro-D-phenylalanyl]piperidin-4-yl}-Λ/',Λ/'- diethyl-A/-phenylurea37: Λ- {1 - [Λ- (α-4-aminocyclohexyl) -4-chloro-D-phenylalanyl] piperidin-4-yl} -α, Λ-diethyl-A / - phenylurea
38 : Λ/-{1-[Λ/-(c/s-4-aminocyclohexyl)-4-chloro-D-phenylalanyl]piperidin-4-yl}-Λ/- cyclohexyl-Λ/1-(2,2,2-trifluoroethyl)urea38: Λ- {1- [Λ- (α-4-aminocyclohexyl) -4-chloro-D-phenylalanyl] piperidin-4-yl} -Λ-cyclohexyl-Λ / 1 - (2.2 , 2-trifluoroethyl) urea
45 : Λ/-{1-[4-chloro-Λ/-(4-hydroxycyclohexyl)-D-phenylalanyl]piperidin-4-yl}-A/- cyclohexyl-ΛΛ/V-diethylurea45: Λ- {1- [4-chloro-Λ- (4-hydroxycyclohexyl) -D-phenylalanyl] piperidin-4-yl} -N-cyclohexyl-ΛΛ-V-diethylurea
48 : Λ/-{1-[A/-(c/s-4-aminocyclohexyl)-4-chloro-D-phenylalanyl]-3-methylpiperidin-4- yl)-Λ/-cyclohexyl~Λ/1,Λ/'-diethylurea (trans)48: Λ- {1- [N- (c-β-4-aminocyclohexyl) -4-chloro-D-phenylalanyl] -3-methylpiperidin-4-yl) Λ -cyclohexyl-Λ / 1 , Λ / '- diethylurea (trans)
49 : A/-{1 -[A/-(c/s-4-aminocyclohexyl)-4-chloro-D-phenylalanyl]-3-methylpiperidin-4- yl}-/V-cyclohexyl-/V,/V-diethylurea (cis)49: N - {1 - [N- (cs-4-aminocyclohexyl) -4-chloro-D-phenylalanyl] -3-methylpiperidin-4-yl} -N-cyclohexyl- / V, / V -diethylurea (cis)
50 : /V-{1 -[Λ/-(fraπs-4-aminocyclohexyl)-4-chloro-D-phenylalanyl]-3-methylpiperidin- 4-yl)-/V-cyclohexyl-Λ/1,Λ/1-diethylurea (trans)50: / V- {1 - [Λ / - (trif-4-aminocyclohexyl) -4-chloro-D-phenylalanyl] -3-methylpiperidin-4-yl) - β-cyclohexyl-Λ / 1 , Λ / 1 -diethylurea (trans)
51 : Λ/-{1-[/\/-(trans-4-aminocyclohexyl)-4-chloro-D-phenylalanyl]-3-nnethylpiperidin- 4-yl}-A/-cyclόhexyl-A/',Λ/1-diethylurea (cis)51: Λ- {1- [1- [1- (trans-4-aminocyclohexyl) -4-chloro-D-phenylalanyl] -3-nnethylpiperidin-4-yl} -N-cyclohexyl-A] - / 1- diethylurea (cis)
64 : Λ/-{1 -[Λ/-(c/s-4-aminocyclohexyl)-4-chloro-D-phenylalanyl3piperidin-4-yl}-Λ/1,Λ/1- diethyl-/V-(tetrahydro-2/-/-pyran-4-yl)urea64: Λ- {1 - [Λ- (c-β-4-aminocyclohexyl) -4-chloro-D-phenylalanyl] -piperidin-4-yl} -Λ / 1 , Λ- 1 -diethyl- / V- (tetrahydro) -2 / - / - pyran-4-yl) urea
65 : Λ/-{1-[Λ/-(c/s-4-aminocyclohexyl)-4-chloro-D-phenylalanyl]piperidin-4-yl)-Λ/l JΛ/1- diethyl-Λ/-piperidin-4-ylurea65: Λ- {1- [Λ- (cs-4-aminocyclohexyl) -4-chloro-D-phenylalanyl] piperidin-4-yl} -1 / 1 J Λ / 1 -diethyl-Λ / - piperidin-4-ylurea
67 : Λ/-{1 -[Λ/-(c/s-4-aminocyclohexyl)-4-chloro-D-phenylalanyl]piperidin-4-yl}-Λ/- cyclohexyl-Λr-ethyl-ΛT-isopropylurea67: Λ- {1 - [Λ- (α-4-aminocyclohexyl) -4-chloro-D-phenylalanyl] piperidin-4-yl} -Λ-cyclohexyl-Λr-ethyl-Λ-t-isopropylurea
71 : Λ/-{1 -[Λ/-(c/s-4-aminocyclohexyl)-4-chloro-D-phenylaIanyl]piperidin-4-yl}-Λ/- cyclohexyl-2,2-dimethylhydrazinecarboxamide71: Λ- {1 - [Λ- (α-4-aminocyclohexyl) -4-chloro-D-phenylanyl] piperidin-4-yl} Λ-cyclohexyl-2,2-dimethylhydrazinecarboxamide
74 : Λ/-(c/s-4-{[(1R)-1-(4-chlorobenzyl)-2-(4-74: Λ / - (c / s-4 - {[(1R) -1- (4-chlorobenzyl) -2- (4-
{cyclohexyl[(diethylamino)carbonyl]amino}piperidin-1-yl)-2-oxoethyl]amino)cyclohexyl)- 2,2,2-trifluoroacetamide{cyclohexyl [(diethylamino) carbonyl] amino} piperidin-1-yl) -2-oxoethyl] amino) cyclohexyl) 2,2,2-trifluoroacetamide
Λ/-(trans-4-{[(1R)-1-(4-chlorobenzyl)-2-(4-Λ / - (trans-4 - {[(1R) -1- (4-chlorobenzyl) -2- (4-
{cyclohexyl[(diethylamino)carbonyl]amino}piperidin-1-yl)-2-oxoethyl]amino)cyclohexyl)- 2,2,2-trifluoroacetamide{cyclohexyl [(diethylamino) carbonyl] amino} piperidin-1-yl) -2-oxoethyl] amino) cyclohexyl) 2,2,2-trifluoroacetamide
76 : A/-{1 -[yV-(frans-4-aminocyclohexyl)-4-chloro-D-phenylalanyl]piperidin-4-yl)-Λ/- cyclohexyl-Λ/')Λ/1-bis(2-fluoroethyl)urea76: A / - {1 - [yV- (trans-4-aminocyclohexyl) -4-chloro-D-phenylalanyl] piperidin-4-yl) -Λ / - cyclohexyl-Λ / ') Λ / 1 -bis (2 -fluoroethyl) urea
Parmi les composés préférés de formule I dans laquelle X est CR6R7, on peut encore citer ceux dont les noms suiventAmong the preferred compounds of formula I in which X is CR 6 R 7 , mention may also be made of those whose names follow
77 : Λ/-[(1fi)-1-(4-chlorobenzyl)-2-(4-{cyclohexyl[2- (diethylamino)ethyl]amino}piperidin-1-yl)-2-oxoethyl]cyclohexane-1 ,4-diamine77: Λ / - [(1fi) -1- (4-chlorobenzyl) -2- (4- {cyclohexyl [2- (Diethylamino) ethyl] amino} piperidin-1-yl) -2-oxoethyl] cyclohexane-1,4-diamine
79 : Λ/-(1-{4-chloro-Λ/-[c/s-4-(dimethylamino)cyclohexyl]-D-phenylalanyl}piperidin- 4-yl)-A/-cyclohexyl-3,4-difluorobenzamide79: Λ- (1- {4-chloro-Λ- [α] -4- (dimethylamino) cyclohexyl] -D-phenylalanyl} piperidin-4-yl) -N-cyclohexyl-3,4-difluorobenzamide
80 : Λ/-(1 -{4-chloro-Λ/-[c/s-4-(dimethylamino)cyclohexyl]-D-phenylaIanyl}piperidin- 4-yl)-Λ/-cycloheptyl-ΛΛΛ/1-dimethylurea80: Λ- (1 - {4-chloro-Λ- [α] -4- (dimethylamino) cyclohexyl] -D-phenylanyanyl} piperidin-4-yl) Λ -cycloheptyl-ΛΛΛ- 1- dimethylurea
81 : (2R,5S)-Λ/-{1 -[Λ/-(c/s-4-aminocyclohexyl)-4-chloro-D-phenylalanyl]piperidin-4- yl}-Λ/-cyclohexyl-2,5-dimethylpyrrolidine-1-carboxamide81: (2R, 5S) -Λ- {1 - [Λ] - (α-4-aminocyclohexyl) -4-chloro-D-phenylalanyl] piperidin-4-yl} -β-cyclohexyl-2, 5-dimethylpyrrolidine-1-carboxamide
82 : (2R5S)-Λ/-(1 -{4-chloro-Λ/-[c/s-4-(dimethylamino)cyclohexyl]-D- phenylalanyI}piperidin-4-yl)-/V-cyciohexyl-2,5-dimethylpyrrolidine-1-carboxamide82: (2R5S) -Λ- (1 - {4-chloro-Λ [- / c- [4- (dimethylamino) cyclohexyl] -D-phenylalanyl} piperidin-4-yl) - β-cyclohexyl-2 , 5-dimethylpyrrolidine-1-carboxamide
93 : Λ/-{1 -[4-chloro-Λ/-(c/s-4-hydroxy-4-phenylcyclohexyl)-D-phenylalanyl]piperidin- 4-yl}-/V-cyclohexyl-Λ/\Λ/'-dimethylurea93: Λ- {1 - [4-chloro-Λ- (c-β-4-hydroxy-4-phenylcyclohexyl) -D-phenylalanyl] piperidin-4-yl} - β-cyclohexyl-Λ / Λ / '- dimethylurea
Λ/-{1-[4-chloro-Λ/-(frans-4-hydroxy-4-phenylcyclohexyl)-D- phenylalanyl]piperidin-4-yl}-Λ/-cyclohexyl-Λ/',Λ/l-dimethylureaΛ / - {1- [4-chloro-Λ / - (trans-4-hydroxy-4-phenylcyclohexyl) -D-phenylalanyl] piperidin-4-yl} -Λ / -cyclohexyl-Λ / ', Λ / l - dimethylurea
94 : N-(c/s-4-{[(1R)-1-(4-chlorobenzyl)-2-(4- {cyclohexyl[(dimethylamino)carbonyl]amino}piperidin-1-yi)-2-oxoethyl]amino}cyclohexyl)- 2,2,2-trifluoroacetamide94: N- (c / s-4 - {[(1R) -1- (4-chlorobenzyl) -2- (4- {cyclohexyl [(dimethylamino) carbonyl] amino} piperidin-1-yl) -2-oxoethyl ] amino} cyclohexyl) 2,2,2-trifluoroacetamide
Λ/-(fraA7s-4-{[(1 R)-1 -(4-chlorobenzyl)-2-(4-Λ / - (fraA7s-4 - {[(1 R) -1 - (4-chlorobenzyl) -2- (4-
{cyclohexyl[(dimethylamino)carbonyl]amino}piperidin-1-yl)-2-oxoethyl]amino}cyclohexyl)- 2,2,2-trifluoroacetamide{cyclohexyl [(dimethylamino) carbonyl] amino} piperidin-1-yl) -2-oxoethyl] amino} cyclohexyl) 2,2,2-trifluoroacetamide
95 : Λ/-[1 -(4-chloro-Λ/-{c/s-4-[(4-fiuorophenyl)amino]cyclohexyl}-D- phenylalanyl)piperidin-4-yl]-Λ/-cyclohexyl-Λ/',Λ/'-dimethylurea95: Λ- [1- (4-chloro-Λ) - [[α] -4 - [(4-fluorophenyl) amino] cyclohexyl} -D-phenylalanyl) piperidin-4-yl] -Λ-cyclohexyl- Λ / ', Λ /' - dimethylurea
Λ/-[1-(4-chloro-A/-{frans-4-[(4-fluorophenyl)amino]cyclohexyl}-D- phenylalanyl)piperidin-4-yl]-Λ/-cyclohexyl-Λ/1,Λ/'-dimethylureaΛ- [1- (4-chloro-N- (4-fluorophenyl) amino] cyclohexyl} -D-phenylalanyl) piperidin-4-yl] -NH-cyclohexyl-Λ / 1 Λ / '- dimethylurea
96 : A/-{1-[4-chloro-Λ/-(4-methoxycyclohexyl)-D-phenylalanyl]piperidin-4-yl}-Λ/- cyclohexyl-ΛΛ/V-dimethylurea96: N- {1- [4-chloro-Λ] - (4-methoxycyclohexyl) -D-phenylalanyl] piperidin-4-yl} -ocyclohexyl-N-dimethylurea
97 : Λ/-[1-(4-chloro-Λ/-{c/s-4-[(4-methoxyphenyl)amino]cyclohexyI}-D- phenylalanyl)piperidin-4-yl]-Λ/-cyclohexyl-Λ/1,Λ/'-dimethylurea97: Λ- [1- (4-Chloro-Λ) - {cs-4 - [(4-methoxyphenyl) amino] cyclohexyl} -D-phenylalanyl) piperidin-4-yl] Λ -cyclohexyl- Λ / 1 , Λ / '- dimethylurea
A/-[1-(4-chloro-Λ/-{?rans-4-[(4-methoxyphenyl)amino]cyclohexyl}-D- phenylalanyl)piperidin-4-yl]-Λ/-cyclohexyl-Λ/1,Λ/'-dimethylureaN - [1- (4-chloro-Λ) -N- [4 - ((4-methoxyphenyl) amino] cyclohexyl} -D-phenylalanyl) piperidin-4-yl] -α-cyclohexyl-Λ / 1 , Λ / '- dimethylurea
98 : Λ/-[1 -(4-chloro-Λ/-{c/s-4-[(2-hydroxyphenyl)amino]cyclohexyl}-D- phenylalanyl)piperidin-4-yl]-Λ/-cyclohexyl-Λ/',/\/1-dimethylurea98: Λ- [1- (4-chloro-Λ) - {cs-4 - [(2-hydroxyphenyl) amino] cyclohexyl} -D-phenylalanyl) piperidin-4-yl] -Λ-cyclohexyl- Λ / ', / \ / 1- dimethylurea
Λ/-[1-(4-chloro-Λ/-{frans-4-[(2-hydroxyphenyl)amino]cyclohexyl}-D- phenylalanyl)piperidin-4-yl]-Λ/-cyclohexyl-/V,Λ/1-dimethylureaΛ / - [1- (4-chloro-Λ) - {4-enans-4 - [(2-hydroxyphenyl) amino] cyclohexyl} -D-phenylalanyl) piperidin-4-yl] -cyclohexyl- / V, Λ / 1- dimethylurea
99 : Λ/-[1 -(4-chloro-Λ/-{4-[(dimethylamino)methyl]-4-phenylcyclohexyl}-D- phenyialanyl)piperidin-4-yl]-Λ/-cyclohexyl-Λ/'JΛ/'-dimethylurea99: Λ- [1- (4-chloro-Λ) - {4 - [(dimethylamino) methyl] -4-phenylcyclohexyl} -D-phenylialanyl) piperidin-4-yl] -β-cyclohexyl-β J Λ / '- dimethylurea
100 : (2S,5S)-Λ/-(1 -{4-chloro-N-[c/s-4-(dimethylamino)cyclohexyl]-D- phenylalanyl}piperidin-4-yl)-A/-cyclohexyl-2I5-dimethylpyrrolidine-1-carboxamide 101 : (2R,5R)-Λ/-(1-{4-chloro-Λ/-[c/s-4-(dimethylamino)cyclohexyl]-D- phenylalanyl}piperidin-4-yl)-Λ/-cyclohexyl-2)5-dimethylpyrrolidine-1-carboxamide100: (2S, 5S) -Λ- (1 - {4-chloro-N- [α] -4- (dimethylamino) cyclohexyl] -D-phenylalanyl} piperidin-4-yl) -N-cyclohexyl- 2 I 5-dimethylpyrrolidine-1-carboxamide 101: (2R, 5R) -Λ- (1- {4-chloro-Λ [- / c- [4- (dimethylamino) cyclohexyl] -D-phenylalanyl} piperidin-4-yl} -Λ-cyclohexyl -2 ) 5-dimethylpyrrolidine-1-carboxamide
102 : A/-{1 -[4-chloro-Λ/-(4-methoxycyclohexyl)-D-phenylalanyl]-3-methylpiperidin-4- yl}-A/-cyclohexyl-A/',A/'-dimethylurea102: N- {1- [4-chloro-Λ] - (4-methoxycyclohexyl) -D-phenylalanyl] -3-methylpiperidin-4-yl} -N-cyclohexyl-N, N-dimethylurea;
103 : Λ/-{1 -[4-chloro-Λ/-(4-phenylcyclohexyl)-D-phenylalanyl]-3-methylpiperidin-4- yl}-A/-cyclohexyl-A/',A/'-dimethylurea103: Λ- {1- [4-chloro-Λ] - (4-phenylcyclohexyl) -D-phenylalanyl] -3-methylpiperidin-4-yl} -N-cyclohexyl-N, N-dimethylurea
105 : A/-(4-{[(1 R)-1-(4-chlorobenzyl)-2-(4-105: A / - (4 - {[(1 R) -1- (4-chlorobenzyl) -2- (4-
{cyclohexyl[(dimethylamino)carbonyl]amino}-3-methylpiperidin-1-yl)-2- oxoethyl]amino}cyclohexyl)acetamide{cyclohexyl [(dimethylamino) carbonyl] amino} -3-methylpiperidin-1-yl) -2-oxoethyl] amino} cyclohexyl) acetamide
107 : A/-(4-{[(1R)-1-(4-chlorobenzyl)-2-(4-107: A / - (4 - {[(1R) -1- (4-chlorobenzyl) -2- (4-
{cyclohexyl[(dimethylamino)carbonyl]amino}-3-methylpiperidin-1-yl)-2- oxoethyl]amino}cyclohexyl)-2,2,2-trifluoroacetamide{cyclohexyl [(dimethylamino) carbonyl] amino} -3-methylpiperidin-1-yl) -2-oxoethyl] amino} cyclohexyl) -2,2,2-trifluoroacetamide
110 : A/-{1-[4-chloro-A/-(4-hydroxy-4-phenylcyc!ohexyl)-D-phenylalanyl]-3- methylpiperidin-4-yl}- AZ-CyClOhIeXyI-A/1, Ay-dimethylurea110: N- {1- [4-chloro-N- (4-hydroxy-4-phenylcyclohexyl) -D-phenylalanyl] -3-methylpiperidin-4-yl} -NH-CyClO-hexyl-A / 1 , Ay-dimethylurea
111 : A/-[1 -(4-chloro-A/-{4-[(4-fluorophenyl)amino]cyclohexyl}-D-phenylalanyl)-3- methylpiperidin-4-yl]-A/-cyclohexyl-A/',A/I-dimethylurea111: N - [1- (4-chloro-N) - {4 - [(4-fluorophenyl) amino] cyclohexyl} -D-phenylalanyl) -3-methylpiperidin-4-yl] -N-cyclohexyl-A / ', A / I- dimethylurea
112 : A/-(1-{4-chloro-A/-[c/s-4-(dimethylamino)cyclohexyl]-D-phenylalanyl}piperidin- 4_yl)_yV_CyClohexyl-A/',Λ/'-dinnethiylurea112: A / - (1- {4-chloro-A / - [c / s-4- (dimethylamino) cyclohexyl] -D-phenylalanyl} piperidin 4_yl) _yV_ C y C lohexyl-A / ', Λ /' -dinnethiylurea
113 : A/-{1-[A/-(c/s-4-aminocyclohexyl)-4-chloro-D-phenylalanyl]-3-nnethylpiperidin- 4_yl}./\/_Cyciohexyl-A/',A/1-dimethylurea113: A / - {1- [A / - (c / s-4-aminocyclohexyl) -4-chloro-D-phenylalanyl] -3-nnethylpiperidin- 4_yl} ./\/_ yciohexyl C-A / ', A / 1- dimethylurea
115 : A/-[1-(4-chloro-A/-{c/s-4-[(2-methoxyphenyl)amino]cyclohexyl}-D- phenylalanyl)piperidin-4-yl]-A/-cyclohexyl-A/1,A/τ-dimethylurea115: N - [1- (4-chloro-N- [α] -4 - [(2-methoxyphenyl) amino] cyclohexyl} -D-phenylalanyl) piperidin-4-yl] -N-cyclohexyl- A / 1 , A / τ- dimethylurea
A/-[1-(4-chloro-A/-{c/s-4-[(2-methioxyphenyl)amino]cyclohexyl}-D- phenylalanyl)piperidin-4-yl]-A/-cyclohexyl-A/',A/'-dimethylureaN - [1- (4-Chloro-N- {cs-4 - [(2-methioxyphenyl) amino] cyclohexyl} -D-phenylalanyl) piperidin-4-yl] -N-cyclohexyl-A / 'A /' - dimethylurea
116 : A/-(c/s-4-{[(1 ft)-1 -(4-chlorobenzyl)-2-(4- {cyclohexyl[(dimethylamino)carbonyl]amino}piperidin-1-yl)-2- oxoethyl]amino}cyclohexyl)acetamide116: N- (c / s-4 - {[(1-yl) -1- (4-chlorobenzyl) -2- (4- {cyclohexyl [(dimethylamino) carbonyl] amino} piperidin-1-yl) -2 - oxoethyl] amino} cyclohexyl) acetamide
A/-(frans-4-{[(1 R)-1 -(4-chlorobenzyl)-2-(4- {cyclohexyl[(dimethylamino)carbonyl]amino}piperidin-1-yl)-2- oxoethyl]amino}cyclohexyl)acetamideA / - (4-Frans - {[(1 R) -1- (4-chlorobenzyl) -2- (4- {cyclohexyl [(dimethylamino) carbonyl] amino} piperidin-1-yl) -2-oxoethyl] amino } cyclohexyl) acetamide
117 : Λ/-(1-{4-chloro-A/-[c/s-4-(4-hydroxyphenyl)cyclohexyl]-D-phenylalanyl}-3- methylpiperidin-4-yl)-A/-cyclohexyl-A/',A/'-dimethiylurea117: Λ- (1- {4-chloro-N- [α] -4- (4-hydroxyphenyl) cyclohexyl] -D-phenylalanyl} -3-methylpiperidin-4-yl) -N-cyclohexyl- A / 'A /' - dimethiylurea
A/-(1-{4-chloro-A/-[^ans-4-(4-hydroxyphenyl)cyclohexyl]-D-phenylalanyl}-3- methylpiperidin-4-yl)-A/-cyclohexyl-A/',A/'-dimethylureaN - (1- {4-chloro-N- [4-yl-4- (4-hydroxyphenyl) cyclohexyl] -D-phenylalanyl} -3-methylpiperidin-4-yl) -N-cyclohexyl-A]; A / '- dimethylurea
118 : A/-(1-{4-chIoro-A/-[4-(2-oxo-1,3-oxazolidin-3-yl)cyclohexyl]-D-phenylalanyl}-3- methylpiperidin-4-yl)-A/-cyclohexyl-A/',A/l-dimethiylurea118: N- (1- {4-chloro-N- [4- (2-oxo-1,3-oxazolidin-3-yl) cyclohexyl] -D-phenylalanyl} -3-methylpiperidin-4-yl) -A / -cyclohexyl-A / ', A / l- dimethylurea
120 : A/-(1-{4-chloro-A/-[c/s-4-(1 ,3-dihydro-2H-isoindol-2-yl)cyclohexyl]-D- phenylalany]}-3-rnethylpiperidin-4-yl)-/V-cycIόhexyl-Λ/,A/1-dimethylurea120: N - (1- {4-chloro-N- [c / s-4- (1,3-dihydro-2H-isoindol-2-yl) cyclohexyl] -D- phenylalanyl} -3-methylpiperidin-4-yl) -N-cyclohexyl-Λ, A / 1- dimethylurea
122 : A/-(1 -{4-chloro-Λ/-[4-(3-oxopiperazin-1 -yl)cyclohexyl]-D-phenylalanyl}-3- methylpiperidin-4-yl)-Λ/-cyclohexyl-Λ/\Λ/'-dimethylurea122: N- (1 - {4-chloro-Λ- [4- (3-oxopiperazin-1-yl) cyclohexyl] -D-phenylalanyl} -3-methylpiperidin-4-yl) -NH-cyclohexyl- Λ / \ Λ / '- dimethylurea
Parmi les composés préférés de formule I dans laquelle X est NR™, on peut citer ceux dont les noms suiventAmong the preferred compounds of formula I in which X is NR ™, mention may be made of those whose names follow
4 : Λ/-[1-(Λ/-8-azabicyclo[3.2.1]oct-3-yl-4-chloro-D-phenylalanyl)piperidin-4-yl]-Λ/- cyclohexyl-Λ/1 , /V-diethyl u rea4: Λ- [1- (Λ) -8-azabicyclo [3.2.1] oct-3-yl-4-chloro-D-phenylalanyl) piperidin-4-yl] -oc-cyclohexyl-Λ / 1 , / V-diethyl u rea
5 : Λ/-[1 -(AM -azabicyclo[2.2.2]oct~3-yl-4-chloro-D-phenylalanyl)piperidin-4-yl]-Λ/- cyclohexyl-Λ/'.Λ/'-diethylurea5: Λ- [1 - (AM-azabicyclo [2.2.2] oct-3-yl-4-chloro-D-phenylalanyl) piperidin-4-yl] -ocyclohexyl-β- -diethylurea
30 : Λ/-[1-(Λ/-8-azabicyclo[3.2.1]oct-3-yl-4-chloro-D-phenylalanyl)piperidin-4-yl]-Λ/- cyclobutyl-Λ/\Λ/1-diethylurea30: Λ- [1- (Λ -8-azabicyclo [3.2.1] oct-3-yl-4-chloro-D-phenylalanyl) piperidin-4-yl] -Λ-cyclobutyl-Λ / Λ / 1- diethylurea
75 : Λ/-{1-[A/-(1-benzoylpiperidin-4-yl)-4-chloro-D-phenylalanyl]piperidin-4-yl}-Λ/- cyclohexyl-Λ/1,Λ/1-diethylurea75: Λ- {1- [N- (1-benzoylpiperidin-4-yl) -4-chloro-D-phenylalanyl] piperidin-4-yl} -Λ-cyclohexyl-Λ / 1 , Λ / 1 - diethylurea
Parmi les composés préférés de formule I dans laquelle X est NRi0, on peut citer ceux dont les noms suiventAmong the preferred compounds of formula I in which X is NRi 0 , mention may be made of those whose names follow
83 : 4-{[(1R)-1-(4-chlorobenzyl)-2-(4-83: 4 - {[(1R) -1- (4-chlorobenzyl) -2- (4-
{cyclohexyl[(dimethylamino)carbonyl]amino}piperidin-1-yl)-2-oxoethyl]amino}-Λ/,Λ/- dimethylpiperidine-1-carboxamide{cyclohexyl [(dimethylamino) carbonyl] amino} piperidin-1-yl) -2-oxoethyl] amino} -α, β-dimethylpiperidine-1-carboxamide
84 : 4-{[(1 R)-1-(4-chlorobenzyl)-2-(4-84: 4 - {[(1 R) -1- (4-chlorobenzyl) -2- (4-
{cyclohexyl[(dimethylamino)carbonyl]amino}piperidin-1-yl)-2-oxoethyl]amino}-Λ/,Λ/- diethylpiperidine-1 -carboxamide{cyclohexyl [(dimethylamino) carbonyl] amino} piperidin-1-yl) -2-oxoethyl] amino} -α, β-diethylpiperidine-1-carboxamide
85 : Λ/-(1-{4-chloro-Λ/-[1-(pyrrolidin-1-ylcarbonyl)piperidin-4-yl]-D- phenylalanyl}piperidin-4-yl)-N-cyclohexyl-Λ/'IΛ/'-dimethylurea85: Λ- (1- {4-chloro-Λ- [1- (pyrrolidin-1-ylcarbonyl) piperidin-4-yl] -D-phenylalanyl} piperidin-4-yl) -N-cyclohexyl} / ' I Λ /' - dimethylurea
86 : Λ/-(1-{4-chloro-Λ/-[1-(piperidin-1-ylcarbonyl)piperidin-4-yl]-D- phenylalanyl}piperidin-4-yl)-Λ/-cyclohexyl-Λ/',Λ/'-dimethylurea86: Λ- (1- {4-chloro-Λ- [1- (piperidin-1-ylcarbonyl) piperidin-4-yl] -D-phenylalanyl} piperidin-4-yl) -Λ-cyclohexyl-Λ / ', Λ /' - dimethylurea
87 : Λ/-(1-{4-chloro-Λ/-[1-(morpholin-4-ylcarbonyl)piperidin-4-yl]-D- phenylalanyl}piperidin-4-yl)-A/-cyclohexyl-A/',Λ/'-dimethylurea87: Λ- (1- {4-chloro-Λ- [1- (morpholin-4-ylcarbonyl) piperidin-4-yl] -D-phenylalanyl} piperidin-4-yl) -N-cyclohexyl-A / ', Λ /' - dimethylurea
88 : 4-{[(1R)-1-(4-chiorobenzyl)-2-(4-88: 4 - {[(1R) -1- (4-chlorobenzyl) -2- (4-
{cyclohexyl[(dimethylamino)carbonyl]amino}piperidin-1-yl)-2-oxoethyl]amino}-Λ/- phenylpiperidine-1 -carboxamide{cyclohexyl [(dimethylamino) carbonyl] amino} piperidin-1-yl) -2-oxoethyl] amino} -α-phenylpiperidine-1-carboxamide
89 : • 4-{[(1R)-1-(4-chlorobenzyl)-2-(4-89: • 4 - {[(1R) -1- (4-chlorobenzyl) -2- (4-
{cyclohexyl[(dimethylamino)carbonyl]amino}piperidin-1-yl)-2-oxoethyl]amino}-Λ/-methyl-A/- phenylpiperidine-1 -carboxamide{cyclohexyl [(dimethylamino) carbonyl] amino} piperidin-1-yl) -2-oxoethyl] amino} -α-methyl-N-phenylpiperidine-1-carboxamide
90 : A/-benzyl-4-{[(1f?)-1-(4-chlorobenzyl)-2-(4-90: N-benzyl-4 - {[(1f)) - 1- (4-chlorobenzyl) -2- (4-
{cyclohexyl[(dimethylamino)carbonyl]amino}piperidin-1-yl)-2-oxoethyl]amino}-/\/- methylpiperidine-1 -carboxamide{Cyclohexyl [(dimethylamino) carbonyl] amino} piperidin-1-yl) -2-oxoethyl] amino} - / \ / - methylpiperidine-1-carboxamide
91 : Λ/-(1-{4-chloro-Λ/-[1-(trifluoroacetyl)piperidin-4-yl]-D-phenylalanyl}piperidin-4- yl)-Λ/-cyclohexyl-Λ/I,Λ/1-dimethylurea91: Λ- (1- {4-chloro-Λ- [1- (trifluoroacetyl) piperidin-4-yl] -D-phenylalanyl} piperidin-4-yl) -β-cyclohexyl-Λ / I , Λ / 1- dimethylurea
92 : Λ/-{1-[Λ/-(1 -acetylpiperidin-4-yl)-4-chloro-D-phenylalanyl]piperidin~4-yl}-A/- cyclohexyl-Λ/'.'Λ/'-dimethylurea92: Λ- {1- [Λ- (1-acetylpiperidin-4-yl) -4-chloro-D-phenylalanyl] piperidin-4-yl} -N-cyclohexyl-Λ. ' Λ /' - dimethylurea
104 : Λ/-{1 -[A/-(1 -acetylpiperidin-4-yl)-4-chloro-D-phenylalanyl]-3-methylpiperidin-4- yl}-Λ/-cyclohexyl-Λ/I,Λ/'-dimethylurea104: Λ- {1 - [N- (1-acetylpiperidin-4-yl) -4-chloro-D-phenylalanyl] -3-methylpiperidin-4-yl} -Λ / -cyclohexyl-Λ / I , Λ / '- dimethylurea
106 : Λ/-(1-{4-chloro-Λ/-[1-(trifluoroacetyl)piperidin-4-yl]-D-phenylalanyl}-3- methylpiperidin-4-yl)-A/-cyclohexyl-A/',A/1-dimethylurea106: Λ- (1- {4-chloro-Λ- [1- (trifluoroacetyl) piperidin-4-yl] -D-phenylalanyl} -3-methylpiperidin-4-yl) -N-cyclohexyl-A / ', A / 1 -dimethylurea
108 : Λ/-{1-[Λ/-(1-benzoylpiperidin-4-yl)-4-chloro-D-phenylalanyl]-3-methylpiperidin- 4-yi}-Λ/-cyclohexyl-Λ/',Λ/'-dimethylurea108: Λ- {1- [Λ- (1-benzoylpiperidin-4-yl) -4-chloro-D-phenylalanyl] -3-methylpiperidin-4-yl} -α-cyclohexyl-Λ, Λ / '- dimethylurea
109 : Λ/-(1-{4-chloro-Λ/-[1-(methylsulfonyl)piperidin-4-yl]-D-phenylalanyl}-3- methylpiperidin-4-yl)-Λ/-cyclohexyl-Λ/',Λ/'-dimethylurea109: Λ- (1- {4-chloro-Λ- [1- (methylsulfonyl) piperidin-4-yl] -D-phenylalanyl} -3-methylpiperidin-4-yl} -Λ-cyclohexyl-Λ / 'Λ /' - dimethylurea
114 : Λ/-(1-{4-chloro-Λ/-[1-(methylsulfonyl)piperidin-4-yl]-D-phenylalanyl}piperidin- 4-^)-AZ-CyCIoHeXyI-A/1, yV-dimethylurea114: Λ- (1- {4-chloro-Λ- [1- (methylsulfonyl) piperidin-4-yl] -D-phenylalanyl} piperidin-4-yl) -ZC-CyCIoHeXyI-A / 1 , yV- dimethylurea
119 : A/-{1-[4-chloro-A/-(1-isonicotinoylpiperidin-4-yl)-D-phenylalanyl]-3- methylpiperidin-4-yl}-/\/-cyclohexyl-A/I,A/'-dimethylurea119: N- {1- [4-chloro-N- (1-isonicotinoylpiperidin-4-yl) -D-phenylalanyl] -3-methylpiperidin-4-yl} -N-cyclohexyl-A / I , A / '- dimethylurea
121 : A/-{1 -[4-chloro-A/-(2-phenylpiperidin-4-yl)-D-phenylalanyl]-3-methylpiperidin- 121: N - {1 - [4-chloro-N- (2-phenylpiperidin-4-yl) -D-phenylalanyl] -3-methylpiperidin
Selon un autre objet l'invention se rapporte à un médicament caractérisé en ce qu'il comprend un composé de formule (I) tel que décrit ci-dessus ou un sel d'addition de ce composé à un acide pharmaceutiquement acceptable, ou encore un hydrate ou un solvat du composé de formule (I).According to another object the invention relates to a medicinal product characterized in that it comprises a compound of formula (I) as described above or a salt of addition of this compound to a pharmaceutically acceptable acid, or a hydrate or a solvate of the compound of formula (I).
Selon un autre objet l'invention se rapporte à une composition pharmaceutique, caractérisée en ce qu'elle comprend un composé de formule (I) tel que décrit ci-dessus, ou un sel pharmaceutiquement acceptable, un hydrate ou un solvat de ce composé, ainsi qu'au moins un excipient pharmaceutiquement acceptable.According to another object the invention relates to a pharmaceutical composition, characterized in that it comprises a compound of formula (I) as described above, or a pharmaceutically acceptable salt, a hydrate or a solvate of this compound, as well as at least one pharmaceutically acceptable excipient.
Selon un autre objet, l'invention se rapporte à l'utilisation d'un composé de formule (I) pour la préparation d'un médicament destiné au traitement et à la prévention de l'obésité, du diabète et des dysfonctions sexuelles pouvant affecter les deux sexes en particulier des dysfonctionnements érectilës, au traitement des maladies cardiovasculaires ainsi que dans des applications anti-inflammatoires ou dans le traitement de la dépendance alcoolique. Selon un autre objet l'invention se rapporte à un procédé de préparation d'un composé de formule (I) tel que décrit ci-dessus caractérisé en ce que l'on réalise une amination réductrice d'un composé de formule (V) :According to another subject, the invention relates to the use of a compound of formula (I) for the preparation of a medicament for the treatment and prevention of obesity, diabetes and sexual dysfunction which may affect both sexes in particular erectile dysfunction, the treatment of cardiovascular diseases as well as in anti-inflammatory applications or in the treatment of alcohol dependence. According to another object the invention relates to a process for the preparation of a compound of formula (I) as described above characterized in that a reductive amination of a compound of formula (V) is carried out:
en présence d'un dérivé du groupe R4 de type cétone, R1, R2, R3, R4, R5, Ra et Ra> étant tels que définis dans l'une quelconque des revendications 1 à 23. in the presence of a ketone-type R 4 derivative, R 1 , R 2 , R 3 , R 4 , R 5 , R a and R a > being as defined in any one of claims 1 to 23.
Dans ce qui suit, on entend par groupe protecteur (Pg) un groupe qui permet, d'une part, de protéger une fonction réactive telle qu'un hydroxy ou une aminé pendant une synthèse et, d'autre part, de régénérer la fonction réactive intacte en fin de synthèse. Des exemples de groupes protecteurs ainsi que des méthodes de protection et de déprotection sont données dans « Protective Groups in Organic Synthesis », Green W. et al., 1999, 3rd Edition (John Wiley & Sons, Inc., New York).In what follows, a protective group (Pg) is understood to mean a group which makes it possible, on the one hand, to protect a reactive function such as a hydroxyl or an amine during a synthesis and, on the other hand, to regenerate the function reactive intact at the end of synthesis. Examples of protective and methods of protecting and deprotecting groups are given in "Protective Groups in Organic Synthesis", W. Green et al., 1999, 3 rd Edition (John Wiley & Sons, Inc., New York).
On entend par groupe partant (Lg), dans ce qui suit, un groupe pouvant être facilement clivé d'une molécule par rupture d'une liaison hétérolytique, avec départ d'une paire électronique. Ce groupe peut ainsi être remplacé facilement par un autre groupe lors d'une réaction de substitution, par exemple. De tels groupes partants sont, par exemple, les halogènes ou un groupe hydroxy activé tel qu'un mésyle, tosyle, triflate, acétyle, etc. Des exemples de groupes partants ainsi que des références pour leur préparation sont donnés dans « March's Advanced Organic Chemistry », J. March et al., 5th Edition, 2001 ,- EMInter Ed.By leaving group (Lg) is meant, in what follows, a group that can be easily cleaved from a molecule by breaking a heterolytic bond, with the departure of an electronic pair. This group can thus be easily replaced by another group during a substitution reaction, for example. Such leaving groups are, for example, halogens or an activated hydroxy group such as mesyl, tosyl, triflate, acetyl, etc. Examples of leaving groups as well as references for their preparation are given in "March's Advanced Organic Chemistry", J. March et al, 5 th Edition, 2001, -. EMInter Ed.
On entend par groupement Boc un groupement t-butoxycarbonyl, Bn un groupement benzyle, CBz un groupement benzyloxycarbonyl, Fmoc un groupement 9- fluorenylmethyl-carbamate, et par h les heures.By Boc group is meant a t-butoxycarbonyl group, Bn a benzyl group, CBz a benzyloxycarbonyl group, Fmoc a 9-fluorenylmethyl-carbamate group, and h the hours.
Selon un autre objet l'invention se rapporte aux composés de formules (Vl)1 (XVIII) et (XIX), dans lesquelles Ri, R2, R3, R4, R5, Ra et Ra> sont tels que définis plus haut dans le texte et Pg représente un groupe protecteur : According to another object the invention relates to the compounds of formulas (VI) 1 (XVIII) and (XIX), in which R 1, R 2 , R 3, R 4 , R 5, R a and R a are as defined above. high in the text and Pg represents a protecting group:
Conformément à l'invention, on peut préparer les composés de formule générale (I) selon le procédé présenté dans le schéma 1.According to the invention, the compounds of general formula (I) can be prepared according to the process shown in Scheme 1.
Schéma 1 :Figure 1:
Selon le schéma 1, les composés de formule (IV) peuvent être préparés par couplage entre les intermédiaires de formule (II) et un aminoacide de formule (III) dont la fonction aminé est protégée par un groupement protecteur Pg (par exemple un groupement Boc, CBz ou Fmoc), dans des conditions de couplage peptidique classiques, en utilisant par exemple comme agent couplant Ie dicyclocarbodiimide, le chlorhydrate du 1-(3-diméthylaminopropyl)-3-éthylcarbodiimide ou le bromo-tris-pyrrolidino-phosphonium hexafluorophosphate, en présence ou non d'hydroxybenzo-triazole, et comme base la triéthylamine ou la diisopropyléthylamine dans un solvant tel que le dioxane, le dichlorométhane ou l'acétonitrile.According to Scheme 1, the compounds of formula (IV) may be prepared by coupling between the intermediates of formula (II) and an amino acid of formula (III), the amino function of which is protected by a protective group Pg (for example a Boc group) , CBz or Fmoc), under conventional peptide coupling conditions, using for example as coupling agent dicyclocarbodiimide, the hydrochloride of the 1- (3-Dimethylaminopropyl) -3-ethylcarbodiimide or bromo-tris-pyrrolidino-phosphonium hexafluorophosphate, in the presence or absence of hydroxybenzo-triazole, and as base triethylamine or diisopropylethylamine in a solvent such as dioxane, dichloromethane or acetonitrile.
Les aminoacides de formule générale (III) sont disponibles commercialement ou peuvent être préparés par des méthodes décrites dans la littérature (Williams, R.M., Synthesis of Optically Active α-Aminoacids, Pergamon Press, Oxford, 1989).The amino acids of general formula (III) are commercially available or can be prepared by methods described in the literature (Williams, R. M., Synthesis of Optically Active α-Aminoacids, Pergamon Press, Oxford, 1989).
Les composés de formule (V) sont obtenus par déprotection de la fonction aminé des composés de formule (IV), par des méthodes choisies parmi celles connues de l'Homme de l'art. Elles comprennent entre autres l'utilisation d'acide trifluoroacétique ou d'acide chlorhydrique dans le dichlorométhane, le dioxane, le tétrahydrofurane ou le diéthyléther dans Ie cas d'une protection par un groupement Boc, l'hydrogénation avec le métal approprié dans le méthanol ou l'éthanol dans le cas d'un CBz, et de pipéridine pour un groupement Fmoc, à des températures variant de -1O0C à 1000C.The compounds of formula (V) are obtained by deprotection of the amine function of the compounds of formula (IV), by methods chosen from those known to those skilled in the art. They include inter alia the use of trifluoroacetic acid or hydrochloric acid in dichloromethane, dioxane, tetrahydrofuran or diethyl ether in the case of protection by a Boc group, hydrogenation with the appropriate metal in methanol or ethanol in the case of a CBz, and piperidine for a Fmoc group, at temperatures ranging from -1O 0 C to 100 0 C.
Dans une dernière étape, les composés de formule (I) sont obtenus par amination réductrice, réalisée en mettant les composés de formule (V) en présence d'un dérivé du groupe R4 de type cétone, en utilisant un réducteur tel que le borohydrure de sodium, le triacétoxyborohydrure de sodium ou le cyanoborohydrure de sodium, en présence ou non d'un acide de Bronsted (tel que l'acide chlorhydrique) ou de Lewis (tel que le tétraisopropoxyde de titane) dans un solvant tel que le dichloroéthane, le dichlorométhane, l'acide acétique ou le méthanol, à des températures comprises entre -10°C et 300C.In a final step, the compounds of formula (I) are obtained by reductive amination, carried out by bringing the compounds of formula (V) in the presence of a ketone-type derivative R 4 , using a reducing agent such as borohydride sodium, sodium triacetoxyborohydride or sodium cyanoborohydride, in the presence or absence of a Bronsted acid (such as hydrochloric acid) or Lewis acid (such as titanium tetraisopropoxide) in a solvent such as dichloroethane, dichloromethane, acetic acid or methanol at temperatures between -10 ° C. and 30 ° C.
Les dérivés du groupe R4 de type cétone peuvent être commerciaux ou obtenus par des méthodes connues de l'Homme de l'art, par exemple par acylation de la fonction aminé ou hydroxyle libre du dérivé de type cétone.The R 4 ketone group derivatives may be commercial or obtained by methods known to those skilled in the art, for example by acylation of the amine or free hydroxyl function of the ketone derivative.
Les composés de formule générale (I) peuvent également être préparés selon le procédé présenté dans le schéma 2.The compounds of general formula (I) may also be prepared according to the process shown in Scheme 2.
Schéma 2 :Figure 2:
Selon le schéma 2, les composés de formule (V), obtenus comme décrit précédemment dans le schéma 1, sont mis en présence avec un dérivé du groupe R4 de type cétone (réaction d'amination réductrice, comme décrit ci-dessus en rapport avec le schéma 1), ledit groupe R4 portant un groupe Pg protecteur d'aminé, pour donner les composés de formule (Vl). La fonction aminé des composés de formule (Vl) est ensuite déprotégée par des méthodes connues de l'Homme de l'art, comme décrit précédemment. According to Scheme 2, the compounds of formula (V), obtained as described previously in Scheme 1, are brought into contact with a ketone-type derivative of the R 4 group (reductive amination reaction, as described above in relation to with Scheme 1), said group R 4 carrying an amine protecting group Pg, to give the compounds of formula (VI). The amine function of the compounds of formula (VI) is then deprotected by methods known to those skilled in the art, as described above.
Alternativement, les composés de formule (Vl) conduisant aux composés de formule (I) peuvent être préparés selon le procédé présenté dans le schéma 3.Alternatively, the compounds of formula (VI) leading to the compounds of formula (I) can be prepared according to the process shown in scheme 3.
Schéma 3 :Figure 3:
Selon le schéma 3, les composés de formule (VIII) peuvent être obtenus par amination réductrice, comme décrit précédemment, réalisée à partir des aminoacides de formule (VII). L'aminoacide de formule (VII) est disponible commercialement quand R5 = H, ou peut être préparé par des méthodes décrites dans la littérature (Williams, R.M., • Synthesis of Optically Active α-Aminoacids, Pergamon Press, Oxford, 1989). Dans les cas où R5 représente un groupe alkyle, les aminoacides de formule (VII) peuvent être préparés par alkylation de l'aminoacide commercial protégé sur la fonction aminé, selon les méthodes d'alkylation connues de l'Homme de l'art.According to Scheme 3, the compounds of formula (VIII) can be obtained by reductive amination, as described above, carried out from the amino acids of formula (VII). The amino acid of formula (VII) is commercially available when R 5 = H, or can be prepared by methods described in the literature (Williams, RM, Synthesis of Optically Active α-Aminoacids, Pergamon Press, Oxford, 1989). In cases where R 5 represents an alkyl group, the amino acids of formula (VII) can be prepared by alkylation of the protected commercial amino acid on the amine function, according to the alkylation methods known to those skilled in the art.
Les composés de formule (IX) peuvent être synthétisés par saponification des esters de formule (VIII), par exemple en présence d'hydroxyde de sodium ou d'hydroxyde de lithium dans un solvant tel que le méthanol, le tétrahydrofurane ou l'eau, ou un mélange de ces solvants.The compounds of formula (IX) may be synthesized by saponification of the esters of formula (VIII), for example in the presence of sodium hydroxide or of lithium hydroxide in a solvent such as methanol, tetrahydrofuran or water, or a mixture of these solvents.
Les composés de formule générale (Vl) peuvent être préparés par couplage peptidique entre les intermédiaires de formule (II) et l'aminoacide de formule (IX), dans des conditions de couplage peptidique telles que décrites dans le schéma 1.The compounds of general formula (VI) may be prepared by peptide coupling between the intermediates of formula (II) and the amino acid of formula (IX), under peptide coupling conditions as described in scheme 1.
Les composés de formules (II) peuvent être obtenus selon le procédé présenté dans le schéma 4.The compounds of formulas (II) can be obtained according to the process shown in scheme 4.
Schéma 4Figure 4
(X) (H)(X) (H)
Selon le schéma 4, les composés de formule (II) peuvent être préparés à partir du composé de formule (X) (où Pg est un groupement protecteur d'aminé, tel que défini dans le schéma 1 ), après déprotection de la fonction aminé par des méthodes choisies parmi celles connues de l'Homme de l'art, comme décrit précédemment.According to scheme 4, the compounds of formula (II) may be prepared from the compound of formula (X) (where Pg is an amine protecting group, as defined in scheme 1), after deprotection of the amine function by methods selected from those known to those skilled in the art, as described above.
Le composé de formule (X) est préparé selon les méthodes décrites dans la littérature ou connues de l'Homme de l'art, adaptées en fonction de la nature des groupes R1 et R2. Les schémas 5 à 9 ci-après présentent des exemples de préparation des composés de formule (X) selon différentes natures du groupe R2. Par exemple dans le cas où R2 représente un groupe -CO-R15, où R15 est tel que défini ci-avant, la préparation du composé (Xa) correspondant peut être effectuée selon le schéma 5. Schéma 5 :The compound of formula (X) is prepared according to the methods described in the literature or known to those skilled in the art, adapted according to the nature of the groups R 1 and R 2 . Diagrams 5 to 9 below show examples of the preparation of compounds of formula (X) according to different types of group R 2 . For example, in the case where R 2 represents a group -CO-R 15 , where R 15 is as defined above, the preparation of the corresponding compound (Xa) can be carried out according to scheme 5. Figure 5:
(Xl) (Xa)(X1) (Xa)
Selon le schéma 5, les composés de formule (Xl) peuvent être obtenus par aniination réductrice, dans les conditions décrites précédemment, de la pipéridone dont la fonction aminé est protégée (par exemple la Boc-pipéridone commerciale). On obtient ensuite les composés de formule (Xa) par réaction des composés de formule (Xl) avec un chlorure d'acide de formule R15COCI, en présence d'une base organique telle que la triéthylamine ou la pyridine, dans un solvant tel que le dichlorométhane ou le tétrahydrofurane.According to Scheme 5, the compounds of formula (XI) can be obtained by reductive anionization, under the conditions described above, of the piperidone whose amine function is protected (for example commercial Boc-piperidone). The compounds of formula (Xa) are then obtained by reacting the compounds of formula (XI) with an acid chloride of formula R 15 COCI, in the presence of an organic base such as triethylamine or pyridine, in a solvent such as than dichloromethane or tetrahydrofuran.
Une variante du schéma 5 consiste à faire réagir une aminopipéridine protégée (telle que la 1-Boc-4-aminopipéridine commerciale) avec un dérivé oxo du groupe R1 dans des conditions d'amination réductrice décrites précédemment.An alternative to Scheme 5 is to react a protected aminopiperidine (such as commercial 1-Boc-4-aminopiperidine) with an oxo derivative of the R 1 group under reductive amination conditions described above.
Le schéma 6 présente une voie de préparation des composés de formule (Xb) et (Xc), qui correspondent respectivement aux composés de formule (X) dans lesquels R2 représente un groupe -CO-NRi6Ri7 et -CO-NR15-NR16Ri7, où Ri5, Ri6 et Ri7 sont tels que définis ci-avant.Scheme 6 shows a route of preparation of the compounds of formula (Xb) and (Xc), which respectively correspond to the compounds of formula (X) in which R 2 represents a group -CO-NRi 6 Ri 7 and -CO-NR 15 -NR 16 Ri 7 , where Ri 5 , Ri 6 and Ri 7 are as defined above.
Schéma 6Figure 6
Selon le schéma 6, les composés de formule (XII) peuvent être préparés à partir des composés de formule (Xl) par réaction avec du phosgène, du triphosgène ou du trichlorométhyle chloroformate dans le dichlorométhane ou le toluène en présence de triéthylamine ou de pyridine et une aminé à des températures variant de -100C, et 8O0C. La réaction des composés de formule (XII) avec une aminé de formule HN(R16)(R17) ou une hydrazine de formule HN(Ri5)(NR16Ri7) aboutit respectivement aux composés de formules (Xb) et (Xc).According to Scheme 6, the compounds of formula (XII) may be prepared from the compounds of formula (XI) by reaction with phosgene, triphosgene or trichloromethyl chloroformate in dichloromethane or toluene in the presence of triethylamine or pyridine and an amine at temperatures ranging from -10 ° C. to 80 ° C. The reaction of the compounds of formula (XII) with an amine of formula HN (R 16 ) (R 17 ) or a hydrazine of formula HN (Ri 5 ) (NR 16 R 17 ) results respectively in the compounds of formulas (Xb) and (Xc).
Le schéma 7 présente une voie de préparation des composés de formule (Xd), correspondant aux composés de formule (X) dans lesquels R2 représente un groupe -(CH2)χ-NR16Ri7, où x = 2, 3 ou 4 et où R16 et Ri7 sont tels que définis ci-avant.Scheme 7 shows a route of preparation of the compounds of formula (Xd), corresponding to the compounds of formula (X) in which R 2 represents a group - (CH 2 ) χ -NR 16 Ri 7 , where x = 2, 3 or 4 and wherein R 16 and R 17 are as defined above.
Schéma 7 :Figure 7:
Selon le schéma 7, les composés de formule (XIII) peuvent être obtenus par amination réductrice réalisée sur les composés de formule (Xl) en présence d'un aldéhyde de formule Q-CO-(CH2)χ-2-CHO, où Q représente un groupe -O-alkyle ou -N(O-alkyle)(alkyle), en utilisant un réducteur tel que décrit précédemment en rapport avec le schéma 1.According to Scheme 7, the compounds of formula (XIII) can be obtained by reductive amination carried out on the compounds of formula (Xl) in the presence of an aldehyde of formula Q-CO- (CH 2 ) χ- 2 -CHO, where Q is -O-alkyl or -N (O-alkyl) (alkyl), using a reductant as described above in connection with Scheme 1.
Puis les composés de formule générale (XIII) peuvent être réduits pour conduire aux aldéhydes de formule (XIV), en utilisant un réducteur tel que l'hydrure de diisobutyl aluminium ou le tétraaluminohydrure de sodium dans le cas où Q est un groupe -O-alkyle, ou par réduction avec l'hydrure de lithium aluminium dans Ie cas où Q est un groupe -N(O-alkyle)(alkyle) (par exemple -N(OMe)Me)1 obtenu par exemple par réaction d'un organomagnésien, tel que le chlorure de diisopropylmagnésien, sur les composés de formule (XIII) où Q = -O-alkyle en présence d'une alkylhydroxylalkyle aminé telle que la N,O-diméthylhydroxylamine, dans des solvants tels que le tétrahydrofurane ou le diéthyléther à des températures variant de -78°C à 2O0C.Then the compounds of general formula (XIII) can be reduced to yield aldehydes of formula (XIV), using a reducing agent such as diisobutyl aluminum hydride or sodium tetraaluminohydride in the case where Q is a group -O- alkyl, or by reduction with lithium aluminum hydride in the case where Q is a group -N (O-alkyl) (alkyl) (for example -N (OMe) Me) 1 obtained for example by reaction of an organomagnesium , such as diisopropylmagnesium chloride, on the compounds of formula (XIII) where Q = -O-alkyl in the presence of an alkylhydroxylalkyl amine such as N, O-dimethylhydroxylamine, in solvents such as tetrahydrofuran or diethyl ether. temperatures ranging from -78 ° C. to 20 ° C.
Les composés de formule (Xd) peuvent ensuite être préparés par amination réductrice réalisée en présence d'une aminé .de formule R17R16NH, en utilisant un réducteur tel que décrit ci-dessus.The compounds of formula (Xd) can then be prepared by amination reducing agent prepared in the presence of an amine of formula R 17 R 16 NH, using a reducing agent as described above.
Le schéma 8 présente une voie de préparation des composés de formule (Xe),. correspondant aux composés de formule (X) dans lesquels R2 représente un groupe -(CH2)x-aryle (où x = O1 1 , 2, 3 ou 4) ou -(CH2)x-hétéroaryle (où x = 1 , 2, 3 ou 4).Scheme 8 shows a route of preparation of the compounds of formula (Xe) ,. corresponding to the compounds of formula (X) in which R 2 represents a group - (CH 2 ) x -aryl (where x = O 1 1, 2, 3 or 4) or - (CH 2 ) x -heteroaryl (where x = 1, 2, 3 or 4).
Schéma 8Figure 8
Selon le schéma 8, les composés de formules (Xe), dans lesquels R2 représente un groupe -(CH2)x-hétéroaryle (où x = 1 , 2, 3 ou 4), peuvent être obtenus par amination réductrice à partir des composés de formule (Xl)i, réalisée en présence d'un aldéhyde de formule : hétéroaryle-(CH2)x-1-CHO, en utilisant un réducteur tel que décrit précédemment en rapport avec le schéma 1.According to Scheme 8, the compounds of formulas (Xe) in which R 2 represents a - (CH 2 ) x -heteroaryl group (where x = 1, 2, 3 or 4) can be obtained by reductive amination from compounds of formula (Xl) i, carried out in the presence of an aldehyde of formula: heteroaryl- (CH 2 ) x-1 -CHO, using a reducing agent as described above in connection with scheme 1.
La même réaction peut également être utilisée pour obtenir les composés de formule (Xd), et ce en utilisant un aldéhyde de formule R17Ri6N-(CH2)x-1-CHO.The same reaction can also be used to obtain the compounds of formula (Xd), using an aldehyde of formula R 17 Ri 6 N- (CH 2 ) x-1 -CHO.
Les composés de formules (Xl)ii, dans lesquels R2 représente un groupe -(CH2)x-aryle (où x = 0, 1 , 2, 3 ou 4), peuvent être obtenus par amination réductrice à partir de la pipéridone protégée sur la fonction aminé, réalisée en présence d'une aminé de formule : aryle-(CH2)x-NH2, en utilisant un réducteur tel que décrit précédemment en rapport avec le schéma 1. Les composés de formules (Xe) dans lesquels R2 représente un groupe -(CH2)x-aryle peuvent ensuite être obtenus par amination réductrice à partir des composés de formule (Xl)ii, réalisée en présence d'un dérivé de groupe R1 de type oxo.Compounds of formulas (XI) ii in which R 2 represents a group - (CH 2 ) x -aryl (where x = 0, 1, 2, 3 or 4) can be obtained by reductive amination from piperidone protected on the amine function, carried out in the presence of an amine of formula: aryl- (CH 2 ) x -NH 2 , using a reducing agent as described above in relation to Scheme 1. The compounds of formulas (Xe) in which R 2 represents a - (CH 2 ) x -aryl group may then be obtained by reductive amination from the compounds of formula (XI) ii, carried out in the presence of an oxo-type derivative of R 1 group.
Le schéma 9 détaille une alternative pour la synthèse des composés de formule (Xe) dans lesquels R2 représente un groupe -(CH2)x-hétéroaryle, où x est égal à 2 ou 3. Schéma 9 :Scheme 9 details an alternative for the synthesis of compounds of formula (Xe) in which R 2 represents a - (CH 2 ) x -heteroaryl group, where x is 2 or 3. Figure 9:
Selon le schéma 9, les composés de formule (XIII), dans lesquels Q représente un groupe -O-alkyle, peuvent être réduits en alcools correspondants en utilisant un réducteur tel que l'hydrure de lithium aluminium dans un solvant tel que le diéthyléther ou le tétrahydrofurane, à des températures variant de -600C à 20°C.According to Scheme 9, the compounds of formula (XIII), in which Q represents a -O-alkyl group, can be reduced to the corresponding alcohols by using a reducing agent such as lithium aluminum hydride in a solvent such as diethyl ether or tetrahydrofuran, at temperatures ranging from -60 ° C. to 20 ° C.
Le groupement hydroxyle des composés de formule (XV) est ensuite transformé en groupement partant (Lg), tels que le chlorure ou le mésylate, par exemple par action de tétrabromométhane et de triphénylphosphine dans un solvant tel que le dichlorométhane ou par action de chlorure de méthanesulfonyle en présence d'une base organique telle que la triéthylamine à des températures variant de -200C à la température ambiante, pour conduire aux composés de formule (XVI).The hydroxyl group of the compounds of formula (XV) is then converted into a leaving group (Lg), such as chloride or mesylate, for example by the action of tetrabromomethane and triphenylphosphine in a solvent such as dichloromethane or by the action of sodium chloride. methanesulfonyl in the presence of an organic base such as triethylamine at temperatures ranging from -20 ° C. to room temperature, to yield compounds of formula (XVI).
Les composés de formule (Xe) sont ensuite synthétisés par une réaction de substitution nucléophile entre les composés de formule (XVI) et l'anion d'un hétéroaryle (groupe « Het »).The compounds of formula (Xe) are then synthesized by a nucleophilic substitution reaction between the compounds of formula (XVI) and the anion of a heteroaryl ("Het" group).
Selon une variante du schéma 1 , dans le cas où les composés de formule (I) comprennent, en tant que groupe R4, un groupe de formule (a) de type cyclohexyle, c'est- à-dire un groupe de formule (a) où p = 2 et X = -C(R6XR7)-, où R6 représente un groupe -OR8, R7 et R8 étant tels que définis ci-avant, alors la préparation des composés de formule (I) peut être réalisée comme décrit dans le schéma 10. According to a variant of Scheme 1, in the case where the compounds of formula (I) comprise, as R 4 group, a group of formula (a) of cyclohexyl type, that is to say a group of formula ( a) where p = 2 and X = -C (R 6 XR 7 ) -, where R 6 represents a group -OR 8 , R 7 and R 8 being as defined above, then the preparation of the compounds of formula ( I) can be performed as described in Figure 10.
Selon le schéma 10, les composés de formule (XVIII) peuvent être obtenus par une amination réductrice entre le composé de formule (XVlI) commercial et les composés de formule (V), dans des conditions telles que décrites dans le schéma 1.According to Scheme 10, the compounds of formula (XVIII) can be obtained by reductive amination between the compound of formula (XVII) and the compounds of formula (V) under conditions as described in Scheme 1.
La déprotection de la fonction oxo du composé de formule (XVIII) en présence d'un acide tel que l'acide chlorhydrique ou le pyridinium tosylate dans le tétrahydrofurane ou l'acétone, à des températures comprises entre 00C et 800C, conduit au composé de formule (XIX).Deprotection of the oxo function of the compound of formula (XVIII) in the presence of an acid such as hydrochloric acid or pyridinium tosylate in tetrahydrofuran or acetone, at temperatures of between 0 ° C. and 80 ° C., leads to the compound of formula (XIX).
Les composés de formule (If) sont préparés par réduction des composés de formule (XIX) dans des conditions telles que décrites dans Ie schéma 6.The compounds of formula (If) are prepared by reducing the compounds of formula (XIX) under conditions as described in Scheme 6.
Quand R8 est différent d'un atome d'hydrogène, on réalise une fonctionnalisation des composés de formule (If), par exemple une alkylation en présence d'une base telle que l'hydrure de sodium et d'un dérivé du groupe R8 comportant un groupement partant Lg, ce qui aboutit aux composés de formule (Ig).When R 8 is different from a hydrogen atom, functionalization of the compounds of formula (If) is carried out, for example alkylation in the presence of a base such as sodium hydride and a group R derivative. 8 having a leaving group Lg, which leads to the compounds of formula (Ig).
Dans les schémas 1 à 10, les composés de départ et les réactifs, quand leur mode de préparation n'est pas décrit, sont disponibles dans le commerce ou décrits dans la littérature, ou bien peuvent être préparés selon des méthodes qui y sont décrites ou qui sont connues de l'Homme de l'art. La présente invention a également pour objet les composés de formule (II), (IV), (V), (Vl)1 (VIII), (IX), (X), (XVIII) et (XIX) : ces composés sont utiles en tant qu'intermédiaires de synthèse des composés de formule (I).In Schemes 1 to 10, starting compounds and reagents, when their method of preparation is not described, are commercially available or described in the literature, or may be prepared according to methods described therein or which are known to those skilled in the art. The subject of the present invention is also the compounds of formula (II), (IV), (V), (VI) 1 (VIII), (IX), (X), (XVIII) and (XIX): these compounds are useful as synthetic intermediates for the compounds of formula (I).
Les exemples suivants décrivent la préparation de certains composés conformes à l'invention. Ces exemples ne sont pas limitatifs et ne font qu'illustrer la présente invention. Les numéros des composés exemplifiés renvoient à ceux donnés dans le tableau ci-après, qui illustre les structures chimiques et les propriétés physiques de quelques composés selon l'invention.The following examples describe the preparation of certain compounds according to the invention. These examples are not limiting and only illustrate the present invention. The numbers of the compounds exemplified refer to those given in the table below, which illustrates the chemical structures and the physical properties of some compounds according to the invention.
Exemple 1 : Λ/-[1-(4-chloro-Λ/-piperidin-4-yl-D-phenylalanyI)piperidîn-4-yl]-Λ/- cyclohexyI-Λf,Λ/I-dïethylurea (composé n° 1 )Example 1: Λ / - [1- (4-chloro-Λ / -piperidin-4-yl-D-phenylalanyI) piperidin-4-yl] -Λ / - cyclohexyI-Λf, Λ / I -dïethylurea (Compound No. 1)
1.1 : te/t-butyl 4-(cyclohexylamino)piperidine-1-carboxylate1.1: tert-butyl 4- (cyclohexylamino) piperidine-1-carboxylate
On place 15,0 g de 1-Boc-pipéridone dans 370 mL de dichlorométhane sous N2 en présence de 7,47 g de cyclohexylamine et de 20,7 g de triacétoxyborohydrure de sodium. Le milieu réactionnel est agité pendant 16h à température ambiante. Après addition de 30 mL de méthanol, 300g de résine DOWEX® 50X2 sont ajoutés et l'ensemble est agité pendant 45 min. La résine est ensuite essorée et lavée avec du tétrahydrofurane, puis du méthanol. Le composé attendu est alors relargué avec une solution 2N d'ammoniaque dans le méthanoi. Après concentration à sec, on obtient 13,85 g de ferf-butyl 4-(cyclohexylamino)piperidine-1-carboxylate qui est utilisé tel quel par la suite.15.0 g of 1-Boc-piperidone are placed in 370 ml of dichloromethane under N 2 in the presence of 7.47 g of cyclohexylamine and 20.7 g of sodium triacetoxyborohydride. The reaction medium is stirred for 16 hours at room temperature. After addition of 30 mL of methanol, 300 g of DOWEX ® 50X2 are added and the whole is stirred for 45 min. The resin is then dewatered and washed with tetrahydrofuran and then methanol. The expected compound is then salted out with a 2N solution of ammonia in the methanol. After concentration to dryness, 13.85 g of 4- (cyclohexylamino) -piperidine-1-carboxylic acid-4-butferr which is used as such thereafter.
1.2 : ferf-butyl 4-{cyclohexyl[(diethylamino)carbonyl]amino}piperidine-1- carboxylate1.2: 4-butyl-4- {cyclohexyl [(diethylamino) carbonyl] amino} piperidine-1-carboxylate
On place 5,92 mL de diphosgène dans 150 mL de dichlorométhane à 0°C sous N2. Une solution de 13,85 g de ferf-butyl 4-(cyclohexylamino)piperidine-1-carboxylate et de 34,18 mL de triéthylamine est ajoutée goutte à goutte. La solution est agitée 30 min à O0C puis 1h à température ambiante. Le milieu réactionnel est de nouveau placé à 00C et 5,92 mL de diphosgène et 34,18 mL de triéthylamine sont de nouveau additionnés. Après agitation pendant 1h à température ambiante, 25,4 mL de diéthylamine sont ajoutés. Le mélange est agité à température ambiante pendant 16h. Après évaporation du dichlorométhane, on ajoute 200 mL d'acide chlorhydrique 0,5N. On extrait au dichlorométhane jusqu'à épuisement de la phase aqueuse. Après séchage sur MgSO4, et concentration à sec, le résidu obtenu est chromatographié sur gel de silice en éluant avec un mélange 98/2 puis 95/5 de dichlorométhane et de méthanol pour conduire à 16,77g de te/t-butyl 4-{cyclohexyl[(diethyIamino)carbonyl]amino}piperidine-1-carboxylate.5.92 ml of diphosgene are placed in 150 ml of dichloromethane at 0 ° C. under N 2 . A solution of 13.85 g of tert-butyl 4- (cyclohexylamino) piperidine-1-carboxylate and 34.18 mL of triethylamine is added dropwise. The solution is stirred for 30 min at 0 ° C. then for 1 h at room temperature. The reaction medium is again placed at 0 ° C. and 5.92 ml of diphosgene and 34.18 ml of triethylamine are again added. After stirring for 1h at room temperature, 25.4 mL of diethylamine are added. The mixture is stirred at ambient temperature for 16 hours. After evaporation of the dichloromethane, 200 ml of 0.5N hydrochloric acid are added. It is extracted with dichloromethane until the aqueous phase is exhausted. After drying over MgSO 4 and concentration to dryness, the residue obtained is chromatographed on silica gel, eluting with with a 98/2 then 95/5 mixture of dichloromethane and methanol to yield 16.77 g of tert-butyl 4- {cyclohexyl [(diethylamino) carbonyl] amino} piperidine-1-carboxylate.
1.3 : Λ/-cyclohexyl-Λ/1,Λ/1-diethyI-/V-piperidin-4-ylurea1.3: Λ / -cyclohexyl-Λ / 1, Λ / -diethyI- 1 / V-piperidin-4-ylurea
On place 16,77g de ferf-butyl 4-{cyclohexyI[(diethylamino)carbonyl]amino} piperidine-1-carboxylate en mélange avec la diéthylurée dans 54,9 mL d'acide chlorhydrique 4N dans le dioxane. Le milieu réactionnel est agité pendant 16h à température ambiante. Après évaporation à sec, on ajoute de la soude 1 N jusqu'à pH 10 et on extrait au dichlorométhane jusqu'à épuisement de la phase aqueuse. Après séchage sur MgSO4 et évaporation à sec, le brut est chromatographié sur gel de silice en éluant avec un mélange 98/2/0,2, 95/5/0,5 puis 9/1/0,1 et 5/5/0,5 de dichlorométhane, de méthanol et d'ammoniaque pour obtenir 11,27g de Λ/-cyclohexyl-/v\ W-diethyl-AA-piperidin- 4-ylurea.16.77 g of 4- (cyclohexyl [(diethylamino) carbonyl] amino] piperidine-1-carboxylate ferf-butyl are mixed with the diethylurea in 54.9 ml of 4N hydrochloric acid in dioxane. The reaction medium is stirred for 16 hours at room temperature. After evaporation to dryness, 1N sodium hydroxide solution is added until pH 10 and the mixture is extracted with dichloromethane until the aqueous phase is exhausted. After drying over MgSO 4 and evaporation to dryness, the crude product is chromatographed on silica gel, eluting with a mixture of 98/2 / 0.2, 95/5 / 0.5 and then 9/1 / 0.1 and 5/5 0.5 g of dichloromethane, methanol and ammonia to give 11.2 g of β-cyclohexyl-diethyl-AA-piperidin-4-ylurea.
1.4 : terf-butyl [(1R)-1-(4-chlorobenzyl)-2-(4-{cyclohexyl[(diethylamino)carbonyl] amino}piperidin-1 -yl)-2-oxoethyl]carbamate1.4: tert-butyl [(1R) -1- (4-chlorobenzyl) -2- (4- {cyclohexyl [(diethylamino) carbonyl] amino} piperidin-1-yl) -2-oxoethyl] carbamate
On solubilise 2,85 g de Λ/-cyclohexyl-Λ/',Λ/I-diethyl-Λ/-piperidin-4-ylurea dans 101 mL de dichlorométhane en présence de 3,04 g de 4-chloro-D-Boc-phénylalanine, de 1 ,37 g d'hydroxybenzotriazole, de 1 ,95 g de chlorhydrate de 1-(3-diméthylaminopropyl)-3- éthyl-carbodiimide et de 1 ,77 mL de dϋsopropyléthylamine. Le mélange est agité 16h à température ambiante. Après évaporation à sec, le résidu est hydrolyse et extrait à l'acétate d'éthyle jusqu'à épuisement de la phase aqueuse. Les phases organiques sont lavées avec une solution de soude 1 N puis à l'eau. Après séchage sur MgSO4 et concentration à sec, le brut est chromatographié sur gel de silice en éluant avec un mélange 98/2 puis 95/5 de dichlorométhane et de méthanol pour conduire à 5,04 g de te/t-butyl [(1R)-1-(4-chlorobenzyl)-2-(4-{cyclohexyl[(diethylamino)carbonyl]amino} piperidin-1 -yl)-2-oxoethyl]carbamate .Is dissolved 2.85 g of Λ / -cyclohexyl-Λ / ', Λ / I -diethyl-Λ / -piperidin-4-ylurea in 101 mL of dichloromethane in the presence of 3.04 g of 4-chloro-D-Boc phenylalanine, 1.37 g of hydroxybenzotriazole, 1.95 g of 1- (3-dimethylaminopropyl) -3-ethyl-carbodiimide hydrochloride and 1.77 ml of de-isopropylethylamine. The mixture is stirred 16h at room temperature. After evaporation to dryness, the residue is hydrolyzed and extracted with ethyl acetate until the aqueous phase is exhausted. The organic phases are washed with a 1N sodium hydroxide solution and then with water. After drying over MgSO 4 and concentration to dryness, the crude is chromatographed on silica gel, eluting with a 98/2 then 95/5 mixture of dichloromethane and methanol to yield 5.04 g of tert-butyl [( 1R) -1- (4-chlorobenzyl) -2- (4- {cyclohexyl [(diethylamino) carbonyl] amino} piperidin-1-yl) -2-oxoethyl] carbamate.
1.5 : Λ/-[1-(4-chIoro-D-phenylalanyl)piperidin-4-yl]-Λ/-cyclohexyI-Λ/',A/l-diethylurea On place 5,16 g de terf-butyl [(1R)-1-(4-chlorobenzyl)-2-(4-{cyclohexyl1.5: Λ / - [1- (4-chloro-D-phenylalanyl) piperidin-4-yl] -Λ / -cyclohexyI-Λ / ', A / l -diethylurea was placed 5.16 g of tert-butyl [( 1R) -1- (4-chlorobenzyl) -2- (4- {cyclohexyl
[(diethylamino)carbonyl]amino}piperidin-1-yl)-2-oxoethyl]carbamate dans 22,89 mL d'acide chlorhydrique 4N dans le dioxane. Le milieu réactionnel est agité pendant 24h à température ambiante. Après évaporation à sec, le résidu est repris à l'acétate d'éthyle et lavé avec une solution aqueuse saturée d'hydrogénocarbonate de sodium puis avec une solution aqueuse saturée de chlorure de sodium. Après séchage sur MgSO4 et concentration à sec, le brut est chromatographié sur gel de silice en éluant avec un mélange 95/5 de dichlorométhane et de méthanol. On obtient 2,9 g de Λ/-[1-(4-chloro-D- pheny]alanyl)piperidin-4-yl]-Λ/-cyclohexyl-A/I,A/'-diethylurea.[(diethylamino) carbonyl] amino) piperidin-1-yl) -2-oxoethyl] carbamate in 22.89 mL of 4N hydrochloric acid in dioxane. The reaction medium is stirred for 24 hours at room temperature. After evaporation to dryness, the residue is taken up in ethyl acetate and washed with a saturated aqueous solution of sodium hydrogencarbonate and then with a saturated aqueous solution of sodium chloride. After drying over MgSO 4 and concentration to dryness, the crude is chromatographed on silica gel, eluting with a 95/5 mixture of dichloromethane and methanol. 2.9 g of Λ / - [1- (4-chloro-D- phenylalanyl) piperidin-4-yl] -NH-cyclohexyl-A / I , N '- diethylurea.
1.6 : fe/t-butyl 4-{[(1R)-1-(4-chlorobenzyl)-2-(4-{cyclohexyI[(diethylamino) carbonyl]amino} piperidin-1 -yl)-2-oxoethyl]amino}piperidine-1 -carboxylate1.6: tert-butyl 4 - {[(1R) -1- (4-chlorobenzyl) -2- (4- {cyclohexyl [(diethylamino) carbonyl] amino} piperidin-1-yl) -2-oxoethyl] amino } piperidine-1-carboxylate
On solubilise 0,5 g de Λ/-[1-(4-chloro-D-phenylalanyl)piperidin-4-yl]-Λ/-cyclohexyl- A/'.W-diethylurea dans 5 mL de dichlorométhane en présence de 0,30 g de N-Boc- piperidone et de 0,42 g de triacétoxyborohydrure de sodium sous N2. L'agitation est maintenue pendant 18h à température ambiante. Après hydrolyse, on extrait au dichlorométhane jusqu'à épuisement de la phase aqueuse. La phase organique est lavée avec de l'eau. Après séchage sur MgSO4 et concentration à sec, le brut obtenu est chromatographié sur gel de silice en éluant avec un mélange de cyclohexane et d'acétate d'éthyle (9/1 ). On obtient 0,2 g de terf-butyl 4-{[(1R)-1-(4-chlorobenzyl)-2-(4- {cyclohexyl[(diethylamino) carbonyl]amino}piperidin-1-yl)-2-oxoethyl]amino}piperidine-1- carboxylate.0.5 g of N- [1- (4-chloro-D-phenylalanyl) piperidin-4-yl] -NH-cyclohexyl-N, N-diethylurea are dissolved in 5 mL of dichloromethane in the presence of 30 g of N-Boc-piperidone and 0.42 g of sodium triacetoxyborohydride under N 2 . Stirring is maintained for 18h at room temperature. After hydrolysis, the mixture is extracted with dichloromethane until the aqueous phase is exhausted. The organic phase is washed with water. After drying over MgSO 4 and concentration to dryness, the crude obtained is chromatographed on silica gel, eluting with a mixture of cyclohexane and ethyl acetate (9/1). 0.2 g of tert-butyl 4 - {[(1R) -1- (4-chlorobenzyl) -2- (4- {cyclohexyl [(diethylamino) carbonyl] amino} piperidin-1-yl) are obtained. oxoethyl] amino} piperidine-1-carboxylate.
1.7 : Λ/-[1-(4-chloro-Λ/-piperidin-4-yl-D-phenylalanyl)piperidin-4-yl]-Λ/-cyclohexyl- /V.ΛΛ-diethylurea1.7: Λ- [1- (4-chloro-Λ-piperidin-4-yl-D-phenylalanyl) piperidin-4-yl] -NH-cyclohexyl-β-diethylurea
On solubilise 0,26 g de terf-butyl 4-{[(1R)-1-(4-chlorobenzyl)-2-(4-{cyclohexyl [(diethylamino)carbonyl]amino}piperidin-1-yl)-2-oxoethyl]amino}piperidine-1-carboxylate dans 2 mL de diéthyléther puis on ajoute 2,74 mL d'acide chlorhydrique 2N dans le diéthyléther. Le milieu réactionnel est agité pendant 16h à température ambiante. Après concentration partielle, on essore le précipité obtenu qui est ensuite trituré dans un mélange d'éthanol et de dichlorométhane. Les cristaux sont essorés et rincés à Péthanol. Le chlorhydrate ainsi obtenu est séché sur P2O5 sous pression réduite. On obtient 0,18 g de Λ/-[1-(4-chloro-Λ/-piperidin-4-yl-D-phenylalanyl)piperidin-4-yl]-Λ/-cyclohexyl-Λ/',Λ/'- diethylurea attendu sous forme d'un solide blanc.0.26 g of tert-butyl 4 - {[(1R) -1- (4-chlorobenzyl) -2- (4 - {cyclohexyl [(diethylamino) carbonyl] amino} piperidin-1-yl) are solubilized. oxoethyl] amino} piperidine-1-carboxylate in 2 mL of diethyl ether and then 2.74 mL of 2N hydrochloric acid in diethyl ether. The reaction medium is stirred for 16 hours at room temperature. After partial concentration, the precipitate obtained is filtered off, which is then triturated in a mixture of ethanol and dichloromethane. The crystals are dewatered and rinsed with ethanol. The hydrochloride thus obtained is dried over P 2 O 5 under reduced pressure. 0.18 g of Λ- [1- (4-chloro-β-) -piperidin-4-yl-D-phenylalanyl) piperidin-4-yl] -cyclohexyl-βH- is obtained. - diethylurea expected in the form of a white solid.
Point de fusion >220°C; M+H+ = 546 ; [α]D 20 = +7,0° (c=0,995g/100mL, DMSO).Melting point> 220 ° C; M + H + = 546; [α] D 20 = +7.0 ° (c = 0.995g / 100mL, DMSO).
RMN 1H (200MHz, DMSO-d ) : 9,95 - 8,95 (H échangeables), 7,39 (d, J=8 Hz, 2H), 7,20 (d, J=8 Hz, 2H), 4,78 (m, 1H), 4,29 (t, J = 12 Hz, 1H), 3,32 (massif, 6H + H2O), 3,64-2,84 (m, 9H), 2,24-1 ,10 (m, 18H), 0,98 (t, J=6Hz, 3H), 0,95 (t, J= 6Hz, 3H). Analyse élémentaire : exp %C= 52,51 , %H : 7,86, %N : 10,15 ; th : %57,88, %H : 8,65 ,%N : 11 ,25 1 H NMR (200 MHz, DMSO-d): 9.95 - 8.95 (exchangeable H), 7.39 (d, J = 8 Hz, 2H), 7.20 (d, J = 8 Hz, 2H) , 4.78 (m, 1H), 4.29 (t, J = 12 Hz, 1H), 3.32 (solid, 6H + H 2 O), 3.64-2.84 (m, 9H), 2.24-1, 10 (m, 18H), 0.98 (t, J = 6Hz, 3H), 0.95 (t, J = 6Hz, 3H). Elemental Analysis: Exp. C = 52.51,% H: 7.86,% N: 10.15; th:% 57.88,% H: 8.65,% N: 11, 25
Exemple 2 : Chlorhydrate de /V-[1-(Λ/-1-azabicyclo[2.2.2]oct-3-yl-4-chloro-D- phenylalanyl)piperidin-4-yl]-/V-cyclohexyl-Λ/1 >ΛT-diethylurea (composé n° 5) 2.1 : Λ/-[1-(Λ/-1-azabicycIo[2.2.2]oct-3-yl-4-chloro-D-phenylalanyl)piperidin-4-yl]-Λ/- cyclohexyl-Λ/'.Λ/'-diethylureaExample 2: [1- [1- [1-Azabicyclo [2.2.2] oct-3-yl-4-chloro-D-phenylalanyl) piperidin-4-yl] -N-cyclohexyl-hydrochloride / 1 > ΛT-diethylurea (Compound No. 5) 2.1: Λ- [1- (Λ / -1-azabicyclo [2.2.2] oct-3-yl-4-chloro-D-phenylalanyl) piperidin-4-yl] -α-cyclohexyl-β. Λ / '- diethylurea
On solubilise 0,23 g de Λ/-[1-(4-chloro-D-phenylalanyl)piperidin-4-yl]-Λ/-cyclohexyl- /V./V-diethylurea, obtenu à l'étape 1.5 ci-dessus, dans 3 ml_ de dichlorométhane en présence de 0,089 g du chlorhydrate de 3-quinuclidinone et de 0,22 g de triacétoxyborohydrure de sodium sous N2. L'agitation est maintenue pendant 18h à température ambiante. Après addition de 0,044 g de cétone et 0,222g de triacétoxyborohydrure, le milieu réactionnel est agité pendant 48h. Après addition de 2 ml_ de méthanol, la solution est déposée sur une cartouche contenant 4g de résine DOWEX® 50X2. La résine est lavée au THF, à l'eau puis au méthanol. Le composé attendu est ensuite relargué avec de l'ammoniaque 2N dans le méthanol. Après concentration à sec, on obtient 0,212 g d'un mélange de diastéréoisomères (R1S) et (R1R) de Λ/-[1-(Λ/-1-azabicyclo[2.2.2]oct-3-yl-4-chloro-D-phenylalanyl)piperidin-4-yl]-Λ/- cyclohexyl-Λ/'.Λ/'-diethylurea.0.23 g of Λ- [1- (4-chloro-D-phenylalanyl) piperidin-4-yl] -NH -cyclohexyl-N-diethylurea, obtained in step 1.5 below, are solubilized. above, in 3 ml of dichloromethane in the presence of 0.089 g of 3-quinuclidinone hydrochloride and 0.22 g of sodium triacetoxyborohydride under N 2 . Stirring is maintained for 18h at room temperature. After addition of 0.044 g of ketone and 0.222 g of triacetoxyborohydride, the reaction medium is stirred for 48 h. After addition of 2 mL of methanol, the solution is deposited on a cartridge containing 4 g of DOWEX ® 50X2. The resin is washed with THF, with water and then with methanol. The expected compound is then salted out with 2N ammonia in methanol. After concentration to dryness, 0.212 g of a mixture of diastereoisomers (R 1 S) and (R 1 R) of Λ / - [1- (Λ / -1-azabicyclo [2.2.2] oct-3-yl) are obtained. 4-chloro-D-phenylalanyl) piperidin-4-yl] -N-cyclohexyl-β-diethylurea.
2.2 : Chlorhydrate de diastéréoisomères (R1S) et (R1R) de A/-[1-(Λ/-1- azabicyclo[2.2.2]oct-3-yl-4-chloro-D-phenylalanyl)piperidin-4-yl]-Λ/-cyclohexyl-Λ/1 1Λ/1- diethylurea2.2 Hydrochloride of diastereomers (R 1 S) and (R 1 R) A / - [1- (Λ / -1-azabicyclo [2.2.2] oct-3-yl-4-chloro-D-phenylalanyl) piperidin -4-yl] -Λ-cyclohexyl-Λ / 1 1 Λ / 1 -diethylurea
On mélange 0,21 g de diastéréoisomères (R,S) et (R1R) de Λ/-[1-(Λ/-1- azabicyclo[2.2.2]oct-3-yl-4-chloro-D-phenylalanyl)pipehdin-4-yl]-Λ/-cyclohexyl-Λ/',Λ/'- diethylurea et 0,37 mL d'acide chlorhydrique 2N dans le diéthyléther. La solution est triturée. Les cristaux obtenus sont rincés au diéthyléther et essorés. On obtient 0,204 g du chlorhydrate de diastéréoisomères (R1S) et (R1R) de Λ/-[1-(ΛM-azabicyclo[2.2.2]oct-3- yl-4-chloro-D-phenylalanyl)piperidin-4-yl]-N-cyclohexyl-N',N'-diethylurea sous forme d'un solide blanc.0.21 g of (R, S) and (R 1 R) diastereoisomers of Λ- [1- (Λ / -1-azabicyclo [2.2.2] oct-3-yl-4-chloro-D- phenylalanyl) pipaddin-4-yl] -β-cyclohexyl-β, β-diethylurea and 0.37 ml of 2N hydrochloric acid in diethyl ether. The solution is triturated. The crystals obtained are rinsed with diethyl ether and drained. There is obtained 0.204 g of di (T 1 S) and (R 1 R) of Λ- [1- (ΛM-azabicyclo [2.2.2] oct-3-yl-4-chloro-D-phenylalanyl) piperidine hydrochloride. 4-yl] -N-cyclohexyl-N ', N'-diethylurea as a white solid.
Point de fusion =169°C; M+H+ = 572.M.p. = 169 ° C; M + H + = 572.
Exemple 3 : 1-[(2/?)-3-(4-chlorophenyl)-2-(piperidin-4-ylamino)propanoyl]-/V- cyclohexyl-Λ/-{2-[methoxy(methyl)amino]ethyl}piperidin-4-amine (composé n° 16)Example 3: 1 - [(2H) -3- (4-chlorophenyl) -2- (piperidin-4-ylamino) propanoyl] -N-cyclohexyl-Λ- {2- [methoxy (methyl) amino] ethyl} piperidin-4-amine (Compound No. 16)
3.1 : fert-butyl 4-[cyclohexyl(2-ethoxy-2-oxoethyl)amino]piperidine-1-carboxylate On solubilise 4,5 g de te/t-butyl 4-(cyclohexylamino)piperidine-1-carboxylate dans 159 mL de dichlorométhane en présence de 4,88 g de glyoxilate d'éthyle et de 13,5 g de triacétoxyborohydrure de sodium sous N2. L'agitation est maintenue pendant 18h à température ambiante. Après hydrolyse aqueuse, on extrait au dichlorométhane jusqu'à épuisement de la phase aqueuse. La phase organique est lavée avec une solution aqueuse saturée d'hydrogénocarbonate de sodium puis avec de l'eau. Après séchage sur MgSO4 et concentration à sec, le brut obtenu est chromatographié sur gel de silice en éluant avec un mélange 99/1 de dichlorométhane et de méthanol. On obtient 3 g de tert- butyl 4-[cycIohexyl(2-ethoxy-2-oxoethyl)aminό]piperidine-1-carboxylate.3.1: Fert-butyl 4- [cyclohexyl (2-ethoxy-2-oxoethyl) amino] piperidine-1-carboxylate 4.5 g of tert-butyl 4- (cyclohexylamino) piperidine-1-carboxylate are solubilized in 159 ml. dichloromethane in the presence of 4.88 g of ethyl glyoxilate and 13.5 g of sodium triacetoxyborohydride under N 2 . Stirring is maintained for 18h at room temperature. After aqueous hydrolysis, the mixture is extracted with dichloromethane until the aqueous phase is exhausted. The organic phase is washed with a saturated aqueous solution of sodium hydrogencarbonate and then with water. After drying on MgSO 4 and concentration to dryness, the crude product obtained is chromatographed on silica gel, eluting with a 99/1 mixture of dichloromethane and methanol. 3 g of tert-butyl 4- [cyclohexyl (2-ethoxy-2-oxoethyl) aminyl] piperidine-1-carboxylate are obtained.
3.2 : fe/t-butyl 4~(cyclohexyl{2-[methoxy(methyl)amino]-2-oxoethyl}amino) piperidine-1 -carboxylaté3.2: Fe / t-butyl 4 - (cyclohexyl {2- [methoxy (methyl) amino] -2-oxoethyl} amino) piperidine-1-carboxylate
On dissout 3,09 g de fe/t-butyl 4-[cyclohexyl(2-ethoxy-2-oxoethyl)amino] piperidine-1 -carboxylaté dans 84 ml_ de tétrahydrofurane sous N2 et la solution est refroidie à -200C. Après addition de 1,54 g de chlorhydrate de Ia N,O-diméthylhydroxyl aminé, on ajoute 20,96 mL de chlorure d'isopropylmagnésien 2M dans le tétrahydrofurane de telle sorte que le température ne dépasse pas -1O0C. Après 1h30 d'agitation, on ajoute de nouveau 0,51 g de chlorhydrate de la N,O-diméthylhydroxyl aminé et 4,2 ml_ d'isopropylmagnésien 2M dans le tétrahydrofurane à -10°C. L'agitation est maintenue 30 min. Après évaporation du tétrahydrofurane, le brut obtenu est repris au dichlorométhane et hydrolyse. On extrait au dichlorométhane jusqu'à épuisement de la phase aqueuse. La phase organique est lavée à l'eau puis avec une solution aqueuse saturée de chlorure de sodium. Après séchage sur MgSO4 et concentration à sec, le brut obtenu est chromatographié sur gel de silice en éluant avec un mélange 95/5 de dichlorométhane et de méthanol. On obtient 1,11 g de ferî-butyl 4-(cyclohexyl{2- [methoxy(methyl)amino]-2-oxoethyl}amino)piperidine-1-carboxylate.3.09 g of tert-butyl 4- [cyclohexyl (2-ethoxy-2-oxoethyl) amino] piperidine-1-carboxylate are dissolved in 84 ml of tetrahydrofuran under N 2 and the solution is cooled to -20 ° C. After addition of 1.54 g of N, O-dimethylhydroxylamine hydrochloride, 20.96 ml of 2M isopropylmagnesium chloride in tetrahydrofuran is added so that the temperature does not exceed -1O 0 C. After 1h30 After stirring, 0.51 g of N, O-dimethylhydroxylamine hydrochloride and 4.2 ml of 2M isopropylmagnesium in tetrahydrofuran were added at -10.degree. Stirring is maintained for 30 minutes. After evaporation of the tetrahydrofuran, the crude obtained is taken up in dichloromethane and hydrolyzed. It is extracted with dichloromethane until the aqueous phase is exhausted. The organic phase is washed with water and then with a saturated aqueous solution of sodium chloride. After drying over MgSO 4 and concentration to dryness, the crude obtained is chromatographed on silica gel, eluting with a 95/5 mixture of dichloromethane and methanol. 1.11 g of tert-butyl 4- (cyclohexyl {2- [methoxy (methyl) amino] -2-oxoethyl} amino) piperidine-1-carboxylate are obtained.
3.3 : te/t-butyl 4-[cyclohexyl(2-oxoethyl)amino]piperidine~1 -carboxylaté3.3: tert-butyl 4- [cyclohexyl (2-oxoethyl) amino] piperidine ~ 1 -carboxylate
On dissout 4,02 g de fe/t-butyl 4-(cyclohexyl{2-[methoxy(methyl)amino]-2- oxoethyl}amino)piperidine-1-carboxylate dans 105 mL de diéthyléther anhydre sous N2 à -100C. On ajoute 12,6 mL d'hydrure de lithium aluminium 1 M dans Ie tétrahydrofurane. Après agitation 1h à O0C, on ajoute une solution saturée de sulfate de potassium jusqu'à pH 6-7. On extrait au dichlorométhane jusqu'à épuisement de la phase aqueuse. La phase organique est lavée à l'eau puis avec une solution aqueuse saturée de chlorure de sodium. Après séchage sur MgSO4 et concentration à sec, on obtient 3,39 g de fe/t-butyl 4-[cyclohexyl(2-oxoethyl)amino]piperidine-1 -carboxylaté qui est utilisé tel quel dans la suite.4.02 g of tert-butyl 4- (cyclohexyl {2- [methoxy (methyl) amino] -2-oxoethyl} amino) piperidine-1-carboxylate are dissolved in 105 ml of anhydrous diethyl ether under N 2 to -10. 0 C. was added 12.6 mL of lithium aluminum hydride 1 M in tetrahydrofuran Ie. After stirring for 1 hour at 0 ° C., saturated potassium sulfate solution is added until pH 6-7. It is extracted with dichloromethane until the aqueous phase is exhausted. The organic phase is washed with water and then with a saturated aqueous solution of sodium chloride. After drying over MgSO 4 and concentration to dryness, 3.39 g of Fe / t-butyl 4- [cyclohexyl (2-oxoethyl) amino] piperidine-1-carboxylate is obtained, which is used as it is in the following.
3.4 : fe/t-butyl 4-(cyclohexyl{2-[methoxy(methyl)amino]ethyl}amino)piperidine-1- carboxylate3.4: Fe / t-butyl 4- (cyclohexyl {2- [methoxy (methyl) amino] ethyl} amino) piperidine-1-carboxylate
On solubilise 1,69 g de fe/t-butyl 4-[cyclohexyI(2-oxoethyI)amino]piperidine-1- carboxylate dans 52 mL de dichlorométhane en présence de 5,10 g de chlorhydrate de la N,O-diméthylhydroxyl aminé et de 4,43 g de triacétoxyborohydrure de sodium sous N2. L'agitation est maintenue pendant 5 jours à température ambiante. Après addition de méthanol et évaporation à sec, on extrait au dichlorométhane jusqu'à épuisement de la phase aqueuse. La phase organique est lavée avec une solution aqueuse saturée d'hydrόgénocarbonate de sodium, à l'eau puis avec une solution saturée aqueuse de chlorure de sodium. Après séchage sur MgSO4 et concentration à sec, le brut obtenu est chromatographié sur gel de silice en éluant avec un mélange 98/2 de dichlorométhane et de méthanol. On obtient 1 ,03 g de ferf-butyl 4-(cyclohexyl{2-[methoxy(methyl) amino]ethyl}amino)piperidine-1-carboxylate.1.69 g of tert-butyl 4- [cyclohexyl (2-oxoethyl) amino] piperidine-1-carboxylate are solubilized in 52 ml of dichloromethane in the presence of 5.10 g of N, O-dimethylhydroxylamine hydrochloride. and 4.43 g of sodium triacetoxyborohydride under N 2 . Stirring is maintained for 5 days at room temperature. After addition of methanol and evaporation to dryness, the mixture is extracted with dichloromethane until the aqueous phase is exhausted. The organic phase is washed with a saturated aqueous solution of sodium hydrogen carbonate, with water and then with a saturated aqueous solution of sodium chloride. After drying over MgSO 4 and concentration to dryness, the crude obtained is chromatographed on silica gel, eluting with a 98/2 mixture of dichloromethane and methanol. 1.03 g of tert-butyl 4- (cyclohexyl {2- [methoxy (methyl) amino] ethyl} amino) piperidine-1-carboxylate are obtained.
3.5 : Λ/-cyclohexyl-Λ/-{2-[methoxy(methyl)amino]ethyl}piperidin-4-amine3.5: Λ -cyclohexyl-Λ / - {2- [methoxy (methyl) amino] ethyl} piperidin-4-amine
On place 1 ,033 g de ferf-butyl 4-(cyclohexyl{2-[methoxy(methyl) amino]ethyl}amino)piperidine-1-carboxylate dans 28 mL de diéthyléther et on ajoute 14 mL d'acide chlorhydrique 2N dans le diéthyléther. Le milieu réactionnel est agité pendant 16h à température ambiante. Après évaporation à sec, on reprend le brut au dichlorométhane et on ajoute une solution saturée d'hydrogénocarbonate de sodium et on extrait au dichlorométhane jusqu'à épuisement de la phase aqueuse. Après séchage sur MgSO4 et évaporation à sec, on obtient 0,18 g de A/-cyclohexyl-Λ/-{2- [methoxy(methyl)amino]ethyl}piperidin-4-amine.1.033 g of 4- (cyclohexyl {2- [methoxy (methyl) amino] ethyl} amino) piperidine-1-carboxylate are placed in 28 ml of diethyl ether and 14 ml of 2N hydrochloric acid are added to the mixture. diethyl ether. The reaction medium is stirred for 16 hours at room temperature. After evaporation to dryness, the crude product is taken up in dichloromethane and a saturated solution of sodium hydrogen carbonate is added and the mixture is extracted with dichloromethane until the aqueous phase is exhausted. After drying over MgSO 4 and evaporation to dryness, 0.18 g of β-cyclohexyl-β- {2- [methoxy (methyl) amino] ethyl} piperidin-4-amine are obtained.
3.6 : Methyl Λ/-[1-(fe/t-butoxycarbonyl)piperidin-4-yl]-4-chloro-D-phenylalaninate On solubilise 10 g d'ester méthylique de la p-D-chlorophenyl alanine dans 248 mL de dichlorométhane en présence de 8,8 g de N-Boc-pipéridone et de 14,4 g de triacétoxyborohydrure de sodium sous N2. L'agitation est maintenue pendant 18h à température ambiante. Après addition de méthanol et évaporation à sec, le brut est repris avec solution aqueuse saturée d'hydrogénocarbonate de sodium, et on extrait à l'acétate d'éthyle jusqu'à épuisement de la phase aqueuse. Après séchage sur MgSO4 et concentration à sec, on obtient 15,87 g de methyl Λ/-[1-(fe/f~butoxycarbonyl)piperidin-4- yl]-4-chloro-D-phenylalaninate.3.6: Methyl Λ- [1- (tert-butoxycarbonyl) piperidin-4-yl] -4-chloro-D-phenylalaninate 10 g of pD-chlorophenylalanine methyl ester are solubilized in 248 ml of dichloromethane. presence of 8.8 g of N-Boc-piperidone and 14.4 g of sodium triacetoxyborohydride under N 2 . Stirring is maintained for 18h at room temperature. After addition of methanol and evaporation to dryness, the crude is taken up with saturated aqueous sodium hydrogencarbonate solution and extracted with ethyl acetate until the aqueous phase is exhausted. After drying over MgSO 4 and concentration to dryness, 15.87 g of methyl β- [1- (Fe / f-butoxycarbonyl) piperidin-4-yl] -4-chloro-D-phenylalaninate are obtained.
3.7 : Λ/-[1-(ferf-butoxycarbonyl)piperidin-4-yl]-4-chloro-D-phenylalanine3.7: Λ- [1- (1-tert-butoxycarbonyl) piperidin-4-yl] -4-chloro-D-phenylalanine
On solubilise 15,8 g de methyl Λ/-[1-(te/t-butoxycarbonyl)piperidin-4-yl]-4-chloro-D- phenylalaninate dans 200 mL d'un mélange tétrahydrofurane/eau (1/1 ) et on ajoute 3,35 g d'hydroxyde de lithium hydrate. L'agitation est maintenue 16h à température ambiante. On ajoute du sulfate de potassium jusqu'à pH 7. Le précipité obtenu est essoré et rincé au diéthyléther. Après séchage sur PaO5, on obtient 11,38 g de N-[\-(tert- butoxycarbonyl)piperidin-4-yl]-4-chIoro-D-phenylalanine. 3.8 : te/ï-butyl 4-({(1ft)-1-(4-chlorobenzyl)-2-[4-(cyclohexyl{2-[methoxy(methyl) amino]ethyl}aminό)piperidin-1-yl]-2-oxoethyl}amino)piperidine-1 -carboxylate15.8 g of methyl Λ- [1- (tert-butoxycarbonyl) piperidin-4-yl] -4-chloro-D-phenylalaninate are solubilized in 200 ml of a tetrahydrofuran / water mixture (1/1). and 3.35 g of lithium hydroxide hydrate are added. Stirring is maintained 16h at room temperature. Potassium sulphate is added to pH 7. The precipitate obtained is drained and rinsed with diethyl ether. After drying on PaO 5 , 11.38 g of N - [1- (tert-butoxycarbonyl) piperidin-4-yl] -4-chloro-D-phenylalanine are obtained. 3.8: tert-butyl 4 - (((1-yl) -1- (4-chlorobenzyl) -2- [4- (cyclohexyl) -2- (methoxy (methyl) amino] ethyl) aminyl) piperidin-1-yl] -2-oxoethyl} amino) piperidine-1-carboxylate
On solubilise 0,18 g de Λ/-cyclohexyl-Λ/-{2-[methoxy(methyl)amino]ethyl}piperidin- 4-amine, obtenu à l'étape 3.5, dans 6,8 ml_ de dichlorométhane en présence de 0,26 g de Λ/-[1-(fert-butoxycarbonyl)piperidin-4-yl]τ4-chloro-D-phenylalanine (obtenu à l'étape 3.7), de 0,092 g d'hydroxybenzotriazole, de 0,13 g de chlorhydrate de 1-(3- diméthylaminopropyl)-3-éthyl-carbodiimide et de 0,12 ml_ de diisopropyléthylamine. Le mélange est agité 16h à température ambiante. Après hydrolyse, on extrait au dichlorométhane jusqu'à épuisement de la phase aqueuse. La phase organique est lavée à l'eau puis avec une solution saturée de chlorure de sodium. Après séchage sur MgSO4 et concentration à sec, le brut est chromatographié' sur gel de silice en éluant avec un mélange 98/2 puis 97/3 de dichlorométhane et de méthanol pour conduire à 0,15 g de fe/f-butyl 4-(((1R)-I -(4-chIorobenzyl)-2-[4-(cyclohexyl{2-[methoxy(methyl)amino]ethyl} amino)piperidin-1 -yl]-2-oxoethyi}amino)piperidine-1 -carboxylate.0.18 g of β-cyclohexyl-β- {2- [methoxy (methyl) amino] ethyl} piperidin-4-amine, obtained in step 3.5, are solubilized in 6.8 ml of dichloromethane in the presence of 0.26 g Λ / - [1- (tert-butoxycarbonyl) piperidin-4-yl] τ4-chloro-D-phenylalanine (obtained in step 3.7), 0.092 g of hydroxybenzotriazole, 0.13 g 1- (3-dimethylaminopropyl) -3-ethyl-carbodiimide hydrochloride and 0.12 ml of diisopropylethylamine. The mixture is stirred 16h at room temperature. After hydrolysis, the mixture is extracted with dichloromethane until the aqueous phase is exhausted. The organic phase is washed with water and then with a saturated solution of sodium chloride. After drying over MgSO 4 and concentration to dryness, the crude is chromatographed 'on silica gel eluting with a 98/2 then 97/3 mixture of dichloromethane and methanol to yield 0.15 g of fe / f-butyl 4 - (((1R) -1- (4-Chlorobenzyl) -2- [4- (cyclohexyl) -2- [methoxy (methyl) amino] ethyl} amino) piperidin-1-yl] -2-oxoethyl} amino) piperidine -1-carboxylate.
3.9 : Chlorhydrate de 1-[(2R)-3~(4-chlorophenyl)-2-(piperidin-4-ylamino) propanoyl]-Λ/-cyclohexyl-Λ/-{2-[methoxy(methyl)amino]ethyl}piperidin-4-amine3.9: 1 - [(2R) -3- (4-Chlorophenyl) -2- (piperidin-4-ylamino) propanoyl] -α-cyclohexyl-Λ / - {2- [methoxy (methyl) amino] ethyl hydrochloride } piperidin-4-amine
On place 0,147 g de tert-butyl 4-({(1R)-1-(4-chlorobenzyl)-2-[4-(cyclohexyl{2- [methoxy(methyl)amino]ethyl}amino)piperidin-1-yl]-2-oxoethyl}amino)piperidine-1- carboxylate dans 2,3 mL de diéthyléther et on ajoute 0,58 mL d'acide chlorhydrique 2N dans le diéthyléther. Le milieu réactionnel est agité pendant 16h à température ambiante. Après évaporation-à sec et hydrolyse, on extrait au dichlorométhane jusqu'à épuisement de la phase aqueuse. La phase organique est lavée avec une solution saturée d'hydrogénocarbonate de sodium, à l'eau puis avec une solution saturée aqueuse de chlorure de sodium. Après séchage sur MgSO4 et concentration à sec, on ajoute 2 mL d'isopropanol et 2,43 mL d'acide chlorhydrique 0,1 N dans l'isopropanol. Après concentration à sec, on reprend au diéthyléther et on triture le solide. Les cristaux obtenus sont essorés et rincés au diéthyléther. Après séchage sur P2O5, on obtient 0,08 g de chlorhydrate de 1-[(2R)-3~(4-chlorophenyl)-2-(piperidin-4-ylamino)propanoyl]-/V- cyclohexyl-Λ/-{2-[methoxy(methyl)amino]ethyl}piperidin-4-amine.0.147 g of tert-butyl 4 - ({(1R) -1- (4-chlorobenzyl) -2- [4- (cyclohexyl) -2- (methoxy (methyl) amino] ethyl} amino) piperidin-1-yl are placed therein. ] -2-oxoethyl} amino) piperidine-1-carboxylate in 2.3 mL of diethyl ether and 0.58 mL of 2N hydrochloric acid in diethyl ether. The reaction medium is stirred for 16 hours at room temperature. After evaporating to dryness and hydrolysis, the mixture is extracted with dichloromethane until the aqueous phase is exhausted. The organic phase is washed with a saturated solution of sodium hydrogencarbonate, with water and then with a saturated aqueous solution of sodium chloride. After drying over MgSO 4 and concentration to dryness, 2 ml of isopropanol and 2.43 ml of 0.1 N hydrochloric acid in isopropanol are added. After concentrating to dryness, the mixture is taken up in diethyl ether and the solid is triturated. The crystals obtained are drained and rinsed with diethyl ether. After drying over P 2 O 5 , 0.08 g of 1 - [(2R) -3 - (4-chlorophenyl) -2- (piperidin-4-ylamino) propanoyl] -] - V-cyclohexyl-hydrochloride is obtained. / - {2- [methoxy (methyl) amino] ethyl} piperidin-4-amine.
Point de fusion = 1660C; M+H+ = 534.Melting point = 166 ° C .; M + H + = 534.
Exemple 4 : Chlorhydrate de Λ/-[1-(4-chloro-Λ/-piperidin-4-yl-D-phenyIalanyl) piperidin-4-ylï-Λ/-cyclohexyl-2-ethylbutanamide (composé n° 19)Example 4: Λ- [1- (4-Chloro-Λ-piperidin-4-yl-D-phenylalanyl) piperidin-4-yl] -cyclohexyl-2-ethylbutanamide Hydrochloride (Compound No. 19)
4.1 : fert-butyl 4-[cyclohexyl(2-ethylbutanoyl)amino]piperidine-1 -carboxylate4.1: 4-butyl-4- [cyclohexyl (2-ethylbutanoyl) amino] piperidine-1-carboxylate
On place 1 ,5 g de ferf-butyl 4-(cyclohexylamino)piperidine-1 -carboxylate, obtenu à l'étape 1.1 , dans 27 ml_ de dichlorométhane sous N2 à 00C. On ajoute 0,89 ml_ de triéthylamine puis. 0,73 ml_ de chlorure de l'acide 2-éthylbutyrique. L'agitation est maintenue pendant 16h à température ambiante. Après évaporation à sec et hydrolyse, on extrait à l'acétate d'éthyle jusqu'à épuisement de Ia phase aqueuse. La phase organique est lavée avec une solution aqueuse saturée de chlorure de sodium, séchée sur MgSO4 et concentrée à sec. Le brut obtenu est chromatographié sur gel de silice en éluant avec un gradient de méthanol dans le dichlorométhane variant de 0% à 3%. On obtient 1 ,39 g de tert-butyl 4-[cyclohexyl(2-ethylbutanoyl)amino]piperidine-1-carboxylate.1.5 g of 4-butyl 4- (cyclohexylamino) piperidine-1-carboxylate, obtained by step 1.1, in 27 ml of dichloromethane under N 2 at 0 ° C. 0.89 ml of triethylamine are added then. 0.73 ml of 2-ethylbutyric acid chloride. Stirring is maintained for 16 hours at room temperature. After evaporation to dryness and hydrolysis, the mixture is extracted with ethyl acetate until the aqueous phase is exhausted. The organic phase is washed with a saturated aqueous solution of sodium chloride, dried over MgSO 4 and concentrated to dryness. The crude product obtained is chromatographed on silica gel, eluting with a gradient of methanol in dichloromethane ranging from 0% to 3%. 1.39 g of tert-butyl 4- [cyclohexyl (2-ethylbutanoyl) amino] piperidine-1-carboxylate are obtained.
4.2 : Λ/-cyclohexyl-2-ethyl-Λ/-piperidin-4-ylbutanamide4.2: Λ -cyclohexyl-2-ethyl-β-piperidin-4-ylbutanamide
On place 1,5 g de ferf-butyl 4-[cyclohexyl(2-ethylbutanoyl)amino]piperidine-1- carboxylate dans 9,9 mL d'acide chlorhydrique 4N dans le dioxane. Le milieu réactionnel est agité pendant 16h à température ambiante. Après évaporation à sec, on ajoute de la soude 1 N jusqu'à pH 10 et on extrait à l'acétate d'éthyle jusqu'à épuisement de la phase aqueuse. La phase organique est lavée avec une solution saturée de chlorure de sodium. Après séchage sur MgSO4 et évaporation à sec,- le brut est chromatographié sur gel de . silice en éluant avec gradient de méthanol dans le dichlorométhane variant de 0% à 5%. On obtient 1 ,2 g de Λ/-cyclohexyl-2-ethyl-/V-piperidin-4-ylbutanamide.1.5 g of 4- (cyclohexyl (2-ethylbutanoyl) amino] piperidine-1-carboxylate ferf-butyl in 9.9 ml of 4N hydrochloric acid in dioxane are placed. The reaction medium is stirred for 16 hours at room temperature. After evaporation to dryness, 1 N sodium hydroxide is added until pH 10 and is extracted with ethyl acetate until the aqueous phase is exhausted. The organic phase is washed with a saturated solution of sodium chloride. After drying over MgSO 4 and evaporation to dryness, the crude is chromatographed on a gel of. silica eluting with gradient of methanol in dichloromethane ranging from 0% to 5%. 1.2 g of β-cyclohexyl-2-ethyl-β-piperidin-4-ylbutanamide are obtained.
4.3 : ferf-butyl 4-[((1R)-1-(4-chlorobenzyl)-2-{4-[cyclohexyl(2-ethylbutanoyl)amino] piperidin-1-yl}-2-oxoethyl)amino]piperidine-1-carboxylate4.3: 4-[((1R) -1- (4-chlorobenzyl) -2- {4- [cyclohexyl (2-ethylbutanoyl) amino] piperidin-1-yl} -2-oxoethyl) amino] piperidine-4-tert-butyl 1-carboxylate
On solubilise 0,3 g de Λ/-cyclohexyl-2-ethyl-Λ/-piperidin-4-ylbutanamide dans 9 mL de dichlorométhane en présence de 0,36 g de 4-chloro-Λ/-(1-Boc-piperidin-4-yl)-D- phenylalanine (obtenu à l'étape 3.7), de 0,128 g d'hydroxybenzotriazole, de 0,182 g de chlorhydrate de 1-(3-diméthylaminopropyl)-3-éthyl-carbodiimide et de 0,49 mL de diisopropyléthylamine. Le mélange est agité 16h à température ambiante. Après concentration et hydrolyse, on extrait à l'acétate d'éthyle jusqu'à épuisement de la phase aqueuse. La phase organique est lavée à l'eau puis avec une solution saturée de chlorure de sodium. Après séchage sur MgSO4 et concentration à sec, le brut est chromatographié sur gel de silice en éluant avec un gradient de méthanol dans le dichlorométhane variant de 0% à 5% pour conduire à 0,23 g de ferf-butyl 4-[((1/R)-1-(4- chlorobenzyl)-2-{4-[cyclohexyl(2-ethylbutanoyl)amino]piperidin-1-yl}-2-oxoethyl)amino] piperidine-1 -carboxylate.0.3 g of β-cyclohexyl-2-ethyl-β-piperidin-4-ylbutanamide are solubilized in 9 ml of dichloromethane in the presence of 0.36 g of 4-chloro-Λ- (1-Boc-piperidin). 4-yl) -D-phenylalanine (obtained in step 3.7), 0.128 g of hydroxybenzotriazole, 0.182 g of 1- (3-dimethylaminopropyl) -3-ethyl-carbodiimide hydrochloride and 0.49 mL of diisopropylethylamine. The mixture is stirred 16h at room temperature. After concentration and hydrolysis, the mixture is extracted with ethyl acetate until the aqueous phase is exhausted. The organic phase is washed with water and then with a saturated solution of sodium chloride. After drying over MgSO 4 and concentration to dryness, the crude product is chromatographed on silica gel, eluting with a gradient of methanol in dichloromethane ranging from 0% to 5% to yield 0.23 g of 4-f-ferf-butyl. (1 R) -1- (4-chlorobenzyl) -2- {4- [cyclohexyl (2-ethylbutanoyl) amino] piperidin-1-yl} -2-oxoethyl) amino] piperidine-1-carboxylate.
4.4 : Λ/-[1-(4-chloro-A/-piperidin-4-yl-D-phenylalanyl)piperidin-4-yl]-Λ/-cyclohexyl-2- ethylbutanamide On place 0,23 g de fe/t-butyl 4-[((1R)-1-(4-chlorobenzyl)-2-{4-[cyclohexyl(2- ethylbutanoyl)amino]piperidin-1-yl}-2-oxoethyl)amino]piperidine-1-carboxylate dans 1 ,35 ml_ d'acide chlorhydrique 4N dans le dioxane. Le milieu réactionnel est agité pendant 16h à température ambiante. Après évaporation à sec, on ajoute de la soude 1N jusqu'à pH 10 et on extrait à l'acétate d'éthyle jusqu'à épuisement de la phase aqueuse. La phase organique est lavée avec une solution saturée de chlorure de sodium. Après séchage sur MgSO4 et évaporation à sec, le brut est chromatographié sur gel de silice* en éluant avec un gradient de méthanol/ammoniaque dans le dichlorométhane variant de 0% à 5/0,5/95. On obtient 0,16 g de Λ/-[1-(4-chloro-Λ/-piperidin-4-yl-D-phenylalanyl)piperidin-4-yl]-A/- cyclohexyl-2-ethylbutanamide.4.4: Λ- [1- (4-Chloro-N -piperidin-4-yl-D-phenylalanyl) piperidin-4-yl] -cyclohexyl-2-ethylbutanamide 0.23 g of tert-butyl 4 - [((1R) -1- (4-chlorobenzyl) -2- {4- [cyclohexyl (2-ethylbutanoyl) amino] piperidin-1-yl} -2.0 g are placed therein. -oxoethyl) amino] piperidine-1-carboxylate in 1.35 ml of 4N hydrochloric acid in dioxane. The reaction medium is stirred for 16 hours at room temperature. After evaporation to dryness, 1 N sodium hydroxide solution is added until pH 10 and the mixture is extracted with ethyl acetate until the aqueous phase is exhausted. The organic phase is washed with a saturated solution of sodium chloride. After drying over MgSO 4 and evaporation to dryness, the crude is chromatographed on silica gel * eluting with a gradient of methanol / ammonia in dichloromethane ranging from 0% to 5 / 0.5 / 95. 0.16 g of Λ- [1- (4-chloro-Λ-piperidin-4-yl-D-phenylalanyl) piperidin-4-yl] -N-cyclohexyl-2-ethylbutanamide are obtained.
4.5 : Chlorhydrate de /V-[1-(4-chloro-Λ/-piperidin-4-yl-D-phenylalanyl)piperidin-4- yl]-/V-cyciohexyl-2-ethylbutanamide4.5: / V- [1- (4-Chloro-β-piperidin-4-yl-D-phenylalanyl) piperidin-4-yl] - β-cyclohexyl-2-ethylbutanamide hydrochloride
On place 0,16 g de Λ/-[1-(4-chloro-Λ/-piperidin-4-yl-D-phenylalanyl)piperidin-4-yl]- Λ/-cyclohexyl-2-ethylbutanamide dans 2 mL de dichlorométhane et on ajoute 5,5 mL d'acide chlorhydrique 0,1 N dans l'isopropanol. Après concentration à sec, on reprend à l'acétate d'éthyle et on triture. Les cristaux obtenus sont essorés et rincés à l'acétate d'éthyle. Après séchage sur P2θ5, on obtient 0,13 g de chlorhydrate de Λ/-[1-(4-chloro-Λ/- piperidin-4-yl-D-phenylalanyl)piperidin-4-yl]-A/-cyclohexyl-2-ethylbutanamide.0.16 g of Λ- [1- (4-chloro-Λ-piperidin-4-yl-D-phenylalanyl) piperidin-4-yl] -NH-cyclohexyl-2-ethylbutanamide are placed in 2 ml of dichloromethane and 5.5 ml of 0.1 N hydrochloric acid in isopropanol. After concentration to dryness, it is taken up in ethyl acetate and triturated. The crystals obtained are dewatered and rinsed with ethyl acetate. After drying over P 2 θ 5 , 0.13 g of Λ- [1- (4-chloro-Λ-piperidin-4-yl-D-phenylalanyl) piperidin-4-yl] -A / hydrochloride are obtained. cyclohexyl-2-ethylbutanamide.
Point de fusion = 2850C; M+H+ = 545 ; [α]Hg36520 = +5° (c=0,8945g/100mL, DMSO).Melting point = 285 0 C; M + H + = 545; [α] Hg 365 20 = + 5 ° (c = 0.8945g / 100mL, DMSO).
Exemple 5 : Chlorhydrate de N-{1-[4-chloro-/V-(tetrahydro-2H-pyran-4-yl)-D- phenylalanyl]piperidin-4-yl}-Λ^cyclohexyl-Λf,ΛP-diethylurea (composé n° 3)EXAMPLE 5 N- {1- [4-Chloro-N- (tetrahydro-2H-pyran-4-yl) -D-phenylalanyl] piperidin-4-yl} -cyclohexyl-Λf, Λ P-diethylurea hydrochloride (compound 3)
5.1 : Λ/-{1-[4-chIoro-Λ/-(tetrahydro-2H-pyran-4-yl)-D-phenylalanyl]piperidin-4-yl}-Λ/- cyclohexyl-Λ/'.A/'-diethylurea5.1: Λ- {1- [4-chloro-β- (tetrahydro-2H-pyran-4-yl) -D-phenylalanyl] piperidin-4-yl} -Λ-cyclohexyl-Λ / A. '-diethylurea
On solubilise 0,23 g de A/-[1-(4-chloro-D-phenylalanyl)piperidin-4-yl]-Λ/-cyclohexyl- Λ/'.Λ/'-diethylurea, obtenu à l'étape 1.5 ci-dessus, dans 3 mL de dichlorométhane en présence de 0,05 mL de tetrahydro-4/-/-4-one et de 0,22 g de triacétoxyborohydrure de sodium sous N2. L'agitation est maintenue pendant 18h à température ambiante. Après addition de 0,044 g de cétone et 0.222g de triacétoxyborohydrure, le milieu réactionnel est agité pendant 48h. Après addition de 2 mL de méthanol, la solution est déposée sur une cartouche contenant 4g de résine DOWEX® 50X2. La résine est lavée au THF, à l'eau puis au méthanol. Le composé attendu est ensuite relargué avec de l'ammoniaque 2N dans le méthanol. Après concentration à sec, on obtient 0,23 g de A/-{1-[4-chloro-Λ/- (tetrahydro-2H-pyran-4-yl)-D-phenylalanyl]piperidin-4-yl}-Λ/-cyclohexyl-Λ/',Λ/'-diethylurea. 5.2 : Chlorhydrate de Λ/-{1-[4-chloro-Λ/-(tetrahydro-2H-pyran-4-yl)-D-phenylalanyl] piperidin-4-yl}-Λ/-cyclohexyl-/V\ Λ/'-diethylurea0.23 g of N- [1- (4-chloro-D-phenylalanyl) piperidin-4-yl] -NH -cyclohexyl-βH-diethylurea, obtained in step 1.5, are solubilized. above, in 3 ml of dichloromethane in the presence of 0.05 ml of tetrahydro-4 / -4-one and 0.22 g of sodium triacetoxyborohydride under N 2 . Stirring is maintained for 18h at room temperature. After addition of 0.044 g of ketone and 0.222 g of triacetoxyborohydride, the reaction medium is stirred for 48 h. After addition of 2 ml of methanol, the solution is deposited on a cartridge containing 4 g of DOWEX ® 50X2. The resin is washed with THF, with water and then with methanol. The expected compound is then salted out with 2N ammonia in methanol. After concentration to dryness, 0.23 g of A / - {1- [4-chloro-Λ- (tetrahydro-2H-pyran-4-yl) -D-phenylalanyl] piperidin-4-yl} -Λ are obtained. / -cyclohexyl-Λ / ', Λ /' - diethylurea. 5.2: Λ- {1- [4-chloro-Λ- (tetrahydro-2H-pyran-4-yl) -D-phenylalanyl] piperidin-4-yl} -Λ-cyclohexyl- / V \Λ-hydrochloride / '- diethylurea
On mélange 0,23 g de Λ/-{1-[4-chloro-Λ/-(tetrahydro-2H-pyran-4-yl)-D- phenylalanyl]piperidin-4-yl}-Λ/-cyclohexyl-ΛT,Λ/'-diethylurea et 0,37 mL d'acide chlorhydrique 2N dans le diéthyléther. La solution est triturée. Les cristaux obtenus sont rincés au diéthyléther et essorés. On obtient 0,22 g du chlorhydrate de Λ/-{1-[4-chloro-Λ/- (tetrahydro-2H-pyran-4-yl)-D-phenylalanyl]piperidin-4-yl}-Λ/-cyclohexyl-Λ/',Λ/'-diethylurea . sous forme d'un solide blanc.0.23 g of Λ- {1- [4-chloro-Λ- (tetrahydro-2H-pyran-4-yl) -D-phenylalanyl] piperidin-4-yl} -Λ-cyclohexyl-ΛT are mixed , Λ / '- diethylurea and 0.37 mL of 2N hydrochloric acid in diethyl ether. The solution is triturated. The crystals obtained are rinsed with diethyl ether and drained. 0.22 g of Λ- {1- [4-chloro-Λ- (tetrahydro-2H-pyran-4-yl) -D-phenylalanyl] piperidin-4-yl} -Λ-cyclohexyl hydrochloride are obtained. -Λ ', Λ /' - diethylurea. in the form of a white solid.
Point de fusion > 2000C ; M+H+ = 547; [α]D 20 = +2,7° (c=0,537g/100mL, DMSO).Melting point> 200 ° C. M + H + = 547; [α] D 20 = + 2.7 ° (c = 0.537 g / 100 mL, DMSO).
Exemple 6 : Chlorhydrate de yV-{1-[/V-(4-aminocyclohexyl)-4-chloro-D- phenyIalanyl]piperidin-4-yl}-Λ^cyclohexyl-Λf ,Λf-dîethylurea (composé n° 2)Example 6: N- {1 - [[N- (4-Aminocyclohexyl) -4-chloro-D-phenylalanyl] piperidin-4-yl} -cyclohexyl-Λf, Λ-diethylurea Hydrochloride (Compound No. 2)
6.1 : Λ/-{1-[Λ/-(4-Boc-aminocyclohexyl)-4-chloro-D-phenylalanyl]piperidin-4-yl}-A/- cyclohexyl-Λ/', Λ/'-diethylurea6.1: Λ- {1- [Λ- (4-Boc-aminocyclohexyl) -4-chloro-D-phenylalanyl] piperidin-4-yl} -N-cyclohexyl-β-diethylurea
On solubilise 0,23 g de Λ/-[1-(4-chloro-D-phenylalanyl)piperidin-4-yl]-Λ/-cyclohexyl- Λ/1, Λ/'-diethylurea, obtenu à l'étape 1.5 ci-dessus, dans 3 mL de dichlorométhane en présence de 0,12 g de N-4-Boc-aminocyclohexanone et de 0,22 g de triacétoxyborohydrure de sodium sous N2. L'agitation est maintenue pendant 18h à température ambiante. Après addition de 2 mL de méthanol, la solution est déposée sur une cartouche contenant 4g de résine DOWEX® 50X2. La résine est lavée au THF, à l'eau puis au méthanol. Le composé attendu est ensuite relargué avec de l'ammoniaque 2N dans le méthanol. Après concentration à sec, on obtient 0,18 g de fe/t-butyl (4-{[(1f?)- 1-(4-chlorobenzyl)-2-(4-{cyclohexyl[(diethylamino)carbonyl]amino}piperidin-1-yl)-2- oxoethyl]amino}cyclohexyl)carbamate.Is dissolved 0.23 g of Λ / - [1- (4-chloro-D-phenylalanyl) piperidin-4-yl] -Λ / -cyclohexyl- Λ / 1, Λ / '- diethylurea, obtained in step 1.5 above, in 3 mL of dichloromethane in the presence of 0.12 g of N-4-Boc-aminocyclohexanone and 0.22 g of sodium triacetoxyborohydride under N 2 . Stirring is maintained for 18h at room temperature. After addition of 2 ml of methanol, the solution is deposited on a cartridge containing 4 g of DOWEX ® 50X2. The resin is washed with THF, with water and then with methanol. The expected compound is then salted out with 2N ammonia in methanol. After concentration to dryness, 0.18 g of tert-butyl (4 - {[(1f)) - 1- (4-chlorobenzyl) -2- (4- {cyclohexyl [(diethylamino) carbonyl] amino} is obtained. piperidin-1-yl) -2-oxoethyl] amino} cyclohexyl) carbamate.
6.2 : Chlorhydrate de Λ/-{1-[Λ/-(4-aminocyclohexyl)-4-chloro-D-phenylalanyl] piperidin-4-yl}-Λ/-cyclohexyl-Λ/\ Λ/'-diethylurea6.2: Λ- {1- [Λ- (4-Aminocyclohexyl) -4-chloro-D-phenylalanyl] piperidin-4-yl} -α-cyclohexyl-β-diethylurea hydrochloride
On place 0,18 g de ferf-butyl (4-{[(1R)-1-(4-chlorobenzyl)-2-(4-{cyclohexyl [(diethylamino)carbonyl]amino}piperidiή-1-yl)-2-oxoethyl]amino}cyclohexyl)carbamate dans 2 mL de diéthyléther et on ajoute 0,77 mL d'acide chlorhydrique 2N dans le diéthyléther. Le milieu réactionnel est agité à température ambiante pendant 18h. Les cristaux obtenus sont rincés au diéthyléther et essorés. On obtient 0,14 g du chlorhydrate d'un mélange d'isomères cis et trans de Λ/-{1-[Λ/-(4-aminocyclohexyl)-4-chloro-D- phenylalanyl]piperidin-4-yl}-Λ/-cyclohexyl-Λ/r, Λ/'-diethylurea.0.18 g of tert-butyl (4 - {[(1R) -1- (4-chlorobenzyl) -2- (4 - {cyclohexyl [(diethylamino) carbonyl] amino} piperidin-1-yl) are placed therein. -oxoethyl] amino} cyclohexyl) carbamate in 2 mL of diethyl ether and 0.77 mL of 2N hydrochloric acid in diethyl ether. The reaction medium is stirred at ambient temperature for 18 h. The crystals obtained are rinsed with diethyl ether and drained. 0.14 g of the hydrochloride of a mixture of cis and trans isomers of Λ- {1- [Λ- (4-aminocyclohexyl) -4-chloro-D-phenylalanyl] piperidin-4-yl are obtained. Λ / -cyclohexyl-Λ / r , Λ / '- diethylurea.
Point de fusion = 195°C; M+H+ = 560. Exemple 7 : Chlorhydrate de /V-[1-(/V-8-azabicyclo[3.2.1]oct-3-yl-4-chloro-D- phenylalanyl)piperidin-4-yl]-Λ/-cyclohexyl-Λ/1,ΛT-diethylurea (composé n° 4)Melting point = 195 ° C; M + H + = 560. Example 7: [V- (1-8 -azabicyclo [3.2.1] oct-3-yl-4-chloro-D-phenylalanyl) piperidin-4-yl] -l-cyclohexyl hydrochloride / 1 , ΛT-diethylurea (Compound No. 4)
7.1 : te/t-butyl 3-{[(1f?)-1-(4-chlorobenzyl)-2-(4-{cyclohexyl[(diethylamino)carbonyl] amino}piperidin-1-yl)-2-oxoethyl]amino}-8-azabicyclo[3.2.1]octane-8-carboxylate7.1: tert-butyl 3 - {[(1f)) - 1- (4-chlorobenzyl) -2- (4- {cyclohexyl [(diethylamino) carbonyl] amino} piperidin-1-yl) -2-oxoethyl] amino} -8-azabicyclo [3.2.1] octane-8-carboxylate
On solubilise 0,46 g de Λ/-[1-(4-chloro-D-phenylalanyl)piperidin-4-yl]-Λ/-cyclohexyl- ΛΛ/V-diethylurea, obtenu à l'étape 1.5 ci-dessus, dans 10 mL de dichlorométhane en présence de 0,034 g de Boc-nortopinone et de 0,42 g de triacétoxyborohydrure de sodium sous N2. L'agitation est maintenue pendant 18h à température ambiante. On ajoute 0,10 g de Boc-nortropinone et 0,10 g de triacétoxyborohydrure de sodium. L'agitation est maintenue 24h. Après hydrolyse, on extrait au dichlorométhane jusqu'à épuisement de la phase aqueuse. La phase organique est lavée avec H2O, puis avec une solution aqueuse de chlorure de sodium. Après séchage sur MgSO4 et concentration à sec, le brut obtenu est chromatographié sur gel de silice en éluant avec un mélange 90/10 de cyclohexane et d'acétate d'éthyle. On obtient 0,37 g de terf-butyl 3-{[(1R)-1-(4- chlorobenzyl)-2-(4-{cyclohexyl[(diethylamino)carbonyl]amino}piperidin-1-yl)-2- oxoethyl]amino}-8-azabicyclo[3.2.1]octane-8-carboxylate.0.46 g of Λ- [1- (4-chloro-D-phenylalanyl) piperidin-4-yl] -NH -cyclohexyl-β-diethylurea, obtained in step 1.5 above, are solubilized. in 10 ml of dichloromethane in the presence of 0.034 g of Boc-nortopinone and 0.42 g of sodium triacetoxyborohydride under N 2 . Stirring is maintained for 18h at room temperature. 0.10 g of Boc-nortropinone and 0.10 g of sodium triacetoxyborohydride are added. The agitation is maintained 24h. After hydrolysis, the mixture is extracted with dichloromethane until the aqueous phase is exhausted. The organic phase is washed with H 2 O and then with an aqueous solution of sodium chloride. After drying over MgSO 4 and concentration to dryness, the crude obtained is chromatographed on silica gel, eluting with a 90/10 mixture of cyclohexane and ethyl acetate. 0.37 g of tert-butyl 3 - {[(1R) -1- (4-chlorobenzyl) -2- (4- {cyclohexyl [(diethylamino) carbonyl] amino} piperidin-1-yl) are obtained. oxoethyl] amino} -8-azabicyclo [3.2.1] octane-8-carboxylate.
7.2 : Chlorhydrate de Λ/-[1-(Λ/-8-azabicyclo[3.2.1]oct-3-yl-4-chloro-D-phenylalanyl) piperidin-4-yl]-/V-cyclohexyl-Λ/\ /V-diethylurea7.2: Λ - [1- (Λ -8-Azabicyclo [3.2.1] oct-3-yl-4-chloro-D-phenylalanyl) piperidin-4-yl] - β-cyclohexyl-Λ hydrochloride \ / V-diethylurea
On place 0,37 g de fert-butyl 3-{[(1R)-1-(4-chlorobenzyl)-2-(4-{cyclohexyl [(diethylamino)carbonyl]amino}piperidin-1-yl)-2-oxoethyl]amino}-8- azabicyclo[3.2.1]octane-8-carboxylate dans 2 mL de diéthyléther et on ajoute 2,74 mL d'acide chlorhydrique 2N dans le diéthyléther. Le milieu réactionnel est agité à température ambiante pendant 18h. On ajoute 2 mL supplémentaires d'acide chlorhydrique 2N dans le diéthyléther. Les cristaux obtenus sont rincés au diéthyléther et essorés. On obtient 0,30 g du chlorhydrate de A/-[1-(Λ/-8-azabicyclo[3.2.1]oct-3-yl-4- chloro-D-phenylalanyl)piperidin-4-yl]-Λ/-cyclohexyl-Λ/',Λ/'-diethylurea.0.37 g of tert-butyl 3 - {[(1R) -1- (4-chlorobenzyl) -2- (4- {cyclohexyl [(diethylamino) carbonyl] amino} piperidin-1-yl) are placed therein. oxoethyl] amino} -8-azabicyclo [3.2.1] octane-8-carboxylate in 2 mL of diethyl ether and 2.74 mL of 2N hydrochloric acid in diethyl ether. The reaction medium is stirred at ambient temperature for 18 h. An additional 2 mL of 2N hydrochloric acid in diethyl ether is added. The crystals obtained are rinsed with diethyl ether and drained. 0.30 g of A / - [1- (Λ -8-azabicyclo [3.2.1] oct-3-yl-4-chloro-D-phenylalanyl) piperidin-4-yl]-chlor hydrochloride are obtained. -cyclohexyl-Λ / ', Λ /' - diethylurea.
Point de fusion = 182°C ; M+H+ = 572 ; [α]D 20 = +9,2° (c=0,667g/100mL, DMSO).Mp = 182 ° C; M + H + = 572; [α] D 20 = + 9.2 ° (c = 0.667 g / 100 mL, DMSO).
Exemple 8 : Chlorhydrate de Λ/-{1-[4-chloro-Λ/-(1-isobutylpiperidin-4-yl)-D- phenylalanyl]piperidin-4-yl}-W-cyclohexyl-/y,Λr-diethylurea (composé n° 6)Example 8: Λ - {1- [4-Chloro-Λ- (1-isobutylpiperidin-4-yl) -D-phenylalanyl] piperidin-4-yl} -N-cyclohexyl-β-diethylurea hydrochloride (compound 6)
8.1 : Λ/-{1-[4-chloro-Λ/-(1-isobutylpiperidin-4-yl)-D-phenylalanyl]piperidin-4-yl}-Λ/- cycIohexyl-Λf, /V-diethylurea8.1: Λ- {1- [4-chloro-Λ] - (1-isobutylpiperidin-4-yl) -D-phenylalanyl] piperidin-4-yl} -cyclohexyl-,f, N-diethylurea
On solubilise 0,25 g de Λ/-[1-(4-chloro-Λ/-piperidin-4-yl-D-phenylalanyl)piperidin-4- yl]-Λ/-cyclohexyl-Λ/',Λ/'-diethylurea> obtenu à l'étape 1.7 ci-dessus, dans 4 mL de dichlorométhane en présence de 0,05 ml_ d'isobutyraldéhyde et de 0,16 g de triacétoxyborohydrure de sodium sous N2. L'agitation est maintenue pendant 3 jours à température ambiante. Après hydrolyse avec une solution aqueuse de soude jusqu'à pH 10, on extrait à l'acétate d'éthyle jusqu'à épuisement de la phase aqueuse. La phase organique est lavée avec H2O, puis avec une solution aqueuse de chlorure de sodium. Après séchage sur MgSO4 et concentration à sec, le brut obtenu est chromatographié sur gel de silice en éluant avec gradient d'un mélange 9/1/0,1 de dichlorométhane, méthanol et ammoniaque aqueuse dans le dichlorométhane variant de 0% à 100%. On obtient 0,14 g de Λ/-{1-[4-chloro-Λ/-(1-isobutylpiperidin-4-yl)-D-phenylalanyl]piperidin-4-yI}-Λ/- cyclohexyl-Λ/'.Λ/'-diethylurea .0.25 g of Λ- [1- (4-chloro-β-) -piperidin-4-yl-D-phenylalanyl) piperidin-4-yl] -cyclohexyl-β- [1] was solubilized. -diethylurea > obtained in step 1.7 above, in 4 mL of dichloromethane in the presence of 0.05 ml of isobutyraldehyde and 0.16 g of sodium triacetoxyborohydride under N 2 . Stirring is maintained for 3 days at room temperature. After hydrolysis with aqueous sodium hydroxide solution to pH 10, the mixture is extracted with ethyl acetate until the aqueous phase is exhausted. The organic phase is washed with H 2 O and then with an aqueous solution of sodium chloride. After drying over MgSO 4 and concentration to dryness, the crude obtained is chromatographed on silica gel, eluting with a gradient of a 9/1 / 0.1 mixture of dichloromethane, methanol and aqueous ammonia in dichloromethane ranging from 0% to 100 %. 0.14 g of Λ- {1- [4-chloro-Λ] - (1-isobutylpiperidin-4-yl) -D-phenylalanyl] piperidin-4-yl} -ocyclohexyl are obtained. .Λ / '- diethylurea.
8.2 : Chlorhydrate -de Λ/-{1-[4-chloro-Λ/-(1-isobutylpiperidin-4-yl)-D-phenylalanyl] piperidin-4-yl}- Λ/-cyc!ohexyl-Λ/\ W-diethylurea8.2: Λ- {1- [4-Chloro-Λ] - (1-isobutylpiperidin-4-yl) -D-phenylalanyl] piperidin-4-yl} -α-cyclohexyl} -hydrochloride W-diethylurea
On place 0,14 g de dans 2 mL de dichlorométhane et on ajoute 4,48 mL d'acide chlorhydrique 0,1 N dans l'isopropanol. Après concentration à sec, le résidu est trituré dans un mélange de diéthyléther et d'acétate d'éthyle. Les cristaux obtenus sont rincés au diéthyléther, essorés et séchés sur P2O5. On obtient 0,115 g du chlorhydrate de Λ/-{1- [4-chloro-Λ/-(1-isobutylpiperidin-4-yl)-D-phenylalanyl]piperidin-4-yl}-Λ/-cyclohexyl-/vn,A/'- diethylurea.0.14 g of in 2 ml of dichloromethane are placed and 4.48 ml of 0.1 N hydrochloric acid in isopropanol are added. After concentration to dryness, the residue is triturated in a mixture of diethyl ether and ethyl acetate. The crystals obtained are rinsed with diethyl ether, drained and dried over P 2 O 5 . Obtained 0.115 g of the hydrochloride of Λ / - {1- [4-chloro-Λ / - (1-isobutylpiperidin-4-yl) -D-phenylalanyl] piperidin-4-yl} -Λ / -cyclohexyl- / w A / '- diethylurea.
Point de fusion > 25O0C ; M+H+ = 602 ; [α]D 20 = +10,6° (c=0,881g/100mL, DMSO).Mp> 250 ° C .; M + H + = 602; [α] D 20 = + 10.6 ° (c = 0.881g / 100mL, DMSO).
Exemple 9 : Chlorhydrate de 1-[(2fî)-3-(4-chlorophenyl)-1-methylene-2- (piperidîn-4-ylamîno)propyl]-Λ/-cyclohexyl-Λ/-(4-methoxyphenyl)piperidin-4-amineExample 9: 1 - [(2 R) -3- (4-Chlorophenyl) -1-methylene-2- (piperidin-4-ylamino) propyl] -NH-cyclohexyl-N - (4-methoxyphenyl) piperidine Hydrochloride -4-amine
(composé n° 40)(compound no. 40)
9.1 : ferf-butyl 4-[(4-methoxyphenyl)amino]piperidine-1-carboxylate9.1: Ferf-butyl 4 - [(4-methoxyphenyl) amino] piperidine-1-carboxylate
On place 2,0 g de 1-Boc-pipéridone dans 85 mL d'acide acétique sous N2 en présence de 6,47 g de 4-méthoxy-aniline, de 23 g de sulfate de sodium et de 10,3 g de triacétoxyborohydrure de sodium et le milieu réactionnel est agité pendant 16h à température ambiante. Après concentration à sec, on ajoute de la soude aqueuse 30% jusqu'à pH basique. On extrait à l'acétate d'éthyle jusqu'à épuisement de la phase aqueuse. La phase organique est lavée à l'eau, puis avec une solution saturée de chlorure de sodium. Après séchage sur MgSO4 et concentration à sec, on obtient 9 g de fe/f-butyl 4-[(4-methoxyphenyl)amino]piperidine-1-carboxylate utilisé tel quel dans la suite.2.0 g of 1-Boc-piperidone are placed in 85 ml of acetic acid under N 2 in the presence of 6.47 g of 4-methoxyaniline, 23 g of sodium sulphate and 10.3 g of sodium triacetoxyborohydride and the reaction medium is stirred for 16h at room temperature. After concentration to dryness, 30% aqueous sodium hydroxide is added until basic pH. It is extracted with ethyl acetate until the aqueous phase is exhausted. The organic phase is washed with water and then with a saturated solution of sodium chloride. After drying over MgSO 4 and concentration to dryness, 9 g of Fe / f-butyl 4 - [(4-methoxyphenyl) amino] piperidine-1-carboxylate are obtained, which is used as it is in the following.
9.2 : fe/if-butyl 4-[cyclohexyl(4-methoxyphenyl)amino]piperidine-1-carboxylate On place 5,0 g de fe/f-butyl 4-[(4-methoxyphenyl)amino]piperidine-1-carboxylate dans 55 mL de dichlorométhane sous N2 en présence de 5,78 ml_ de cyclohexanone et de 4,84. g de triacétoxyborohydrure de sodium. Après 18h d'agitation, on rajoute 2,9 mL de cyclohexanone et 2,4 g de triacétoxyborohydrure de sodium et le milieu réactionnel est agité pendant 5 jours à température ambiante. Après addition de 20 mL de méthanol et d'environ 0,5 g d'acide citrique et 50 mL d'eau, et agitation pendant 18h, on extrait au dichlorométhane jusqu'à épuisement de la phase aqueuse. Après séchage sur Na2SO4 et concentration à sec, le brut obtenu est chromatographié sur gel de silice en éluant avec un- mélange heptane/AcOEt 7/3. On obtient 4 g de te/t-butyl 4-[cyclohexyl(4- methoxyphenyl)amino]piperidine-1-carboxylate en mélange.9.2: Fe / if-butyl 4- [cyclohexyl (4-methoxyphenyl) amino] piperidine-1-carboxylate 5.0 g of Fe / f-butyl 4 - [(4-methoxyphenyl) amino] piperidine-1-carboxylate are placed in 55 ml of N 2 dichloromethane in the presence of 5.78 ml of cyclohexanone and 4.84 ml. g of sodium triacetoxyborohydride. After stirring for 18 h, 2.9 ml of cyclohexanone and 2.4 g of sodium triacetoxyborohydride are added and the reaction mixture is stirred for 5 days at room temperature. After addition of 20 ml of methanol and approximately 0.5 g of citric acid and 50 ml of water and stirring for 18 h, the mixture is extracted with dichloromethane until the aqueous phase is exhausted. After drying over Na 2 SO 4 and concentration to dryness, the crude obtained is chromatographed on silica gel, eluting with a heptane / AcOEt 7/3 mixture. 4 g of tert-butyl 4- [cyclohexyl (4-methoxyphenyl) amino] piperidine-1-carboxylate are obtained in a mixture.
9.3 : Λ/-cyclohexyl-Λ/-(4-methoxyphenyl)piperidin-4-amine9.3: Λ -cyclohexyl-Λ / - (4-methoxyphenyl) piperidin-4-amine
On place 10 g de fe/t-butyl 4-[cyclohexyl(4-methoxyphenyl)amino]piperidine-1- carboxylate dans 50 mL d'acide chlorhydrique 4N dans le dioxane. Le milieu réactionnel est agité pendant 18h à température ambiante. Après évaporation à sec, le résidu est chromatographié en éluant avec . un mélange de dichlorométhane, méthanol, ammoniaque variant de 95/5/0,5 à 85/15/1 ,5. On obtient 2,1 g de Λ/-cyclohexyl-Λ/-(4- methoxyphenyl)piperidin-4-amine.10 g of Fe / t-butyl 4- [cyclohexyl (4-methoxyphenyl) amino] piperidine-1-carboxylate are placed in 50 ml of 4N hydrochloric acid in dioxane. The reaction medium is stirred for 18h at room temperature. After evaporation to dryness, the residue is chromatographed eluting with. a mixture of dichloromethane, methanol, ammonia ranging from 95/5 / 0.5 to 85/15/1, 5. 2.1 g of β-cyclohexyl-β- (4-methoxyphenyl) piperidin-4-amine are obtained.
9.4 : tert-butyl 4-[((1R)-1-(4-chlorobenzyl)-2-{4-[cyclohexyl(4-methoxyphenyl) amino]piperidin-1-yl}-2-oxoethyl)amino]piperidine-1-carboxylate9.4: tert-butyl 4 - [((1R) -1- (4-chlorobenzyl) -2- {4- [cyclohexyl (4-methoxyphenyl) amino] piperidin-1-yl} -2-oxoethyl) amino] piperidine 1-carboxylate
On solubilise 0,29 g de Λ/-cyclohexyl-Λ/-(4-methoxyphenyl)piperidin-4-amine obtenu à l'étape 9.3 dans 10 mL de dichlorométhane en présence de 0,38 g de Λ/-[1-(tert- butoxycarbonyl)piperidin-4-yl]-4-chloro-D-phenylalanine obtenu à l'étape 3.7, de 0,14 g d'hydroxybenzotriazole, de 0,19 g de chlorhydrate de 1-(3-diméthylaminopropyl) -3-éthyl- carbodiimide et de 0,17 mL de diisopropyléthylamine. Le mélange est agité 16h à température ambiante. Après hydrolyse, on extrait au dichlorométhane. jusqu'à épuisement de la phase aqueuse. La phase organique est lavée avec une solution saturée aqueuse d'hydrogénocarbonate de sodium. Après séchage sur Na2SO4 et concentration à sec, le brut obtenu est chromatographié en éluant avec un mélange de dichlorométhane, méthanol, ammoniaque variant de 95/5/0 à 9/1/0,5. On obtient 0,32 g de fe/t-butyl 4-[((1 R)- 1 -(4-chlorobenzyl)-2-{4-[cyclohexyl(4-methoxyphenyl)amino] piperidin-1-yl}-2-oxoethyl)amino]piperidine-1-carboxylate.0.29 g of β-cyclohexyl-β- (4-methoxyphenyl) piperidin-4-amine obtained in step 9.3 are solubilized in 10 ml of dichloromethane in the presence of 0.38 g of Λ- [1- (tert-butoxycarbonyl) piperidin-4-yl] -4-chloro-D-phenylalanine obtained in step 3.7, 0.14 g of hydroxybenzotriazole, 0.19 g of 1- (3-dimethylaminopropyl) hydrochloride 3-ethylcarbodiimide and 0.17 ml of diisopropylethylamine. The mixture is stirred 16h at room temperature. After hydrolysis, the mixture is extracted with dichloromethane. until the aqueous phase is exhausted. The organic phase is washed with saturated aqueous sodium hydrogencarbonate solution. After drying over Na 2 SO 4 and concentration to dryness, the crude obtained is chromatographed eluting with a mixture of dichloromethane, methanol and ammonia ranging from 95/5/0 to 9/1 / 0.5. 0.32 g of tert-butyl 4 - [((1R) -1- (4-chlorobenzyl) -2- {4- [cyclohexyl (4-methoxyphenyl) amino] piperidin-1-yl are obtained. 2-oxoethyl) amino] piperidine-1-carboxylate.
9.5 : 1 -[(2R)-3-(4-chlorophenyl)-2-(piperidin-4-yIamino)propanoyl]-Λ/-cyclohexyl-Λ/- (4-methoxyphenyl)piperidin-4-amine9.5: 1 - [(2R) -3- (4-Chlorophenyl) -2- (piperidin-4-yl) amino) propanoyl] -NH-cyclohexyl-N - (4-methoxyphenyl) piperidin-4-amine
On place 0,32 g de fert-butyl 4-[((1 R)-1-(4-chlorobenzyl)-2-{4-[cyclohexyl(4- methoxyphenyl)amino]piperidin-1-yI}-2-oxoethyl)amino]piperidine-1-carboxy|ate dans 5 mL de dioxane et on ajoute 1,22 ml_ d'acide chlorhydrique 4N dans le dioxane. Le milieu réactionnel est agité pendant 18h à température ambiante. Après évaporation à sec, le résidu est repris au méthanol et de nouveau concentré à sec. Le brut obtenu est chromatographié en éluant avec un gradient d'un mélange de méthanol et d'ammoniaque dans le dichlorométhane variant de 95/5/0,5 à 9/1/0,1. On obtient 0,176 g de 1 -[(2R)-3-(4- chlorophenyl)-2-(piperidin-4-yIamino)propanoyl]-Λ/-cyclohexyl-Λ/-(4-methoxyphenyl) piperidin-4-amine.0.32 g of fert-butyl 4 - [((1R) -1- (4-chlorobenzyl) -2- {4- [cyclohexyl (4- methoxyphenyl) amino] piperidin-1-yl} -2-oxoethyl) amino] piperidine-1-carboxyate in 5 mL of dioxane and 1.22 mL of 4N hydrochloric acid in dioxane. The reaction medium is stirred for 18h at room temperature. After evaporation to dryness, the residue is taken up in methanol and again concentrated to dryness. The crude product obtained is chromatographed eluting with a gradient of a mixture of methanol and ammonia in dichloromethane ranging from 95/5 / 0.5 to 9/1 / 0.1. 0.176 g of 1 - [(2R) -3- (4-chlorophenyl) -2- (piperidin-4-ylamino) propanoyl] -NH-cyclohexyl-β- (4-methoxyphenyl) piperidin-4-amine are obtained. .
9.6 : Chlorhydrate de 1-[(2f?)-3-(4-chlorophenyl)-2-(piperidin-4-ylamino)propanoyl] -Λ/-cyclohexyl-Λ/-(4-methoxyphenyl)piperidin-4-amine9.6: 1 - [(2f) -3- (4-Chlorophenyl) -2- (piperidin-4-ylamino) propanoyl] -NH -cyclohexyl-β- (4-methoxyphenyl) piperidin-4-amine Hydrochloride
On place 0,17 g de 1-[(2f?)-3-(4-chlorophënyl)-2-(piperidin-4-ylamino)propanoyl]- Λ/-cyclohexyl-Λ/-(4-methoxyphenyl)piperidin-4-amine dans 5 mL de dichlorométhane et on ajoute 3,2 mL d'acide chlorhydrique 0,1 N dans l'isopropanol. Après concentration à sec, le résidu est recristallisé dans l'éthanol. On obtient 0,036 g de chlorhydrate de 1- [(2R)-3-(4-chlorophenyl)-2-(piperidin-4-ylamino)propanoyl]-Λ/-cyclohexyl-Λ/-(4- methoxyphenyl)piperidin-4-amine. Point de fusion = 195°C ; M+H+ = 5530.17 g of 1 - [(2f) -3- (4-chlorophenyl) -2- (piperidin-4-ylamino) propanoyl] -NH -cyclohexyl-β- (4-methoxyphenyl) piperidine are placed therein. 4-amine in 5 mL of dichloromethane and 3.2 mL of 0.1 N hydrochloric acid in isopropanol. After concentration to dryness, the residue is recrystallized from ethanol. 0.036 g of 1 - [(2R) -3- (4-chlorophenyl) -2- (piperidin-4-ylamino) propanoyl] -NH-cyclohexyl-4 - (4-methoxyphenyl) piperidin-4 hydrochloride are obtained. -amine. Melting point = 195 ° C; M + H + = 553
Exemple 10 : Chlorhydrate de 1-[(2/?)-3-(4-chlorophenyl)-2-(piperidin-4- ylamino)propanoyl]-N-cyclohexyI-/V-[2-(1H-imida2ol-1-yl)ethyl]piperidin-4-amineExample 10: 1 - [(2 R) -3- (4-Chlorophenyl) -2- (piperidin-4-ylamino) propanoyl] -N-cyclohexyl-N- [2- (1H-imidazol-1) hydrochloride yl) ethyl] piperidin-4-amine
(composé n° 44)(Compound No. 44)
10.1 : fe/t-butyl 4-[cyclohexyl(2-ethoxy-2-oxoethyl)amino]piperidine-1-carboxylate On solubilise 4,64 g de terf-butyl 4-(cyclohexylamino)piperidine-1-carboxylate, obtenu à l'étape 1.1 dans 164 mL de dichlorométhane, et on ajoute 9,77 mL de ethyl oxoacetate. On ajoute lentement 13,93 g de triacétoxyborohydrure de sodium. L'agitation est maintenue pendant 18h à température ambiante. On ajoute de nouveau 3,25 mL de glyoxilic acid ethyl ester et 3,48 g de triacétoxyborohydrure de sodium. Après agitation pendant 72h, le milieu réactionnel est méthanolisé et on concentre à sec. Le résidu est repris avec une solution saturée aqueuse d'hydrogénocarbonate de sodium. On extrait à l'acétate d'éthyle jusqu'à épuisement de la phase aqueuse. La phase organique est lavée avec une solution aqueuse saturée de chlorure de sodium. Après séchage sur MgSO4 et concentration à sec, le brut obtenu est chromatographié sur gel de silice en éluant avec gradient de méthanol dans le dichlorométhane variant de 0% à 10%. On obtient 6,44 g de te/t-butyl 4-[cyclohexyl(2-ethoxy-2-oxoethyl)amino]piperidine-1 -carboxylate.10.1: tert-butyl 4- [cyclohexyl (2-ethoxy-2-oxoethyl) amino] piperidine-1-carboxylate 4.64 g of tert-butyl 4- (cyclohexylamino) piperidine-1-carboxylate, obtained at room temperature, are solubilized. step 1.1 in 164 mL of dichloromethane, and 9.77 mL of ethyl oxoacetate are added. 13.93 g of sodium triacetoxyborohydride are slowly added. Stirring is maintained for 18h at room temperature. 3.25 ml of glyoxilic acid ethyl ester and 3.48 g of sodium triacetoxyborohydride are added again. After stirring for 72h, the reaction medium is methanolized and concentrated to dryness. The residue is taken up with saturated aqueous sodium hydrogencarbonate solution. It is extracted with ethyl acetate until the aqueous phase is exhausted. The organic phase is washed with a saturated aqueous solution of sodium chloride. After drying over MgSO 4 and concentration to dryness, the crude obtained is chromatographed on silica gel, eluting with a gradient of methanol in dichloromethane ranging from 0% to 10%. 6.44 g of tert-butyl 4- [cyclohexyl (2-ethoxy-2-oxoethyl) amino] piperidine-1-carboxylate are obtained.
10.2 : ferî-butyl 4-[cyclohexyl(2-hydroxyethyl)amino]piperidine-1 -carboxylate On place 6,44 g de tert-butyl 4-[cyclohexyl(2-ethoxy-2-oxoethyl)amino]piperidine- 1-carboxylate dans 175 mL de diéthyléther à O0C sous N2. On ajoute lentement 29,71 mL d'hydrure de lithium aluminium 1 N dans le diéthyléther. Après agitation 1 h à O0C, on ajoute une solution saturée aqueuse de sulfate de potassium jusqu'à pH 5-6. Après addition de soude aqueuse 1 N, on extrait au dichlorométhane jusqu'à épuisement de la phase aqueuse. La phase organique est lavée à l'eau, puis avec une solution aqueuse saturée de chlorure de sodium. Après, séchage sur MgSO4 et concentration à sec, on obtient 4,04 g de fe/t-butyl 4-[cyclohexyl(2-hydroxyethyl)amino]piperidine-1-carboxylate utilisé tel quel dans Ia suite de la synthèse.10.2: tert-butyl 4- [cyclohexyl (2-hydroxyethyl) amino] piperidine-1-carboxylate 6.44 g of tert-butyl 4- [cyclohexyl (2-ethoxy-2-oxoethyl) amino] piperidine-1-carboxylate are placed in 175 ml of diethyl ether at 0 ° C. under N 2 . 29.71 mL of 1N lithium aluminum hydride in diethyl ether is slowly added. After stirring for 1 h at 0 ° C., saturated aqueous potassium sulphate solution is added until pH 5-6. After adding 1N aqueous sodium hydroxide, the mixture is extracted with dichloromethane until the aqueous phase is exhausted. The organic phase is washed with water and then with a saturated aqueous solution of sodium chloride. After drying over MgSO 4 and concentration to dryness, 4.04 g of tert-butyl 4- [cyclohexyl (2-hydroxyethyl) amino] piperidine-1-carboxylate is obtained, which is used as it is in the course of the synthesis.
10.3 : tert-butyl 4-(cyclohexyl{2-[(methylsulfonyl)oxy]ethyl}amino)piperidine-1- carboxylate.10.3: tert-butyl 4- (cyclohexyl {2 - [(methylsulfonyl) oxy] ethyl} amino) piperidine-1-carboxylate.
On solubilise 0,75 g de ferf-butyl 4-[cyclohexyl(2-hydroxyethyl)amino]piperidine-1- carboxylate dans 23 mL de diéthyléther. On ajoute 0,63 mL de triéthylamine et 0,28 mL de chlorure de mésyle. Après agitation à température ambiante pendant 2h, le chlorhydrate de triéthylamine formé est filtré et le filtrat est concentré à sec. On obtient 0,82 g de te/t-butyl 4-(cyclohexyl{2-[(methylsulfonyl)oxy]ethyl}amino)piperidine-1- carboxylate utilisé tel quel dans la suite de la synthèse.0.75 g of 4- (cyclohexyl (2-hydroxyethyl) amino] piperidine-1-carboxylate ferf-butyl is solubilized in 23 ml of diethyl ether. 0.63 ml of triethylamine and 0.28 ml of mesyl chloride are added. After stirring at room temperature for 2 hours, the triethylamine hydrochloride formed is filtered and the filtrate is concentrated to dryness. 0.82 g of tert-butyl 4- (cyclohexyl {2 - [(methylsulfonyl) oxy] ethyl} amino) piperidine-1-carboxylate is obtained, which is used as it is in the following synthesis.
10.4 : ferf-butyl 4-{cyclohexyl[2-(1H-imidazol-1-yl)ethyl]amino}piperidine-1- carboxylate10.4: 4- (Cyclohexyl [2- (1H-imidazol-1-yl) ethyl] amino} piperidine-1-carboxylate
On solubilise 0,82 g de te/t-butyl 4-(cyclohexyl{2-[(methylsulfonyl) oxy]ethyl}amino)piperidine-1-carboxylate dans 4 mL d'un mélange acétonitrile/diméthylformamide (1/1 ) puis on ajoute 0,41 g de 1 ,2,4-triazole sodique. Après agitation à température pendant 18h, on hydrolyse et on extrait au dichlorométhane jusqu'à épuisement de la phase aqueuse. La phase organique est lavée à l'eau. Après séchage sur MgSO4 et concentration à sec, le brut obtenu est chromatographié sur gel de silice en éluant avec un gradient de méthanol dans le dichlorométhane de 0% à 10%. On obtient 0,37 g de fert-butyl 4-{cyclohexyi[2-(1f/- imidazol-1-yl)ethyl]amino}piperidine-1-carboxylate sous forme de cristaux rouges.0.82 g of tert-butyl 4- (cyclohexyl {2 - [(methylsulfonyl) oxy] ethyl} amino) piperidine-1-carboxylate are solubilized in 4 ml of an acetonitrile / dimethylformamide mixture (1/1) then 0.41 g of 1,2,4-triazole sodium are added. After stirring at room temperature for 18 h, the mixture is hydrolyzed and extracted with dichloromethane until the aqueous phase is exhausted. The organic phase is washed with water. After drying over MgSO 4 and concentration to dryness, the crude obtained is chromatographed on silica gel, eluting with a gradient of methanol in dichloromethane from 0% to 10%. 0.37 g of tert-butyl-4- (cyclohexyl [2- (1H-imidazol-1-yl) ethyl] amino] piperidine-1-carboxylate are obtained in the form of red crystals.
10.5 : A/-cyclohexyl-Λ/-[2-(1 H-imidazol-1 -yl)ethyl]piperidin-4-amine10.5: N -cyclohexyl-Λ- [2- (1H-imidazol-1-yl) ethyl] piperidin-4-amine
On place 0,45 g de terf-butyl 4-{cycIohexyl[2-(1H-imidazol-1-yl)ethyl] amino}piperidine-1-carboxylate dans 12 mL d'acide chlorhydrique 4N dans le dioxane. Le milieu réactionnel est agité pendant 18h à température ambiante. Après évaporation à sec, le résidu est repris au méthanol et de nouveau concentré à sec. Cette opération est répétée plusieurs fois, on obtient 0,51 g de Λ/-cyclohexyl-Λ/-[2-(1H-imidazol-1- yl)ethyl]piperidin-4-amine utilisé tel quel par la suite.0.45 g of tert-butyl-4- (cyclohexyl [2- (1H-imidazol-1-yl) ethyl] amino] piperidine-1-carboxylate are placed in 12 ml of 4N hydrochloric acid in dioxane. The reaction medium is stirred for 18h at room temperature. After evaporation to dryness, the residue is taken up in methanol and again concentrated to dryness. This operation is repeated several times, 0.51 g of Λ -cyclohexyl-Λ / - [2- (1H-imidazol-1) are obtained. yl) ethyl] piperidin-4-amine used as it is subsequently.
10.6 : ferf-butyl 4-{[(1/R)-1-(4-chlorobenzyl)-2-(4-{cyclohexyl[2-(1 /-/-imidazol-1- yl)ethyl]amino}piperidin-1-yl)-2-oxoethyl]amino}piperidine-1-carboxylate10.6: tert-butyl 4 - {[(1 R) -1- (4-chlorobenzyl) -2- (4- {cyclohexyl [2- (1H-imidazol-1-yl) ethyl] amino} piperidine -1-yl) -2-oxoethyl] amino} piperidine-1-carboxylate
On solubilise 0,05 g de Λ/-cycIohexyl-Λ/-[2-(1/-/-imidazol-1-yl)ethyl]piperidin-4- amine obtenu à l'étape 10.5 dans 13 mL de dichlorométhane en présence de 0,51 g de /V-[1-(te/f-butoxycarbonyl)piperidin-4-yl]-4-chloro-D-phenylalanine obtenu à l'étape 3.7, de 0,18 g d'hydroxybenzotriazole, de 0,25 g de chlorhydrate de 1-(3-diméthylaminopropyl) - 3-éthyl-carbodiimide et de 0,92 mL de diisopropyléthylamine. Le mélange est agité 16h à température ambiante. Après hydrolyse, on extrait au dichlorométhane jusqu'à épuisement de la phase aqueuse. La phase organique est lavée avec H2O, puis une solution saturée aqueuse de chlorure de sodium. Après séchage sur MgSO4 et concentration à sec, le brut obtenu est chromatographié en éluant avec un gradient de méthanol dans le dichlorométhane variant de 0% à 10%. On obtient 0,37 g de terf-butyl 4-{[(1R)-1-(4-chlorobenzyl)-2-(4-{cyclohexyl[2-(1/-/-imidazol-1-yl)ethyl]amino}piperidin-1- yl)-2-oxoethyl]amino}piperidine-1 -carboxylate.0.05 g of β-cyclohexyl-β- [2- (1H-imidazol-1-yl) ethyl] piperidin-4-amine, obtained in step 10.5, are solubilized in 13 ml of dichloromethane in the presence of 0.51 g of N- [1- (tert-butoxycarbonyl) piperidin-4-yl] -4-chloro-D-phenylalanine obtained in step 3.7, 0.18 g of hydroxybenzotriazole, 0.25 g of 1- (3-dimethylaminopropyl) -3-ethyl-carbodiimide hydrochloride and 0.92 ml of diisopropylethylamine. The mixture is stirred 16h at room temperature. After hydrolysis, the mixture is extracted with dichloromethane until the aqueous phase is exhausted. The organic phase is washed with H 2 O and then a saturated aqueous solution of sodium chloride. After drying over MgSO 4 and concentration to dryness, the crude obtained is chromatographed eluting with a gradient of methanol in dichloromethane ranging from 0% to 10%. 0.37 g of tert-butyl 4 - {[(1R) -1- (4-chlorobenzyl) -2- (4- {cyclohexyl [2- (1H-imidazol-1-yl) ethyl] are obtained. amino} piperidin-1-yl) -2-oxoethyl] amino} piperidine-1-carboxylate.
10.7 : 1-[(2f?)-3-(4-chlorophenyl)-2-(piperidin-4-ylamino)propanoyl]-/V-cyclohexyl- Λ/-[2-(1/-/-imidazol-1-yl)ethyl]piperidin-4-amine10.7: 1 - [(2f)) - 3- (4-Chlorophenyl) -2- (piperidin-4-ylamino) propanoyl] - N -cyclohexyl- [- (2- (1H-imidazol-1 yl) ethyl] piperidin-4-amine
On place 0,37 g de terf-butyl 4-{[(1R)-1-(4-chlorobenzyl)-2-(4-{cyclohexyl[2-(1H- imidazol-1 -yl)ethyl]amino}piperidin-1 -yl)-2-oxoethyl]amino}piperidine-1 -carboxylate dans 5,7 mL de dioxane et on ajoute 1 ,43 mL d'acide chlorhydrique 4N dans le dioxane. Le milieu réactionnel est agité pendant 18h à température ambiante. Après évaporation à sec, on reprend le résidu avec une solution saturée aqueuse d'hydrogénocarbonate de sodium. On extrait au dichlorométhane jusqu'à épuisement de la phase aqueuse. La phase organique est lavée avec H2O. Après séchage sur MgSO4 et concentration à sec, le brut obtenu est chromatographié en éluant avec un gradient d'un mélange de méthanol et d'ammoniaque dans le dichlorométhane variant de 100/0/0 à 8/2/0,2. On obtient 0,19 g de 1 -[(2R)-3-(4-chlorophenyl)-2-(piperidin-4-ylamino)propanoyl]-A/-cyclohexyl-Λ/-[2-(1 H- imidazol-1 -yl)ethy|]piperidin-4-amine.0.37 g of tert-butyl 4 - {[(1R) -1- (4-chlorobenzyl) -2- (4- {cyclohexyl [2- (1H-imidazol-1-yl) ethyl] amino} piperidine 1-yl) -2-oxoethyl] amino} piperidine-1-carboxylate in 5.7 ml of dioxane and 1.43 ml of 4N hydrochloric acid in dioxane are added. The reaction medium is stirred for 18h at room temperature. After evaporation to dryness, the residue is taken up with saturated aqueous sodium hydrogencarbonate solution. It is extracted with dichloromethane until the aqueous phase is exhausted. The organic phase is washed with H 2 O. After drying over MgSO 4 and concentration to dryness, the crude obtained is chromatographed eluting with a gradient of a mixture of methanol and ammonia in dichloromethane ranging from 100/0/0. at 8/2 / 0.2. 0.19 g of 1 - [(2R) -3- (4-chlorophenyl) -2- (piperidin-4-ylamino) propanoyl] -NH -cyclohexyl-Λ- [2- (1H-imidazole) are obtained. -1-yl) ethyl] piperidin-4-amine.
10.8 : Chlorhydrate de 1-[(2R)-3-(4-chlorophenyl)-2-(piperidin-4-ylamino) propanoyl]-A/-cyclohexyl-Λ/-[2-(1H-imidazol-1-yl)ethyl]piperidin-4-amine10.8: 1 - [(2R) -3- (4-Chlorophenyl) -2- (piperidin-4-ylamino) propanoyl] -N-cyclohexyl-β- [2- (1H-imidazol-1-yl) hydrochloride) ) ethyl] piperidin-4-amine
On place 0,19 g de 1-[(2R)-3-(4-chlorophenyl)-2-(piperidin-4-ylamino)propanoyl]- Λ/-cyclohexyl-Λ/-[2-(1H-imidazol-1-yl)ethyl]piperidin-4-amine dans 5 mL de méthanol et on ajoute 3,5 mL d'acide chlorhydrique 0,1 N dans Pisopropanol. Après évaporation à sec, le milieu réactionnel est trituré dans le diéthyléther, puis on essore le précipité obtenu et on rince au diéthyléther. Le chlorhydrate ainsi obtenu est séché sur P2O5 sous pression réduite. On obtient 0,175 g du chlorhydrate de 1-[(2R)-3-(4-chlorophenyl)-2-(piperidin-4- ylamino)propanoyl]-Λ/-cyclohexyl-Λ/-[2-(1/-/-imidàzol-1-yl)ethyl]piperidin-4-amine sous forme d'un solide bjanc.0.19 g of 1 - [(2R) -3- (4-chlorophenyl) -2- (piperidin-4-ylamino) propanoyl] -NH -cyclohexyl-Λ- [2- (1H-imidazole)] were placed therein. 1-yl) ethyl] piperidin-4-amine in 5 mL of methanol and 3.5 mL of 0.1 N hydrochloric acid in isopropanol. After evaporation to dryness, the reaction medium is triturated in diethyl ether, and then the precipitate obtained is filtered off and rinsed with diethyl ether. The hydrochloride thus obtained is dried over P 2 O 5 under reduced pressure. 0.175 g of 1 - [(2R) -3- (4-chlorophenyl) -2- (piperidin-4-ylamino) propanoyl] -α-cyclohexyl-Λ / - [2- (1 / - /) hydrochloride are obtained. imidazol-1-yl) ethyl] piperidin-4-amine as a solid.
Point de fusion = 162°C; M+H+ = 541 ; [α]D 20 = -3,9° (c=0,418g/100mL, DMSO).M.p. = 162 ° C; M + H + = 541; [α] D 20 = -3.9 ° (c = 0.418g / 100mL, DMSO).
Exemple 11 : Chlorhydrate de Λ/-{1-[Λ/-(c/s-4-aminocyclohexyl)-4-chloro-D- phenyIalanyl]piperidin-4-yl}-N-cyclohexyl-2,2-dimethylhydrazinecarboxamideExample 11: Λ- {1- [Λ- (α-4-aminocyclohexyl) -4-chloro-D-phenylalanyl] piperidin-4-yl} -N-cyclohexyl-2,2-dimethylhydrazinecarboxamide hydrochloride
(composé n° 71)(Compound No. 71)
11.1 : fe/f-butyl 4-{cyclohexyl[(2,2-dimethylhydrazino)carbonyl]amino}piperidine-1- carboxylate11.1: Fe / f-butyl 4- {cyclohexyl [(2,2-dimethylhydrazino) carbonyl] amino} piperidine-1-carboxylate
On place 0,43 ml_ de diphosgène dans 18 mL de dichlorométhane à 0°C sous N2. Une solution de 1 ,0 g de ferf-butyl 4-(cyclohexylamino)piperidine-1-carboxylate et de 2 ,47 mL de triéthylamine est ajoutée goutte à goutte. La solution est agitée 2h à température ambiante. Le milieu réactionnel est de nouveau placé à 00C et 0,43 mL de diphosgène sont de nouveau additionnés. Après agitation pendant 2h à température ambiante, 5,39 mL de diméthylhydrazine sont ajoutés. Le mélange est agité à température ambiante pendant 18h. On ajoute 30 mL d'acide chlorhydrique 0,5N. On extrait au dichlorométhane jusqu'à épuisement de Ia phase aqueuse. Après séchage sur MgSO4, et concentration à sec, le résidu obtenu est chromatographié sur gel de silice en éluant avec un gradient de méthanol dans le dichlorométhane variant de 2% à 10% pour conduire à 0,28 g de fe/f-butyl 4-{cyclohexyl[(2,2-dimethylhydrazino)carbonyl]amino} piperidine-1 -carboxylate.0.43 ml of diphosgene are placed in 18 ml of dichloromethane at 0 ° C. under N 2 . A solution of 1.0 g of tert-butyl 4- (cyclohexylamino) piperidine-1-carboxylate and 2.47 mL of triethylamine is added dropwise. The solution is stirred for 2 hours at room temperature. The reaction medium is again placed at 0 ° C. and 0.43 ml of diphosgene are again added. After stirring for 2h at room temperature, 5.39 mL of dimethylhydrazine is added. The mixture is stirred at ambient temperature for 18 hours. 30 ml of 0.5N hydrochloric acid are added. It is extracted with dichloromethane until the aqueous phase is exhausted. After drying over MgSO 4 and concentration to dryness, the residue obtained is chromatographed on silica gel, eluting with a gradient of methanol in dichloromethane ranging from 2% to 10% to give 0.28 g of Fe / F-butyl. 4- {cyclohexyl [(2,2-dimethylhydrazino) carbonyl] amino} piperidine-1-carboxylate.
11.2 : Λ/-cyclohexyl-2,2-dimethyl-Λ/-piperidin-4-ylhydrazinecarboxamide On place 0,28 g de fe/t-butyl 4-{cyclohexyl[(2,2-dimethylhydrazino) carbonyl]amino}piperidine-1 -carboxylate dans 3,8 mL d'acide chlorhydrique 4N dans le dioxane. Le milieu réactionnel est agité pendant 18h à température ambiante. Après évaporation à sec, le résidu est repris avec une solution de soude 1 N et on extrait au dichlorométhane jusqu'à épuisement de la phase aqueuse. Après séchage sur MgSO4, on obtient 0,2 g de Λ/-cyclohexyl-2,2-dimethyl-/V-piperidiή-4-ylhydrazinecarboxamide utilisé tel quel par la suite.11.2: Λ -cyclohexyl-2,2-dimethyl-β-piperidin-4-ylhydrazinecarboxamide 0.28 g of Fe / t-butyl 4- (cyclohexyl [(2,2-dimethylhydrazino) carbonyl] amino} piperidine are placed -1-carboxylate in 3.8 mL of 4N hydrochloric acid in dioxane. The reaction medium is stirred for 18h at room temperature. After evaporation to dryness, the residue is taken up with a 1N sodium hydroxide solution and extracted with dichloromethane until the aqueous phase is exhausted. After drying over MgSO 4 , 0.2 g of β-cyclohexyl-2,2-dimethyl-β-piperidin-4-ylhydrazinecarboxamide, which is subsequently used as it is, is obtained.
11.3 : Methyl Λ/-{c/s-4-[(fe/?-butoxycarbonyl)amino]cyclohexyl}-4-chloro-D- phenylalaninate11.3: Methyl Λ / - {c / s-4 - [(n-butoxycarbonyl) amino] cyclohexyl} -4-chloro-D-phenylalaninate
On place 10 g H-p-chloro-D-CI-Phe-OMe,HCI, et 8,5 g de fert-butyl (4- oxocyclohexyl)carbamate dans 200 ml_ de dichlorométhane. On ajoute 11 g de NaBH(OAc)3 et 5,57 ml_ de NEt3. L'agitation à température ambiante est maintenue pendant 18h. La solution est hydrolysée avec une solution aqueuse de soude 1 N et extraite au dichlorométhane jusqu'à épuisement de la phase aqueuse. Après séchage sur MgSO4 et concentration à sec, le brut obtenu est chromatographié sur gel de silice en éluant avec un gradient d'un mélange AcOEt/MeOH dans le CH2CI2 variant de 95/5/1 à 85/15/3 (CH2CI2/Ac0Et/Me0H). On obtient 5,7 g de methyl N-{cis-4-[(tert- butoxycarbonyl)amino]cyclohexyl}-4-chloro-D-phenylalaninate.10 g of H 2 P-chloro-D-Cl-Phe-OMe, HCl, and 8.5 g of fert-butyl (4- oxocyclohexyl) carbamate in 200 ml of dichloromethane. 11 g of NaBH (OAc) 3 and 5.57 ml of NEt 3 are added . Stirring at ambient temperature is maintained for 18 hours. The solution is hydrolysed with an aqueous 1N sodium hydroxide solution and extracted with dichloromethane until the aqueous phase is exhausted. After drying over MgSO 4 and concentration to dryness, the crude obtained is chromatographed on silica gel, eluting with a gradient of a mixture of AcOEt / MeOH in CH 2 CI 2 ranging from 95/5/1 to 85/15/3. (CH 2 Cl 2 / AcOEt / MeOH). 5.7 g of methyl N- {cis-4 - [(tert-butoxycarbonyl) amino] cyclohexyl} -4-chloro-D-phenylalaninate are obtained.
11.4 : Λ/-{c/s-4-[(fe/t-butoxycarbonyl)amino]cyclohexyl}-4-chloro-D-phenylalanine On place 5,5 g de methyl Λ/-{c/s-4-[(te/t-butoxycarbonyl)amino]cyclohexyl}-4- chloro-D-phenylalaninate dans 133 mL de MeOH puis on ajoute 40,15 mL de soude 1N aqueuse. L'agitation est maintenue à température ambiante pendant 18h. Après évaporation du MeOH, on ajoute 4éq d'une solution aqueuse d'acide chlorhydrique 1 N. Le précipité blanc ainsi obtenu est filtré à froid et rincé à l'eau froide. Après séchage sur P2O5, on obtient 3,8 g de Λ/-{c/s-4-[(te/t-butoxycarbonyl)amino]cyclohexyl}-4-chloro-D- phenylalanine.11.4: Λ- {c / s-4 - [(tert-butoxycarbonyl) amino] cyclohexyl} -4-chloro-D-phenylalanine 5.5 g of methyl Λ / - {c / s-4- [(tert-butoxycarbonyl) amino] cyclohexyl} -4-chloro-D-phenylalaninate in 133 mL of MeOH and then 40.15 mL of 1 N aqueous sodium hydroxide. Stirring is maintained at room temperature for 18 hours. After evaporation of the MeOH, 4 eq of a 1N aqueous solution of hydrochloric acid is added. The white precipitate thus obtained is filtered cold and rinsed with cold water. After drying over P 2 O 5 , 3.8 g of Λ- {c / s-4 - [(tert-butoxycarbonyl) amino] cyclohexyl} -4-chloro-D-phenylalanine are obtained.
11.5 : terf-butyl (c/s-4-{[(1R)-1-(4-chlorobenzyl)-2-(4-{cyclohexyl[(2,2-dimethyl- hydrazino)carbonyl]amino}piperidin-1-yl)-2-oxoethyl]amino}cyclohexyl)carbamate11.5: tert-butyl (c / s-4 - {[(1R) -1- (4-chlorobenzyl) -2- (4- {cyclohexyl [(2,2-dimethylhydrazino) carbonyl] amino} piperidin-1 -yl) -2-oxoethyl] amino} cyclohexyl) carbamate
On solubilise 0,22 g de Λ/-cyclohexyl-2,2~dimethyl-Λ/-piperidin-4-yl- hydrazinecarboxamide obtenu à l'étape 11.2 dans 10 mL de dichlorométhane en présence de 0,28 g de Λ/-{c/s-4-[(fe/t-butoxycarbonyl)amino]cyclohexyl}-4-chloro-D- phenylalanine obtenu à l'étape 11.4, de 0,11 g d'hydroxybenzotriazole, de 0,24 g de chlorhydrate de 1-(3-diméthylaminopropyl) -3-éthyl-carbodiimide et de 0,5 mL de diisopropyléthylamine et 0,82 mL d'acide chlorhydrique dans le dioxane. Le mélange est agité 18h à température ambiante. Après hydrolyse avec une solution aqueuse d'hydrogénocarbonate de sodium, on extrait à l'acétate d'éthyle jusqu'à épuisement de la phase aqueuse. Après séchage sur MgSO4 et concentration à sec, le brut obtenu est chromatographié en éluant avec un gradient de méthanol dans le dichlorométhane variant de 1% à 4%. On obtient 0,22 g de te/t-butyl (c/s-4-{[(1R)-1-(4-chlorobenzyl)-2-(4- {cyclohexyl[(2,2-dimethylhydrazino)carbonyl]amino}piperidin-1-yl)-2-oxoethyl]amino} cyclohexyl)carbamate.0.22 g of Λ -cyclohexyl-2,2-dimethyl-β-piperidin-4-yl-hydrazinecarboxamide obtained in step 11.2 are solubilized in 10 ml of dichloromethane in the presence of 0.28 g of Λ / - {c / s-4 - [(tert-butoxycarbonyl) amino] cyclohexyl} -4-chloro-D-phenylalanine obtained in step 11.4, 0.11 g of hydroxybenzotriazole, 0.24 g of hydrochloride 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide and 0.5 mL of diisopropylethylamine and 0.82 mL of hydrochloric acid in dioxane. The mixture is stirred for 18h at room temperature. After hydrolysis with an aqueous solution of sodium hydrogencarbonate, the mixture is extracted with ethyl acetate until the aqueous phase is exhausted. After drying over MgSO 4 and concentration to dryness, the crude obtained is chromatographed eluting with a gradient of methanol in dichloromethane ranging from 1% to 4%. 0.22 g of tert-butyl (c / s-4 - {[(1R) -1- (4-chlorobenzyl) -2- (4- {cyclohexyl [(2,2-dimethylhydrazino) carbonyl] are obtained. amino} piperidin-1-yl) -2-oxoethyl] amino} cyclohexyl) carbamate.
11.6 : Λ/-{1 -[Λ/-(c/s-4-aminocyclohexyl)-4-chloro-D-phenylalanyl3piperidin-4-yI}-A/- cyclohexyl-2,2-dimethylhydrazinecarboxamide11.6: Λ- {1 - [Λ- (α-4-aminocyclohexyl) -4-chloro-D-phenylalanyl] -piperidin-4-yl} -N-cyclohexyl-2,2-dimethylhydrazinecarboxamide
On place 0,22 g de fe/t-butyl (c/s-4-{[(1R)-1-(4-chlorobenzyl)-2-(4-{cyclohexyl[(2,2- dimethyIhydrazino)carbonyl]amino}piperidin-1-yl)-2-oxoethyl]amino}cyclohexyl)carbamate dans 1 ,7 mi de dioxane et on ajoute 1 ,43 m!_ d'acide chlorhydrique 4N dans le dioxane. Le milieu réactionnel est agité pendant 3h à température ambiante. Après évaporation à sec, on reprend le résidu avec une solution aqueuse de soude 1N. On extrait au dichlorométhane jusqu'à épuisement de la phase aqueuse. Après séchage sur MgSO4 et concentration à sec, le brut obtenu est chromatographié en éluant avec un gradient d'un mélange de méthanol et d'ammoniaque dans le dichlorométhane variant de 95/5/0,5 à 9/1/0,1. On obtient 0,05 g de Λ/-{1-[Λ/-(c/s-4-aminocyclohexyl)-4-chloro-D-phenylalanyl] piperidin-4-yl}-A/-cyclohexyl-2,2-dimethylhydrazinecarboxamide.0.22 g of Fe / t-butyl (c / s-4 - {[(1R) -1- (4-chlorobenzyl) -2- (4- {cyclohexyl [(2,2- dimethyl (Hydrazino) carbonyl] amino) piperidin-1-yl) -2-oxoethyl] amino} cyclohexyl) carbamate in 1.7 ml of dioxane and 1.43 m of 4N hydrochloric acid in dioxane are added. The reaction medium is stirred for 3h at room temperature. After evaporation to dryness, the residue is taken up with a 1N aqueous sodium hydroxide solution. It is extracted with dichloromethane until the aqueous phase is exhausted. After drying over MgSO 4 and concentration to dryness, the crude obtained is chromatographed eluting with a gradient of a mixture of methanol and ammonia in dichloromethane ranging from 95/5 / 0.5 to 9/1 / 0.1 . 0.05 g of Λ- {1- [Λ- (c-s-4-aminocyclohexyl) -4-chloro-D-phenylalanyl] piperidin-4-yl} -N-cyclohexyl-2,2 are obtained. -dimethylhydrazinecarboxamide.
11.7 : Chlorhydrate de Λ/-{1-[A/-(c/s-4-aminocyclohexyl)-4-chloro-D-phenylalanyl] piperidin-4-yl}-Λ/-cyclohexyl-2,2-dimethylhydrazinecarboxamide11.7: Λ- {1- [N- (α-4-aminocyclohexyl) -4-chloro-D-phenylalanyl] piperidin-4-yl} -β-cyclohexyl-2,2-dimethylhydrazinecarboxamide hydrochloride
On place 0,05 g de Λ/-{1-[A/-(c/s-4-aminocyclohexyl)-4-chloro-D-phenylalanyl] piperidin-4-yl}-Λ/-cyclohexyl-2,2-dimethylhydrazinecarboxamide dans 10 ml_ de diéthyléther et on ajoute 0,09 ml_ d'acide chlorhydrique 2N dans le diéthyléther. Le précipité obtenu est et séché sur P2O5. On obtient 0,06 g du chlorhydrate de Λ/-{1-[Λ/-(c/s- 4-aminocyclohexyl)-4-chloro-D-phenyIalanyl]piperidin-4-yl}-Λ/-cyclohexyl-2,2-dimethyl- hydrazinecarboxamide. Point de fusion = 124°C; M+H+ = 547.0.05 g of Λ- {1- [N- (c-s-4-aminocyclohexyl) -4-chloro-D-phenylalanyl] piperidin-4-yl} -α-cyclohexyl-2,2 are placed therein. -dimethylhydrazinecarboxamide in 10 ml of diethyl ether and 0.09 ml of 2N hydrochloric acid in diethyl ether. The precipitate obtained is and dried over P 2 O 5 . 0.06 g of Λ- {1- [Λ- (α-4-aminocyclohexyl) -4-chloro-D-phenylalanyl] piperidin-4-yl} Λ -cyclohexyl-2 hydrochloride are obtained. 2-dimethylhydrazinecarboxamide. M.p. = 124 ° C; M + H + = 547.
Exemple 12 : Chlorhydrate de W-{1-[Λ/-(c/s-4-aminocyclohexyl)-4-chloro-D- phenylalanyl]piperïdin-4-yl}-/V-cycloheptyl-ΛP,ΛT-diethylurea (composé n° 33)Example 12: W- {1- [Λ- (α-4-aminocyclohexyl) -4-chloro-D-phenylalanyl] piperidin-4-yl} - β-cycloheptyl-ΛP, ΛT-diethylurea hydrochloride ( compound no. 33)
12.1 : ferf-butyl 4-(cycloheptylamino)piperidine-1-carboxylate12.1: 4-butyl-4- (cycloheptylamino) piperidine-1-carboxylate
On place 6,98 g de 1-Boc-pipéridone dans 175 mL de dichlorométhane sous N2 en présence de 4,46 mL de cycloheptylamine et de 9,65 g de triacétoxyborohydrure de sodium et le milieu réactionnel est agité pendant 16h à température ambiante. Après addition de 80 mL d'une solution aqueuse de soude 0,5N, on extrait à l'acétate d'éthyle jusqu'à épuisement de la phase aqueuse. Après séchage sur MgSO4 et concentration à sec, on obtient 5,6 g de fe/t-butyl 4-(cycloheptylamino)piperidine-1-carboxylate utilisé tel quel dans la suite de la synthèse.6.98 g of 1-Boc-piperidone are placed in 175 ml of dichloromethane under N 2 in the presence of 4.46 ml of cycloheptylamine and 9.65 g of sodium triacetoxyborohydride and the reaction medium is stirred for 16 hours at room temperature. . After addition of 80 ml of a 0.5N aqueous sodium hydroxide solution, the mixture is extracted with ethyl acetate until the aqueous phase is exhausted. After drying over MgSO 4 and concentration to dryness, 5.6 g of tert-butyl 4- (cycloheptylamino) piperidine-1-carboxylate are obtained, which is used as it is in the remainder of the synthesis.
12.2 : ferf-butyl 4-{cycloheptyl[(diethylamino)carbonyl]amino}piperidine-1- carboxylate12.2: 4- {4- {cycloheptyl [(diethylamino) carbonyl] amino} piperidine-1-carboxylate
On place 0,98 mL de diphosgène dans 20 mL de dichlorométhane à 00C sous N2. Une solution de 1 ,2 g de te/if-butyl 4-(cycloheptylamino)piperidine-1-carboxylate et de 5,64 mL de triéthylamine est ajoutée goutte à goutte. La solution est agitée 30 min à 00C puis 3h à température ambiante. On ajoute alors 4,23 mL de diéthylamine ajoutés. Le mélange est agité à température ambiante pendant 16h. Après évaporation du dichlorométhane, on ajoute 50 mL d'acide chlorhydrique 0,5N. On extrait au dichlorométhane jusqu'à épuisement de Ia phase aqueuse. Après séchage sur.MgSO4 et concentration à sec, le résidu obtenu est chromatographié sur gel de silice en éluant avec un mélange 99/1 puis 98/2 de dichlorométhane et de méthanol pour conduire à 4,18 g de teAf-butyl 4-{cycloheptyl[(diethylamino)carbonyl]amino}piperidine-1-carboxylate.0.98 ml of diphosgene are placed in 20 ml of dichloromethane at 0 ° C. under N 2 . A solution of 1.2 g of tert-butyl 4- (cycloheptylamino) piperidine-1-carboxylate and 5.64 ml of triethylamine is added dropwise. The solution is stirred for 30 min at 0 ° C. and then for 3 h at room temperature. 4.23 mL of added diethylamine are then added. The The mixture is stirred at ambient temperature for 16 hours. After evaporation of the dichloromethane, 50 ml of 0.5N hydrochloric acid are added. It is extracted with dichloromethane until the aqueous phase is exhausted. After drying over MgSO 4 and concentration to dryness, the residue obtained is chromatographed on silica gel, eluting with a 99/1 and then 98/2 mixture of dichloromethane and methanol to yield 4.18 g of 4-tert-butyl. cycloheptyl {[(diethylamino) carbonyl] amino} piperidine-1-carboxylate.
12.3 : Λ/-cycloheptyl-Λ/',Λ/'-diethyl-Λ/-piperidin-4-ylurea12.3: Λ / -cycloheptyl-Λ / ', Λ' - diethyl-Λ / -piperidin-4-ylurea
On place 1 ,6 g de te/f-butyl 4-{cycloheptyl[(diethylamino)carbonyl]amino} piperidine-1 -carboxylate dans 20,25 mL d'acide chlorhydrique 4N dans le dioxane. Le milieu réactionnel est agité pendant 16h à température ambiante. Après évaporation à sec, on ajoute environ 10 mL de dichlorométhane, 10 mL de tétrahydrofurane, 5mL d'eau et 5 mL de méthanol. Puis on ajoute 25g de résine DOWEX® 50X2. On laisse agiter 1h à température ambiante. Après lavage successivement de la résine avec du tétrahydrofurane, du dichlorométhane, et du méthanol, le composé attendu est relargué avec une solution 2N d'ammoniaque dans le méthanol. Après concentration à sec, on obtient 1 g de Λ/-cycloheptyl-Λ/1,Λ/'-diethyl-Λ/-piperidin-4-ylurea sous la forme d'une huile rouge.1.6 g of tert-butyl 4- {cycloheptyl [(diethylamino) carbonyl] amino} piperidine-1-carboxylate are placed in 20.25 ml of 4N hydrochloric acid in dioxane. The reaction medium is stirred for 16 hours at room temperature. After evaporation to dryness, about 10 ml of dichloromethane, 10 ml of tetrahydrofuran, 5 ml of water and 5 ml of methanol are added. Then 25g of DOWEX ® 50X2 resin is added. The mixture is stirred for 1 hour at room temperature. After successively washing the resin with tetrahydrofuran, dichloromethane and methanol, the expected compound is salted out with a 2N solution of ammonia in methanol. After concentration to dryness, 1 g of Λ -cycloheptyl-Λ / 1 , Λ-diethyl-β-piperidin-4-ylurea is obtained in the form of a red oil.
12.4 : fert-butyl (c/s-4-{[(1R)-1-(4-chlorobenzyl)-2-(4-{cycloheptyl[(diethylamino) carbonyl]amino}piperidin-1-yl)-2-oxoethyl]amino}cyclohexyl)carbamate12.4: tert-butyl (cs-4 - {[(1R) -1- (4-chlorobenzyl) -2- (4- {cycloheptyl [(diethylamino) carbonyl] amino} piperidin-1-yl) -2- oxoethyl] amino} cyclohexyl) carbamate
On solubilise 0,24 g de Λ/-cycloheptyl-Λ/1 !Λ/1-diethyl-Λ/-piperidin-4-ylurea obtenu à l'étape 12.3 dans 10 mL de dichlorométhane en présence de 0,28 g de N-{cis-4-[(tert- butoxycarbonyl)amino]cyclohexyl}-4-chloro-D-phenylalanine obtenu à l'étape 11.4, de 0,11 g d'hydroxybenzotriazole, de 0,23 g de chlorhydrate de 1-(3-diméthylaminopropyl) - 3-éthyl-carbodiimide et de 0,5 mL de diisopropyléthylamine, puis 0,81 mL d'acide chlorhydrique 2N dans le dioxane. Le mélange est agité 18h à température ambiante. Après hydrolyse avec une solution saturée aqueuse d'hydrogénocarbonate de sodium, on extrait à l'acétate d'éthyle jusqu'à épuisement de la phase aqueuse. Après séchage sur MgSO4 et concentration à sec, le brut obtenu est chromatographié en éluant avec un gradient de méthanol dans le dichlorométhane variant de 1% à 4%. On obtient 0,34 g de fert-butyl (c/s-4-{[(1 R)-1 -(4-chlorobenzyl)-2-(4-{cycloheptyl[(diethylamino)carbonyl]amino} piperidin-1-yl)-2-oxoethyl]amino}cyclohexyl)carbamate.0.24 g of Λ -cycloheptyl-Λ / 1 are solubilized . Λ / 1- diethyl-β-piperidin-4-ylurea obtained in step 12.3 in 10 ml of dichloromethane in the presence of 0.28 g of N- {cis-4 - [(tert-butoxycarbonyl) amino] cyclohexyl} 4-chloro-D-phenylalanine obtained in step 11.4, 0.11 g of hydroxybenzotriazole, 0.23 g of 1- (3-dimethylaminopropyl) -3-ethyl-carbodiimide hydrochloride and 0.5 mL of diisopropylethylamine and then 0.81 mL of 2N hydrochloric acid in dioxane. The mixture is stirred for 18h at room temperature. After hydrolysis with saturated aqueous sodium hydrogencarbonate solution, the mixture is extracted with ethyl acetate until the aqueous phase is exhausted. After drying over MgSO 4 and concentration to dryness, the crude obtained is chromatographed eluting with a gradient of methanol in dichloromethane ranging from 1% to 4%. 0.34 g of tert-butyl (c / s-4 - {[(1R) -1- (4-chlorobenzyl) -2- (4- {cycloheptyl [(diethylamino) carbonyl] amino} piperidin-1 are obtained. -yl) -2-oxoethyl] amino} cyclohexyl) carbamate.
12.5 : Λ/-{1 -[Λ/-(c/s-4-aminocyclohexyl)-4-chloro-D-phenylalanyl]piperidin-4-yl}-Λ/- cycloheptyl-W.Λ/'-diethylurea12.5: Λ- {1 - [Λ- (α-4-aminocyclohexyl) -4-chloro-D-phenylalanyl] piperidin-4-yl} -Λ-cycloheptyl-Λ-diethylurea
On place 0,34 g de te/f-butyl (c/s-4-{[(1R)-1-(4-chlorobenzyl)-2-(4- {cycloheptyl[(diethylamino)carbOnyl]amino}piperidin-1-yl)-2-oxoethyl]amino}cyclohexyl) carbamate dans 1 ,43 ml_ d'acide chlorhydrique 4N dans le dioxane. Le milieu réactionnel est agité pendant 3h à température ambiante. Après évaporation à sec, on reprend le résidu avec une solution aqueuse de soude 1 N. On extrait au dichlorométhane jusqu'à épuisement .de. la phase aqueuse. Après séchage sur MgSO4 et concentration à sec, le brut obtenu est chromatographié en éluant avec un gradient d'un mélange de méthanol. et d'ammoniaque dans le dichlorométhane variant de 95/5/0,5 à 8/2/0,2. On obtient 0,22 g de /y-{1-[Λ/-(c/s-4-aminocyclohexyl)-4-chloro-D-phenylalanyl]piperidin-4-yl}-Λ/- cycloheptyl-Λ/I,Λ/'-diethylurea.0.34 g of tert-butyl (c / s-4 - {[(1R) -1- (4-chlorobenzyl) -2- (4-) {cycloheptyl [(diethylamino) carbonyl] amino} piperidin-1-yl) -2-oxoethyl] amino} cyclohexyl) carbamate in 1.43 ml of 4N hydrochloric acid in dioxane. The reaction medium is stirred for 3h at room temperature. After evaporation to dryness, the residue is taken up with a 1N aqueous sodium hydroxide solution. The mixture is extracted with dichloromethane until exhaustion. the aqueous phase. After drying over MgSO 4 and concentration to dryness, the crude obtained is chromatographed eluting with a gradient of a mixture of methanol. and ammonia in dichloromethane ranging from 95/5 / 0.5 to 8/2 / 0.2. 0.22 g of γ- {1- [Λ- (α-4-aminocyclohexyl) -4-chloro-D-phenylalanyl] piperidin-4-yl} -Λ-cycloheptyl-Λ / I are obtained. , Λ / '- diethylurea.
12.7 : Chlorhydrate de Λ/-{1-[Λ/-(c/s-4-aminocyclohexyl)-4-chloro-D-phenylalanyl] piperidin-4-yl}-/V-cycloheptyl-Λ/\Λ/'-diethylurea12.7: Λ- {1- [Λ- (α-4-aminocyclohexyl) -4-chloro-D-phenylalanyl] piperidin-4-yl} - β-cycloheptyl-Λ / Ch hydrochloride -diethylurea
On place 0,22 g de A/-{1-[Λ/-(c/s-4-aminocyclohexyl)-4-chloro-D- phenylalanyl]piperidin-4-yl}-Λ/-cycloheptyl-Λ/τ,Λ/'-diethylurea dans 10 mL de diéthyléther et on ajoute 0,38 mL d'acide chlorhydrique 2N dans le diéthyléther. Le précipité obtenu est et séché sur P2O5. On obtient 0,23 g du chlorhydrate de Λ/-{1-[Λ/-(c/s-4-aminocyclohexyl)- 4-chloro-D-phenylalanyl]piperidin-4-yl}-/V-cycloheptyl-Λ/\Λ/'-diethylurea.0.22 g of A / - {1- [Λ- (c-s-4-aminocyclohexyl) -4-chloro-D-phenylalanyl] piperidin-4-yl} -Λ / -cycloheptyl-Λ / τ are placed , Λ / '- diethylurea in 10 mL of diethyl ether and 0.38 mL of 2N hydrochloric acid in diethyl ether. The precipitate obtained is and dried over P 2 O 5 . 0.23 g of Λ- {1- [Λ- (α-4-aminocyclohexyl) -4-chloro-D-phenylalanyl] piperidin-4-yl} - β-cycloheptyl-chlor hydrochloride are obtained. / \ Λ / '- diethylurea.
Point de fusion = 1050C; M+H+ = 574 ; [α]D 20 = +3° (c=0,899g/100mL, DMSO).Melting point = 105 0 C; M + H + = 574; [α] D 20 = + 3 ° (c = 0.899g / 100mL, DMSO).
Exemple 13 : Chlorhydrate de /V-(c/s-4-{[(1fî)-1-(4-chlorobenzyl)-2-(trans-4- {cyclohexyl[(dimethylamino)carbonyl]amino}-3-methylpîperidin-1-yl)-2- oxoethyl]amino}cyclohexyl)acetamide (composé n°105)Example 13: N- (c / s-4 - {[(1 H) -1- (4-Chlorobenzyl) -2- (trans-4- {cyclohexyl [(dimethylamino) carbonyl] amino} -3-methylpiperidine Hydrochloride 1-yl) -2-oxoethyl] amino} cyclohexyl) acetamide (Compound No. 105)
13.1 : Λ/-(4-oxocyclohexyl)acetamide13.1: Λ / - (4-oxocyclohexyl) acetamide
On place 1 ,5 g de 4-aminocyclohexanone dans 50 mL d'acétonitrile et on ajoute 0,86 mL d'acetyl chloride puis 4,2 g de carbonate de potassium. Le milieu réactionnel est agité 18h à température ambiante. Après concentration à sec, le résidu est repris avec une solution aqueuse d'acide chlorhydrique 1 N. On extrait au dichlorométhane jusqu'à épuisement de la phase aqueuse. La phase organique est lavée avec une solution aqueuse d'acide chlorhydrique 1N. Après séchage sur MgSO4 et concentration à sec, on obtient 0,45 g de Λ/-(4-oxocyclohexyl)acetamide, utilisé tel quel par la suite.1. 5 g of 4-aminocyclohexanone are placed in 50 ml of acetonitrile and 0.86 ml of acetyl chloride and then 4.2 g of potassium carbonate are added. The reaction medium is stirred for 18 h at room temperature. After concentration to dryness, the residue is taken up with a 1N aqueous hydrochloric acid solution. The mixture is extracted with dichloromethane until the aqueous phase is exhausted. The organic phase is washed with a 1N aqueous hydrochloric acid solution. After drying over MgSO 4 and concentration to dryness, 0.45 g of Λ- (4-oxocyclohexyl) acetamide is obtained, used as it is subsequently.
13.2 : 3~methylpiperidin-4-one13.2: 3 ~ methylpiperidin-4-one
On place 12,2 g de 1-benzyl-3-methylpiperidin-4-one dans un flacon de Parr en présence de 2,44 g de d'hydroxyde de palladium dans 24OmL d'éthanol. Le mélange réactionnel est mis sous hydrogène à une pression de 50 psi et agité à température ambiante durant 4h. La solution est filtrée sur célite puis concentrée à sec. On obtient ainsi 6,8 g de 3-methylpiperidin-4-one, utilisé tel quel par Ia suite.12.2 g of 1-benzyl-3-methylpiperidin-4-one are placed in a Parr flask in the presence of 2.44 g of palladium hydroxide in 24OmL of ethanol. The reaction mixture was placed under hydrogen at 50 psi and stirred at room temperature for 4h. The solution is filtered on celite and then concentrated to dryness. We obtain thus 6.8 g of 3-methylpiperidin-4-one, used as is thereafter.
13.3: ferf-butyl 3-methyl-4-oxopiperidine-1-carboxylate13.3: Ferf-butyl 3-methyl-4-oxopiperidine-1-carboxylate
On place 6,8 g de 3-methylpiperidin-4-one, 16,7 mL de triéthylamine, 19,6 g de di-f-butyl dicarbonate et 0,7 g de diméthyaminopyridine dans un mélange de 300ml de THF et de 30 ml d'eau. L'agitation est maintenue à température ambiante pendant 18h. Après évaporation du THF, on traite le milieu réactionnel par une solution aqueuse saturée d'hydrogénosulfâte de potassium jusqu'à pH 1 puis on extrait à l'acétate d'éthyle jusqu'à épuisement de la phase aqueuse. La phase organique est alors lavée avec une solution aqueuse saturée d'hydrogénosulfate de potassium, puis avec une solution aqueuse saturée d'hydrogénocarbonate de sodium, et enfin avec une solution aqueuse saturée de chlorure de sodium. Après séchage, sur MgSO4 et concentration à sec, le brut obtenu est chromatographié sur gel de silice en éluant avec un mélange dichlorométhane/méthanol 98/2. On obtient 10,3 g de ferf-butyl 3-methyl-4-oxopiperidine- 1-carboxylate.6.8 g of 3-methylpiperidin-4-one, 16.7 ml of triethylamine, 19.6 g of di-t-butyl dicarbonate and 0.7 g of dimethylaminopyridine are placed in a mixture of 300 ml of THF and 30 ml of triethylamine. ml of water. Stirring is maintained at room temperature for 18 hours. After evaporation of the THF, the reaction medium is treated with a saturated aqueous solution of potassium hydrogen sulphate to pH 1 and then extracted with ethyl acetate until the aqueous phase is exhausted. The organic phase is then washed with a saturated aqueous solution of potassium hydrogen sulphate, then with a saturated aqueous solution of sodium hydrogencarbonate, and finally with a saturated aqueous solution of sodium chloride. After drying, over MgSO 4 and concentration to dryness, the crude obtained is chromatographed on silica gel, eluting with a 98/2 dichloromethane / methanol mixture. 10.3 g of tert-butyl-3-methyl-4-oxopiperidine-1-carboxylate are obtained.
13.4 : fert-butyl trans-4-(cyclohexylamino)-3-methylpiperidine-1-carboxylate On place 7,7 g de te/t-butyl 3-methyl-4-oxopiperidine-1-carboxylate et 4,1 mL de cyclohexylamine dans 180 mL de méthanol et on ajuste le pH à 6 avec 4 ml d'acide acétique. On additionne alors 4,5 g de cyanoborohydrure de sodium. Le milieu réactionnel est mis au reflux du méthanol durant 18h. La solution est alors hydrolysée avec une solution aqueuse de soude 1 N et extraite à l'acétate d'éthyle jusqu'à épuisement de la phase aqueuse. Après séchage sur MgSO4 et concentration à sec, le brut obtenu est chromatographié sur gel de silice avec un mélange de dichlorométhane/acétate d'éthyle/méthanol/ammoniaque variant de 97/3/0,5/0,05 à 90/10/2/0,2. On obtient 1 ,9 g de ferf-butyl trans-4-(cyclohexylamino)-3-methylpiperidine- 1-carboxylate et 2,25 g de ferf-butyl cis-4-(cyclohexylamino)-3-methylpiperidine-1- carboxylate.13.4: Fert-butyl trans-4- (cyclohexylamino) -3-methylpiperidine-1-carboxylate 7.7 g of tert-butyl-3-methyl-4-oxopiperidine-1-carboxylate and 4.1 ml of cyclohexylamine are placed in 180 mL of methanol and adjust the pH to 6 with 4 mL of acetic acid. 4.5 g of sodium cyanoborohydride are then added. The reaction medium is refluxed with methanol for 18 h. The solution is then hydrolysed with an aqueous solution of 1N sodium hydroxide and extracted with ethyl acetate until the aqueous phase is exhausted. After drying over MgSO 4 and concentration to dryness, the crude obtained is chromatographed on silica gel with a mixture of dichloromethane / ethyl acetate / methanol / ammonia ranging from 97/3 / 0.5 / 0.05 to 90/10. / 2 / 0.2. 1.9 g of tert-butyl trans-4- (cyclohexylamino) -3-methylpiperidine-1-carboxylate and 2.25 g of tert-butyl cis-4- (cyclohexylamino) -3-methylpiperidine-1-carboxylate are obtained.
13.5 : te/f-butyl trans-4-{cyclohexyl[(dimethylamino)carbonyl]amino}-3- methylpiperidine-1 -carboxylate13.5: tert-butyl trans-4- {cyclohexyl [(dimethylamino) carbonyl] amino} -3-methylpiperidine-1-carboxylate
On place 0,5 g de fe/f-butyl trans-4-(cyclohexylamino)-3-methylpiperidine-1- carboxylate dans 8,5 mL de dichlorométhane, puis on ajoute la 0,35 mL de triéthylamine et on refroidit le milieu à 00C. On additionne alors lentement 0,2 mL de diphosgène. Le milieu réactionnel est agité à 00C pendant 15 min puis à température ambiante pendant 5h. Après hydrolyse sur un mélange de glace et une solution de soude aqueuse 1 N, on extrait à l'acétate d'éthyle jusqu'à épuisement de la phase aqueuse. La phase organique est lavée avec H2O, puis avec une solution aqueuse saturée de chlorure de sodium, séchée sur MgSO4 et concentrée à sec. Le brut obtenu est solubilisé dans 8 mL d'acétonitrile. On rajoute 0,71 g de chlorhydrate de diméthylamine et 1,21 g de carbonate de potassium. L'agitation est maintenue 4Oh à température ambiante. On hydrolyse et on extrait à l'acétate d'éthyle jusqu'à épuisement de la phase aqueuse. La phase organique est lavée à l'eau, puis avec une solution aqueuse d'acide chlorhydrique 1 N et enfin avec une solution aqueuse saturée de chlorure de sodium. Elle est séchée sur MgSO4 et concentrée à sec. On obtient 0,6 g • de ferf-butyl trans-4- {cyclohexyl[(dimethylamino)carbonyl]amino}-3-methylpiperidine-1-carboxylate.0.5 g of Fe / f-butyl trans-4- (cyclohexylamino) -3-methylpiperidine-1-carboxylate are placed in 8.5 ml of dichloromethane, then the 0.35 ml of triethylamine is added and the medium is cooled. at 0 ° C. 0.2 ml of diphosgene is then added slowly. The reaction medium is stirred at 0 ° C. for 15 min and then at room temperature for 5 h. After hydrolysis on a mixture of ice and 1 N aqueous sodium hydroxide solution, extracted with ethyl acetate until the aqueous phase is exhausted. The organic phase is washed with H 2 O, then with a saturated aqueous solution of sodium chloride, dried over MgSO 4 and concentrated to dryness. The crude obtained is solubilized in 8 mL of acetonitrile. 0.71 g of dimethylamine hydrochloride and 1.21 g of potassium carbonate are added. Stirring is maintained 40h at room temperature. It is hydrolyzed and extracted with ethyl acetate until the aqueous phase is exhausted. The organic phase is washed with water, then with a 1N aqueous solution of hydrochloric acid and finally with a saturated aqueous solution of sodium chloride. It is dried over MgSO 4 and concentrated to dryness. 0.6 g of tert-butyl trans-4- {cyclohexyl [(dimethylamino) carbonyl] amino} -3-methylpiperidine-1-carboxylate are obtained.
13.6 : Λ/^cyclohexyl-Λ/',Λ/1-dimethyl-Λ/-[trans-3-methylpiperidin-4-yl]urea13.6: cyclohexyl-β, β- 1- dimethyl-β- [trans-3-methylpiperidin-4-yl] urea
On place 0,6 g de terf-butyl trans-4-{cyclohexyl[(dimethylamino)carbonyl]amino}- 3-methy!piperidine-1-carboxylate dans 2 mL de dioxane, puis on ajoute 6,12 mL d'acide chlorhydrique 4N dans le dioxane et on laisse agiter 4h à température ambiante. Après concentration à sec, on reprend le résidu avec de une solution aqueuse de soude 1 N, et on extrait à l'acétate d'éthyle jusqu'à épuisement de la phase aqueuse. La phase organique est lavée avec une solution aqueuse de soude 1 N, puis avec H2O et enfin avec une solution aqueuse saturée de chlorure de sodium. Après séchage sur MgSO4, le brut obtenu est chromatographié sur gel de silice avec un mélange de dichlorométhane/méthanol/ammoniaque variant de 10/0/0 à 9/1/0.1. On obtient 0,35 g de Λ/-cyclohexyl-Λ/',Λ/1-dimethyl-Λ/-[trans-3-methylpiperidin-4-yl]urea.0.6 g of tert-butyl trans-4- {cyclohexyl [(dimethylamino) carbonyl] amino} -3-methylpiperidine-1-carboxylate are placed in 2 ml of dioxane and then 6.12 ml of acid is added. 4N hydrochloric acid in dioxane and the mixture is stirred for 4 hours at room temperature. After concentration to dryness, the residue is taken up in 1N aqueous sodium hydroxide solution and extracted with ethyl acetate until the aqueous phase is exhausted. The organic phase is washed with an aqueous solution of 1N sodium hydroxide, then with H 2 O and finally with a saturated aqueous solution of sodium chloride. After drying over MgSO4, the crude obtained is chromatographed on silica gel with a dichloromethane / methanol / ammonia mixture ranging from 10/0/0 to 9/1 / 0.1. 0.35 g of β-cyclohexyl-α, β- 1- dimethyl-β- [trans-3-methylpiperidin-4-yl] urea are obtained.
13.7 : fe/f-butyl [(1 ft)-1 -(4-chlorobenzyl)-2-(trans-4- {cyclohexyl^dimethylamino^arbonyllaminoî-S-methylpiperidin-i-yO^-oxoethyljcarbamate13.7: tert-butyl [(1 f) -1- (4-chlorobenzyl) -2- (trans-4- {cyclohexyl} dimethylamino] arbonyllamino] -S-methylpiperidin-1-yl] oxoethyl] carbamate
On solubilise 3,16 g de W-cyclohexyl-Λ/I,Λ/l-dimethyl-Λ/-[trans-3-methylpiperidin-4- yljurea obtenu à l'étape 13.6 dans 118 mL de dichlorométhane en présence de 3,5 g de 4-chloro-D-Boc-phenylalanine, de 1 ,60 g d'hydroxybenzotriazole, de 2,27 g de chlorhydrate de 1-(3-diméthylaminopropyi)-3-éthyl-carbodiimide et de 2,10 mL de diisopropyléthylamine. Le mélange est agité 18h à température ambiante sous N2. Après évaporation à sec, le résidu est repris à l'acétate d'éthyle et H2O. On extrait à l'acétate d'éthyle jusqu'à épuisement de la phase aqueuse. La phase organique est lavée avec une solution aqueuse saturée de chlorure de sodium. Après séchage sur MgSO4 et concentration à sec, le brut obtenu est chromatographié en éluant avec un gradient de méthanol dans Ie dichlorométhane variant de 0% à 10%. On obtient 5,29 g de terf-butyl [(1/:?)-1-(4-chIorobenzyl)-2-(trans-4-{cyclohexyl[(dimethylamino)carbonyl]amino}-3- methylpiperidin-1-yl)-2-oxoethyl]carbamate. 13.8 : Λ/-[trans-1 -(4-chloro-D-phenyIalanyl)-3-methylpiperidin-4-yl]-/V-cyclohexyl- /V.Λ/'-dimethylureaIs dissolved 3.16 g of N-cyclohexyl-Λ / I, Λ / -dimethyl-l Λ / - [trans-3-methylpiperidin-4- yljurea obtained in step 13.6 in 118 mL of dichloromethane in the presence of 3, 5 g of 4-chloro-D-Boc-phenylalanine, 1.60 g of hydroxybenzotriazole, 2.27 g of 1- (3-dimethylaminopropyl) -3-ethyl-carbodiimide hydrochloride and 2.10 ml of diisopropylethylamine. The mixture is stirred for 18h at room temperature under N 2 . After evaporation to dryness, the residue is taken up in ethyl acetate and H 2 O. It is extracted with ethyl acetate until the aqueous phase is exhausted. The organic phase is washed with a saturated aqueous solution of sodium chloride. After drying over MgSO 4 and concentration to dryness, the crude obtained is chromatographed eluting with a gradient of methanol in dichloromethane ranging from 0% to 10%. Was obtained 5.29 g of tert-butyl [(1 /?) - 1- (4-chIorobenzyl) -2- (trans-4- {cyclohexyl [(dimethylamino) carbonyl] amino} -3-methylpiperidin-1- yl) -2-oxoethyl] carbamate. 13.8: Λ- [trans-1 - (4-chloro-D-phenylalanyl) -3-methylpiperidin-4-yl] - β-cyclohexyl-β-dimethylurea
On place 5,29 g de fe/t-butyl [(1f?)-1-(4-chlorobenzyl)-2-(trans-4- {cyclohexyl[(dimethylamino)carbonyl]amino}-3-methylpiperidin-1-yl)-2-oxoethyl]carbamate dans 5 mL de dioxane. Puis on ajoute 24,1 ml_ d'acide chlorhydrique 4N dans le dioxane. Le milieu réactionnel est agité pendant 18h à température ambiante. Après évaporation à sec, on reprend le résidu au dichlorométhane et avec une solution aqueuse saturée d'hydrogénocarbonate de sodium. On extrait au dichlorométhane jusqu'à épuisement de la phase aqueuse. La phase organique est lavée avec H2O, puis avec une solution aqueuse saturée de chlorure de sodium. Après séchage sur MgSO4 et concentration à sec, on obtient 4,3 g de Λ/-[trans-1-(4-chloro-D-phenylalanyl)-3-methylpiperidin-4-yl]-Λ/- cyclohexyl-Λ/'.Λ/'-dimethylurea.5.29 g of tert-butyl [(1f)) - 1- (4-chlorobenzyl) -2- (trans-4- {cyclohexyl [(dimethylamino) carbonyl] amino} -3-methylpiperidin-1 are placed yl) -2-oxoethyl] carbamate in 5 mL of dioxane. 24.1 ml of 4N hydrochloric acid in dioxane are then added. The reaction medium is stirred for 18h at room temperature. After evaporation to dryness, the residue is taken up in dichloromethane and with a saturated aqueous solution of sodium hydrogencarbonate. It is extracted with dichloromethane until the aqueous phase is exhausted. The organic phase is washed with H 2 O and then with a saturated aqueous solution of sodium chloride. After drying over MgSO 4 and concentration to dryness, 4.3 g of Λ- [trans-1- (4-chloro-D-phenylalanyl) -3-methylpiperidin-4-yl] -Λ-cyclohexyl-Λ are obtained. /'.Λ/'-dimethylurea.
13.9 : Λ/-(c/s-4-{[(1 R)-1-(4-chlorobenzyl)-2-(trans-4-13.9: Λ / - (c / s-4 - {[(1 R) -1- (4-chlorobenzyl) -2- (trans-4-
{cyclohexyl[(dimethylamino)carbonyl]amino}-3-methylpiperidin-1-yl)-2- oxoethyi]amino}cyclohexyl)acetamideCyclohexyl [(dimethylamino) carbonyl] amino} -3-methylpiperidin-1-yl) -2-oxoethyl] amino} cyclohexyl) acetamide
On solubilise 0,5 g de Λ/-[trans-1-(4-chloro-D-phenylalanyl)-3-methylpiperidin-4-yl]- Λ/-cyclohexyl-Λ/1,Λ/'-dimethylurea obtenu à l'étape 13.8 dans 11 mL de dichlorométhane en présence de 0,21 g de Λ/-(4-oxocyclohexyl)acetamide obtenu à l'étape 13.2. On additionne ensuite 0,35 g de triacétoxyborohydrure de sodium sous N2. L'agitation est maintenue pendant 18h à température ambiante. Après hydrolyse avec une solution aqueuse saturée d'hydrogénocarbonate de sodium, on extrait au dichlorométhane jusqu'à épuisement de la phase aqueuse. La phase organique est lavée avec H2O puis avec une solution aqueuse saturée de chlorure de sodium. Après séchage sur MgSO4 et concentration à sec, le brut obtenu est chromatographié sur gel de silice en éluant avec un mélange de dichlorométhane/acétone/méthanol variant de 100/0/0 à 70/25/5. On obtient 0,19 g et 0,34g de Λ/-(4-{[(1R)-1-(4-chlorobenzyl)-2-(trans-4- {cyclohexyl[(dimethylamino)carbonyl]amino}-3-methylpiperidin-1-yl)-2- oxoethyl]amino}cyclohexyl)acetamide, mélange de stéréoisomères de configuration non déterminée.0.5 g of Λ / - [trans-1- (4-chloro-D-phenylalanyl) -3-methylpiperidin-4-yl] - Λ -cyclohexyl-Λ / 1 , Λ-dimethylurea are dissolved in step 13.8 in 11 mL of dichloromethane in the presence of 0.21 g of Λ- (4-oxocyclohexyl) acetamide obtained in step 13.2. 0.35 g of sodium triacetoxyborohydride are then added under N 2 . Stirring is maintained for 18h at room temperature. After hydrolysis with a saturated aqueous sodium hydrogencarbonate solution, the mixture is extracted with dichloromethane until the aqueous phase is exhausted. The organic phase is washed with H 2 O and then with a saturated aqueous solution of sodium chloride. After drying over MgSO 4 and concentration to dryness, the crude obtained is chromatographed on silica gel, eluting with a dichloromethane / acetone / methanol mixture ranging from 100/0/0 to 70/25/5. 0.14 g and 0.34 g of Λ- (4 - {[(1R) -1- (4-chlorobenzyl) -2- (trans-4- {cyclohexyl [(dimethylamino) carbonyl] amino} -3 are obtained. -methylpiperidin-1-yl) -2-oxoethyl] amino} cyclohexyl) acetamide, a mixture of stereoisomers of undetermined configuration.
13.10 : chlorhydrate de Λ/-(4-{[(1F?)-1-(4-chlorobenzyl)-2-(trans-4-13.10: Λ / - (4 - {[(1F)) - 1- (4-chlorobenzyl) -2- (trans-4) hydrochloride
{cyclohexyl[(dimethylamino)carbonyl]amino}-3-methylpiperidin-1-yl)-2- oxoethyl]amino}cyclohexyl)acetamide .{cyclohexyl [(dimethylamino) carbonyl] amino} -3-methylpiperidin-1-yl) -2-oxoethyl] amino} cyclohexyl) acetamide.
On place 0,19 g de Λ/-(4-{[(1R)-1-(4-chlorobenzyl)-2-(trans-4- {cyclohexyI[(dimethylamino)carbonyl]amino}-3-methylpiperidin-1-yl)-2- oxoethyl]amino}cyclohexyl)acetamide, dans 2 ml_ d'acétate d'éthyle et on ajoute 0,16 mL d'acide chlorhydrique 2N dans le diéthyléther. Après concentration à sec, le milieu réactionne! est repris dans du diéthyléther d'éthyle et trituré. Puis on essore le précipité obtenu et on rince au diéthyléther. Le chlorhydrate ainsi obtenu est séché sur P2O5 sous pression réduite. On obtient 0,19 g du chlorhydrate de Λ/-(4-{[(1R)-1-(4-chlorobenzyl)-2- (trans-^cycIohexyl^dimethylaminoJcarbonylJaminoJ-S-methylpiperidin-i-yl)^- oxoethyl]amino}cyclohexyl)acetamide.0.19 g of Λ- (4 - {[(1R) -1- (4-chlorobenzyl) -2- (trans-4- {cyclohexyl [(dimethylamino) carbonyl] amino} -3-methylpiperidin-1 are placed therein. yl) -2- oxoethyl] amino} cyclohexyl) acetamide in 2 ml of ethyl acetate and 0.16 ml of 2N hydrochloric acid in diethyl ether. After dry concentration, the medium reacts! is taken up in ethyl diethyl ether and triturated. Then the precipitate obtained is filtered off and rinsed with diethyl ether. The hydrochloride thus obtained is dried over P 2 O 5 under reduced pressure. 0.19 g of Λ- (4 - {[(1R) -1- (4-chlorobenzyl) -2- (trans) -cyclohexyl-dimethylamino] -carbonyl-amino-5-methylpiperidin-1-yl) -oxoethyl hydrochloride are obtained. ] amino} cyclohexyl) acetamide.
Point de fusion = 1680C; M+H+ = 588Melting point = 168 ° C .; M + H + = 588
Exemple 14 : Chlorhydrate de /V-{(trans)-1-[4-chloro-W-(4-hydroxy-4- phenylcyclohexyl)-D-phenyIalanyl]-3-methylpiperidin-4-yl}-Λ/-cyclohexyl-Λr,Λr- dimethylurea (composé n°110)Example 14: - [(Trans) -1- [4-Chloro-N- (4-hydroxy-4-phenylcyclohexyl) -D-phenylalanyl] -3-methylpiperidin-4-yl} -Λ-cyclohexyl hydrochloride -R, dimethylurea (Compound No. 110)
14.1 : 4-phenyl-4-hydroxycyclohexanone14.1: 4-phenyl-4-hydroxycyclohexanone
On place 2,0 g de 1,4-cyclohexanedione dans 20 mL de diéthyléther et 40 mL de tétrahydrofurane anhydre sous N2 à -78°C. On ajoute lentement du phenyl lithium 1 ,8N dans un mélange cyclohexane/éther. L'agitation du milieu à -78°C est maintenue 2h20. Après hydrolyse avec une solution aqueuse saturée de chlorure d'ammonium, on extrait la phase aqueuse à l'acétate d'éthyle jusqu'à épuisement de la phase aqueuse. La phase organique est lavée avec une solution aqueuse saturée de chlorure de sodium. Après séchage sur MgSO4 et concentration à sec, le brut obtenu est chromatographié sur gel de silice en éluant avec un mélange de cyclohexane/acétate d'éthyle variant de 8/2 à 6/4. On obtient 0,64 g de 4-phenyl-4-hydroxycyclohexanone2.0 g of 1,4-cyclohexanedione are placed in 20 ml of diethyl ether and 40 ml of anhydrous tetrahydrofuran under N 2 at -78 ° C. 1.8 N phenyl lithium is slowly added to a cyclohexane / ether mixture. Stirring of the medium at -78 ° C is maintained 2h20. After hydrolysis with a saturated aqueous solution of ammonium chloride, the aqueous phase is extracted with ethyl acetate until the aqueous phase is exhausted. The organic phase is washed with a saturated aqueous solution of sodium chloride. After drying over MgSO 4 and concentration to dryness, the crude obtained is chromatographed on silica gel, eluting with a mixture of cyclohexane / ethyl acetate varying from 8/2 to 6/4. 0.64 g of 4-phenyl-4-hydroxycyclohexanone is obtained
14.2 : Λ/-{(trans)-1-[4-chloro-Λ/-(4-hydroxy-4-phenylcyclohexyl)-D-phenylalanyl]-3- methylpiperidin-4-yl}- Λ/-cyclohexyl-Λ/\ Λy-dimethylurea14.2: Λ - {(trans) -1- [4-chloro-Λ] - (4-hydroxy-4-phenylcyclohexyl) -D-phenylalanyl] -3-methylpiperidin-4-yl} - Λ -cyclohexyl-Λ / \ Λy-dimethylurea
On solubilise 0,50 g de Λ/-[trans-1-(4-chloro-D-phenylalanyl)-3-methylpiperidin-4- yl]-Λ/-cyclohexyl-Λ/',Λ/'-dimethylurea obtenu à l'étape 13.8 dans 11 ,3 mL de dichlorométhane en présence de 0,25 g de 4-phenyl-4-hydroxycyclohexanone obtenu à l'étape 14.1. On additionne ensuite 0,35 g de triacétoxyborohydrure de sodium sous N2. L'agitation est maintenue pendant 18h à température ambiante. Après ajout de 0,125 g de 4-phenyl-4-hydroxycyclohexanone et 0,175 g de triacétoxyborohydrure de sodium, l'agitation est maintenue 24h. On hydrolyse et on extrait au dichlorométhane jusqu'à épuisement de la phase aqueuse. La phase organique est lavée avec H2O, puis avec une solution aqueuse saturée de chlorure de sodium. Après séchage sur MgSO4 et concentration à sec, le brut, obtenu est chromatographié sur gel de silice en éluant avec un mélange de dichlorométhane/acétone/méthanol variant de 100/0/0 à 70/25/5. On obtient 0,17 g de et 0,22 g de Λ/-{(trans)-1-[4-chloro-Λ/-(4-hydroxy-4-phenylcyclohexyl)-D- phenylalanyl]-3-methylpiperidin-4-yi}-Λ/-cyclohexyl-Λ/1,Λ/'-dinnethylurea, mélange de stéréoisomères de configuration non déterminée.0.50 g of Λ / - [trans-1- (4-chloro-D-phenylalanyl) -3-methylpiperidin-4-yl] -Λ-cyclohexyl-β ', Λ-dimethylurea was solubilized at step 13.8 in 11.3 mL of dichloromethane in the presence of 0.25 g of 4-phenyl-4-hydroxycyclohexanone obtained in step 14.1. 0.35 g of sodium triacetoxyborohydride are then added under N 2 . Stirring is maintained for 18h at room temperature. After addition of 0.125 g of 4-phenyl-4-hydroxycyclohexanone and 0.175 g of sodium triacetoxyborohydride, the stirring is maintained 24h. It is hydrolyzed and extracted with dichloromethane until the aqueous phase is exhausted. The organic phase is washed with H 2 O and then with a saturated aqueous solution of sodium chloride. After drying over MgSO 4 and concentration to dryness, the crude product obtained is chromatographed on silica gel, eluting with a dichloromethane / acetone / methanol mixture ranging from 100/0/0 to 70/25/5. We 0.17 g of and 0.22 g of Λ / - {(trans) -1- [4-chloro-Λ] - (4-hydroxy-4-phenylcyclohexyl) -D-phenylalanyl] -3-methylpiperidin-4 are obtained. -yi -cyclohexyl-Λ / 1 , Λ / '- dinnethylurea, mixture of stereoisomers of undetermined configuration.
14.3 : chlorhydrate de Λ/-{(trans)-1-[4-chloro-Λ/-(4-hydroxy-4-phenylcyclohexyl)-D- phenylalanyl]-3-methylpiperidin-4-yl}-Λ/-cyclohexyl-Λ/',Λ/1-dimethylurea14.3: Λ - {(trans) -1- [4-chloro-Λ] - (4-hydroxy-4-phenylcyclohexyl) -D-phenylalanyl] -3-methylpiperidin-4-yl} -Λ-cyclohexyl hydrochloride -Λ / ', Λ / 1- dimethylurea
On place 0,22 g de Λ/-{(trans)-1-[4-chloro-Λ/-(4-hydroxy-4-pheny!cyclohexyl)-D- phenylalanyl]-3-methylpiperidin-4-yl}-Λ/-cyclohexyl-Λ/',Λ/I-dimethylurea, dans 2 mL d'acétate d'éthyle et on ajoute 0,71 ml_ d'acide chlorhydrique 0,5N dans le diéthyléther. Après concentration à sec, le milieu réactionnel est repris au diéthyléther et trituré. Puis on essore le précipité obtenu et on rince au diéthyléther. Le chlorhydrate ainsi obtenu est séché sur P2O5 sous pression réduite. On obtient 0,20 g du chlorhydrate de Λ/-{(trans)-1- [4-chloro-/V-(4-hydroxy-4-phenylcyclohexyl)-D-phenylalanyl]-3-methylpiperidin-4-yl}-/V- CyClOhIeXyI-ZV1A/1 -dimethylurea.0.22 g of Λ / - {(trans) -1- [4-chloro-Λ] - (4-hydroxy-4-phenylcyclohexyl) -D-phenylalanyl] -3-methylpiperidin-4-yl are placed -Λ / -cyclohexyl-Λ / 'Λ / I -dimethylurea, in 2 mL of ethyl acetate and hydrochloric acid was added 0.71 mL 0.5 N in diethyl ether. After concentration to dryness, the reaction medium is taken up in diethyl ether and triturated. Then the precipitate obtained is filtered off and rinsed with diethyl ether. The hydrochloride thus obtained is dried over P 2 O 5 under reduced pressure. 0.20 g of Λ / - {(trans) -1- [4-chloro] -N- (4-hydroxy-4-phenylcyclohexyl) -D-phenylalanyl] -3-methylpiperidin-4-yl hydrochloride are obtained. - / V- CyClOhIeXyI ZV 1-A / 1 -dimethylurea.
Point de fusion = 1940C; M+H+ = 623 ;Melting point = 194 ° C .; M + H + = 623;
Exemple 15 : Chlorhydrate de Λ/-(trans-1-{4-chloro-Λ/'-[4-(2-oxo-1,3- oxazolidin-3-yI)cyclohexyl]-D-phenylalanyl}-3-methylpiperidîn-4-yl)-Λ/-cyclohexyl- ΛTjΛf-dimethylurea (composé n° 118)Example 15: Λ- (trans-1- {4-chloro-Λ [4- [2-oxo-1,3-oxazolidin-3-yl] cyclohexyl] -D-phenylalanyl} hydrochloride methylpiperidin-4-yl) -NH-cyclohexyl-N-dimethylurea (Compound No. 118)
15.1 : 2-(1,4-dioxaspiro[4.5]dec-8-ylamino)ethanol15.1: 2- (1,4-dioxaspiro [4.5] dec-8-ylamino) ethanol
On solubilise 3,12 g de 1 ,4-dioxaspiro[4.5]decan-8-one dans 80 m!_ de dichlorométhane en présence de 1 ,16 g d'éthanol aminé. On additionne ensuite 6,75 g de triacétoxyborohydrure de sodium sous N2. L'agitation est maintenue pendant 18h à température ambiante. Après hydrolyse avec une solution aqueuse de soude 1 N, on extrait au dichlorométhane jusqu'à épuisement de la phase aqueuse. Après séchage sur MgSO4 et concentration à sec, on obtient 4,0 g de. 2-(1 ,4-dioxaspiro[4.5]dec-8- ylamino)ethanol utilisé tel quel par la suite.3.12 g of 1,4-dioxaspiro [4.5] decan-8-one are solubilized in 80 ml of dichloromethane in the presence of 1.16 g of ethanolamine. 6.75 g of sodium triacetoxyborohydride are then added under N 2 . Stirring is maintained for 18h at room temperature. After hydrolysis with a 1N aqueous sodium hydroxide solution, the mixture is extracted with dichloromethane until the aqueous phase is exhausted. After drying over MgSO 4 and concentrating to dryness, 4.0 g of is obtained. 2- (1,4-dioxaspiro [4.5] dec-8-ylamino) ethanol used as it is subsequently.
15.2: 3-(1 ,4-dioxaspiro[4.5]dec-8-yl)-1 ,3-oxazolidin-2-one15.2: 3- (1,4-dioxaspiro [4.5] dec-8-yl) -1,3-oxazolidin-2-one
On place 1 ,47 g de disphosgène dans 50 mL de dichlorométhane sous N2 et à 00C. On ajoute goutte à goutte 1 ,0 g de 2-(1 ,4-dioxaspiro[4.5]dec-8-ylamino)ethanol obtenu à l'étape 13.1 en mélange avec 3,59 mL de triéthylamine. L'agitation est maintenue 5h à température ambiante. Après évaporation à sec, le brut obtenu est repris au dichlorométhane. La phase organique est lavée deux fois avec une solution aqueuse d'acide chlorhydrique 1 N, puis avec H2O et une solution aqueuse saturée de chlorure de sodium. Après séchage sur MgSO4 et concentration à sec, le brut obtenu est chromatographié sur gel de silice en éluant avec un gradient de méthanol dans le dichlorométhane variant de 0% à 2%. On obtient 1,19 g de 3-(1,4-dioxaspiro[4.5]dec-8- yl)-1 ,3-oxazolidin-2-one.1.47 g of disphosgene are placed in 50 ml of dichloromethane under N 2 and at 0 ° C. 1.0 g of 2- (1,4-dioxaspiro [4.5] dec-8-ylamino) ethanol are added dropwise. obtained in stage 13.1 in a mixture with 3.59 ml of triethylamine. Stirring is maintained for 5 hours at room temperature. After evaporation to dryness, the crude obtained is taken up in dichloromethane. The organic phase is washed twice with a 1N aqueous hydrochloric acid solution, then with H 2 O and a saturated aqueous solution of sodium chloride. After drying over MgSO 4 and concentration to dryness, the crude obtained is chromatographed on silica gel eluting with a gradient of methanol in dichloromethane ranging from 0% to 2%. 1.19 g of 3- (1,4-dioxaspiro [4.5] dec-8-yl) -1,3-oxazolidin-2-one are obtained.
15.3 : 3-(4-oxocyclohexyl)-1 ,3-oxazolidin-2-one15.3: 3- (4-oxocyclohexyl) -1,3-oxazolidin-2-one
On solubilise 0,75 g de 3-(1 ,4-dioxaspiro[4.5]dec-8-yl)-1 ,3-oxazolidin-2-one dans 27,5 ml_ d'HCI 6N. Le milieu réactionnel est chauffé à 65°C pendant 5h. Après retour à température ambiante, on ajoute lentement du carbonate de sodium jusqu'à pH 9. On extrait au dichlorométhane jusqu'à épuisement de la phase aqueuse. La phase organique est. lavée avec H2O. Après séchage sur MgSO4, le brut obtenu est chromatographié sur gel de silice en éluant avec un gradient de méthanol dans le dichlorométhane de 0% à 10% On obtient 0,11g de 3-(4-oxocyclohexyl)-1 ,3-oxazolidin-2-one.0.75 g of 3- (1,4-dioxaspiro [4.5] dec-8-yl) -1,3-oxazolidin-2-one are solubilized in 27.5 ml of 6N HCl. The reaction medium is heated at 65 ° C. for 5 hours. After returning to ambient temperature, sodium carbonate is slowly added to pH 9. The mixture is extracted with dichloromethane until the aqueous phase is exhausted. The organic phase is. washed with H 2 O. After drying over MgSO 4 , the crude obtained is chromatographed on silica gel eluting with a gradient of methanol in dichloromethane from 0% to 10% is obtained 0.11 g of 3- (4-oxocyclohexyl) -1,3-oxazolidin-2-one.
15.4 : Λ/-((3S,4S)-1-{4-chloro-Λ/-[4-(2-oxo-1 ,3-oxazolidin-3-yl)cyclohexyl]-D- phenylalanyl}-3-methylpiperidin-4-yl)-Λ/-cyclohexyl-Λ/',/\/'-dimethylurea15.4: Λ- ((3S, 4S) -1- {4-chloro-Λ- [4- (2-oxo-1,3-oxazolidin-3-yl) cyclohexyl] -D-phenylalanyl} -3- methylpiperidin-4-yl) -Λ / -cyclohexyl-Λ / ', / \ /' - dimethylurea
On solubilise 0,4 g de Λ/-[trans-1-(4-chIoro-D-phenylalanyl)-3-methylpiperidin-4-yl]- /V-cyclohexyl-ΛΛΛ/'-dimethylurea obtenu à l'étape 13.8 dans 9 mL de dichlorométhane en présence de 0,20 g de 3-(4-oxocyclohexyl)-1 ,3-oxazolidin-2-one obtenu à l'étape 15.3. On additionne ensuite 0,28 g de triacétoxyborohydrure de sodium sous N2. L'agitation est maintenue pendant 18h à température ambiante. On hydrolyse avec une solution aqueuse saturée d'hydrogénocarbonate de sodium et on extrait au dichlorométhane jusqu'à épuisement de la phase aqueuse. La phase organique est lavée avec H2O, puis avec une solution aqueuse saturée de chlorure de sodium. Après séchage sur MgSO4 et concentration à sec, le brut obtenu est chromatographié sur gel de silice en éluant avec un mélange de dichlorométhane/acétone/méthanol variant de 100/0/0 à 70/25/5. On obtient 0,21 g de et 0,19 g de Λ/-((3S,4S)-1-{4-chloro-Λ/-[4-(2-oxo-1,3-oxazolidin-3- yl)cyclohexyl]-D-phenylalanyl}-3-methylpiperidin-4-yl)-Λ/-cyclohexyl-A/',Λ/'-dimethylurea, mélange de stéréoisomères de configuration non déterminée.0.4 g of Λ- [trans-1- (4-chloro-D-phenylalanyl) -3-methylpiperidin-4-yl] - β-cyclohexyl-ΛΛΛ-dimethylurea obtained in step 13.8 are solubilized. in 9 mL of dichloromethane in the presence of 0.20 g of 3- (4-oxocyclohexyl) -1,3-oxazolidin-2-one obtained in step 15.3. 0.28 g of sodium triacetoxyborohydride are then added under N 2 . Stirring is maintained for 18h at room temperature. It is hydrolyzed with a saturated aqueous solution of sodium hydrogencarbonate and extracted with dichloromethane until the aqueous phase is exhausted. The organic phase is washed with H 2 O and then with a saturated aqueous solution of sodium chloride. After drying over MgSO 4 and concentration to dryness, the crude obtained is chromatographed on silica gel, eluting with a dichloromethane / acetone / methanol mixture ranging from 100/0/0 to 70/25/5. 0.21 g of and 0.19 g of Λ- ((3S, 4S) -1- {4-chloro-Λ] - [4- (2-oxo-1,3-oxazolidin-3-yl) are obtained. ) cyclohexyl] -D-phenylalanyl} -3-methylpiperidin-4-yl) -NH-cyclohexyl-N, N-dimethylurea, a mixture of stereoisomers of undetermined configuration.
15.5 : chlorhydrate de Λ/-(trans-1-{4-chloro-/V-[4-(2-oxo-1,3-oxazolidin-3- yl)cyclohexyl]-D-phenylalanyl}-3-methylpiperidin-4-yl)-Λ/-cyclohexyl-Λ/',Λ/1-dimethylurea15.5: Λ- (trans-1- {4-chloro-N- [4- (2-oxo-1,3-oxazolidin-3-yl) cyclohexyl] -D-phenylalanyl} -3-methylpiperidine-hydrochloride 4-yl) -cyclohexyl-,, 1- dimethylurea
On place 0,21 g de Λ/-(trans-1-{4-chloro-/V-[4-(2-oxo-1 ,3-oxazolidin-3- yl)cyclohexyl]-D-phenylalanyl}-3-methylpiperidin-4-yl)-Λ/-cyclohexyl-Λ/',/\/'-dimethylurea, dans 2 mL d'acétate d'éthyle et on ajoute 1 ,7 mL d'acide chlorhydrique 0,2N dans le diéthyléther. Après concentration à sec, le milieu réactionnel est repris au diéthyléther et trituré. Puis on essore le précipité obtenu et on rince au diéthyléther. Le chlorhydrate ainsi obtenu est séché sur P2Os sous pression réduite. On obtient 0,18 g du chlorhydrate de Λ/-(trans-1 -{4-chloro-Λ/-[4-(2-oxo-1 ,3-oxazolidin-3-yl)cyclohexyl]-D-phenylalanyl}-3- methylpiperidin-4-yl)-Λ/-cyclohexyl-Λ/\Λ/'-dimethylurea. Point de fusion = 189°C; M+H+ = 616 ;0.21 g of Λ- (trans-1- {4-chloro-N- [4- (2-oxo-1,3-oxazolidin-3-yl) cyclohexyl] -D-phenylalanyl} -3 is placed. 4-methylpiperidin-4-yl) -cyclohexyl-α-dimethylurea in 2 ml of ethyl acetate and 1.7 ml of 0.2 N hydrochloric acid in diethyl ether are added. . After concentration to dryness, the reaction medium is taken up in diethyl ether and triturated. Then the precipitate obtained is filtered off and rinsed with diethyl ether. The hydrochloride thus obtained is dried over P 2 Os under reduced pressure. 0.18 g of hydrochloride is obtained Λ- (trans-1 - {4-chloro-Λ- [4- (2-oxo-1,3-oxazolidin-3-yl) cyclohexyl] -D-phenylalanyl} -3-methylpiperidin-4-yl ) -Λ / -cyclohexyl-Λ / \ Λ / '- dimethylurea. M.p. = 189 ° C; M + H + = 616;
Exemple 16 : Chlorhydrate de /V-{trans-1-[4-chloro-/V-(1- isonicotinoylpiperidin-4-yl)-D-phenylalanyl]-3-methylpiperidin-4-yl}-Λ/-cyclohexyl- Λf.ΛT-dimethylurea (composé n°119)Example 16: N- (trans-1- [4-Chloro-N- (1-isonicotinoylpiperidin-4-yl) -D-phenylalanyl] -3-methylpiperidin-4-yl} -α-cyclohexyl) hydrochloride Λf.ΛT-dimethylurea (Compound No. 119)
16.1 : 8-isonicotinoyl-1 ,4-dioxa-8-azaspiro[4.5]decane16.1: 8-isonicotinoyl-1,4-dioxa-8-azaspiro [4.5] decane
On solubilise 1 ,34 ml_ de 1 ,4-dioxaspiro[4.5]decan-8-one dans 104 mL de dichlorométhane en présence de 1,4 g d'isonicotinic acid, de 1,56 g d'hydroxybenzotriazole, de 2,21 g de chlorhydrate de 1-(3-diméthylaminopropyl)-3-éthyl- carbodiimide et de 1,49 mL de diisopropyléthylamine. Le mélange est agité 18h à température ambiante sous N2. Après évaporation à sec, on hydrolyse le résidu avec une solution aqueuse de soude 1N. On extrait au dichlorométhane jusqu'à épuisement de la phase aqueuse. Après séchage sur Na2SO4 et concentration à sec, le brut obtenu .est chromatographié en éluant avec un mélange dichlorométhane/méthanol 85/5. On obtient 2,63 g de 8-isonicotinoyl-1 ,4-dioxa-8-azaspiro[4.5]decane1.34 ml of 1,4-dioxaspiro [4.5] decan-8-one are solubilized in 104 ml of dichloromethane in the presence of 1.4 g of isonicotinic acid, 1.56 g of hydroxybenzotriazole, 2.21 g of g of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and 1.49 ml of diisopropylethylamine. The mixture is stirred for 18h at room temperature under N 2 . After evaporation to dryness, the residue is hydrolyzed with a 1N aqueous sodium hydroxide solution. It is extracted with dichloromethane until the aqueous phase is exhausted. After drying over Na 2 SO 4 and concentration to dryness, the crude product obtained is chromatographed eluting with a 85/5 dichloromethane / methanol mixture. 2.63 g of 8-isonicotinoyl-1,4-dioxa-8-azaspiro [4.5] decane is obtained.
16.2 : 1-isonicotinoylpiperidin-4-one16.2: 1-isonicotinoylpiperidin-4-one
On solubilise 2,6 g de 8-isonicotinoyl-1 ,4-dioxa-8-azaspiro[4.5]decane dans 43 mL d'HCI 6N. Le milieu réactionnel est chauffé à 65°C pendant 18h. on place le milieu réactionnel à 00C et on ajoute lentement du carbonate de sodium jusqu'à pH 9. On extrait au dichlorométhane jusqu'à épuisement de la phase aqueuse. Après séchage sur Na2SO4, le brut obtenu est chromatographié sur gel de silice en éluant avec un gradient de méthanol dans le dichlorométhane de 0% à 10% On obtient 0,19 g de 1- isonicotinoylpiperidin-4-one.2.6 g of 8-isonicotinoyl-1,4-dioxa-8-azaspiro [4.5] decane are solubilized in 43 ml of 6N HCl. The reaction medium is heated at 65 ° C. for 18 h. the reaction medium is placed at 0 ° C. and sodium carbonate is slowly added to pH 9. The mixture is extracted with dichloromethane until the aqueous phase is exhausted. After drying over Na 2 SO 4 , the crude obtained is chromatographed on silica gel, eluting with a gradient of methanol in dichloromethane from 0% to 10%. 0.19 g of 1-isonicotinoylpiperidin-4-one is obtained.
16.3 : Λ/-{trans-1-[4-chloro-A/-(1-isonicotinoylpiperidin-4-yl)-D-phenylalanyl]-3- methylpiperidin-4-yl}-Λ/-cyclohexyl-/V,Λ/'-dimethylurea16.3: Λ- {trans-1- [4-chloro-N- (1-isonicotinoylpiperidin-4-yl) -D-phenylalanyl] -3-methylpiperidin-4-yl} -α-cyclohexyl- / V, Λ / '- dimethylurea
On solubilise 0,3 g de Λ/-[trans-1-(4-chloro-D-phenylalanyl)-3-methylpiperidin-4-yl]- Λ/-cyclohexyl-Λ/\/V-dimethylurea obtenu à l'étape 13.8 dans 7 mL de dichlorométhane en présence de 0,18 g de 1-isonicotinoylpiperidin-4-one obtenu à l'étape 16.3. On additionne ensuite 0,21 g de triacétoxyborohydrure de sodium sous N2. L'agitation est maintenue pendant 18h à température ambiante. On hydrolyse avec une solution aqueuse saturée d'hydrogénocarbonate de sodium et on extrait au dichlorométhane jusqu'à épuisement de la phase aqueuse. La phase organique est lavée avec H2O, puis avec une solution aqueuse saturée de chlorure de sodium. Après séchage sur MgSO4 et concentration à sec, le brut obtenu est chromatographié sur gel de silice en éluant avec un mélange de dichlorométhane/méthanol/ammoniaque variant de 100/0/0 à 90/10/1. On obtient 0,075 g de et 0,23 g de A/-{trans-1-[4-chloro-Λ/-(1-isonicotinoylpiperidin-4-yl)-D-phenylalanyl]-3- methylpiperidin-4-yl}-Λ/-cyclohexyl-Λ/',N'-dimethylurëa, mélange de diastéréoisomères de configuration non déterminée.0.3 g of Λ / - [trans-1- (4-chloro-D-phenylalanyl) -3-methylpiperidin-4-yl] - Λ -cyclohexyl-Λ / N-dimethylurea obtained from step 13.8 in 7 mL of dichloromethane in the presence of 0.18 g of 1-isonicotinoylpiperidin-4-one obtained in step 16.3. 0.21 g of sodium triacetoxyborohydride are then added under N 2 . Stirring is maintained for 18h at room temperature. It is hydrolyzed with a saturated aqueous solution of sodium hydrogencarbonate and extracted with dichloromethane until the aqueous phase is exhausted. The organic phase is washed with H 2 O and then with a solution saturated aqueous sodium chloride. After drying over MgSO 4 and concentration to dryness, the crude obtained is chromatographed on silica gel, eluting with a dichloromethane / methanol / ammonia mixture ranging from 100/0/0 to 90/10/1. 0.075 g of and 0.23 g of N- {trans-1- [4-chloro-Λ] - (1-isonicotinoylpiperidin-4-yl) -D-phenylalanyl] -3-methylpiperidin-4-yl are obtained. Α-Cyclohexyl-α, N'-dimethylurea, a mixture of diastereoisomers of undetermined configuration.
16.4 : Λ/-{trans-1-[4-chloro-Λ/-(1-isonicotinoylpiperidin-4-yl)-D-phenylalanyl]-3- methylpiperidin-4-yl}-Λ/-cyclohexyl-/V,Λ/'-dimethylurea16.4: Λ- {1- [trans-1- [4-chloro-Λ] - (1-isonicotinoylpiperidin-4-yl) -D-phenylalanyl] -3-methylpiperidin-4-yl} -α-cyclohexyl- / V, Λ / '- dimethylurea
On place 0,23 g de Λ/-{trans-1-[4-chloro-Λ/-(1-isonicotinoylpiperidin-4-yl)-D- phenylalanyl]-3-methylpiperidin-4-yl}-Λ/-cyclohexyl-Λ/',Λ/l-dimethylurea, dans 2 ml_ d'acétate d'éthyle et on ajoute 1 ,8 mL d'acide chlorhydrique 0,2N dans le diéthyléther. Après concentration à sec, le milieu réactionnel est repris au diéthyléther et trituré. Puis on essore le précipité obtenu et on rince au diéthyléther. Le chlorhydrate ainsi obtenu est séché sur P2O5 sous pression réduite. On obtient 0,18 g du chlorhydrate de Λ/-{trans-1-[4- chloro-A/-(1-isonicotinoylpiperidin-4-yl)-D-phenylalanyl]-3-methylpiperidin-4-yl}-Λ/- cyclohexyl-Λ/'.Λ/'-dimethylurea.0.23 g of Λ- {trans-1- [4-chloro-Λ] - (1-isonicotinoylpiperidin-4-yl) -D-phenylalanyl] -3-methylpiperidin-4-yl} -Λ- cyclohexyl-Λ / ', Λ / l -dimethylurea, in 2 ml of ethyl acetate, and 1, 8 mL of 0.2N hydrochloric acid in diethyl ether. After concentration to dryness, the reaction medium is taken up in diethyl ether and triturated. Then the precipitate obtained is filtered off and rinsed with diethyl ether. The hydrochloride thus obtained is dried over P 2 O 5 under reduced pressure. 0.18 g of Λ- (trans-1- [4-chloro-N- (1-isonicotinoylpiperidin-4-yl) -D-phenylalanyl] -3-methylpiperidin-4-yl} -Λ hydrochloride are obtained. / - cyclohexyl-Λ /. / '- dimethylurea.
Point de fusion = 2060C; M+H+ = 640 ;M.p. = 206 0 C; M + H + = 640;
Le tableau qui suit illustre les structures chimiques et les propriétés physiques de quelques exemples de composés selon l'invention, à savoir des composés de formule (I bis), correspondant à des composés de formule (I) dans lesquels Ra> = R5 = H, R3 représente un atome de chlore situé en position para sur le noyau phényle auquel il est rattaché.The following table illustrates the chemical structures and the physical properties of some examples of compounds according to the invention, namely compounds of formula (Ia), corresponding to compounds of formula (I) in which R a > = R 5 = H, R 3 represents a chlorine atom located in the para position on the phenyl ring to which it is attached.
Dans ce tableau :In this table :
- l'atome de carbone portant le groupe 4-CI-benzyle présente la configuration (R),the carbon atom carrying the 4-Cl-benzyl group has the (R) configuration,
- dans la colonne « sel », « - » représente un composé sous forme de base libre, alors que « HCI » représente un composé sous forme de chlorhydrate et « CF3COOH » un composé sous forme de trifluoroacétatein the "salt" column, "-" represents a compound in free base form, while "HCl" represents a compound in the form of hydrochloride and "CF 3 COOH" a compound in the form of trifluoroacetate;
- dans le cas où Ra est un gourpement méthyl, le composé est obtenu sous la forme d'un mélange de diastéréoisomèresin the case where Ra is a methyl feed, the compound is obtained in the form of a mixture of diastereoisomers
- « PF » représente le point de fusion du composé, et"PF" represents the melting point of the compound, and
- Me, Et et iPr représentent respectivement des groupes méthyle, éthyle et isopropyle. TableauMe, Et and iPr respectively represent methyl, ethyl and isopropyl groups. Board
selon l'isomère (cis ou trans) * selon les mélanges de stéréoisomères according to the isomer (cis or trans) * according to the mixtures of stereoisomers
Les composés selon l'invention ont fait l'objet d'essais pharmacologiques permettant de déterminer leur effet agoniste des récepteurs aux mélanocortines, en particulier leur effet agoniste du récepteur MC3 et/ou MC4.The compounds according to the invention have been the subject of pharmacological tests for determining their agonist effect of melanocortin receptors, in particular their agonist effect of the MC3 and / or MC4 receptor.
Evaluation de l'affinité des composés de formule (I) selon l'invention envers les récepteurs MC3 et MC4Evaluation of the affinity of the compounds of formula (I) according to the invention for MC3 and MC4 receptors
Ce test d'affinité est réalisé par la mesure de la liaison du [125l]-[Nle4-D-Phe7]-α- MSH aux membranes cellulaires : le déplacement de ce radio-ligand est utilisé pour , identifier des inhibiteurs de la liaison spécifique aux récepteurs recombinants mélanocortine.This affinity test is carried out by measuring the binding of [ 125 I] - [Nle 4 -D-Phe 7 ] -α-MSH to cell membranes: the displacement of this radioligand is used to identify inhibitors. specific binding to melanocortin recombinant receptors.
Pour ce test, on utilise des membranes préparées à partir des cellules CHO-K1 exprimant le récepteur humain MC4 à forte densité (Euroscreen) ou des membranes achetées (Perkin Elmer Life Sciences, Receptor Biology) des cellules HEK-293 exprimant des récepteurs hMC3. Les cellules CHO-K1 transfectées avec le gène du récepteur hMC4 (Euroscreen) sont ensemencées dans le milieu de culture DMEM/ Nutrient Mix F12 contenant 10% sérum de veau (Biowhittaker), 1 % pyruvate de sodium, 1% L-glutamine, 1 % acides aminés non-essentiels, 0.4 mg/ml généticine (G418) et 0.5% PenStrep, ces produits étant fournis par Gibco/BRI, sauf le sérum de veau. Les cellules sont grattées à 80% de confluence et les culots de cellules sont congelés à -80°C. Un tube de cellules (environ 70 x 106 cellules) est décongelé sur glace et resuspendu dans 10 ml de tampon de binding [25 mM HEPES, pH 7.0, 1 mM MgCI2, 1.5 mM CaCI2, 100 mM NaCI, 1 mM 1,10-phenanthroline et 1 tablette de Complète™ (inhibiteur de protéases de Roche) dans 50 ml de tampon] par polytronnage 20 s. La suspension est centrifugée 20 min à 19500 t/min à 4°C. Le surnageant est jeté et le culot est resuspendu dans 5 ml tampon de binding. Par un test de Bradford, on dose la quantité de protéines présentes dans l'échantillon et on ajuste la concentration à 3 μg/25 μl par dilution dans du tampon de binding.For this test, membranes prepared from CHO-K1 cells expressing the high density human MC4 receptor (Euroscreen) or purchased membranes (Perkin Elmer Life Sciences, Receptor Biology) of HEK-293 cells expressing hMC3 receptors are used. The CHO-K1 cells transfected with the hMC4 receptor gene (Euroscreen) are seeded in the DMEM / Nutrient Mix F12 culture medium containing 10% calf serum (Biowhittaker), 1% sodium pyruvate, 1% L-glutamine, 1 % non-essential amino acids, 0.4 mg / ml geneticin (G418) and 0.5% PenStrep, these products being supplied by Gibco / BRI, except calf serum. The cells are scraped at 80% confluency and the cell pellets are frozen at -80 ° C. A tube of cells (approximately 70 x 10 6 cells) is thawed on ice and resuspended in 10 ml of binding buffer [25 mM HEPES, pH 7.0, 1 mM MgCl 2 , 1.5 mM CaCl 2 , 100 mM NaCl, 1 mM 1 , 10-phenanthroline and 1 tablet of Complete ™ (Roche protease inhibitor) in 50 ml buffer] by 20 sec. The suspension is centrifuged for 20 minutes at 19500 rpm at 4 ° C. The supernatant is discarded and the pellet is resuspended in 5 ml of binding buffer. Using a Bradford test, the amount of protein present in the sample is measured and the concentration is adjusted to 3 μg / 25 μl by dilution in binding buffer.
[125I]-[NIe4, D-Phe7]-α-MSH est dilué dans du tampon de binding + 0.2% BSA. Des billes SPA (wheatgerm agglutinine polyvinyltoluene, Amersham Pharmacia Biotech), sont hydratées dans le tampon de binding + 0.2% BSA et ensuite mélangées avec l'homogénat de cellules pour obtenir 3 μg de protéines cellulaires et 250 μg de billes dans 50 μl. Les produits à tester (dilués dans 10% DMSO), en quantité de 10 μl à une concentration de 10 fois la concentration finale, sont distribués dans une plaque blanche 96 puits à fond clair (CORNING 3604 Polystyrène Non-Binding Surface). Le binding non- spécifique est défini par NDP-αMSH à 10"7 M. Le binding total est mesuré par le nombre de coups par minute en présence du radio-ligand seul. La distribution de la suspension membranes-billes (50 μl/puits) est suivie par la distribution de la solution de [125I]-[NIe4, D-Phe7]-α-MSH, 40 μl/puits (100 pM concentration finale), pour un volume final de 100 μl/puits. Après 6 h d'incubation à température ambiante, le comptage est fait dans un compteur de scintillation Microbeta TriLux. La valeur IC50 des composés correspond à la concentration qui déplace la liaison spécifique du radio-ligand de 50%. On détermine ainsi que les composés selon l'invention présentent une affinité pour les récepteurs MC3 et/ou MC4. Leurs IC5O envers les récepteurs MC3 et MC4 sont inférieures à 10 μM, pour la plupart comprises entre 1 nM et 1 μM. A titre d'exemples, le composé n° 2 du tableau présente une IC50 de 300' nM envers le récepteur MC4.[ 125 I] - [NIe 4 , D-Phe 7 ] -α-MSH is diluted in binding buffer + 0.2% BSA. SPA beads (wheatgerm agglutinin polyvinyltoluene, Amersham Pharmacia Biotech) are hydrated in the binding buffer + 0.2% BSA and then mixed with the cell homogenate to obtain 3 μg of cellular proteins and 250 μg of beads in 50 μl. The products to be tested (diluted in 10% DMSO), in an amount of 10 μl at a concentration of 10 times the final concentration, are distributed in a white-filled 96-well plate (CORNING 3604 Polystyrene Non-Binding Surface). The nonspecific binding is defined by NDP-αMSH 10 "7 M. The total binding is measured by the number of cpm in the presence of the radioligand alone. The distribution of the membranes-beads suspension (50 .mu.l / well ) is followed by the distribution of the solution of [ 125 I] - [NIe 4 , D-Phe 7 ] -α-MSH, 40 μl / well (100 μM final concentration), for a final volume of 100 μl / well. After incubation for 6 h at room temperature, the count is made in a Microbeta TriLux scintillation counter. The IC 50 value of the compounds corresponds to the concentration which displaces the specific binding of the radioligand by 50%. It is thus determined that the compounds according to the invention have an affinity for the MC3 and / or MC4 receptors. Their IC 5 O to the MC3 and MC4 receptors are less than 10 microM, mostly between 1 nM and 1 microM. By way of example, Compound No. 2 of the table has an IC 50 of 300 ' nM towards the MC4 receptor.
Evaluation de l'activité agoniste des composés de formule (I) selon l'invention envers les récepteurs MC3 et MC4Evaluation of the agonist activity of the compounds of formula (I) according to the invention towards MC3 and MC4 receptors
Un test fonctionnel est utilisé pour discriminer l'activité agoniste de l'activité antagoniste. Pour cela, on dose la formation d'adénosine - mono-phosphate cyclique (AMPc) générée par l'activation du récepteur MC3 ou du récepteur MC4. Les cellules CHO-K1, exprimant le récepteur humain MC4 à une densité modéréeA functional test is used to discriminate the agonist activity of the antagonist activity. For this purpose, the adenosine-cyclic mono-phosphate (cAMP) formation generated by the activation of the MC3 receptor or of the MC4 receptor is measured. CHO-K1 cells, expressing the human MC4 receptor at moderate density
(Euroscreen), sont ensemencées dans le milieu de culture DMEM / Nutrient Mix F12 (Gibco/BRI) contenant 10% de sérum de veau, 0.5% pyruvate de sodium, 1% L-glutamine, 1 % acides aminés non-essentiels, 200 mg/l hygromycine B et 0.5% PenStrep, ces produits étant fournis par Gibco/BRI, sauf le sérum de veau (Biowhittaker) et l'hygromycine B (Sigma).(Euroscreen) are inoculated in DMEM / Nutrient Mix F12 culture medium (Gibco / BRI) containing 10% calf serum, 0.5% sodium pyruvate, 1% L-glutamine, 1% non-essential amino acids, 200 mg / l hygromycin B and 0.5% PenStrep, these products being supplied by Gibco / BRI, except calf serum (Biowhittaker) and hygromycin B (Sigma).
Les cellules CHO(dhfr-) exprimant le récepteur humain MC3 sont ensemencées dans le milieu de culture MEM Eagle (Sigma) contenant 10% de sérum de veau dialyse, 1% L-glutamine, 1 % pyruvate de sodium, 20mg/500 ml L-proline, 0.3 mg/ml Geneticin et 0.5% PenStrep, ces produits étant fournis par Gibco/BRI, sauf le sérum de veau dialyse (Cambrex) et la L-proline (Sigma).The CHO cells (dhfr-) expressing the human MC3 receptor are inoculated into the Eagle MEM culture medium (Sigma) containing 10% dialyzed calf serum, 1% L-glutamine, 1% sodium pyruvate, 20 mg / 500 ml. -proline, 0.3 mg / ml Geneticin and 0.5% PenStrep, these products being supplied by Gibco / BRI, except dialysis calf serum (Cambrex) and L-proline (Sigma).
Les composés à tester (dilués dans 10% DMSO), en quantité de 10 μl à une concentration de 10 fois la concentration finale, sont ajoutés aux plaques de cellules (volume final = 100 μl/puits). Après 1 heure d'incubation (37°C, 5% CO2), la quantité du AMPc est dosée utilisant des kits du TROPIX (Appelera) selon la documentation du fournisseur. L'activité intrinsèque des composés est calculée en comparant la stimulation d'AMPc par ces composés à la stimulation induite par 3O nM de NDPaMSH (100% maximum). La valeur EC50 des composés correspond à la concentration qui produit 50% de la stimulation maximale obtenue avec ce composé.The compounds to be tested (diluted in 10% DMSO), in an amount of 10 μl at a concentration of 10 times the final concentration, are added to the cell plates (final volume = 100 μl / well). After 1 hour of incubation (37 ° C., 5% CO 2 ), the amount of cAMP is assayed using TROPIX kits (Appelera) according to the supplier's documentation. The intrinsic activity of the compounds is calculated by comparing the cAMP stimulation by these compounds to the stimulation induced by 30 nM NDPaMSH (100% maximum). The EC 50 value of the compounds corresponds to the concentration which produces 50% of the maximal stimulation obtained with this compound.
On détermine ainsi que les composés selon l'invention sont des agonistes des récepteurs MC3 et/ou MC4. Ils présentent des EC50 envers les récepteurs MC3 et MC4 inférieures à 10 μM, pour la plupart comprises entre 1 nM et 1 μM. A titre d'exemples, les composés n° 1 et 2 du tableau présentent respectivement des EC50 de 590 nM et 370 nM envers le récepteur MC3, et de 80 nM et 30 nM envers le récepteur MC4.It is thus determined that the compounds according to the invention are agonists of the MC3 and / or MC4 receptors. They have EC 50 towards the MC3 and MC4 receptors of less than 10 μM, mostly between 1 nM and 1 μM. By way of example, the compounds No. 1 and 2 of the table respectively have EC 50 of 590 nM and 370 nM to the MC3 receptor, and 80 nM and 30 nM to the MC4 receptor.
Les composés selon l'invention présentant une activité agoniste des récepteurs aux mélanocortines, ils peuvent donc être utilisés pour la préparation de médicaments. Ainsi, selon un autre de ses aspects, l'invention a pour objet des médicaments qui comprennent un composé de formule (I), ou un sel d'addition de ce dernier à un acide pharmaceutiquement acceptable, ou encore un hydrate ou un solvat du composé de formule (I).The compounds according to the invention having a melanocortin receptor agonist activity, they can therefore be used for the preparation of medicaments. Thus, according to another of its aspects, 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 of compound of formula (I).
Ces médicaments trouvent leur emploi en thérapeutique, dans les pathologies dans lesquelles les récepteurs aux mélanocortines, en particulier les récepteurs MG3 et/ou MC4, sont impliquées : il s'agit notamment du traitement et de la prévention de l'obésité, du diabète et des dysfonctions sexuelles pouvant affecter les deux sexes, telles que les dysfonctionnements érectiles, les maladies cardiovasculaires telles que les infarcus du myocarde ou l'hypertension ainsi que dans des applications antiinflammatoires ou dans le traitement de la dépendance alcoolique..These drugs find their use in therapeutics, in the pathologies in which the melanocortin receptors, in particular the MG3 and / or MC4 receptors, are involved: these include the treatment and prevention of obesity, diabetes and sexual dysfunction that can affect both sexes, such as erectile dysfunction, cardiovascular diseases such as myocardial infarction or hypertension, as well as anti-inflammatory applications or in the treatment of alcohol dependence.
Selon un autre de ses aspects, la présente invention concerne des compositions pharmaceutiques comprenant, en tant que principe actif, un composé selon l'invention. Ces compositions pharmaceutiques contiennent une dose efficace d'au moins un composé selon l'invention, ou un sel pharmaceutiquement acceptable, un hydrate . ou solvat dudit composé, ainsi qu'au moins un excipient pharmaceutiquement acceptable. Lesdits excipients sont choisis selon la forme pharmaceutique et le mode d'administration souhaité, parmi les excipients habituels qui sont connus de l'Homme de l'art.According to another of its aspects, the present invention relates to pharmaceutical compositions comprising, as active principle, a compound according to the invention. These pharmaceutical compositions contain 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.
Dans les compositions pharmaceutiques de la présente invention pour l'administration orale, sublinguale, sous-cutanée, intramusculaire, intra-veineuse, topique, locale, intratrachéale, intranasale, transdermique ou rectale, le principe actif de formule . (I) ci-dessus, ou son sel, solvat ou hydrate éventuel, peut être administré sous forme unitaire d'administration, en mélange avec des excipients pharmaceutiques classiques, aux animaux et aux êtres humains pour la prophylaxie ou le traitement des troubles ou des maladies ci-dessus.In the pharmaceutical 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 disorders or disorders. diseases above.
Les formes unitaires d'administration appropriées comprennent les formes par voie orale telles que les comprimés, les gélules molles ou dures, les poudres, les granules et les solutions ou suspensions orales, les formes d'administration sublinguale, buccale, intratrachéale, intraoculaire, intranasale, par inhalation, les formes d'administration topique, transdermique, sous-cutanée, intramusculaire ou intraveineuse, les formes d'administration rectale et les implants. Pour l'application topique, on peut utiliser les composés selon l'invention dans des crèmes, gels, pommades ou lotions.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, forms topical, transdermal, subcutaneous, intramuscular or intravenous administration, rectal administration forms and implants. For topical application, the compounds according to the invention can be used in creams, gels, ointments or lotions.
Une forme d'administration préférée est la voie orale.A preferred form of administration is the oral route.
A titre d'exemple, une forme unitaire d'administration d'un composé selon l'invention sous forme de comprimé peut comprendre les composants suivants :By way of example, a unitary form of administration of a compound according to the invention in tablet form may comprise the following components:
Composé selon l'invention 50,0 mg Mannitol 223,75 mgCompound according to the invention 50.0 mg Mannitol 223.75 mg
Croscaramellose sodique 6,0 mgCroscaramellose sodium 6.0 mg
Amidon de maïs 15,0 mgCorn starch 15.0 mg
Hydroxypropyl-méthylcellulose 2,25 mgHydroxypropyl methylcellulose 2.25 mg
Stéarate de magnésium 3,0 mgMagnesium stearate 3.0 mg
II peut y avoir des cas particuliers où des dosages plus élevés ou plus faibles sont appropriés ; de tels dosages ne sortent pas du cadre de l'invention. Selon la pratique habituelle, le dosage approprié à chaque patient est déterminé par le médecin selon le mode d'administration, le poids et la réponse dudit patient.There may be special cases where higher or lower dosages are appropriate; such dosages are not outside the scope of the invention. According to the usual practice, 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.
La présente invention, selon un autre de ses aspects, concerne également une méthode de traitement des pathologies ci-dessus indiquées qui comprend l'administration, à un patient, d'une dose efficace d'un composé selon l'invention, ou un de ses sels pharmaceutiquement acceptables ou hydrates ou solvats. The present invention, according to another of its aspects, 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 one of its pharmaceutically acceptable salts or hydrates or solvates.

Claims

REVENDICATIONS
1. Composé répondant à la formule (I) :1. Compound corresponding to formula (I):
dans laquelle : in which :
Ra et Ra', identiques ou différents l'un de l'autre, représentent un atome d'hydrogène ou un groupe alkyle ou cycloalkyle,R a and Ra ' , which are identical or different from one another, represent a hydrogen atom or an alkyl or cycloalkyl group,
R1 représente un atome d'hydrogène ou un groupe alkyle, cycloalkyle, hétérocycloalkyle ou aryle,R 1 represents a hydrogen atom or an alkyl, cycloalkyl, heterocycloalkyl or aryl group,
R2 représente un groupe de formule -(CH2)χ-(CO)y-Y ou -(CO)y-(CH2)x-Y, dans laquelle :R 2 represents a group of formula - (CH 2 ) χ- (CO) yY or - (CO) y - (CH 2 ) x -Y, in which:
. x = 0, 1 , 2, 3 ou 4, . y = 0 ou 1,. x = 0, 1, 2, 3 or 4,. y = 0 or 1,
. Y représente un atome d'hydrogène ou un groupe hydroxyle, alkyle, cycloalkyle, alcoxy, aryle, hétéroaryle ou -NR11Ri2, Y étant différent d'un atome d'hydrogène lorsque x = y = 0,. Y represents a hydrogen atom or a hydroxyl, alkyl, cycloalkyl, alkoxy, aryl, heteroaryl or -NR 11 Ri 2 group , Y being different from a hydrogen atom when x = y = 0,
. Rii et R12, identiques ou différents l'un de l'autre, représentent un atome d'hydrogène ou un groupe alkyle, cycloalkyle, alcoxy ou -NRi3R14, ou bien R-n et Ri2 forment ensemble, avec l'atome d'azote auquel ils sont rattachés, une structure mono- ou bicyclique comportant de 4 à 10 chaînons et comprenant éventuellement 1 à 3 hétéroatomes supplémentaires et/ou 1 à 3 insaturations éthyléniques ou acétyléniques, ce cycle étant éventuellement substitué en des positions quelconques par 1 à 3 groupes choisis parmi les atomes d'halogène et les groupes hydroxyles, alkyles, cycloalkyles et alcoxy,. R 1 and R 12 , which are identical to or different from each other, represent a hydrogen atom or an alkyl, cycloalkyl, alkoxy or -NR 1 R 14 group , or R 1 and R 2 together with the atom form nitrogen to which they are attached, a mono- or bicyclic structure comprising from 4 to 10 members and optionally comprising 1 to 3 additional heteroatoms and / or 1 to 3 ethylenic or acetylenic unsaturations, this ring being optionally substituted in any position by 1 3 groups chosen from halogen atoms and hydroxyl, alkyl, cycloalkyl and alkoxy groups,
. R^ et R-I4, identiques ou différents l'un de l'autre, représentent un atome d'hydrogène ou un groupe alkyle, cycloalkyle ou alcoxy, ou bien Ri3 et Ri4 forment ensemble, avec l'atome d'azote auquel ils sont rattachés, une structure . mono- ou bicyclique telle que définie ci-dessus, R3 représente 1 à 3 groupes, identiques ou différents les uns des autres, situés en des positions quelconques du noyau auquel ils sont rattachés et choisis parmi les atomes d'halogène et les groupes alkyles, cycloalkyles, -OR, -NRR', -CO-NRR', -NR-CO-R', -NR-CO-NRR', -NR-COOR', -NO2, -CN et -COOR,. R 4 and R 14 , which are identical to or different from one another, represent a hydrogen atom or an alkyl, cycloalkyl or alkoxy group, or R 1 and R 4 together with the nitrogen atom form to which they are attached, a structure. mono- or bicyclic as defined above, R 3 represents 1 to 3 groups, identical or different from each other, located in any positions of the nucleus to which they are attached and selected from halogen atoms and alkyl, cycloalkyl groups, -OR, -NRR ', - CO-NRR ', -NR-CO-R', -NR-CO-NRR ', -NR-COOR', -NO 2 , -CN and -COOR,
R5 représente un atome d'hydrogène ou un groupe alkyle,R 5 represents a hydrogen atom or an alkyl group,
R4 est choisi parmi les groupes de formules (a), (b) et (c), éventuellement substitués par un groupe oxo ou mono ou polysubstitué par un groupe aryle ou hétéroaryle, ci-dessous :R 4 is selected from the groups of formulas (a), (b) and (c), optionally substituted by an oxo group or mono or polysubstituted by an aryl or heteroaryl group, below:
(a) (b) (c)(a) (b) (c)
dans lesquelles:in which:
P = O, 1, 2 ou 3, m = O, 1 ou 2, et soit a) X représente un chaînon -N(Ri0)-, oùP = 0, 1, 2 or 3, m = 0, 1 or 2, and either a) X represents a -N (Ri 0 ) -, where
Rio est choisi parmi : un groupe -(CH2)X-OR8, -(CH2)X-COOR8, -(CH2)X-NR8R9> -(CH2)X-CO-NR8R9 ou -(CH2)x-NR8-CORg, -(CH2)X-COR8 dans lesquels x = 1 , 2, 3 ou 4, . un groupe cycloalkyle ou hétérocycloalkyle fusionné avec un groupe aryle ou hétéroaryle, . ' un groupe cycloalkyle, hétérocycloalkyle, aryle, hétéroaryle, alkylaryle, alkylhétéroaryle, -CO-alkyle, -CO-cycloalkyle, -CO-hétérocycloalkyle, -CO-aryle, -CO-hétéroaryle, -CO-alkylaryle, -CO-alkylhétéroaryle, -CS-alkyle, -CS-cycloalkyle, -CS-hétérocycloalkyle, -CS-aryle, -CS-hétéroaryle, -CS-alkylaryle, -CS-alkylhétéroaryle, -CS-NR8R9, -C(=NH)-NR8R9, -SO2-alkyle, -S02-cycloalkyle, -S02-hétérocycloalkyle, -SO2-aryle, -SO2-hétéroaryle, -Sθ2-alkylaryle, -SO2-alkylhétéroaryle ou -SO2-NR8Rg, les groupes alkyles, cycloalkyles, hétérocycloalkyles, aryles ou hétéroaryles étant éventuellement substitués par 1 ou plusieurs groupes choisis parmi les groupes R, R', - OR, -NRR', -CO-NRR', -NR-CO-R", -NR-CO-NRR', -NO2, -CN et -COOR, OCOR, COR, OCONRR', NRCOOR' les groupes cycloalkyles ou hétérocycloalkyles étant éventuellement fusionnés avec un groupe aryle ou hétéroaryle, ou bien R10 forme, avec l'atome d'azote auquel il est rattaché et un atome de carbone situé en une position quelconque de la structure cyclique de la formule (a), mais non adjacent audit atome d'azote, un pont comprenant de 3 à 5 chaînons,Rio is selected from: - (CH 2 ) X -OR 8 , - (CH 2 ) X -COOR 8 , - (CH 2 ) X -NR 8 R 9> - (CH 2 ) X -CO-NR 8 R 9 or - (CH 2 ) x -NR 8 -COR g , - (CH 2 ) X -COR 8 in which x = 1, 2, 3 or 4,. a cycloalkyl or heterocycloalkyl group fused with an aryl or heteroaryl group, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, alkylheteroaryl, -CO-alkyl, -CO-cycloalkyl, -CO-heterocycloalkyl, -CO-aryl, -CO-heteroaryl, -CO-alkylaryl, -CO-alkylheteroaryl, -CS-alkyl, -CS-cycloalkyl, -CS-heterocycloalkyl, -CS-aryl, -CS-heteroaryl, -CS-alkylaryl, -CS-alkylheteroaryl, -CS-NR 8 R 9 , -C (= NH) - NR 8 R 9, -SO 2 -alkyl, -S0 2 -cycloalkyl, -S0 2 -heterocycloalkyl, -SO 2 -aryl, -SO 2 -heteroaryl, -Sθ 2 -alkylaryl, -SO 2 or -SO 2 -alkylhétéroaryle -NR 8 Rg, the alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl groups being optionally substituted with 1 or more groups selected from R, R ', -OR, -NRR', -CO-NRR ', -NR-CO-R ", -NR-CO-NRR', -NO 2 , - And -COOR, OCOR, COR, OCONRR ', NRCOOR' wherein the cycloalkyl or heterocycloalkyl groups are optionally fused with an aryl or heteroaryl group, or R 10 forms with the nitrogen atom to which it is attached and an atom of carbon located at any position of the ring structure of formula (a), but not adjacent to said nitrogen atom, a bridge comprising from 3 to 5 members,
R8 et R9 sont choisis indépendamment l'un de l'autre parmi un atome d'hydrogène et les groupes alkyles, cycloalkyles, hétérocycloalkyles, aryles, hétéroaryle.s, alkylaryles, alkylhétéroaryles, -CO-alkyles, -CO-cycloalkyles, -CO-hétérocycloalkyles, -CO-aryles, -.CO-hétéroaryles, -CO-alkylaryles, -CO-alkylhétéroaryles, -SO2-alkyles,R 8 and R 9 are chosen independently of one another from a hydrogen atom and alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, alkylheteroaryl, -CO-alkyl, -CO-cycloalkyl groups, -CO-heterocycloalkyls, -CO-aryls, -CO-heteroaryls, -CO-alkylaryls, -CO-alkylheteroaryls, -SO 2 -alkyls,
-SO2-cycloalkyles, -SO2-hétérocycloalkyles, -SO2-aryles, -SO2-hétéroaryles, -SO2-alkylaryles, -S02-alkylhétéroaryles, -C(=NH)-NRR\ -COOR, -CO-NRR', -CS-NRR' et -(CH2)X-OR, où x = O, 1 , 2, 3 ou 4, ou bien R8 et R9 forment ensemble un cycloalkyle ou un hétérocycloalkyle-Cycloalkyles -SO 2, -SO 2 -hétérocycloalkyles, -SO 2 -aryles, -SO 2 -hétéroaryles, -SO 2 -alkylaryles, -S0 2 -alkylhétéroaryles, -C (= NH) -NRR \ -COOR, -CO -NRR ', -CS-NRR' and - (CH 2 ) X -OR, where x = O, 1, 2, 3 or 4, or R 8 and R 9 together form a cycloalkyl or a heterocycloalkyl
R et R' représentent indépendamment l'un de l'autre un atome d'hydrogène ou un groupe alkyle, cycloalkyle, hétérocycloalkyle, aryle, hétéroaryle, alkylaryle ou alkylhétéroaryle, ou peuvent former ensemble un cycloalkyle ou un hétérocycloalkyle.R and R 'independently of one another represent a hydrogen atom or an alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl or alkylheteroaryl group, or may together form a cycloalkyl or a heterocycloalkyl.
Soit, b) X représente un chaînon -C(R6)(R7)- où R6 est choisi parmi :Let b) X represent a -C (R 6 ) (R 7 ) - chain - where R 6 is chosen from:
. un atome d'hydrogène, un atome d'halogène,. a hydrogen atom, a halogen atom,
. un groupe -(CH2)X-OR8, -(CH2)X-COOR8, -(CH2)X-NR8R9, -(CH2)X-CO-NR8R9 ou -(CH2)X-NR8-COR9, dans lesquels x = O, 1 , 2, 3 ou 4,. a group - (CH 2 ) X -OR 8 , - (CH 2 ) X -COOR 8 , - (CH 2 ) X -NR 8 R 9 , - (CH 2 ) X -CO-NR 8 R 9 or - ( CH 2 ) X -NR 8 -COR 9 , in which x = O, 1, 2, 3 or 4,
. un groupe alkyle, cycloalkyle, hétérocycloalkyle, aryle, hétéroaryle, alkylaryle, alkylhétéroaryle, -CO-alkyle, -CO-cycloalkyle, -CO-hétérocycloalkyle, -CO-aryle,. alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, alkylheteroaryl, -CO-alkyl, -CO-cycloalkyl, -CO-heterocycloalkyl, -CO-aryl,
-CO-hétéroaryle, -CO-alkylaryle ou -CO-alkylhétéroaryle, -CS-alkyle, -CS-cycloalkyle,-CO-heteroaryl, -CO-alkylaryl or -CO-alkylheteroaryl, -CS-alkyl, -CS-cycloalkyl,
-CS-hétérocycloalkyle, -CS-aryle, -CS-hétéroaryle, -CS-alkylaryle, -CS-alkylhétéroaryle,-CS-heterocycloalkyl, -CS-aryl, -CS-heteroaryl, -CS-alkylaryl, -CS-alkylheteroaryl,
-CS-NR8R9, -C(=NH)-NR8R9,-CS-NR 8 R 9 , -C (= NH) -NR 8 R 9 ,
. un groupe cycloalkyle ou hétérocycloalkyle fusionné ou non situé en position spiro sur le cycle de formule (a) auquel il est rattaché,. a cycloalkyl or heterocycloalkyl group fused or not located in the spiro position on the ring of formula (a) to which it is attached,
. un groupe cycloalkyle ou hétérocycloalkyle fusionné avec un groupe aryle ou hétéroaryle, - les groupe alkyles, cycloalkyles, hétérocycloalkyles, aryles ou hétéroaryles étant éventuellement substitués par 1 ou plusieurs groupes choisis parmi les groupes R, R', -OR, -NRR1, -CO-NRR', -NR-CO-R', -NR-CO-NRR', -NO2, -CN et -COOR, OCOR, COR, OCONRR', NRCOOR' ; les groupes cycloalkyles ou hétérocycloalkyles étant éventuellement fusionnés avec un groupe aryle ou hétéroaryle,. a cycloalkyl or heterocycloalkyl group fused with an aryl or heteroaryl group, the alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl groups being optionally substituted by one or more groups chosen from the groups R, R ', -OR, -NRR 1 , -CO-NRR', -NR-CO-R ', -NR-CO-NRR ', -NO 2 , -CN and -COOR, OCOR, COR, OCONRR', NRCOOR '; the cycloalkyl or heterocycloalkyl groups being optionally fused with an aryl or heteroaryl group,
R7 est choisi parmi les atomes d'hydrogène et d'halogène et les groupes alkyles, cycloalkyles, aryles, hétéroaryles, alkylaryles, alkylhétéroaryles, -OR, -O-aryles, -O-hétéroaryles, -O-alkylaryles, -O-alkylhétéroaryles, -NRR', -CO-NRR", -NR-CO-R', -NR-CO-NRR', -NR-COOR', -NO2, -CN et -COOR,R 7 is selected from hydrogen and halogen and alkyl, cycloalkyl, aryl, heteroaryl, alkylaryl, alkylheteroaryl, -OR, -O-aryl, -O-heteroaryl, -O-alkylaryl, -O- alkylheteroaryls, -NRR ', -CO-NRR ", -NR-CO-R', -NR-CO-NRR ', -NR-COOR', -NO 2 , -CN and -COOR,
- R8 et Rg sont choisis indépendamment l'un de l'autre parmi un atome d'hydrogène et les groupes alkyles, cycloalkyles, hétérocycloalkyles, aryles, hétéroaryles, alkylaryles, alkylhétéroaryles, -CO-alkyles, -CO-cycloalkyles, -CO-hétérocycloalkyles, - CO-aryles, -CO-hétéroaryles, -CO-alkylaryles, -CO-alkylhétéroaryles, -SO2-alkyles, -SO2-cycloalkyles, -S02-hétérocycloalkyles, -S02-aryles, -SO2-hétéroaryles, -SO2-alkylaryles, -SO2-alkylhétéroaryles, -C(=NH)-NRR', -COOR, -CO-NRR', -CS-NRR' et -(CH2)X-OR, où x = O, 1 , 2, 3 ou 4, les groupes alkyles et aryles étant éventuellement substitués par un ou plusieurs groupes choisis parmi les groupes R, R', -OR, -NRR', -CO- NRR', -NR-CO-R', -NR-CO-NRR', -NO2, -CN et -COOR, OCOR, COR, OCONRR', NRCOOR' ou bien R8 et R9 forment ensemble un cycloalkyle ou un hétérocycloalkyleR 8 and R 8 are chosen independently of one another from a hydrogen atom and the alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, alkylheteroaryl, -CO-alkyl, -CO-cycloalkyl, -CO groups; -hétérocycloalkyles, - CO-aryl, -CO-heteroaryl, -CO-alkylaryl, -CO-alkylhétéroaryles, -SO 2 -alkyl, -SO 2 -cycloalkyles, -S0 2 -hétérocycloalkyles, -S0 2 -aryles, -SO 2 heteroaryls, -SO 2 -alkylaryls, -SO 2 -alkylheteroaryls, -C (= NH) -NRR ', -COOR, -CO-NRR', -CS-NRR 'and - (CH 2 ) X -OR, where x = O, 1, 2, 3 or 4, the alkyl and aryl groups being optionally substituted by one or more groups chosen from the groups R, R ', -OR, -NRR', -CO-NRR ', -NR- CO-R ', -NR-CO-NRR', -NO 2 , -CN and -COOR, OCOR, COR, OCONRR ', NRCOOR' or R 8 and R 9 together form a cycloalkyl or a heterocycloalkyl
- R et R' représentent indépendamment l'un de l'autre un atome d'hydrogène ou un groupe alkyle, cycloalkyle, hétérocycloalkyle, aryle, hétéroaryle, alkylaryle ou alkylhétéroaryle, ou peuvent former ensemble un cycloalkyle ou un hétérocycloalkyle.- R and R 'independently of one another represent a hydrogen atom or an alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl or alkylheteroaryl group, or may together form a cycloalkyl or a heterocycloalkyl.
à l'état de base ou de sel d'addition à un acide, ainsi qu'à l'état d'hydrate ou de solvat.in the form of a base or an addition salt with an acid, as well as with the hydrate or solvate state.
2. Composé de formule (I) selon la revendication 1 , caractérisé en ce que R4 est choisi parmi les groupes de formules (a), (b) et (c), éventuellement mono ou polysubstitué par un groupe aryle ou hétéroaryle, où X représente un chaînon -C(Re)(R7)- , dans lequel R6 est choisi parmi : . un atome d'hydrogène, . un groupe -(CH2)X-OR8, -(CH2)X-COOR8> -(CH2)X-NR8R9, -(CH2)X-CO-NR8R9 ou -(CH2)x-NR8-CORg,danslesquelsx=0, 1,2, 3ou4,2. Compound of formula (I) according to claim 1, characterized in that R 4 is chosen from groups of formulas (a), (b) and (c), optionally mono or polysubstituted by an aryl or heteroaryl group, where X represents a -C (Re) (R 7 ) - chain, wherein R 6 is selected from: a hydrogen atom, . a group - (CH 2 ) X-OR 8 , - (CH 2 ) X -COOR 8> - (CH 2 ) X -NR 8 R 9 , - (CH 2 ) X -CO-NR 8 R 9 or - ( CH 2 ) x -NR 8 -CORg, in which x = 0, 1,2, 3 or 4,
. un groupe alkyle, cycloalkyle, hétérocycloalkyle, aryle, hétéroaryle, alkyiaryle, alkylhétéroaryle, -CO-alkyle, -CO-cycloalkyle, -CO-hétérocycloalkyle, -CO-aryle, 5 -CO-hétéroaryle, -CO-alkylaryle ou -CO-alkylhétéroaryle,. alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, alkylheteroaryl, -CO-alkyl, -CO-cycloalkyl, -CO-heterocycloalkyl, -CO-aryl, 5 -CO-heteroaryl, -CO-alkylaryl or -CO- alkylheteroaryl,
. un groupe cycloalkyle ou hétérocycloalkyle situé en position spiro sur le cycle de formule (a) auquel il est rattaché,. a cycloalkyl or heterocycloalkyl group located in a spiro position on the ring of formula (a) to which it is attached,
. un groupe cycloalkyle ou hétérocycloalkyle fusionné avec un groupe aryle ou hétéroaryle, 0. a cycloalkyl or heterocycloalkyl group fused with an aryl or heteroaryl group,
R7 est choisi parmi les atomes d'hydrogène et d'halogène et les groupes alkyles, cycloalkyles, aryles, hétéroaryles, alkylaryles, alkylhétéroaryles, -OR, -O-aryles, -O-hétéroaryles, -O-alkylaryles, -O-alkyihétéroaryles, -NRR', -CO-NRR', -NR-CO-R', -NR-CO-NRR', -NR-COOR', -NO2, -CN et -COOR, 5R 7 is selected from hydrogen and halogen and alkyl, cycloalkyl, aryl, heteroaryl, alkylaryl, alkylheteroaryl, -OR, -O-aryl, -O-heteroaryl, -O-alkylaryl, -O- alkyl-heteroaryl, -NRR ', -CO-NRR', -NR-CO-R ', -NR-CO-NRR', -NR-COOR ', -NO 2 , -CN and -COOR,
R8 et R9 sont choisis indépendamment l'un de l'autre parmi un atome d'hydrogène et les groupes alkyles, cycloalkyles, hétérocycloalkyles, aryles, hétéroaryles, alkylaryles, alkylhétéroaryles, -CO-alkyles, -CO-cycloalkyles, -CO-hétérocycloalkyles, -CO-aryles,R 8 and R 9 are chosen independently of one another from a hydrogen atom and alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, alkylheteroaryl, -CO-alkyl, -CO-cycloalkyl, -CO groups; heterocycloalkyls, -CO-aryls,
, -CO-hétéroaryles, -CO-alkylaryles, -CO-alkylhétéroaryles, -SO2-alkyles, -SO2-cycloalkyles, -SO2-hétérocycloalkyles, -SO2-aryles, -SO2-hétéroaryles,, -CO-heteroaryl, -CO-alkylaryl, -CO-alkylheteroaryl, -SO 2 -alkyl, -SO 2 -cycloalkyl, -SO 2 -heterocycloalkyl, -SO 2 -aryl, -SO 2 -heteroaryl,
-SO2-alkylaryles, -SO2-alkylhétéroaryles, -C(=NH)-NRR', -COOR, -CO-NRR', -CS-NRR' et -(CH2)X-OR, où x = O, 1 , 2, 3 ou 4,-SO 2 -alkylaryls, -SO 2 -alkylheteroaryls, -C (= NH) -NRR ', -COOR, -CO-NRR', -CS-NRR 'and - (CH 2 ) X -OR, where x = O , 1, 2, 3 or 4,
R et R' représentent indépendamment l'un de l'autre un atome d'hydrogène ou un groupe alkyle, cycloalkyle, hétérocycloalkyle, aryle, hétéroaryle, alkyiaryle ou alkylhétéroaryle,R and R 'represent, independently of one another, a hydrogen atom or an alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl or alkylheteroaryl group,
3. Composé de formule (I) selon la revendication 1 , caractérisé en ce que R4 est choisi parmi les groupes de formules (a), (b) et (c) où X représente un chaînon - C(Re)(R7)-, dans lequel R6 est choisi parmi un atome d'halogène ou un groupe cycloalkyle ou hétérocycloalkyle fusionné ou non situé en position spiro sur le cycle de formule (a) auquel il est rattaché,3. Compound of formula (I) according to claim 1, characterized in that R 4 is chosen from groups of formulas (a), (b) and (c) where X represents a - C (Re) (R 7) in which R 6 is chosen from a halogen atom or a cycloalkyl or heterocycloalkyl group fused or not located in a spiro position on the ring of formula (a) to which it is attached,
4. Composé de formule (I) selon la revendication 1, caractérisé en ce que R4 est choisi parmi les groupes de formules (a), (b) et (c) où X représente un chaînon - C(R6)(R7)-, dans lequel R6 est choisi parmi -CS-alkyle, -CS-cycloalkyle, -CS-hétérocycloalkyle, -CS-aryle, -CS-hétéroaryle, -CS-alkylaryle, -CS-alkylhétéroaryle, -CS-NR8R9, -C(=NH)-NR8R9. 4. Compound of formula (I) according to claim 1, characterized in that R 4 is chosen from groups of formulas (a), (b) and (c) where X represents a - C (R 6 ) - (R) 7 ) - wherein R 6 is selected from -CS-alkyl, -CS-cycloalkyl, -CS-heterocycloalkyl, -CS-aryl, -CS-heteroaryl, -CS-alkylaryl, -CS-alkylheteroaryl, -CS-NR 8 R 9 , -C (= NH) -NR 8 R 9 .
5. Composé de formule (I) selon la revendication 1, caractérisé en ce que R4 est choisi parmi les groupes de formules (a), (b) et (c) où X représente un chaînon - C(R6)(R7)-, dans lequel les groupes .alkyles, cycloalkyles, hétérocycloalkyles, aryles ou hétéroaryles sont éventuellement substitués par 1 ou plusieurs groupes choisis parmi R, R', OCOR, COR, OCONRR', NRCOOR' .5. Compound of formula (I) according to claim 1, characterized in that R 4 is chosen from groups of formulas (a), (b) and (c) where X represents a - C (R 6 ) - (R) 7 ) - wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl groups are optionally substituted with one or more groups selected from R, R ', OCOR, COR, OCONRR', NRCOOR '.
6. Composé de formule (I) selon la revendication 1 , caractérisé en ce que .R4 est choisi parmi les groupes de formules (a), (b) et (c) où X représente , un chaînon - C(R6)(R7)-, dans lequel les groupes cycloalkyles ou hétérocycloalkyles sont éventuellement fusionnés avec un groupe aryle ou hétéroaryle.6. Compound of formula (I) according to claim 1, characterized in that R 4 is chosen from the groups of formulas (a), (b) and (c) in which X represents a - C (R 6 ) (R 7 ) -, wherein the cycloalkyl or heterocycloalkyl groups are optionally fused with an aryl or heteroaryl group.
7. Composé de formule (I) selon la revendication 1 , caractérisé en ce R4 est choisi parmi les groupes de formules (a), (b) et (c) où X représente un chaînon -C(R6)(R7)-, dans lequel R8 et R9 choisis indépendamment l'un de l'autre représentent des groupes alkyles et aryles étant éventuellement substitués par un ou plusieurs groupes choisis parmi les groupes R, R', OCOR, COR, OCONRR' ou NRCOOR' .7. Compound of formula (I) according to claim 1, characterized in that R 4 is chosen from groups of formulas (a), (b) and (c) where X represents a -C (R 6 ) - (R 7 ) -, wherein R 8 and R 9 independently selected from each other represent alkyl and aryl groups being optionally substituted with one or more groups selected from R, R ', OCOR, COR, OCONRR' or NRCOOR groups; '.
8. Composé de formule (I) selon la revendication 1 , caractérisé en ce que R4 est choisi parmi les groupes de formules (a), (b) et (c) où X représente un chaînon - C(R6)(R7)-, dans lequel R et R' peuvent former ensemble un cycloalkyle ou un hétérocycloalkyle.8. Compound of formula (I) according to claim 1, characterized in that R 4 is chosen from groups of formulas (a), (b) and (c) where X represents a - C (R 6 ) - (R) 7 ) -, wherein R and R 'may together form a cycloalkyl or a heterocycloalkyl.
9. Composé de formule (I) selon l'une quelconque des revendication 1 à 8, caractérisé en ce que R7 est l'hydrogène.9. Compound of formula (I) according to any one of claims 1 to 8, characterized in that R 7 is hydrogen.
10. Composé de formule (I) selon l'une des revendications 1 à 9, caractérisé en ce que R4 représente le groupe de formule a) où p=2 tel que défini ci-dessous :10. Compound of formula (I) according to one of claims 1 to 9, characterized in that R 4 represents the group of formula a) where p = 2 as defined below:
11. Composé de formule (I) selon la revendication 1 , caractérisé en ce que11. Compound of formula (I) according to claim 1, characterized in that
R4 est choisi parmi les groupes de formules (a), (b) et (c), éventuellement mono ou poiysubstitué par un groupe aryle ou hétéroaryle, où X représente un chaînon -N(R10)- dans lequelR 4 is selected from the groups of formulas (a), (b) and (c), optionally mono or poly-substituted with aryl or heteroaryl, where X is -N (R 10 ) - in which
Rio est choisi parmi : un groupe -CO-NR8R9 , -COOR8 un groupe -(CH2)X-OR8, -(CH2)X-COOR8, -(CH2)χ-NR8R9, -(CH2)X-CO-NR8R9 ou -(CH2)χ-NR8-COR9, dans lesquels x = 1 , 2, 3 ou 4,Rio is chosen from: a group -CO-NR 8 R 9 , -COOR 8 a group - (CH 2 ) X -OR 8 , - (CH 2 ) X -COOR 8 , - (CH 2 ) χ-NR 8 R 9 , - (CH 2 ) X- CO-NR 8 R 9 or - (CH 2 ) χ-NR 8 -COR 9 , in which x = 1, 2, 3 or 4,
. un groupe cycloalkyle ou hétérocycloalkyle fusionné avec un groupe aryle ou hétéroaryle, un groupe cycloalkyle, hétérocycloalkyle, aryle, hétéroaryle, alkylaryle, alkylhétéroaryle, , -CO-cycloalkyle, -CO-hétérocycloalkyle, , -CO-hétéroaryle, -CO- alkylaryle, -CO-alkylhétéroaryle, -CS-alkyle, -CS-cycloalkyle, -CS-hétérocycloalkyle, -CS- aryle, -CS-hétéroaryle, -CS-alkylaryle, -CS-alkylhétéroaryle, -CS-NR8R9, -C(=NH)-NR8R9, , -S02-cycloalkyle, -S02-hétérocycloalkyle, , -SO2-hétéroaryle, -SO2-alkylaryle, -SO2- alkylhétéroaryle ou -SO2-NR8R9 ; ou bien R10 forme, avec l'atome d'azote auquel il est rattaché et un atome de carbone situé en une position quelconque de la structure cyclique de la formule (a), mais non adjacent audit atome d'azote, un pont comprenant de 3 à 5 chaînons.. a cycloalkyl or heterocycloalkyl group fused with an aryl or heteroaryl group, a cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, alkylheteroaryl, -CO-cycloalkyl, -CO-heterocycloalkyl, -CO-heteroaryl, -CO-alkylaryl group; CO-alkylheteroaryl, -CS-alkyl, -CS-cycloalkyl, -CS-heterocycloalkyl, -CS-aryl, -CS-heteroaryl, -CS-alkylaryl, -CS-alkylheteroaryl, -CS-NR 8 R 9 , -C ( = NH) -NR 8 R 9, -S0 2 -cycloalkyl, -S0 2 -heterocycloalkyl, -SO 2 -heteroaryl, -SO 2 -alkylaryl, -SO 2 - or alkylheteroaryl -SO 2 -NR 8 R 9; or R 10 forms, with the nitrogen atom to which it is attached and a carbon atom at any position in the ring structure of formula (a), but not adjacent to said nitrogen atom, a bridge comprising from 3 to 5 links.
R8 et R9 sont choisis indépendamment l'un de l'autre parmi un atome d'hydrogène et les groupes alkyles, cycloalkyles, hétérocycloalkyles, aryles, hétéroaryles, alkylaryles, alkylhétéroaryles, -CO-alkyles, -CO-cycloalkyles, -CO-hétérocycloalkyles, -CO-aryles, -CO-hétéroaryles, -CO-alkylaryles, -CO-alkylhétéroaryles, -SO2-alkyles, -S02-cycloalkyles, -SO2-hétérocycloalkyles, -S02-aryles, -SO2-hétéroaryles, -SO2-alkylaryles, -SO2-alkylhétéroaryles, -C(=NH)-NRR', -COOR, -CO-NRR', -CS-NRR' et -(CH2)X-OR, où x = O1 1 , 2, 3 ou 4,R 8 and R 9 are chosen independently of one another from a hydrogen atom and alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, alkylheteroaryl, -CO-alkyl, -CO-cycloalkyl, -CO groups; -hétérocycloalkyles, -CO-aryl, -CO-heteroaryl, -CO-alkylaryl, -CO-alkylhétéroaryles, -SO 2 -alkyl, -S0 2 -cycloalkyles, -SO 2 -hétérocycloalkyles, -S0 2 -aryles, -SO 2 heteroaryls, -SO 2 -alkylaryls, -SO 2 -alkylheteroaryls, -C (= NH) -NRR ', -COOR, -CO-NRR', -CS-NRR 'and - (CH 2 ) X -OR, where x = O 1 1, 2, 3 or 4,
R et R' représentent indépendamment l'un de l'autre un atome d'hydrogène ou un groupe alkyle, cycloalkyle, hétérocycloalkyle, aryle, hétéroaryle, alkylaryle ou alkylhétéroaryle,R and R 'represent, independently of one another, a hydrogen atom or an alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl or alkylheteroaryl group,
12. Composé de formule (I) selon la revendication 1 , caractérisé en ce que12. Compound of formula (I) according to claim 1, characterized in that
R4 est choisi parmi les groupes de formules (a), (b) et (c) éventuellement substitué par un groupe oxo où X représente un chaînon -N(Ri0).R 4 is selected from groups of formulas (a), (b) and (c) optionally substituted by an oxo group where X represents a -N (Ri 0 ) linkage.
13. Composé de formule (I) selon la revendication 1 , caractérisé en ce que R4 est choisi parmi les groupes de formules (a), (b) et (c) où X représente un chaînon -N(R10)- dans lequel13. Compound of formula (I) according to claim 1, characterized in that R 4 is chosen from the groups of formulas (a), (b) and (c) where X represents a linkage -N (R 10 ) - in which
R8 et R9 forment ensemble un cycloalkyle ou un hétérocycloalkyle.R 8 and R 9 together form cycloalkyl or heterocycloalkyl.
14. Composé de formule (I) selon la revendication 1 , caractérisé en ce que R4 est choisi parmi les groupes de formules (a), (b) et (c) où X représente un chaînon -N(R10)- dans lequel R10 est, -(CH2)X-COR8 dans lequel x = 1 , 2, 3 ou 4 .14. Compound of formula (I) according to claim 1, characterized in that R 4 is chosen from the groups of formulas (a), (b) and (c) where X represents a linkage -N (R 10 ) - in which R 10 is - (CH 2 ) X -COR 8 wherein x = 1, 2, 3 or 4.
15. Composé de formule (I) selon la revendication 1 , caractérisé en ce que, R4 est choisi parmi les groupes de formules (a), (b) et (c) où X représente un chaînon -N(R10)- dans lequel les groupes alkyles, cycloalkyles, hétérocycloalkyles, aryles ou hétéroaryles sont éventuellement substitués par 1 ou plusieurs groupes choisis parmi R, R',. OCOR, COR, OCONRR' ou NRCOOR1 .15. Compound of formula (I) according to claim 1, characterized in that R 4 is chosen from groups of formulas (a), (b) and (c) where X represents a -N (R 10 ) - wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl groups are optionally substituted with 1 or more groups selected from R, R ',. OCOR, COR, OCONRR 'or NRCOOR 1 .
16. Composé de formule (I) selon la revendication 1, caractérisé en ce que R4 est choisi parmi les groupes de formules (a), (b) et (c) où X représente un chaînon -N(R10)- dans lequel les groupes cycloalkyles ou hétérocycloalkyles sont éventuellement fusionnés avec un groupe aryle ou hétéroaryle.16. Compound of formula (I) according to claim 1, characterized in that R 4 is chosen from groups of formulas (a), (b) and (c) where X represents a -N (R 10 ) - - wherein the cycloalkyl or heterocycloalkyl groups are optionally fused with an aryl or heteroaryl group.
17. Composé de formule (I) selon l'une des revendications 1 , 11 à 16, caractérisé en ce que R4 représente le groupe de formule a) où p=2 tel que défini ci-dessous :17. Compound of formula (I) according to one of claims 1, 11 to 16, characterized in that R4 represents the group of formula a) where p = 2 as defined below:
18. Composé de formule (I) selon l'une des revendications 1 à 17, caractérisé en ce que R1 représente un groupe alkyle, cycloalkyle ou hétérocycloalkyle, à l'état de base ou de sel d'addition à un acide, ainsi qu'à l'état d'hydrate ou de solvat.18. Compound of formula (I) according to one of claims 1 to 17, characterized in that R 1 represents an alkyl, cycloalkyl or heterocycloalkyl group, in the form of a base or of an addition salt with an acid, and than in the state of hydrate or solvate.
19. Composé de formule (I) selon l'une des revendications 1 à 18, caractérisé en ce que R2 est choisi parmi les groupes suivants : -CO-R15, -CO-NRI6RI7, -CO-NR15- NR16R17, -CO-aryle, -CO-hétéroaryle, -CO-(CH2)X-NR16R17, -(CH2)χ-NR16R17, ~(CH2)X-OH, -(CH2)x-aryle, -(CH2)x-hétéroaryle, -(CH2)x-CO-Ri5 et -(CH2)X-CO-N R16R17, dans lesquels : . x = 0, 1 , 2, 3 ou 4 et x' = 1 , 2, 3 ou 4,19. Compound of formula (I) according to one of claims 1 to 18, characterized in that R 2 is chosen from the following groups: -CO-R 15 , -CO-NRI 6 RI 7 , -CO-NR 15 - NR 16 R 17 , -CO-aryl, -CO-heteroaryl, -CO- (CH 2 ) X -NR 16 R 17 , - (CH 2 ) χ -NR 16 R 17 , - (CH 2 ) X -OH - (CH 2 ) x -aryl, - (CH 2 ) x -heteroaryl, - (CH 2 ) x -CO-R 5 and - (CH 2 ) X -CO-N R 16 R 17 , wherein: x = 0, 1, 2, 3 or 4 and x '= 1, 2, 3 or 4,
. R15 représente un atome d'hydrogène ou un groupe alkyle, cycloalkyle ou alcoxy, et . R16 et Ri7, identiques ou différents l'un de l'autre, représentent un atome d'hydrogène ou un groupe alkyle, cycloalkyle ou alcoxy, ou bien R16 et Ri7 forment ensemble, avec l'atome d'azote auquel ils sont rattachés, une structure mono- ou bicyclique comportant de 4 à 10 chaînons et comprenant éventuellement 1 à 3 hétéroatomes supplémentaires et/ou 1 à 3 insaturations éthyléniques ou acétyléniques, ce cycle étant éventuellement substitué en des positions quelconques par 1 à 3 groupes choisis parmi les atomes d'halogène et les groupes hydroxyles, alkyles, cycloalkyles et alcoxy, à l'état. de base ou de sel d'addition à un acide, ainsi qu'à l'état d'hydrate ou de solvat.. R 15 represents a hydrogen atom or an alkyl, cycloalkyl or alkoxy group, and R 16 and R 17 , which are identical to or different from each other, represent a hydrogen atom or an alkyl, cycloalkyl or alkoxy group, or R 16 and R 17 together with the nitrogen atom to which they are attached, a mono- or bicyclic structure comprising from 4 to 10 members and optionally comprising 1 to 3 additional heteroatoms and / or 1 to 3 ethylenic or acetylenic unsaturations, this ring being optionally substituted at any position by 1 to 3 groups selected from halogen atoms and hydroxyl, alkyl, cycloalkyl and alkoxy groups, in the state. base or salt of addition to an acid, and in the state of hydrate or solvate.
20. Composé de formule (I) selon l'une quelconque des revendications 1 à 19, caractérisé en ce que R2 représente un groupe -CO-NRi6Ri7, où Ri6 et R17 représentent des groupes alkyles ou alcoxy, à l'état de base ou de sel d'addition à un acide, ainsi qu'à l'état d'hydrate ou de solvat.20. Compound of formula (I) according to any one of claims 1 to 19, characterized in that R 2 represents a group -CO-NRi 6 R 17 , where R 16 and R 17 represent alkyl or alkoxy groups, the basic state or acid addition salt, as well as the hydrate or solvate state.
21. Composé de formule (I) selon l'une quelconque des revendications 1 à 20, caractérisé en ce que R3 représente 1 à 3 groupes, identiques ou différents les uns des autres, choisis parmi les atomes d'halogène, à l'état de base ou de sel d'addition à un acide, ainsi qu'à l'état d'hydrate ou de solvat.21. Compound of formula (I) according to any one of claims 1 to 20, characterized in that R 3 represents 1 to 3 groups, identical or different from each other, chosen from halogen atoms, basic state or salt of addition to an acid, and in the state of hydrate or solvate.
22. Composé de formule (I) selon l'une quelconque des revendications 1 à 21 , caractérisé en ce que R5 représente un atome d'hydrogène, à l'état de base ou de sel d'addition à un acide, ainsi qu'à l'état d'hydrate ou de solvat.22. Compound of formula (I) according to any one of claims 1 to 21, characterized in that R 5 represents a hydrogen atom, in the form of a base or of an addition salt with an acid, as well as in the hydrate or solvate state.
23. Composé de formule (I) selon l'une quelconque des revendications 1 à 22, caractérisé en ce que Ra et Ra> représentent des atomes d'hydrogène ou des groupes alkyles comprenant de 1 à 4 atomes de carbone, à l'état de base ou de sel d'addition à un acide, ainsi qu'à l'état d'hydrate ou de solvat.23. Compound of formula (I) according to any one of claims 1 to 22, characterized in that R a and R a > represent hydrogen atoms or alkyl groups comprising 1 to 4 carbon atoms, base state or addition salt with an acid, as well as with the hydrate or solvate state.
24. Composés dont les noms suivent24. Compounds whose names follow
Λ/-{1-[Λ/-(4-aminocyclohexyl)-4-chloro-D-phenylalanyl]piperidin-4-yl}-A/-cyclohexyl-Λ / - {1- [Λ / - (4-aminocyclohexyl) -4-chloro-D-phenylalanyl] piperidin-4-yl} -A / -cyclohexyl-
W./V-diethylureaW./V-diethylurea
Λ/-{1-[/V-(c/s-4-aminocyclohexyl)-4-chloro-D-phenylalanyl]piperidin-4-yl}-A/- cyclohexyl-1 ,3-dihydro-2H-isoindole-2-carboxamide A/-{1-[Λ/-(c/s-4-aminocyclohexyl)-4-chloro-D-phenylalanyl]piperidin-4-yl}-Λ/- cyclohexyl-2,5-dimethylpyrrolidine-1-carboxamideΛ- {1- [N- (cs-4-aminocyclohexyl) -4-chloro-D-phenylalanyl] piperidin-4-yl} -N-cyclohexyl-1,3-dihydro-2H-isoindole 2-carboxamide A - {1- [N- (c-S-4-aminocyclohexyl) -4-chloro-D-phenylalanyl] piperidin-4-yl} -oc-cyclohexyl-2,5-dimethylpyrrolidine-1 carboxamide
Λ/-{1-[Λ/-(c/s-4-aminocyclohexyl)-4-chloro-D-phenylalanyl]piperidin-4-yl}-Λ/- cyclohexyl-ΛΛ/V-dimethylureaΛ / - {1- [Λ / - (c / s-4-aminocyclohexyl) -4-chloro-D-phenylalanyl] piperidin-4-yl} -Λ / - cyclohexyl-ΛΛ / V-dimethylurea
A/-{1-[Λ/-(c/s-4-aminocyclohexyl)-4-ch!oro-D-phenylalanyl]piperidin-4-yl}-Λ/- cyclo hexyl-/V-m ethoxy-Λ/1-m ethyl u reaN - {1- [N- (c-S-4-aminocyclohexyl) -4-chloro-D-phenylalanyl] piperidin-4-yl} -cyclohexyl- / Vm ethoxy-Λ / 1 -methyl u rea
Λ/-{1-[Λ/-(c/s-4-aminocyclohexyl)-4-chloro-D-phenylalanyl]piperidin-4-yl}-/V- cyclohexyl-2,5-dimθthyl-2,5-dihydro-1 H-pyrro!e-1-carboxamideΛ- {1- [Λ- (α-4-aminocyclohexyl) -4-chloro-D-phenylalanyl] piperidin-4-yl} - β-cyclohexyl-2,5-dimethyl-2,5- 1-dihydro-2-pyrrole-1-carboxamide
A/-{1-[Λ/-(c/s-4-aminocyclohexyl)-4-chloro-D-phenylalanyl]piperidin-4-yl}-Λ/- cycloheptyl-Λ/',Λ/'-diethylureaN - {1- [N- (c-S-4-aminocyclohexyl) -4-chloro-D-phenylalanyl] piperidin-4-yl} -cycloheptyl-N, N-diethylurea
Λ/-{1-[/V-(c/s-4-aminocyc!ohexyl)-4-chloro-D-phenylalanyl]piperidin-4-yl}-Λ/- cyclooctyl-Λ/'.Λ/'-diethylurea Λ/-{1-[Λ/-(c/s-4-aminocyclohexyl)-4-chloro-D-phenylalanyl]piperidin-4-yl}-Λ/- cyciohexyl-Λ/τ-(2,2)2-trifluoroethyl)ureaΛ- {1- [N- (c-β-4-aminocyclohexyl) -4-chloro-D-phenylalanyl] piperidin-4-yl} -ocyclooctyl-β- diethylurea Λ- {1- [Λ- (c-s-4-aminocyclohexyl) -4-chloro-D-phenylalanyl] piperidin-4-yl} -Λ-cyclohexyl-Λ / τ / (2,2 ) 2-trifluoroethyl) urea
Λ/-{1-[Λ/-(c/s-4-aminocyclohexyl)-4-chloro-D-phenylalanyl]-3-methylpiperidin-4-yl}- /V-cyclohexyl-Λ/'.Λ/'-diethylurea (trans)Λ / - {1- [Λ- (α-4-aminocyclohexyl) -4-chloro-D-phenylalanyl] -3-methylpiperidin-4-yl} - β-cyclohexyl- Λ '. -diethylurea (trans)
Λ/-{1-[Λ/-(fraπs-4-aminocyclohexyl)-4-chloro-D-phθnylalanyl]-3-methylpiperidin-4- yl}-Λ/-cyclohexyl-Λ/',Λ/'-diethylurea (trans)Λ / - {1- [Λ / - (trif-4-aminocyclohexyl) -4-chloro-D-phenylalanyl] -3-methylpiperidin-4-yl} -β-cyclohexyl-β-diethylurea (trans)
/V-{1-[Λ/-(c/s-4-aminocyclohexyl)-4-chloro-D-phenylalany!]piperidin-4-yl}-Λ/- cyclohexyl-Λ/'-ethyl-Λ/'-isopropylureaN- [1- [N- (c-S-4-aminocyclohexyl) -4-chloro-D-phenylalanyl] piperidin-4-yl} -alkylcyclohexyl-ethyl] -ethyl] -2- -isopropylurea
N-(c/s-4-{[(1R)-1-(4-chlorobenzyl)-2-(4-N- (c / s-4 - {[(1R) -1- (4-chlorobenzyl) -2- (4-
{cyclohexyl[(diethylamino)carbonyl]amino}piperidin-1-yl)-2-oxoethyl]amino}cyclohexyl)- 2,2,2-trifluoroacetamide{cyclohexyl [(diethylamino) carbonyl] amino} piperidin-1-yl) -2-oxoethyl] amino} cyclohexyl) 2,2,2-trifluoroacetamide
Λ/-(trans-4-{[(1f?)-1-(4-chlorobenzyl)-2-(4-Λ / - (trans-4 - {[(1f?) - 1- (4-chlorobenzyl) -2- (4-
{cyclohexyl[(diethylamino)carbonyl]amino}piperidin-1-yl)-2-oxoethyl]amino}cyclohexyl)- 2,2,2-trifluoroacetamide{cyclohexyl [(diethylamino) carbonyl] amino} piperidin-1-yl) -2-oxoethyl] amino} cyclohexyl) 2,2,2-trifluoroacetamide
Λ/-{1-[Λ/-(1-benzoylpiperidin-4-yl)-4-chloro-D-phenylalanyl]piperidin-4-y!}-Λ/- cyclohexyl-Λ/'.Λ/'-diethylureaΛ- {1- [Λ- (1-benzoylpiperidin-4-yl) -4-chloro-D-phenylalanyl] piperidin-4-yl} -cyclohexyl-β-diethylurea
Λ/-{1-[/V-(frans-4-aminocyclohexyl)-4-chloro-D-phenylalanyl]piperidin-4-yl}-Λ/- cyclohexyl-Λ/I,Λ/'-bis(2-fluoroethyl)ureaΛ / - {1 - [[V- (4-aminocyclohexyl) -4-chloro-D-phenylalanyl] piperidin-4-yl} -Λ-cyclohexyl-Λ / I , Λ 'bis (2- fluoroethyl) urea
(2f?,5S)-Λ/-{1-[A/-(c/s-4-aminocyclohexyl)-4-chloro-D-phenylalanyl]piperidin-4-yl}- Λ/-cyclohexyl-2,5-dimethylpyrrolidine-1-carboxamide (2f?,5S)-Λ/-(1-{4-chloro-Λ/-[c/s-4-(dimethylamino)cyclohexyl]-D- phenylalanyl}piperidin-4-yl)-Λ/-cyc!ohexyl-2,5-dimethylpyrrolidine-1-carboxamide(2f?, 5S) -Λ- {1- [N- (cs-4-aminocyclohexyl) -4-chloro-D-phenylalanyl] piperidin-4-yl} -? - cyclohexyl-2,5 -dimethylpyrrolidine-1-carboxamide (2f, 5S) -Λ- (1- {4-chloro-Λ [- [(4- (dimethylamino) cyclohexyl] -D-phenylalanyl} piperidin-4-yl) -Λ / -Cyc! ohexyl-2,5-dimethylpyrrolidine-1-carboxamide
4-{[(1 R)--\ -(4-chlorobθnzyl)-2-(4-4 - {[(1 R) - - (4-chlorobenzyl) -2- (4-
{cyclohexyl[(dimethylamino)carbonyl]amino}piperidin-1-yl)-2-oxoethyl]arnino}-Λ/,A/- dimethylpiperidine-1-carboxamide 4-{[(1 R)-1-(4-chIorobenzyl)-2-(4-{cyclohexyl [(dimethylamino) carbonyl] amino} piperidin-1-yl) -2-oxoethyl] arnino} -α, α-dimethylpiperidine-1-carboxamide 4 - {[(1 R) -1- (4-chlorobenzyl)} ) -2- (4-
{cyclohexyl[(dimethylamino)carbonyl]amino}piperidin-1-yl)-2-oxoethyi]amino}-A/,Λ/- diethylpiperidine-1-carboxamide Λ/-(1-{4-chloro-Λ/-[1-(pyrrolidin-1-ylcarbonyl)piperidin-4-yl]-D- phenylalanyl}piperidin-4-yl)-Λ/-cyclohexyl-Λ/1 JΛ/'-dimethylurea{cyclohexyl [(dimethylamino) carbonyl] amino} piperidin-1-yl) -2-oxoethy] amino} -N, Λ-diethylpiperidine-1-carboxamide Λ- (1- {4-chloro-Λ- [1- (pyrrolidin-1-ylcarbonyl) piperidin-4-yl] -D-phenylalanyl} piperidin-4-yl} -Λ-cyclohexyl-Λ / 1 J Λ / '- dimethylurea
Λ/-(1-{4-chloro-Λ/-[1-(piperidin-1-ylcarbonyl)piperidin-4-yl]-D- . . phenylalanyl}piperidin-4-yl)-/V-cyclohexyl-Λ/',Λ/1-dimethylurea . Λ/-(1-{4-chloro-Λ/-[1-(morpho!in-4-ylcarbonyl)piperidin-4-yl]-D- phenylalanyl}piperidin-4-yl)-N-cyclohexyl-Λ/\Λ/'-dimethylureaΛ- (1- {4-chloro-Λ- [1- (piperidin-1-ylcarbonyl) piperidin-4-yl] -D- phenylalanyl} piperidin-4-yl) -N-cyclohexyl-Λ / ', Λ / 1- dimethylurea. Λ- (1- {4-chloro-Λ- [1- (morpho-4-ylcarbonyl) piperidin-4-yl] -D-phenylalanyl} piperidin-4-yl) -N-cyclohexyl-Λ / \ Λ / '- dimethylurea
4-{[(1R)-1-(4-chlorobenzyl)-2-(4-4 - {[(1R) -1- (4-chlorobenzyl) -2- (4-
{cyclohexyl[(dimθthylamino)carbonyl]amino}piperidin-1-yl)-2-oxoethyl]amino}-N- phenylpiperidine-1-carboxamide 4-{[(1R)-1-(4-chlorobenzyl)-2-(4-{cyclohexyl [(dimethylamino) carbonyl] amino} piperidin-1-yl) -2-oxoethyl] amino} -N-phenylpiperidine-1-carboxamide 4 - {[(1R) -1- (4-chlorobenzyl) -2- ( 4-
{cyclohexyl[(dimethylamino)carbonyl]amino}piperidin-1-yl)-2-oxoethyl]amino}-Λ/-methyl-Λ/- phenylpiperidine-1-carboxamide - .{cyclohexyl [(dimethylamino) carbonyl] amino} piperidin-1-yl) -2-oxoethyl] amino} -α-methyl-β-phenylpiperidine-1-carboxamide.
Λ/-benzyl-4-{[(1ft)-1-(4-chlorobenzyl)-2-(4-Λ / -benzyl-4 - {[(1ft) -1- (4-chlorobenzyl) -2- (4-
{cyclohexyl[(dimethylamino)carbonyl]amino}piperidin-1-yl)-2-oxoethyl]amino}-Λ/- methylpiperidine-1 -carboxamide{cyclohexyl [(dimethylamino) carbonyl] amino} piperidin-1-yl) -2-oxoethyl] amino} -α-methylpiperidine-1-carboxamide
Λ/-(1-{4-chloro-/V-[1-(trifluoroacetyl)piperidin-4-yl]-D-phenylalanyl}piperidin-4-yl)-A/- cyclohexyl-/V1Λ/I-dimethylureaΛ- (1- {4-chloro-N- [1- (trifluoroacetyl) piperidin-4-yl] -D-phenylalanyl} piperidin-4-yl) -N-cyclohexyl- / V 1 Λ / I - dimethylurea
Λ/-{1-[A/-(1-acetylpiperidin-4-yl)-4-chloro-D-phenylalanyl]piperidin-4-yl}-Λ/- cyclohexyl-Λ/'.Λ/'-dimethylurea Λ/-{1-[4-chIoro-Λ/-(c/s-4-hydroxy-4-phenylcyclohexyl)-D-phenylalanyl]piperidin-4- yl}-Λ/-cyclohexyl-Λ/1, Λ/'-dimethylureaΛ / - {1- [N- (1-acetylpiperidin-4-yl) -4-chloro-D-phenylalanyl] piperidin-4-yl} -α-cyclohexyl-β-dimethylurea / - {1- [4-Chloro-Λ] - (c-α-4-hydroxy-4-phenylcyclohexyl) -D-phenylalanyl] piperidin-4-yl} -β-cyclohexyl-β / 1 ; -dimethylurea
Λ/-{1-[4-chloro-Λ/-(/ra/?s-4-hydroxy-4-phenylcyc!ohexy!)-D- phenyla!anyl]piperidin-4-yl}-Λ/-cyclohexyl-Λ/')Λ/'-dimethylureaΛ- {1- [4-chloro-Λ- (1H-α-4-hydroxy-4-phenylcyclohexyl) -D-phenylanyl] piperidin-4-yl} -Λ-cyclohexyl -Λ / ' ) Λ /' - dimethylurea
Λ/-(c/s-4-{[(1 R)-1 -(4-chlorobenzyl)^2-(4- {cyclohexyl[(dimethylamino)carbonyl]amino}piperidin-1-yl)-2-oxoethyl]amino}cyclohexyl)- 2,2,2-trifluoroacetamideΛ / - (c / s-4 - {[(1 R) -1 - (4-chlorobenzyl) -2- (4- {cyclohexyl [(dimethylamino) carbonyl] amino} piperidin-1-yl) -2-oxoethyl ] amino} cyclohexyl) 2,2,2-trifluoroacetamide
N-(trans-4-φ R)-I -(4-chlorobenzyl)-2-(4-N- (trans-4-φR) -I- (4-chlorobenzyl) -2- (4-
{cyclohexyl[(dimethylamino)carbonyl]amino}piperidin-1-yl)-2-oxoethyl]amino}cyclohexyl)- 2,2,2-trifluoroacetamide /V-[1-(4-chloro-Λ/-{c/s-4-[(4-fluorophenyl)amino]cyclohexyl}-D- phenylalanyl)piperidin-4-yl]-Λ/-cyclohexyl-Λ/1,Λ/'-dimethylurea{cyclohexyl [(dimethylamino) carbonyl] amino} piperidin-1-yl) -2-oxoethyl] amino} cyclohexyl) -2,2,2-trifluoroacetamide / V- [1- (4-chloro-Λ] - / c) s-4 - [(4-fluorophenyl) amino] cyclohexyl} -D-phenylalanyl) piperidin-4-yl] -Λ / -cyclohexyl-Λ / 1, Λ / '- dimethylurea
Λ/-[1-(4-chloro-Λ/-{fΛans-4-[(4-fluorophenyl)amino]cyclohexyl}-D- phenylalanyl)piperidin-4-yl]-Λ/-cyclohexyl-Λ/',Λ/'-dimethylureaΛ- [1- (4-chloro-Λ) - {f-4 - [(4-fluorophenyl) amino] cyclohexyl} -D-phenylalanyl) piperidin-4-yl] -α-cyclohexyl-Λ, Λ / '- dimethylurea
Λ/-[1-(4-chloro-A/-{c/s-4-[(2-hydroxyphenyl)amino]cyclohexyl}-D- phenylalanyl)piperidin-4-yl]-Λ/-cyclohexyl-Λ/',Λ/'-dimethylureaΛ- [1- (4-Chloro-N- [α] -4 - [(2-hydroxyphenyl) amino] cyclohexyl} -D-phenylalanyl) piperidin-4-yl] Λ -cyclohexyl-Λ 'Λ /' - dimethylurea
Λ/-[1-(4-chloro-Λ/-{^aπs-4-[(2-hydroxyphenyl)amino]cyclohexyl}-D- phenylalanyl)piperidin-4-yl]-Λ/-cyclohexyl-Λ/',A/'-dimethylurea Λ/-{1-[4-chloro-Λ/-(4-methoxycyclohexyl)-D-phenylalanyl]-3-methylpiperidin-4-yl}- Λ/-cyclohexyl-Λ/',Λ/'-dimethylurea (trans)Λ- [1- (4-Chloro-Λ) - {[N- [4 - [(2-hydroxyphenyl) amino] cyclohexyl} -D-phenylalanyl) piperidin-4-yl] -NH-cyclohexyl] A / "- dimethylurea Λ- {1- [4-chloro-Λ] - (4-methoxycyclohexyl) -D-phenylalanyl] -3-methylpiperidin-4-yl} - Λ -cyclohexyl-β ', Λ-dimethylurea (trans) )
Λ/-{1 -[4-chloro-/V-(4-phenylcyclohexyl)-D-phenylaIanyl]-3-methylpiperidin-4-yl}-Λ/- . cyclohexyl-Λ/'.Λ/'-dimethylurea (trans) Λ/-{1-[Λ/-(1-acetylpiperidin-4-yl)-4-ch!oro-D-phenylalanyl]-3-methylpiperidin-4-yl}-Λ- {1- [4-chloro-N - (4-phenylcyclohexyl) -D-phenylanyl] -3-methylpiperidin-4-yl} -Λ-. Cyclohexyl-α, β-dimethylurea (trans) --- {1- [Λ] - (1-acetylpiperidin-4-yl) -4-chloro-D-phenylalanyl] -3-methylpiperidin-4 yl} -
Λ/-cyclohexyl-Λ/',Λ/'-dimethylurea (trans)Λ / -cyclohexyl-Λ / ', Λ /' - dimethylurea (trans)
Λ/-(4-{[(1R)-1-(4-chlorobenzyl)-2-(4-{cyclohexyl[(dimethylamino)carbonyl]amino}- 3-methylpiperidin-1-yl)-2-oxoethyl]amino}cyclohexyl)acetamide (trans)(4 - {[(1R) -1- (4-Chlorobenzyl) -2- (4- {cyclohexyl [(dimethylamino) carbonyl] amino} -3-methylpiperidin-1-yl) -2-oxoethyl] amino } cyclohexyl) acetamide (trans)
Λ/-(1-{4-chloro-A/-[1-(trifluoroacetyl)piperidin-4-yl]-D-phenylalanyl}-3- methylpiperidin-4-yl)-Λ/-cyclohexyl-Λ/',Λ/'-dimethylurea (trans)Λ- (1- {4-chloro-N- [1- (trifluoroacetyl) piperidin-4-yl] -D-phenylalanyl} -3-methylpiperidin-4-yl) -NH-cyclohexyl}, Λ / '- dimethylurea (trans)
Λ/-(4-{[(1/?)-1-(4-chlorobenzyl)-2-(4-{cyclohexyl[(dimethylamino)carbonyl]amino}- S-methylpiperidin-i-yO^-oxoethyOaminolcyclohexyO^^^-trifluoroacetamide (trans)Λ / - (4 - {[(1 R)) - 1- (4-chlorobenzyl) -2- (4 - {cyclohexyl [(dimethylamino) carbonyl] amino} -S-methylpiperidin-1-yl] oxoethyO-aminocyclohexyl} ^ -trifluoroacetamide (trans)
Λ/-{1-[Λ/-(1-benzoylpiperidin-4-yl)-4-chloro-D-phenylalanyl]-3-methylpiperidin-4-yl}- /V-CyClOrIeXyI-A/1, /V-dimethylurea Λ/-(1-{4-chloro-Λ/-[1-(methylsulfonyl)piperidin-4-yl]-D-phenylalanyl}-3- methylpiperidin-4-yl)-Λ/-cyclohexyl-Λ/',Λ/'-dimethylurea (trans)Λ- {1- [Λ- (1-benzoylpiperidin-4-yl) -4-chloro-D-phenylalanyl] -3-methylpiperidin-4-yl} - / V-CyClOrIeXyI-A / 1 , / V- dimethylurea Λ- (1- {4-chloro-Λ- [1- (methylsulfonyl) piperidin-4-yl] -D-phenylalanyl} -3-methylpiperidin-4-yl) -NH-cyclohexyl} , Λ / '- dimethylurea (trans)
Λ/-{1-[4-chloro-Λ/-(4-hydroxy-4-phenylcyclohexyl)-D-phenylalanyl]-3- methylpiperidin-4-yl}-Λ/-cyclohexyl-Λ/',Λ/I-dimethylurea (trans)Λ / - {1- [4-chloro-Λ] - (4-hydroxy-4-phenylcyclohexyl) -D-phenylalanyl] -3-methylpiperidin-4-yl} -α-cyclohexyl-β / β / I -dimethylurea (trans)
A/-[1-(4-chloro-/V-{4-[(4-fluorophenyl)amino]cyclohexyl}-D-phenylalanyl)-3- methylpiperidin-4-yl]-Λ/-cyclohexyl-Λ/',Λ/'-dimethylureaN - [1- (4-chloro-N- [4 - [(4-fluorophenyl) amino] cyclohexyl} -D-phenylalanyl) -3-methylpiperidin-4-yl] -NH-cyclohexyl] , Λ / '- dimethylurea
Λ/-{1-[Λ/-(c/s-4-aminocyclohexyl)-4-chloro-D-phenylalanyl]'3-methylpiperidin-4-yl}- Λ/-cyclohexyl-Λ/',/V-dimethylurea (trans)Λ / - {1- [Λ- (α-4-aminocyclohexyl) -4-chloro-D-phenylalanyl]--methylpiperidin-4-yl}-Λ -cyclohexyl-β / N- dimethylurea (trans)
Λ/-[1-(4-chloro-/V-{c/s-4-[(2-methoxyphenyl)amino]cyclohexyl}-D- phenylalanyl)piperidin-4-yl]-Λ/-cyclόhexyl-Λ/'IΛ/'-dimethylurea Λ/-[1-(4-chloro-Λ/-{^ans-4-[(2-methoxyphenyl)amino]cyclohexyl}-D- phenylalanyl)piperidin-4-yl]-Λ/-cyclohexyl-Λ/1,Λ/1-dimethylureaΛ- [1- (4-chloro-β- [α] -4 - [(2-methoxyphenyl) amino] cyclohexyl} -D-phenylalanyl) piperidin-4-yl] Λ -cyclohexyl-Λ 'I Λ /' - dimethylurea Λ / - [1- (4-chloro-Λ / - {^ ans-4 - [(2-methoxyphenyl) amino] cyclohexyl} -D-phenylalanyl) piperidin-4-yl] -Λ / -cyclohexyl-Λ / 1 , Λ / 1- dimethylurea
A/-(c/s-4-{[(1 /?)-1 -(4-chlorobenzyl)-2-(4- {cyclohexyl[(dimethylamino)carbonyl]amino}piperidin-1-yl)-2- oxoethyl]amino}cyclohexyl)acetamide Λ/-(frans-4-{[(1f?)-1-(4-chlorobenzyl)-2-(4- {cyclohexyl[(dimethylamino)carbonyl]amino}piperidin-1-yl)-2- oxoethyl]amino}cyclohexyl)acetamideA / - (c / s-4 - {[(1H) -1 - (4-chlorobenzyl) -2- (4 - {cyclohexyl [(dimethylamino) carbonyl] amino} piperidin-1-yl} -2- oxoethyl] amino} cyclohexyl) acetamide Λ / - (frans-4 - {[(1f)) - 1- (4-chlorobenzyl) -2- (4- {cyclohexyl [(dimethylamino) carbonyl] amino} piperidin-1-yl 2-oxoethyl] amino} cyclohexyl) acetamide
Λ/-(1-{4-chloro-A/-[c/s-4-(4-hydroxyphenyl)cyclohexyl]-D-phenylalanyl}-3- methylpiperidin-4-yl)-Λ/-cyclohexyl-Λ/1,Λ/'-dimethylureaΛ- (1- {4-chloro-N- [α] -4- (4-hydroxyphenyl) cyclohexyl] -D-phenylalanyl} -3-methylpiperidin-4-yl} -Λ-cyclohexyl-Λ 1 , Λ / '- dimethylurea
Λ/-(1-{4-chloro-Λ/-[frans-4-(4-hydroxyphenyl)cyclohexyl]-D-phenylalanyl}-3- methylpiperidin-4-yl)-Λ/-cyclohexyl-A/',Λ/'-dimethylureaΛ- (1- {4-chloro-Λ- [frans-4- (4-hydroxyphenyl) cyclohexyl] -D-phenylalanyl} -3-methylpiperidin-4-yl) Λ -cyclohexyl-A ', Λ / '- dimethylurea
Λ/-(1-{4-chloro-Λ/-[4-(2-oxo-1,3-oxazolidin-3-yl)cyclohexyl]-D-phenylalanyl}-3- . methylpiperidin-4-yl)-A/-cyclohexyl-A/',Λ/'-dimethylurea (trans) ^41-[4-chloro-Λ/-(1-isonicotinoyfpipeπdiπ-4-yl)-D-phenyIalanyl]-3-methylpiperidin-Λ- (1- {4-chloro-Λ- [4- (2-oxo-1,3-oxazolidin-3-yl) cyclohexyl] -D-phenylalanyl} -3-methylpiperidin-4-yl) Aβ-cyclohexyl-α, β-dimethylurea (trans) ^ 4 1 - [4 - c hloro-Λ / - (1-isonicotinoyfpipeπdiπ-4-yl) -D-phenyIalanyl] -3-methylpiperidin
4-yl}-Λ/-cyclohexyl-Λ/1,Λ/1-dimethylurea (trans)4-yl} -Λ / -cyclohexyl-Λ / 1 , Λ / 1- dimethylurea (trans)
Λ/-(1-{4-chloro-A/r-[c/s-4-(1 ,3-dihydro-2H-isoindol-2-yl)cyclohexyl]-D-phenylalanyl}- 3-methylpiperidin-4-yl)-Λ/-cyclohexyl-Λ/',Λ/I-dimethylurea (trans) Λ/-{1-[4-chloro-Λ/-(2-phenylpiperidin-4-yl)-D-phenylalanyl]-3-methylpiperidin-4-yl}-Λ- (1- {4-chloro-N- [α] -4- (1,3-dihydro-2H-isoindol-2-yl) cyclohexyl] -D-phenylalanyl} -3-methylpiperidin-4 yl) -Λ / -cyclohexyl-Λ / ', Λ / I -dimethylurea (trans) Λ / - {1- [4-chloro-Λ / - (2-phenylpiperidin-4-yl) -D-phenylalanyl] - 3-methylpiperidin-4-yl} -
Λ/-cyclohexyl-Λ/,Λr-dimethylurea (trans)Λ / -cyclohexyl-Λ /, Λr-dimethylurea (trans)
Λ/-(1-{4-chloro-Λ/-[4-(3-oxopiperazin-1-yl)cyclohexyl]-D-phenylalanyl}-3- methylpiperidin-4-yl)-Λ/-cyclohexyl-/V)Λ/'-dimethylurea (trans)Λ- (1- {4-chloro-Λ- [4- (3-oxopiperazin-1-yl) cyclohexyl] -D-phenylalanyl} -3-methylpiperidin-4-yl} -Λ-cyclohexyl- / V ) Λ / '- dimethylurea (trans)
25. Composés dont les noms suivent25. Compounds whose names follow
Λ/-{1-[Λ/-(4-aminocyclohexyl)-4-chloro-D-ρheny!alanyl]piperidin-4-yl}-Λ/-cyclohexyl-Λ / - {1- [Λ / - (4-aminocyclohexyl) -4-chloro-D-alanyl ρheny!] Piperidin-4-yl} -Λ / -cyclohexyl-
/V,/V-diethylurea/ V, / V-diethylurea
Λ/-{1-[Λ/-(c/s-4-aminocyclohexyl)-4-chloro-D-phenylalanyl]piperidin-4-yl}-Λ/- cyclohexyl-1 ,3-diHydro-2W-isoindole-2-carboxamide Λ/-{1 -[Λ/-(c/s-4-aminocyclohexyl)-4-chloro-D-phenylalanyl]piperidin-4-yl}-Λ/- cyclohexyl-2,5-dimethy.lpyrrolidine-1-carboxamideΛ / - {1- [Λ- (α-4-aminocyclohexyl) -4-chloro-D-phenylalanyl] piperidin-4-yl} -α-cyclohexyl-1,3-dihydro-2H-isoindole 2-Carboxamide Λ- {1 - [Λ / - (c-s-4-aminocyclohexyl) -4-chloro-D-phenylalanyl] piperidin-4-yl} -Λ-cyclohexyl-2,5-dimethyl-1-pyrrolidine -1-carboxamide
Λ/-{1-[/V-(c/s-4-aminocyclohexyl)-4-chloro-D-phenylalanyl]piperidin-4-yl}-Λ/- cyclohexyl-Λ/'.Λ/'-dimethylureaΛ- {1- [N- (cs-4-aminocyclohexyl) -4-chloro-D-phenylalanyl] piperidin-4-yl} -ocyclohexyl-β-dimethylurea
Λ/-{1-[Λ/-(c/s-4-aminocyclohexyl)-4-chloro-D-phenylalanyl]piperidin-4-yl}-/V- cyclohexyl-Λ/'-methoxy-Λ/'-methylureaΛ- {1- [Λ- (α-4-aminocyclohexyl) -4-chloro-D-phenylalanyl] piperidin-4-yl} -N-cyclohexyl-β-methoxy-β- Methylurea
Λ/-{1-[Λ/-(c/s-4-aminocyclohexyl)-4-chloro-D-phenylalanyl]piperidin-4-yl}-/V- cyclohexyl-2,5-dimethyl-2,5-dihydro-1A/-pyrrole-1-carboxamideΛ / - {1- [Λ- (α-4-aminocyclohexyl) -4-chloro-D-phenylalanyl] piperidin-4-yl} - β-cyclohexyl-2,5-dimethyl-2,5- dihydro-1A / -pyrrole-1-carboxamide
Λ/-{1-[Λ/-(c/s-4-aminocyclohexyl)-4-chloro-D-phenylalanyl]piperidin-4-yl}-Λ/- cyclobutyl-Λ/',Λ/'-diethylurea Λ/-{1-[Λ/-(c/s-4-aminocyclohexyl)-4-chloro-D-phenylalanyl]piperidin-4-yl}-/V- cyclopentyl-A/'.Λ/'-diethylureaΛ / - {1- [Λ- (α-4-aminocyclohexyl) -4-chloro-D-phenylalanyl] piperidin-4-yl} -Λ-cyclobutyl-β, Λ-diethylurea N- (1- [N- (c-S-4-aminocyclohexyl) -4-chloro-D-phenylalanyl] piperidin-4-yl} - N -cyclopentyl-N-diethylurea
Λ/-{1-[Λ/-(c/s-4-aminocyclohexyl)-4-chloro-D-phenylalanyl]piperidin-4-yl}-Λ/- cycloheptyl-Λ/',Λ/'-dietriylureaΛ- {1- [Λ- (α-4-aminocyclohexyl) -4-chloro-D-phenylalanyl] piperidin-4-yl} -Λ-cycloheptyl-β, β-dihydro-urea
Λ/-{1-[A/-(c/s-4-aminocyclohexyl)-4-chloro-D-phenylalanyl]piperidin-4-yl}-Λ/- cyclooctyl-Λ/',Λ/'-diethylureaΛ / - {1- [N- (α-4-aminocyclohexyl) -4-chloro-D-phenylalanyl] piperidin-4-yl} -Λ-cyclooctyl-N, N-diethylurea
Λ/-{1-[Λ/-(c/s-4-aminocyclohexy!)-4-chloro-D-phenylalanyl]piperidin-4-yl}-Λ/l,Λ/'- diethy!-A/-phenylureaΛ / - {1- [Λ / - (c / s-4-aminocyclohexy!) - 4-chloro-D-phenylalanyl] piperidin-4-yl} -Λ / l, Λ / '- diethylamino -A / - phenylurea
Λ/-{1-[Λ/-(c/s-4-aminocyclohexyl)-4-chloro-D-pheny!alanyl]piperidin-4-yl}-A/- cyclohexyl-Λ/I-(2,2,2-trifluoroethyl)urea . Λ/-{1 -[4-chloro-Λ/-(4-hydroxycyclohexyl)-D-phenylalanyl]piperidin-4-yl}-Λ/- cyclohexyl-Λ/'.Λ/'-diethylureaΛ- {1- [Λ- (α-4-aminocyclohexyl) -4-chloro-D-phenylalanyl] piperidin-4-yl} -N-cyclohexyl-Λ / I - (2.2 , 2-trifluoroethyl) urea. Λ- {1 - [4-chloro-Λ] - (4-hydroxycyclohexyl) -D-phenylalanyl] piperidin-4-yl} -ocyclohexyl-β-diethylurea
Λ/-{1-[/V-(c/s-4-aminocyc!ohexyl)-4-chloro-D-phenylalanyl]-3-methylpiperidin-4-yl}- Λ/-cyclohexyl-Λ/1,Λ/'-diethylurea (trans)Λ / - {1 - [/ V- (c / s-4-aminocyc ohexyl!) -4-chloro-D-phenylalanyl] -3-methylpiperidin-4-yl} - Λ / -cyclohexyl-Λ / 1 , Λ / '- diethylurea (trans)
Λ/-{1-[Λ/-(c/s-4-aminocyclohexyl)-4-chloro-D-phenylalanyl]-3-nnethylpiperidin-4-yl}- Λ/-cyclohexyi-Λ/\Λ/'-diethylurea (cis)Λ- {1- [Λ- (α-4-aminocyclohexyl) -4-chloro-D-phenylalanyl] -3-nnethylpiperidin-4-yl} - Λ -cyclohexyl-β / --- diethylurea (cis)
Λ/-{1-[Λ/-(ifraA?s-4-aminocyclohexyl)-4-chloro-D-phenylalanyl]-3-methylpiperidiπ-4- yl}-Λ/-cyclohexyI-Λ/',Λ/'-diethylurea (trans)Λ / - {1- [Λ / - (1-alfa-4-aminocyclohexyl) -4-chloro-D-phenylalanyl] -3-methylpiperidi-4-yl} -Λ / -cyclohexy-Λ / ', / -diethylurea (trans)
Λ/-{1-[Λ/-(trans-4-aminocyclohexyl)-4-chloro-D-phenylalanyl]-3-methylpiperidin-4- yl}-Λ/-cyclohexyl-Λ/',Λ/'-diethylurea (cis)Λ / - {1- [Λ- (trans-4-aminocyclohexyl) -4-chloro-D-phenylalanyl] -3-methylpiperidin-4-yl} -β-cyclohexyl-β-diethylurea (cis)
Λ/-{1-[Λ/-(c/s-4-aminocyclohexyl)-4-ch!oro-D-phenylalanyl]ρiperidin-4-yl}-Λ/'JΛ/'- diethyl-A/-(tetrahydro-2H-pyran-4-yl)urea Λ/-{1 -[Λ/-(c/s-4-aminocyclohexyl)-4-chloro-D-phenylalanyl]piperidin-4-yl}-Λ/1, /V- diethyl-Λ/-piperidin-4-ylureaΛ / - {1- [Λ / - (c / s-4-aminocyclohexyl) -4-Chloro-D-phenylalanyl] ρiperidin-4-yl} -Λ / 'J Λ /' - diethyl-A / - (tetrahydro-2H-pyran-4-yl) urea Λ- {1 - [Λ- (c-s-4-aminocyclohexyl) -4-chloro-D-phenylalanyl] piperidin-4-yl} -Λ / 1 , / V-diethyl-Λ / -piperidin-4-ylurea
Λ/-{1-[A/-(c/s-4-aminocyclohexyl)-4-chloro-D-phenylalanyl]piperidin-4-yl}-Λ/- cyclohexyl-Λ/'-ethyl-Λ/'-isopropylureaΛ- {1- [N- (α-4-aminocyclohexyl) -4-chloro-D-phenylalanyl] piperidin-4-yl} -Λ-cyclohexyl-β-ethyl-β- isopropylurea
Λ/-{1-[Λ/-(c/s-4-aminocyclohexyl)-4-chloro-D-phenylalanyl]piperidin-4-yl}-Λ/- cyclohexyl-2,2-dimethylhydrazinecarboxamide Λ/-(c/s-4-{[(1 R)-1 -(4-chlorobenzyl)-2-(4-Λ- {1- [Λ- (α-4-aminocyclohexyl) -4-chloro-D-phenylalanyl] piperidin-4-yl} -Λ-cyclohexyl-2,2-dimethylhydrazinecarboxamide Λ / - (c / s-4 - {[(1 R) -1 - (4-chlorobenzyl) -2- (4-
{cyclohexyl[(diethylamino)carbonyl]amino}piperidin-1-y!)-2-oxoethyl]amino}cyclohexyl)- 2,2,2-trifluoroacetamide{cyclohexyl [(diethylamino) carbonyl] amino} piperidin-1-yl) -2-oxoethyl] amino} cyclohexyl) 2,2,2-trifluoroacetamide
Λ/-(trans-4-{[(1f?)-1-(4-chloroben2y!)-2-(4- {cyc!ohexyl[(diethylamino)carbonyl]amino}piperidin-1-yl)-2-oxoethyl]amino}cyclohexyl)- 2,2,2-trifluoroacetamideΛ / - (trans-4 - {[(1f)) - 1- (4-chlorobenzyl) -2- (4- {cyclohexyl [(diethylamino) carbonyl] amino} piperidin-1-yl} -2- oxoethyl] amino} cyclohexyl) 2,2,2-trifluoroacetamide
Λ/-{1-[Λ/-(^a/7S-4-aminocycloriexyl)-4-ch!oro-D-pheny!alanyl]piperidin-4-yl}-Λ/- cyclohexyl-Λ/',Λ/'-bis(2:fluoroethyl)urea.Λ / - {1- [Λ- (N-) -7S-4-aminocycloriexyl) -4-chloro-D-phenylalanyl] piperidin-4-yl} -ocyclohexyl-,; Bis (2 : fluoroethyl) urea.
26. Composés dont les noms suivent26. Compounds whose names follow
Λ/-[(1R)-1-(4-chlorobenzyl)-2-(4-{cyclohexyl[2-(diethylamino)ethyl]amino}piperidin-Λ / - [(1R) -1- (4-chlorobenzyl) -2- (4- {cyclohexyl [2- (diethylamino) ethyl] amino} piperidin
1 -y|)-2-oxoethyl]cyclohexane-1 ,4-diamine1-yl) -2-oxoethyl] cyclohexane-1,4-diamine
Λ/-(1-{4-chloro-Λ/-[c/s-4-(dimethylamino)cyclohexyl]-D-phenylalanyl}piperidin-4-yl)- Λ/-cyc!ohexyl-3,4-difluorobenzamide Λ/-(1-{4-chloro-/V-[c/s-4-(dimethy!amino)cyclohexyl]-D-phenylalanyl}piperidin-4-yl)-Λ- (1- {4-chloro-Λ- [α] -4- (dimethylamino) cyclohexyl] -D-phenylalanyl} piperidin-4-yl) Λ-cyclohexyl-3,4-difluorobenzamide Λ / - (1- {4-chloro- / V- [c / s-4- (dimethyl amino) cyclohexyl!] -D-phenylalanyl} piperidin-4-yl) -
Λ/-cycloheptyl-Λ/',Λ/'-dimethylureaΛ / -cycloheptyl-Λ / ', Λ /' - dimethylurea
(2R,5S)-A/-{1-[Λ/-(c/s-4-aminocyclohexyl)-4-chloro-D-phenylalanyl]piperidin-4-yl}- Λ/-cyclohexyl-2,5-dimethylpyrrolidine-1-carboxamide(2R, 5S) -N- [1- [Λ- (α-4-aminocyclohexyl) -4-chloro-D-phenylalanyl] piperidin-4-yl} - Λ -cyclohexyl-2,5- dimethylpyrrolidine-1-carboxamide
(2/?,5S)-Λ/-(1-{4-chloro-Λ/-[c/s-4-(dimethylamino)cyclohexyl]-D- phenylalanyl}piperidin-4-yl)-Λ/-cyclohexyl-:2,5-dimethylpyrrolidine-1-carboxamide(2 R, 5 S) -Λ- (1- {4-chloro-Λ- [α] -4- (dimethylamino) cyclohexyl] -D-phenylalanyl} piperidin-4-yl) Λ -cyclohexyl -: 2,5-dimethylpyrrolidine-1-carboxamide
Λ/-{1-[4-chloro-Λ/-(c/s-4-hydroxy-4-phenylcyc!ohexy!)-D-phenylalanyl]piperidin-4- yl}-Λ/-cyclohexyl-Λ/',Λ/'-dimethylurea Λ/-{1-[4-chloro-Λ/-(/ra/7s-4-hydroxy-4-phenylcyclohexyl)-D- phenylalanyl]piperidin-4-yl}-Λ/-cyclohexyl-Λ/'.IA/'-dimethylureaΛ- {1- [4-chloro-Λ- (α-4-hydroxy-4-phenylcyclohexyl) -D-phenylalanyl] piperidin-4-yl} -β-cyclohexyl} , Λ / '- dimethylurea Λ- {1- [4-chloro-Λ- (1α, 7α-4-hydroxy-4-phenylcyclohexyl) -D-phenylalanyl] piperidin-4-yl} -α-cyclohexyl-β. I A / '- dimethylurea
/V-(c/s-4-{[(1R)-1-(4-chlorobenzyl)-2-(4-/ V- (c / s-4 - {[(1R) -1- (4-chlorobenzyl) -2- (4-
{cyciohexyl[(dimethylamino)carbonyl]amino}piperidin-1-yl)-2-oxoethyl]amino}cyclohexyl)- 2,2,2-trifluoroacetamide{cyclohexyl [(dimethylamino) carbonyl] amino} piperidin-1-yl) -2-oxoethyl] amino} cyclohexyl) -2,2,2-trifluoroacetamide
Λ/-(frans-4-{[(1 R)~1 -(4-chlorobenzyl)-2-(4-Λ / - (frans-4 - {[(1 R) -1- (4-chlorobenzyl) -2- (4-
{cyclohexyl[(dimethylamino)carbonyl]amino}piperidin-1-yl)-2-oxoethyl]amino}cyclohexyl)- 2,2,2-trifluoroacetamide{cyclohexyl [(dimethylamino) carbonyl] amino} piperidin-1-yl) -2-oxoethyl] amino} cyclohexyl) 2,2,2-trifluoroacetamide
Λ/-[1-(4-chloro-A/-{c/s-4-[(4-fluorophenyl)amino]cyc!ohexyl}-D- phenylalanyl)piperidin-4-yl]-Λ/-cyclohexyl-Λ/'1Λ/'-dimethylureaΛ- [1- (4-Chloro-N- [α] -4 - [(4-fluorophenyl) amino] cyclohexyl} -D-phenylalanyl) piperidin-4-yl] Λ -cyclohexyl- Λ / ' 1 Λ /' - dimethylurea
Λ/-[1-(4-chloro-Λ/-{frans-4-[(4-fluorophenyl)amino]cyclohexyl}-D- phenyllanyl)piperidin-4-y!]-Λ/-cyclohexyl-Λ/',Λ/'-dimethylureaΛ- [1- (4-chloro-Λ) - {4-enans-4 - [(4-fluorophenyl) amino] cyclohexyl} -D-phenyl-yl) piperidin-4-yl] - Λ -cyclohexyl-Λ , Λ / '- dimethylurea
Λ/-{1-[4-chloro-Λ/-(4-methoxycyclohexyl)-D-phenylalanyl]piperidin-4-yl}-A/- cyclohexyl-Λ/1,Λ/'-dimethy!urea Λ/-[1 -(4-chloro-Λ/-{c/s-4-[(4-methoxyphenyl)amino]cyclohexyl}-D- phenylalanyl)piperidin-4-yl]-yV-cyclohexyl-Λ/',Λ/'-dimethylureaΛ- {1- [4-chloro-Λ] - (4-methoxycyclohexyl) -D-phenylalanyl] piperidin-4-yl} -N-cyclohexyl-β- 1 , Λ-dimethyl-urea [1 - (4-chloro-Λ) - [α] -4 - [(4-methoxyphenyl) amino] cyclohexyl} -D-phenylalanyl) piperidin-4-yl] -N-cyclohexyl-Λ / ', Λ '-dimethylurea
Λ/-[1-(4-chloro-Λ/-{fraπs-4-[(4-methoxyphenyl)amino]cyclohexyl}-D- phenylalanyl)piperidin-4-yl]-Λ/-cyclohexyl-Λ/',Λ/'-dimethylureaΛ- [1- (4-chloro-Λ) - -Frank-4 - [(4-methoxyphenyl) amino] cyclohexyl} -D-phenylalanyl) piperidin-4-yl] -NH-cyclohexyl-Λ, Λ / '- dimethylurea
Λ/-[1-(4-ch!oro-Λ/-{c/s-4-[(2-hydroxyphenyl)amino]cyclohexyl}-D- phenyla!anyl)pipeπdin-4-yl]-/V-cyclohexyl-Λ/'1Λ/'-dimethylureaΛ- [1- (4-Chloro-Λ) - [[β-4 - [(2-hydroxyphenyl) amino] cyclohexyl} -D-phenyl] anyl) piperidin-4-yl] - / V- cyclohexyl- 1 / dimethylurea
Λ/-[1-(4-chloro-Λ/-{fra/7s-4-[(2-hydroxyphenyl)amino]cyclohexyl}-D- phenylalanyl)piperidin-4-yl]-Λ/-cyclohexy!-/V,A/1-dimethylureaΛ- [1- (4-Chloro-Λ) - [η] -7 - [(2-hydroxyphenyl) amino] cyclohexyl} -D-phenylalanyl) piperidin-4-yl] Λ -cyclohexy] - V, A / 1- dimethylurea
Λ/-[1-(4-chloro-Λ/-{4-[(dimethylamino)methyl]-4-phenylcyclohexyl}-D- phenylalanyl)pipθridin-4-yl]-Λ/-cyclohexyl-Λ/',Λ/'-dimethylurea (2S,5S)-Λ/-(1-{4-chloro-Λ/-[c/s-4-(dimethylamino)cyclohexyl]-D- phenylalanyl}piperidin-4-yl)-Λ/-cyclohexyl-2,5-dimethylpyrrolidine-1-carboxamideΛ- [1- (4-chloro-Λ) - {4 - [(dimethylamino) methyl] -4-phenylcyclohexyl} -D-phenylalanyl) piperidin-4-yl] -cyclohexyl-,, Λ (2S, 5S) -β- (1- {4-chloro-Λ [- [(4- (dimethylamino) cyclohexyl] -D-phenylalanyl} piperidin-4-yl) -dimethylurea -cyclohexyl-2,5-dimethylpyrrolidine-1-carboxamide
(2R5/:?)-Λ/-(1-{4-chloro-Λ/-[c/s-4-(dimethylamino)cyclohexyl]-D- phenylalanyl}piperidin-4-yl)-Λ/-cyclohexy!-2,5-dimethylpyrrolidine-1-carboxamide(2R5 : N) - N - (1- {4-chloro-N - [(n-4- (dimethylamino) cyclohexyl] -D-phenylalanyl} piperidin-4-yl) -NH-cyclohexyl]; -2,5-dimethylpyrrolidine-1-carboxamide
Λ/-{1-[4-chloro-Λ/-(4-methoxycyclohexyl)-D-phenylaianyl]-3-methylpiperidin-4-yl}- /V-CyCIoHeXyI-A/1, /V-dimethylureaΛ- {1- [4-chloro-Λ- (4-methoxycyclohexyl) -D-phenyla-ylyl] -3-methylpiperidin-4-yl} - ν-CyCiOH-Xyl-A / 1 , ν-dimethylurea
Λ/-{1-[4-chloro-Λ/-(4-phenylcyclohexyl)-D-phenylalanyl]-3-methylpiperidin-4-yl}-Λ/- cyclohexyl-Λ/',Λ/'-dimethylureaΛ / - {1- [4-chloro-Λ] - (4-phenylcyclohexyl) -D-phenylalanyl] -3-methylpiperidin-4-yl} -Λ-cyclohexyl-β ', β-dimethylurea
1 Λ/-(4-{[(1f?)-1-(4-chlorobenzyl)-2-(4-{cyclohexyl[(dimethylamino)carbonyl]amino}- 3-methylpiperidin-1-yl)-2-oxoethyl3amino}cyclohexyl)acetamide A/-(4-{[(1 R)- 1 -(4-chlorobenzyl)-2-(4-{cyclohexyl[(dimethylamino)carbonyl]amino}- 1 Λ / - (4 - {[(1f)) - 1- (4-chlorobenzyl) -2- (4- {cyclohexyl [(dimethylamino) carbonyl] amino} -3-methylpiperidin-1-yl) -2-oxoethyl] amino } cyclohexyl) acetamide A / - (4 - {[(1R) -1- (4-chlorobenzyl) -2- (4- {cyclohexyl [(dimethylamino) carbonyl] amino} -
3-methylpiperidin-1-yl)-2-oxoethyl]amino}cyclohexyl)-2,2,2-trifluoroacetamide A/-{-l-[4-chioro-Λ/-(4-hydroxy-4-phenylcyclohexyl)-D-phenylalanyl]-3- methylpipéridin-4-yl}-Λ/-cyclohexyl-Λ/I,Λ/'-dimethylurea3-methylpiperidin-1-yl) -2-oxoethyl] amino} cyclohexyl) -2,2,2-trifluoroacetamide N- {1- [4-chloro-Λ] - (4-hydroxy-4-phenylcyclohexyl) - D-phenylalanyl] -3- methylpiperidin-4-yl} -Λ / -cyclohexyl-Λ / I , Λ / '- dimethylurea
Λ/-[1-(4-chloro-Λ/-{4-[(4-fluorophenyl)amino]cyclohexyl}-D-phenylalanyl)-3- methy!piperidin-4-yl]-Λ/-cyclohexy!-ΛΛ/\^dimethylureaΛ- [1- (4-chloro-Λ) - {4 - [(4-fluorophenyl) amino] cyclohexyl} -D-phenylalanyl) -3-methylpiperidin-4-yl] -β-cyclohexyl ΛΛ / \ ^ dimethylurea
Λ/-(1-{4-chloro-Λ/-[c/s-4-(dimethylamino)cyclohexyl]-D-phenyla!anyl}piperidin-4-yl)- /V-cyclohexyl-Λ/YΛ/'-dimethylureaΛ- (1- {4-chloro-Λ- [α] -4- (dimethylamino) cyclohexyl] -D-phenylanyl} piperidin-4-yl) -N-cyclohexyl-Λ / YΛ / -dimethylurea
Λ/-{1-[/V-(c/s-4-aminocyclohexyl)-4-chloro-D-phenylalanyl]-3-methylpiperidin-4-yi}- /V-cyclohexyl-Λ/',A/1-dimethylureaΛ- {1- [N- (c-β-4-aminocyclohexyl) -4-chloro-D-phenylalanyl] -3-methylpiperidin-4-yl} -N-cyclohexyl-Λ, A / 1 -dimethylurea
Λ/-[1-(4-chloro-Λ/-{c/s-4-[(2-methoxyphenyl)amino]cyclohexyl}-D- phenyla!anyl)piperidin-4-yl]-N-cyclohexyl-Λ/\Λ/1-dimethylurea Λ/-[1-(4-chloro-/V-{c/s-4-[(2-methoxyphenyl)amino]cyclohexyl}-D- phenylalanyl)pipθridin-4-yl]-Λ/-cyclohexyl-Λ/',Λ/'-dimethylureaΛ- [1- (4-chloro-Λ) - {cs-4 - [(2-methoxyphenyl) amino] cyclohexyl} -D-phenylanyl) piperidin-4-yl] -N-cyclohexyl-Λ / 1 - [(4-chloro- 1- dimethylurea)] - [1- (4-chloro-N- [α] -4 - [(2-methoxyphenyl) amino] cyclohexyl} -D-phenylalanyl) piperidin-4-yl] Λ / -cyclohexyl-Λ / ', Λ /' - dimethylurea
N-(c/s-4-{[(1 R)-1-(4-chlorobenzyl)-2-(4- {cyclohexyl[(dimethylamino)carbonyl]amiήo}piperidin-1-yl)-2- oxoethyl]amino}cyclohexyl)acetamide Λ/-(fra/?s-4-{[(1 R)-1-(4-chlorobenzyl)-2-(4-N- (c / s-4 - {[(1R) -1- (4-chlorobenzyl) -2- (4- {cyclohexyl [(dimethylamino) carbonyl] amido} piperidin-1-yl) -2-oxoethyl] amino} cyclohexyl) acetamide Λ / - (si-4 - {[(1 R) -1- (4-chlorobenzyl) -2- (4-
{cyclohexyl[(dimethylamino)carbonyl]amino}piperidin-1-yl)-2- oxoethyl]amino}cyc!ohexyl)acetamide{cyclohexyl [(dimethylamino) carbonyl] amino} piperidin-1-yl) -2-oxoethyl] amino} cyclohexyl) acetamide
A/-(1-{4-chloro-Λ/-[c/s-4-(4-hydroxyphenyl)cyclohexyl]-D-phenylalanyl}-3- methylpiperidin-4-yl)-Λ/-cyclohexyl-Λ/',Λ/'-dimethylurea Λ/-(1-{4-chloro-Λ/-[frans-4-(4-hydroxyphenyl)cyclohexyl]-D-phenylalanyl}-3- methylpiperidin-4-yl)-Λ/-cyclohexyl-Λ/',Λ/'-dimethylureaN - (1- {4-chloro-Λ [- / c- [4- (4-hydroxyphenyl) cyclohexyl] -D-phenylalanyl} -3-methylpiperidin-4-yl} -α-cyclohexyl} / ', Λ /' - dimethylurea Λ / - (1- {4-chloro-Λ [-] - [4- (4-hydroxyphenyl) cyclohexyl] -D-phenylalanyl} -3-methylpiperidin-4-yl} -Λ -cyclohexyl-Λ / ', Λ /' - dimethylurea
Λ/-(1-{4-chloro-Λ/-[4-(2-oxo-1 ,3-oxazolidin-3-yl)cyclohexyl]-D-phenylalanyl}-3- methylpiperidin-4-yl)-Λ/-cyclohexyl-Λ/',Λ/'-dimethylureaΛ- (1- {4-chloro-Λ- [4- (2-oxo-1,3-oxazolidin-3-yl) cyclohexyl] -D-phenylalanyl} -3-methylpiperidin-4-yl} -Λ / -cyclohexyl-Λ / ', Λ /' - dimethylurea
Λ/-(1-{4-chloro-Λ/-[c/s-4-(1,3-dihydro-2/V-isoindol-2-yl)cyclohexyl]-D-phenylalanyl}- 3-methylpiperidin-4-yl)-/V-cyclohexyl-Λ/'!Λ/l-dimethylureaΛ- (1- {4-chloro-Λ- [α] -4- (1,3-dihydro-2H-isoindol-2-yl) cyclohexyl] -D-phenylalanyl} -3-methylpiperidin 4-yl) - / V-cyclohexyl-Λ / ' ! Λ / l- dimethylurea
Λ/-(1-{4-chloro-A/-[4-(3-oxopiperazin-1-yi)cyclohexyl]-D-phenylalanyl}-3- methylpiperidin-4-yl)-Λ/-cyclohexyl-Λ/'JΛ/1-dimethylurea.Λ- (1- {4-chloro-N- [4- (3-oxopiperazin-1-yl) cyclohexyl] -D-phenylalanyl} -3-methylpiperidin-4-yl} -Λ-cyclohexyl-Λ / J / 1- dimethylurea.
27. Composés dont les noms suivent Λ/-[1-(Λ/-8-azabicyclo[3.2.1]oct-3-yl-4-chloro-D-phenylalanyl)piperidin-4-yl]-A/- cyclohexyl-ΛΛ yV-diethylurea27. Compounds whose names follow Λ / - [1- (Λ / -8-azabicyclo [3.2.1] oct-3-yl-4-chloro-D-phenylalanyl) piperidin-4-yl] -N-cyclohexyl -ΛΛ yV-diethylurea
Λ/-[1-(A/-1-azabicyclo[2.2.2]oct-3-yl-4-chloro-D-phenylalanyl)piperidin-4-yl]-Λ/- cyclohexyl-Λ/'.Λ/'-diethylureaΛ- [1- (A / -1-azabicyclo [2.2.2] oct-3-yl-4-chloro-D-phenylalanyl) piperidin-4-yl] -ocyclohexyl}. '-diethylurea
Λ/-[1-(Λ/-8-azabicyclo[3.2.1]oct-3-yl-4-chloro-D-phenylalanyl)piperidin-4-yl]-Λ/- cyclobutyl-Λ/'.Λ/'-diethylureaΛ- [1- (Λ) -8-azabicyclo [3.2.1] oct-3-yl-4-chloro-D-phenylalanyl) piperidin-4-yl] -β-cyclobutyl-β- / '-diethylurea
Λ/-{1-[Λ/-(1-benzoylpiperidin-4-yl)-4-chloro-D-phenylalanyl]piperidin-4-yI}-Λ/- cyclohexyl-Λ/'.Λ/'-diethylurea. Λ- {1- [Λ- (1-benzoylpiperidin-4-yl) -4-chloro-D-phenylalanyl] piperidin-4-yl} -α-cyclohexyl-β-diethylurea.
28. Composés dont les noms suivent 4-{[(1R)-1-(4-chlorobenzyl)-2-(4-28. Compounds whose names follow 4 - {[(1R) -1- (4-chlorobenzyl) -2- (4-
{cyclohexyl[(dimethylamino)carbonyl]amino}piperidin-1-yl)-2-oxoethyl]amino}-Λ/,/V- dimethylpiperidine-1-carboxamide{cyclohexyl [(dimethylamino) carbonyl] amino} piperidin-1-yl) -2-oxoethyl] amino} -α, N-dimethylpiperidine-1-carboxamide
4-{[(1 R)-I -(4-chlorobenzyl)-2-(4-4 - {[(1 R) -1 - (4-chlorobenzyl) -2- (4-
{cyclohexyl[(dimethylamino)carbonyl]amino}piperidin-1-yl)-2-oxoethyl]amino}-Λ/,Λ/- diethylpiperidine-1-carboxamide{cyclohexyl [(dimethylamino) carbonyl] amino} piperidin-1-yl) -2-oxoethyl] amino} -α, β-diethylpiperidine-1-carboxamide
Λ/-(1-{4-ch!oro-Λ/-[1-(pyrrolidin-1-ylcarbonyl)piperidin-4-yl]-D- phenylatanyl}piperidin-4-yl)-Λ/-cyclohexyl-Λ/',Λ/'-dimethylureaΛ- (1- {4-chloro-Λ- [1- (pyrrolidin-1-ylcarbonyl) piperidin-4-yl] -D-phenyl-ylanyl} piperidin-4-yl) -β-cyclohexyl-Λ / ', Λ /' - dimethylurea
Λ/-(1-{4-chloro-Λ/-[1-(piperidin-1-ylcarbonyl)piperidin-4-yl]-D-phenylalanyl}piperidin- 4-yl)-/V-cyclohexyl-Λ/',Λ/'-dimethylureaΛ- (1- {4-chloro-Λ- [1- (piperidin-1-ylcarbonyl) piperidin-4-yl] -D-phenylalanyl} piperidin-4-yl) -N-cyclohexyl-Λ , Λ / '- dimethylurea
Λ/-(1-{4-chloro-Λ/-[1-(morpholin-4-ylcarbonyl)piperidin-4-yl]-D- phenylalanyl}piperidin-4-yl)-Λ/-cyclohexyl-Λ/',Λ/I-dimethylurea 4-{[(1 R)-1 -(4-chlorobenzyl)-2-(4-Λ- (1- {4-chloro-Λ- [1- (morpholin-4-ylcarbonyl) piperidin-4-yl] -D-phenylalanyl} piperidin-4-yl) -NH-cyclohexyl} , Λ / I- dimethylurea 4 - {[(1 R) -1 - (4-chlorobenzyl) -2- (4-
{cyclohexyl[(dimethylamino)carbonyl]amino}piperidin-1-yl)-2-oxoethyl]amino}-Λ/- phenylpiperidine-1-carboxamide{cyclohexyl [(dimethylamino) carbonyl] amino} piperidin-1-yl) -2-oxoethyl] amino} -α-phenylpiperidine-1-carboxamide
4-{[(1 R)-1 -(4-chlorobenzyl)-2-(4-4 - {[(1 R) -1 - (4-chlorobenzyl) -2- (4-
{cyclohexyl[(dimethylamino)carbonyl]amino}piperidin-1-yl)-2-oxoethyl]amino}-Λ/-methyl-A/- phenylpiperidine-1 -carboxamide{cyclohexyl [(dimethylamino) carbonyl] amino} piperidin-1-yl) -2-oxoethyl] amino} -α-methyl-N-phenylpiperidine-1-carboxamide
Λ/-benzyl-4-{[(1R)-1-(4-chlorobenzyl)-2-(4-Λ / -benzyl-4 - {[(1R) -1- (4-chlorobenzyl) -2- (4-
{cyclohexyl[(dimethylamino)carbonyl]amino}piperidin-1-yl)-2-oxoethyl]amino}-/V- methylpiperidine-1 -carboxamide{cyclohexyl [(dimethylamino) carbonyl] amino} piperidin-1-yl) -2-oxoethyl] amino} -N-methylpiperidine-1-carboxamide
Λ/-(1-{4-chloro-Λ/-[1-(trifluoroacetyl)piperidin-4-yl]-D-phenylalanyl}piperidin-4-yl)-Λ/- cyclohexyl-Λ/'.Λ/'-dimethylureaΛ- (1- {4-chloro-Λ- [1- (trifluoroacetyl) piperidin-4-yl] -D-phenylalanyl} piperidin-4-yl) -ocyclohexyl} '/' -dimethylurea
Λ/-{1-[Λ/-(1-acetylpiperidin-4-yl)-4-chloro-Drphenylalanyl]piperidin-4-yl}-Λ/- cyclohexyl-Λ/'.Λ/'-dimethylureaΛ- {1- [Λ- (1-acetylpiperidin-4-yl) -4-chloro-phenylalanyl] piperidin-4-yl} -α-cyclohexyl-β-dimethylurea
Λ/-{1-[Λ/-(1-acetylpiperidin-4-yl)-4-chloro-D-phenylalanyl]-3-methylpiperidin-4-yl}- Λ/-cyclohexyl-/V,/\/1-dimethylurea Λ/-(1-{4-chloro-Λ/-[1-(trifluoroacetyl)piperidin-4-yl]-D-phenylalanyl}-3- methylpiperidin-4-yl)-Λ/-cyclohexyl-Λ/',Λ/'-dimetriylureaΛ / - {1- [Λ- (1-acetylpiperidin-4-yl) -4-chloro-D-phenylalanyl] -3-methylpiperidin-4-yl} - Λ -cyclohexyl- / V, \ / 1 -dimethylurea Λ- (1- {4-chloro-Λ- [1- (trifluoroacetyl) piperidin-4-yl] -D-phenylalanyl} -3-methylpiperidin-4-yl} -Λ-cyclohexyl-Λ / 'Λ /' - dimetriylurea
Λ/-{1-[Λ/-(1-benzoylpiperidin-4-yl)-4-chloro-D-phenylalanyl]-3-methylpiperidin-4-yl}- A/-cyclohexyl-Λ/'lΛ/'-dimethylureaΛ / - {1- [Λ- (1-benzoylpiperidin-4-yl) -4-chloro-D-phenylalanyl] -3-methylpiperidin-4-yl} -N-cyclohexyl-β / 1 ' -dimethylurea
Λ/-(1-{4-chloro-/V-[1-(methylsulfonyl)piperidin-4-yl]-D-phenylalanyl}-3- methylpiperidin-4-yl)-Λ/-cyclohexyl-/V,Λ/'-dimethylureaΛ- (1- {4-chloro-N - [1- (methylsulfonyl) piperidin-4-yl] -D-phenylalanyl} -3-methylpiperidin-4-yl) -cyclohexyl- / V, Λ / '- dimethylurea
Λ/-(1-{4-chloro-Λ/-[1-(methylsulfonyl)piperidin-4-yl]-D-phenylalanyl}piperidin-4-yl)- Λ/-cyclohexyl-Λ/',Λ/'-dimetriylurea ^-{1-[4-chloro-Λ/-(1-isonicotinoy]piperidin-4-yl)-D-phenylalanyl]-3-methylpiperidin-Λ- (1- {4-chloro-Λ- [1- (methylsulfonyl) piperidin-4-yl] -D-phenylalanyl} piperidin-4-yl) -NH-cyclohexyl-Λ, [Λ] -dimetriylurea - {1- [4-chloro-Λ / - (1-isonicotinoy] piperidin-4-yl) -D-phenylalanyl] -3-methylpiperidin
4~yl}-Λ/-cyclohexyl-ΛΛΛ/I-dimethylurea4 ~ yl} -Λ / -cyclohexyl-ΛΛΛ / I- dimethylurea
A/-{1-[4-ch!oro-Λ/-(2-phθnylpiperidin-4-yl)-D-phenylalanyl]-3-methylpiperidin-4-yl}- /V-cyclohexyl-Λ/'.Λ/'-dinnethylurea.A / - {1- [4-chloro-Λ] - (2-phenylpiperidin-4-yl) -D-phenylalanyl] -3-methylpiperidin-4-yl} - β-cyclohexyl-Λ- / '- dinnethylurea.
29. Médicament, caractérisé en ce qu'il comprend un composé de formule (I) selon l'une quelconque des revendications 1 à 28, ou un sel d'addition de ce composé à un acide pharmaceutiquement acceptable, ou encore un hydrate ou un solvat . du composé de formule (I).29. Medicament, characterized in that it comprises a compound of formula (I) according to any one of claims 1 to 28, or a salt of addition of this compound to a pharmaceutically acceptable acid, or a hydrate or a solvat. of the compound of formula (I).
30. Composition pharmaceutique, caractérisée en ce qu'elle comprend un composé de formule (I) selon l'une quelconque des revendications 1 à 28, ou un sel pharmaceutiquement acceptable, un hydrate ou un solvat de ce composé, ainsi qu'au moins un excipient pharmaceutiquement acceptable.30. Pharmaceutical composition, characterized in that it comprises a compound of formula (I) according to any one of claims 1 to 28, or a pharmaceutically acceptable salt, a hydrate or a solvate of this compound, and at least one a pharmaceutically acceptable excipient.
31. Utilisation d'un composé de formule (I) selon l'une quelconque des revendications 1 à 28 pour la préparation d'un médicament destiné au traitement et à la prévention de l'obésité, du diabète et des dysfonctions sexuelles pouvant affecter les deux sexes, au traitement des maladies cardiovasculaires ainsi que dans des applications anti-inflammatoires ou dans le traitement de la dépendance alcoolique.31. Use of a compound of formula (I) according to any one of claims 1 to 28 for the preparation of a medicament for the treatment and prevention of obesity, diabetes and sexual dysfunction which may affect both sexes, the treatment of cardiovascular diseases as well as in anti-inflammatory applications or in the treatment of alcohol dependence.
32. Utilisation selon la revendication 31 , caractérisée en ce que lesdites dysfonctions sexuelles consistent en des dysfonctionnements érectiles.32. Use according to claim 31, characterized in that said sexual dysfunctions consist of erectile dysfunctions.
33. Procédé de préparation d'un composé de formule (I) selon l'une quelconque des revendications 1 à 23, caractérisé en ce que l'on réalise une amination réductrice d'un composé de formule (V) :33. Process for preparing a compound of formula (I) according to any one of claims 1 to 23, characterized in that a reductive amination of a compound of formula (V) is carried out:
en présence d'un dérivé du groupe R4 de type cétone, R1, R2, R3, R4, R5, Ra et Ra> étant tels que définis dans l'une quelconque des revendications 1 à 23. in the presence of a ketone-type R 4 derivative, R 1 , R 2 , R 3 , R 4 , R 5 , R a and R a > being as defined in any one of claims 1 to 23.
34. Composés de formules (Vl), (XVIII) et (XIX), dans lesquelles R1, R2, R3, R4, R5, Ra et Ra> sont tels que définis dans l'une quelconque des revendications 1 à 23 et Pg représente un groupe protecteur :34. Compounds of formulas (VI), (XVIII) and (XIX), wherein R 1 , R 2 , R 3 , R 4 , R 5 , R a and R a > are as defined in any one of claims 1 to 23 and Pg represents a protecting group:
EP05790800A 2004-07-29 2005-07-20 Aminopiperidine derivatives, preparation thereof and use thereof as melanocortin receptor agonists Withdrawn EP1786809A2 (en)

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