HK1070361B

HK1070361B - 5-sulphanyl-4h-1,2,4-triazole derivatives and their use to treat disorders associated with somatostatine

Info

Publication number: HK1070361B
Application number: HK05103025.8A
Authority: HK
Inventors: Marie-Odile Galcera Contour; Alban Sidhu; Pierre Roubert; Christophe Thurieau
Original assignee: Ipsen Pharma S.A.S.
Priority date: 2001-11-28
Filing date: 2002-11-27
Publication date: 2010-04-23

Description

The present application concerns novel derivatives of 5-sulfanyl-4H-1,2,4-triazoles and their preparation processes by parallel synthesis methods in the liquid phase. These products have a good affinity for certain subtypes of somatostatin receptors and are of particular interest for the treatment of pathological conditions or diseases in which one or more somatostatin receptors are involved. The invention also concerns pharmaceutical contents of these products and their use in the preparation of a medicinal product.

Somatostatin (SST) is a cyclic tetradecapeptide that was first isolated from the hypothalamus as a growth hormone inhibitor (Brazeau P. et al., Science 1973, 179, 77-79). It also acts as a neurotransmitter in the brain (Reisine T. et al., Neuroscience 1995, 67, 777-790; Reisine et al., Endocrinology 1995, 16, 427-442). The heterogeneity of somatostatin's biological functions and the structure-activity relationships of its peptide analogues led to the discovery of 5 subtypes of membrane-bound receptors (Yamada et al., Proc.l. Sci.U.S.A., 89, 251-255, 1992; Raynor, K. and al. 44, 1993). These five subtypes of receptor directly depend on the molecular activity of the clot (Molysatin, 1993).

The functional roles of these receptors are currently being actively studied. Preferential activation of subtypes 2 and 5 has been associated with the suppression of growth hormone GH (acromegaly), TSH and prolactin in the adenomas secreting these hormones; but the precise role of each subtype remains to be determined.

The pathological disorders associated with somatostatin (Moreau J.P. et al., Life Sciences, 1987, 40, 419; Harris A.G. et al., The European Journal of Medicine, 1993, 2, 97-105) include endocrine disorders associated with excess of hormones such as growth hormone, insulin or glucagon. The compounds of the present invention are therefore indicated for the treatment of such diseases as acromegaly, pituitary adenomas, Cushing's disease, gonadotrophinomas and prolactomas, diabetes and its complications, diabetic retinopathy, diabetic nephropathy, hyperthyroidism, pancreatitis.The compounds of the present invention are indicated for the treatment of diseases such as endocrine gastroenteropankreatic tumours including carcinoid syndrome, VIPoma, insulinoma, nesidioblastosis, hyperinsulinemia, glucagonoma, gastrinoma and Zollinger-Ellison syndrome, GRFoma and acute esophageal varicose vein bleeding, gastroesophageal reflux, gastroodular reflux, pancreatitis, intracutaneous and pancreatic troubles but also diarrhoea, gastric peptide-related diseases, secondary intestinal grafts, hypertension and hemorrhoids in patients with surgery,The compounds of the present invention are indicated for the treatment of diseases associated with cell proliferation such as cancers and in particular breast cancer, prostate cancer, thyroid cancer as well as pancreatic and colorectal cancer, brain cancer, lung cancer, fibrosis and in particular kidney fibrosis, liver fibrosis, lung fibrosis, skin fibrosis,also central nervous system and nasal fibrosis and chemotherapy-induced fibrosis. Other treatment areas such as headaches including headaches associated with pituitary tumours, pain, mental disorders such as anxiety, depression and schizophrenia, chemotherapy, wound healing, stunted renal function, obesity and stunted growth due to obesity, uterine stunted growth, skeletal dysplasia, Noonan's syndrome, sleep apnea syndrome, Graves' disease, polycystic ovary disease, pseudocystic ovaries and asemia,The Commission has also been involved in the preparation of a communication on the future of the European Union.

Imidazole derivatives useful for the treatment of somatostatin-associated disorders have been described in previous art (WO 99/64401, WO 01/09090).

As somatostatin and its peptide analogues often have poor oral bioavailability and poor selectivity (Robinson, C., Drugs of the Future, 1994, 19, 992; Reubi, J.C. et al., TIPS, 1995, 16, 110), the non-peptide agonists or antagonists of somatostatin, described below, can be advantageously used to treat pathological conditions or diseases such as those described above in which one or more of the somatostatin receptors is (are) involved.

The compounds of the invention are also analogues of urotensin II and are therefore of particular interest in the treatment of pathological conditions or diseases in which urotensin II is involved.

Human urotensin (hU-II) is a cyclic undecapeptide where the cyclic hexapeptide portion is conserved and also present in other animal forms of the protein (P. Grieco et al., 2002; Bioorg. Med. Chem. 10, MaguJom 2002, 3731-3739). In humans, urotensin II has been shown to be an important vector on the nervous system and in vitro, the neurotransmitter V.J. Dactylosporin, present in the brain and the brain, and possibly 578 neurotransmitters (P.J. Dactylosporin, 2002; A.J. Brodom, 2002; J.J. Dactylosporin, 2002).

The compounds of the general formula described below, as analogues of urotensin II, may be used to treat pathological conditions related to hypertension (portal, pulmonary, renal, cerebral), cardiovascular disorders (hypertrophy of the heart, cardiac arrhythmia, angina), pulmonary disorders (asthma), as well as atherosclerosis and stroke. Furthermore, since U-II and its receptor are present in the central nervous system of mammals, the compounds of the invention may also be used in the treatment of anxiety, stress, schizophrenia, depression and neuromuscular function.

The present invention therefore concerns compounds of general formula - What? in racemic, enantiomeric or any combination of these forms, in which: R1 represents a radical of formula -(CH2)n-[Q]p-(CH2)m-NXY in which X and Y are the hydrogen atom or a (C1-C6) alkyl, independently; p and n are 0, and m is an integer from 2 to 6. and the other two radicals R2 and R3 are independently a radical of the formula -(CH2)n[Q']p'[C(X')(Y')]m'Z' in which Q' is -O-, -S-, -C(O), -NH-, -CH=CH- or -CC-; X', Y' and Z' are independently hydrogen atoms, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) alkoxy-carbonyl, cyano, amino, (C1-C6) alkylamino, di((C1-C6) alkyl) amino, (C3-C7) cycloalkyl, heterocycloalkyl, aryl or heteroaryl, or a radical with the formula - What? a thickness of not more than 0,05 mm,Err1:Expecting ',' delimiter: line 1 column 200 (char 199)- What? Excluding compounds for which: R3 represents a hydrogen atom, R2 the methyl radical and R1 the 2-dimethylaminoethyl radical;R3 and R2 represent a hydrogen atom, and R1 the 2-dimethylaminoethyl radical, 3-dimethylaminopropyl, 6-dimethylaminohexyl, 2-dipropylaminoethyl or 2-diethylaminoethyl;R3 represents a hydrogen atom, R2 the amino radical and R1 the 2-dimethylaminoethyl radical,R3 represents a hydrogen atom, R2 the 2-hydroxyl radical and R1 the 2-diethylaminoethyl radical.

In the definitions given above, the term halo represents the fluoro, chloro, bromo or iodine radical, preferably chlorine, fluorine or bromo. The term alkyl (if not specified), preferably represents an alkyl radical with 1 to 6 carbon atoms, linear or branched, such as the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, dry-butyl and tert-butyl, pentyl or amyl, isopentyl, neopentyl, hexyl or hexyl radicals. In addition, in this application, the radical -CH2) 'n' represents a hydrocarbon chain of non-carbon atoms which may be branched or branched; the radical -CH2-n' may represent the alkyl radicals as defined above.

The term (C3-C7) cycloalkyl refers to a monocyclic carbon system consisting of 3 to 7 carbon atoms, and preferably cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl cycles. The term heterocycloalkyl refers to a saturated cycloalkyl containing 2 to 7 carbon atoms and at least one heteroatom. This radical may contain several identical or different heteroatoms.

Alkoxy radicals may be the alkyl radicals indicated above, such as methoxy, ethoxy, propyloxy or isopropyloxy radicals, but also linear, secondary or tertiary butoxy, pentyloxy.

The term heteroaryle refers to an aromatic radical, consisting of a cycle or cycles, with at least one cycle containing one or more identical or different heteroatoms chosen from sulfur, nitrogen or oxygen. Examples of heteraryle radicals include thienyle, furyl, pyrothiyl, imidazole, aryolyl, pyrazothiazole, pyrozole, isoxazole, oxazole, triazole, thiol, pyrol, pyrol, pyrimidyl, quinyl, quinyl, quinyl, benzyl, benzyl, benzyl, benzyl, benzyl, benzyl, and benzyl, and the above terms may be defined as the following: xylenol, xylenol, xylenol, and benzyl, and onyl, thiazoyl, thiazoyl, thiazoyl, and onyl.

The terms alkylamino and dialkylamino refer preferably to radicals in which the alkyl radicals are as defined above, such as methyllamino, ethyllamino, dimethyllamino, diethyllamino or (methyl) ((ethyl) amino.

Err1:Expecting ',' delimiter: line 1 column 574 (char 573)

R2 is most preferably an aryl or heteroaryl radical which may be substituted, and more particularly a naphthyte, phenyl, benzothienyl, quinoxalyl, quinolyl, isoquinolyl or indoyl; the phenyl, e-naphthyl and quinolyl radicals may be substituted by one or more (C1-C6) alkoxy, halo, nitro, hydroxy, (C1-C6) alkyl radicals which are identical or different, the (C1-C6) alkyl itself being possibly substituted by one or more identical or different halo radicals.

Err1:Expecting ',' delimiter: line 1 column 382 (char 381)

The present invention also relates in particular to compounds of general formula I as defined above in which the

R1 represents a radical of formula -(CH2)n-[Q]p-(CH2)m-NXY in which X and Y represent, independently, the hydrogen atom or a (C1-C6) alkyl; p and n are 0 , and m is an integer from 2 to 6.

R2 represents quinoxalyl, quinolyl or naphthyl, where the quinolyl and naphthyl radicals may be replaced by one or more (C1-C6) alkyl, (C1-C6) alkoxy, halo radicals, identical or different;

Err1:Expecting ',' delimiter: line 1 column 307 (char 306)

In this application, the symbol -> * corresponds to the point of attachment of the radical. When the attachment site is not specified on the radical, this means that the attachment takes place at one of the sites available for this radical for such an attachment.

The compounds of the invention may be prepared in the liquid phase according to the following general scheme: - What?

Preparation of isothiocyanates (1)

Isothiocyanates of general formula (1) can be prepared from the corresponding primary amines by two methods:

1.1 Method A:

A primary amine is converted to isothiocyanate by the action of O,O-di (((2-pyridinyl) thiocarbonate (1 equ.) in anhydrous aprotic solvents such as dichloromethane, tetrahydrofuran or dimethylformamide (Kim, S. ; Lee, J.I. Tetrahedron Lett. 1985, 26 (13), 1661-1664). The reaction mixture is agitated at room temperature for 1 to 4 hours and then the solvents are evaporated and the residue used in the next step without further purification.

Preparation 1 : tert-butyl 4-isothiocyanate butylcarbamate (C10H18N2O2S, M = 230,33)

A solution of O,O-di- ((2-pyridinyl) thiocarbonate (3.9 g; 17 mmol) dissolved in tetrahydrofuran is added to tert-butyl 4-aminobutylcarbamate (3.2 ml; 17 mmol). The solution is agitated for 2 hours at room temperature. The solvent is evaporated and the resulting solid is used without delay in the next step.

Isothiocyanates of general formula R1NCS have been synthesised in this way with the following R1 groups whose primary and secondary amines are protected by a tert-butoxycarbonyl group:

1.2 Method B:

A primary amine is converted to isothiocyanate by action of dithioxomethane (10 eq.) in the presence of N-cyclohexylcarbodiimide, N-methylpolystyrene (Novabiochem; charge greater than 1.5 mmol/g, 1.1 eq.) resin, inflated in an aprotic solvent such as dichloromethane or tetrahydrofuran, agitated at room temperature for 1 to 4 hours, and the filtrate evaporated and used in the next step without further purification.

The following is added to the list of active substances:

Add dithioxomethane (1 ml; 16.6 mmol) to N-cyclohexylcarbodiimide resin, N-methylpolystyrene (1 g; 1.69 mmol/g; Novabiochem) in dichloromethane (15 ml). The suspension is agitated for 30 minutes and then N,N-dimethyl-1,4-butanediamine (0.19 ml; 1.5 mmol) is added. The reaction mixture is agitated for 3 hours and then filtered. The filtrate is filtered and used immediately in the next step.

Isothiocyanates of general formula R1NCS have been synthesised by this method with the following R1 groups whose primary amines are protected by a tert-butoxycarbonyl group:

Preparation of hydrazides (4):

2.1 Preparation of carboxylic acids (2):

When not commercially available, carboxylic acids of general formula (2), in which R2 is an aryl or heteroaryl group, may be prepared from the corresponding methyl derivative by oxidation to aldehyde, e.g. selenium dioxide, followed by a second oxidation to carboxylic acid, e.g. sodium chlorite (Bu, X.; Deady, L. W. ; Finlay, G. J. ; Baguley, B. C. Denny, W. A. J. Med. Chem. 2001, 44, 2004-2014).

Preparation 3 : 6-chloroquinoline-2-carboxylic acid (C10H6ClNO2, M = 207,62) is obtained by the addition of a solution of

Add 6-chloro-2-methylquinoline (500 mg; 2.8 mmol) to a suspension of selenium dioxide (1.87 g; 16.9 mmol; 6 eq.) in dioxane (25 ml) at 80 °C. Agitate the reaction mixture for 3 hours at the reflux and then filter the insoluble at hot temperatures. The dioxane is then evaporated at reduced pressure and the resulting aldehyde is used without purification in the next step.

The frequency range of the signal is defined as the frequency range of the signal, which is the frequency range of the signal.

Add a solution of sodium chlorite (2.4 g) and sodium dihydrogen phosphate (2.4 g) in water (24 ml) to a solution of 6-chloroquinoline-2-carbaldehyde (536 mg; 2.8 mmol) in ter-butyl alcohol (56 ml) and 2-methylbutene-2-ene (14 ml) for 5 minutes. Stir the resulting mixture for 4 hours at room temperature. Evaporate the organic solvents at reduced pressure and add water (30 ml) to the residue. Filter the precipitate with water and vacuum in the presence of P2O5.

The frequency range of the signal is defined as the frequency range of the signal.

Carboxylic acids of general formula R2COOH have been synthesised by this method with the following R2 groups: - What?

2.2 Preparation of methyl esters (3):

A carboxylic acid is first converted into a methyl ester, for example by the action of an excess of diazomethane or a diazomethane substitute such as trimethylsilyldiazomethane in methanol, in the presence or absence of an aprotic solvent such as diethyl ether or dichloromethane (Caturla, F.; Najera, C. Varea, M. Tetrahedron, 1999, 40 (32), 5957-5960).

The methyl esters are isolated after extraction and washing and used without further purification in the next step.

Repair 4 : 4-fluoro-1-methylnaphtoate (C12H9FO2, M = 204,20) is obtained by the reaction of 4-fluoro-1-naphtoate with a phosphorus content of less than 0,5% by weight.

A solution of 4-fluoro-1-naphtoic acid (1 g; 5.3 mmol) dissolved in a mixture of dichloromethane (10 ml) and methanol (15 ml) is added to a solution of (trimethylsilyl) diazomethane in solution in hexane (6 ml, 2 mol/l) until the solution retains a slight yellow colour and no longer degassed. The excess of (trimethylsilyl) diazomethane is neutralized by adding a few drops of acetic acid until the solution is colourless. The reaction solution is evaporated, then dissolved in ethyl acetate (20 ml, 2 mol/l) and washed with distilled water (10 ml), then a saturated sodium chloride solution is made to a white phase (SM = 11.23 g/m2) and then evaporated to give sodium sulphate (H = 11.78 g/m3) (sodium chloride + sodium sulphate) (SM = 0.21 mL).

Methyl esters of formula R2COOMe have been synthesised with the following R2 groups whose primary and secondary amines are protected by a tert-butoxycarbonyl group:

2.3 Preparation of hydrazides (4):

The hydrazides of general formula (4) can be obtained by the action of hydrazine hydrate (3 to 10 equ) on the esters of general formula (3) in a protic polar solvent such as ethanol or methanol (Leung, H. K.; Phillips, B. A.; Cromwell, N. H.; J. Heterocycl. Chem. 1976, 13, 247-252). The reaction is maintained for 18 to 96 hours at room temperature or 50°C. After evaporation, the reaction medium is taken up by a solvent such as ethyl acetate and washed with water.

The following formulae are used: - What?

The reaction mixture is agitated at room temperature for 60 hours and the solvent is evaporated. The residue is solubilised in ethyl acetate (20 ml) and washed with distilled water (15 ml) and then an aqueous solution saturated with sodium chloride (15 ml). The organic phase is dried on magnesium sulphate, then evaporated and vacuum dried to a white powder (0.94 g; yield = 83%).

The frequency of the signal is measured at a frequency of approximately 1 MHz (see Figure 1).

Hydrazides of formula R2CONHNH2 have been prepared with the following R2 groups whose primary and secondary amines are protected by a tert-butoxycarbonyl group:

Preparation of hydrazine carbothioamides (5):

The isothiocyanates of general formula (1) (1,1 equ.) are added to the hydrazides of general formula (4) in an aprotic solvent such as dichloromethane or dimethylformamide and the reaction medium is agitated at room temperature for 18 to 24 hours.

Preparation 6 : N-phenyle-2- (phenyl) acetylated) hydrazine carbothioamide (C15H15N3OS, M = 285,37)

A 2-phenylacetohydrazide (1.5 g; 10 mmol) solubilised in dichloromethane (20 ml) is added to the phenylisothiocyanate (1.3 ml; 11 mmol). The solution is agitated at room temperature until the product precipitates. The white solid formed is filtered and washed with ethyl ether (10 ml), vacuum dried (2,1 g; yield = 74%).

Hydrazine carbothioamides of general formula (5) have been synthesized for the preparation of the compounds of the invention with the following groups R1 and R2 whose primary and secondary amines are protected by a tert-butoxycarbonyl group:

R1 is: - What?

R2 , please . - What?

Preparation of triazoles (6):

After dissolving the general formula hydrazinethiocarbamide (5) in a solvent of the dioxane or toluene type, the cycling step takes place in a protic solvent such as ethanol or methanol in the presence of a solution of soda (1M to 4M) or potash (1M to 4M). The reaction is maintained at 85°C for a period ranging from 4 to 18 hours and then, after evaporation of the solvents, the thiolate is transformed into thiol (6) e.g. by an ion exchange resin such as Amberlite IRN 77 (H+) (Prolabratation). The resin is filtered and the wire concentrated.

The following formula is used for the preparation of the product:

To N-phenyle-2- ((phenylacetyl) hydrazinecarbothioamide (3.7 g; 13 mmol) dissolved in a mixture of dioxane (30 ml) and methanol (10 ml) a normal aqueous solution of sodium hydroxide (20 ml) is added. The solution is agitated and heated to 85°C for 4 hours. The solvents are evaporated and the residue is soluble in methanol (25 ml). An ion exchange resin pre-rinsed with methanol (Amberlite IRN 77, 50 g, Pro) is added to the solution, agitated for 15 minutes and then filtered. The filtrate is then evaporated under vacuum (3.4 g; efficiency = 98 %).

The triazoles of general formula (6) have been prepared with the same R1 and R2 groups as those described for the preparation of hydrazine carbothioamides (5) above.

Preparation of brominated intermediates (8): 5.1 Preparation of benzyl bromides (8a) 5.1.1 General case:

Benzyl bromides of general formula (8a) can be obtained from corresponding alcohols (7a) according to the procedures described in the literature, for example by treatment with aqueous hydrobromic acid at the reflux (Kinoshita, T.; Okunaka, T.; Ohwada, H.; Furukawa, S. J. Heterocycl. Chem. 1991, 28 (8), 1901-1909) or by an inorganic acid halide such as P;3 or SOBr2 (Nagle, A. S. Salvatore, R. N.; Chong, B.-D. Jung; K. W. Jung; Tetrahedron, 2000, aproport (17), 3011-3014) or by a mixture of N-bromosuccinide of tetrahydrange and triphosphenyl in a solvent such as chlorophyll or chlorophyll; or by a dichlorophenol; or by a dihydrophenol; or by a dihydrophenol (Ambrosio, P. P. 117, M. 633; R. C. Campbell, M. 637, J. C. Rapport, 1996, 1117-13, or a dihydrophenol; or a dichlorophenol; or a dihydrophenol; or a dihydrophenol; or a dihydrophenol; or a dihydrophenol; or a dihydrophenol; or a dihydrate; or a dihydrate; or dihydrate; or a dihydrate; or dihydrate; or dihydrate; or dihydrate; or dihydrate; or dihydrate; or dihydrate; or dihydrate; or dihydrate; or dihydrate; or dihydrate; or dihydrate; or dihydrate; or dihydrate; or dihydrate; or dihydrate; or dihydrate; or dihydrate; or dihydrate; or dihydrate; or dihydrate; or dihydrate; or dihydrate; or dihydrate; or dihydrate; or dihydrate; or dihydrate; or dihydrate; or dihydrate; or dihydrate; or dihydrate; or dihydrate; or dihydrate; or dihydrate; or dihydrate; or dihydrate;

Preparation 8 : 5- (bromomethyl) - 1,3-benzodioxol (C8H7BrO2, M = 215,05) is obtained from the following formula:

Add carbon tetrabromide (3.8 g; 11.5 mmol) to 5-methanol) -1.3-benzodioxol (1.5 g; 10 mmol) dissolved in dichloromethane (30 ml); cool the mixture to 0 °C. Add triphenylphosphine (3.0 g; 11.5 mmol) by half, stir the solution for two hours at room temperature. Evaporate the solvent and purify the resulting solid by silica column chromatography (elevant: heptane/ethyl acetate: 3 / 1).

A benzyl bromide of formula R3Br has been synthesized with the following R3 group: - What?

5.1.2 Special case of methylindolic bromides (8a):

In the case of brominated intermediates of general formula (8a) of the methylindolic type, they can be obtained in three steps from the corresponding indole-carbaldehydes, first by protecting the indole, then by reducing the aldehyde function followed finally by bromination of the alcohol function thus obtained.

5.1.2.1 Protection of the indole:

An adequate protective group such as, for example, a carbamate-type group (e.g. tert-butoxycarbonyl group) is introduced into the indole by the classic methods known to the art (P. J. Kocienski, Protecting Groups, 192 (Georg Thiem Verlag Stuttgart, 1994)), e.g. by di-tert-butyl dicarbonate in acetonitrile or dimethylformamide at room temperature in the presence of a catalyst such as dimethyaminopyridine.

Preparation 9 : tert-butyl 6-formyl-1H-indole-1-carboxylate (C14H15NO3, M=245,28) is obtained by the addition of a solution of

The mixture is agitated at room temperature for 16 hours. The acetonitrile is evaporated; the residue dissolved in ethyl acetate (30 ml) is washed twice in distilled water (20 ml) by an aqueous solution saturated with sodium chloride (20 ml). The organic phase is dried on magnesium sulphate, evaporated and vacuum dried. The product is obtained as a white solid (0.514; yield = 61%).

The frequency of the signal is measured at a frequency of approximately 1 Hz (dMSO-d6, 400 MHz) δ: 10.06 (s, 1H, CHO) ; 8.60 (s, 1H, arom.); 7.92-7.91 (d, J = 3.7Hz, 1H, arom.), 7.81-7.75 (m, 2H, arom.); 6.84-6.83 (d, J=3.7Hz, 1H, arom.) ; 1.65 (s, 9H, t-Bu).

5.1.2.2 Preparation of alcohols (7a)

Alcohols of general formula (7a) can be obtained by reduction of aldehydes of general formula (10) by the classical methods known to the art, such as by the action of the system: NiCl2.6H2O-Zn in a water/DMF mixture at room temperature (Baruah, R. N. Tetrahedron Lett. 1992, 33 (37), 5417-5418) or by the use of NaBH4 in ethanol at room temperature (Cho, Y. J. Lee, S. H. Bae, J. W. ; P. H. Yeon; C. M. Tetrahedron; 2000 (20), 41; 3915-3917) or by the use of BuSnH3 in a solvent such as proti, e.g., the methanol (Kami, K. Lett., 1999, M. M. 906-991).

Preparation 10 : tert-butyl 6- ((hydroxymethyl) - 1H-indole-1-carboxylate (C14H17NO3; M = 247,30) is obtained by the addition of a solution of

The tert-butyl 6-formyl-1H-indole-1-carboxylate (0.514 g: 2.1 mmol) is dissolved in ethanol (5 ml) and then sodium borohydride (0.159 g; 4.2 mmol) is added slowly and the solution is stirred at room temperature for 2 hours. The solvent is evaporated, and the residues dissolved in ethyl ether (20 ml) are washed with a solution of sodium hydroxide (1N; 10 ml) and then with a solution saturated with sodium chloride (10 ml). The organic phase is dried on magnesium sulphate, then evaporated and vacuum dried. The alcohol is obtained as a white solid (0.48 g, yield = 93 %).

The frequency range of the measurement is defined as the frequency range of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measurement of the measur

5.1.2.3 Preparation of methylindolic bromides (8a)

Methylindolic bromides of general formula (8a) are obtained from general formula (7a) alcohols by the general bromination processes described above for the preparation of benzyl bromides.

A methylindolic bromide of formula R3Br has been synthesized with the following R3 group: - What?

5.2 Preparation of ethylindolic bromides (8b)

In the case of brominated intermediates of general formula (8) of the ethylindole type, they can be obtained in four steps from the corresponding indoles, first by conversion to α-ketoacid chloride (11) followed by transformation to α-ketoester (12) then reduction to alcohol (7b), and finally by preparation of the brominated intermediate (8b).

5.2.1 Obtaining α-cetoacid chlorides (11):

The α-ketose chlorides (11) can be obtained by the action of oxalyl chloride in an apolar aprotic solvent such as diethyl ether at room temperature (Woodward, R. B.; Bader, F. E.; Bickel, H.; Frey, A. J.; Kierstead, R. W. Tetrahedron 1952 2, 1).

Preparation 11 : chloride of (6-methoxy-1H-indol-3-yl) oxoacetyl_C11H8ClNO3, M = 237,64) is obtained by the reaction of the two hydrocarbons methacrylate and methacrylate with the hydrocarbons methacrylate.

5-Methoxyindole (1g; 6.8 mmol) dissolved in ethyl ether (25 ml) is cooled to 0 °C. Oxalyl chloride (8.8 mmol; 0.77 ml) is added drop by drop under argon and the mixture is agitated at room temperature under argon atmosphere for three hours. The expected product is obtained as a yellow powder after filtration and washing with ethyl ether.

The frequency range of the signal is defined as the frequency range of the signal at which the signal is received.

α-Cetoacid chlorides of formula R3'C(O)C(O)Cl have been prepared with the following R3 indolic groups: - What?

5.2.2 Esterification of α-cetoacid chlorides (11) into α-cetoesters (12):

Indol α-ketosters (12) are obtained by the conventional esterification methods known to man of science, such as, for example, the treatment of the corresponding α-ketoster chloride by an alcohol (such as methanol or ethanol) in the presence of an organic base such as, for example, triethylamine or diisopropylethylamine.

Preparation 12 : (6-methoxy-1H-indol-3-yl) ((oxo) ethyl acetate (C13H13NO4, M = 247,25) is obtained by the treatment of a mixture of ethyl acetate and methyl acetate with a pH of less than 0,01

The (6-methoxy-1H-indol-3-yl) oxoacetyl chloride (1.44 g; 6.06 mmol) dissolved in ethanol (15 ml) is cooled to 0 °C and triethylamine (1.04 ml; 7.5 mmol) is added drop by drop. The mixture is heated at low temperature for 2 hours. The precipitate is filtered, washed with ethanol (5 ml) and ethyl ether (5 ml) and vacuum dried. The expected product is obtained as a yellow powder (1.36 g; yield = 91%).

α-ketosteres of formula R3'C(O)C(O)OEt have been prepared with the following R3' indolic groups:

5.2.3 Reduction of α-ketones (12) to ethylindolic alcohols (7b):

The α-ketosteres of general formula (12) can be reduced to general formula (7b) ethyl alcohols by treatment e.g. by lithium and aluminium hydride in an aprotic solvent such as tetrahydrofuran at reflux (Feldman, P. L.; Rapoport, H. Synthesis 1986 (9), 735-737).

The following formula is used for the preparation of the product:

The reaction mixture is brought to reflux, and agitated for 2 hours. The excess lithium and aluminium acetate is neutralized by the addition of ethyl acetate (1 g; 5.5 mmol) in the tetrahydrofuran (15 ml) is cooled to 0 °C. The lithium and aluminium hydride in solution in the tetrahydrofuran (1 M; 16.5 ml; 16.5 mmol) is then added slowly. The reaction mixture is brought to reflux, and agitated for 2 hours. The excess lithium and aluminium hydride is neutralized by the addition of ethyl acetate (1 ml) and filtered water (1 ml). The reaction is clarified under hot conditions and the solid is dissolved with ethanol (10 ml). The evaporated phase is evaporated in sodium chloride (0.15 g; 15 ml) with the evaporated phase produced by distillation of the sodium chloride (15 g; 15 ml) with an organic solution of sodium chloride (0.15 g; 15 ml).

Ethylindolic alcohols of formula R3' (CH2) 2OH have been prepared with the following R3' indolic groups:

5.2.4 Preparation of ethylindolic bromides (8b)

Ethylindolic bromides of general formula (8b) may be prepared by bromination of the corresponding alcohols (7b) by the general methods described above for the preparation of benzyl bromides.

Preparation 14 : 3-(2-bromoethyl)-6-methoxy-1H-indole (C11H12BrNO, M = 254.13) is obtained from the following compounds:

The 2- (((6-methoxy-1H-indol-3-yl) ethanol (0.815 g, 4.3 mmol) and the carbon tetrabromide (1.6 g; 5 mmol) dissolved in dichloromethane (25 ml) are cooled to 0 °C. Triphenylphosphine is added (1.3 g; 5 mmol). The reaction mixture is agitated at room temperature for 2 hours. The dichloromethane is evaporated and the resulting residue purified on silica (elevant: heptane / ethyl acetate: 3 / 1). The fractions are evaporated and the solid is dried under vacuum (0.69 g = 63).

Indol bromides of formula R3'CH2) 2Br have been prepared with the following R3'Indol groups: - What?

Preparation of brominated derivatives of general formula (8d):

Brominated derivatives of general formula Br-(CH2)n'[Q']p'[C(X') ((Y')]m'Z' where Q' represents C(O), p' represents 0 or 1, m' represents 0, Z' represents the indoyl group and (CH2)n' has the meaning given above, (8d), can be obtained by methods known to the art, e.g. by acylation of an indole (O. Ottoni et al. Org. Lett., 2001, 3(7), 1005-1007), followed or not by a reduction of the carbonyl group (E. Wenkert et al. J. Org. Chem. 1986, 51(12), 2343-2351).

The following is added to the list of active substances:

7-Methyl-1H-indole (131 mg; 1 mmol) is dissolved in 2 ml of dichloromethane at 0 °C. A molar solution of tin tetrachloride in dichloromethane (1,2 ml; 1.2 mmol) is added at 0 °C and the reaction mixture is agitated at room temperature for 30 minutes. 3-bromopropionyl chloride (101 μl; 1 mmol) and nitromethane (1,5 ml) are then added to the medium and the reaction is maintained for 24 hours. Then 5 ml of water is extracted and the product is extracted by 3 times 5 ml of ethyl acetate. The organic phases are collected, dried on sodium sulphate and evaporated.

Brominated derivatives of general formula (8d) have been prepared with the following groups - (CH2) n[Q']p'[C(X') ((Y') ]m'Z':

Preparation of compounds of general formula (I): Substitution of thiols (6) by benzyl bromides (8a):

Thiols of general formula (6) can be replaced by benzyl bromides of general formula (8a) after activation of the sulphur atom by a base such as NaOAc, KOH, K2CO3 in a protic solvent such as methanol or ethanol (Shetgiri, N. P.; Kokitkar, S. V. Indian J. Chem, Sect B: Org Chem Incl Med Chem 2001, 40 (2), 163-166) or by an organic base such as triethylamine or diisopropylamine in an apolar solvent such as acetone or dichloromethane or by a resin-based base such as morphinomethyl polystyrene resin (Nochbiomethyl) or resin-1-methyl.5,7-triazabicyclo[4,4,0]dec-5-ene polystyrene (Novabiochem) after inflation of the resin in an aprotic solvent such as dichloromethane. The reaction takes place at room temperature for a duration of 12 to 36 hours. Excess reagent of general formula (8a) can be trapped by adding e.g. a thiophenol resin (Argonaut) and stirring for 4 to 8 hours. The suspension is filtered, the silica thread evaporated and purified by chromatography on a column of molasses.The final product is then obtained in salicylated form and in the case of trifluoroacetate, the salt is treated with a basic resin of the Amberlite type and then re-salicylated by a molar solution of hydrochloric acid in an aprotic solvent such as ethyl ether, ethyl acetate or dioxane.

The following is the list of active substances which are to be used in the preparation of the active substance:

Add diisopropylamine (0.14 ml; 1 mmol) to tert-butyl-2-butyl-5-sulphanyl-4H-1,2,4-triazol-4-yl) ethylcarbamate (320 mg; 1 mmol) dissolved in tetrahydrofuran (5 ml), then benzyl bromide (0.12 ml; 1 mmol). The solution is agitated at room temperature for 24 hours, then the solvent is evaporated. Add dichloromethane (2 ml) and trifluoroacetic acid (2 ml) and the resulting solution is agitated for 10 minutes at room temperature. The solvents are evaporated, the base is dissolved in methanol during treatment in a solution of amber to form free chlorophyll; the base is then purified in a solution of dichloromethyl chloride (methyl chloride) and chlorophyll chloride (methyl chloride) (this is then treated in a solution of etheric chloride) (1/80 mg/ml) and the resulting solution is made into a chlorophyll chloride solution.

Benzyl bromides (8a) of general formula R3Br have been used with the following R3 groups:

6.2. substitution of thiols (6) by α-bromo ketones (8c):

The reaction takes place at room temperature for a period of 12 to 24 hours. Excess general formula (8c) reagent can be trapped by adding e.g. a thiophenol (Argonaut) or an aminomethyl-polystyrene (Novabiochem) resin and stirring for 4 to 8 hours. The suspension is filtered, the filter evaporated and purified on a silicon column. If the amine present on the molecule is protected by a carbamate-type group (e.g. tertiary carbonyl-acetyl chloride) for 16 to 20 hours, then the final product is obtained by treatment in a molybdenum chloride solution, which is then treated in a chloride chloride-hydrochloride solution.

The suspension is agitated at room temperature for 30 minutes and then 2-bromo-1-[3-(2-naphtliyl) -5-sulphanyl-4H-1,2-triazol-4-yl]hexylcarbamate (30 mg; 0.07 mmol) dissolved in tetrahydrofuran (1 ml) is added to the resin 2-tert-butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diazophosphorine on polystyrene. The suspension is agitated at room temperature for 30 minutes and then 2-bromo-1-[4-diethylamino]phenyl]ethanol (22 mg; 0.08 mmol) is added to the vacuum. The mixture is agitated at room temperature for 16 hours. For excess 2-bromo-1-diethylamino-1,3-dimethyl-perhydro-1,3,2-diazophosphorine (1 hour); the resulting solution is agitated in a thiophenol (temperature of 0.60 mmol) and a solvent (temperature of 0.6 to 6 mmol) is added to the solution. The solution is filtered and filtered (filtrated) to a minimum of 63 mg/mL (6.5 to 6 mmol) of the solvent.

Bromo ketones (8c) of general formula R3Br have been used with the following R3 groups: - What?

6.3. Substitution of thiols (6) by aliphatic halides, ethylindolic bromides (8b) or brominated derivatives of general formula (8d):

The general formula thiols (6) can be replaced by aliphatic halogenides, general formula ethylindolic bromides (8b) or brominated derivatives of general formula (8d) after activation of the sulphur atom by the 2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diaza-phosphorine on polystyrene (Fluka) resin. The reaction takes place at room temperature for 3 to 6 hours. The suspension is filtered, the filter evaporated and purified on a silica column. If the amine present on the submolecule is protected by a carbamate group (such as the tert-carbonyl-hydroxy group), then the final product is obtained in the form of a solution of chloride etheric acid for 16 hours.

The following is the list of active substances which are to be classified in the Annex to Regulation (EC) No 1907/2006 as substances with a specific chemical composition:

The following is the list of active substances that are to be classified in the additive:

The solution is agitated for 10 minutes at room temperature, then 3-bromethyl-4H-1,2,4-triazol-4-yl-butylcarbamate (149 mmol) is added. The mixture is agitated at room temperature for 4 hours, then filtered. The filtrate is evaporated by flash chromatography of white acetone (acetone) on silicon (acetone) and the remaining fractions are filtered (2,49 mg/ml) and then evaporated.

The following is the list of active substances that may be used in the preparation of the active substance:

The previously formed tert-butyl-3[[3-{[2-(1H-indol-3-yl) ethyl]sulfanyl}-5-(2-naphthyl) -4H-1,2,4-triazol-4-yl]propylcarbamate is dissolved in anhydrous dichloromethane (3 ml) and methanol (2 ml) and then a molar solution of hydrochloric acid in ethyl ether (3.1 ml) is added to the solution. The mixture is agitated for 45 minutes and then evaporated and the resulting beige solid is vacuum dried (188 mg, yield = 94%).

The following is a list of the most commonly used methods of measuring the relative humidity of the atmosphere:

Aliphatic halides, brominated derivatives (8b) or (8d) of general formula R3Br have been used with the following R3 groups:

6.4. special case where R3 has an amide function:

Compounds of general formula (I) such as R3 is a radical of formula -CH2-C(O) -NH-CH(CH2)m-NXY, where m, X and Y are as defined above, can be obtained in 3 steps from the thiol of general formula (6). - What?

6.4.1 Substitution of sulphur and hydrolysis of the ester:

Thiols of general formula (6) can be replaced by ethyl iodine acetate after activation of the sulphur atom by a base such as NaH or by using the 2-tert-t-butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diazaphosphorine resin on polystyrene (Fluka) in a solvent such as dichloromethane or dimethylformamide. The reaction is carried out at room temperature for 12 to 24 hours, then the reaction mixture is washed and concentrated under vacuum. The ester is hydrolysed by a water treatment such as a solution of HH hydroxide in the presence of an organic solvent such as T. acroprophrase or T. acrophrase; after the following hours, the solution is removed from the liquid, and then by a water treatment such as a solution of R. H. Ramlington, Chemical 14 (R. E. H. 1440-92), a chemical that is used in the following conditions; the solution is then removed by a water treatment such as a solution of HH hydroxideoproprophrase in the presence of a solvent such as T. Acrophrase; and the chemical is then removed at a temperature of approximately 6 °C.

Preparation 16 : Acid {[4-(2,2-diphenylethyl) -5-(2-naphthylmethyl) -4-H-1,2,4-triazol-3-yl]sulfanyl} acetic (C29H25N3O2S, M = 479,61) The substance is used as a solvent in the manufacture of other products.

4- ((2,2-diphenyl) -5- ((2-naphthyl) -methyl) -4-H-1,2,4-triazol-3-thiol (4 g; 9,5 mmol) dissolved in dichloromethane (100 ml) is added to sodium hydride (0.4 g; 10 mmol); the solution is agitated at room temperature for 30 minutes. Ethyl iodide acetate is added (1,2 ml 10 mmol) and the mixture is agitated at room temperature for 16 ml. This reaction mixture is then mixed with distilled water (50 ml); dissolved in saturated sodium chloride (50 ml); the following phase is dissolved in the ambient atmosphere. The acid is obtained by hydrolysis: the residue is used twice in normal tethylenedioxylated acid (80 ml) before being evaporated in the solution; the solution is added to the pH of 44 ml (2,1 ml) and then the organic acids are mixed with this solution and evaporated in the water (2,4 ml) and then the solution is filtered to make a solution of lithium chloride (2,1 ml) and then the organic acids are mixed with the solution.

6.4.2 Peptide coupling:

Compounds of general formula (I) such as R3 is a radical of formula -CH2-C(O) -NH-CH(2)m-NXY, where m, X and Y are as defined above, can be obtained by the classical methods of peptide synthesis (M. Bodansky, The Practice of Peptide Synthesis, 145 (Springer-Verlag, 1984)), for example in tetrahydrofuran, dichloromethane or dimethylformamide in the presence of a coupling reagent such as cyclohexylcarbodiimide (DCC), 1,1'-carbonyldiimidazole (CDI) (J. Castro Chem. 1992, 35 (264), 44-447), 31, the chemical compound 1-hydrochlorophosphor-1-benzoyl-2-benzoyl-3-phenyl; or 1-hydrochlorophosphor-1-benzoyl-benzoyl-benzoyl (J. Jones, 1991); the chemical compound is obtained from the purification of hexylphosphorone (C. C. Benzenephor, 1991).

The following is the list of active substances which are to be classified in the additive:

The solution is agitated at room temperature for 30 minutes and then diisopropyl-ethyl-acetate (48 mg; 0.22 mmol) and 3-thyl-1-pipproperazinyl) acetic acid (48 mg; 0.1 mmol) dissolved in dichloromethane (5 ml) are added to benzotriazol-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate (52 mg; 0.1 mmol). The mixture is agitated at room temperature for 16 hours. The evaporators are evaporated and the residues are purified by means of a dichloromethane filter (SM = 11 / M = 8 mmol), after which the chloromethane is reduced to a minimum of 8 mg/mL (H = 11 / M = 11 / M = 11 mmol).

The following R3' ' groupings have been used: - What?

The invention also concerns a process for the preparation, in the liquid phase, of compounds of formula I according to the invention, characterised by the reaction of isothiocyanates of formula R1-NCS on hydrazides of formula R2-C(O) -NH-NH2 in which R1 and R2 have the above meanings, to obtain compounds of formula (5) - What? compounds of formula (5) which can be subjected to a basic treatment to obtain the corresponding compounds of formula (6) - What? Compounds of formula (6) reacted with (A) either a compound of formula Br-(CH2)n'[Q']p'[C(X') ((Y')]m'Z' where n' = 1, p' = m' = 0 and Z' has the meaning given above to obtain,after unprotection of the amine function present on the molecule, the compound of formula (I) corresponding,B) is a compound of formula Br-(CH2)n'[Q']p'[C(X') ((Y')]m'Z' where n' = 1, Q' = -C(O)-, m' = 0 and Z' has the meaning given above to obtain, after unprotection of the amine function present on the molecule, the compound of formula (I) corresponding,C) is a compound of formula Br-(CH2)n'[Q']p'[CX') ((Y')]m'Z' where Y', Q', X', Z', n', p' and m' have the meaning given above to obtain, after unprotection of the amine function present on the molecule, the compound of formula (I) corresponding.

The compounds I of the present invention have interesting pharmacological properties, and it has been found that the compounds I of the present invention have a high affinity for one (or more) of the somatostatin receptors and may be used as non-peptide agonists or antagonists of somatostatin selectively or not.

The compounds of the present invention can thus be used in various therapeutic applications and can be advantageously used to treat pathological conditions or diseases as described above in which one (or more) of the somatostatin receptors is (are) involved.

An illustration of the pharmacological properties of the compounds of the invention is given below in the experimental section.

This application also concerns pharmaceutical formulations containing as an active substance at least one of the formula I products as defined above and the addition salts with the pharmaceutically acceptable mineral or organic acids of those formula I products in combination with a pharmaceutically acceptable medium.

Compounds of formula I in which either R1 represents (CH2) 2-W and W represents morpholine or piperazinyl, R2 phenyl, m-chlorophenyl or 4-pyridyl, and R3 the hydrogen atom, or R1 represents (CH2) 2-W and W represents pyrrolidinyl, R2 p-chlorophenyl and R3 the hydrogen atom, have been described in Phosphorus.Sulfur and Silicon, 2000, vol.164 pp.67-81, but only as synthetic intermediates and no therapeutic activity has been envisaged for these compounds. Other triazole derivatives have been described in the literature but in fields other than that of the present indication; or; or; or; or; or; or; or; or; or; or; or; or; or; or; or; or; or; or; or; or; or; or; or; or; or; or; or; or; or; or; or; or; or; or; or; or; or; or; or; or; or; or; or; or; or; or; or; or; or; or; or; or; or; or; or; or; or; or; or; or; or; or; or; or; or; or; or; or; or; or; or; or; or; or; or; or; or; or; or; or; or; or; or; or; or; or; or; or; or; or; or; or; or; or; or; or; or; or; or; or; or; or; or; or; or; or; or; or; or; or; or; or; or; or; or; or; or; or; or; or; or; or; or; or; or; or; or; or; or; or; or; or; or; or; or; or; or; or; or; or; or; or; or; or; or; or; or; or; or; or; or; or; or; or; or; or; or; or; or; or; or; or; or; or; or; or; or; or; or; or; or;

The present invention therefore also concerns a pharmaceutical composition for use as a medicinal product and containing, as an active ingredient, in combination with a pharmaceutically acceptable medium, at least one compound of general formula - What? in racemic, enantiomeric or any combination of these forms, in which:

Err1:Expecting ',' delimiter: line 1 column 928 (char 927)Err1:Expecting ',' delimiter: line 1 column 131 (char 130)

A pharmaceutical composition according to the invention may be in the form of a solid, e.g. powders, granules, tablets, capsules or suppositories. Suitable solids may be, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine and wax.

Pharmaceutical formulations containing a compound of the invention may also be in liquid form, e.g. solutions, emulsions, suspensions or syrups. Suitable liquid media may be, for example, water, organic solvents such as glycerol or glycols, and mixtures thereof, in varying proportions, in water, added to pharmaceutically acceptable oils or fats. Sterile liquid formulations may be used for intramuscular, intra- and subcutaneous injections and sterile formulations may also be administered intravenously.

All technical and scientific terms used in this text have the meaning known to the artisan. In addition, all patents (or patent applications) and other bibliographical references are incorporated by reference.

The experimental part:

Other compounds of the invention obtained by the procedures of examples A, B, C and D described above are summarised in the table below.

The compounds are characterized by their retention time (tr), expressed in minutes, determined by liquid chromatography (LC) and their molecular peak (M + H) + determined by mass spectrometry (SM).

The conditions for the examples presented are as follows: Eluent: A: Water + 0.02 % trifluoroacetic acid; B: acetonitrile

:

T (min)	A (%)	B (%)
0	95	5
8,5	10	90
10,5	10	90
10,6	95	5
15	95	5

- What? The following shall be used: Injection: 10 μl The temperature of the room The wavelength (% UV): 220 nm The test shall be carried out in accordance with the procedure described in paragraph 5.2.3. - What?

:

T (min)	A (%)	B (%)
0	100	0
6	20	80
8	20	80
8,1	100	0
10	100	0

- What? The test shall be carried out in accordance with the instructions given in Appendix 1. Injection: 5 μl The temperature of the room The wavelength (% UV): 220 nm The following column is used:

The conditions following the examples are: - What?

Exemples	Conditions	Exemples	Conditions	Exemples	Conditions
1 à 15	1	163 à 164	1	374 à 466	1
16 à 30	2	165 à 191	2	467 à 489	2
31 à 45	1	192 à 210	1	490	1
46 à 59	2	211 à 213	2	491 à 495	2
60	1	214	1	496 à 533	1
61 à 81	2	215 à 234	2	534 à 537	2
82 à 98	1	235 à 236	1	538 à 551	1
99 à 145	2	237 à 260	2	552	2
146 à 151	1	261	1	553 à 582	1
152 à 153	2	262 à 269	2	583 à 638	1
155	1	270 à 368	1	639 à 708	1
155 à 162	2	369 à 373	2

These examples are presented to illustrate the above procedures and should in no way be considered as limiting the scope of the invention.

In each illustration of the radicals R1, R2 and R3, the radicals X1, X2 and X3 represent, respectively, the remaining part of the compound of general formula (I).

	R1	R2	R3	TR	MH+
1				7,46	355,23
2				7,39	375,27
3				7,11	405,33
4				7,17	420,33
5				7,29	393,21
6				7,26	389,36
7				7,70	443,21
8				7,02	400,33
9				7,30	389,29
10				7,22	450,35
11				7,72	451,36
12				7,50	425,35
13				7,14	438,32
14				7,56	505,32
15				7,75	449,37
16				3,71	311,24
17				3,84	341,21
18				3,97	325,24
19				3,86	356,20
20				3,82	356,20
21				3,82	369,21
22				3,82	329,20
23				3,62	336,22
24				3,79	329,17
25				4,60	367,20
26				3,37	389,16
27				3,99	325,25
28				3,90	386,10
29				4,36	379,18
30				3,90	371,23
31				7,31	361,28
32				7,03	391,31
33				7,09	406,32
34				7,21	379,21
35				7,11	375,38
36				7,61	429,18
37				6,92	386,32
38				7,27	375,30
39				7,13	436,32
40				7,64	437,33
41				7,41	411,33
42				7,45	389,37
43				7,04	424,30
44				7,48	491,29
45				7,73	435,35
46				3,87	341,25
47				3,95	371,28
48				4,02	386,18
49				3,98	386,18
50				3,96	399,20
51				3,96	399,20
52				3,98	359,21
53				4,02	355,24
54				4,20	375,18
55				3,90	359,20
56				4,83	397,26
57				4,49	409,17
58				3,54	419,23
59				4,14	355,24
60				7,57	385,23
61				4,09	345,08
62				4,16	375,05
63				4,31	359,06
64				4,23	390,03
65				4,19	390,04
66				4,20	403,19
67				4,17	403,02
68				4,02	370,06
69				4,43	379,16
70				4,62	413,00
71				4,03	370,06
72				4,25	420,05
73				4,68	413,00
74				4,83	421,07
75				4,59	395,04
76				4,26	359,06
77				4,55	373,07
78				4,40	377,10
79				4,12	390,04
80				4,08	407,99
81				4,54	413,17
82				7,74	389,16
83				6,55	401,32
84				6,62	416,31
85				6,70	389,20
86				6,64	385,37
87				7,11	439,21
88				6,47	396,30
89				6,79	385,29
90				6,68	446,32
91				7,21	447,33
92				6,96	421,32
93				6,97	399,37
94				6,57	434,30
95				6,73	371,28
96				7,23	445,36
97				6,99	376,33
98				7,65	407,36
99				4,18	369,31
100				4,07	345,27
101				4,08	339,31
102				4,21	365,21
103				3,82	356,23
104				4,87	387,26
105				4,45	381,23
106				4,61	347,36
107				4,55	359,34
108				5,01	421,33
109				3,54	383,19
110				4,23	353,31
111				4,65	389,27
112				4,51	420,24
113				4,47	433,25
114				4,53	393,24
115				4,33	400,25
116				4,22	359,22
117				4,34	382,30
118				4,27	382,30
119				4,14	386,29
120				4,66	436,29
121				4,13	329,29
122				3,96	360,27
123				3,94	373,26
124				4,04	329,29
125				3,91	333,27
126				4,47	383,24
127				3,78	340,29
128				3,47	393,23
129				4,45	399,31
130				4,35	430,30
131				4,29	443,32
132				4,37	399,31
133				4,26	403,27
134				4,76	453,29
135				4,16	410,28
136				3,90	463,28
137				4,48	399,31
138				4,57	389,31
139				4,46	420,28
140				4,40	433,29
141				4,51	389,31
142				4,39	393,28
143				4,87	443,30
144				4,28	400,28
145				4,01	453,26
146				6,11	346,28
147				6,50	334,35
148				6,37	354,30
149				6,17	328,30
150				5,73	336,28
151				6,30	352,30
152				3,52	383,19
153				3,58	413,18
154				7,99	523.30
155				3,60	384,15
156				3,66	414,14
157				3,35	345,16
158				3,40	375,14
159				2,74	277,19
160				2,84	307,18
161				3,93	347,26
162				3,94	377,25
163				8,04	400,37
164				8,25	501,33
165				3,85	359,25
166				3,87	389,25
167				3,50	353,21
168				3,94	403,18
169				3,98	433,21
170				3,04	369,20
171				3,12	399,18
172				3,90	339,20
173				4,07	369,16
174				4,08	384,10
175				4,08	397,11
176				4,12	357,14
177				3,90	364,13
178				4,32	373,08
179				4,06	357,15
180				4,54	407,25
181				3,94	364,30
182				4,94	395,17
183				4,14	414,09
184				4,58	407,08
185				4,51	389,12
186				4,22	353,17
187				4,51	367,17
188				4,00	402,06
189				4,47	407,25
190				4,14	357,29
191				4,31	371,14
192				7,96	433,90
193				7,80	413,93
194				8,01	402,95
195				8,15	422,88
196				7,83	413,93
197				8,28	456,90
198				7,83	413,92
199				8,57	445,02
200				8,03	403,02
201				7,99	463,90
202				8,51	464,93
203				8,25	438,94
204				8,04	402,96
205				7,89	451,88
206				8,13	442,95
207				8,23	492,96
208				8,33	518,86
209				8,20	442,20
210				8,03	433,25
211				4,22	415,18
212				4,16	369,24
213				4,24	445,21
214				8,19	444,94
215				4,21	399,23
216				4,38	383,23
217				4,25	414,20
218				4,20	414,19
219				4,24	387,20
220				4,05	394,22
221				4,31	383,23
222				4,06	394,22
223				4,19	387,20
224				4,62	437,21
225				5,01	425,28
226				4,28	444,24
227				4,68	437,21
228				4,84	445,27
229				4,60	419,25
230				4,32	383,23
231				4,60	397,24
232				4,56	437,21
233				4,42	401,21
234				4,28	427,22
235				7,73	413,24
236				8,26	459,27
237				4,84	443,26
238				4,34	373,18
239				4,39	403,16
240				4,56	387,17
241				4,44	418,14
242				4,40	418,14
243				4,37	431,17
244				4,38	431,18
245				4,44	391,17
246				4,25	398,15
247				4,80	441,14
248				4,26	398,14
249				5,17	429,24
250				4,86	441,14
251				4,99	449,22
252				4,77	423,18
253				4,50	387,18
254				4,32	436,14
255				4,59	405,17
256				4,72	441,15
257				4,44	391,17
258				4,36	418,15
259				4,86	503,21
260				4,50	448,20
261				7,90	417,19
262				5,00	447,19
263				4,93	491,19
264				5,29	479,27
265				5,13	499,24
266				4,62	481,21
267				4,83	477,18
268				4,93	527,24
269				4,97	553,19
270				8,10	458,96
271				8,13	473,89
272				7,98	453,96
273				8,19	442,97
274				7,97	453,95
275				8,49	496,91
276				7,98	453,94
277				8,17	503,91
278				8,70	504,95
279				8,43	478,96
280				8,18	442,97
281				8,07	491,89
282				8,14	446,92
283				8,46	532,87
284				8,51	558,83
285				8,17	473,28
286				8,71	502,91
287				8,33	485,89
288				8,21	465,93
289				8,41	454,95
290				8,55	474,88
291				8,17	465,93
292				8,69	511,31
293				8,19	465,93
294				8,50	455,00
295				8,36	515,87
296				8,92	516,91
297				8,67	490,91
298				8,31	503,87
299				8,59	494,88
300				8,65	544,86
301				8,37	485,29
302				8,92	514,89
303				8,23	459,91
304				8,07	439,94
305				8,30	428,97
306				8,41	448,90
307				8,08	439,94
308				8,54	482,90
309				8,09	439,94
310				8,94	470,96
311				8,36	428,97
312				8,24	489,91
313				8,77	490,93
314				8,54	464,94
315				8,31	428,98
316				8,18	477,89
317				8,22	432,95
318				8,46	468,89
319				8,59	518,90
320				8,60	544,85
321				8,79	488,96
322				8,07	442,30
323				8,19	543,29
324				8,20	460,29
325				8,34	561,26
326				8,40	484,34
327				8,54	585,30
328				8,64	479,36
329				8,81	459,36
330				8,18	478,30
331				8,51	471,28
332				8,65	479,37
333				8,41	453,32
334				8,48	507,34
335				8,12	466,29
336				8,50	502,40
337				8,51	533,30
338				8,30	456,30
339				8,41	557,30
340				8,10	447,27
341				8,78	493,36
342				8,14	442,29
343				8,94	473,36
344				8,61	485,31
345				8,79	493,36
346				8,55	467,32
347				8,24	480,30
348				8,61	521,35
349				8,60	516,40
350				8,61	547,30
351				8,40	470,30
352				8,48	571,30
353				8,23	461,28
354				7,56	429,26
355				7,39	459,39
356				7,45	474,39
357				7,59	447,27
358				7,54	443,43
359				8,03	497,25
360				7,29	454,40
361				7,59	443,38
362				7,50	504,41
363				8,07	505,42
364				7,78	479,43
365				7,84	457,43
366				7,45	492,38
367				7,55	447,39
368				8,18	503,46
369				4,76	508,21
370				5,18	531,21
371				4,85	521,22
372				5,07	517,21
373				5,17	567,23
374				7,56	457,26
375				10,90	488,31
376				7,48	488,21
377				7,38	501,23
378				12,40	465,28
379				7,25	468,24
380				7,30	468,24
381				8,12	519,26
382				7,84	493,34
383				7,48	457,26
384				7,40	506,23
385				11,16	511,31
386				7,42	488,23
387				7,89	573,20
388				8,98	623,35
389				9,29	633,34
390				9,77	621,41
391				9,52	641,39
392				9,28	615,35
393				6,95	439,28
394				6,86	469,39
395				6,91	484,42
396				7,01	457,29
397				7,45	507,26
398				6,76	464,41
399				7,08	453,39
400				7,01	514,40
401				7,59	515,41
402				7,28	489,44
403				6,90	502,40
404				6,98	457,41
405				7,43	569,36
406				7,67	435,22
407				7,49	465,36
408				7,58	480,37
409				7,70	453,27
410				7,69	449,38
411				8,16	503,23
412				7,40	460,35
413				7,71	449,33
414				7,60	510,35
415				8,16	511,37
416				7,94	485,38
417				7,99	463,40
418				7,59	498,34
419				7,68	453,36
420				8,38	509,41
421				7,43	399,31
422				7,30	429,44
423				7,46	417,33
424				7,49	413,45
425				7,92	467,31
426				7,19	424,45
427				7,48	413,40
428				7,39	474,44
429				8,01	475,47
430				7,70	449,45
431				7,79	427,46
432				7,37	462,42
433				7,45	417,43
434				7,79	529,46
435				8,03	473,48
436				8,10	428,20
437				8,97	427,28
438				9,02	495,23
439				8,62	445,21
440				8,68	441,31
441				9,07	503,39
442				8,34	457,36
443				8,84	477,40
444				8,35	502,38
445				9,25	501,39
446				8,14	452,37
447				8,31	472,35
448				8,64	441,37
449				8,50	445,33
450				9,02	455,39
451				8,35	490,35
452				9,27	457,35
453				9,23	525,26
454				8,84	475,30
455				8,91	471,39
456				9,33	533,42
457				8,55	487,42
458				9,01	507,45
459				8,53	532,43
460				8,88	587,37
461				9,53	531,47
462				8,34	482,43
463				8,48	502,46
464				8,91	471,44
465				9,24	485,47
466				8,58	520,40
467				5,49	451,23
468				5,81	519,22
469				5,52	469,23
470				5,67	465,25
471				6,05	527,28
472				5,46	481,25
473				5,83	501,27
474				5,43	526,25
475				5,39	496,22
476				5,37	509,26
477				5,39	509,26
478				5,71	581,22
479				6,06	525,26
480				5,26	476,24
481				5,79	519,23
482				5,68	465,25
483				5,25	476,25
484				5,25	476,25
485				5,39	496,23
486				5,71	485,21
487				5,66	465,25
488				5,51	469,24
489				5,65	465,24
490				11,53	511,31
491				5,91	479,28
492				5,38	514,23
493				5,70	483,28
494				5,53	509,26
495				5,39	496,24
496				9,20	469,12
497				8,87	419,10
498				9,09	415,14
499				9,55	477,18
500				8,82	431,14
501				9,25	451,15
502				8,85	476,15
503				8,81	446,11
504				8,75	459,14
505				9,18	531,14
506				8,61	426,13
507				9,21	469,11
508				8,64	426,13
509				8,64	426,13
510				8,77	446,11
511				9,01	415,14
512				8,74	464,11
513				9,11	433,14
514				9,77	457,21
515				9,28	469,12
516				8,77	446,11
517				9,09	455,09
518				9,25	505,17
519				9,56	497,37
520				9,51	565,28
521				9,11	515,32
522				9,15	511,44
523				9,58	573,42
524				8,83	527,44
525				9,24	547,45
526				8,83	572,42
527				9,78	571,48
528				8,61	522,47
529				8,80	542,45
530				9,12	511,51
531				9,00	515,46
532				9,49	525,49
533				8,90	560,41
534				4,74	401,2
535				4,67	387,2
536				5,43	455,18
537				5,46	437,21
538				8,40	461,29
539				7,63	432,24
540				8,62	435,39
541				9,46	511,45
542				8,63	465,43
543				9,08	485,44
544				8,59	510,40
545				9,40	509,43
546				8,54	480,41
547				8,62	453,41
548				8,52	498,39
549				9,51	570,89
550				9,21	544,90
551				9,51	568,87
552				3,70	325,20
553				8,09	520,34
554				8,50	479,30
555				8,90	521,30
556				8,95	465,33
557				7,90	458,20
558				8,40	619,30
559				8,39	401,31
560				8,71	443,35
561				8,30	461,30
562				8,70	493,30
563				8,80	437,29
564				8,21	542,33
565				9,50	505,20
566				8,74	462,93
567				9,10	463,30
568				8,40	554,20
569				8,38	554,33
570				9,40	521,20
571				6,90	398,20
572				8,68	429,30
573				8,72	437,26
574				9,05	479,34
575				8,62	431,34
576				8,31	375,31
577				8,37	415,29
578				8,72	439,31
579				8,68	425,29
580				8,16	530,37
581				9,02	473,29
582				8,90	487,20
583				7,84	422,16
584				7,95	420,18
585				7,90	482,20
586				8,35	448,21
587				8,22	460,08
588				8,22	448,13
589				7,81	435,19
590				8,90	597,10
591				8,30	496,20
592				8,30	460,00
593				8,30	486,20
594				7,98	437,15
595				8,07	470,06
596				8,07	470,08
597				7,91	406,20
598				8,02	426,13
599				7,93	406,19
600				8,00	437,20
601				7,80	452,20
602				8,58	528,16
603				7,88	410,16
604				8,27	476,17
605				8,19	460,15
606				8,09	420,20
607				7,99	452,19
608				8,14	518,07
609				8,15	518,07
610				8,20	472,20
611				8,20	456,20
612				8,00	485,20
613				8,20	460,20
614				8,50	520,09
615				7,90	445,20
616				8,16	443,18
617				7,55	443,18
618				7,90	443,20
619				8,00	443,20
620				8,30	443,20
621				8,60	410,10
622				8,10	431,10
623				8,50	479,10
624				8,40	520,10
625				8,10	472,20
626				8,10	472,10
627				8,50	476,20
628				8,30	460,10
629				8,43	460,19
630				8,20	460,10
631				8,19	474,11
632				8,60	522,07
633				8,38	462,16
634				8,38	462,18
635				8,40	478,10
636				8,13	444,16
637				8,20	462,20
638				8,50	496,20
639				8,31	473,03
640				8,70	520,93
641				8,46	461,02
642				8,48	461,02
643				8,64	477,02
644				8,43	461,02
645				7,80	443,20
646				8,10	443,10
647				8,74	521,03
648				8,58	479,16
649				8,49	461,13
650				8,56	457,12
651				8,66	477,13
652				8,67	477,09
653				8,62	477,06
654				8,50	522,06
655				8,39	480,11
656				8,24	462,13
657				8,30	458,10
658				8,39	478,09
659				8,45	478,09
660				8,42	478,09
661				8,57	520,06
662				8,41	478,14
663				8,31	460,13
664				8,37	456,16
665				8,46	476,10
666				8,50	476,10
667				7,77	429,09
668				8,05	463,05
669				7,91	447,08
670				7,92	457,13
671				8,17	491,07
672				8,03	475,12
673				8,7	521,01
674				8,52	520,02
675				8,66	491,09
676				8,83	507,11
677				8,77	507,11
678				8,73	471,19
679				8,68	477,20
680				8,62	507,22
681				8,94	511,17
682				8,77	495,22
683				8,5	457,20
684				8,5	457,20
685				8,77	511,08
686				7,77	462,08
687				7,91	478,03
688				7,83	458,14
689				8,08	512,13
690				8,79	539,06
691				8,64	475,17
692				8,72	495,13
693				8,48	461,16
694				8,56	479,15
695				8,55	479,17
696				8,6	521,00
697				8,60	477,11
698				8,66	495,13
699				8,67	495,11
700				8,83	511,08
701				8,77	521,03
702				8,86	539,02
703				8,85	539,04
704				9,03	555,01
705				8,62	470,16
706				8,64	484,15
707				8,73	498,20
708				8,72	485,13

Pharmacological study

The compounds of the present invention have been tested for their affinity for different subtypes of somatostatin receptors in the following procedures.

Affinity study for human somatostatin receptor subtypes:

The affinity of a compound of the invention for somatostatin receptor subtype 2 is determined by measuring the inhibition of binding of [125I-Tyr11]SRIF-14 to CHO-K1 transfected cells. Compounds showing affinity are tested on other subtypes, and possibly undergo a functional test for their inhibition of intracellular cAMP production.

The human somatostatin sst1 receptor gene has been cloned as a genomic fragment. A 1.5 Kb PstI-XmnI segment containing 100 pb of the untranscribed 5' region, 1.17 Kb of the coding region as a whole, and 230 bp of the untranscribed 3' region is altered by the addition of the linker Bg1II. The resulting DNA fragment is subcloned into the BamHI site of a pCMV-81 to yield the mammalian expression plasmid (provided by Dr. Bell, University of Chicago). A cloned cell line containing a stable expression of the sst1 receptor is multiplied by transfection of CHO-CCAT1 (KATK) cells in the co-stimulation method of phosphate culture. Cells containing 0.5 mg/mL of the clone are selected in a cell culture, including G-CCAT1 (GRSP18), and a selection of G-CLC4 (GRSP18), which is selected in a calcium-phosphate culture medium.

The human somatostatin sst2 receptor gene, isolated as a 1.7 Kb BamHI-HindIII genomic DNA fragment and subcloned in a pGEM3Z plasmid vector (Promega), was provided by Dr. G. Bell (University of Chicago). The mammalian cell expression vector is constructed by inserting the 1.7 Kb BamH1-HindII fragment into endonuclease restriction sites compatible with the pCMV5 plasmid. A cloned cell line is obtained by transfection into CHO-K1 cells by the calcium phosphate co-precipitation method. The pneo-RSV plasmid is included as a selection marker.

The sst3 receptor is isolated as a genomic fragment, and the complete coding sequence is contained in a 2.4 Kb BamHI/HindIII fragment. The mammalian expression plasmid, pCMV-h3, is constructed by insertion of the 2.0 Kb NcoI-HindIII fragment into the EcoR1 site of the pCMV vector after termination modification and addition of EcoR1 liners. A cloned cell line that stably expresses the sst3 receptor is obtained by transfection into CHO-K1 (ATCC) cells by the calcium phosphate co-precipitation method. The pRSV-neo plasmid (ATCC) is included as a marker of selection. Selected cell lines were selected in a culture medium containing 1640 mg/Gb of RCO (GMI), and multiplied in clones of 0.518 mg/Gb.

The human sst4 receptor expression plasmid, pCMV-HX, was provided by Dr. Graeme Bell (Univ. Chicago). This vector contains the genomic fragment coding for the human sst4 receptor of 1.4 Kb NheI-NheI, 456 pb of the 5' untranscribed region, and 200 pb of the 3' untranscribed region, cloned from PCMV-HX XbaI/EcoR1 sites. A cloned cell line stablely expressing sst4 is obtained by transfection into cells containing CHO-K1 (CCAT) by the calcium phosphate co-precipitation method. Pneomine plasmid (CCAT-RSV) is included as a selection marker. 16 cloned cells, containing 0.518 mg/ml, were cultured and multiplied in a clone culture medium, and were selected in a clone culture medium, RGMI 1640 (Globulin C), which is bound to a clone medium.

The DNA of the human sst5 receptor, obtained by PCR using a genome clone λ as a probe, was provided by Dr. Graeme Bell (University of Chicago). The resulting 1.2 Kb PCR fragment contains 21 base pairs of the untranscribed 5' region, the entire coding region, and 55 pb of the untranscribed 3' region. The clone is inserted into an EcoR1 site of the pBSSK+ plasmid. The insert is recovered as a 1.2 Kb HindIII-XbaI fragment for subcloning into a mammalian expression vector, pCVM5. A clone containing 0.5 ml of cells expressed in a stable manner in the sst5 receptor is transcribed into cells of C-KAT (GATH) and 16 mg of C-PAT (GATH) are obtained in a culture medium, GATH (GATH) and a clone of cells of GATH (GATH) is obtained in a calcium-binding medium, pCCM4 (GATH) and a clone is produced in a culture medium, pCCM4 (GATH) by a cell culture medium.

Cells CHO-K1 that express one of the human sst receptors in a stable manner are cultured in a medium RPMI 1640 containing 10% calf fetal serum and 0.4 mg/ml of geneticin. The cells are collected with 0.5 mM EDTA and centrifuged at 500 g for about 5 min at about 4°C. The centrifuge is resuspended in a 50 mM Tris buffer medium at pH 7.4 and centrifuged twice at 500 g for about 5 min at about 4°C. The cells are lysed by sonication and centrifuged at 39000 g for about 10 min at about 4°C. The centrifuge is resuspended in the buffer medium and centrifuged at about 500 g for about 10 min at about 4°C and the centrifuges are stored in the same membranes at about -80 °C.

Competitive inhibition of binding of [125I-Tyr11]SRIF-14 is performed in duplicate using 96-well polypropylene plates. Cell membranes are incubated with [125I-Tyr11]SRIF-14 for approximately 60 min at approximately 37°C in a buffer medium 50 mM HEPES (pH 7.4) comprising 0.2% BSA, 5 mM MgCl2, 200 KIU/ml Trasylol, 0.02 mg/ml Bacitracin and 0.02 mg/ml Phenylmethylsulphonyl fluoride.

The bound [125I-Tyr11]SRIF-14 is separated from the free [125I-Tyr11]SRIF-14 by immediate filtration through GF/C glass fibre filter plates (Unifilter, Packard) pre-impregnated with 0.1% polyethylene (P.E.I.), using Filtermate 196 - (Packard). The filters are washed with 50 mM HEPES buffer at approximately 0-4°C for approximately 4 seconds and their radioactivity is determined by a Packard Top Count.

Specific binding is obtained by subtracting the non-specific binding (determined in the presence of 0,1 μM SRIF-14) from the total binding.

The determination of the agonist or antagonist character of a compound of the present invention is performed by the test described below.

The functional test is to inhibit the production of intracellular cAMP.

CHO-K1 cells expressing human somatostatin receptor subtypes (SRIF-14) are cultured in 24-well plates in a 1640 RPMI medium with 10% calf foetal serum and 0.4 mg/ml of geneticin.

Wash cells at 105 cells/well twice with 0.5 ml of new RPMI medium containing 0.2% BSA supplemented with 0.5 mM of 3-isobutyl-1-methylxanthine (IBMX) and incubate for approximately 5 min at approximately 37°C. The cyclic AMP production is stimulated by the addition of 1 μM of forskolin (FSK) for 15-30 minutes at approximately 37°C; the somatostatin inhibitory effect of an agonist compound is measured by the simultaneous addition of FSK (1 μM) and the test compound (10-10 M at 10-5 M); the antagonistic effect of a compound is measured by the simultaneous addition of FSK (1 μM), SRIF-14 (1 nM) and the test compound (10-10 M at 10-5 M).

The reaction medium is removed and 200 μl of HCl 0,1 N is added. The amount of cAMP is measured by a radioimmunological test (Kit FlashPlate SMP001A, New England Nuclear).

Results:

Tests performed according to the protocols described above have shown that the products of general formula (I) defined in this application have good affinity for at least one of the somatostatin receptor subtypes, with the Ki inhibition constant being lower than the micromolar for some of the compounds exemplified.

Claims

Compounds of general formula in racemic, enantiomeric form or any combination of these forms, in which: R₁ represents a radical of formula -(CH₂)_n-[Q]_p-(CH₂)_m-NXY in which, X and Y represent, independently, the hydrogen atom, a (C₁-C₆)alkyl, p and n represent 0, and m represents an integer from 2 to 6; and the two other radicals R₂ and R₃ represent, independently, a radical of formula -(CH₂)_n'[Q']_p'[C(X')(Y')]_m'Z' in which Q' represents -O-, -S-, -C(O)-, -NH-, -CH=CH- or -C≡C- ; X', Y' and Z' represent, independently, a hydrogen atom, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, (C₁-C₆)alkoxy-carbonyl, cyano, amino, (C₁-C₆)alkylamino, di((C₁-C₆)alkyl)amino, (C₃-C₇)cycloalkyl, heterocycloalkyl, aryl or heteroaryl, or a radical of formula the (C₃-C₇)cycloalkyl, heterocycloalkyl, aryl and heteroaryl radicals being optionally substituted by one or more identical or different substituents chosen from: -(CH₂)_q'-X"-Y", hydroxy, halo, nitro, cyano, amino, (C₁-C₆)alkylamino and di((C₁-C₆)alkyl)amino; X" represents -O-, -S-, -C(O)-, -C(O)-O-, -SO₂ or a covalent bond; Y" represents a (C₁-C₆)alkyl radical optionally substituted by one or more identical or different halo radicals; or aryl or heteroaryl radical optionally substituted by one or more identical or different substituents chosen from: (C₁-C₆)alkoxy, hydroxy, halo, nitro cyano, amino, (C₁-C₆)alkylamino and di((C₁-C₆)alkyl)amino; p' represents 0 or 1, and n', m' and q' represent, independently, an integer from 0 to 6; or their addition salts with pharmaceutically acceptable mineral or organic acids, excluding compounds in which:
- R₃ represents a hydrogen atom, R₂ the methyl radical, and R₁ the 2-(dimethylamino)ethyl radical;

- R₃ and R₂ represent a hydrogen atom, and R₁ the 2-(dimethylamino)ethyl, 3-(dimethylamino)propyl, 6-(dimethylamino)hexyl, 2-(dipropylamino)ethyl or 2-(diethylamino)ethyl radical ;

- R₃ represents a hydrogen atom, R₂ the amino radical, and R₁ the 2-(dimethylamino)ethyl radical ;

- R₃ represents a hydrogen atom, R₂ the 2-hydroxyethyl radical, and R₁ the 2-(diethylamino)ethyl radical ;
Compounds of general formula I according to claim 1, characterized in that R₂ represents a radical of formula -(CH₂)_n'[Q']_p'[C(X')(Y')]_m'Z'; Q' represents -O-; X' represents the hydrogen atom; Y' and Z' represent, independently, a hydrogen atom, (C₁-C₆)alkyl, cyano, amino, (C₃-C₇)cycloalkyl, aryl or heteroaryl; the aryl and heteroaryl radicals being optionally substituted by one or more identical or different substituents chosen from: -(CH₂)_q'-X"-Y", hydroxy, halo, nitro, amino, (C₁-C₆)alkylamino, di((C₁-C₆)alkyl)amino; X" represents -O-, -S- or a covalent bond; Y" represents a (C₁-C₆)alkyl radical optionally substituted by one or more identical or different halo radicals, or aryl radical optionally substituted by one or more identical or different halo radicals; p' represents 0 or 1; n' represents 0, 1 or 2; and m' represents an integer from 0 to 6.
Compounds of general formula I according to one of claims 1 or 2, characterized in that R2 represents a aryl or heteroaryl radical optionally substituted and more particularly naphthyl, phenyl, benzothienyl, quinoxalyl, quinolyl, isoquinolyl, or indolyl, the phenyl, naphthyl and quinolyl radicals being optionally substituted by one or more identical or different (C₁-C₆)alkoxy, halo, nitro, hydroxyl, (C₁-C₆)alkyl radicals, the (C₁-C₆)alkyl being optionally substituted by one or more identical or different halo radicals.
Compounds of general formula I according to one of claims 1 to 3, characterized in that R₃ represents a radical of formula -(CH₂)_n'[Q']_p'[C(X')(Y')]_m'Z' in which X' and Y' represent the hydrogen atom; Z' represents indolyl or benzothienyl, the indolyl radical being optionally substituted by one or more identical or different substituents chosen from: -(CH₂)_q'-X"-Y", (C₁-C₆)alkoxy or halo; X" represents -SO₂ or a covalent bond; Y" represents phenyl or alkyl optionally substituted by one or more identical or different halo radicals.; q' represents 0 or 1; p' represents 0; n' represents 0 or 1; and m' represents 0 or 1.
Compounds of general formula I according to claim 1, characterized in that R₁ represents a radical of formula -(CH₂)_n-[Q]_p-(CH₂)_m-NXY in which, X and Y represent, independently, the hydrogen atom or (C₁-C₆)alkyl ; p and n represent 0 , and m represents an integer from 2 to 6. R₂ represents quinoxalyl, quinolyl or naphthyl, the quinolyl and naphthyl radicals being optionally substituted by one or more identical or different (C₁-C₆)alkyl, (C₁-C₆)alkoxy or halo radicals ; R₃ represents a radical of formula -(CH₂)_n'[Q']_p'[C(X')(Y')]_m'Z' X' and Y' represent the hydrogen atom ; Z' represents indolyl optionally substituted by one or more identical or different substituents chosen from : -(CH₂)_q'-X"-Y", (C₁-C₆)alkoxy or halo ; X" represents a covalent bond ; Y" represents alkyl optionally substituted by one or more identical or different halo radicals ; q' represents 0 or 1 ; p' representse 0 ; n' represents 0 or 1 ; and m' represents 0 or 1.
Process for the preparation, in liquid phase, of compounds of general formula I as defined in claim 1, characterized in that it comprises the reaction of the isothiocyanates of formula R₁-NCS on of the hydrazides of formula R₂-C(O)-NH-NH₂ in which R₁ and R₂ have the meaning indicated in claims 1 and 2 respectively, in order to obtain the compounds of formula (5) which compounds of formula (5) can be subjected to a basic treatment in order to obtain the corresponding compounds of formula (6) which compounds of formula (6) are reacted with
A) either a compound of formula Br-(CH₂)_n'[Q']_p'[C(X')(Y')]_m'Z' where n' = 1, p' = m' = 0 and Z' has the meaning indicated in claim 1 in order to obtain, after deprotection of the amine function present on the molecule, the corresponding compound of formula (I),

B) or a compound of formula Br-(CH₂)_n-[Q']_p'[C(X')(Y')]_m'Z' where n' = 1, Q' = -C(O)-, m' = 0 and Z' has the meaning indicated in claim 1 in order to obtain, after deprotection of the amine function present on the molecule, the corresponding compound of formula (I),

C) or a compound of formula Br-(CH₂)_n'[Q']_p'[C(X')(Y')]_m'Z' where Q', X', Y', Z', n', p' and m' have the meaning indicated in claim 1 in order to obtain, after deprotection of the amine function present on the molecule, the corresponding compound of formula (I).
Pharmaceutical compositions containing, as active ingredient, at least of the compounds as defined in one of claims 1 to 5, combined with a pharmaceutically acceptable support.
Pharmaceutical compositions for use as medicament and containing, as active ingredient, in association with a pharmaceutically acceptable support, at least one compound of the general formula in racemic, enantiomeric form or all combinations of these forms, in which:
R_1a, represents a radical of formula -(CH₂)_n-[Q]_p-(CH₂)_m-NXY in which, X and Y represent, independently, the hydrogen atom, or a (C₁-C₆)alkyl,; p and n represent 0, and m represents an integer from 2 to 6; and the two other radicals R_2a and R_3a represent, independently, a radical of formula -(CH₂)_n'[Q']_p'[C(X')(Y')]_m'Z' in which, Q' represents -O-, -S-, -C(O)-, -NH-, -CH=CH- or -C≡C- ; X', Y' and Z' represent, independently, a hydrogen atom, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, (C₁-C₆)alkoxy-carbonyl, cyano, amino, (C₁-C₆)alkylamino, di((C₁-C₆)alkyl)amino, (C₃-C₇)cycloalkyl, heterocycloalkyl, aryl or heteroaryl, or a radical of formula the (C₃-C₇)cycloalkyl, heterocycloalkyl, aryl and heteroaryl radicals being optionally substituted by one or more identical or different substituents chosen from: -(CH₂)_q'-X"-Y", hydroxy, halo, nitro, cyano, amino, (C₁-C₆)alkylamino and die((C₁-C₆)alkyl)amino; X" represents -O-, -S-, -C(O)-, -C(O)-O-, -SO₂ or a covalent bond; Y" represents a (C₁-C₆)alkyl radical optionally substituted by one or more identical or different halo radicals; or aryl or heteroaryl radical optionally substituted by one or more identical or different substituents chosen from: (C₁-C₆)alkoxy, hydroxy, halo, nitro cyano, amino, (C₁-C₆)alkylamino and di((C₁-C₆)alkyl)amino; p' represents 0 or 1, and n', m' and q' represent, independently, an integer from 0 to 6 ; or their addition salts with pharmaceutically acceptable mineral or organic acids, combined with a pharmaceutically acceptable support.