Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/04—Ortho-condensed systems
• • 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
• • 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
  • A61P1/06—Anti-spasmodics, e.g. drugs for colics, esophagic dyskinesia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • 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
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
  • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
  • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
  • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

• Carboxamidothiazole derivatives their preparation, pharmaceutical compositions containing them.
• the third invention relates to derivatives of thiazole agomsts of cholecystoinin (CCK) and more particularly agomsts of type A receptors of cholecystokirune (CCK-A), their preparation process and the drugs containing them ⁇ _a CCK is a peptide which, in response to a feed intake, is secret peripherally and participates in regulating many processes Endocytosis Digestion t ifs
• CCK has also been identified in the brain, and could be the most abundant neuropeptide acting as a neuromodulator of brain functions by stimulation of CCK-B receptors (Crawley J N et al, Peptides. 1994, 15 (4),
• CCK In the central nervous system, CCK interacts with dopamine-mediated neuronal transmission (Crawley J N et al, ISIS Atlas of Sci, Pharmac,
• CCK exerts its biological activity through at least two types of receptors CCK-A receptors located mainly in pe ⁇ phe ⁇ e, and CCK-B receptors present mainly in the cerebral cortex
• CCK-A receptors of peripheral type are also present in certain areas of the system central nervous system including area postrema.
• CCK-A receptors (Moran TH et ai, Bra Research, 1986, 362, 175-179)
• CCK delays gastric emptying, modulates intestinal motility, stimulates vesicular contraction, increases bile secretion and controls pancreatic secretion (McHugh PR et al, Fed Proc, 1986, 45, 1384- 1390, Pendleton RG et al, J Pharmacol Exp Ther, 1987, 241, 1 10-116)
• the role of CCK in the signal of satiety is supported by the fact that the plasma concentrations of CCK, dependent on the composition of the meals (high concentrations of proteins or lipids) are, after meals, higher than those observed before meals.
• devazepide a selective antagonist of CCK-A receptors, inhibits the anorectic effect of CCK whereas the selective agomsts of these receptors inhibit food p ⁇ se (Asin KE et al. Pharmacol Biochem Behav, 1992, 42, 699-704, Elliott RL et al, J Med Chem, 1994, 37, 309-313, Elhott RL et al 7 Med Chem, 1994, 37, 1562-1568)
• OLEFT rats not expressing the receptor
• CCK-A are insensitive to the appetite suppressing effect of CCK (Miyasaka K et al, 1994, 180. 143-146)
• CCK receptor agonist can also be used therapeutically in the treatment of disorders of emotional, sexual and physical behavior (Itoh S et al., Drug. Develop Res, 1990, 21, 257-276), schizophrenia, psychoses (Crawley JN et al, Isis Atlas of Sci, Pharmac, 1988, 84-90 and Crawley JN, Trends in Pharmacol Sci, 1991, 12, 232-265),
• Parkinson's (Bednar l et al, Biogemc amine, 1996, 12 (4), 275-284), dyskmesias tardives ⁇ ⁇ ' ⁇ sh ⁇ kaw a T ét al Prog Neuropsychopnarmacol Biol Psych, 1988 2 , 803-8 12 Kampen JV et al Eur J Pharmacol 1996, 2 8, O i) and various disorders of the gastrointestinal sphere (Drugs of the Future, 1992 / "(3), 197-206) the agomstes receptor CCK-A i.
• CCK are described ⁇ ans the bed side ra t ure for example, some products before such properties are described in EP-383690 and ⁇ ans WO9O06937, WO95 / 28419, VVO96 / 1 1701 or also WO96 / 1 1940
• FPL 14294 derived from CCK-7 is a powerful agoms t e receptor CCK-A non-selective vis-a-vis the CCK receptors B II poss è powerful inhibit ⁇ ce activity of food intake in rats and dogs after è s intranasal administration (Simmons RD et al, Pharmacol Biochem Behav 1994 4 ⁇ (3), 701 -708 Kaiser EF et al Faseb 19 1, 5 A864)
• a-71623 a selective agonist tetrapeptide of CCK-a receptors, is effective in models of anorexia over a pe ⁇ ode 1 1 days and leads to a reduction t ion significati e of the weight relative to the control, in rodents and cynomological monkeys (Asin KE et al, Pharmacol Biochem Behav, 1992, 42 699
• EP-51873 1 describes compounds which interact with the receptors formula
• Z> can in particular represent a dolyle group of formula in which Xj has different meanings and R z can represent hydrogen, a group (C ⁇ -C ⁇ alkyl, an optionally esterified carboxyalkylene group of formula Z2COOR in which ⁇ 2 represents a (C; -C4) alkylene and R represents H , a benzyl, a (C j -C6) alkyl, a carbamoylalkylene group of formula Z2CONR j ⁇ R ⁇ in which R ⁇ y e ⁇ RN each independently represent hydrogen, a (Ci - Cô) alkyl or form with nitrogen a heterocycle saturated, an acyl group of formula COR ⁇ / I in which R ⁇
• phenyl 2 5- d ⁇ methoxy-4-methylphenyle, 4-t ⁇ fluorometh l-2,6-d ⁇ methoxy phenyle 2 , 4- d ⁇ methoxy-5-methylphenvle, 5-ethyl-2,4-d ⁇ methoxyphenyle.
• R [ ⁇ represents a hydrogen a (C '-C4) alkyl or a benzyl, with the limitation that] ⁇ is necessarily hydrogen when is a phenyl substituted simultaneously at positions 2 and 6 or when ⁇ iH is a 3-p radical ⁇ nyle substituted simultaneously at positions 2 and 4 or RVJT is a ra d ⁇ ca ⁇ 5-py ⁇ mid ⁇ nvle substituted simultaneously at positions 4 and 6,
• Z3 represents a group 3- quoleoleyl or a 2-indolyl group of the formula
• R is hydrogen, an acetyl group or a CH2COOR 'group, R being 1 hydrogen or a (C 1 -C_
• the object of the present invention is precisely to propose a new family of tmazole derivatives which are particularly advantageous for their agonist activity of CCK-A receptors.
• the compounds according to the invention have been the subject of systematic studies to characterize
• the tmazole derivatives manifest an ability to bind to CCK-A receptors and to stimulate, like CCK, the mobilization of intracellular calcium in a cell line expressing the recombinant human CCK-A receptor.
• CCK-A receptor agomsts be CCK-A receptor agomsts
• the compounds of the present invention have also been studied in vivo, by evaluating their capacity to block gastric emptying in the stomach. Like CCK, these compounds block in gastric emptying and therefore behave in vivo like receptor agomsts. CCK-A Surprisingly, they prove to be more powerful agonists than the thiazole derivatives described in. patent application EP- ⁇ l 1766. These better performances have been assessed on the one hand in vitro on the mobilization of intracellular calcium, and on the other hand, in vivo, via their administration by the intraperitoneal route, by their capacity to block gastric emptying in mice.
• R2 represents a group chosen from
• R3 represents i) an indol-2-yl of formula.
• R4 represents hydrogen or a methoxy group
• R5 represents hydrogen, or a methyl or ethyl group. isopropyl, methoxv , ethoxy or halogen,
• Q - Rg represents hydrogen, a methyl, ethyl, methoxy group or a halogen.
• R_5 and R considered together, represent a methylèr.e ⁇ ioxy group, on the condition that the substituents R4, R5.
• R_5 simultanémen t are not hydrogen
• s- - R7 represents a (C5-C7) cycloalkyl unsubstituted or substituted by one or two methyls.
• Rg represents a group (CH2) n Ri 5 or a group
• 0 - R9 represents hydrogen or a methyl group
• R] i, R [2- -13 each represent independently of one another hydrogen, a methyl group. ethyl, hydroxy, acetyloxy. methoxy. ethoxy, methylthio. trifluoromethyl, amino or halogen,
• - ⁇ g represents a (C j-C4) alkyl group
• al yl means a linear or branched alkyl group and more particularly methyl, ethyl, isopropyl, isobutyl and tert-butyl.
• (C5-Cg) alkyl is meant a linear or branched alkyl and more particularly the n-pentyl, n-hexyl, n-octyl and 5,5-dimethylhexyl groups.
• 5 Halogen means a chlorine, fluorine or bromine atom, chlorine being preferred.
• the addition salts of these compounds are those obtained with inorganic or organic bases the non-toxic pharmaceutically acceptable salts are preferred but other salts which can be used to isolate or purify the compounds of formula (I) are also an object of the invention
• the salts of the compounds of formula (I) include the salts with orgamic or mineral bases, for example the salts of alkali or alkaline earth metals , such as the sodium, potassium, calcium salts, the sodium and potassium salts being preferred, or with an amine, such as trometamol. or else the argimne salts of lysine, of N-methyl-D-glucamine or of any physiologically acceptable amine
• the present invention also extends to the solvates formed by the compounds of formula I with water or mineral or orgamic acids such as 1 hydrochloric acid, bromhyd ⁇ que acid. t ⁇ fluoroacetic acid, sulfuric acid, sulfuric acid phosphonic acid, naphthalene-2-sulfonic acid, p-toluenesulfonic acid
• the present invention relates to the compounds of formula
• - Ri represents a substituted phenyl group of formula
• R3 represents
• R4 represents hydrogen or a methoxy group
• - R5 represents hydrogen, or a methyl group. ethyle, methoxy, ethoxy or halogen
• Q - R-6 represents hydrogen, a methyl or ethyl group. methoxy or halogen
• R4 and R5 and R5 taken together, represent a methylenedioxy group, provided that the substituents R4, R5, R ⁇ are not simultaneously hydrogen é ment, 15 - RJO, R 1, R 2 R-13 each independently of one another represents hydrogen, a methyl, ethyl, methoxy, ethoxy, methylthio, trifluoromethyle, armno or halogen group,
• Rg, R9 are as defined above, as well as their salts or their solvates
• the present invention more particularly relates to compounds of formula
• R2 represents a group chosen from (CH 2 ) 2-R7 and S-CH2-R7. with Ri, R3 and 7 being as defined above for (I), as well as their salts and • yc- solvates
• R7 represents a cyclopentyl, a cyclohexyl, a 4,4-dimethylcyclohexyl or a cycloheptyie
• a particular group of compounds is constituted by the compounds of formula (I) in which R3 represents a pyrrolo-py ⁇ dyle of formula
• Another particular group of compounds is constituted by the compounds of formula (I) in which R3 represents a mdol-2-yl group of formula
• Rg, R9, R ⁇ Q, K ⁇ ⁇ , Rj 2 , Ri 3 being as defined for (I), as well as its salts and solvates
• Rj and R 2 are as defined above for (I) and R3 is an indol-2-yl group in which one of the substituents R ⁇ Q, RU, RJ 2 OR RI 3, is different from hydrogen
• R3 is an indol-2-yl group
• the compounds in which P represents a carboxyaikylene group of formula (CH 2 ) r ⁇ -COOH are preferred, especially Carboxymethyiene group
• RjQ, K ⁇ ⁇ , Ri 3 represent a methyl, methoxy, trifluoro methyl, chlorine or fluorine group, the third thus as Rj 2 and R9 representing hydrogen, as well as their salts and solvates.
• R2 a represents a group chosen from
• R7, Rg, R9, Rio, R 1- R 12 'R 13 being as defined above for (I) with the limitation that at least one of the RIQ substituents, RU, Rj2, R13 or differen t of 'hydrogen. as well as their salts and solvates - the compounds of formula
• RjOa, R l la ⁇ R l 3a represent a methyl, a methoxy. a chlorine, a fluorine or a t ⁇ fluoromethyl, the others or the other representing hvdrogene as well as their salts and solvates
• a second object of the present invention is a process for the preparation of the compounds (I) according to the invention.
• This process is characterized in that it comprises the following stages a) condensing a de ⁇ ve 2-am ⁇ noth ⁇ azole of formula in which Ri and R2 are as defined above for (I), on an acid of formula
• Step a) of the process is generally carried out in basic medium.
• an activated acid an anhydride, a mixed anhydride or an activated ester of said carboxylic acid can be used.
• an ester is used such as for example an ester of (C ⁇ -C4) alkyl.
• the mixed anhydrides can be prepared by reacting an alkyl chloroformate with the acid, in the presence of a base, usually a tertiary amine such as t ⁇ ethyla ⁇ une. this reaction is most often carried out in a solvent such as dichloromethane. dichloroethane or chloroform Condensation of aminotmazole (II) with acid (III) in the form of an active ester, prepared for example by the action of 1-hydroxybenzotriazole on the acid in the presence of dicyciohexyicarbodiimide according to the procedure described in J Am Chem.
• R13 represents a hydroxy are obtained from the compounds of formula (I) in which the substituent (s ) represents an acetyloxy, the other subs t i t uan t s being identical, by hydrolysis in basic medium
• Triflic acid trifluoromethanesulfonic acid
• halogenated ketones of formula (IV) can be prepared by methods the principles of which are described in general works.
• bromoketones can be obtained by the action of bromine in an acid medium, of bromide
• R 2 CH 2 COR ⁇ (V) in which R ⁇ , R 2 , have the meanings indicated above for (I), in an organic solvent such as ethyl acetate, a chlorine solvent or their mixture 0 Cetones (V) are generally prepared by Friedel and Crafts reaction in the presence of a Lewis acid such as AICI3 or TiCl4 for example.
• Aminot an azole of formula (II) may also be prepared in a single waypoint from a substituted acetophenone of formula (V) by successively act bromine or PTT in a solvent such as dichloromethane or carbon tetrachloride , then the thiouree. in an alcohol such as ethanol or methanol for example
• aminothiazoles of formula (II) can also be prepared using the Hoesch reaction, (according to Dubois, Orgamc Reactions. 1945. 5. 387 or according to Sa t chell t al .. The Chemistry of the Carbonyl Group, ed S Patai, Interscience, 1966. ⁇ (5), 233-302) followed by condensation with thiourea
• the acid halides of formula (VI) are prepared from the corresponding acid of formula R2CH2COOH (VII) by conventional methods, for example by the action of thionyl chloride or oxalyl chloride
• t ⁇ ethylphosphonocrotonate can be used and proceed according to the reaction scheme below to prepare compounds of formula R - ( CH) 3-CO 2 H in which R ' 2 represents a (C5-C7) cycloalkvle
• An acid of formula R '-S- (CH 2 ) -COOH in which R' represents a (C5-C7) cycloalkyl can be prepared from a compound of formula R ' 2 SH by the action of cesium hydroxide then a haloalkanoic acid ester according to the reaction scheme below
• R '15 represents Ri 5 or a group whose carboxyhque acid function is esté ⁇ fiee
• X ' ⁇ , X' 2 , X'3 and X'4 represent a group C ⁇ optionally substituted by a methyl group or one of the X ' ⁇ , X' 2 , X'3, 4 is N, and the others represent CR14 with R14 representing hydrogen or a methoxy, useful as intermediates for the preparation of compounds of formula (I).
• This process is characterized in that it comprises the stages consisting in: a) protecting the amine function of a compound of formula.
• step b) the lithiation is carried out according to D Hands and coil, Synthesis, 1996 , 877-882 or RD Clark et al, Synthesis, 1991, 871-878
• step c) benzyl oxalate instead of ethyl oxalate. avoids the intermediate stages of saponification and estestification
• Step d) can be carried out in the presence of t ⁇ fluoroacetic acid or, by heating in the presence of 6N HCl
• the claimed process comprises the steps consisting of aa) protecting the amine function of an ort / 70-methylaniline of formula
• ester by an alkyllithium such as n-BuLi or sec-BuLi, c) condensing the lithiated derivative thus formed with an oxalic ester such as ethyl oxalate or benzyl oxalate, d) cychser in acid medium, e) saponify the formula obtained ester
• R'g represents Rg such as defim above for (I) or a precursor of Rg, from an ortho -methylaminopy ⁇ dine
• R'g represents Rg as defined above for (I) or a precursor of Rg in which the carboxylic acid function is esterified can also be prepared by known methods
• the acid derivatives the pyrrolo [2.3-c] py ⁇ d ⁇ ne-2-carboxyhques, e: acid ⁇ H- pyrrolo [3,2-c] py ⁇ d ⁇ ne-2-carboxyl ⁇ ques can be prepared from the methylpy ⁇ dines rutrees position corresponding methyl ortho, according to a modification of Reissert's method. as described for example in B Frydman et t , J Org Chem 1968. 3762-3766 or MH Fisher et al, J Het Chem 1969 , 775-776
• the compounds of formula (I) also include those in which one or more atoms of hydrogen, carbon or halogen, in particular chlorine or fluorine have been replaced by their radioactive isotope, for example tritium or carbon-14
• radioactive isotope for example tritium or carbon-14
• the agonist activity of the compounds with respect to CCK-A receptors was evaluated in vitro in 3T3 cells expressing the human CCK-A receptor, by measuring the
• the products (suspended in a solution of 1% carboxymethylcellulose or 0.6% methylcellulose) or the corresponding vehicle are administered intraperitoneally, 30 minutes before the administration of a meal of carbon (0.3 ml per mouse of a suspension in water of
• mice are sacrificed 5 minutes later by cervical dislocation, and gastric emptying is evaluated by the presence of charcoal in the intestine beyond the pyioric sphincter (Eur. J. Pharmacol., 1993, 232, 13-19).
• compounds of formula (I) block gastric emptying like CCK itself, and therefore behave like CCK-A receptor agonists.
• Some compounds according to the invention have ED ,,, (effective dose inducing 50 of the effect of CCK) less than or equal to 0 1 mg / kg by the intrape ⁇ toneale route
• the compounds dec ⁇ ts in EP 61 1766 does my t rent no significant agomste property vis-a-vis the gastnque drain a dose of 0, 1 mg kg and have THAN 5 o supe ⁇ eures 1 mg / kg by the intrape ⁇ toneale route
• the compound of Example 5 is very active in vitro or it completely inhibits gastric emptying with an ED o of 1.9 ⁇ g / kg by the intrape ⁇ toneale route
• the compounds of formula (I) are particularly effective, as agomsts of the CCK-A receptors of CCK, for the preparation of medicaments intended for combating diseases whose treatment requires stimulation of the CCK-A receptors of the inine cholecvstui
• the compounds of formula (I) are used for the intended fab ⁇ cation of drugs in treatment of certain disorders of the gastrointestinal sphere ry (prevention of gallstones, syndrome îr ⁇ table colon), feeding behavior, obesity. or associated pathologies such as diabetes and hypertension
• the compounds of formula (I) induce a state of satiety, and can thus be used to reduce food p ⁇ se, treat bulimia, obesity and cause weight loss
• the compounds (I) are also useful for the manufacture of medicaments intended for the treatment of disorders of the central nervous system, in particular disorders of emotional, sexual and nervous behavior, psychoses and in particular, schizophrenia, Parkinson's disease.
• dyskinesia such as late skinesia or facial dyskmesia after prolonged treatment with neuroleptics They can also be used to treat appetite disorders, ie to regulate the desire for consumption, in particular the consumption of sugars , fat, alcohol or drugs and more generally appetizing ingredients
• a subject of the present invention is also pharmaceutical compositions containing an effective dose of at least one compound according to the invention or of a pharmaceutically acceptable salt or solvate thereof, and as a mixture if appropriate with suitable excipients. are chosen according to the pharmaceutical form and the mode of administration desired
• the active ingredients of formula (I) above, or their optional salts can be administered in unit administration forms, in admixture with conventional pharmaceutical carriers, in ammals and in human beings for the prophylaxis or treatment of the disorders or diseases mentioned above.
• the unit forms of administration suitable include oral forms such as tablets, capsules, powders, granules and oral solutions or suspensions, forms of sublingual, buccal, intratracheal, intranasal administration, forms of subcutaneous, intramuscular or intravenous and rectal administration forms
• oral forms such as tablets, capsules, powders, granules and oral solutions or suspensions
• forms of sublingual, buccal, intratracheal, intranasal administration forms of subcutaneous, intramuscular or intravenous and rectal administration forms
• the compounds can be used according to the invention in creams, ointments, lotions or eye drops
• the dose of active ingredient may vary between 0.01 and 50 mg per kg of body weight per day
• Each unit dose may contain from 0.5 to 1000 mg, preferably from 1 to 500 mg, of active ingredients in combination with a pharmaceutical carrier. This unit dose may be administered 1 to 5 times a day so as to administer a daily dosage. from 0.5 to 5000 mg, preferably from 1 to 2500 mg
• a pharmaceutical vehicle such as gelatin
• the tablets can be coated with sucrose, cellulose, or other suitable materials, or they can be treated so that they have a prolonged or delayed activity and that they continuously release a quantity predetermined active principle
• a capsule formulation is obtained by mixing the active ingredient with a diluent and pouring the resulting mixture into soft or hard capsules
• a composition in the form of a syrup or elixir or for administration in the form of drops may contain the active ingredient together with a sweetener, preferably alcoholic, methylparaben and propylparaben as an antiseptic, as well as a flavoring agent and a suitable dye
• Water dispersible powders or granules may contain the active ingredient in admixture with dispersants or wetting agents, or suspending agents, such as polyvinylpyrrolidone, as well as with sweeteners or correctors taste
• dispersants or wetting agents such as polyvinylpyrrolidone
• suspending agents such as polyvinylpyrrolidone
• sweeteners or correctors taste For rectal administration, recourse is had to suppositories which are p re pares with binders melting the rectal temperature, for example cocoa butter or polyéthylenegiycols
• aqueous suspensions, isotonic saline solutions or sterile injectable solutions which contain pharmacologically compatible dispersing agents and / or wetting agents, for example propyleneglycol or butyleneglycol
• the active principle can also be formulated as microcapsules, optionally with one or more carriers or additives, or else with matnces such that a polymer or a cyclodextrin (patch, sustained-release forms have)
• compositions according to the invention can be used in the treatment or prevention of various conditions or CCK is of therapeutic interest
• compositions of the present invention may contain, in addition to the products of formula (I) above or their pharmaceutically acceptable salts, other active ingredients which may be useful in the treatment of the disorders or diseases indicated above
• compositions of the present invention contain, as active principle, at least one compound of formula (I) above or one of its pharmaceutically acceptable salts, solvates or hydrates.
• compounds of formula (I) above or one of its pharmaceutically acceptable salts, solvates or hydrates are presented as illustrative and not limiting of the present invention.
• PREPARATION 1 2-Amino-5-cyclohexylethyl-4- (2,5-dimethoxy-4-methylphenyl) thiazole.
• the entire product of the previous step is placed in 200 ml of methanol and a solution of 17 g of NaOH in 50 ml of water is added. After one night at RT, the methanol is evaporated, taken up in water, then the aqueous phase is extracted with ether. The ethereal phases are eliminated, the aqueous phase is acidified to pH2 by adding concentrated Cl then extracted 3 times with DCM, dried over MgS ⁇ 4 and evaporated to obtain 31.1 g of the expected product in oily form.
• PREP.ARATION 1 2-Am ⁇ no-5-cyclohexylmethylth ⁇ o-4- (2,5-d ⁇ methoxy-4-methylphenyl) th ⁇ azole
• a suspension of 17.52 g of aluminum chloride in a mixture of 100 ml of CCI4 and 100 ml of DCM is cooled to -4 ° C under nitrogen, 10.4 g of acetyl chloride are added dropwise and then a solution of 20 g of 2,5-d ⁇ methoxytoluene in 20 ml of DCM After 4 hours of stirring at + 4 ° C, the reaction medium is poured onto ice with the addition of a few ml of concentrated HCl and left to stir 30 minutes Decanted, extracted with DCM, the combined orgamous phases are washed with a 5% aqueous solution of NaC03, dried over MgS04 and evaporated. The product is cnstalled, closed in 150 ml of heptane, filtered and then washed with heptane to get
• a solution of 21.03 g of the compound of the previous step in 300 ml of DCM is treated dropwise with a solution of 17.35 g of bromine in 70 ml of DCM After decantation, the orgasmic phase is washed with water, dried over MgS04 and then evaporated. Take up in 200 ml of absolute ethanoi then add 15.2 g of thiourea and heat overnight at reflux. Cool in an ice bath, filter the formed c ⁇ staux, then take up the c ⁇ staux with a solution.
• the entire compound of the previous step is hydrogen at room temperature and at atmospheric pressure in 20 ml of EtOH, in the presence of 190 mg of
• a mixture of 300 g of zinc powder and 40 g of mercuric chloride is prepared, which is added to a solution of 24 g of the compound of the previous step in 400 ml of benzene and 100 ml of concentrated HCl at 80 °. vs. After 2 hours with stirring at 80 ° C, filter then separate the organic phase which is dried over MgS ⁇ 4 and evaporated, then chromatographed on silica eluting with a DCM-heptane mixture (50/50, v / v) to obtain 8.6 g of the expected product.
• PREPARATION 1 2-Ammo-5-cyclohexylethyl-4- (2,6-dimethoxy-4-methylphenyl) thiazole
• PREPARATION 1 14 2-Amino-4- (2,5-dimethoxy-4-methylphenyl) -5- (5,5-dimethyihexyl) thiazole A) (2,5-Dimethoxy-4-methylphenyl) -7,7-dimethyloctan-1-one.
• R'g is the precursor of Rg and R9, RJQ, Rj 1, Ri 2 and R 13 are as defined above for (I)
• This compound is prepared from 3-t ⁇ fluoromethvlamlene using the procedure ⁇ ec ⁇ t to the previous PREPARATION
• PREP.ARATION 2 1 1 5-methyl- l- (ethoxycarbonylpropyl) indole-2-carboxylic acid
• the whole of the compound obtained in the preceding stage is hydrogen for 2 hours at ambient temperature and pressure in the presence of 1 g of Pd / C at 10% in 80 ml of MeOH and 20 ml of DMF
• the catalyst is filtered on Celite After evaporation solvents, the product obtained is triturated in heptane and 1.54 g of the expected compound is obtained.
• F 142 ° C
• the entire compound of the previous step is hydrogen at ambient temperature and pressure in the presence of 100 mg of Pd / C at 5%, in 5 ml of ethanol and 20 ml of AcOEt.
• the catalyst is filtered through Celite® and then evaporates to obtain 596 mg of the expected compound.
• F 210 ° C
• 16 g of the compound obtained in the preceding step are hydrogenated in 200 ml of DNfF, at ambient pressure and temperature in the presence of 200 mg of Pd / C at 5%.
• R'g is the precursor of Rg and the groups X ⁇ , X 2 , X3, X4 are as defined above for (I).
• a catalytic hydrogenation is carried out in the presence of 170 mg of Pd / C at 10%, at ambient pressure and temperature for 4 hours, of 1 g of the compound obtained in the previous step.
• the precipitate formed is dissolved in DMF and then filtered.
• Pd / C on Célite® evaporate to dryness and then wash the c ⁇ staux with Et 2 0 to obtain
• 30 ml of n-butyllithium is added to 5 g of 2- ( N-Boc) am ⁇ no-3-methylpy ⁇ dine in 100 ml of THF
• the lithia de ⁇ ve thus formed is added to a solution of 7 g of ethyl oxalate in 50 ml of THF to - 3 ° C.
• Dissou is t 0 5 g of the compound of the previous step in 30 ml of dioxane and 10 ml of propan-2-ol and 0.9 g of 30% sodium hydroxide after 15 hours under ag i ti on a TA es solvent evaporates ty is taken up in iPrOH, the c ⁇ staux forms are filtered, washed with iPrOH, with ethyl ether and then dried in an oven is obt i ent 0.46 g of the expected compound F> 350 ° C The sodium salt crystallizes with a molecule of NaOH .
• Acid potassium salt 2- (4- (4-chioro-2,5-d ⁇ methoxyphenyl) -5-cyclohexyl ethylth ⁇ azol-2-ylcarbamoyl) -5,7-d ⁇ methyhndole-l -acetic, t ⁇ hydrate
• 0.6 g of the compound of PREPARATION 2 are mixed in 2 ml of DMF . 18 with 0.6 g of the compound of PREPARATION 1.1, 0.7 g of BOP and 0.21 ml of NEt 3 and left to stir overnight. 5 ml of buffer solution pH 2 are added, filtered and then the precipitate is taken up in AcOEt. Washing is carried out with a buffer solution pH 2, with a solution of Na 2 Cinstall3 and then dried over MgSO4. The residue is chromatographed on silica eluting with DCM / AcOEt (100/3, v / v). The fractions containing the product are combined and then taken up in 10 ml of TFA and left stirring for two hours. The solvents are evaporated and then triturated in water at pH 4 to obtemr 740 mg of the expected compound, F "183 ° C.

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