Classifications

• • 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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
• • 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
  • A61P5/00—Drugs for disorders of the endocrine system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P5/00—Drugs for disorders of the endocrine system
  • A61P5/02—Drugs for disorders of the endocrine system of the hypothalamic hormones, e.g. TRH, GnRH, CRH, GRH, somatostatin
  • A61P5/04—Drugs for disorders of the endocrine system of the hypothalamic hormones, e.g. TRH, GnRH, CRH, GRH, somatostatin for decreasing, blocking or antagonising the activity of the hypothalamic hormones
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
  • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
  • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
  • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D277/38—Nitrogen atoms
  • C07D277/42—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals

Definitions

• the subject of the present invention is novel branched amino derivatives of thiazole and a process for their preparation. These new derivatives are generally provided with CRF antagonist activity (corticotropin releasing factor) and can therefore constitute active principles of pharmaceutical compositions.
• CRF antagonist activity corticotropin releasing factor
• corticotropic hormone releasing factor is a peptide whose sequence of 41 amino acids has been characterized by VALE W. et al. in 1981 (Science, 1981, 213, 1394-1397).
• CRF is the main endogenous factor involved in the regulation of the hypothalamic-pituitary-adrenal axis (release of the adrenocorticotropic hormone: ACTH) and its pathologies, as well as in the resulting depressive syndromes.
• CRF also causes the secretion of ⁇ -endorphin, ⁇ -lipotropin and corticosterone.
• CRF is therefore the physiological regulator of the secretion of the adrenocorticotropic hormone (ACTH) and more generally of peptides derived from proopiomelanocortin (POMC). Although localized in the hypothalamus, CRF is also widely distributed in the central nervous system (limbic zone) in which it plays the role of neurotransmitter and / or neuromodulator, independently of its effects on the hypothalamic-pituitary-adrenal axis .
• ACTH adrenocorticotropic hormone
• POMC proopiomelanocortin
• CRF central administration of CRF causes various anxiety-inducing effects such as behavior modification in general: for example neophobia, reduction in sexual receptivity, reduction in food consumption and slow sleep in rats.
• the intracerebroventricular injection of CRF also increases the excitation of the noradrenergic neurons of the locus coeruleus which is often associated in animals with a state of anxiety.
• central or peripheral administration of CRF induces changes in gastric emptying, intestinal transit, faecal excretion, acid secretion, as well as blood pressure effects.
• CRF-dependent neurons the dysfunction of CRF-dependent neurons is even suggested in severe pathologies such as Alzheimer's disease, Parkinson's disease, Huntington's chorea and amyotrophic lateral sclerosis (De Souza, EB, Hospital Practice, 1988,23,59) .
• the central administration of CRF in many animal species produces behavioral effects similar to those obtained in humans in stressful situations.
• ah-CRF The intracerebroventricular injection of the reference peptide antagonist, ah-CRF prevents the effects obtained either by the administration of exogenous CRF, or by the use of stressors (ether, stress, noise, electric shock , ethanolic withdrawal, surgery) capable by themselves induce an increase in the endogenous CRF level.
• Patent application EP 462 264 describes derivatives of 2-aminothiazole, including the tertiary amine in position 2, comprises two substituents each having at least one heteroatom including an amine derivative.
• These compounds are PAF-acether antagonists and find their applications in the treatment of: asthma, certain allergic or inflammatory conditions, cardiovascular diseases, hypertension and various renal pathologies or even as contraceptive agents.
• Application GB 2022 285 describes compounds having an activity regulating the immune response and having anti-inflammatory properties. They are derivatives of thiazole substituted in position 2 by secondary amino groups.
• 2-acylaminothiazole Certain heterocyclic derivatives of 2-acylaminothiazole have been described in patent application EP 432 040. These compounds are antagonists of cholecystokinin and gastrin. 2-amino-4,5-diphenylthiazole derivatives having anti-inflammatory properties are also known (patent application JP-01 75 475). Also known are derivatives of 2-amino-4- (4-hydroxyphenyl) thiazole useful as synthesis intermediates for the preparation of derivatives of 2,2-diarylchromenothiazole (patent application EP 205 069). 2- (N-methyl-N- derivatives) benzylamino) thiazole are also described in J. Chem. Soc. Perkin, Trans 1, 1984, 2, 147-153 and in J. Chem. Soc. Perkin, Trans 1, 1983, 2, 341-347.
• Patent application EP 283 390 described among other thiazole derivatives, 2- (N-alkyl-N-pyridylalkylamino) thiazole derivatives of formula:
• R 1 and R 2 which may be identical or different, each independently represent a halogen atom; hydroxyalkyl radical in C j -C 5 alkyl; C1-C5 alkyl; a C7-C 10; C1-C5 alkoxy; trifluoromethyl; a nitro; a nitrile; a group -SR in which R represents hydrogen, a C1-C5 alkyl radical or a C7-C10 aralkyl radical; an S-CO-R group in which R represents a C 1 -C 5 alkyl or aralkyl radical in which the aryl part is in C 1 -C 5 and the alkyl part is in C 1 -C 4; a group
• R ' represents hydrogen or C1-C5 alkyl
• R ' represents hydrogen or C1-C5 alkyl
• R ' represents hydrogen or C1-C5 alkyl
• R ' represents hydrogen or C1-C5 alkyl
• R ' represents hydrogen or C1-C5 alkyl
• R ' represents hydrogen or C1-C5 alkyl
• R ' represents hydrogen or C1-C5 alkyl
• R a group -NR'R "with R 'and R” as defined above for R'
• Ra and Rb constitute, with the nitrogen atom to which they are linked, a 5 to 7-membered heterocycle
• a group -NHCO-NR'R "with R 'and R” as defined above for R'
• R 3 represents hydrogen or is as defined above for R-
• ⁇ 4 represents a hydrogen atomj a C-
• R 5 represents a C r Cs alkyl; a C3-C7 cycloalkyl group; a cycloalkylalkyl group in which the cycloalkyl is C 3 -C 7 and alkyl C 1 -C 5; or an alkenyl of 5 to 6 carbon atoms;
• R 6 represents a C1-C5 alkyl; alkoxyalkyl in which the alkyls are C1-C5; C3-C7 cycloalkyl; a cycloalkylalkyl group in which the cycloalkyl is C3-C7 and alkyl C1-C5; a cycloalkyloxyalkyl radical in which the cycloalkyl is C3-C7 and the alkyl is C1-C4; a hydroxyalkyloxyalkyl radical in which the alkyls are C 2 -C 10; or an alkoxyalkyloxyalkyl radical in which the alkyls are in
• - Z represents a bi- or tricyclic aromatic or heteroaromatic group optionally substituted; their stereoisomers and / or their addition salts.
• bi- or tricyclic aromatic or heteroaromatic group is particularly meant a C10-C14 bi- or tricyclic aryl group or C5-C13 bi- or tricyclic heteroaryl group comprising 1 to 5 heteroatoms chosen from N, S and O; said groups being preferably chosen from naphthalene, quinoline, isoquinoline, quinoxaline, quinazoline, cinnoline, phthalazine, 1,5-naphthyridine, 1,7-naphthyridine, indole, isoindole, benzothiophene, benzofuran, benzimidazole, indane, indazole, quinolizidine pyrolopyrimidine, pyrazolopyrimidine; said groups possibly being substituted.
• the substituents of group Z are preferably chosen from halogen, C r C 3 alkyl, C1-C3 alkoxy, trifluoromethyl, nitro, -NRdRe with Rd and Re independently representing hydrogen or C r C3 alkyl, aicoxycarbonylalkyl, carboxyalkyl , morpholinocarbonylalkyle, alkylcarbonylalkyle, dialkylaminocarbonylalkyle or alkoxy-alkoxy in which the alkyls are C1-C3.
• the alkyl groups or the alkoxy groups are linear or branched.
• Advantageous compounds according to the invention are those in which Z represents a naphthyl group or a heteroaromatic group chosen from quinolyl, isoquinolyl, quinazolyl, quinoxalyl, indolyl, indazolyl, said groups being optionally substituted, R 1 t R 2 , R 3 , R 4 , R 5 , n and R ⁇ being as defined for (I), one of their stereoisomers and / or one of their salts.
• R 3 represents hydrogen
• R 4 represents methyl
• R 5 represents propyl
• n is 0 and R 1 , R 2 and Z are as defined for (I), one of their stereoisomers and / or one of their salts.
• R 3 represents hydrogen
• R4 represents methyl
• R 5 represents propyl
• n is 1
• Re represents cyclopropyl
• R ⁇ R 2 and Z are as defined for (I), a of their stereoisomers and / or one of their salts.
• R 3 represents hydrogen
• R4 represents a methyl
• R 5 represents a propyl
• n is 1
• R 6 represents a methoxymethyl radical
• R 1 ( R 2 and Z are as defined for ( I), one of their stereoisomers and / or one of their salts.
• R3 represents hydrogen
• R 4 represents methyl
• R 5 represents propyl
• R- represents methyl
• R 2 represents a halogen, a C1-C5 alkyl or alkoxy
• n, R 6 and Z being as defined for (I), one of their stereoisomers and / or one of their salts.
• salts of the compounds of formula (I) with pharmaceutically acceptable acids or bases are the preferred salts, but those which can make it possible to isolate the compounds of formula (I) in particular to purify them or to obtaining pure isomers are also subject of the invention.
• reaction schemes 2, 3 and 4 illustrate the synthesis of particular compounds of formula (I) via routes A, B and C.
• the present invention also relates to a process for preparing the compounds of formula (I) caracté ⁇ sé in that one reacts an alpha-halogenated derivative, preferably alpha-brominated or alpha-chlorinated of formula (II)
• Rj, R 2 , R 3 , R 4 , n, R 6 and Z are as defined for (I) and then subject it to an alkylation reaction to provide the compound (I), and obtain in particular in the case where Z represents a nitrogen heterocycle such as indole or indazole - either monoalkylated compounds by substituting the reactive nitrogen of the cycle beforehand with a protective group preferably of tetrahydropyranyl type, - or dialkylated compounds by proceeding, after deprotection of the cycle from the monoalkylated compound obtained, to an alkylation of the reactive nitrogen released, these dialkylated compounds which, depending on the nature of the second alkyl group, can lead to dialkylated products having different or identical alkyl groups, in the latter case, these compounds being obtainable also directly by dialkylation from compound (IV) in which the reactive nitrogen of the heterocycle is not protected
• R ⁇ R 2 , R 3 and R 4 are as defined for (I) which is optionally reacted with an aldehyde of formula HCO-Z to obtain an imine, which by action with an organomagnesium or ofganolithian of formula R ⁇ Li or R ⁇ MgX (where X is a halide) leads to a compound of formula (IV) which is subjected to an alkylation for example by the action of a compound of formula R5X (where X is a leaving group such that a halide) to obtain the compound (I) and where appropriate, the compounds of formula (I) thus obtained are then optionally separated into their possible stereoisomers and / or salified to form the corresponding salts.
• alkylation reactions used in the above process are carried out under the usual conditions known to those skilled in the art by the action of a suitable alkylating agent such as, for example, an alkyl halide.
• a suitable alkylating agent such as, for example, an alkyl halide.
• the derivatives of formula (II) can be obtained from the corresponding non-halogenated ketones of formula either by the action of bromine in an appropriate organic solvent, such as acetic acid, carbon tetrachloride or diethyl ether, or by the action of quaternary ammonium tribromides according to the method described in Bull. Chem. Soc. Japan 1987, 60, 1159-1160 and 2667-2668, or again by the action of cupric bromide in an organic solvent, such as a mixture of chloroform and ethyl acetate according to J. Org. Chem. 1964, 29, 3451-3461.
• the compounds of formula (II) can be obtained by the action of 2-bromopropionyl bromide on a substituted benzene of formula
• Ketones are generally known or commercially available products. These compounds can be prepared by Friedel and Crafts reaction, in the presence of a Lewis acid according to methods well known to those skilled in the art.
• Prot represents a protective group, for example benzoyl, pivaloyy or tetrahydropyranyl, F - necessarilyR ⁇ , n and Z are as defined above for (I) either by basic treatment, using preferably ammonia, sodium hydroxide or hydrazine at a temperature ranging from room temperature to reflux of the reaction mixture, either by acid treatment, preferably using hydrochloric acid.
• a protective group for example benzoyl, pivaloyy or tetrahydropyranyl
• F - necessarilyR ⁇ , n and Z are as defined above for (I) either by basic treatment, using preferably ammonia, sodium hydroxide or hydrazine at a temperature ranging from room temperature to reflux of the reaction mixture, either by acid treatment, preferably using hydrochloric acid.
• the compounds of formula (Via) and (Vlb) are prepared by reacting, according to known methods, an isothiocyanate, for example a benzoyl isothiocyanate or a pivaloyl isothiocyanate, on the corresponding amines HNXY of formula (Vlla) and (Vllb)
• an isothiocyanate for example a benzoyl isothiocyanate or a pivaloyl isothiocyanate
• the route B is used, taking the precaution of blocking the reactivity of the reactive cyclic nitrogen by substituting it with a protective group of the tetrahydropyranyl type.
• the protected nitrogen of the heterocycle can be deprotected by an acid treatment, preferably with hydrochloric acid.
• the compound obtained can then be substituted by nucleophilic reaction on halogenated derivatives such as alkyl bromides or iodides to obtain the compound of formula (I).
• Certain derivatives can then give rise to conventional reactions such as for example hydrolysis of the ester or nitrile function to obtain acids, reaction of a magnesium on a nitrile to obtain the corresponding ketones.
• the activation of the acid function either in the form of acid chloride, or in the form of activated ester, makes it possible, by the action of a nitrogenous base such as morpholine, to obtain the corresponding amides.
• Secondary amines (Vlla) are prepared from primary amines
• R'5-CH2- represents R5
• reduction of the imine for example by NaBH 4 preferably in ethanol or methanol at room temperature
• Another method of preparing the compounds of formula (Vlla) consists in condensing a ketone
• Z and R ⁇ have the same meaning as for formula (I) with an amine R5NH2 in which R 5 is as defined for (I) in a dehydrating medium, to form the corresponding imine which is then reduced in a conventional manner with a metal hydride, preferably sodium borohydride, or with hydrogen in the presence of a suitable catalyst.
• a metal hydride preferably sodium borohydride, or with hydrogen in the presence of a suitable catalyst.
• the compounds of formula (I) above also include those in which one or more hydrogen or carbon atoms, for example those located on R4 in particular when it represents a methyl group, have been replaced by their radioactive isotope for example tritium or carbon-14.
• radioactive isotope for example tritium or carbon-14.
• the compounds of the present invention have been the subject of biochemical and pharmacological studies. They have very interesting pharmacological properties.
• the compounds of the invention displace in particular at concentrations below 10 ⁇ M (0.01-10 ⁇ M) the binding of 125 I-CRF to the specific receptors present on the membranes of the human brain (or of transfected CHO cells expressing the cloned receptor of human brain) and / or animal brains (rat, mouse), according to the method described by De Souza EB (J. Neurosci., 1987, 7 (1), pp. 88-100).
• CRF is a neuropeptide that controls the activity of the hypothalamic-pituitary-adrenal axis. This factor is responsible for the endocrine and behavioral responses linked to stress.
• CRF can modulate behavior as well as certain functions of the autonomic nervous system (GF Koob, FE Bloom, Fed. Proc. 1985, 44, p. 259; MR Brown, LA Fisher, Fed. Proc 1985, 44, p. 243). More specifically, CRF induces the secretion of corticotropin (ACTH), ⁇ -endorphins and other peptides derived from PEQ-opiomelanocortin (A. Tazi et al, Régul. Peptides 1987 18, p. 37; MR Brown et al, Regul. Peptides 1986 16, p. 321; CL. Williams et al., Am. J. Physiol., 1987, G 582, p. 253).
• ACTH corticotropin
• the compounds of the invention can therefore be useful for regulating the secretion of these endogenous substances. They find more particularly their applications as active principles of the drugs for reducing the stress response (behavior, emotional states, gastrointestinal and cardiovascular disorders, disorders of the immune system) and more generally in pathologies involving CRF, for example disorders psychiatric, anxiety, depression, anorexia nervosa, disorders of sexual activity and fertility, Alzheimer's disease or others.
• the compounds of the invention are very stable and are therefore particularly suitable for constituting the active principle of medicaments.
• the invention also extends to pharmaceutical compositions containing as active ingredient, a compound of formula (I) or one of its pharmaceutically acceptable salts, optionally in combination with one or more inert and suitable excipients.
• each dosage unit the active ingredient of formula (I) is present in the quantities adapted to the daily doses envisaged.
• each dosage unit is suitably adjusted according to the dosage and the type of administration intended, for example tablets, capsules and the like, sachets, ampoules, syrups and the like, drops, transdermal or transmucosal patch so that a such dosage unit contains 0.5 to 200 mg of active ingredient, preferably 0.5 to 800 mg to be administered daily.
• the compounds according to the invention can also be used in combination with another active ingredient useful for the desired therapy, such as, for example, anxiolytics, antidepressants or anorectics.
• the compounds of formula (I) are not very toxic; their toxicity is compatible with their use as a medicament for the treatment of the above disorders and diseases.
• the compounds of formula (I) can be formulated in pharmaceutical compositions for administration to mammals, including humans, for the treatment of the abovementioned diseases.
• compositions containing as active principle at least one compound of formula (I) or one of its salts are in particular useful for the preventive or curative treatment of stress-related diseases and more generally in the treatment of all pathologies involving CRF, such as for example: neuropsychiatric disorders such as anxiety, panic, phobias, disorders of the mood, behavioral disorders, anorexia, bulimia, hyperglycemia, stunted growth, sleep disturbances and depressions of all types; Alzheimer's, Parkinson's disease; Huntington's chorea; amyotrophic lateral sclerosis; cardiovascular disorders; sexual activity and fertility disorders; immunosuppression, immunosuppression and their associated diseases such as inflammatory processes, multiple infections, cancers, rheumatoid arthritis, osteoarthritis, psoriasis and diabetes; gastrointestinal disorders
• the dosage can vary widely depending on the age, weight and state of health of the patient, the nature and severity of the condition, as well as the route of administration.
• This dosage includes the administration of one or more doses of about 0.5 mg to 200 mg per day, preferably about 0.5 to 800 mg per day.
• the active principle can be administered in unit administration forms, in admixture with conventional pharmaceutical carriers, animals and humans.
• Suitable unit administration forms include oral forms such as tablets, capsules, powders, granules and oral solutions or suspensions, sublingual and oral administration forms, subcutaneous administration forms , intramuscular, intravenous, intranasal or intraocular and forms of rectal administration.
• the main active principle is mixed with a pharmaceutical vehicle such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic or the like.
• a pharmaceutical vehicle such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic or the like.
• the tablets can be coated with saccha ⁇ rose or other suitable materials or they can be treated as such. so that they have a prolonged or delayed activity and that they continuously release a predetermined amount of active ingredient.
• a preparation in capsules is obtained by mixing the active principle with a diluent and by pouring the mixture obtained into soft or hard capsules.
• a preparation in the form of a syrup or elixir may contain the active principle together with a sweetener, preferably calorie-free, methyl paraben and propylparaben as an antiseptic, as well as a flavoring agent and an appropriate color.
• a sweetener preferably calorie-free, methyl paraben and propylparaben as an antiseptic, as well as a flavoring agent and an appropriate color.
• the water-dispersible powders or granules may contain the active ingredient in admixture with dispersing agents or wetting agents, or suspending agents, such as polyvinylpyrrolide, as well as with sweeteners or taste correctors.
• Suppositories are used for rectal administration which are prepared with binders that melt at rectal temperature, for example cocoa butter or polyethylene glycols.
• aqueous suspensions, isotonic saline solutions or sterile and injectable solutions which contain pharmacologically compatible dispersing agents and / or wetting agents, for example propylene glycol or butylene glycol.
• the active principle can be formulated in the presence of a promoter such as a bile salt, of a hydrophilic polymer such as for example hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, ethylcellulose, carboxymethylcellulose, dextran, polyvinylpyrrolidone, pectins, starches, gelatin, casein, acrylic acids, acrylic esters and their copolymers, vinyl polymers or copolymers, vinyl alcohols, alkoxypolymers, polyethylene oxide polymers, polyethers or their mixture.
• a promoter such as a bile salt
• a hydrophilic polymer such as for example hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, ethylcellulose, carboxymethylcellulose, dextran, polyvinylpyrrolidone, pectins, starches, gelatin, casein, acrylic acids, acrylic esters and their copolymers, vinyl polymers or
• the active principle can also be formulated in the form of microcapsules, optionally with one or more carriers or additives.
• the active component can also be presented in the form of a complex with a cyclodextrin, for example ⁇ , ⁇ or ⁇ cyclodextrin, 2-hydroxypropyl- ⁇ -cyclodextrin or methyl- ⁇ -cyclodextrin.
• a cyclodextrin for example ⁇ , ⁇ or ⁇ cyclodextrin, 2-hydroxypropyl- ⁇ -cyclodextrin or methyl- ⁇ -cyclodextrin.
• the melting points were measured according to the Micro-K ⁇ fler technique and are expressed in degrees Celsius.
• the compounds of the invention exhibit a percentage analysis in accordance with theory.
• Step 2 A solution of 3.6 g of the product prepared above in 50 ml of benzene is stirred at 20 ° C and added with 11.7 ml of a 3M solution of ethylmagnesium bromide in diethyl ether. The reaction mixture is stirred at reflux for 2 hours then cooled to 0 ° C. and slowly added with 17.5 ml of 6N hydrochloric acid. After stirring at reflux for 3 hours then cooling, the reaction mixture is extracted with diethyl ether. The extract is washed with salt water, dried over sodium sulfate and evaporated to dryness.
• Step 3 A solution of 3.5 g of the product prepared above in 150 ml of dichloromethane is added with 7.65 g of tetrabutylammonium tribromide. The reaction mixture is stirred at 35 ° C for 4 hours 30 minutes then, after cooling, is washed 3 times with water until neutral. The organic phase is evaporated and the residue is taken up in diethyl ether. The ethereal phase is washed successively with water, with salt water and then dried over sodium sulfate and evaporated to dryness to provide 4.6 g of 2 ⁇ romo-1 - (2-chloro-4-trifluoromethylphenyl) propan-1 - one.
• Step 1 4.0 g of 1-naphthylamine are dissolved in 40 ml of tetrahydrofuran, then 2.6 g of propanoyl chloride are added dropwise, the reaction mixture is stirred for 2 hours, then evaporated to dryness. The residue obtained is taken up in dichloromethane and washed with an aqueous solution of sodium chloride. Dried over sodium sulfate and evaporated to dryness to obtain 5.5 g of white crystals of N propionyl-1-naphthylamine, melting at 127 ° C.
• Step 2 In a three-necked flask surmounted by a dropping funnel and maintained under argon, 5.5 g of amide previously prepared is dissolved in 50 ml of anhydrous tetrahydrofuran, then it is heated to 50 ° C and added dropwise 42 ml of 2M dimethyl sulfide borane and leaves the reaction mixture under reflux for 3 hours and overnight at room temperature. The mixture is cooled in an ice bath; 100 ml of 6N hydrochloric acid are then added and the mixture is heated at reflux for 3 hours.
• Step 1 The magnesium of 1-naphthalene bromide is prepared from 25 g of 1-bromonaphthalene and 3.5 g of magnesium in 50 ml of diethyl ether, then the solution is cooled in ice and added dropwise. drop 9 ml of methoxyacetonitrile dissolved in 20 ml of diethyl ether. The reaction mixture is then stirred for 2 hours at room temperature and then cooled to 0 ° C. 100 ml of a saturated ammonium chloride solution are then added and the mixture is extracted with diethyl ether. The organic phase is successively washed with a saturated solution of sodium chloride, dried over sodium sulfate and evaporated to dryness, to provide 29 g of oily residue of methoxymethyl -1-naphthyl ketone.
• Step 2 The ketone previously obtained is dissolved in 350 ml of dichloromethane, then 50 ml of propylamine are added and then, at 5 ° C., and drop by drop, 120 ml of a 1M solution of TiCl 4 in dichloromethane.
• the reaction mixture is left under stirring at room temperature for 20 hours and then 200 ml of methanol are added.
• the solution is cooled in an ice bath, then 4.6 g of NaBH 4 are added in small quantities and the mixture is gradually allowed to return to room temperature.
• the reaction mixture is filtered through celite and the filtrate is evaporated to dryness. The residue is taken up in dichloromethane.
• the solution is washed with 1N hydrochloric acid.
• Step 1 Dissolve 4.0 g of 6-methoxyquinoline in 70 ml of acetic acid and then cooled to 0 C C and 5.5 g of KNO 3. The reaction mixture is stirred at 0 ° C for 1 hour and then basified with 10 N sodium hydroxide. The yellow precipitate obtained is filtered and washed thoroughly with water to obtain 4.9 g of yellow powder of 6 -methoxy-5-nitroquinoline.
• Step 2 4.9 g of 6-methoxy-5-nitroquinoline are dissolved in 100 ml of acetic acid and 60 ml of 37% hydrochloric acid, then 51 g of SnCl 2 are added and the reaction mixture is heated to reflux for 3 hours then at room temperature for 12 hours. It is then evaporated to dryness, the residue is taken up in water and basified with a saturated NaHCO 3 solution. Extracted with ethyl acetate, dried over sodium sulfate and then evaporated to dryness to obtain 2.9 g of yellow powder of 6-methoxy-5-quinolylamine.
• Step 1 10 g of 1-methoxynaphthalene are dissolved in 100 ml of acetic anhydride and then 2.6 ml of concentrated HNO3 dissolved in 15 ml of acetic anhydride are added dropwise. The reaction mixture is stirred for 30 minutes at room temperature and then basified with a saturated NaHCO3 solution. The brown precipitate formed is filtered, taken up in ethyl acetate, then successively washed thoroughly with a saturated NaCl solution, dried over sodium sulfate and evaporated to dryness.
• Step 2 2.45 g of the product obtained above are dissolved in 50 ml of acetic acid and 25 ml of concentrated HCl. 8.2 g of SnCl2, H2 ⁇ are added, the mixture is heated at reflux for 3 hours and then the reaction mixture is stirred for 12 hours at room temperature. The precipitate is filtered then taken up in a saturated NaHCO3 solution and extracted with acetate ethyl. The filtrate is evaporated, basified with a saturated NaHCO3 solution and then extracted with ethyl acetate. The two ethyl acetate solutions are combined, then dried and evaporated to dryness.
• Step 2 4 g of the product obtained above are dissolved in 80 ml of anhydrous THF at 0 ° C. and then a magnesium solution is added (0.96 g of magnesium in 50 ml of anhydrous THF to which 2.9 ml of bromide are added ethyl and some iodine crystals). The reaction mixture is stirred for 1 minute at 0 ° C., then 50 ml of a saturated NH4Cl solution are added. Extracted with ethyl acetate, dried over sodium sulfate and then evaporated to dryness.
• Step 1 In an assembly fitted with a Dean Stark, 9.5 g of 4-methoxybenzaldehyde and 7.8 g of aminoacetaldehyde dimethylacetal diluted in 50 ml of benzene are introduced. The reaction mixture is heated at reflux for 12 hours. The solution is evaporated to dryness, then taken up twice in benzene before being evaporated to dryness. The oil obtained is dissolved in anhydrous tetrahydrofuran and is maintained at -10 ° C. then an equivalent of ethyl chloroformate is added with rapid stirring and the reaction mixture is left stirring for 5 minutes more and the ice bath is removed (appearance of a yellow precipitate). 10.5 ml of trimethylphosphite are added at room temperature.
• the solution is filtered and extracted with a 3N hydrochloric acid solution, the aqueous phase is washed with dichloromethane, basified with a strong base and extracted with dichloromethane, dried over sodium sulfate and evaporated to dryness to obtain 6.2 g of light orange oil of 6-methoxyisoquinoline.
• Step 2 1.2 g of potassium nitrate are added to a solution of 1.0 g of 6-methoxyisoquinoline previously prepared in 20 ml of concentrated sulfuric acid, the whole being kept in an ice bath. After 1 hour of stirring, distilled water is added, then successively basified, filtered the precipitate and dried to obtain 1.2 g of yellow crystals of 6-methoxy-5-nitroisoquinoline.
• Step 3 0.9 g of the nitro derivative prepared above is dissolved in a solution of 40 ml of acetic acid and 22 ml of concentrated hydrochloric acid, then 10.2 g of tin chloride are added and the reaction mixture is heated at reflux for 3 hours, then 12 hours at room temperature. Basified and extracted with dichloromethane, the organic phase is dried and evaporated to dryness to obtain 0.7 g of yellow crystals of the expected amine.
• 6-methyl-5-nitroisoquinoline is prepared.
• 4.0 g of 6-methyl-5-nitroisoquinoline are dissolved in a solution of 80 ml of acetic acid and 40 ml of concentrated hydrochloric acid, then 40.0 g of tin chloride are added and the reaction mixture is heated to reflux for 3 hours, then it is left for 12 hours at room temperature.
• the crystals formed are filtered, taken up in water and made basic with 10 N sodium hydroxide. Extraction is carried out with dichloromethane, the organic phase is dried and evaporated to dryness to give 0.52 g of yellow crystals.
• Step 2 17 g of 5-nitro-1-tetrahydropyran-2-yl-indole are dissolved in 170 ml of methanol and then 3 g of Pd 10% on carbon are added, then in small quantities and at 0 ° C 20.6 g ammonium formate. After 1 hour 30 minutes of stirring at room temperature, the reaction mixture is filtered and the filtrate is evaporated to dryness. The residue is taken up with 300 ml of ethyl acetate. The solution is washed with 800 ml of water, dried over sodium sulfate and evaporated to dryness. 14.2 g of 5-amino-1-tetrahydropyran-2-ylindole are obtained in solid form.
• the organic products are extracted with diethyl ether, then successively basified with 33% sodium hydroxide, extracted with ethyl acetate, evaporated to dryness and purified on a column of silica gel eluted with a hexane mixture / ethyl acetate 75/25 (v / v) to obtain 3.2 g of white crystals, melting at 170-171 ° C.
• the compound thus obtained is deprotected by treatment with 30 ml of a 15% ammonia solution in ethanol at reflux for 1 night, then successively, the solvent is evaporated, extracted with dichloromethane, dried over sodium sulfate and evaporated to dryness. The residue is purified on a column of silica gel eluent: ethyl acetate / hexane 6/4 (v / v). 1.5 g of yellow powder are isolated from the expected thiourea.
• N- (1-Napht-1-yl-2-methoxyethyl) -N-propylthiourea (Compound 33) Step 1: 1.68 g of ammonium thiocyanate are suspended in 65 ml of acetone. The reaction mixture is cooled in ice and added with 2.5 ml of benzoyl chloride dissolved in 5 ml of acetone. After 15 minutes of stirring, at 5 ° C., 5.1 g of N- (1-naphth-1-yl-2-methoxyethyl) -N-propylamine dissolved in 60 ml of acetone are added dropwise.
• Step 2 5.50 g of the compound prepared above are dissolved in 100 ml of methanol and then 0.60 ml of hydrazine hydrate is added. The reaction mixture is left under stirring, at room temperature, for 20 hours. The methanol is evaporated and the residue is purified by chromatography on silica gel eluted with a 3/1 (v / v) cyclohexane / ethyl acetate mixture to provide 2.19 g of thiourea in the form of a yellow solid.
• the thiourea is prepared under normal conditions using 3.8 g of amine obtained previously (Compound 27), 1.8 g of ammonium thiocyanate and 4.8 ml of benzoyl chloride in anhydrous acetone.
• the deprotection is carried out in basic medium in 33% ammonia and makes it possible to obtain, after purification by chromatography on a column of silica gel eluted with ethyl acetate, 3.24 g of white crystals melting at 186 ° vs.
• Step 1 A methanolic solution containing 0.5 g of N- [6-methylisoquinol-5-yl] thiourea (Compound 35) and 0.6 g of 2-bromo-1- (2,4-dichlorophenyl) is heated to reflux. ) propan-1-one. The mixture is evaporated to dryness, the residue is taken up in a saturated potassium bicarbonate solution then extracted with dichloromethane, dried over sodium sulfate and evaporated to dryness to obtain 0.3 g of pale yellow crystals, melting at 187-188 ° C.
• Step 2 To a solution of 0.3 g of amine prepared above according to Step 1 in 50 ml of anhydrous dimethylformamide is added 0.05 g of 55% NaH and the reaction mixture is left under stirring and under argon for 15 minutes, before adding 0.3 ml of 1-bromopropane. The mixture is then heated at 80 ° C. for 2 hours, then 1 equivalent of NaH and 1 equivalent of bromopropane is added and the reaction mixture is stirred at room temperature for 12 hours. Evaporated to dryness, the residue is taken up in a saturated solution of sodium hydrogencarbonate and extracted with dichloromethane.
• R-, Cl;
• R 2 OCH 3 ;
• R 3 H;
• R 4 CH 3 ;
• R 5 -CH 2 CH 2 CH 3 ;
• n 0;
• Step 1 1.5 g of N- [6-methylisoquinol-5-yl] thiourea (Compound 36) are dissolved in 40 ml of methanol and then 2.1 g of 2-bromo-1- (2-chloro- 4-methoxyphenyl) propan-1-one and heat the reaction mixture at reflux for 12 hours. Evaporated to dryness, taken up in a saturated sodium hydrogen carbonate solution, then successively extracted with ethyl acetate, dried over sodium sulfate, filtered and concentrated in vacuo.
• the residue is purified by chromatography on a column of silica gel, eluting with an ethyl acetate / hexane mixture 75/25 (v / v) to obtain, after concentration of pure fractions, 1.3 g of yellow powder of 4- (2 -chloro-4-methoxyphenyl) -5-methyl-2- [N- (6-methylisoquinol-5-yl) amino] thiazole.
• Step 2 Add to a solution of 0.2 g of 55% NaH in 20 ml of anhydrous dimethylformamide 1, 3 g of the preceding amine prepared according to Step 1 and leave the reaction mixture with stirring and under argon for 15 minutes, before adding 0.6 ml of 1-bromopropane.
• reaction mixture is stirred at room temperature for 1 hour, 100 ml of a saturated NH 4 CI solution are added and then successively extracted with ethyl acetate, this phase is washed with a saturated NaCl solution, evaporated to dry and purified on a column of silica gel eluted with an ethyl acetate / hexane mixture 25/75 (v / v) to obtain, after concentration of the pure fractions, 0.8 g of yellow oil.
• Step 1 In a flask fitted with a Dean Stark, 3.0 g of 4-quinolinecarboxaldehyde and 5.0 g of 2-amino-4- (2,4-dichlorophenyl) -5-methylthiazole are dissolved in 50 ml of benzene. The reaction mixture is maintained at reflux for 24 hours. Evaporated to dryness, taken up in a saturated solution of sodium hydrogencarbonate and extracted with dichloromethane. Evaporated to dryness, and the residue is purified by chromatography on a column of silica gel eluted with ethyl acetate + 2% triethylamine.
• the concentration of the pure fractions provides 8.2 g of bright yellow crystals melting at 140-141 ° C from 4- (2,4-dichlorophenyl) -5-methyl-2- (N- (quinol-4-yl-methyl) imino) thiazoie.
• Step 2 In a three-necked flask kept under argon, 8.5 g of imine prepared previously according to Step 1 diluted in anhydrous tetrahydrofuran are slowly added to a solution containing an organomagnesium obtained from 1.0 g of magnesium and 4.8 g of cyclopropyl bromide. The excess magnesium is destroyed by adding a saturated solution of ammonium chloride and extracted with diethyl ether.
• Step 3 To a solution of 5.46 g of amine prepared according to step 2 in 50 ml of anhydrous dimethylformamide is added 0.6 g of 55% NaH and the reaction mixture is left under stirring and under argon for 15 minutes, before adding 1.8 g of 1-bromopropane. The reaction mixture is heated at 80 ° C for 2 hours, added one equivalent of NaH and 1 equivalent of bromopropane and allowed to stir at room temperature for 12 hours. Evaporated to dryness, taken up in a saturated solution of sodium hydrogencarbonate and extracted with dichloromethane.
• oxalic acid diluted in a minimum of isopropanol is added to a solution of diethyl ether containing 0.8 g of aminothiazole prepared previously according to step 3 and then the precipitate obtained is recrystallized from isopropanol to obtain yellow crystals melting at 164-165 ° C.
• Step 1 10.9 g of 4- (2-chloro-4-methoxyphenyl) -5-methyl-2- [N- (1- (tetrahydropyran-2-yl) indo! -5-yl) -amino] thiazole are dissolved in 110 ml of dimethylformamide. 1.06 g of 60% sodium hydride are added at 0 ° C. in oil then 3.2 ml of propyl bromide. After 16 hours of stirring at room temperature, the reaction mixture is poured into 500 ml of water and extracted with 3 times 250 ml of ethyl acetate. The organic phase is washed with 3 times 200 ml of water, dried over sodium sulfate and evaporated to dryness.
• Step 1 With 1.2 g of 4- (2-chloro-4-methoxyphenyl) -5-methyl-2- [N- (indol-5-yl) -N-propylamino] thiazole previously obtained (EXAMPLE 7) solution in 20 ml of methanol, are added at 0 ° C under argon 0.14 g of sodium hydride at 55% in oil then 1.6 ml of methyl 2-bromo ⁇ ropionate. After 24 hours of stirring, the reaction mixture is poured into ice water and extracted with ethyl acetate. After drying and evaporation to dryness under vacuum, the residue is taken up in 20 ml of methanol.
• Step 2 0.8 g of product obtained above ⁇ iment dissolved in 15 ml of dimethylformamide are added 0.294 g of Cs2CO3 and 0.31 ml of iodide methyl. After 3 hours of stirring the reaction mixture is diluted with ethyl acetate, washed several times with water saturated with sodium chloride, dried over sodium sulfate and then evaporated to dryness under vacuum. The residue is purified by chromatography on a column of silica gel eluted with a cyclohexane / ethyl acetate 5/1 (v / v) mixture. The expected product is isolated in the form of a colorless oil (0.66 g).
• the hydrochloride monohydrate is obtained by adding a 0.1N HCl solution in isopropanol in the form of a white solid; Mp 80 ° C. 1 H NMR (CDCl3): 0.92 (f, 3H); 1.62-1.74 (m, 2H); 1.83 (d, 3H); 2.02 (s, 3H); 3.74 (s, 3H); 3.81 (s, 3H); 3.88-3.98 (m, 2H); 5.13-5.20 (m, 1H); 6.59 (d, 1H); 6.82-7.62 (m, 7H).
• the residue is purified by chromotography on a column of silica gel eluted with a CH2Cl2 / CH3OH 98/2 mixture (v / v).
• the hydrochloride obtained in hydrated form (dihydrate) is prepared using a 0.1 N HCl solution in isopropanol; Mp 134 ° C.
• Step 1 At 1.1 g of 4- (2-chioro-4-methoxy ⁇ henyl) -5-methyl-2- [N- (indol-5-yl) N-propylamino] thiazole previously obtained (EXAMPLE 7) 0.35 g of 55% sodium hydride in oil and then 1 ml of bromoacetonitrile are added to 10 ° C. in argon in 10 ml of dimethylformamide under argon. After 18 hours of stirring at room temperature, the reaction mixture is poured into ice water. The mixture is extracted with ethyl acetate and the organic phase is washed several times with water, dried over sodium sulfate and evaporated to dryness. The residue is purified by chromatography on a column of silica gel eluted with a cyclohexane / ethyl acetate mixture 9/1 (v / v).
• Step 2 To 0.66 g of the product obtained in the previous step dissolved in 10 ml of anhydrous diethyl ether is added at 0 ° C 1.3 ml of a 1.4 M solution of methyl magnesium bromide. After 5 hours at room temperature, the reaction mixture is hydrolyzed by addition of a saturated solution of ammonium chloride. The mixture is extracted with ethyl acetate and the organic phase is washed several times with water, dried and then evaporated to dryness. The residue is purified by chromatography on a column of silica gel eluted with a CH2Cl2 / CH3OH 98/2 mixture (v / v). The expected product is isolated in the form of an oil.
• the hydrochloride is obtained by adding a 0.1 M HCl solution in isopropanol in the form of a white solid monohydrate; Mp 189 ° C. 1 H NMR (CDCl3): 0.90 (f, 3H); 1.41 (s, 3H); 1.57-1.68 (m, 2H); 2.01 (s, 3H); 2.10 (s, 2H); 3.81 (s, 3H); 3.85-3.92 (m, 2H); 6.60-7.63 (m, 8H).

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