EP2283007A2 - Pyrrolderivate, ihre herstellung und ihre therapeutische verwendung - Google Patents

Pyrrolderivate, ihre herstellung und ihre therapeutische verwendung

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Publication number
EP2283007A2
EP2283007A2 EP09750013A EP09750013A EP2283007A2 EP 2283007 A2 EP2283007 A2 EP 2283007A2 EP 09750013 A EP09750013 A EP 09750013A EP 09750013 A EP09750013 A EP 09750013A EP 2283007 A2 EP2283007 A2 EP 2283007A2
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Prior art keywords
group
substituted
unsubstituted
substituent
independently selected
Prior art date
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EP09750013A
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English (en)
French (fr)
Inventor
Francis Barth
Daniel Bichon
Christian Congy
Murielle Rinaldi-Carmona
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Sanofi SA
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Sanofi Aventis France
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Publication of EP2283007A2 publication Critical patent/EP2283007A2/de
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    • 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
    • C07D401/06—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 carbon chain containing only aliphatic carbon atoms

Definitions

  • the present invention relates to 1,5-diphenylpyrrole-3-carboxamide derivatives, to their preparation and to their therapeutic application.
  • 1,5-Diphenylpyrrole-3-carboxamide derivatives active as antiobesity agents, have been described in patent application WO 2003/027 069.
  • 1,5-diphenylpyrrole-3-carboxamide derivatives having an affinity for cannabinoid CB 1 receptors have been described in patent applications WO 2004/058249 and WO 2005/080328.
  • New derivatives of 1,5-diphenylpyrrole-3-carboxamide bearing a particular substituent on the 2-position of pyrrole have now been found which possess CB1 receptor antagonist properties of cannabinoids.
  • these new derivatives have peripheral CB 1 receptor antagonist properties and have low penetration in the brain.
  • - A represents a (C 1 -C 4) alkylene group which is unsubstituted or substituted one or more times with a (C 1 -C 3) alkyl group or a fluorine atom;
  • R 1 represents a hydrogen atom or a (C 1 -C 4) alkyl group which is unsubstituted or substituted by one or more fluorine atoms;
  • R2 represents: o either a homopiperidin-1-yl, piperidin-1-yl, pyrrolidin-1-yl or azetidin-1-yl radical, said radicals being unsubstituted or substituted once or twice with a substituent each independently selected from a fluorine atom, a (C 1 -C 4) alkoxy, (C 1 -C 4) alkyl, trifluoromethyl, -OCF 3 , -CH 2 OH, -CONH 2 group and / or a phenyl group, said phenyl group being unsubstituted or substituted once or twice by a substituent each independently selected from a halogen atom, a -CF3 group, a methoxy group and / or a trifluoromethoxy group; o is amino (Ci-C6) alkyl unsubstituted or substituted by one or more substituents each independently selected from a fluorine atom, a hydroxy
  • benzyl group which is unsubstituted or substituted one or more times with a substituent each independently chosen from a halogen atom, a (C 1 -C 4) alkyl, trifluoromethyl, hydroxyl and (C 1 -C 4) alkoxy group and / or cyano;
  • R3, R4, R5, Rg, R7, Rg are each independently a hydrogen atom, a halogen atom, -CN, -S (O) n R 4, -OS (O) n R 4, u * 1 group (Ci-C6) alkyl unsubstituted or substituted one or more times with a substituent selected independently from a fluorine atom, -OH, -OR14, -S (O) n R 4, -OSO2R14 and or -NHSO2R14, or a group (
  • - RQ represents a group -OR12, -CN, -CO 2 H, NRi 2 R ⁇ , -CONRi 2 R ⁇ , -NRi 5 COR 12 , -CONHNH 2 , -CONHOH, -CONHSO 2 Ri 4 , -S (O ) n Ri 4 ,
  • Rio represents a hydrogen or a (C 1 -C 4 ) alkyl group
  • R 1 represents: (C 1 -C 4 ) alkyl, phenyl, benzyl, (C 1 -C 4 ) alkoxy, or (C 1 -C 3) alkylene-O- (C 1 -C 3) alkyl, said groups being unsubstituted or substituted with one or more substituents each independently selected from a (C 1 -C 4 ) alkoxy group, a hydroxy group and / or a fluorine atom; trifluoromethyl; o and / or a group NRigRi ⁇ ; R-12 R t 3 each independently represent a hydrogen atom or a (Ci-Cg) alkyl each optionally substituted by one or more substituents independently selected from halogen atoms, a (C3- C7) cycloalkyl, cyano, -OH and / or -ORj 4, - or Rj 2 and Rj 3 together with the nitrogen atom to which they are attached constitute a heterocyclic radical
  • R 4 represents a group (C 1 -C 4) alkyl unsubstituted or substituted by one or more fluorine atoms;
  • R 5 represents a hydrogen atom or a (C 1 -C 4) alkyl group
  • R 1 and R 7 each independently represent: a hydrogen atom; and / or a benzyl group which is unsubstituted or substituted one or more times with a substituent each independently chosen from a halogen atom, a methyl, trifluoromethyl, hydroxyl or (C 1 -C 4) alkoxy and / or cyano group; and / or a (C 1 -C 6) alkyl group optionally substituted by one or more substituents each independently chosen from a halogen atom, a (C 3 -C 7) cycloalkyl, cyano -OH, and / or -OR 14 group;
  • the compounds of formula (I) may comprise one or more asymmetric carbon atoms. They can therefore exist in the form of enantiomers or diastereoisomers. These enantiomers, diastereoisomers, as well as their mixtures, including the racemic mixtures are part of the invention.
  • the compounds of formula (I) can exist in the form of bases (ie as such in their free form), addition salts with acids or addition salts with bases. These salts are advantageously prepared with pharmaceutically acceptable salts, but the salts of other acids that are useful, for example, for the purification or the isolation of the compounds of formula (I) are also part of the invention.
  • group (C 1 -C 3) alkyl, (C 1 -C 4) alkyl or (C 1 -C 6) alkyl is meant respectively a linear or branched alkyl radical of one to three carbon atoms, of one to four carbon atoms or of one with six carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, n-hexyl, isohexyl. Methyl is preferred for (C1-C3) alkyl, (C1-C4) alkyl and (C1-C4) alkyl.
  • group (C 1 -C 3) alkylene or (C 1 -C 8) alkylene is meant respectively a bivalent linear carbon radical of one to three carbon atoms or of one to six carbon atoms such that - (CH 2 ) -, - ( CH 2 ) 2-, - (CH 2 ) 3 -, - (CH 2 ) 4-, - (CH 2 ) 5- and - (CH 2 ) 6 .
  • (C 1 -C 4) alkoxy is meant an oxygen atom linked to a linear or branched carbon radical of one to four carbon atoms such as the methoxy, ethoxy, propoxy, isopropoxy, butoxy or sec-butoxy radical, tert.
  • the butoxy group is preferred.
  • halogen atom is meant a fluorine, chlorine, bromine or iodine atom; the fluorine, chlorine or bromine atoms being preferred.
  • cycloalkyl is meant a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl radical.
  • amino-cycloalkyl group is meant for the cycloalkyl part, a carbon radical cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl.
  • heterocyclic radical saturated or unsaturated, of 4 to 7 members, containing or not a second heteroatom such as O, N or S, is meant in particular radicals such as homopiperidin-1-yl morpholin-4-yl, piperidin-1- yl, piperazin-1-yl, pyrrolidin-1-yl, azetidin-1-yl, piperidin-1-yl and pyrrolidin-1-yl being preferred.
  • R1 represents a hydrogen atom or a (C1-C4) alkyl group unsubstituted or substituted by one or more fluorine atoms;
  • R 2 represents: o either a homopiperidin-1-yl, piperidin-1-yl, pyrrolidin-1-yl or azetidin-1-yl radical, said radicals being substituted once or twice with a substituent each independently selected from an atom fluoride, a group
  • o is a (C 1 -C 6) alkyl amino group substituted with one or more substituents each independently chosen from a fluorine atom, a hydroxyl group, -CONH 2 and / or a phenyl group, said phenyl group being unsubstituted or substituted one or twice with a substituent each independently selected from a halogen atom, a -CF3 group, a methoxy group and / or a trifluoromethoxy group;
  • compounds of formula (IB) in which R4 and R2 together with the nitrogen atom to which they are attached are: o either a piperazin-1-yl radical or 1,4 -diazepan-1-yl, said radicals being substituted with phenyl, benzodioxolyl, benzodioxolylmethyl, tetrahydrofuranylcarbonyl, -CORn, -CH2COR11; the phenyl group being itself substituted one or more times with a substituent each independently selected from a halogen atom, a methyl, trifluoromethyl, hydroxyl, (C 1 -C 4) alkoxy and / or cyano; or a homopiperidine radical; 1-yl, piperidin-1-yl, pyrrolidin-1-yl or azetidin-1-yl, said radicals being substituted once or twice with a substituent each independently selected from:
  • phenyl or pyridinyl group said groups being unsubstituted or substituted one or more times with a substituent each independently selected from a halogen atom, a methyl, trifluoromethyl, hydroxyl, (C 1 -C 4) alkoxy and / or cyano;
  • a substituent each independently selected from a halogen atom, a methyl, trifluoromethyl, hydroxyl, (C 1 -C 4) alkoxy and / or cyano group; and / or a piperidin-1-yl, pyrrolidin-1-yl or azetidin-1-yl group, said groups being unsubstituted or substituted one or more times with a substituent each independently selected from a fluorine atom, a group ( C ⁇ - C4) alkyl, (C j-C4) alkoxy, hydroxyl, trifluoromethyl and / or -OCF 3; and / or an aminophenyl, aminobenzyl group, said groups being unsubstituted or substituted one or more times with a substituent each independently selected from a halogen atom, a methyl, trifluoromethyl, hydroxyl, (C 1 -C 4)
  • the compounds in which: R1 and R-2 together with the nitrogen atom to which they are attached constitute a homopiperidin-1-yl, piperidin-1-yl, pyrrolidin-1-yl radical are preferred or azetidin-1-yl, said radical being substituted one or two times with a substituent each independently selected from: o a fluorine atom, a cyano group, -CORn, -CONR ⁇ Rl 3, -NRi 2R13 >
  • the other substituents being as defined for the compounds of formula (I).
  • the compounds in which R 1 and R 2 together with the nitrogen atom to which they are bonded are preferably a piperidin-1-yl radical substituted one or two times with a substituent.
  • the substituent (s) are each independently selected from those indicated above for this second variant (IB).
  • - A represents an unsubstituted (C 1 -C 5 ) alkylene group
  • R 9 represents a group -OR 12 , -NR 12 R 13 , -CONR 12 R 13 , -NR 15 -COR 12, -CONHNH 2 , -CONHOH 5 -S (O) n R 14 , -SO 2 NR 1 Rn, -NR 8 SO 2 RH, Or -NR 15 SO 2 NR 12 R 13 ;
  • a group -OR 12 , -NR 12 R 13 , -CONR 12 R 13 , -NR 15 COR 12 or -NR 18 SO 2 R 14 are preferred.
  • the groups -OR 12 and -NR 12 R 13 , R 12 and R 13, which are different from hydrogen, are more particularly preferred.
  • the present invention also relates to a process for preparing the compounds according to the invention.
  • R3, R4, R5, R6, R7, R8, R6Q and A-R9 are as defined for (I) with an amine of formula HNRi R2 in which R1 and R2 are as defined for (I).
  • the compound thus obtained is converted into one of its salts.
  • the functional derivative of the acid (II) it is possible to use the acid chloride, the anhydride, a mixed anhydride, a C 1 -C 4 alkyl ester in which the alkyl is straight or branched, a benzyl ester, a activated ester, for example the p-nitrophenyl ester, or the opportunely activated free acid, for example with N, N-dicyclohexylcarbodiimide or with benzotriazol-1-yloxotris (dimethylamino) phosphonium hexafluorophosphate (BOP) or benzotriazol-1-yloxotris- (pyrrolidino) phosphonium hexafluorophosphate (PyBOP) or N- [N- (dimethylamino) -1,1,2,3-triazolo [4,5-b] pyridin-1-ylmethylene
  • One variant consists in preparing the mixed anhydride of the acid of formula (II) by reacting ethyl chloroformate with the acid of formula (II), in the presence of a base such as triethylamine, and in doing so react with an amine HNR 2 R 2, in a solvent such as dichloromethane, under an inert atmosphere, at room temperature, in the presence of a base such as triethylamine.
  • the compounds of formula (I) in which R 9 corresponds to NHSC 3 AIk can be synthesized from derivatives (IIa) in which Z corresponds to A-OCH2PI1 by reaction with an amine HNR 2 R 2, then by Debenylation as described in step (d2) of Scheme 2 below, and application of the reaction sequence described in Scheme 4 below.
  • the compounds of formula (I) obtained by the various procedures can be subsequently separated from the reaction medium and purified by conventional methods, for example by crystallization or chromatography.
  • Step (a2) is a regioselective alkylation of methylacetoacetate according to the procedure described in particular in JACS 96 (4) 1974, page 1082 to 1087.
  • Step (b2) is an alkylation of the compound (III) with a bromoacetophenone in the presence of NaH.
  • Step (c2) is a cyclization of diketone (III) with a substituted aniline (Paal-Knorr reaction).
  • This cyclization is conventionally carried out in a solvent such as toluene under reflux in the presence of paratoluene sulphonic acid, or in acetic acid.
  • This cyclization can also be performed with better yields in the presence of catalysts such as Montmorillonite KlO and in a microwave oven, as described in Adv. Synth. Catal. 2006, 348, 2191-2196.
  • Step (d2) is a deprotection of benzyl ether which can be carried out for example using BBr 3 or BCl 3 in dichloromethane.
  • the alcohol (VI) obtained is then saponified, preferably with LiOH, at 70 ° C. in a methanol / water mixture.
  • the acid (II) thus obtained is treated with the amine HN-R 1 R 2 to form the product (I) of the invention.
  • the alcohol (VI) is converted to a compound with a mesylate group (VIII) which is then treated with the sulfonamide H 2 NSO 2 AIk to obtain the alkylsulfonamide derivative (IX).
  • One variant consists in operating according to the scheme 5 below by transforming the compound with the mesylate group (VIII) into an amine and then treating it with a compound of the AlkSO 2 Cl type in order to obtain the ester (IX).
  • the conversion of the alcohol (VI) to amine (XIV) can be carried out by various methods known to those skilled in the art, such as for example the Mitsunobu method.
  • the synthesis can be carried out according to scheme 6 below by oxidizing the compound (VI) to acid using an oxidant such as CrO 3 , protecting the acid obtained by a t-butyl ester group.
  • the methyl ester of the compound (XI) is saponified to obtain the acid (XII), which is then coupled to the amine HNR 1 R 2 to obtain the ester (XIII) which is finally deprotected to give the compound according to invention (I).
  • a compound of formula (I) can be directly oxidized with R 9 equal to OH by chromium VI in order to obtain the desired acid.
  • This acid can then be treated so as to obtain the groups R 9 , the definition of which is given in the general formula.
  • Amines of formula HNR 1 R 2 are known or prepared by known methods, for example that described in J. Med. Chem .; 7; 1964; 619.622.
  • the subject of the present invention is also the compounds of formula (II) and their functional derivatives (Ilbis) used for the preparation of compounds of formula (I).
  • these compounds of formula (II) and (IIbis) there are especially those of formula
  • X represents a halogen atom, a hydroxyl group, (C 1 -C 4) alkoxy or benzyloxy
  • A, R 3, R 4, R 5, R 6, R 7, R 6 and R 5 are as defined for the compounds of formula (I) .
  • X represents a halogen atom, a hydroxyl group, (C 1 -C 4) alkoxy or benzyloxy;
  • - A represents a group - (CH 2 ) 2 -, - (CH 2 ) 3 -, - (CH 2) 4 -, - (CH 2 ) 5-;
  • R9 represents a group -ORi 2 , -NR12R13, -CONRi 2 R1, -NR1 CORJ 2 OR
  • R 2 and R 3 which are different from hydrogen, are more particularly preferred. More particularly, R 9 is -OH, -NHSO 2 CH 3, -NHSO 2 CF 3, -O- (CH 2 ) 2 -OH.
  • DIPEA diisopropylethylamine
  • Nuclear magnetic resonance spectra are recorded at 250 MHz or 400 MHz in DMSO-dg.
  • s singlet
  • t triplet
  • m massive
  • me expanded multiplet
  • mt multiplet
  • se expanded singlet
  • d doublet
  • dd doublet of doublet
  • dt doublet of triplet
  • te expanded triplet
  • 2s 2 singlet
  • q quadruplet
  • quin quintuplet.
  • the compounds according to the invention are analyzed by LC / UV / MS coupling (liquid chromatography / UV detection / mass spectrometry).
  • the molecular characteristic peak (MH + , MNa + , etc.) and the retention time (tr) are measured in minutes (min).
  • a Symmetry Cl 8 column of 2.1 x 50 mm, 3.5 ⁇ m is used.
  • the eluent is composed as follows:
  • solvent A 0.005% trifluoroacetic acid (TFA) in water at pH 3.1;
  • UV detection is performed by an iodine array detector between 210 and 400 nm and ESI positive mass detection.
  • the eluent is composed as follows:
  • the eluent is composed as follows:
  • This step is performed according to information published in: Tetrahedron Letters 46 (2005) 22159-2161.
  • step 2C In a flask, 8 g of the product of step 2C) are dissolved in 150 ml of CH 2 Cl 2. It is cooled to 0 ° C., and 13 g of BCl 3- dimethylsulfide complex dissolved in 50 ml of CH 2 Cl 2 are added dropwise. After 1 hour of reaction, the mixture is neutralized with solid NaHCO 3 until the evolution of gas ceases. The organic phase is dried and, after chromatography, 4.5 g of oil are obtained, whose NMR spectrum confirms the structure.
  • Example 2 1- [1- (4-Chloro-phenyl) -5- (2,4-dichloro-phenyl) -2-hydroxymethyl-1H-pyrrole-3-carbonyl] - [1,4 '] bipiperidinyl-4 '-carboxamide.
  • 0.3 g of the product obtained in step 2E) of Preparation 2 are dissolved in 20 ml of CH 2 Cl 2 with 27 ml of DIPEA. 0.16 g of [1,4 '] bipiperidinyl-4'-carboxamide and 0.22 g of TBTU are then added.
  • Table 1 shows the chemical structures of some compounds according to the invention and their physical properties (analysis by LC / UV / MS coupling: liquid chromatography / UV detection / mass spectrometry).
  • Me means methyl.
  • the compounds listed are prepared according to the methods of preparations described above and in particular by following procedures similar to those described in Examples 1 to 3. TABLEAUl
  • NMRI compound 45 1 H: DMSO-d6 (250 MHz): ⁇ (ppm) 0.94 - l, 15: m: 2H; 17 -
  • the compounds of formula (I) have a very good affinity in vitro (IC50 ⁇ 5 ⁇ 10 -7 M) for cannabinoid CB 1 receptors under the conditions experimental studies described by M. Rinaldi-Carmona et al. (FEBS Letters, 1994, 350, 240- 244).
  • - Measurement (1) the quantification of the compounds of formula (I) (unchanged) in brain samples from mice after intravenous or oral administration, using analytical technique (LC-MS / MS). amount present in the brain
  • Measurement (2) the measurement of the interaction of the compounds of formula (I) with the CB 1 receptors present in the brain in mice using an ex vivo binding test of [3 H] -CP55940 (agonist CBj) after intravenous administration (10 mg / kg) as described in M. Rinaldi-Carmona et al., FEBS Letters, 1994, 350, 240-244 and M. Rinaldi-Carmona et al., Life Sciences, 1995 , 56, 1941-1947, M. Rinaldi-Carmona et al., J. Pharmacol. Exp. Ther., 2004, 310, 905-
  • a percentage inhibition of [3HJ-CP55940 binding at the brain level of less than 50% at 10 mg / kg indicates low penetration of the brain.
  • this percentage is less than 40% and more preferably less than 30%.
  • Measurement (3) measurement of the blocking by the compounds of formula (I) of the hypothermic effect induced by a CB 1 receptor agonist (CP55940), after an intravenous administration, as described in Rinaldi-Carmona M. et al., JPET 2004, 310, 905-914). A reversion percentage of the effect of CP55940 less than or equal to 60%
  • 10 mg / kg indicates low penetration of the brain.
  • this percentage is less than 40% and more preferably less than 30%.
  • the compounds of formula (I) are compatible with their use as a medicament.
  • the invention relates to medicaments for human or veterinary medicine which comprise a compound of formula (I), or an addition salt thereof to a pharmaceutically acceptable acid.
  • the compounds according to the invention can be used in humans or animals (in particular in mammals including, but not limited to, dogs, cats, horses, cattle, sheep) in the treatment or prevention of diseases involving cannabinoid receptors CBj.
  • the compounds of formula (I) are useful as psychotropic drugs, especially for the treatment of disorders mental disorders including anxiety, depression, mood disorders, insomnia, delusional disorders, obsessive disorders, psychoses in general, schizophrenia, attention-deficit and hyperactivity disorders ( ADHD) in hyperkinetic children as well as for the treatment of disorders related to the use of psychotropic substances, particularly in the case of substance abuse and / or substance dependence, including alcohol dependence and nicotine addiction.
  • disorders mental disorders including anxiety, depression, mood disorders, insomnia, delusional disorders, obsessive disorders, psychoses in general, schizophrenia, attention-deficit and hyperactivity disorders ( ADHD) in hyperkinetic children
  • ADHD attention-deficit and hyperactivity disorders
  • the compounds of formula (I) according to the invention can be used as medicaments for the treatment of migraine, stress, psychosomatic diseases, panic attacks, epilepsy, movement disorders , especially dyskinesias or Parkinson's disease, tremors and dystonia.
  • the compounds of formula (I) according to the invention can also be used as medicaments in the treatment of memory disorders, cognitive disorders, in particular in the treatment of senile dementias, of Alzheimer's disease, as well as in the treatment of disturbances of attention or alertness.
  • the compounds of formula (I) may be useful as neuroprotective agents, in the treatment of ischemia, head trauma and the treatment of acute or chronic neurodegenerative diseases: including chorea, Huntington's chorea, Tourrette's syndrome.
  • the compounds of formula (I) according to the invention can be used as medicaments in the treatment of pain: neuropathic pain, peripheral acute pain, chronic pain of inflammatory origin, pain induced by anticancer treatment.
  • the compounds of formula (I) according to the invention can be used as medicaments in human or veterinary medicine in the prevention and treatment of appetite disorders, palatability (for sugars, carbohydrates, drugs, alcohols or any appetizing substance) and / or eating behaviors, especially for the treatment of obesity or bulimia as well as for the treatment of type II diabetes or non-insulin-dependent diabetes and for the treatment of dyslipidemia, metabolic syndrome.
  • the compounds of formula (I) according to the invention are useful in the treatment of obesity and the risks associated with obesity, in particular cardiovascular risks.
  • the compounds of formula (I) according to the invention can be used as medicaments in the treatment and prevention of gastrointestinal disorders, diarrheal disorders, ulcers, vomiting, bladder and urinary disorders, liver diseases of alcoholic or non-alcoholic origin such as chronic cirrhosis, fibrosis, hepatic steatosis, steatohepatitis; as well as endocrine disorders, cardiovascular disorders, hypotension, atherosclerosis, hemorrhagic shock, septic shock, asthma, chronic bronchitis, chronic obstructive pulmonary disease, Raynaud's syndrome, glaucoma, fertility disorders, premature birth, termination of pregnancy, inflammatory phenomena, diseases of the immune system, particularly autoimmune and neuroinflammatory such as rheumatoid arthritis, reactive arthritis, diseases causing demyelination, multiple sclerosis, infectious and viral diseases such as encephalitis, accidents and as drugs for cancer chemotherapy, for the treatment of Guillain-Barré syndrome and for the treatment of bone diseases and osteoporosis
  • the compounds of formula (I) are particularly useful for the preparation of medicaments useful for the prevention and treatment of psychiatric disorders, in particular schizophrenia, attention and alertness disorders, disorders attention deficit hyperactivity disorder (ADHD) in hyperkinetic children; for the prevention and treatment of memory deficits and cognitive disorders; substance dependence and withdrawal, particularly alcohol dependence, nicotine addiction, alcohol withdrawal and smoking cessation; acute or chronic neurodegenerative diseases.
  • the compounds of formula (I) according to the present invention are useful in the preparation of medicaments useful in the treatment and prevention of appetite disorders, appetite disorders, metabolic disorders, obesity , type II diabetes, metabolic syndrome, dyslipidemia, gastrointestinal disorders, inflammatory phenomena, immune system diseases, psychotic disorders, alcohol dependence, nicotine addiction.
  • the present invention relates to the use of a compound of formula (I) and its pharmaceutically acceptable salts for the treatment of the disorders and diseases indicated above.
  • the present invention relates to pharmaceutical compositions comprising, as active principle, a compound according to the invention.
  • compositions contain an effective dose of at least one compound according to the invention, or a pharmaceutically acceptable salt of said compound, as well as at least one pharmaceutically acceptable excipient.
  • 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.
  • the pharmaceutical compositions according to the present invention may contain, besides a compound of formula (I), one (or more) other active ingredient useful in the treatment of the disorders and diseases indicated above.
  • an antihyperlipidemic agent or an antihypercholesterolemic agent an antihyperlipidemic agent or an antihypercholesterolemic agent
  • a nicotinic agonist a partial nicotinic agonist
  • an antidepressant an antipsychotic, an anxiolytic
  • an anticancer agent or an antiproliferative agent an anticancer agent or an antiproliferative agent
  • an agent improving the memory an agent useful in the treatment of alcoholism or withdrawal symptoms;
  • angiotensin II AT 1 receptor antagonist is meant a compound such as candesartan cilexitil, eprosartan, irbesartan, losartan potassium, olmesartan medoxomil, telmisartan, valsartan, each of these compounds may itself be associated with a diuretic such as hydrochlorothiazide.
  • inhibitor of the conversion enzyme is meant a compound such as alacepril, benazepril, captopril, cilazapril, enalapril, enalaprilat, fosinopril, imidapril, lisinopril, moexipril, perindopril, quinapril, ramipril, spirapril, temocapril, trandolapril, zofenopril, each of these compounds which may itself be associated with a diuretic such as hydrochlorothiazide or indapamide or a calcium antagonist such as amlodipine, diltiazem, felodipine or verapamil.
  • a diuretic such as hydrochlorothiazide or indapamide
  • a calcium antagonist such as amlodipine, diltiazem, felodipine or verapamil.
  • calcium antagonist is meant a compound such as amlodipine, aranidipine, benidipine, bepridil, cilnidipine, diltiazem, efonidipine hydrochloride ethanol, fasudil, felodipine, isradipine, lacidipine, lercanidipine hydrochloride, manidipine, mibefradil hydrochloride, nicardipine, nifedipine, nilvadipine, nimodipine, Nisoldipine, Nitrendipine, Terodiline, Verapamil.
  • beta-blocker is meant a compound such as acebutolol, alprenolol, amosulalol, arotinolol, atenolol, befunolol, betaxolol, bevololol, bisoprolol, bopindolol, bucumolol, bufetolol, bunitrolol, butofilolol, carazolol, cardolol, carvedilol, cloranolol, epanolol, esmolol.
  • Antihyperlipidemic or antihypercholesterolaemic means a compound selected from fibrates such as alufibrate, beclobrate, bezafibrate, ciprofibrate, clinofibrate, clofibrate, etofibrate, fenofibrate; statins (HMG-CoA reductase inhibitors), such as atorvastatin, fluvastatin sodium, lovastatin, pravastatin, rosuvastatin, simvastatin, or a compound such as acipimox, aluminum nicotinate, azacosterol, cholestyramine, dextrothyroxine, meglutol, niceritrol, nicoclonate, nicotinic acid , beta-sitosterol, tiadenol.
  • statins HMG-CoA reductase inhibitors
  • antidiabetic means a compound belonging to one of the following classes: sulfonylureas, biguanidines, alpha glucosidase inhibitors, thiazolidinedione, methaglinides, such as acarbose, acetohexamide, carbutamide, chlorpropamide, glibenclamide, glibornuride, gliclazide , glimepiride, glipizide, gliquidone, glisoxepide, glybuzole, glymidine, metahexamide, metformin, miglitol, nateglinide, pioglitazone, repaglinide, rosiglitazone, tolazamide, tolbutamide, troglitazone, voglibose, as well as insulin and insulin analogues.
  • sulfonylureas biguanidines
  • alpha glucosidase inhibitors such
  • a compound such as amfepramone, benfluorex, benzphetamine, indanorex, mazindole, mefenorex, methamphetamine, D-norpseudoephedrine, sibutramine, a topiramate, a lipase inhibitor (orlistat cetilistat ), a PPAR (Peroxisome Proliferator Activated Receptor Agonist) agonist, a dopamine agonist, a leptin receptor agonist, a serotonin reuptake inhibitor, a beta-3 agonist, a CCK-A agonist, an NPY inhibitor, an MC 4 (melanocortin 4) receptor agonist, a Melanin Concentrating Hormone (MCH) receptor antagonist, an orexin antagonist, a phosphodiesterase inhibitor, an inhibitor of 11 DHSD (11-D-hydroxy)
  • SCD a modulator of phosphate, glucose, fatty acid, dicarboxylate, 5HT2 antagonist, 5HT6 antagonist, bombesin agonist.
  • opioid antagonist is meant a compound such as naltrexone, naloxone or nalmefene.
  • agent useful in the treatment of alcoholism and withdrawal symptoms is meant acamprosate, benzodiazepines, beta-blockers, clonidine, carbamazepine.
  • beneficial agent for treating osteoporosis, is meant, for example, bisphosphonates such as etidronate, clodronate, tiludronate, risedronate.
  • inhibitors of PTP 1 B English Protein Tyrosine Phosphase -IB
  • agonists of the VPAC 2 receptors modulators of GLK, retinoid modulators, glycogen phosphorylase inhibitors (HGLPa), glucagon antagonists, glucose-6 phosphate inhibitors, pyruvate dehydrogenase kinase (PKD) activators, RXR modulators, FXR, LXR, SGLT inhibitors (English Sodium Dependent Glucose Transporter), CETP inhibitors (English Cholesterylester
  • the compound of formula (I), one of its pharmaceutically acceptable salts and the other associated active ingredient can be administered simultaneously, separately or spread over time.
  • “separate use” is meant the administration, at the same time, of the two compounds of the composition according to the invention each included in a distinct pharmaceutical form.
  • Extended use means the sequential administration of the first compound of the composition of the invention, included in a pharmaceutical form, then the second compound of the composition according to the invention, included in a separate pharmaceutical form. . In this case, the lapse of time elapsing between the administration of the first compound of the composition according to the invention and the administration of the second compound of the same composition according to the invention generally does not exceed 24 hours.
  • the active ingredient of formula (I) above, or its salt may be administered in unit dosage form, in admixture with conventional pharmaceutical excipients, to animals and humans for the prophylaxis or treatment of the above disorders or diseases.
  • Suitable unit dosage forms include oral forms such as tablets, soft or hard capsules, powders, granules and oral solutions or suspensions, sublingual, oral, intratracheal, intraocular, intranasal forms of administration by inhalation, topical, transdermal, subcutaneous, intramuscular or intravenous administration forms, rectal administration forms and implants.
  • the compounds according to the invention can be used in creams, gels, ointments or lotions.
  • a unitary form of administration of a compound according to the invention in tablet form may comprise the following components:
  • the dose of active ingredient administered per day may be as high as 0.01 mg
  • 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 administering to a patient an effective dose of a compound according to the invention, or a pharmaceutically acceptable salt thereof.

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