HK1074444B - Acyloxypyrrolidine derivatives, preparation and therapeutic use thereof - Google Patents

Description

The present invention relates to acyloxypyrrolidine derivatives, their preparation and their therapeutic application.

The compounds of the present invention have affinity and selectivity for V1b or both V1b and V1a arginine-vasopressin (AVP) receptors.

AVP is a hormone known for its antidiuretic effect and its effect in regulating blood pressure. It stimulates several types of receptors: V1 (V1a,V1b), V2. These receptors are located particularly in the liver, vessels (coronary, kidney, brain), platelets, kidney, uterus, adrenal glands, pancreas, central nervous system, pituitary. AVP thus exerts cardiovascular, hepatic, pancreatic, antidiuretic, platelet aggregant effects and effects on the central and peripheral nervous system, and on the uterine sphere.

The location of the different receptors is described in: S. JARD et al., Vasopressin and oxytocin receptors: an overview, in Progress in Endocrinology. H. IMURA and K. SHIZURNE ed., Experta Medica, Amsterdam, 1988, 1183-1188, as well as in the following articles: J. Lab. Clin. Med., 1989, 114 (6), 617-632 and Pharmacol. Rev., 1991, 43 (1), 73-108.

In particular, the V1a AVP receptors are located in many peripheral organs and in the brain. They have been cloned, particularly in rats and humans, and they regulate most of the known effects of AVP: platelet aggregation; uterine contractions; vessel contraction; secretion of aldosterone, cortisol, CRF (corticotropin-releasing factor) and adrenocorticotrophic hormone (ACTH); hepatic glycogenesis, cell proliferation and the main effects of AVP (hypothermia, melitothermia, ...).

V1b receptors were originally identified in the pituitary gland of various animal species (rat, pig, beef, sheep, etc.) including humans (S. JARD et al., Mol. Pharmacol., 1986, 30, 171-177; Y. ARSENIJEVIC et al., J. Endocrinol., 1994, 141, 383-391; J. SCHWARTZ et al., Endocrinology, 1991, 129 (2), 1107-1109; Y. DE KEYSER et al., FEBS Letters, 1994, 356, 215-220) where they stimulate the release of adrenocornootrophic hormone by AVP and potentiate the effects of CRF on the release of ACTH (G.E. GILLIES et al., Nature, 1982, 299, 355). In the hypothalamus, these receptors also directly induce release of CRF in various situations (Neurocrinology, 1994, 60, 503-505).

These V1b receptors have been cloned in rats, humans and mice (Y. DE KEYSER, FEBS Letters, 1994, 356, 215-220; T. SUGIMOTO et al., J. Biol. Chem., 1994, 269 (43), 27088-27092; M. SAITO et al., Biochem. Biophys. Res. Commun., 1995, 212 (3), 751-757; S.J. LOLAIT et al., Neurobiology, 1996, 92, 6783-6787; M.A. VENTURA et al., Journal of Molecular Endocrinology, 1999, 22, 251-260) and various studies (hybridation in situ, PCR, Polymerase Chain Reaction, heart ...) suggest a potential ubiquitous location of these receptors in various tissues (particularly in the central and retina, mesothelium and hypothalamus), and a role in various pathological diseases (thymus, lung, pancreas, and pancreas, and in particular in the retina, pituitary, pancreas, and periphyroid, thyroid, lung, lung, lung, lung, lung, and thyroid, and some types of other pathological reactions, including inflammation, inflammation, and/thymphysiology, and inflammation of the lungs, pancreas, pancreas, pancreas, pancreas, pancreas, pancreas, pancreas, pancreas, and pancreas, pancreas, pancreas, pancreas, and other organs, and kidney, and kidney, and kidney, etc.).

For example, in rats, work has shown that AVP via the V1b receptors regulates the endocrine pancreas by stimulating insulin and glucagon secretion (B. LEE et al., Am. J. Physiol. 269 (Endocrinol. Metab. 32) : E1095-E1100, 1995) or catecholamine production in the adrenal medulla which is the site of local synthesis of AVP cortisol (E. GRAZZINI et al., Endocrinology, 1996, 137 (a), 3906-3914). Thus, in this tissue, AVP via these receptors is thought to play a crucial role in certain types of potent adrenal pheromone converters involving the AVP receptor-inducing receptor and a receptor-resistant receptor called glucagon-inducing enzyme (AVP. G. G. A. G. A. A. G. A. G. A. G. A. G. A. G. A. G. A. G. A. G. A. A. G. A. G. A. G. A. G. A. G. A. G. A. G. A. G. A. G. A. G. A. G. A. G. A. G. A. G. A. G. A. G. A. G. A. G. G. A. G. A. G. A. G. G. A. G. A. G. A. G. A. G. G. A. G. A. G. A. G. G. A. A. G. G. A. G. A. G. A. G. A. G. G. A. G. G. A. A. G. A. G. G. A. G. G. A. A. G. G. A. G. G. A. A. G. A. A. G. G. A. G. G. A. A. G. G. A. G. A. A. G. G. G. A. G. A. G. G. A. A. G. G. A. G. G. A. G. A. A. G. G. A. G. A. G.

Recent work has also shown that the adrenals are able to release CRF and/or ACTH directly via activation of V1b and/or V1a receptors carried by the cells of the spinal cord (G. MAZZOCCHI et al., Peptides, 1997, 18 (2), 191-195 ; E. GRAZZINI et al., J. Clin. Endocrinol. Metab., 1999, 84 (6), 2195-2203).

V1b receptors are also considered to be markers of tumours. For example, ACTH-secreting tumours such as certain pituitary tumours, some bronchial carcinomas (small cell lung cancers or SCLC), pancreatic, adrenal and thyroid cancers, inducing Cushing's syndrome in some cases (J. BERTHERAT et al., Eur. J. Endocrinol., 1996, 135,173; G.A. WITTERT et al., Lancet, 1990, diagnosis 335, 991-994; G. DICKSTEIN et al., J. C. Endocrinol. Metanner, 1996, 16484 (81), 2934-21) reject V1b receptors. V1a receptors, which are obvious markers, are specific to small cells and are therefore more common in the development of cancer than other tumours (P. P. W. P. PETRON, 1989), and the invention of the new drug, Sclerotherapy, is a new development in the field of cancer detection.

The abundant presence of the messenger of the V1b receptors in the stomach and intestinal area suggests that the AVP via this receptor is involved in the release of gastrointestinal hormones such as cholecystokinin, gastrin and secretin (T. SUGIMOTO et al., Molecular cloning and functional expression of V1b receptor gene, in Neurohypophysis: Recent Progress of Vasopressin and Oxytocin Research; T. SAITO, K. KUROKAWA and S. YOSHIDA ed., Elvesier Science, 1995, 409-413).

International patent application WO 01/55130 describes a family of compounds that exhibit affinity and selectivity for V1b or both V1b and V1a arginine-vasopressin receptors.

In particular, a selective antagonist of the V1b receptor, (2S,4R)-1-[5-chloro-1-[2,4-dimethoxyphenyl) sulfonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-N,N-dimethyl-2-pyrrolidinecarboxamide, levogyre isomer, (hereinafter referred to as compound A) was described (WO/55130 J. 01 Pharmacol. Exp. Ther., 2002, 300 (3), 1122-1130).

New compounds derived from acyloxypyrrolidine have now been found that exhibit affinity and selectivity for V1b or both V1b and V1a arginine-vasopressin receptors.

The present invention relates to compounds of formula (I): R1 represents a hydrogen atom, a (C1-C6) alkyl, a (C3-C6) cycloalkyl, a -CH2CH2COOH group or a -NR2R3 group; R2 and R3 each independently represent a hydrogen atom or a (C1-C6) alkyl.

The compounds of formula (I) consist of three asymmetric carbon atoms, the carbon atom bearing the substituent -CON(CH3)2 in the configuration (S), the carbon atom bearing the substituent -OCOR1 in the configuration (R), and the carbon atom at the indole-2-one position 3 in the configuration (R).

Compounds of formula (I) may exist as bases or salts of addition to organic or inorganic bases such as salts with alkaline or alkaline earth metals, or salts with organic or inorganic amines.

These salts are advantageously prepared with pharmaceutically acceptable bases, but salts of other bases useful, e.g., for purification or isolation of compounds of formula (I) are also part of the invention.

The compounds of formula (I) may exist as hydrates or solvates, i.e. as associations or combinations with one or more water molecules or with a solvent.

Alkyl is a linear or branched alkyl radical of one to six carbon atoms such as the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, hexyl, isohexyl radical.

Cycloalkyl means a cyclic alkyl radical with three to six carbon atoms such as the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl radical.

The compounds of formula (I) covered by the invention include the preferred compounds defined as follows: R1 represents a hydrogen atom, a methyl radical, an ethyl radical, an isopropyl radical, a cyclohexyl radical, a -CH2CH2COOH group, an amino group or a dimethylamino group; in the basic state or as an addition salt to an organic or inorganic base, as well as in the hydrate or solvate state.

The following compounds are among the compounds of formula (I) covered by the invention: The following substances are to be classified in the immediate vicinity of the place of dispatch: - in the form of a mixture of organic solvents, - in the form of a mixture of organic solvents, - in the form of a mixture of organic solvents, - in the form of a mixture of organic solvents, - in the form of a mixture of organic solvents, - in the form of a mixture of organic solvents, - in the form of a mixture of organic solvents, - in the form of a mixture of organic solvents, - in the form of a mixture of organic solvents, - in the form of a mixture of organic solvents, - in the form of a mixture of organic solvents, - in the form of a mixture of organic solvents, - in the form of a mixture of organic solvents, - in the form of a mixture of organic solvents, - in the form of a mixture of organic solvents, - in the form of a mixture of organic solvents, - in the form of a mixture of organic solvents, - in the form of a mixture of organic solvents, - in the form of a mixture of organic solvents, - in the form of organic solvents, - in the form of a mixture of organic solvents, - in the form of organic solvents, - in the form of a mixture of organic solvents, - in the form of organic solvents, - in the form of organic solvents, - in the form of a mixture of organic solvents, - in the form of organic solvents, - in the form of a mixture of organic solvents, - in the form of organic solvents, - in the form of a mixture of organic solvents, - in the form of organic solvents, - in the form of - in the form of - in the form of - in the form of - in the form of - in the form of - in the form of - in the - in the - in - in - in - in - in - in - in - in

The present invention is also concerned with a process for the preparation of compounds of formula (I) characterized by: The reaction is carried out with (2S,4R)-1-[5-chloro-1-[2,4-dimethoxyphenyl) sulphonyl]-3-(2-dimethoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-N,N-dimethyl-2-pyrrolidinecarboxamide, a levogyl isomer, of the formula: with a functional derivative of an acid of formula: where R1 is as defined for a compound of formula (I).

Eventually, the compound of formula (I) is transformed into one of its salts of addition to a base.

As a functional derivative of acid of formula (II) acid chloride, an anhydride or the free acid itself may be used.

When an acid chloride is used, the reaction is carried out in a solvent such as a chlorinated solvent such as dichloromethane, dichlororoethane, chloroform, an ether such as tetrahydrofuran, dioxane, an amide such as N,N-dimethylformamide, in the presence of a base such as triethylamine, N-methylmorpholine, pyridine, 4-dimethylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylamylam

When using an anhydride, the reaction is carried out in the absence or presence of a base such as pyridine, 4-dimethylamino) pyridine, in a solvent or in the absence of a solvent at a temperature between room temperature and the reflux temperature of the reaction medium.

A compound of formula (I) in which R1 represents a -CH2CH2COOH group may also be prepared by reaction of compound A with succinic anhydride, in the presence of a base such as pyridine, in a solvent or in the absence of a solvent and at a temperature between room temperature and the reflux temperature of the reaction medium.

When the acid itself is used, the reaction is carried out using a condensing agent such as a carbodiimide such as 1,3-dicyclohexylcarbodiimide or 1,3-diisopropylcarbodiimide, an imidazole such as 1,1'-oxalyldiimidazole or N,N'-carbonyldiimidazole. The reaction is carried out in the absence or presence of a base such as triemelamine, N,N-diisopropylterylterylteryl, pyridine, 4-dimethylpropyridine or N-thylmormoronine, in a solvent such as chloromethane, dichloromethane, chlorone, such as diethyl acetate, an aromatic form such as diethyl nitrate, and a solvent such as diethyl nitrate, such as diethyl nitrate, and an ammonium nitrate, such as diethyl nitrate, an ammonium nitrate, an ammonium nitrate, and a diethyl nitrate.

When using the acid itself, the reaction can also be carried out in the presence of an acid catalyst such as an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, an organic acid such as acetic acid, formic acid, oxalic acid, p-toluenesulfonic acid, a Lewis acid such as boron trichloride, boron trifluoride or boron tribromide. The reaction is carried out in a solvent such as a solvent such as dichloromethane, dichloronite, chloroform, a solvent such as diethyl ether, diethyl nitrite, diethyl nitrocyl nitrate, a solvent such as diethyl nitrite, a diluent such as diethyl nitrite, a diluent such as diethyl nitrite, a diluent such as diethyl nitrite, a diluent such as diethyl nitrite, a diluent such as diethyl nitrite, a diluent such as diethyl nitrite, a diluent such as diethyl nitrite, a diluent such as diethyl nitrite, a diluent such as diethyl nitrite, and a diluent such as diethyl nitrite.

A compound of formula (I) in which R1 represents a hydrogen atom may also be prepared by reaction of compound A with formic acid, in the presence of acetic anhydride and a base such as pyridine, at a temperature between 0 °C and room temperature.

In a variant of the process, where R1 represents a group -NR2R3: (a) the compound A is reacted in the presence of a base with phenyl chloroformate to obtain the compound B of formula: (b) the B compound is reacted with a compound of formula: - What? HNR2R3 (III) - What? where R2 and R3 are as defined for a compound of formula (I) to obtain a compound of formula (I) where R1 = NR2R3.

In step (a), compound A is reacted with phenyl chloroformate in the presence of a base such as pyridine or triethylamine in a solvent such as dichloromethane or without solvent and at a temperature of 0 to 100 °C.

In step (b), the reaction of compound B with the compound of formula (III) is carried out in a solvent such as dichloromethane or tetrahydrofuran or a mixture of these solvents and at a temperature between -60°C and the reflux temperature of the solvent.

The resulting compounds of formula (I) can then be separated from the reaction medium and purified by conventional methods, e.g. by crystallization or chromatography.

Compound A shall be prepared in accordance with the method described in application WO 01/55130.

The functional derivatives of formula (II) acids are commercially available, known or prepared by known methods.

The invention, in another aspect, also concerns compound B. This compound is useful as an intermediate for the synthesis of compounds of formula (I) in which R1 = NR2R3.

The following EXAMPLES describe the preparation of certain compounds according to the invention. These examples are not exhaustive and are merely illustrative of the present invention. The numbers of the compounds illustrated refer to those given in the following table, which illustrates the chemical structures and physical properties of some compounds according to the invention.

In the Examples we use the following abbreviations: AcO: Ethyl acetateEther: diethyl ether iso: diisopropyl etherDCM: dichloromethaneF: melting pointTA: ambient temperatureEb: boiling temperatureCLHP: high performance liquid chromatography

The proton magnetic resonance spectra (MNR 1H) are recorded at 200 MHz in DMSO-d6, using the peak of DMSO-d6 as a reference. Chemical displacements δ are expressed in parts per million (ppm). The observed signals are expressed as: s: singlet; se: enlarged singlet; d: double; d.d.: split-double; t: triple q: quadruplet m: massive; mt; multiplet.

The MRI spectra confirm the structures of the compounds.

EXAMPLE 1: compound number 1 The active substance is a compound containing a mixture of hydrocarbons obtained from the distillation of hydrocarbons from the distillation of hydrocarbons.

- What? - What? (I) R1 = -CH3 - What? - What?

After cooling the mixture at room temperature, 170 ml of absolute ethanol is added. The mixture is left under vacuum, the residue is extracted with 1000 ml of Acetyl-Other, the organic residue is washed by repeatedly immersing the saturated phase in a solution of 670 ml of NH4O4 and NH4O4 and the resulting product is isolated from the liquid solution, and the resulting product is obtained at a temperature of 190°C. The resulting product is isolated from the liquid solution, and the resulting product is obtained at a temperature of 190°C. α $\frac{\text{25}}{\text{D}}$ The maximum value of the product obtained is -133.9° (c = 0.5; acetonitrile). RMN 1H: DMSO-d6 : δ (ppm) : 1.7 to 2.8 : m: 13H ; 3.3 : se: 3H ; 3.7 : s: 3H ; 3.9 : s: 3H ; 4.6 : mt: 1H ; 5.2 : mt: 1H ; 6.6 to 8.2 m: 10H .

EXAMPLE 2: compound number 2 The following substances are to be classified in the same category as the active substance:

- What? - What? (I) R1 = -CH2CH3 - What? - What?

After cooling the reaction mixture at TA, 28 ml of absolute ethanol is added. The residue is concentrated under vacuum, extracted with 160 ml of AcOEt, the organic phase washed with 100 ml of a saturated aqueous NaCl solution, 110 ml of a 10% NaHCO3 aqueous solution three times, and the solvent is evaporated under vacuum. The residue is taken back into the ether and the precipitate is ejected. The result is 4.31 g of the desired product. α $\frac{\text{25}}{\text{D}}$ The maximum value of the product obtained from the product is -107° (c = 0,5; acetonitrile). The following are the main features of the newly introduced EMAS: the introduction of a new EMAS-based EMAS-based EMAS-based EMAS-based EMAS-based EMAS-based EMAS-based EMAS-based EMAS-based EMAS-based EMAS-based EMAS-based EMAS-based EMAS-based EMAS-based EMAS-based EMAS-based EMAS-based EMAS-based EMAS-based EMAS-based EMAS-based EMAS-based EMAS-based EMAS-based EMAS-based EMAS-based EMAS-based EMAS-based EMAS-based EMAS-based EMAS-based EMAS-based EMAS-based EMAS-based EMAS-based EMAS-based EMAS-based EMAS-based EMAS-based EMAS-based EMAS-based EMAS-based EMAS-based EMAS-based EMAS-based EMAS-based EMAS-based EMAS-based EMAS-based EMAS-based EMAS-based EMAS-based EMAS-based EMAS-based EMAS-based EMAS-based EMAS-based EMAS-based EMAS-based EMAS-based EMAS-based EMAS-based EMAS-based EMAS-based EMAS-based EMAS-based EMAS-based EMAS-based EMAS-based EMAS-based EMAS-based EMAS-based EMAS-based EMAS-based EMAS-based EMAS-based EMAS-based EMAS-based EMAS-based EMAS-based EMAS-based EMAS-based EMAS-based EMAS-based EMAS-based EMAS-based EMAS-based EMAS-based EMAS-based EMAS-based EMAS-based EMAS-based EMAS-based EMAS-based EMAS-based EMAS-based EMAS-based EMAS-based EMAS-based EMAS-based EMAS-based EMAS-based EMAS-based EMAS-based EMAS-based EMAS-based EMAS-based EMAS-based EMAS-based EMAS-based EMAS-based EMAS-based EMAS-based EMAS-based EMAS-based EMAS-based EMAS-based EMAS-based EMAS-based EMAS-based EMAS-based EMAS

The following is the list of substances which are to be used in the preparation of the product: Formiate of (3R,5S)-1-[(3R)-5-chloro-1-[(2,4-dimethoxyphenyl) sulfonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-5-[(dimethylamino) carbonyl]-3-pyrrolidinyl.

- What? - What? (I) R1 = H. - What? - What?

Cool 4 ml of formic acid to 0°C, add 1.6 ml of acetic anhydride drop by drop and then leave for 4 hours to be stirred at a temperature below 20°C. Cool the reaction mixture in an ice bath, add in 5 minutes a solution of 0.63 g of compound A in 7 ml of dry pyridine previously cooled in an ice bath and leave for 48 hours to be stirred in TA. Add water to the reaction mixture, extract it from AcOEt, wash the organic phase with water, with a saturated solution of NaSOCl, dry on Na2/204 and chromatise underground. Freeze the residue on a molar of silica by evaporating the mixture by DCM/Other (70°C); and then mix it in a concentrated form, after isolating the product at 127°C. The resulting product is obtained in the form of a solid solution of 0,5 g of DCO/Other (70°C). α $\frac{\text{25}}{\text{D}}$ The following is the list of substances which are to be classified in the Annex to this Regulation:

EXAMPLE 4: compound No 4 is used in the manufacture of Cyclohexanecarboxylate of (3R,5S)-1-[(3R)-5-chloro-1-[(2,4-dimethoxyphenyl) sulfonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-'dihydro-1H-indol-3-yl]-5-[(dimethylamino) carbonyl]-3-pyrrolidinyl

A mixture of 1.5 g of compound A, 0.630 ml of cyclohexanecarbonyl chloride, 0.62 g of N,N-diisopropylethylamine and a few crystals of 4-dimethylamino) pyridine are left to agitate in 20 ml of DCM for 8 days under TA. The residue is concentrated under vacuum, taken up in a mixture of AcOEt/water, alkalinized by addition of solid NaHCO3, decanted, the organic phase washed twice with a saturated solution of K2CO3, by a juice solution of NaCl, saturated on Na2SO4 and evaporated. The residue is videographed under a silica gel by mixing with the mixture of AcODC/M/80 (80/20 g/h); the product is then recovered in 48 ml of isolated water, isolated from the product, and obtained at a temperature of 197°C, and the product is obtained in the form of a single crystal, and the expected precipitation is between 0.9 and 0.9 g/h. The product is obtained at 197°C, and the expected precipitation is between 197 and 1.0 °C. α $\frac{\text{25}}{\text{D}}$ The following is the list of substances which are to be classified in the Annex to this Regulation:

EXAMPLE 5: compound No 5 is used in the manufacture of The substance is to be classified in the additive category 'Chemical products' as defined in point 1 of Annex I to Regulation (EC) No 1907/2006 of the European Parliament and of the Council.

- What? - What? (I) R1 = -CH(CH3) 2. - What? - What?

A mixture of 1.5 g of Compound A, 0.75 ml of isobutyryl chloride and 1.22 g of N,N-diisopropylethylamine is left to agitate for 36 hours in TA in 20 ml of DCM. Concentrate under vacuum, take the residue with water, alkalize by addition of solid NaHCO3, extract in AcOEt, wash the organic phase with water, dry on Na2SO4 and evaporate the solvent under vacuum. Chromatise the residue on silica gel by eluting with the mixture DCM/AcOEt (70/30 v/v). α $\frac{\text{25}}{\text{D}}$ The following is the list of substances which are to be classified in the Annex to this Regulation:

EXAMPLE 6 - Compound No 6 is used in the manufacture of The following is added to the list of active substances in the feed additive:

- What? - What? (I) R1 = -CH2CH2COOH. This is the - What? - What?

A mixture of 0.2 g of compound A, 0.2 g of succinic anhydride and 3 ml of pyridine is heated at 50 °C for 5 minutes until dissolved, then left to agitate for 20 hours at 25 °C. The residue is concentrated under vacuum, taken up by a solution of HCl 2N, extracted in ether, decanted, the precipitate formed in the organic phase is ejected and the lava is ejected in ether. α $\frac{\text{25}}{\text{D}}$ The maximum value of the product obtained from the product is -252° (c = 0.25; chloroform). The following are the main features of the newly introduced standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standardised standard

EXAMPLE 7: compound No 7 is used in the manufacture of The active substance is a compound with a specific chemical activity of not more than 0,5% by weight and a specific chemical activity of not more than 0,5% by weight.

- What? - What? (I) = R1 = -NH2. - What? - What?

The substance is classified in the additive category 'Chemical products' as defined in point 1 of Annex I to Regulation (EC) No 1907/2006 of the European Parliament and of the Council.

To a solution of 1.6 g of compound A in 20 ml of pyridine, add 4 ml of phenyl chloroformate at 25 °C and leave to agitate for 20 hours at 25 °C. Concentrate the reaction mixture in a vacuum, take up the residue in a solution of 1N HCl, extract at AcOEt, dry the organic phase on Na2SO4 and evaporate the solvent in a vacuum.

The substance is classified in the additive category 'Chemical products' as defined in point 1 of Annex I to Regulation (EC) No 1907/2006 of the European Parliament and of the Council.

A solution of 0.7 g of the compound obtained in the previous step is cooled to -60°C in 15 ml of THF, 4 g of NH3 gas is added by stirring and left to agitate for 5 hours, allowing the mixture to rise and maintaining the temperature at 0°C. The reaction mixture is concentrated under vacuum and the residue is chromatographed on silica gel by DCM and then at AcOEt. 0.37 g of the expected product is obtained after crushing in iso ether, F = 155-165°C. α $\frac{\text{25}}{\text{D}}$ The following is the list of substances which are to be classified in the additive:

EXAMPLE 8: compound No 8 is used in the manufacture of The active substance is a compound with a specific chemical activity of approximately 10 ppm.

- What? - What? (I) R1 = -N (CH3) 2. - What? - What?

A mixture of 0.35 g of the compound obtained in step A of Example 7 and 10 ml of a 2M solution of dimethylamine are allowed to agitate for 20 hours at 25 °C. The reaction mixture is concentrated in a vacuum, the residue is crushed in the hot iso ether and the precipitate is ejected. α $\frac{\text{25}}{\text{D}}$ The maximum value of the product obtained is -152° (c = 0.25; chloroform).

The following Table I illustrates the chemical structures and physical properties of some examples of compounds of the invention. - What?

The compounds of the invention have been subject to biochemical studies.

The affinity of the compounds of formula (I) of the invention for the V1b arginine-vasopressin receptors was determined in vitro using the method described by Y. DE KEYSER et al., Febs Letters, 1994, 356, 215-220. This method consists of investigating in vitro the movement of tritiated arginine-vasopressin ([3H]-AVP) to the V1b receptors on adeno-pituitary or cellular membrane preparations carrying human or human V1b inhibitors. The rated concentrations of 50% (CI50) of the tritiated arginine-vasopressin binding of the compounds of the invention are generally less than 5.10-90.M. For example, the CI of a human V1b receptor is 3.10-94.M.

The affinity of formula (I) compounds of the invention for arginine-vasopressin V1a receptors was determined in vitro using the method described by THIBONNIER et al., J. Biol. Chem., 1994, 269, 3304-3310. This method involves in vitro studying the movement of tritiated arginine-vasopressin ([3H]-AVP) to V1a receptors on membrane or cellular preparations carrying rat or human V1a receptors. Some formula (I) compounds also have affinity for arginine-vasopressin V1a receptors with receptors in the order of 10-850M. For example, the human CI composition has a CI of 8.10-150M.

The A-compound is prior to the art with a CI50 of 1.0.10-8M for human V1b receptors and a CI50 of 3.1.10-7M for human V1a receptors.

The affinity of the compounds of formula (I) of the invention for vasopressin V2 receptors has also been studied (method described by Birnbaumer et al., Nature (London), 1992, 357, 333-335).

The compounds of the invention can therefore be used for the preparation of medicinal products, in particular medicinal products intended to prevent or treat any disease involving arginine-vasopressin and/or its V1b receptors or both its V1b and V1a receptors.

Thus, according to another aspect of the invention, the subject-matter of the invention is medicinal products which contain a compound of formula (I), or a salt of the compound of formula (I) added to a pharmaceutically acceptable base, or a solvated or hydrated compound of formula (I).

Thus, the compounds of the invention can be used in humans or animals for the treatment or prevention of various vasopressin-dependent conditions such as cardiovascular diseases; such as hypertension, pulmonary hypertension, heart failure, myocardial infarction, or coronary vasospasm, particularly in smoking, Raynaud's disease, unstable angina and PTCA (percutaneous transluminal coronary angioplasty), heart ischemia, central hemostasis disorders; nervous system conditions such as migraine, cerebrovascular disease, cerebral hemorrhage, oedema, depression, panic attacks, anxiety, depression, depression, anxiety, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression,For example, memory disorders; diseases of the renal system such as renal vasospasm, renal cortex necrosis, nephrogenic diabetes insipidus; diseases of the gastric system such as gastric vasospasm, hepatocirrhosis, ulcers, vomiting pathology, e.g. nausea including nausea due to chemotherapy, transportation sickness, diabetic nephropathy. The compounds may also be used in the treatment of sexual behaviour disorders; in women, the compounds may be used to treat dysmenorrhea or preterm labor. The compounds may also be used in the treatment of lung cancer; small cell lung encephalitis; hypoplastic lung cancer;The following are some of the most important factors that can affect the outcome of the study: Meniere's disease; glaucoma, cataracts; obesity; type II diabetes; atherosclerosis; Cushing's syndrome; insulin resistance; hyper triglyceridemia; post-operative treatments, especially after abdominal surgery.

The compounds of the invention may also be used in the treatment or prevention of all stress-related conditions such as fatigue and its syndromes, ACTH-dependent disorders, heart disorders, pain, changes in gastric emptying, fecal excretion (colitis, colon syndrome, Crohn's disease), acid secretion, hyperglycemia, immunosuppression, inflammatory processes (rheumatoid arthritis and osteoarthritis), multiple infections, cancers, asthma, spasm, allergies and stress disorders. They may also be used in the treatment of various neurodegenerative disorders such as anorexia nervosa, pain, hypothyroidism, sleep apnea, chronic hypoglycemia, neuroblastoma, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression, depression,

The compounds of the invention may also be used as psychostimulants, causing increased wakefulness, emotional responsiveness to the environment and facilitating adaptation.

In another aspect, the present invention relates to pharmaceutical compositions containing, as an active ingredient, a compound of the invention, containing an effective dose of at least one compound of the invention, or a pharmaceutically acceptable salt, solvate or hydrate of the compound, and at least one pharmaceutically acceptable excipient.

These excipients are selected according to the pharmaceutical form and the desired route of administration from among the usual excipients known to the professional.

In the pharmaceutical formulations of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, local, intratracheal, intranasal, transdermal or rectal administration, the active substance of formula (I) above, or its salt, solvate or hydrate, if any, may be administered as a unit of administration, in combination with conventional pharmaceutical excipients, to animals and humans for the prophylaxis or treatment of the above disorders or diseases.

Suitable unit forms of administration include oral forms such as tablets, soft or hard capsules, powders, granules and oral solutions or suspensions, sublingual, oral, intratracheal, intraocular, intranasal, inhalation, topical, transdermal, subcutaneous, intramuscular or intravenous, rectal and implant forms. For topical application, the compounds of the invention may be used in creams, gels, ointments or lotions.

For example, a unit form of administration of a compound of the invention in tablet form may include the following components: - What?

Composé selon l'invention	50,0 mg
Mannitol	223,75 mg
Croscaramellose sodique	6,0 mg
Amidon de maïs	15,0 mg
Hydroxypropyl-méthylcellulose	2,25 mg
Stéarate de magnésium	3,0 mg

Orally, the daily dose of active substance may be 0.01 to 100 mg/kg in one or more doses, preferably 0.02 to 50 mg/kg.

There may be special cases where higher or lower doses are appropriate; such doses are not outside the scope of the invention.

The present invention, in another aspect, also relates to a method of treatment of the above conditions which involves administering to a patient an effective dose of a compound of the invention or one of its pharmaceutically acceptable salts or hydrates or solvates.

Claims (9)

1. Compound corresponding to the formula (I): in which:

   - R₁ represents a hydrogen atom, a (C₁-C₆)alkyl, a (C₃-C₆) cycloalkyl, a -CH₂CH₂COOH group or an -NR₂R₃ group;

   - R₂ and R₃ each independently represent a hydrogen atom or a (C₁-C₆) alkyl;

   in the base form or in the form of an addition salt with an organic or inorganic base, and in the hydrate or solvate form.
2. Compound of formula (I) according to Claim 1, in which R₁ represents a hydrogen atom, a methyl radical, an ethyl radical, an isopropyl radical, a cyclohexyl radical, a -CH₂CH₂COOH group, an amino group or a dimethylamino group; in the base form or in the form of an addition salt with an organic or inorganic base, and in the hydrate or solvate form.
3. A compound chosen from:

   - (3R,5S)-1-[(3R)-5-Chloro-1-[(2,4-dimethoxyphenyl)-sulphonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-5-[(dimethylamino)carbonyl]-3-pyrrolidinyl acetate;

   - (3R,5S)-1-[(3R)-5-Chloro-1-[(2,4-dimethoxyphenyl)-sulphonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-5-[(dimethylamino)carbonyl]-3-pyrrolidinyl propionate;

   - (3R,5S)-1-[(3R)-5-Chloro-1-[(2,4-dimethoxyphenyl)-sulphonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-5-[(dimethylamino)carbonyl]-3-pyrrolidinyl formate;

   - (3R,5S)-1-[(3R)-5-Chloro-1-[(2,4-dimethoxyphenyl)-sulphonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-5-[(dimethylamino)carbonyl]-3-pyrrolidinyl cyclohexanecarboxylate;

   - (3R,5S)-1-[(3R)-5-Chloro-1-[(2,4-dimethoxyphenyl)-sulphonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-5-[(dimethylamino)carbonyl]-3-pyrrolidinyl 2-methylpropanoate;

   - 4-[[(3R,5S)-1-[(3R)-5-Chloro-1-[(2,4-dimethoxyphenyl)-sulphonyl]-3-(2-methoxyphenyl)-2,3-dihydro-1H-indol-3-yl]-5-[(dimethylamino)carbonyl]-3-pyrrolidinyl]oxy]-4-oxobutanoic acid;

   - (2S,4R)-4-[(Aminocarbonyl)oxy]-1-[(3R)-5-chloro-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethyl-2-pyrrolidinecarboxamide;

   - (2S,4R)-4-[[(Dimethylamino)carbonyl]oxy]-1-[(3R)-5-chloro-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethyl-2-pyrrolidinecarboxamide;

   in the base form or in the form of an addition salt with an organic or inorganic base, and in the hydrate or solvate form.
4. Process for the preparation of the compounds of formula (I) according to Claim 1, characterized in that:

   (2S,4R)-1-[5-Chloro-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-N,N-dimethyl-2-pyrrolidinecarboxamide, laevorotatory isomer, of formula: is reacted with a functional derivative of an acid of formula:

   in which R₁ is as defined for a compound of formula (I) in Claim 1.
5. Process for the preparation of the compounds of formula (I) according to Claim 1 in which R₁ represents an -NR₂R₃ group, characterized in that:

   a) compound A, as defined in Claim 4, is reacted, in the presence of a base, with phenyl chloroformate to produce compound B of formula:

   b) compound B is reacted with a compound of formula:         HNR₂R₃     (III)

   in which R₂ and R₃ are as defined for a compound of formula (I) in Claim 1, to produce a compound of formula (I) in which R₁ = NR₂R₃.
6. Compound of formula:
7. Medicament, characterized in that it comprises a compound of formula (I) according to any one of Claims 1 to 3 or an addition salt of this compound with a pharmaceutically acceptable base or a hydrate or a solvate of the compound of formula (I).
8. Pharmaceutical composition, characterized in that it comprises a compound of formula (I) according to any one of Claims 1 to 3 or a pharmaceutically acceptable salt, a hydrate or a solvate of this compound, and at least one pharmaceutically acceptable excipient.
9. Use of a compound of formula (I) according to any one of Claims 1 to 3 in the preparation of medicaments intended to treat cardiovascular conditions, stress, anxiety, depression, obsessive-compulsive disorder, panic attacks, conditions of the renal system, conditions of the gastric system, small cell lung cancer, obesity, type I and II diabetes, insulin resistance, hypertriglyceridaemia, atherosclerosis, Cushing's syndrome, dysmenorrhoea and premature labour.