WO2010006962A1 - Derivatives of triazines and uracils, their preparation and their application in human therapeutics - Google Patents

Derivatives of triazines and uracils, their preparation and their application in human therapeutics Download PDF

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WO2010006962A1
WO2010006962A1 PCT/EP2009/058609 EP2009058609W WO2010006962A1 WO 2010006962 A1 WO2010006962 A1 WO 2010006962A1 EP 2009058609 W EP2009058609 W EP 2009058609W WO 2010006962 A1 WO2010006962 A1 WO 2010006962A1
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triazine
dione
trifluoromethyl
groups
methyl
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French (fr)
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Isabelle Leroy
Elisabeth Dupont-Passelaigue
Karine Valeille
Yves Rival
Didier Junquero
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Pierre Fabre Medicament SA
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Pierre Fabre Medicament SA
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Priority to JP2011517863A priority Critical patent/JP5599788B2/ja
Priority to US13/054,293 priority patent/US8618287B2/en
Priority to EP09797466.1A priority patent/EP2328886B1/en
Publication of WO2010006962A1 publication Critical patent/WO2010006962A1/en
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    • 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
    • C07D403/04—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 directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/08—Antiseborrheics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/10—Anti-acne 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
    • 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
    • A61P3/06—Antihyperlipidemics
    • 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
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • 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
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • 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
    • C07D401/04—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 directly linked by a ring-member-to-ring-member bond
    • 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
    • C07D403/14—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 three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • the object of the present invention is derivatives of triazines and uracils inhibiting the activity of the SCD-I enzyme and their application in human therapeutics.
  • the metabolic syndrome is the result of increased peripheral resistance to insulin, and is characterized by obesity, intolerance to glucose, certain dyslipidemias which may be associated with arterial hypertension and vascular inflammation.
  • the conjunction of these multiple risk factors promotes development of atheromatous pathology at the origin of thrombotic episodes and to the development of peripheral, coronary, cerebrovascular and arterial diseases (Grundy, S. M. Drug therapy of the metabolic syndrome: minimizing the emerging crisis in polypharmacy. Nat Rev Drug Discov 5, 295- 309 (2006) ) .
  • Stearoyl-CoA Desaturase-1 also called ⁇ 9- desaturase, is an enzyme which limits the synthesis of mono-unsaturated fatty acids under the control of the transcription factor SREBPic (Miyazaki, M., Kim, Y. C, Ntambi, J. M.
  • SCD-I Stearoyl-CoA Desaturase-1
  • the plasma ratio 18:1/18:0 also called the "desaturation index" appears as the biomarker of SCD-I activity in humans and correlates with the plasma triglyceride level and in an inversely proportional way with the level of HDL (Attie, A. D., Krauss, R. M., Gray-Keller, M. P. et al. Relationship between stearoyl-CoA desaturase activity and plasma triglycerides in human and mouse hypertriglyceridemia. J Lipid Res 43, 1899-1907 (2002)) . Accordingly, inhibition of SCD-I appears as a therapeutic target of choice in the treatment of obesity, of type 2 diabetes and of lipid disorders related to the metabolic syndrome .
  • the compounds of the invention are characterized by their property of inhibiting the activity of the SCD-I enzyme and by their pharmacological profile.
  • the compounds of the invention correspond to the general formula I .
  • the invention relates to the derivatives of 2H- [1,2,4] triazine-3, 5-dione and of H-pyrimidine-2, 4-dione for their use as inhibitors of the activity of the SCD-I enzyme and corresponding to the general formula I :
  • - Ri and R2 represent independently of each other: • a hydrogen or
  • -phenyl or aroyl or benzyloxy or N-arylcarbamoyl for which the phenyl ring is optionally substituted with one or more groups such as a linear or branched Ci-C 4 alkyl, nitro group, a halogen atom) , • a phenyl or pyridyl or naphthyl, or thiophenyl group optionally substituted with one or more groups such as a halogen, a nitro, nitrile, trifluoromethyl, vinyl, methylsulfanyl, linear branched C 1 -C 4 , alkyl, linear or branched C1-C3 alkoxy, phenyl, Ci-C3N-mono- or di- alkylcarbamoyl ou dialkylcarbamoyle, Ci-C 4 alkylcarboxamido group,
  • Z represents a phenyl or cinnamyl or aryloxycarbonyl or 2-phenylacetyl group (the position 2 of which is optionally substituted with a linear or branched C 1 -C 4 alkyl) for which the aromatic group is optionally substituted with one or more trifluoromethyl groups, halogens, linear or branched Ci-C 4 alkyl, linear or branched
  • the present invention also relates to novel derivatives of 2H- [ 1, 2, 4 ] triazine-3, 5-dione and of H- pyrimidine-2 , 4-dione, to their preparation and to their application in human therapeutics.
  • phenyl or aroyl or benzyloxy or N- arylcarbamoylr for which the phenyl ring is possibly substituted with one or more groups such as linear or branched C1-C4 alkyl, nitro groups, halogen atoms) ,
  • a phenyl or pyridyl or naphthyl or thiophenyl group possibly substituted with one or more groups such as halogen atoms, nitro, nitrile, trifluoromethyl, vinyl, methylsulfanyl, linear or branched Ci-C 4 alkyl, linear or branched C1-C3 alkoxy, phenyl, C1-C3 N-mono- or dialkylcarbamoyl, C1-C4 alkylcarboxamido groups,
  • X represents N
  • Z represents a phenyl or cinnamyl or aryloxycarbonyl or 2-phenylacetyl group (the position 2 of which is optionally substituted with a linear or branched C 1 -C 4 alkyl) for which the aromatic group is substituted with one or more trifluoromethyl groups, halogen atoms, linear or branched Ci-C 4 alkyl, linear or branched Ci or C3 alkoxy, nitro groups, and this except for the following compounds:
  • the present invention more particularly relates to derivatives of 2H- [ 1, 2, 4 ] triazine-3, 5-dione and of H- pyrimidine-2, 4-dione corresponding to the general formula I
  • a phenyl or pyridyl or naphthyl or thiophenyl group optionally substituted with one or more groups such as halogen atoms, nitro, nitrile, trifluoromethyl, vinyl, methylsulfanyl, linear or branched Ci-C 4 alkyl, linear or branched C 1 -C3 alkoxy, phenyl, C 1 -C3 N-mono- or di- alkylcarbamoyl, Ci-C 4 alkylcarboxamido groups, • a C5-C6 2-oxocycloalkyl radical optionally fused with a phenyl group,
  • n are equal to 1
  • - Z represents a phenyl group substituted with one or more trifluoromethyl groups, halogen atoms, linear or branched Ci-C 4 alkyl, linear or branched C 1 -C3 alkoxy groups.
  • the present invention still more particularly relates to the derivatives of 2H- [ 1, 2, 4 ] triazine-3, 5-dione and of H-pyrimidine-2 , 4-dione corresponding to the general formula I
  • - Ri and R 2 represent: • a hydrogen (in a non-simultaneous way) or a linear or branched Ci-C 7 alkyl radical or,
  • a phenyl or pyridyl or naphthyl or thiophenyl group optionally substituted with one or more groups such as halogen atoms, nitro, nitrile, trifluoromethyl, vinyl, methylsulfanyl, linear or branched C 1 -C 4 alkyl, linear or branched C 1 -C3 alkoxy, C 1 -C3 N-mono- or di-alkylcarbamoyl, Ci-C 4 alkylcarboxamido groups,
  • - Z represents a phenyl group substituted with one or more trifluoromethyl groups, halogen atoms, linear or branched Ci-C 4 alkyl groups,
  • the present invention particularly relates to the derivatives of 2H- [ 1, 2, 4 ] triazine-3, 5-dione corresponding to the general formula I wherein:
  • - Ri represents: • a hydrogen or a linear or branched Ci-C 5 alkyl radical or,
  • a phenyl or pyridyl or naphthyl or thiophenyl group optionally substituted with one or more groups such as halogen atoms, nitro, nitrile, trifluoromethyl, vinyl, methylsulfanyl, linear or branched C 1 -C 4 alkyl, linear or branched C1-C3 alkoxy, phenyl, C1-C3 N-mono- or di- alkylcarbamoyl, Ci-C 4 alkylcarboxamido groups,
  • R 2 represents: a linear or branched Ci-C 7 alkyl radical, and preferably a methyl,
  • n are equal to 1,
  • - Z represents a phenyl group substituted with one or more trifluoromethyl groups, halogen atoms, or linear Ci-C 4 alkyl groups.
  • the present invention still more particularly relates to the derivatives of 2H- [ 1, 2, 4 ] triazine-3, 5-dione corresponding to the general formula I wherein: - W represents nitrogen,
  • Ci-C 5 alkyl radical • a hydrogen or a linear or branched Ci-C 5 alkyl radical or,
  • a phenyl or pyridyl or thiophenyl group possibly substituted with one or more groups such as halogen atoms, nitrile, linear or branched Ci-C 4 alky, linear or branched C1-C3 alkoxy groups, • a Ce 2-oxocycloalkyl radical,
  • - R 2 represents a methyl or heptyl, - m, n are equal to 1,
  • - Z represents a phenyl group substituted with one or more trifluoromethyl groups, halogen atoms or linear Ci-C 4 alkyl groups.
  • the compounds of the present invention may be synthesized by using the synthesis routes described below or by using synthesis methods known to one skilled in the art .
  • This reaction may be conducted in the presence of a base such as triethylamine in n-butanol or toluene or dimethylformamide;
  • Hal represents a halogen such as Cl, Br or I
  • This reaction may be carried out in the presence of triethylamine in dichloromethane or in toluene (when Y is - CH 2 - ) .
  • X, Y, V, Z, m, n and R2 are as described earlier in formula I, by a halogenated derivative of general formula RiHaI, wherein Hal represents a halogen such as Cl, Br or I and Ri is as described earlier in general formula I, under operating conditions such as NaH or tBuOK in dimethylformamide .
  • the intermediate and final compounds may if desired by purified according to one or several purification methods selected from extraction, filtration, silica gel chromatography, preparative normal or reverse phase HPLC, crystallization.
  • the synthesis of the intermediates 6b-6d is achieved from BOC-piperazine according to the operating procedure described for the synthesis of 6a by using various acid chlorides RCOCl, but without carrying out the final step for salifying the amine.
  • intermediate 7b is achieved from 1- bromomethyl-4-fluoro-2-trifluoromethyl-benzene according to the operating procedure described for synthesis of 4a (clear oil, yield 70%) .
  • This oil is placed in the presence of few drops of 15-crown-5 crown ether in 1OmL of THF at 0 0 C and 0.15g (3.98mmol) of NaH (60% in paraffin) are added.
  • the reaction medium is stirred for 30min at 0 0 C and then 0.55mL (3.06mmol) of benzyl-piperidin-4-one are added at 0 0 C.
  • the mixture is then stirred at room temperature for 24h, and then poured into water at 0 0 C and extracted with AcOEt.
  • the organic phase is washed with a saturated NaHC ⁇ 3 solution, and then with a saturated NaCl solution. After drying on MgSO 4 , the organic phases are dry concentrated.
  • Rf O . 26 .
  • the synthesis of the intermediate 12b is achieved from piperazin-2-one according to the operating procedure described in the synthesis of 12a, in n-butanol at 120 0 C for 24h (solid, yield 55%) .
  • the synthesis of the intermediates 12d-12f is achieved from the intermediates 4a, 4c and 4g respectively according to the operating procedure described for the synthesis of 12a.
  • the compound 1 is prepared according to the synthesis method 1: 0.33 g (1.12mmol) of derivative 6a and 0.41g
  • the compound 2 (yellow powder) is prepared from the triazine 2e and from the intermediate 6a according to the synthesis method 1 in toluene (yield: 25%) .
  • the compound 3 (oil) is prepared from the triazine 4a and from the intermediate 6a according to the synthesis method 1 in n-butanol (yield: 19%) .
  • the compound 4 (solid) is prepared from the triazine 2a and the intermediate 6a according to the synthesis method 1 in toluene (yield: 27%) .
  • the compound 5 (solid) is prepared from the triazine Ib and the intermediate 6a according to the synthesis method 1 in toluene (yield: 55%) .
  • TLC silica gel 60 F 254 Merck, AcOEt: 100, Rf O.37.
  • the compound 6 (solid) is prepared from 5-bromo-lH- pyrimidine-2, 4-dione and from the intermediate 6a according to the synthesis method 1 in dimethylformamide (yield: 47%) .
  • TLC silica gel 60 F 254 Merck, CH 2 Cl 2 -MeOH: 90-10, Rf O.3.
  • the compound 7 (solid) is prepared from the triazine Ib and from 1- (3-trifluoromethyl-phenyl) -piperazine according to the synthesis method 1 in n-butanol (yield: 63%) .
  • TLC silica gel 60 F 254 Merck, CH 2 Cl 2 -MeOH: 95-5, Rf O.78.
  • MP 163°C MS (+ESI) m/z 370 (MH+)
  • Example 8 4-methyl-2- (4,4, 4-trifluoro-butyl) -6- [4- (3- trifluoromethyl-phenyl) -piperazin-1-yl] -2H- [1, 2, 4] triazine- 3, 5-dione (8)
  • the compound 8 (oil) is prepared from the triazine 4a and from 1- (3-trifluoromethyl-phenyl) -piperazine according to the synthesis method 1 in n-butanol (yield: 76%) .
  • TLC silica gel 60 F 254 Merck, CH 2 Cl 2 -AcOEt: 90-10, Rf O.59.
  • Example 9 4-methyl-2- (4,4, 4-trifluoro-butyl) -6- [4- (2- trifluoromethy1-phenyl) -piperazin-1-yl] -2H- [1, 2, 4] triazine- 3,5-dione (9)
  • the compound 9 (solid) is prepared from the triazine 4a and from 1- (2-trifluoromethyl-phenyl) -piperazine according to the synthesis method 1 in n-butanol (yield: 82%) .
  • the compound 10 (oil) is prepared from the triazine Ib and from 4-benzyl-piperidine according to the synthesis method 1 in n-butanol (yield: 93%) .
  • TLC silica gel 60 F 254 Merck, CH 2 Cl 2 -AcOEt: 95-5, Rf O.28.
  • the compound 11 is prepared from the triazine Ib and from the intermediate 8c according to the synthesis method 1 in n-butanol (yield: 56%) .
  • TLC silica gel 60 F 254 Merck, CH 2 Cl 2 -AcOEt: 95-5, Rf O.27.
  • MS (+ESI) m/z 385 (MH+)
  • the compound 12 (oil) is prepared from the triazine 3c and from the intermediate 8c according to the synthesis method 1 in n-butanol (yield: 46%) .
  • the compound 13 (oil) is prepared from the triazine 4c and from the intermediate 8c according to the synthesis method 1 in n-butanol (yield: 44%) .
  • Example 14 N-methyl-2- ⁇ 4-methyl-3, 5-dioxo-6- [4- (2- trifluoromethyl-phenoxy) -piperidin-1-yl] -4, 5-dihydro-3H- [1,2, 4] triazin-2-yl ⁇ -acetamide (14)
  • the compound 14 (oil) is prepared from the triazine 4d and from the intermediate 8c according to the synthesis method 1 in n-butanol (yield: 52%) .
  • the compound 15 (oil) is prepared from the triazine 4e and from the intermediate 8c according to the synthesis method
  • the compound 16 (oil) is prepared from the triazine 4f and from the intermediate 8c according to the synthesis method 1 in n-butanol (yield: 20%) .
  • Example 17 4-methyl-2- (3-methyl-butyl) -6- [4- (2- trifluoromethyl-phenoxy) -piperidin-1-yl] -2H-
  • the compound 17 (oil) is prepared from the triazine 4g and from the intermediate 8c according to the synthesis method 1 in n-butanol (yield: 42%) .
  • Example 18 4-methyl-2- [2- (3-nitro-phenyl) -2-oxo-ethyl] -6- [4- (2-trifluoromethyl-phenoxy) -piperidin-1-yl] -2H- [1, 2, 4] triazine-3, 5-dione (18)
  • the compound 18 (oil) is prepared from the triazine 4h and of the intermediate 8c according to the synthesis method 1 in n-butanol (yield: 32%) .
  • the compound 19 (oil) is prepared from the triazine 4i and from the intermediate 8c according to the synthesis method 1 in n-butanol (yield: 51%) .
  • the compound 20 (oil) is prepared from the triazine 4j and from the intermediate 8c according to the synthesis method
  • the compound 21 (oil) is prepared from the triazine 5c and from the intermediate 8a according to the synthesis method 1 in n-butanol (yield: 60%) .
  • the compound 22 (oil) is prepared from the triazine 5a and from the intermediate 8a according to the synthesis method
  • Example 23 3- ⁇ 6- [4- (2-chloro-phenoxy) -piperidin-1-yl] -4- methyl-3, 5-dioxo-4, 5-dihydro-3H- [1,2,4] triazin-2-yl ⁇ - propionitrile CANAO
  • the compound 23 (oil) is prepared from the triazine 3a and from the intermediate 8a according to the synthesis method 1 in n-butanol (yield: 58%) .
  • Example 24 3- [ 6- [4- (2-chloro-phenoxy) -piperidin-1-yl] -3, 5- dioxo-4- (4, 4, 4-trif luoro-butyl) -4, 5-dihydro-3H-
  • the compound 24 (oil) is prepared from the triazine 3b and from the intermediate 8a according to the synthesis method 1 in n-butanol (yield: 76%) .
  • Example 25 6- [4- (2-chloro-phenoxy) -piperidin-1-yl] -4- methyl-2- (4,4, 4-trifluoro-butyl) -2H- [1,2, 4] triazine-3, 5- dione (25)
  • the compound 25 (oil) is prepared from the triazine 4a and the intermediate 8a according to the synthesis method 1 in n-butanol (yield: 77%) .
  • the compound 26 (oil) is prepared from the triazine 4c and from the intermediate 8a according to the synthesis method 1 in n-butanol (yield: 44%) .
  • the compound 27 (solid) is prepared from the triazine Ib and from the intermediate 8a according to the synthesis method 1 in n-butanol (yield: 60%) .
  • Example 28 6- [4- (2-fluoro-phenoxy) -piperidin-1-yl] -2, 4- dimethyl-2H- [1,2,4] triazine-3, 5-dione (28)
  • the compound 28 (oil) is prepared from the triazine Ib and from the intermediate 8e according to the synthesis method 1 in n-butanol (yield: 63%) .
  • TLC silica gel 60 F 254 Merck, CH 2 Cl 2 -AcOEt: 95-5, Rf O.29.
  • the compound 29 (solid) is prepared from hte triazine Ib and from the intermediate 8f according to the synthesis method 1 in n-butanol (yield: 58%) .
  • the compound 30 (solid) is prepared from the triazine Ib and from the intermediate 8b according to the synthesis method 1 in n-butanol (yield: 77%) .
  • TLC silica gel 60 F 254 Merck, CH 2 Cl 2 -AcOEt: 95-5, Rf O.55.
  • MP 168°C
  • the compound 31 (solid) is prepared from the triazine Ib and from the intermediate 8g according to the synthesis method 1 in n-butanol (yield: 56%) .
  • Example 32 2, 4-dimethyl-6- [4- (4-trifluoromethyl-phenoxy) - piperidin-1-yl] 2H- [1,2, 4] triazine-3, 5-dione (32)
  • the compound 32 (oil) is prepared from the triazine Ib and from the intermediate 8h according to the synthesis method 1 in n-butanol (yield: 51%) .
  • TLC silica gel 60 F 254 Merck, CH 2 Cl 2 -AcOEt: 95-5, Rf O.49.
  • Example 33 6- [4- (4-fluoro-phenoxy) -piperidin-1-yl] -2, 4- dimethyl-2H- [1,2,4] triazine-3, 5-dione (33)
  • the compound 33 (solid) is prepared from the triazine Ib and from the intermediate 8d according to the synthesis method 1 in n-butanol (yield: 35%) .
  • the compound 34 (solid) is prepared from the triazine Ib and from the intermediate 8i according to the synthesis method 1 in n-butanol (yield: 77%) .
  • the compound 35 (oil) is prepared from the uracil Ic and from the intermediate 8a according to the synthesis method
  • Rf O . 25 .
  • the compound 36 (solid) is prepared from the triazine Ib and from the intermediate 10 according to the synthesis method 1 in n-butanol (yield: 50%) .
  • the compound 37 (solid) is prepared from the triazine Ib and from the intermediate 11a according to the synthesis method 1 in n-butanol (yield: 60%) .
  • the compound 38 (solid) is prepared from the triazine Ib and from the intermediate lib according to the synthesis method 1 in n-butanol (yield: 72%) .
  • the compound 39 (oil) is prepared from the triazine Ib and from the intermediate 9 according to the synthesis method 1 in n-butanol (yield: 78%) .
  • Example 40 6- [4- (2, 5-Bis-trifluoromethyl-benzoyl) - piperazin-1-yl ] -2 , 4 -dimethyl-2H- [1,2,4] triazine-3, 5-dione
  • the compound 40 is prepared according to the synthesis method 2: 0.16 g (0.72 mmol) of derivative 12a is placed in ImL of dichloromethane in the presence of 0.15mL (1.08 mmol) of NEt 3 at 0 0 C. 0.2g (0.72 mmol) of 2,5-bis- trifluoromethyl-benzoyl chloride is added. This mixture is stirred for 15min at 0 0 C, and then for Ih at room temperature. The medium is taken up with water and extracted with CH 2 Cl 2 . After drying on MgSO 4 , the organic phase is concentrated. The obtained residue is purified by flash chromatography on silica (CH 2 Cl 2 -AcOEt: 90-10) . 0.24g of white crystals are isolated (yield: 71%) .
  • the compound 41 (solid) is prepared from 4-fluoro-2- trifluoromethyl-benzoyl chloride and from the intermediate 12a according to the synthesis method 2 under the operating conditions described for Example 40 (yield: 61%) .
  • Example 42 6- [4- (5-fluoro-2-trifluoromethyl-benzoyl) - piperazin-1-yl] -2, 4 -dimethyl-2H- [1, 2, 4] triazine-3, 5-dione (42)
  • the compound 42 (solid) is prepared from 5-fluoro-2- trifluoromethyl-benzoyl chloride and from the intermediate 12a according to the synthesis method 2 under the operating conditions described for Example 40 (yield: 86%) .
  • the compound 43 (solid) is prepared from 2-methyl-benzoyl chloride and from the intermediate 12a according to the synthesis method 2 under the operating conditions described for Example 40 (yield: 70%) .
  • the compound 44 (solid) is prepared from 3-trifluoromethyl- benzoyl chloride and from the intermediate 12a according to the synthesis method 2 under the operating conditions described for Example 40 (yield: 75%) .
  • the compound 45 (solid) is prepared from 2-bromo-benzoyl chloride and from the intermediate 12a according to the synthesis method 2 under the operating conditions described for Example 40 (yield: 87%) .
  • TLC silica gel 60 F 254 Merck, CH 2 Cl 2 -AcOEt: 70-30, Rf O.30.
  • MP 119°C
  • the compound 46 (solid) is prepared from benzoyl chloride and from the intermediate 12a according to the synthesis method 2 under the operating conditions described for
  • Example 40 (quantitative yield) .
  • TLC silica gel 60 F 254 Merck, CH 2 Cl 2 -AcOEt: 70-30, Rf O.26.
  • the compound 47 (solid) is prepared from 5-fluoro-2- trifluoromethyl-benzoyl chloride and from the intermediate 12d according to the synthesis method 2 under the operating conditions described for Example 40 (yield: 91%) .
  • Example 48 6- [4- (5-f luoro-2-trif luoromethyl-benzoyl) - piperazin-1-yl] -4 -methyl -2- (3-methyl-butyl) -2H- [1, 2, 4] triazine-3, 5-dione (48)
  • the compound 48 (oil) is prepared from 5-fluoro-2- trifluoromethyl-benzoyl chloride and from the intermediate 12f according to the synthesis method 2 under the operating conditions described for Example 40 (yield: 58%) .
  • TLC silica gel 60 F 254 Merck, CH 2 Cl 2 -MeOH: 90-10, Rf O.28.
  • the compound 49 (solid) is prepared from 2- (4-chloro- phenyl) -3-methyl-butyryl chloride and from the intermediate 12a according to the synthesis method 2 under the operating conditions described for Example 40 (yield: 90%) .
  • TLC silica gel 60 F 254 Merck, petroleum ether-AcOEt: 60-40, Rf O.36.
  • MP 58 0 C
  • the compound 50 (solid) is prepared from (E) -3- (4-nitro- phenyl) -acryloyl chloride and from the intermediate 12a according to the synthesis method 2 under the operating conditions described for Example 40 (yield: 8%) .
  • Example 51 4- (2, 4-dimethyl-3, 5-dioxo-2, 3, 4, 5-tetrahydro- [ 1 , 2 , 4 ] triazin-6-yl) -piperazine-1-carboxylic acid 3- trifluoromethyl-phenyl ester (51)
  • the compound 51 (solid) is prepared from 3-trifluoromethyl- phenylchloroformate and from the intermediate 12a according to the synthesis method 2 under the operating conditions described for Example 40 (yield: 27%) .
  • the compound 52 ( glassy solid) is prepared from the acrylic acid of (E) -3- (2-bromo-phenyl) converted into an acid chloride (SOCl 2 , toluene, 100 0 C, 3h) , and from the intermediate 12a according to the synthesis method 2 under the operating conditions described for Example 40 (yield: 90%) .
  • the compound 53 (solid) is prepared from 2-trifluoromethyl- benzoyl chloride and from the intermediate 12b according to the synthesis method 2 under the operating conditions described for Example 40 (yield: 77%) .
  • Example 54 6- [4- (4-fluoro-2-trifluoromethyl-benzyl) piperazin-1-yl] -2, 4 -dimethyl-2H- [ 1, 2, 4] triazine-3, 5-dione (54)
  • the compound 54 is prepared according to the synthesis method 2: 0.26g (1.17 mmol) of derivative 12a is placed in 3mL of toluene in the presence of 0.24mL (1.75mmol) of NEt3 and of 0.3g (1.17mmol) of l-bromomethyl-4-fluoro-2- trifluoromethyl-benzene . This mixture is stirred 2h at 110 0 C. The medium is taken up with water and extracted with AcOEt. After drying on MgSO 4 , the organic phase is dry concentrated. The obtained residue is purified by flash chromatography on silica (CH 2 Cl 2 -AcOEt : 95-5) . 0.37g of a yellow oil are isolated (yield: 79%) .
  • the compound 55 (solid) is prepared from l-bromomethyl-2- trifluoromethyl-benzene and from the intermediate 12a according to the synthesis method 2 under the operating conditions described for Example 54 (yield: 92%) .
  • the compound 56 (oil) is prepared from l-bromomethyl-2- trifluoromethyl-benzene and from the intermediate 12e according to the synthesis method 2 under the operating conditions described for Example 54 (yield: 84%) .
  • Example 57 4-methyl-2- (4,4, 4-trifluoro-butyl) -6- [4- (2- trifluoromethyl-benzyl) -piperazin-1-yl ]-2H-[l,2,4] triazine-
  • the compound 57 (solid) is prepared from l-bromomethyl-2- trifluoromethyl-benzene and from the intermediate 12d according to the synthesis method 2 under the operating conditions described for Example 54 (yield: 66%) .
  • TLC silica gel 60 F 254 Merck, CH 2 Cl 2 -MeOH: 90-10, Rf O.65.
  • the compound 58 (oil) is prepared from l-bromomethyl-2- trifluoromethyl-benzene and from the intermediate 12c according to the synthesis method 2 under the operating conditions described for Example 54 (yield: 76%) .
  • the compound 60 (solid) is prepared from 4-fluoro-2- trifluoromethyl-benzoyl chloride and from the intermediate 13b according to the synthesis method 2 under the operating conditions described for Example 40 (yield: 65%) .
  • the compound 61 (solid) is prepared from 5-fluoro-2- trifluoromethyl-benzoyl chloride and from the intermediate
  • the compound 62 (solid) is prepared from 2-trifluoromethyl- benzoyl chloride and from the intermediate 13b according to the synthesis method 2 under the operating conditions described for Example 40 (yield: 59%) .
  • the compound 63 (oil) is prepared from l-bromomethyl-4- fluoro-2-trifluoromethyl-benzene and from the intermediate 13b according to the synthesis method 2 under the operating conditions described for Example 54 (yield: 67%) .
  • TLC silica gel 60 F 254 Merck, CH 2 Cl 2 -MeOH: 90-10, Rf O.60.
  • Example 64 4 -methyl-6- [4- (2-trifluoromethyl-benzyl) - piperazin-1-yl] -2H- [1, 2, 4] triazine-3, 5-dione (64)
  • the compound 64 is prepared from the triazine 4b and from the intermediate 7a according to the synthesis method 1 in n-butanol. After deprotection of the nitrogen in position 2 (NH 2 NH 2 . H 2 O, EtOH, 78°C, 3h) , the compound 64 is obtained as a solid (yield: 64%) .
  • the compound 66 is prepared from the triazine 4b and from
  • the compound 67 is prepared from the triazine 4b and from
  • the compound 68 is prepared from the triazine 4b and from the intermediate 6a according to the synthesis method 1 in n-butanol. After deprotection of the nitrogen in position 2 (NH 2 NH 2 . H 2 O, EtOH, 78°C, 3h) , the compound 68 is obtained as a solid (yield: 86%) .
  • Example 70 6- [4- (4-fluoro-2-trifluoromethyl-benzoyl) - piperazin-1-yl] -4 -methyl-2H- [l,2,4]triazine-3,5-dione (70)
  • the compound 70 is prepared from the triazine 4b and from the intermediate 6d according to the synthesis method 1 in n-butanol. After deprotection of thenitrogen in position 2
  • the compound 71 is prepared from the triazine 4b and from the intermediate 7b according to the synthesis method 1 in n-butanol. After deprotection of the nitrogen in position 2 (NH 2 NH 2 -H 2 O, EtOH, 78°C, 3h) , the compound 71 is obtained as a solid (yield: 34%) .
  • Example 72 4- (4, 4, 4-trifluoro-butyl) -6- [4- (2- trifluoromethyl-phenoxy) -piperidin-1-yl] -2H- [1,2, 4] triazine-3, 5-dione (72)
  • the compound 72 is prepared from the triazine 3b and from the intermediate 8c according to the synthesis method 1 in n-butanol. After deprotection of the nitrogen in position 2 (Na, EtOH, 80°C, 5h) , the compound 72 is obtained as a solid (yield: 38%) .
  • the compound 73 is prepared according to the synthesis method 3: 0.2Og (0.52 mmol) of the compound described for
  • Example 4 is placed in 2 mL of dimethylformamide at 0 0 C.
  • the compound 74 (oil) is prepared from 1-bromo-butane and from the compound described for Example 4 according to the synthesis method 3 (yield: 70%) .
  • Example 75 4-methyl-2- (3-methyl-butyl) -6- [4- (2- trifluoromethyl-benzoyl) -piperazin-1-yl] -2H-
  • the compound 75 (oil) is prepared from l-bromo-3-methyl- butane and from the compound described for Example 4 according to the synthesis method 3 (yield: 79%) .
  • TLC silica gel 60 F 254 Merck, petroleum ether-AcOEt: 50- 50, Rf O.35.
  • the compound 76 is prepared from the triazine 3c and from the intermediate 8a according to the synthesis method 1 in n-butanol. After deprotection of the nitrogen in position 2 (NaH, DMF, 20°C, 3h) , the compound 76 is obtained as a solid (yield: 67%) .
  • the compound 77 (oil) is prepared from the triazine Ib and from the intermediate9b according to the synthesis method 1 in n-butanol (yield: 43%) .
  • TLC silica gel 60 F 254 Merck, CH 2 Cl 2 -AcOEt: 95-5, Rf O.48.
  • Example 78 4-methyl-2- (2-thiophen-2-yl-ethyl) -6- [4- (2- trifluoromethyl-phenoxy) -piperidin-1-yl] -2H- [1,2, 4] triazine-3, 5-dione (78)
  • the compound 78 (solid) is prepared from the triazine 4k and from the intermediate 8c according to the synthesis method 1 in n-butanol (yield: 41%) .
  • the compound 79 (solid) is prepared from the triazine 41 and from the intermediate ⁇ c according to the synthesis method 1 in n-butanol (yield: 51%) .
  • the compound 80 (solid) is prepared from the triazine 4m and from the intermediate ⁇ c according to the synthesis method 1 in n-butanol (yield: 48%) .
  • the compound 81 (solid) is prepared from the triazine 4n and from the intermediate ⁇ c according to the synthesis method 1 in n-butanol (yield: 56%) .
  • Example 82 4-methyl-2-thiophen-3-yl-6- [4- (2- trifluoromethyl-phenoxy) -piperidin-1-yl] -2H-
  • the compound 82 (solid) is prepared from the triazine 4o and from the intermediate ⁇ c according to the synthesis method 1 in n-butanol (yield: 57%) .
  • Example 83 4- ⁇ 4-methyl-3, 5-dioxo-6- [4- (2-trifluoromethyl- phenoxy) -piperidin-1-yl] -4, 5-dihydro-3H- [1, 2, 4] triazin-2- yl ⁇ -benzonitrile (83)
  • the compound 83 (solid) is prepared from the triazine 4p and from the intermediate ⁇ c according to the synthesis method 1 in n-butanol (yield: 60%) .
  • Example 84 2- (2-methoxy-phenyl) -4-methyl-6- [4- (2- trifluoromethyl-phenoxy) -piperidin-1-yl] -2H- [1, 2, 4] triazine-3, 5-dione (84)
  • the compound 84 (solid) is prepared from the triazine 4q and from the intermediate ⁇ c according to the synthesis method 1 in n-butanol (yield: 74%) .
  • the compound 85 is prepared from the triazine 3a and from the intermediate 8c according to the synthesis method 1 in n-butanol. After deprotection of the nitrogen in position 2 (NaH, DMF, 20°C, 2Oh), the compound 85 is obtained as a solid (yield: 77%) .
  • Example 86 4-methyl-2- (2-oxo-cyclohexyl) -6- [4- (2- trifluoromethyl-phenoxy) -piperidin-1-yl] -2H-
  • the compound 86 (solid) is prepared from 2-chloro- cyclohexanone and from the compound described for Example 85 according to the synthesis method 3 (yield: 31%) .
  • the compound 87 (solid) is prepared from 2-bromo-indan-l- one and from the compound described for Example 85 according to the synthesis method 3 (yield: 38%) .
  • Example 88 2- [2- (2-ethoxy-ethoxy) -ethyl] -4-methyl-6- [4- (2- trifluoromethyl-phenoxy) -piperidin-1-yl] -2H-
  • the compound 88 (solid) is prepared from l-bromo-2- (2- ethoxy-ethoxy) -ethane and from the compound described for Example 85 according to the synthesis method 3 (yield: 77%) .
  • TLC silica gel 60 F 254 Merck, CH 2 Cl 2 -MeOH: 95-5, Rf O .85.
  • MP 44°C
  • the compound 89 (solid) is prepared from 2-bromo-ethyl acetate and from the compound described for Example 85 according to the synthesis method 3 (yield: 68%) .
  • the compound 90 (white powder) is prepared from the triazine 2e and from the intermediate 8b according to the synthesis method 1 in toluene.
  • Example 91 6- (4- (2, 5-dichlorophenoxy) piperidin-1-yl) -2- methyl- 1 , 2 , 4 -triazine-3 , 5 ( 2H, 4H) -dione ( 91 )
  • the compound 91 (white solid) is prepared from the triazine 2e and from 4- (2, 5-dichlorophenoxy) piperidine (obtained as under the preparative methods of intermediate 8a) according to the synthesis method 1 in toluene.
  • the compound 92 (yellow powder) is prepared from the triazine 2e and from 4- (5-bromo-2-chlorophenoxy) piperidine (obtained as under the preparative conditions of intermediate 8a) according to the synthesis method 1 in toluene .
  • the compound 93 (white solid) is prepared from the triazine 2e and from 4- (2-bromo-4, 5-difluorophenoxy) piperidine (obtained as under the preparative conditions of intermediate 8a) according to the synthesis method 1 in toluene .
  • the compound 94 (white solid) is prepared from the triazine 2e and from 4- (3- (trifluoromethyl) phenoxy) piperidine (obtained as under the preparative conditions of intermediate 8a) according to the synthesis method 1 in toluene .
  • the pellet is taken up in 10 mM Tris buffer (pH 7.4) saccharose (250 mM) at 4°C and the microsomal proteins are assayed and stored at -196°C (liquid nitrogen) .
  • the enzymatic reaction measures the conversion of stearic acid (a C18:0 fatty acid) into oleic acid (C18:l fatty acid) by SCD-I.
  • the enzymatic reaction is started by adding 125 ⁇ g of microsomal fraction of HepG2 cells to tubes (total reaction volume of 500 ⁇ l) containing 62 ⁇ M of stearic acid (45 ⁇ M of stearic acid and 17 ⁇ M of [ 14 C] stearic acid) in a phosphate buffer at 100 mM (pH 7.16) with 7.2 mM of ATP, 0.54 mM of CoA, 6 mM of MgCl 2 , 0.8 mM of NADH and the inhibitory compound or the carrier (0.1% DMSO) .
  • the tubes are incubated fro 20 minutes at 37 0 C and the enzymatic reaction is then stopped by adding KOH (12%) and saponification for 30 minutes at 80 0 C.
  • acidification 3N HCl
  • the fatty acids are extracted twice with ethyl ether, evaporated under nitrogen before being taken up with a methanol/dichloromethane (3:1) mixture.
  • the product of the reaction (C18:l) is separated from the substrate of the reaction (C18:0) by HPLC (Perkin Elmer, C18 reverse phase column) coupled to a on-line radioactivity detector (FlowOne) .
  • Enzymatic activity is calculated in picomoles of stearic acid converted into oleic acid per minute and per mg of protein.
  • an inhibition % is determined relatively to the reference enzymatic activity (carrier 0.1% DMSO) Sterculic acid is the reference inhibitory compound (Gomez F. E., Bauman D. E., Ntambi J. M., Fox B. G. Effects of sterculic acid on stearoyl-CoA desaturase in differentiating 3T3-L1 adipocytes. Biochem Biophys Res Commun. 300 316-326 (2003)) .
  • Table 10 Human SCD-I enzymatic activity inhibition % at 10 ⁇ M) .
  • the invention also relates to the compounds of general formula (I) for their use as drugs intended for treating diseases requiring inhibitors of SCD-I enzyme activity.
  • the invention also relates to compounds of general formula (I) for their use as drugs intended for treating diseases such as obesity, diabetic dyslipidemia, hypertriglyceridemia, hypercholesterolemia, the metabolic syndrome, atherosclerosis, hepatic steatosis, cardiovascular risks.
  • diseases such as obesity, diabetic dyslipidemia, hypertriglyceridemia, hypercholesterolemia, the metabolic syndrome, atherosclerosis, hepatic steatosis, cardiovascular risks.
  • the invention also extends to compounds of general formula (I) for their use as drugs intended for treating pathologies related to lipid disorders of the skin.
  • the invention also relates to compounds of general formula (I) for their use as drugs intended for treating diseases such as acne, psoriasis, hirsutism.

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FR2933979B1 (fr) 2012-08-24
FR2933979A1 (fr) 2010-01-22
AR072510A1 (es) 2010-09-01
TW201006815A (en) 2010-02-16
US8618287B2 (en) 2013-12-31
US20110118266A1 (en) 2011-05-19
JP5599788B2 (ja) 2014-10-01
EP2328886B1 (en) 2016-12-28
EP2328886A1 (en) 2011-06-08
JP2011528007A (ja) 2011-11-10

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