HK1050900B - 1,3-dihydro-2h-indol-2-one derivatives and their use as ligands for v1b or v1b and v1a arginine-vasopressin receptors - Google Patents
1,3-dihydro-2h-indol-2-one derivatives and their use as ligands for v1b or v1b and v1a arginine-vasopressin receptors Download PDFInfo
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Description
The present invention relates to new derivatives of 1,3-dihydro-2H-indol-2-one, a process for their preparation and pharmaceutical compositions containing them.
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 receptors of AVP are located in many peripheral organs and in the brain. They have been cloned in rats and humans and 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 glycoglycosis, hormone proliferation and the main central effects of AVP (hypothermia, hyperthermia, etc.).
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 AVP cortisol synthesis (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 phosphatidylserine converters (3), including the receptor-inducing activator AVP and the receptor-resistant activator glucagon (AVP. This enzyme is also an inhibitor of the production of glucagon, and is comparable in its effectiveness to the production of the antagonists glucagon and glucagon-resistanthormone, and the antagonists of the receptor-resist glucagon (VIAG-135), and glucagon-resistone (VIAG-135), and the production of glucagon-resistone (VIAG-135), and glucagon-resistone (VIAG12), and glucortisone (VIAG, and glucortisone).
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 a marker for ACTH-secreting tumors such as certain pituitary tumors, 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, 335, 991-994 ; G. DICTEIN et al., J. Clinlin E. Endocrinol. Metab., 1996, 81 (8), 2934-2941). V1a receptor, in turn, offers a more obvious marker for small cell lung cancers (J.P. P. P. P. P. P. P., or SPLC); and they are a precursor to the invention of the single cell lung cancer (P. P. P. P. P. P., 1989), and are a novel precursor to the present invention of the TomTom and Tomograph, Scanner, and Photonograph, and the newly developed single cell lung cancer (P. P. P. P. P. P., 1989), and the present invention of the newly developed single cell lung cancer (P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P. P.
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).
Derivatives of 1,3-dihydro-2H-indol-2-one have been described in some patent applications as ligands of the arginine-vasopressin and/or oxytocin receptors: these include patent applications WO 93/15051, EP 636608, EP 636609, WO 95/18105, WO 97/15556 and WO 98/25901.
To date, no non-peptidic compounds with affinity and selectivity for V1b or both V1b and V1a arginine-vasopressin receptors are known.
New derivatives of 1,3-dihydro-2H-indol-2-one have now been found that exhibit affinity and selectivity for V1b or both V1b and V1a arginine-vasopressin receptors.
These compounds can be used to prepare medicinal products useful in the treatment or prevention of any disease in which arginine-vasopressin and/ or V1b receptors or both V1b and V1a receptors are involved, including the treatment or prevention of diseases of the cardiovascular system, for example hypertension; of the central nervous system, for example stress, anxiety, depression, obsessive-compulsive disorder; of the renal system, panic attacks; of the gastric system; and in the treatment of small cell lung cancers; of type II diabetes mellitus; of hyperhidrosis; of Cushing' s syndrome; of stress and all chronic conditions.
Thus, in one aspect, the present invention relates to compounds of formula (Ia) in the form of a levogyre isomer:
in which:
R1 represents a chlorine atom, a methyl radical or a trifluoromethoxy radical;R2 represents a hydrogen atom or is at the -6-position of indol-2-one and represents a chlorine atom, a methyl radical, a methoxy radical or a trifluoromethyl radical;R3 represents a chlorine atom, a fluorine atom, a methoxy radical or an ethoxy radical;R4 represents a hydrogen atom or is at the -3- or -4-position of phenylethyl and represents a fluorine atom or a methoxy radical;or R4 is at the -3-position of phenylethyl and together with R3 represents a methyl diethylammonium radical;R5 represents a dimethyl or dimethyl carboxylic acid;R6 represents a carbonyl radical;R7-hydroxylammonium;R7-methyl or methylammonium;R7-methyl is a radical or a radical of methylammonium;R7-methyl is a radical of methylammonium;R7-methyl is a radical of methylammonium;R7-methyl is a radical of methylammonium;R7-methyl is a radical of methylammonium;R7-methyl is a radical of methylammonium;R7-methyl is a radical of methylammonium;R2-methyl is a radical of methylammonium;R2-methyl is a radical of methylammonium;R2-methyl is a radical of methylammonium is a radical of methylammonium;R2-methyl is a radical of methylammonium is a radical of methylammonium;R2-methyl is a radical of methylammonium is a radical of methylammonium is a radical;R2-methyl is a radical of methylammonium is a radical of methylammonium is a radical is a radical of methylammonium is a radical;R2-methyl is a radical is a radical of a radical of a radical of a methylammonium is one of a methylammonium is one of a rings is one of the other is one or a rings, and a rings, and a rings, andtheir solvates and/or hydrates.
The compounds of formula (Ia) are isomeric levoglycerides and contain at least 3 asymmetric carbon atoms, the carbon atom bearing the substituent COR5 in the configuration (S) and the carbon atom bearing the substituent OR6 in the configuration (R).
Salts are generally prepared with pharmaceutically acceptable acids but salts of other acids useful for purification or isolation of formula (Ia) compounds are also part of the invention. Salts of pharmaceutically acceptable formula (Ia) compounds are for example chlorhydrate, bromohydrate, sulfate, hydrogen sulfate, dihydrogen phosphate, methanesulfonate, benzenesulfonate, naphthalenesulfonate, para-toluenesulfonate, male oxate, fumarate, succinate, citrate, acetate, gluconate, alate.
The following compounds:
The following substances are to be classified in the Annex to Regulation (EC) No 396/2005 as 'organic acids' and 'organic acids' and 'organic acids' and 'organic acids' and 'organic acids' and 'organic acids' and 'organic acids' and 'organic acids' and 'organic acids' and 'organic acids' and 'organic acids' and 'organic acids' and 'organic acids' and 'organic acids' and 'organic acids' and 'organic acids' and 'organic acids' and 'organic acids' and 'organic acids' and 'organic acids' and 'organic acids' and 'organic acids' and 'organic acids' and 'organic acids' and 'organic acids' and 'organic acids' and 'organic acids' and 'organic acids' and 'organic acids' and 'organic acids' and 'organic acids' and 'organic acids' and 'organic acids' and 'organic acids' and 'organicids' and 'organicids' and 'organic acids' and 'organic acids' and 'organic acids' and 'organic acids' and 'organic acids' and 'organic acids' and 'organic acids' and 'organic acids' and 'organic' and 'organicids' and 'organic' and 'organic' acids' and 'organic' and 'organic' acids' and 'organic' and 'organic' acids' and 'organic' and 'organic' acids and 'organic' and 'organic' acids' and 'organic' and 'organic' acids and 'organic' and 'organic' acids' and 'organic' acids and 'organic' and 'organic' acids and 'organic' acids and 'organic' and 'organic' acids 'organic' and 'organic' and 'organic' and 'organic' acids 'organic' and 'organic' and 'organic' and 'organic' and 'organic' 'organi
The following compound:
(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-pyrrolidine carboxamide, isomer of levogyre; is particularly preferred.
The present invention is also concerned with a process for the preparation of compounds of the isomeric formula (Ia) levogyre, their salts, if any, with mineral or organic acids, their solvates and/or their hydrates, characterized by:
a compound with the formula:
in which the carbon atom bearing the substituent OR6 has the configuration (R), R1, R2, R3, R4, R5 and R6 are as defined for a levogyl isomer compound of formula (Ia) with a halogen of formula:
where R7 and R8 are as defined for a compound of formula (Ia) isomeric levogyre and Hal represents a halogen atom.
The compound of formula (Ia) isomer levogyre may be transformed into one of its salts with mineral or organic acids.
The reaction is carried out in the presence of a strong base such as a metal hydride such as sodium hydride or an alkaline alcohol such as potassium tert-butylate in an anhydrous solvent such as N,N-dimethylformamide or tetrahydrofuran and at a temperature between -70°C and +60°C. The reaction is preferably carried out using a compound of formula (III) in which Hal = Cl.
A compound of formula (Ia) in which R6 represents a methyl or ethyl can also be prepared by the reaction of a compound of formula (Ia) in which R6 represents hydrogen with a methyl or ethyl halides in the presence of a base such as a metal hydride in an inert solvent such as N,N-dimethylformamide or tetrahydrofuran by the conventional methods.
A compound of formula (Ia) in which R6 represents a -CH2COOH group is preferably prepared by hydrolysis of a compound of formula (Ia) in which R6 represents a -CH2COOC(CH3) 3 group in an acid medium using a strong acid such as trifluoroacetic acid or hydrochloric acid in a solvent such as dichloromethane or dioxane and at a temperature between 0 °C and room temperature.
A compound of formula (Ia) in which R6 represents a 2-hydroxy-1- ((hydroxymethyl)-1-methyl) amino) carbonyl methyl group, a (1-piperazinyl) carbonyl methyl group or a (4-morpholinyl) carbonyl methyl group is preferably prepared by reaction of a compound of formula (Ia) in which R6 represents a -CH2COOH group with 2-amino-2-methyl-1,3-propanediol, piperazine or morpholine according to the conventional peptide coupling methods.
The resulting compounds of formula (Ia) levogyr isomer can then be separated from the reaction medium and purified by conventional methods, e.g. by crystallization or chromatography.
The resulting compounds of the formula (Ia) levogyr isomer are isolated as free base or salt, according to conventional techniques.
When the compounds of the formula (Ia) isomer levogyre are obtained as free base, salification is carried out by treatment with the selected acid in an organic solvent. By treatment of the free base, dissolved for example in an ether such as diethyl ether or in an alcohol such as propane-2-ol or in acetone or dichloromethane, or in ethyl acetate or acetonitrile with a solution of the selected acid in one of the above solvents, the corresponding salt is obtained which is isolated by the conventional techniques.
For example, hydrochloride, bromohydrate, sulphate, trifluoroacetate, hydrogen sulphate, dihydrogen phosphate, methanesulfonate, oxalate, maleate, succinate, fumarate, naphthalene-2-sulfonate, benzenesulfonate, para-toluenesulfonate, gluconate, citrate and acetate are prepared.
At the end of the reaction, the compounds of formula (Ia) levogyre isomer can be isolated as one of their salts, e.g. hydrochloride, or oxalate; in this case, if necessary, the free base can be prepared by neutralizing this salt with a mineral or organic base, such as sodium hydroxide or triethylamine or with an alkaline carbonate or bicarbonate, such as sodium or potassium carbonate or bicarbonate.
Compounds of formula (II) are prepared by reaction of a 3-halogen-1,3-dihydro-2H-indol-2-one compound of formula: wherein R1, R2, R3 and R4 are as defined for a compound of formula (Ia) isomeric levogyl and Hal represents a halogen atom, preferably chlorine or bromine, with a compound of formula:
in which the carbon atom bearing the substituent OR6 has the configuration (R), R5 and R6 are as defined for a compound of levogyre isomer formula (Ia). The reaction is carried out in the presence of a base such as diisopropylethilamine or triethylamine in an inert solvent such as dichloromethane or tetrahydrofuran or a mixture of these solvents and at a temperature between room temperature and the reflux temperature of the solvent.
For example, formula (III) compounds can be prepared by halogenation of the corresponding benzene sulfonic acids or their salts, e.g. their sodium or potassium salts. The reaction is carried out in the presence of a halogenating agent such as phosphorus oxychloride, thionyl chloride, phosphorus trichloride, phosphorus tribromide or phosphorus pentachloride, without solvent or in an inert solvent such as a hydrocarbon or N,N-dimethyl chloride, at a temperature between -10 °C and 200 °C.
2,4-dimethoxybenzenesulfonyl chloride is prepared according to J. Am. Chem. Soc.,1952, 74, 2008.
The compounds of formula (IV) are known and are prepared by known methods such as those described in WO 95/18105.
For example, a compound of formula : in which R1, R2, R3 and R4 are as defined for a compound of formula (Ia) isomeric levogyre, is transformed into a compound of formula (IV) in which Hal = Cl by action of thionyl chloride in the presence of a base such as pyridine, in an inert solvent such as dichloromethane and at a temperature between 0 °C and room temperature.
In another example of preparation of compounds of formula (IV), a compound of formula is transformed:
wherein R1, R2, R3 and R4 are as defined for a compound of formula (Ia) isomeric levogyre, in a compound of formula (IV) by means of a halogenating agent such as bromine according to the process described in Farm. Zh.(Kiev), 1976,5,30-33.
The compounds of formula (VI) are known and are prepared by known methods such as those described in WO 95/18105.
For example, a compound of formula (VI) is prepared by reaction of a derivative of 1H-indole-2,3-dione of formula:
where R1 and R2 are as defined for a compound of formula (Ia) isomeric levogyr, with an organomagnesium derivative of formula : where R3 and R4 are as defined for a compound of formula (Ia) isomeric levogyr and Hal represents a halogen atom, preferably bromine or iodine, in an inert solvent such as tetrahydrofuran or diethyl ether.
A compound of formula (VI) may also be prepared in which R3 is as defined for a compound of formula (Ia) isomeric levogyre and R4, other than hydrogen, is at the -3- position of the phenyl, by reaction of a compound of formula:
where R3 is as defined for a compound of formula (Ia) isomeric levogyre and R4 is in the -2-position of phenyl, with a lithium derivative such as n-butyllithium, and then the resulting lithium intermediate is reacted with a compound of formula (VIII). The reaction is carried out in a solvent such as diethyl ether, tetrahydrofuran, hexane or a mixture of these solvents, at a temperature between -70 °C and room temperature.
The derivatives of 1H-indole-2,3-dione (VIII) are commercially available or prepared by the methods described in Tetrahedron Letters, 1998, 39, 7679-7682; Tetrahedron Letters, 1994, 35, 7303-7306; J. Org. Chem., 1977, 42 (8), 1344-1348; J. Org. Chem., 1952, 17, 149-156; J. Am. Chem. Soc., 1946, 68, 2697-2703; Organic Syntheses, 1925, V, 71-74 and Advances in Heterocyclic Chemistry, A.R. Katritzky and A.J. Boulton, Academic Press, New York, 1975, 2-18, 2-58.
Organomagnesium (IX) derivatives are prepared according to the classic methods well known to the art.
The compounds of formula (XVII) are known or prepared by known methods.
A compound of formula (VI) may also be prepared by oxidation by air of a compound of formula (VII) in the presence of a base such as sodium hydride and in the presence of dimethyl disulfide.
In particular, compounds of formula (VI) in which R3 = (C1-C2) alcoxy and R4 = H, or R3 = R4 = methoxy with R4 at the -3 position of the phenyl, R2 different from a chlorine atom and R1 as defined for a compound of formula (Ia) isomeric levogyr, may be prepared by following the process described in SCHEME 1.
- What?
In step a1 of SCHEME 1, a compound of formula (X) is first reacted with a lithium derivative such as n-butyllithium, in the absence or presence of a base such as N,N,N',N'-tetramethylenediamine, and then the resulting lithium intermediate is reacted with diethyl oxalate to give the compound of formula (XI). The reaction is carried out in an inert solvent such as diethyl ether, tetrahydrofuran, hexane or a mixture of these solvents at a temperature between -70 °C and room temperature.
In step b1, a compound of formula (XII) is first reacted with two equivalents of a lithium derivative such as tert-butyllithium, and then the lithium intermediate obtained is reacted with the compound of formula (XI) to give the compound of formula (VI) expected.
The compounds of formula (X) are commercially or conventionally synthesised.
The compounds of formula (XII) are prepared by reaction of the corresponding aniline derivatives with di-tert-butyldicarbonate by the conventional methods.
The compounds of formula (VII) are known and are prepared by known methods such as those described in WO 95/18105 or J. Org. Chem., 1968, 33, 1640-1643.
Compounds of formula (V) in which R5 represents a methoxy and R6 = H are commercial.
Compounds of formula (V) in which R5 is a methoxy and R6 = methyl or ethyl are known or are prepared by known methods such as those described in J. Med. Chem., 1988, 31, 875-885 from the (2S, 4R) -hydroxypyrrolidine-2-carboxylic acid protected on the nitrogen atom of pyrrolidine.
Compounds of formula (V) in which R5 is a dimethylamino group and R6 = H or (C1-C2) alkyl are prepared according to SCHEME 2 below in which Pr represents an N-protective group, in particular benzyloxycarbonyl or tert-butoxycarbonyl.
In step a2 of SCHEME 2, the nitrogen atom is protected from 4 ((R) -hydroxy- ((S) -proline by the conventional methods to obtain a compound of formula (XIII).
The acid (XIII) is reacted in step b2 with dimethylamine according to the conventional peptide coupling methods to give the compound (XIV), which is unprotected according to the known methods to give a compound of formula (V) in which R6 = H.
In step d2, the compound (XIV) may be reacted with a (C1-C2) alkyl halide in the presence of a base such as a metal hydride or an alkaline or alkaline earth carbonate such as K2CO3 or Cs2CO3 in an inert solvent such as tetrahydrofuran or N,N-dimethylformamide and at a temperature between 0 °C and the solvent reflux temperature to give a compound (XV).
The reaction of a compound (XIV) with a (C1-C2) alkyl halide can also be carried out under phase transfer catalysis conditions in the presence of a base such as an alkaline metal hydroxide, e.g. sodium hydroxide, and a phase transfer catalyst such as a substituted quaternary ammonium salt, e.g. tetrabutylammonium hydrogen sulphate, in an inert solvent such as benzene chloromethane or dichloromethane mixed with water.
By deprotecting the N-protective group of the compound (XV) the compounds of formula (V) in which R6 = (C1-C2) alkyl are obtained at step e2.
Alternatively, at step f2, the hydroxy of the compound (XIII) is alkylated by reaction with a halogen of (C1-C2) alkyl under the conditions of step d2, and the resulting acid (XVI) is reacted at step g2 with dimethylamine according to the classical peptide coupling methods to give the compound (XV).
The (2S,4R) -4-hydroxypyrrolidine-2-carboxylic acids are commercially available.
Compounds of formula (V) in which R5 represents a dimethylamino or a methoxy group and R6 = -CH2COOC(CH3)3 are prepared according to SCHEME 3 below in which Pr represents an N-protective group, in particular benzyloxycarbonyl or tert-butoxycarbonyl.
- What?
In step a3 of SCHEME 3 a compound of formula (XVIII) prepared as described above is reacted with a compound of formula Hal-CH2-COOC(CH3)3 in which Hal is a halogen atom, preferably chlorine or bromine.
By unprotecting the N-protective group of the compound (XIX), the expected compounds (V) are obtained in step b3.
Compounds of formula (V) in which R5 is as defined for a compound of formula (Ia) and R6 = -CH2-CO-OH are prepared by acid hydrolysis of a compound of formula (XIX) in which Pr is a benzyloxycarbonyl. The reaction is carried out using a strong acid such as trifluoroacetic acid or hydrochloric acid in a solvent such as dichloromethane or dioxane and at a temperature between 0°C and room temperature.
Compounds of formula (V) in which R5 is as defined for a compound of formula (Ia) and R6 represents a 2-hydroxy-1- ((hydroxymethyl)-1-methyl) amino-carbonyl-methyl group, a (1-piperazinyl) carbonyl-methyl group or a (4-morpholinyl) carbonyl-methyl group are prepared by reaction of a corresponding compound in which R6 represents a -CH2COOH group and is shielded on the nitrogen atom of pyrrolidine, with 2-amino-2-methyl-1,3-propanediol, piperazine or morpholine according to the classical peptide coupling methods.
By deprotecting the N-protective group using the conventional methods, the expected (V) compounds are obtained.
Compounds of formula (V) in which R5 represents a dimethylamino group or a methoxy group and R6 represents a 3- ((4-morpholinyl) propanoyl group are prepared according to SCHEME 4 below in which Pr represents an N-protective group, in particular benzyloxycarbonyl or tert-butoxycarbonyl.
In step a4 of SCHEME 4 a compound of formula (XVIII) is reacted with a compound of formula Hal-CO-(CH2) 2-Hal' in which Hal and Hal' each independently represent a halogen atom, preferably chlorine or bromine.
In step b4, the reaction of the compound of formula (XX) thus obtained with morpholine produces a compound of formula (XXI) in the presence of a base such as triethylamine or N,N-diisopropylethylamine, or by using excess morpholine, in a solvent such as dichloromethane or tetrahydrofuran and at a temperature between 0 °C and the reflux temperature of the solvent.
By unprotecting the N-protective group of the compound (XXI), the compound of formula (V) is obtained at step c4.
In particular, a compound of formula (V) in which R6 represents a 3- ((4-morpholinyl) propanoyl group according to SCHEME 5 below in which Pr represents an N-protective group, in particular benzyloxycarbonyl or tert-butoxycarbonyl, can also be prepared.
In step a5 of SCHEME 5 a compound of formula (XVIII) is reacted with acryloyl chloride under the conditions described above in step a4 of SCHEME 4 and the compound of formula (XXII) is obtained.
In step b5, the reaction of the compound (XXII) with morpholine produces a compound of formula (XXIII). The reaction is carried out in the presence of ferric chloride in a solvent such as dichloromethane and at a temperature between ambient and reflux temperature of the solvent.
By unprotecting the N-protective group of the compound (XXIII), the compound of formula (V) is obtained at step c5.
When an optically pure compound of formula Ia is to be prepared, a compound of formula II is preferably reacted with a compound of formula III according to the method of the invention.
Optically pure formula (II) compounds are prepared by reaction of the racemic formula (IV) compound with an optically pure formula (V) compound and then separation of the mixture from the diastereoisomers by conventional methods, e.g. by crystallization or chromatography.
Alternatively, the mixture of diasteroisomers of the compound of formula (II) may be reacted with the compound of formula (III) and the mixture of diasteroisomers of the compound of formula (Ia) obtained may be separated.
During any of the steps of preparation of compounds of formula (Ia) or intermediates of formula (II), (IV), (V) or (VI), it may be necessary and/or desirable to protect reactive or sensitive functional groups, such as amine, hydroxyl or carboxy groups, present on any of the molecules concerned. This protection may be achieved by using conventional protective groups, such as those described in Protective Groups in Organic Chemistry, J.F.W. McOmie, Ed. Plenum Press, 1973, in Protective Groups in Organic Synthesis, T.W. Greene and P.G.M. Wutts, Ed. John Wiley, 1991 and Georg W. Wart, Ed. John Wiley, or in the protective steps of Kochart, P.J. Verki, 1994, and others.
The N-protective groups used may be the classical N-protective groups well known to the artists such as the tert-butoxycarbonyl group, fluorenylmethoxycarbonyl, benzyl, benzhydrylidene or benzyloxycarbonyl.
The compounds of formula (II) are new and are part of the invention.
Thus, according to another aspect of the invention, the subject matter of the invention is compounds with the formula:
in which:
The carbon atom bearing the substituent -OR6 in the configuration (R) ;R1, R2, R3, R4, R5 and R6 are as defined for a compound of formula (Ia) isomeric levoglycerin; and their salts with mineral or organic acids, in the form of optically pure isomers or in the form of a mixture of diastereoisomers.
Salts of formula (II) compounds include those with mineral or organic acids that allow proper separation or crystallization of formula (II) compounds such as hydrochloride, bromohydrate, oxalate, maleate, succinate, fumarate, citrate, acetate.
The above formula (Ia) isomeric levoglycer compounds also include those in which one or more hydrogen, or carbon atoms have been replaced by their radioactive isotope e.g. tritium, or carbon-14. Such labeled compounds are useful in research, metabolism or pharmacokinetics, in biochemical assays as a receptor ligand.
The compounds of the invention have been subject to biochemical studies.
The affinity of the invention's formula (Ia) levogyre isomer compounds for arginine-vasopressin V1b receptors was determined in vitro using the method described by Y. DE KEYSER et al., Febs Letters, 1994, 356, 215-220. This method involves in vitro studying the movement of tritiated arginine-vasopressin ((3H]-AVP) to V1b receptors on adeno-pituitary or human V1b receptor-bearing cell membrane preparations. Inhibitory concentrations of 50% (CI50) of the binding of tritiated arginine-vasopressin to the invention's compounds vary from 10-6 MM, particularly from 10-9 to 10-9M.
The affinity of the invention's formula (Ia) levogyr isomer compounds 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 consists of 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.
The affinity of the compounds of the invention for the V2 receptors of the isomeric levogyrin (Ia) formula has also been investigated (method described by Birnbaumer et al., Nature (London), 1992, 357, 333-335).
The compounds of the present invention are, inter alia, active substances in pharmaceutical formulations, the toxicity of which is compatible with their use as medicinal products.
Another aspect of the present invention relates to the use of compounds of formula (Ia) isomer levogyre, or any of their pharmaceutically acceptable salts, solvates and/or hydrates, in the preparation of drugs for the treatment of any disease in which arginine-vasopressin and/or its V1b receptors or both its V1b and V1a receptors are involved.
Another aspect of the present invention relates to the use of formula Ia, levogyre isomer or one of its pharmaceutically acceptable salts, solvates and/or hydrates in the preparation of medicinal products for the treatment of diseases of the cardiovascular system, central nervous system, renal system, gastric system, small cell lung cancers, obesity, type II diabetes, insulin resistance, hyper triglyceridemia, atherosclerosis, Cushing's syndrome, all stress-related diseases and chronic stress states.
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 conditions 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, cerebral hemorrhage, cerebral oedema; depression, psychotic disorders such as stroke, nervous system disorders, such as renal stress, panic attacks, hypertension, nervous system disorders, such as renal depression, hypertension, hypertension, hypertension, hypertension, hypertension, hypertension, hypertension, hypertension, hypertension, hypertension, hypertension, hypertension, hypertension, hypertension, hypertension, hypertension, hypertension, hypertension, hypertension, hypertension, hypertension, hypertension, hypertension, hypertension, hypertension, hypertension, hypertension, hypertension, hypertension, hypertension, hypertension, hypertension, hypertension, hypertension, hypertension, hypertension, hypertension, hypertension, hypertension, hypertension, hypertension, hypertension, hypertension, hypertension, hypertension, hypertension, hypertension, hypertension, hypertension, hypertension, hypertension, hypertension, hypertension, hypertension, hypertension, hypertension, hypertension, hypertension, hypertension, hypertension, hypertension, hypertension, hypertension, hypertension, hypertension, hypertension, hypertension, hypertension, hypertension, hypertension, hypertension, hypertension, hypertension, hypertension, hypertension, hypertension, hypertension, hypertension, hypertension, hypertension, hypertension, hypertension, hypertension, hypertension, hypertension, hypertension, hypertension, hypertension, hypertension, hypertension, hypertension, hypertension, hypertension, hypertension, hypertension, hypertension, hypertension, hypertension, hypertension, hypertension, hypertension, hypertension, hypertension, hypertension, hypertension, hypertension, hypertension, hypertension,Nephrogenic diabetes insipidus; diseases of the gastric system such as gastric vasospasm, hepatocirrhosis, ulcers, vomiting pathology, e.g. nausea including nausea due to chemotherapy, motion sickness; diabetic nephropathy. The compounds of the invention may also be used in the treatment of sexual behaviour disorders; in women, the compounds of the invention may be used to treat dysmenorrhea or premature labour. The compounds of the invention may also be used in the treatment of small cell lung cancers of the hyponatremic encephalitis pulmonary syndrome;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.
The above formula (Ia) isomer levogyre compounds, or any of their pharmaceutically acceptable salts, solvates and/or hydrates, may be used at daily doses of 0.01 to 100 mg per kilogram of body weight of the mammal to be treated, preferably at daily doses of 0.1 to 50 mg/kg. In humans the dose may vary preferably from 0.1 to 4000 mg per day, more particularly from 0.5 to 1000 mg depending on the age of the subject to be treated or the type of treatment: prophylactic or curative.
For use as medicinal products, compounds of formula (Ia) isomer levogyre are generally administered in dosage units, preferably in pharmaceutical formulations in which the active substance is mixed with one or more pharmaceutical excipients.
Thus, in another aspect, the present invention relates to pharmaceutical compositions containing, as an active ingredient, a compound of formula (Ia) isomeric levogyr or one of its pharmaceutically acceptable salts, solvates and/or hydrates.
In the pharmaceutical formulations of the present invention for oral, sublingual, inhaled, subcutaneous, intramuscular, intravenous, transdermal, local or rectal administration, the active substances may be administered in unit dosage forms, in combination with conventional pharmaceutical media, to animals and humans. The appropriate unit dosage forms include oral forms such as tablets, capsules, powders, granules and oral solutions or suspensions, sublingual and oral dosage forms, aerosols, topical dosage forms, implants, subcutaneous, intramuscular, intravenous, intranasal or intraocular dosage forms and recoupled dosage forms.
When preparing a solid formulation in the form of tablets or capsules, a mixture of pharmaceutical excipients is added to the active substance, whether or not micronized, which may be composed of diluents such as lactose, microcrystalline cellulose, starch, dicalcium phosphate, binders such as polyvinylpyrrolidone, hydroxypropylmethylcellulose, detritants such as rectifying polyvinylpyrrolidone, rectifying carboxymethylcellulose, drainage agents such as silica, talc, lubricants such as magnesium stearate, stearic acid, stearate glycerol, sodium trifumarate.
Moisturizers or surfactants such as sodium lauryl sulphate, polysorbate 80, poloxamer 188 may be added to the formulation.
The tablets can be made by different techniques, direct compression, dry granulation, wet granulation, hot melt.
The tablets may be bare or dragged (e.g. by sucrose) or coated with various polymers or other suitable materials.
Tablets may have flash, delayed or prolonged release by making polymer matrices or using specific polymers at the filming level.
The capsules may be soft or hard, filmed or not so as to have flash, prolonged or delayed activity (e.g. by enteriform form).
They may contain not only a solid formulation as previously formulated for tablets but also liquids or semi-solids.
A preparation in the form of a syrup or elixir may contain the active substance together with a sweetener, preferably a non-caloric sweetener, methylparaben and propylparaben as antiseptic, as well as a flavouring agent and an appropriate colouring.
Water-dispersible powders or granules may contain the active substance mixed with dispersing agents, wetting agents or suspension agents, such as polyvinylpyrrolidone, as well as sweeteners or flavour enhancers.
For rectal administration, suppositories are used which are prepared with binders that melt at rectal temperature, for example cocoa butter or polyethylene glycols.
For parenteral, intranasal or intraocular administration, aqueous suspensions, isotonic saline solutions or sterile solutions for injection containing dispersing agents and/ or pharmacologically compatible solubilising agents, e. g. propylene glycol, are used.
Thus, to prepare an aqueous solution for intravenous injection, a co-solvent such as alcohol such as ethanol or glycol such as polyethylene glycol or propylene glycol and a hydrophilic surfactant such as polysorbate 80 or poloxamer 188 may be used.
For local administration, you can use creams, ointments, gels, eyeliner, sprays.
For transdermal administration, multi-laminated or tank-like patches may be used in which the active substance may be in an alcoholic solution, sprays.
For inhalation administration, an aerosol containing, for example, sorbitol trioleate or oleic acid, trichlorofluoromethane, dichlorofluoromethane, dichlorotetrafluoroethane, freon substitute or any other biologically compatible propellant gas, or a system containing the active substance alone or in combination with an excipient, in powder form, may be used.
The active substance may also be presented as a complex with a cyclodextrin, e.g. α, β-,γ-cyclodextrin, 2-hydroxypropyl-β-cyclodextrin.
The active substance may also be formulated in the form of microcapsules or microspheres, possibly with one or more media or additives.
Implants are one of the long-release forms useful in the case of chronic treatments, which can be prepared as an oil suspension or as a microsphere suspension in an isotonic medium.
In general, each dosage unit is adjusted according to the dosage and type of administration, e.g. tablets, capsules and similar, sachets, ampoules, syrups and similar, drops, so that such a dosage unit contains 0.1 to 1000 mg of active substance, preferably 0.5 to 250 mg to be administered once to four times a day.
Although these dosages are examples of average situations, there may be special cases where higher or lower dosages are appropriate, such dosages also belong to the invention. According to usual practice, the appropriate dosage for each patient is determined by the physician according to the method of administration, age, weight and response of the patient.
The compositions of the present invention may contain, in addition to the compounds of formula (Ia) isomer levogyre, or any of their pharmaceutically acceptable salts, solvates and/or hydrates, other active substances which may be useful in the treatment of the disorders or diseases described above.
Thus, the present invention also concerns pharmaceutical compositions containing several active ingredients in combination, one of which is a compound according to the invention.
Thus, according to the present invention, pharmaceutical compositions can be prepared containing a compound of the invention associated with a compound acting on the CRF receptors.
The compounds of the invention may also be used for the preparation of compositions for veterinary use.
The following preparations and examples illustrate the invention without limiting it.
In the Preparations and Examples the following abbreviations are used:
The following is a list of the active substances which may be used in the preparation of the active substance: ethyl diethyl ether: diethyl ether iso: diisopropyl ether DMF: N,N-dimethylformamideTHF: tetrahydrofuranDCM: dichloromethaneAcOEt: ethyl acetateDIPEA: diisopropylethylamineTFA: trifluoroacetic acidBoc: tert-butoxycarbonylCbz: benzyloxycarbonylBOP: benzotriazol-1-(yloxytrisdimethylamino) phosphonium hexafluorophosphateDCC: 1,3-dicyclohexylcarbodiimideHOBT: 1-hydroxybenzyl acetatePS-tristramine TCL-(2-aminoethyl) polyethylene: high resistivity: 1%, with a melting point of 3,62 millimeter.
The proton magnetic resonance spectra (MNR 1H) are recorded at 200 MHz in DMSO-d6, using the peak of DMSO-d6 as the reference. Chemical displacements δ are expressed in parts per million (ppm). The observed signals are expressed as follows: s: singlet; se: enlarged singlet; d: double; d.d.:
The following are the types of the two-fold; t: triple; q: quadruple; m: massive; mt: multiple.
Mass spectra indicate the value of MH+.
This compound is prepared in accordance with the procedure described in WO 95/18105 by preparing a solution of 2-methoxyphenylmagnesium bromide from 16 g of magnesium in 35 ml ether and a solution of 124 g of 1-bromo-2-methoxybenzene in 175 ml ether. This solution is added, by dripping, under argon atmosphere to a mixture of 30 g of 5-chloro-1H-indole-2,3-dione in 250 ml THF, first cooled in an ice bath, then stirred for 1 hour, allowing the reaction to rise to T.A. After 1 hour of stirring at T.A., the mixture is poured into a saturated solution of NH4Cl and evaporates. The product is washed under the pressure and the resulting isoform is used at the next step.
The compound is prepared according to the procedure described in WO 95/18105 by cooling a mixture of 12.71 g of the compound obtained in the previous step to 0 °C in 105 ml of DCM, adding 5.3 ml of pyridine and then 4.9 ml of thionyl chloride. After 30 minutes of stirring, water is added to the reaction mixture and DCM is evaporated under vacuum. The precipitate is squeezed, washed three times with water and then three times with iso ether and dried.
This compound is prepared in accordance with the procedures described in WO 95/18105 in steps A, B and C of preparation 2.
A solution of 2-methoxyphenylmagnesium bromide is prepared from 6.8 g of magnesium in 15 ml of THF and 52.5 g of 1-bromo-2-methoxybenzene in 75 ml of THF. This solution is added to TA, drop by drop, under argon atmosphere, to a mixture of 8.9 g of 5-methyl-1H-indole-2,3-dione in 80 ml of THF and then heated at low temperature for 3 hours. After cooling in TA, a saturated solution of NH4Cl is added to the reaction mixture, extracted three times with AcOEt, washed twice with the organic phases with water, by a saturated solution of NaCl, dried on NaSO2 and partly concentrated in the soil. The desired concentration of 9 g is obtained by testing and preparation of the product.
A mixture of 2 g of the compound obtained in the previous step is cooled to 0 °C in 15 ml of DCM, 0.82 ml of pyridine is added and then 0.76 ml of thionyl chloride. After 20 minutes of stirring, water is added to the reaction mixture and DCM is evaporated in a vacuum. The aqueous phase is extracted from AcOEt, the organic phase is washed with water, with a saturated solution of NaCl, dried on Na2SO4 and the solvent is evaporated in a vacuum. 1.5 g of the expected product is obtained after crystallization in the DCM/isoether mixture.
A solution of 2-methoxyphenylmagnesium bromide is prepared from 1.9 g of magnesium in 4 ml of ether and 14.54 g of 1-bromo-2-methoxybenzene in 21 ml of ether. This solution is added, drop by drop, under argon atmosphere to a mixture of 5 g of 5-trifluoromethoroxy-1H-indole-2,3-dione in 26 ml of THF, first cooled in an ice bath, then heated at reflux of the ether for 1 hour 30 minutes and allowed to return to TA. The reaction mixture is slowly poured over a saturated solution of NH4Cl, extracted in the OAC phase, washed in an organic solution of 53% KCO2, saturated with water, and finally dried in the NaCl2 solution, and obtained by draining the NaCl2 solution for 2,8 g.
Cool a mixture of 2 g of the compound obtained in the previous step to 0 °C in 20 ml of DCM, add 0.7 g of pyridine, then 1.05 g of thionyl chloride and stir for 15 minutes. Concentrate the reaction mixture to a volume of 10 ml and use this solution as in Preparations 3.7 and 3.8.
After 1 hour of agitation in TA, a saturated solution of NH4Cl, a decantantant, is added to the reaction mixture, the aqueous phase is removed from the ether, the organic phases are washed with water, by a saturated solution of NaCl (50/50 MPa), the mixture is dried on Na2SO4 and the solvents evaporate. The resulting diethyl diethyl diethyl is obtained by vacuum distillation of the product. The resulting product is obtained by vacuum distillation of the product at 87°C (PaPa) (Pa) = 13 m/C; the resulting product is obtained by vacuum distillation of the product from the chromium gel.
(a) 4-Chloro-3-methylphenylcarbamate of tert-butyl.
A mixture of 10 g of 4-chloro-3-methylaniline and 15.26 g of di-tert-butyldicarbonate is agitated in 50 ml of dioxane for 24 hours in a TA. The reaction mixture is concentrated in a vacuum and the residue is chromatographed on silica gel by eluting the DCM/hexane mixture gradient from (50/50; v/v) to (70/30; v/v). 5.6 g of the product is obtained from the product expected to be used as is.Stir for 1 hour, raising the temperature to -10°C and stirring for 1 hour and 45 minutes, raising the temperature to -10°C. Cool the reaction mixture to -70°C, add, drop by drop, a solution of 5 g of the step A compound in 25 ml of THF, stir for 1 hour, raising the temperature to -30°C and then stir overnight, raising the temperature to -30°C. Add a saturated solution of NH4Cl to the reaction mixture, evaporate the THF, extract the resulting aqueous phase three times from AcOEt, wash the organic phase with water, a saturated solution of NaCl,The result is a solution of 2,6 g of the expected product, F = 254-256 °C.
A mixture of 1.25 g of the B-step compound is cooled to 0°C in 20 ml of DCM, 0.51 ml of pyridine is added, then 0.47 ml of thionyl chloride is added and stirred for 1 hour after the temperature is raised to TA. Water and DCM are added to the reaction mixture, after decantation the organic phase is washed four times with water, dried to Na2SO4, concentrated under vacuum to a volume of 20 ml and used as in Preparations 3.9 and 3.10 or 3.29.
A mixture of 50 g of 3,4-dimethylaniline and 76.5 g of DL-2-chloromandelic acid is heated at 227 °C for 7 hours in 250 ml of 1,2-dichlorobenzene by removing the water formed by means of a Dean-Stark apparatus. The half-vacuum reaction volume is concentrated and allowed to crystallize at TA. The crystallized product is squeezed and washed with iso ether. 89.42 g of the expected product is obtained and a sample recalled in the DCM/iso ether mixture, F = 17732-1°C.
Cool 100 ml of sulphuric acid to 95 °C at -10 °C, add, drop by drop for 30 minutes, 12 ml of steaming sulphuric acid (oleum at 65%) and stir until the temperature reaches +10 °C. Cool again to 0 °C, add, in portions and in 10 minutes, 23.8 g of the compound obtained in the previous step and stir until the temperature reaches 29 °C. After 2 hours of stirring, pour the reaction mixture under ice and test the precipitate formed. Dissolve the concentrate in 1000 ml of DCM and 200 ml of THF, bring the mixture to a pH of 2/202 °C; filter the remaining liquid to a pH of 2/203 °C; and then, in the presence of a chromium gradient, remove the remaining solution from the gel (OTH/OTH/F) by means of a VACO filter (OTH/F) at 7.80 °C.
To a 4 g solution of the compound obtained in the previous step in 70 ml of THF, 0.65 g of sodium hydride at 60% in oil is added to TA under argon atmosphere. Then after the gas release has ceased, 1.7 ml of dimethyl disulfide is added and an air phase is boiled in the reaction mixture for 4 hours at TA. The reaction mixture is poured into water, concentrated under vacuum in THF, the aqueous phase is extracted at AcEtO, the organic phase is washed with water, saturated with NaCl solution, dried on Na2SO4, partially condensed the solvent under vacuum and the crystallized product is formed.
Cool a 1 g suspension of the compound obtained in the previous step to 0 °C in 7 ml of DCM, add 0.4 ml of pyridine and then 0.37 ml of thionyl chloride and stir for 30 minutes. Dilute the reaction mixture by adding 30 ml of DCM, wash the organic phase with 20 ml of water, dry on Na2SO4 and partially concentrate the solvent under vacuum at a temperature below 40 °C. Use this solution as in Preparations 3.11 and 3.12.
Cool a mixture of 27.6 g of 1,2-dimethoxybenzene in 160 ml of ether to -40°C, add 250 ml of a 1.6 M solution of n-butyllithium in hexane drop by drop, and then stir for 24 hours, raising the temperature to -40°C. Cool the reaction mixture to -20°C, quickly add 136 ml of diethyl oxalate and stir until the temperature reaches -40°C. After 30 minutes of stirring at TA, pour the reaction mixture into a saturated solution of NH4Cl, decanting, extract the raw phase under the water, wash the organic phases with water, then dissolve the solvent twice on Na2SO4 and evaporate; the resulting diethyl oxalate is removed from the solution by means of a 24°C/90°C filter (see section on the product) by means of a solution of 24 g/90 g/E.
(a) 4-Chlorophenyl butyl tert-carbamate.
A mixture of 12.7 g of 4-chloroaniline and 22 g of di-tert-butyldicarbonate is allowed to agitate in 60 ml of dioxane for 24 hours in TA. The reaction mixture is concentrated in a vacuum, the residue is taken up with pentane, the precipitate is precipitated and dried.
(b) Cool a mixture of 11.4 g of tert-butyl 4-chlorophenylcarbamate in 100 ml of ether to -40°C under dry nitrogen atmosphere, add 80 ml of a 1.5 M solution of tert-butyl lithium in the pentane drop by drop and agitate for 3 hours at -20°C. Cool the reaction mixture to 40°C, add in one hour a solution of 14 g of the compound obtained in step A in 50 ml of THF and agitate for 4 days at TA. Pour the reaction mixture over a saturated solution of NH4Cl, precipitate the precipitate formed and dry.
A mixture of 2 g of the B-step compound in 50 ml of DCM is added to TA with 0.8 ml of pyridine and 1.2 ml of thionyl chloride and stirred until dissolved. The reaction mixture is washed with a solution of 1N HCl, then twice with water, dried on Na2SO4 and evaporated under vacuum in the solvent. The residue is chromatographed on silica gel by eluting with the DCM/AcOEt mixture (95/5 v/v). 1.2 g of the product is obtained as expected.
(a) 4-Chloro-3-trifluoromethylphenylcarbamate of tert-butyl.
The compound is prepared in the manner described in step B (a) of preparation 1.5 from 4-chloro-3-trifluoromethylaniline and di-tert-butyldicarbonate in dioxane to obtain the desired product as a solidifying oil, F = 90°C.
(b) Cool a solution of 4 g 4-chloro-3-trifluoromethylphenylcarbamate of tert-butyl in 30 ml of ether to -70°C under argon atmosphere, add 22 ml of a solution of 1,5 M tert-butyl lithium in the pentane drop by drop, stir for 1 hour by raising the temperature to -10°C and stir for 2 hours 30 minutes at -10°C. Cool the reaction mixture to -70°C,Add, drop by drop, a solution of 3.05 g of the compound obtained in step A of Preparation 1.5 in 15 ml of THF, stir for 1 hour, raising the temperature to - 30°C and then raising the temperature to TA for 16 hours. Add a saturated solution of NH4Cl to the reaction mixture, evaporate the ether and THF, extract the resulting aqueous phase at OEt, then wash the organic phase with water, with a saturated solution of NaCl, dry on Na2SO4 and evaporate under vacuum in the solvent. Chromatise the residue on silica gel by electrolysis to DCM by the mixture DCM/OAcAc (90/10/v);1,48 g of the expected product is obtained after crystallization in the iso/hexane ether mixture, F = 230-231 °C.
Cool a 1.3 g suspension of the step A compound in 8 ml of DCM to 0 °C, add 0.43 ml of pyridine and then 0.4 ml of thionyl chloride and stir for 15 minutes. Wash the reaction mixture with water three times, dry the organic phase on Na2SO4 and partially evaporate the solvent under vacuum to a volume of 10 ml. Use this solution as in Preparations 3.15 and 3.16.
A mixture of 36 g of 2-chloro-5-nitroanisole and Raney nickel® is hydrogenated in a Parr apparatus for 4 hours at 35 °C and 1.3 bar, in 150 ml of MeOH and 200 ml of THF. The catalyst is filtered on Célite® and the filtrate is concentrated under vacuum. 28 g of the product is obtained, which is expected to be used as is.
A mixture of 28 g of the compound obtained in the previous step and 33.13 g of DL-2-chloromandelic acid is heated at 230 °C for 4 hours in 128 ml of 1,2-dichlorobenzene by removing the water formed by means of a Dean-Stark apparatus. The reaction mixture is partially concentrated under vacuum and left to crystallize. The crystallized product is then extruded and washed with iso ether. 40 g of the expected product is obtained.
The reaction mixture is quickly added 40 g of the compound obtained in the previous step to 550 g of polyphosphoric acid and then heated at 60 °C for 8 hours and left overnight stirring, returning the temperature to TA. Ice water is added to the reaction mixture, the precipitate formed is extruded and washed with water. The precipitate is taken back into the AcOEt, the white product obtained after crushing is extruded and washed with iso ether.
To a 17.2 g solution of the compound obtained in the previous step in 220 ml of THF, add to TA, under argon atmosphere, 2.56 g of sodium hydride at 60% in oil. After the gas release has ceased, add 6.85 g of dimethyl disulfide, let air bubble into the reaction mixture and leave 72 hours agitated in TA. Add water to the reaction mixture, evaporate the THF under vacuum, extract the remaining aqueous phase at AcOEt, wash the organic phase with water, with a saturated solution of NaCl, dry on Na2SO4 and leave the soil to evaporate. Dissolve the resulting product part of DCM, concentrating in the solvent, trying crystallization and forming the resulting product, and obtain the resulting product at 6°C.
A 1.5 g suspension of the compound obtained in the previous step is cooled in 20 ml of DCM, 0.375 ml of pyridine is added, then 0.33 ml of thionyl chloride is added and left to agitate for 30 minutes.
In 320 ml of DCM cooled to -70°C, 8.5 ml of chlorine is introduced, then 24 ml of methyl ethyl thioacetate solution is added to 60 ml of DCM in 20 minutes and at -70°C and left to simmer for 15 minutes at -70°C. Then 52.64 g of 3-chloro-4-methylaniline solution is added to 100 ml of DCM in -70°C and left to simmer for 1 hour and 45 minutes at -70°C. Finally, 41.3 ml of triethylamine is added at -70°C and left to simmer for 1 hour and left to simmer at TA. The reaction mixture is washed twice with 250 ml of water,The residue is then chromatographed on silica gel by eluting to the DCM and then by the mixture DCM/AcOEt (85/15; v/v); the resulting mixture is rechromatographed on silica gel and then by eluting to the DCM by the mixture DCM/AcOEt (95/5; v/v).We separate the two isomers:
the least polar isomer which is G-chloro-5-methyl-3-methylthio-1,3-dihydro-2H-indol-2-one and obtains 1,16 g.the most polar isomer which is 4-chloro-5-methyl-3-methylthio-1,3-dihydro-2H-indol-2-one and obtains 0,72 g.
A mixture of 1.16 g of 6-chloro-5-methyl-3-methylthio-1,3-dihydro-2H-indol-2-one obtained in the previous step and 0.681 g of N-chlorosuccinimide in 100 ml of carbon tetrachloride is heated by reflux for 1 hour. The reaction mixture is concentrated under vacuum, the residue is recovered in a mixture of 80 ml of THF and 20 ml of water is heated by reflux for 16 hours. The THF is then evaporated under vacuum, the remaining aqueous phase is extracted at EtO, the organic phase is washed with water, by a saturated solution of Na, dried on Na2SO4 and evaporated under vacuum. The residual gel is chromatographed by emitting a gradient from the mixture to DCM; the result is obtained by fM/O2O/Cl2O (F/O3O/Cl3O) up to the expected temperature of 26°C.
A solution of 2-methoxyphenylmagnesium bromide is prepared from 0.687 g of magnesium in 1.5 ml of ether and 5.35 g of 1-bromo-2-methoxybenzene in 7.55 ml of ether. This solution is added, in a drip, under argon atmosphere, to a 1.4 g mixture of the compound obtained in the previous step in 14 ml of THF, which has been previously cooled in an ice bath, and then allowed to stir by raising the temperature to 1.6 °C. After 1 hour of stirring in TA, the reaction mixture is slowly poured into a saturated solution of NH4Cl, evaporates the mixture under vacuum, extracts the THF, washes the mixture in the OOH, evaporates the saturated phase in water, and then dries the remaining solution on the crystal, leaving the remaining NaOH/OH2O2 (OH2O2O2O2O2O2O2O2O2O2O2O2O2O) on the DCL.
Cool in an ice bath a 2.5 g suspension of the compound obtained in the previous step in 15 ml of DCM, add 1 ml of pyridine and then 1.09 ml of thionyl chloride and leave to agitate for 2 hours.
This compound is prepared in accordance with the procedures described in WO 95/18105 in steps A, B and C of Preparation 72.
After cooling the reaction mixture to TA, extract the AcOEt, wash the organic phase with a NaOH 2N solution, dry on Na2SO4 and evaporate the solvent under vacuum.
A solution of 2-ethoxyphenylamagnesonium bromide is prepared from 2.2 g of magnesium in 10 ml of ether and 16.5 g of the previous step solution in 40 ml of ether. This solution is added, by drip and under nitrogen atmosphere, to a mixture of 5 g of 5-chloro-1H-indole-2,3-dione in 20 ml of THF, maintaining the temperature of the reaction medium below 35°C. After 2 hours of agitation at TA, the reaction mixture is poured over 200 ml of HCl 2N, extracted at AcO, the organic phase is dried leaving Na2SO4 on vacuum and evaporated under the solvents. The residue is taken back into the ether and isolated in a crystalline solution. The product is washed at 5,7 °C and the crystal is formed at the temperature of 25 °C. The product is isolated and washed to obtain the desired product.
A mixture of 3 g of the compound obtained in the previous step and 2 ml of pyridine in 50 ml of DCM is added to TA, 1 ml of thionyl chloride is stirred for 1 hour at TA, and the reaction mixture is chromatographed on silica gel by eluting in DCM, to obtain 2.4 g of the expected product after crystallization in iso ether, F = 198°C.
Cool a 5.6 g solution of 1,2-difluorobenzene in 50 ml of ether to -10°C, add 31 ml of 1.6 M solution of n-butyllithium in hexane drop by drop and leave to agitate for 2 hours at -10°C. Cool the reaction mixture to -50°C, add a 4 g solution of S-chloro-1H-indole-2,3-dione in 40 ml of THF and leave to agitate for 12 hours, raising the temperature to TA. Pour the reaction mixture on a concentrated HCl/ice/water mixture, extract it from the AcO, wash the organic phase under a NaOH 1N solution, water, dry on NaSO2 and evaporate. After isolating the product, the desired temperature is obtained at 2,8 °C, the ether is then isolated to 24°C.
A mixture of 2.8 g of the compound obtained in the previous step and 1 ml of pyridine in 30 ml of DCM is added, 0.9 ml of thionyl chloride is added and left to agitate for 1 hour at TA. The reaction mixture is washed twice with water, dried on Na2SO4 and the solvent is evaporated under vacuum. The residue is chromatographed on silica gel by eluting in DCM. 0.9 g of the expected product is obtained.
A solution of 2,4-dimethoxyphenylmagnesium bromide is prepared from 2,2 g of magnesium in 10 ml of THF and 18 g of 1-bromo-2,4-dimethoxybenzene in 40 ml of THF. This solution is added, by drip, to a mixture of 5 g of 5-chloro-1H-indole-2,3-dione in 50 ml of THF at 30 °C and then heated for 2 hours at low temperature. The reaction mixture is cooled in TA, heated on a saturated solution of NH4Cl, extracted in AcO, organically dried in water, organically washed on Na2SO4 and evaporated in vacuum. 7,2 g of the product is obtained after evaporation in the isolated crystallization phase.
A mixture of 2.5 g of the compound obtained in the previous step and 0.6 ml of pyridine in 20 ml of DCM is cooled to less than 10 °C, 0.6 ml of thionyl chloride is added by dripping and stirred for 15 minutes. The reaction mixture is washed twice with water, dried on Na2SO4 and the solvent is evaporated under vacuum. The product is obtained as expected from Preparations 3.33 and 3.34.
This compound is prepared according to the process described in Tetrahedron Lett., 1995, 36, 6413-6414.
A solution of 1,3-benzodioxol-4-ylmagnesium bromide is prepared from 0,85 g of magnesium in 10 ml of THF and a solution of 6,7 g of the compound obtained in the previous step in 40 ml of THF. This solution is added, drop by drop and at a temperature below 40°C, to a mixture of 3 g of 5-chloro-1H-indole-2,3-dione in 50 ml of THF and then stirred for one hour. The reaction mixture is poured on a solution of NH4Cl, extracted at AcOEt, washed in the organic phase with water, dried on Na2SO4 and vacuum evaporated to obtain 1,12 g of the product after crystallization in DCM1 = 27°C.
To a mixture of 1.1 g of the compound obtained in the previous step and 0.4 ml of pyridine in 20 ml of DCM, 0.3 ml of thionyl chloride is added at a temperature below 25°C and left to agitate for 30 minutes. The reaction mixture is washed twice with water, the organic phase is dried on Na2SO4 and the solvent is evaporated under vacuum. 0.62 g of the expected product is obtained after crystallization in DCM, F = 241°C.
This compound is prepared according to the procedure described in J. Am. Chem. Soc., 1946, 68, 2697-2703 or according to the procedure described in J. Org. Chem., 1952, 17, 149-156.
At the end of the addition, the solution is heated for 2 hours at reflux. Then a 2.7 g solution of 5.6-dichloro-1H-indole-2,3-dione is added in 30 ml of THF and heated at reflux for 30 minutes. After cooling at TA, the reaction mixture is poured over a concentrated water/ice/HCl mixture, extracted at AcO, the organic phase is dried on Na2SO4 and evaporates under vacuum. The residue is tritiated in the ether, washed away and the resulting product is isolated at 3 g.
After 1 hour of stirring at TA, dilute the reaction mixture by adding DCM, wash the organic phase with water to a neutral pH, dry on Na2SO4 and evaporate the solvent under vacuum. 1.5 g of the expected product is obtained as foams used as is.
A mixture of 11.2 g (2S, 4R)-1-tert-butoxycarbonyl) -4-hydroxy-2-pyrrolidine carboxylic acid is cooled to 0°C in 50 ml of DCM, 8.45 ml of DIPEA is added, then 21.2 g of BOP is left to agitate for 10 minutes. Dimethylamine gas is then added by stirring and left to agitate for 3 hours in TA.
A mixture of 6.9 g of the compound obtained in the previous step is left to agitate for 2 hours in TA in 69 ml of a 4 N solution of HCl in the ether. The reaction mixture is concentrated under vacuum, the residue is taken up in the ether, the solvent is evaporated under vacuum and this operation is repeated several times.
A 2.1 g solution of the compound obtained in step A of Preparation 2.1 (a) is cooled to 0°C in 5 ml of DCM, 10 ml of trifluoroacetic acid is added and left to agitate at TA for 2 hours. The reaction mixture is concentrated under vacuum, the residue is taken back into DCM, the solvent is evaporated under vacuum and this operation is repeated several times.
A 6.5 g solution of the compound obtained in step A of Preparation 2.1 (a) is cooled to 0°C in 70 ml of THF, 1.2 g of sodium hydride at 60% added in small fractions in the oil and left to agitate for 30 minutes at 0°C. Then a 2.35 ml solution of methyl iodide is added drop by drop in 10 ml of THF and left to agitate for 2 hours, leaving the temperature to rise to TA. 5 drops of water are added, the reaction mixture is neutralized by the addition of concentrated HCl and a vacuum concentrate. The remaining water is azeotroped with benzene and an empty concentration. The residual silica gel is chromatographed by mixing with DC/OHM (9/Me6 v/g) and the expected result is obtained.
A mixture of 6.1 g of the compound obtained in the previous step and 65 ml of a 4 N solution of HCl are stirred for 2 hours. The reaction mixture is concentrated under vacuum, the residue is taken up in the DCM, the solvent is evaporated under vacuum and the process is repeated several times.
To a solution of 5 g (2S, 4R)-1-(tert-butoxycarbonyl) -4-hydroxy-2-pyrrolidinecarboxylic acid in 100 ml of THF, add 1.72 g of 60% sodium hydride in oil under nitrogen atmosphere and let stand for 45 minutes at TA. Then add 3.27 g of ethyl iodide, reflux heat for 3 hours and 18 hours at TA. Mix under vacuum, take the residue with a 5% solution of KHSO4, extract at OA, dry the organic phase on Na2SO4 and evaporate the solvent. Get the expected 4.5 g of oil.
To a 4.5 g solution of the compound obtained in the previous step in 100 ml of DCM, add 3.5 g of triethylamine and then 7.6 g of BOP and let agitate at TA for 15 minutes. Then add dimethylamine gas by barbiturates and let agitate at TA for 3 hours. Concentrate the reaction mixture in a vacuum, extract the residue at AcOEt, wash the organic phase with a 5% solution of Na2CO3, a 5% solution of KHSO4, dry on Na2SO4 and evaporate under the solvent. Chromatise the residue on silica gel by electing by the DCM/MeOH (95/5 v/v) mixture.
A solution of 2 g of the compound obtained in the previous step is cooled to 0 °C in 10 ml of DCM, 10 ml of trifluoroacetic acid is added and left to agitate at TA for 2 hours.
A mixture of 15 g (2S,4R)-1-(benzyloxycarbonyl) -4-hydroxy-2-pyrrolidinecarboxylic acid, 7.64 g HOT and 11.65 g DCC is allowed to agitate in 250 ml of DCM for 1 hour. The reaction mixture is cooled in an ice bath, dimethylamine gas is added by stirring for 10 minutes and left to agitate in TA for 3 hours. An insoluble vacuum is filtered and concentrated under the filter. The residue is taken up by a saturated solution of Na2CO3, extracted from DCM, the organic phase is dried on Na2SO4, the solvent evaporates and vacuum is obtained.
A mixture of 5 g of the compound obtained in the previous step and 3 g of tetrabutylammonium hydrogen sulphate is cooled to 0 °C in 100 ml of benzene, 50 ml of a 50% NaOH aqueous solution is added, then, drop by drop, 5 g of tert-butyl bromoacetate is stirred for 30 minutes. The reaction mixture is diluted with a benzene/DCM mixture, decanted, the organic phase is dried on Na2SO4 and the solvents videopore. The residue is chromatographed on silica gel by eluting at AcO. 6,3 g is obtained as an oil product.
A mixture of 6.3 g of the compound obtained in the previous step and 0.7 g of palladium on 10% charcoal is hydrogenated for 3 hours at atmospheric pressure at TP and 200 ml of AcOEt. The catalyst is filtered on Cellite and half of the filtrate is concentrated under vacuum. A solution of the product is obtained which is to be used in Preparations 3.38 and 3.39.
- What?
Preparation 2.5
- What?
The following are the active substances which are to be used in the manufacture of the active substances:
- What?
(V) R5 = -N(CH3) 2;
A mixture of 5 g of the compound obtained in step A of Preparation 2.4 and 2.31 g of triethylamine in 100 ml of DCM is cooled to 0 °C, 1.6 ml of acryloyl chloride is added drop by drop and left to agitate for 2 hours at 0 °C. The reaction mixture is washed with water, dried on Na2SO4 and evaporated under vacuum in the solvent. 5.5 g of the expected product is obtained as oil.
To a 5.5 g solution of the compound obtained in the previous step in 100 ml of DCM, 0.265 g of ferric chloride is added and 2.13 g of morpholine is left to agitate at TA for 18 hours. The reaction mixture is washed with a saturated solution of Na2SO4, decanted, dried on Na2SO4 and evaporated in a vacuum. The residue is chromatographed on silica gel by eluting in DCM and then by the DCM/OHMe mixture (94/6 ; v/v). 4.5 g of the expected product is obtained as oil.
A mixture of 4.2 g of the compound obtained in the previous step and 0.45 g of palladium on 10% charcoal is hydrogenated for 3 hours at atmospheric pressure and TA in 200 ml of AcOEt. The catalyst is filtered on Cellite and the filtrate is concentrated in a half-vacuum.
At the end of the reaction, a large precipitate is formed. The precipitate is drained, taken back into a mixture of a 5% solution of K2CO3 and 100 ml of AcOEt containing 10 ml of MeOH, washed in the organic phase in a 5% solution of K2CO3, a saturated solution of NaOH, NaOH2 and NaOH2; the two solvents evaporate and evaporate partially; the precipitate is drained and the aluminium is drained in the water, forming a 0.6/55 g/M2 (9/75 g/M2), and the precipitate is drained in the DC.
The least polar isomer A: composed of Preparation 3.1 and obtains an additional 0.359 g, F = 265-268°C.
α25DThe most polar isomer B: composed of Preparation 3.2, which is recrystallized in the mixture DCM/iso ether and obtained 0.72 g, containing 0.15 moles of iso ether.
α25D- = 193.7° (c = 0.16; chloroform).
To a mixture of 3 g of the compound obtained from Preparation 1.2 in 50 ml of DCM, add 0.8 g of the compound obtained from Preparation 2.1 (a) to TA and then 3.5 ml of DIPEA and leave to agitate at TA for 12 hours. Concentrate the reaction mixture in a vacuum, extract the residue from AcOEt, wash the organic phase with a 5% solution of K2CO3, three times in water, with a saturated solution of NaCl, dry on Na2SO4 and evaporate empty under the solvent.
The least polar isomer A: composed of Preparation 3.3 which is rechromatographed on alumina by electrolysis with the mixture DCM/MeOH (95/5; v/v) and obtained at 0,182 g.
α25DThe most polar isomer B is composed of Preparation 3.4, which is rechromatographed on alumina by electrolysis with the mixture DCM/MeOH (95/5; v/v).
α25D- = 225.6° (c = 0.117; chloroform) and the other two are
To a mixture of 1.5 g of the compound obtained from Preparation 1.3 in 15 ml of DCM and 3 ml of THF, add to TA 3.5 ml of DIPEA and then 1 g of the compound obtained from Preparation 2.1 (a) and let agitate at TA for 5 hours. Concentrate the reaction mixture in a vacuum, extract the residue from AcOEt, wash the organic phase with a 5% solution of K2CO3, three times in water, with a saturated solution of NaCl, dry on Na2SO4 and evaporate under the solvent. Chromatise the residue on silica gel by emptying the mixture with DCM/MeOH (96/OH4; v/v). Separate the two isomers:
The least polar isomer A: composed of Preparation 3.5 which is crystallized in the DCM/iso ether mixture to 0,183 g, F = 257-258 °C.
α25DThe most polar isomer B: composed of Preparation 3.6, which is rechromatographed on alumina by electrolysis by the mixture DCM/MeOH (97/3; v/v).
The reaction mixture is concentrated in a vacuum, the residue is extracted from AcOEt, the organic phase is washed with a 5% solution of K2CO3, twice in water, in a saturated NaCl solution, dried on Na2SO4 and evaporated under the solvent. The residue is chromatographed on alumine by electrolysis in the DCM and then by the gradient of the DCM/OH mix to (95.5/4.5·Mev/v). The two isomers are separated:
The least polar isomer A: composed of the preparation 3.7 which crystallizes in iso ether and obtains 0.09 g, F = 231-233°C.
α25DThe most polar isomer B: composed of the preparation 3.8, and obtains 0.323 g, F = 219-220°C.
α25D- = 220° (c = 0.11; chloroform).
The solution of the compound obtained from Preparation 1.5 is cooled to 0°C in DCM, 2.25 ml of DIPEA is added and then 0.83 g of the compound obtained from Preparation 2.1 (a) is left to agitate for 12 hours, the temperature being raised to TA. The reaction mixture is concentrated in a vacuum, the residue is extracted from AcOEt, the organic phase is washed with a 5% solution of K2CO3, water, a saturated NaCl solution, dried on Na2SO4 and evaporated under the solvent. The residue is chromatographed on silica gel by eluting with the mixture DCM/MeOH (95/5 v/v); the two isomers are separated:
The least polar isomer A: composed of the preparation 3.9 which crystallizes in iso ether and obtains 0.139 g, F = 260-261 °C.
α25DThe most polar isomer B: composed of Preparation 3.10, and obtained 0.606 g when used as is.
The solution of the compound obtained from Preparation 1.6 is cooled to 0°C in DCM, 0.6 ml of DIPEA is added and then 0.7 g of the compound obtained from Preparation 2.1 (a) is stirred overnight, the temperature is raised to TA. The solution is concentrated under vacuum, re-extracted from AcOEt with a 5% solution of K2CO3, the organic phase is dried on Na2SO4 and the solvent is evaporated under vacuum. The residue is chromatographed on silica gel by eluting with the DCM/MeOH mixture (95/5; v/v). The two isomers are separated:
The least polar isomer A: composed of Preparation 3.11. the most polar isomer B: composed of Preparation 3.12, and obtains 0.363 g, as used oil as such.
To a solution of 1.1 g of the compound obtained from Preparation 1.7 in 20 ml of DCM, add 1.71 ml of DIPEA to TA and then 0.75 g of the compound obtained from Preparation 2.2 and leave to agitate at TA for 3 hours. Concentrate the reaction mixture under vacuum, extract the residue from AcOEt, wash the organic phase with a 5% solution of K2CO3, twice in water, with a saturated solution of NaCl, dry on Na2SO4 and evaporate the solvent under vacuum. Chromatograph the residue on alumine by electrolysis of the DCM/OH gradient of (98.5/1.5; v/v) (98/2 v/v); separate the two isomers:
The least polar isomer A: composed of Preparation 3.13 and obtained 0.32 g. The most polar isomer B: composed of Preparation 3.14 which is recrystallized in iso ether and obtained 0.49 g,F = 235-237 °C.
α25D- = 160.7° (c = 0.102; chloroform) and the other
To the solution of the compound obtained from Preparation 1.8 in 10 ml of DCM, add 2.5 ml of DIPEA and 0.870 g of the compound obtained from Preparation 2.2 and leave to agitate at TA for 10 hours. Concentrate the reaction mixture under vacuum, extract the residue from AcOEt, wash the organic phase with a 5% solution of K2CO3, twice in water, with a saturated solution of NaCl, dry on Na2SO4 and evaporate under vacuum in the solvent.
The least polar isomer A: composed of Preparation 3.15 which crystallizes in DCM and obtains 0.23 g, F = 291-293°C.
α25DThe most polar isomer B is composed of Preparation 3.16 precipitated in hexane and obtained at 0.44 g,F = 138-140°C.
α25DThe following table shows the results of the analysis:
To the suspension of the compound obtained in Preparation 1.9 in the DCM, add 1.5 g of the compound obtained in Preparation 2.2 under argon atmosphere and then, drop by drop, a solution of 1.8 g of DIPEA in 2 ml of DCM and leave to agitate for 2 hours at TA. Concentrate the reaction mixture in a vacuum, take up the residue in a 5% solution of K2CO3, extract from AcOEt, wash the organic phase with water, in a saturated solution of NaCl, dry on Na2SO4, partially concentrate AcOEt, allow it to crystallize and exhale the precipitate formed. Separate an isomer:
isomer A: composed of Preparation 3.17 and obtained at 0,581 g, F = 249-250 °C.
α25DThe maximum content of the active substance is not less than the maximum content of the active substance.
The extract is chromatographed on alumina by electrolysis with the DCM/MeOH mixture (98/2· v/v).
The most polar isomer B: composed of Preparation 3.18 and obtained by 0,519 g after crystallization in the DCM/AcOEt mixture, F = 243-244°C.
α25DThe following is the list of substances which are to be classified in the Annex to this Regulation:
The reaction mixture is concentrated in a vacuum, the residue is extracted from AcOEt, the organic phase is washed with a 5% solution of K2CO3, twice in water, in a saturated NaCl solution, dried on Na2SO4 and evaporated under the solvent. The residue is chromatographed on alumine by eluting the DCM/MeOH mixture from (99/1 v/v) to (98/2 v/v). The two isomers are separated:
The least polar isomer A: composed of Preparation 3.19 and obtained by 0,7 g after crystallization in iso ether, F = 264°C.
α25DThe most polar isomer B: composed of Preparation 3.20 and obtained 1,275 g after crystallization in iso ether, F = 245°C.
α25DThe following is the list of substances which are to be classified in the Annex to this Regulation:
A mixture of 2.15 of the compound obtained from Preparation 1.1, 2 g of the compound obtained from Preparation 2.3 and 1.4 g of triethylamine in 50 ml of THF are left to agitate for 48 hours at TA. Concentrate under vacuum, take up the residue with water, extract from the DCM, dry the organic phase on Na2SO4 and evaporate under vacuum in the solvent.
isomer A: composed of Preparation 3.21 and obtained by 1,1 g, F = 236°C.
α25DThe temperature of the water is + 109° (c = 0.22; chloroform).
Chromatograph the silica gel spray juices by elevating them with the mixture AcOEt/MeOH (97/3; v/v) and separating the other isomer:
The most polar isomer B: composed of Preparation 3.22 and yields 1 g.
α25DThe maximum value of the product obtained is -164° (c = 0.25; chloroform).
The precipitate formed corresponding to the isomer A below is drained. The filtrate is concentrated under vacuum, the residue is extracted from AcOEt, the organic phase is washed with a 5% solution of K2CO3, water, a saturated solution of NaCl, dried on NaSO2Cl4 and the solvent is evaporated. The residue is chromatographically stained on silica by freezing under the DCM/MeOH gradient of (99/1v/v) to (93/v/v7); the two isomers are separated.
The least polar isomer A: composed of Preparation 3.23 which is recrystallized with the first jet above in the DCM/iso ether mixture, F = 261-263°C.
α25DThe most polar isomer B: composed of Preparation 3.24 which is recrystallized in the DCM/iso ether mixture and obtained 0.94 g, F = 167-169 °C.
α25DThe following table shows the results of the analysis:
To a mixture of 0.8 g of the compound obtained in Preparation 2.1 (a) in 15 ml of DCM, add to TA 1.6 g of the compound obtained in Preparation 1.11 and then 2.13 ml of DIPEA and let agitate at TA for 15 minutes. Concentrate the reaction mixture under vacuum, extract the residue from AcOEt, wash the organic phase with a 5% solution of K2CO3, water, a saturated NaCl solution, dry on Na2SO4 and evaporate under vacuum under the solvent. Chromatograph the residue on silica gel by eluting the mixture with DCM/OHMe (95/5; v/v). Separate the two isomers:
The least polar isomer A: composed of the preparation 3.25 which crystallizes in iso ether and obtains 0.08 g, F > 260 °C.
α25DThe most polar isomer B is the isomer B, composed of the preparation 3.26 and obtained by 0.661 g when used as is.
Add 4 ml of DIPEA to a 1.4 g mixture of the compound obtained from Preparation 1.1 in 20 ml of DCM, then add 1.64 g of chlorhydrate of the methyl ester of (2S, 4R) -hydroxy-2-pyrrolidinecarboxylic acid to TA and leave to agitate for 12 hours at TA. Concentrate under vacuum, extract the residue from AcOEt, wash with a 5% solution of K2CO3, water, a saturated solution of NaCl, dry on sodium sulphate and evaporate under the solvent.
The least polar isomer, isomer A: composed of Preparation 3.27 and obtained 0,3 g, F = 234-235°C.
α25DThe most polar isomer, isomer B: composed of Preparation 3.28 which is recrystallized in the mixture DCM/iso ether/hexane and yields 1.1 g.
α25DThe following is the list of substances which are to be classified in the additive:
The solution of the compound obtained from Preparation 1.5 is concentrated under vacuum in the DCM, the residue is removed by a mixture of 20 ml of THF and 10 ml of DCM, 0.715 g of methyl ester chloride of (2S, 4R) -hydroxy-2-pyrrolidinecarboxylic acid, then 0.8 g of triethylamine is added to TA, then left to agitate for 48 hours in TA. The residue is concentrated under vacuum, extracted from DCM, washed in the organic phase with water, dried on Na2SO4 and evaporated under vacuum in the solvent. The residue is chromatographed on silica gel by mixing the mixture with DCM/OAcom (50/50; v/v). 1,8 g of the mixture of the two diethylates is obtained.
To a solution of 2 g of the compound obtained from Preparation 1.12 in 20 ml of DCM, add 1.38 g of the compound obtained from Preparation 2.1 (a) and then 1.46 g of DIPEA and leave for 12 hours to agitate at TA. Concentrate under vacuum, extract the residue from AcOEt, wash the organic phase with a 5% solution of K2CO3, dry on Na2SO4 and evaporate the solvent under vacuum. Chromatise the residue on alumine by eluting by the mixture DCM/MeOH (95/5; v/v). Separate the two diastreous isomers and collect the most polar compound which is rechromatised on silica gel by eluting by the mixture DCM/OOH (v60/v); AcOOH/v40; v/v4/MeOH; v/v26; then obtain the expected 0.6 g of DCM (97/v).
The precipitate formed corresponding to the isomer A, the least polar on aluminum, DCM/MeOH (98/2·v/v) (composite of Preparation 3.31) is washed with water, the organic solvent is dried on NaSO2 and the residual is evaporated. The residual is chromatographed on the aluminium by means of a chromatograph (98/MeOH/V2; DC/MeOH is evaporated by means of another solvent).
The most polar isomer B: composed of Preparation 3.32 and yields 0.1 g.
α25D- 231° (c=0.16; chloroform).
To a solution of the compound obtained from Preparation 1.14 and 1 ml of triethylamine in 20 ml of DCM, add 1.5 g of the compound obtained from Preparation 2.1 (a) and leave to agitate at TA for 1 hour. Wash the reaction mixture twice with water, dry the organic phase on Na2SO4 and evaporate the solvent under vacuum. Chromatograph the residue to alumine by eluting in DCM and then by the DCM/MeOH mixture (98/2; v/v). Separate the two isomers:
The least polar isomer A: composed of Preparation 3.33. the most polar isomer B: composed of Preparation 3.34. and obtains 0.26 g.
α25D- = 157° (c = 0.15; chloroform).
A mixture of 1.7 g of the compound obtained from Preparation 1.15.0.9 g of the compound obtained from Preparation 2.1 a) and 1 ml of DIPEA in 20 ml of DCM is left to agitate for 2 hours in TA. The reaction mixture is washed with water, the organic phase is dried on Na2SO4 and the solvent is evaporated in a vacuum. The residue is chromatographed on alumine by eluting with the DCM/MeOH mixture (97/3; v/v). The two diasteroisomers are separated and the most polar compound is collected. 0.42 g of the expected product is obtained.
α The following table shows the data for the calculation of the CO2 savings:
The precipitate formed corresponding to the isomer A, the least polar component on silica gel, DCM/MeOH (94/6; v/v), is washed under vacuum, the organic phase washed with a 5% solution of K2CO3, water, a saturated solution of NaCl, dried on Na2SO4 and evaporated under vacuum. The silica gel is chromatographed by mixing the two components by evaporation.
The least polar isomer A: composed of the preparation 3.36 which crystallizes in the iso/MeOH ether mixture and obtains 0.295 g, F = 261-262 °C.
α25DThe most polar isomer B: composed of Preparation 3.37 and obtained 0.74 g.
To the solution of the compound obtained in Preparation 2.4 add 200 ml of THF, 1.87 g of triethylamine and then 4.5 g of the compound obtained in Preparation 1.1 and reflux heat for 48 hours.
The least polar isomer A: composed of Preparation 3.38 and obtained 1 g. The most polar isomer B: composed of Preparation 3.39 and obtained 3 g as oil.
α25D- = 154° (c = 0.37; chloroform).
- What?
Preparation of the report 3.40
- What?
3- ((4-morpholinyl) propanoate of (3R, 5S)-1-[5-Chloro-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-5-[(dimethylamino) carbonyl]-3-pyrrolidinyl, a mixture of the two diasteroisomers.
- What?
(II) : R1 = Cl ; R2 = H; R3 = OCH3 ; R4 = H ; R5 = N(CH3) 2 .
To the solution of the compound obtained at Preparation 2.5 in AcOEt, add a solution of 3 g of the compound obtained at Preparation 1.1 in 100 ml of THF and leave to agitate at TA for 4 days. Concentrate under vacuum, extract the residue at AcOEt, wash the organic phase with water, dry at Na2SO4 and evaporate the solvent under vacuum. Chromatise the residue on silica gel by eluting with the mixture DCM/MeOH (92/8 v/v). 4.2 g of the expected product is obtained as foams.
A 0.67 g mixture of the compound obtained from Preparation 3.2 (isomer B) is cooled at 0 °C under argon atmosphere in 10 ml DMF, 0.069 g of 60% sodium hydride is added to the oil and stirred until the gas release stops. 0.404 g of 2,4-dimethoxybenzene sulfonyl chloride is then added and stirred for 3 hours in TA. The reaction mixture is poured on a 5% solution of K2CO3, extracted at EtO, washed in the organic phase with water, with a saturated solution of NaCl, dried at Na2SO4 and evaporated under the solvent.
α The temperature of the water is -200° (c = 0.26; chloroform).
The following is a list of the most commonly used methods of measuring the concentration of a substance in a sample:
To a solution of 0.559 g of the compound obtained in EXAMPLE 1 in 6 ml DMF, add 0.04 g of 60% sodium hydride to TA and in an argon atmosphere in the oil and let it agitate until the gas release stops. Then add 0.11 ml of methyl iodide and let it agitate in TA for 24 hours. Add again 0.04 g of 60% sodium hydride to the oil and then 0.33 ml of methyl iodide and let it agitate for 3 days in TA. Pour the reaction solution into water, extract it with OOSO, mix the organic phase with water, dry it with a saturated solution of NaOH, NaCl2 and evaporate it under the soil. After freezing the mixture, the product is obtained by freezing the liquid from the crystal by means of a DC-metallic ether (9°/M/F/M) and then freezing it in the soil.
A mixture of 0.567 g of the compound obtained from Preparation 3.4 (isomer B) is cooled at 0°C under argon atmosphere in 5.5 ml DMF, 0.062 g of 60% sodium hydride is added to the oil and left to agitate for 10 minutes, 0.338 g of 2,4-dimethoxybenzulfenyl chloride is added and left to agitate for 3 hours in TA, water is added to the reaction mixture, extracted three times at AcEtO, the organic phases joined by a saturated NaCl solution are washed, dried on Na2SO4 and evaporated empty under the solvent. The residue is chromatographed on silica gel by ejecting the mixture DCM/OHOHV2 (98/Mev/64); after the isolated product is obtained the expected crystal F = 25°C, 0.74-256 g.
α - = 250° (c = 0.142; chloroform)
To a suspension of 0.719 g of the compound obtained from Preparation 3.18 (isomer B) in 7 ml of DMF, add to TA, under argon atmosphere, 0.072 g of 60% sodium hydride in oil and let agitate until the gas release stops. Then add 0.390 g of 2,4-dimethoxybenzene sulfonyl chloride and agitate for 3 hours in TA. Pour the reaction mixture on a 5% solution of K2CO3, extract with AcOEt and then with DCM, wash the organic phases separately with water, wash them on Na2SO4, mix and partially mix the solvents under vacuum until crystallization. Test the test substance and leave for the expected product to form 0.735 g, F = 28°C3-288°C.
α The following table shows the results of the analysis:
By the methods described in the Examples above, the compounds of formula (II) described in Preparations 3 and 2,4-dimethoxybenzenesulfonyl chloride are prepared to form the compounds of the invention in TABLE I as follows:
This compound is prepared as described in Example 3 from 2.9 g of the compound obtained in Preparation 3.39 (isomer B), 0.233 g of 60% sodium hydride in oil, 15 ml DMF and 1.25 g of 2,4-dimethoxybenzene sulphonyl chloride.
α The following is the list of substances which are to be classified in the additive:
A mixture of 3 g of the compound obtained in Example 22 and 15 ml of TFA in 15 ml of DCM is left to agitate for 3 hours in TA. The reaction mixture is concentrated in a vacuum, the residue is taken up in the iso ether and the precipitate is exsorted.
α - = 179° (c = 0.31; chloroform).
A mixture of 0.5 g of the compound obtained in Example 23 is left to agitate for 3 hours in TA, 0.085 g of 2-amino-2-methyl-1,3-propanediol, 0.290 g of BOP and 0.187 g of triethylamine in 20 ml of DCM. The reaction mixture is diluted by adding DCM, the organic phase is washed with water, by a saturated solution of Na2CO3, dried on Na2SO4 and the solvent is evaporated under vacuum. The residue is chromatographed on silica gel by eluting by the DCM/MeOH mixture (94/6; v/v). 0.31 of the expected product is obtained after crystallization in the isoether, F = 154°C.
α - = 142° (c = 0.19; chloroform).
- What?
The Commission has not yet adopted a decision.
- What?
It consists of a mixture of hydrocarbons having carbon numbers predominantly in the range of C1 through C5 and boiling in the range of approximately -15oC to -15oC.
- What?
(Ia) 2TFA: R1 = Cl; R2 = H; R3 = OCH3; R4 = H; R5 = -N(CH3) 2; R7 = 2-OCH3; R8 = OCH3.
A mixture of 0.7 g of the compound obtained in Example 23 piperazine, 0.404 g of BOP and 0.263 g of triethylamine is left to agitate for 2 hours in TA. Water is added to the reaction mixture, extracted from DCM, the organic phase is washed with a saturated solution of Na2CO3, dried on Na2SO4 and the solvent is evaporated under vacuum. The residue is chromatographed on silica gel by eluting with the DCM/MeOH mixture (97/3; v/v). The resulting product is taken back into the hexane, the precipitate is pressed and 0.7 g is obtained.
A mixture of 0.7 g of the compound obtained in step A and 10 ml of TFA in 10 ml of DCM is agitated for 3 hours.
α - = 133° (c = 0.27; chloroform).
- What?
The Commission has not yet adopted a decision.
- What?
The active substance is a compound containing a mixture of hydrocarbons obtained from the distillation of hydrocarbons from the distillation of hydrocarbons.
- What?
(Ia) : R1 = Cl; R2 = H; R3 = OCH3; R4 = H; R5 = -N(CH3) 2; R7 = 2-OCH3; R8 = OCH3.
A mixture of 0.6 g of the compound obtained in Example 23 is agitated at TA for 2 hours, 0.085 g of morpholine, 0.347 g of BOP and 0.227 g of triethylamine in 20 ml of DCM. The reaction mixture is extracted from DCM, the organic phase washed with water, dried on Na2SO4 and the solvent evaporated in a vacuum. The residue is chromatographed on silica gel by eluting with the DCM/MeOH mixture (95/5; v/v). 0.53 g of the expected product is obtained after crystallization in ether, F = 210 °C.
α - = 153° (c = 0.28; chloroform).
- What?
EXAMPLE 27 and 28
- What?
3- (morpholinyl) propionate of (3R, 5S)-1- (chloro-1- (di-methyl) sulphonyl) -3- (di-methyl) -2- (di-methyl) -2-oxo-2,3-dihydro-1H-indol-3-yl) -5- (dimethylamino) carbonyl) -3-pyrrolidinyl, isomer of levogyre and isomer of dextrogyre.
- What?
(Ia) : R1 Cl ; R2 - H ; R3 - OCH3 ; R4 = H ; R5 = -N(CH3) 2;
The test chemical is used to determine the concentration of the test chemical in the test medium.
These compounds are prepared in the manner described in Example 3 from 3.1 g of the compound obtained in Preparation 3.40, 20 ml DMF, 0.238 g of 60% sodium hydride in oil and 1.27 g of 2,4-dimethoxybenzene sulphonyl chloride.
The least polar: composed of Example 27 which is obtained 2.8 g after concretization in hexane.
α20D- = 154° (c = 0.3 ; chloroform). the most polar: composed of Example 28 of which 1.3 g is obtained after concretization in hexane.
α20DThe temperature of the water is + 127° (c = 0.29; chloroform).
Claims (8)
- Compound of formula (Ia) in the form of a laevorotatory isomer: in which:- R1 represents a chlorine atom, a methyl radical or a trifluoromethoxy radical;- R2 represents a hydrogen atom or is at the 6-position of the indol-2-one and represents a chlorine atom, a methyl radical, a methoxy radical or a trifluoromethyl radical;- R3 represents a chlorine atom, a fluorine atom, a methoxy radical or an ethoxy radical;- R4 represents a hydrogen atom or is at the 3- or 4-position of the phenyl and represents a fluorine atom or a methoxy radical;- or alternatively R4 is at the 3-position of the phenyl and together with R3 represents a methylenedioxy radical;- R5 represents a dimethylamino radical or a methoxy radical;- R6 represents a hydrogen atom; a methyl radical; an ethyl radical; a tert-butyloxycarbonylmethyl radical; a carboxymethyl radical; a [[2-hydroxy-1-(hydroxymethyl)-1-methylethyl]amino]carbonylmethyl radical; a (1-piperazinyl)carbonyl methyl radical; a (4-morpholinyl)carbonylmethyl radical; a 3-(4-morpholinyl)propanoyl radical;- R7 is at the 2-position of the phenyl and represents a methoxy radical;- R8 represents a methoxy radical;and its salts with inorganic or organic acids, its solvates and/or hydrates.
- Compound according to Claim 1, chosen from:- (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;- (2S, 4R)-1-[5-Chloro-1-[(2,4-dimethoxyphenyl)-sulphonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-methoxy-N,N-dimethyl-2-pyrrolidinecarboxamide, laevorotatory isomer;- (2S,4R)-1-[5-Chloro-3-(2-chlorophenyl)-1-[(2,4-dimethoxyphenyl)sulphonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-N,N-dimethyl-2-pyrrolidinecarboxamide, laevorotatory isomer;- (2S,4R)-1-[5-Chloro-3-(2-chlorophenyl)-1-[(2,4-dimethoxyphenyl)sulphonyl]-6-methoxy-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-methoxy-N,N-dimethyl-2-pyrrolidinecarboxamide, laevorotatory isomer;- (2S,4R)-1-[5-Methyl-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;- (2S,4R)-1-[5-Trifluoromethoxy-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;- (2S,4R)-1-[5-Chloro-1-[(2,4-dimethoxyphenyl)-sulphonyl]-3-(2-methoxyphenyl)-6-methyl-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-N,N-dimethyl-2-pyrrolidinecarboxamide, laevorotatory isomer;- (2S,4R)-1-[3-(2-Chlorophenyl)-1-[(2,4-dimethoxyphenyl)sulphonyl]-5,6-dimethyl-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-N,N-dimethyl-2-pyrrolidinecarboxamide, laevorotatory isomer;- (2S,4R)-1-[5-Chloro-1-[(2,4-dimethoxyphenyl)-sulphonyl]-3-(2,3-dimethoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-methoxy-N,N-dimethyl-2-pyrrolidinecarboxamide, laevorotatory isomer;- (2S,4R)-1-[5-Chloro-1-[(2,4-dimethoxyphenyl)-sulphonyl]-3-(2-methoxyphenyl)-6-trifluoromethyl-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-methoxy-N,N-dimethyl-2-pyrrolidinecarboxamide, laevorotatory isomer;- (2S,4R)-1-[6-Chloro-1-[(2,4-dimethoxyphenyl)-sulphonyl]-3-(2-methoxyphenyl)-5-methyl-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-methoxy-N,N-dimethyl-2-pyrrolidinecarboxamide, laevorotatory isomer;- (2S,4R)-1-[5-Chloro-1-[(2,4-dimethoxyphenyl)-sulphonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-ethoxy-N,N-dimethyl-2-pyrrolidinecarboxamide, laevorotatory isomer;- (2S,4R)-1-[5-Chloro-1-[(2,4-dimethoxyphenyl)-sulphonyl]-3-(2,3-dimethoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-N,N-dimethyl-2-pyrrolidinecarboxamide, laevorotatory isomer;- (2S,4R)-1-[5,6-Dichloro-3-(2-chlorophenyl)-1-[(2,4-dimethoxyphenyl)sulphonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-N,N-dimethyl-2-pyrrolidinecarboxamide, laevorotatory isomer;- Methyl ester of (2S,4R)-1-[5-chloro-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl)-4-methoxy-2-pyrrolidinecarboxylic acid, laevorotatory isomer;- Methyl ester of (2S,4R)-1-[5-chloro-1-[(2,4-dimethoxyphenyl)sulphonyl)-3-(2-methoxyphenyl)-6-methyl-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-methoxy-2-pyrrolidinecarboxylic acid, laevorotatory isomer;- (2S,4R)-1-[5-Chloro-1-[(2,4-dimethoxyphenyl)-sulphonyl]-3-(2-ethoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-N,N-dimethyl-2-pyrrolidinecarboxamide, laevorotatory isomer;- (2S,4R)-1-[5-Chloro-1-[(2,4-dimethoxyphenyl)-sulphonyl]-3-(2,3-difluorophenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl)-4-hydroxy-N,N-dimethyl-2-pyrrolidinecarboxamide, laevorotatory isomer;- (2S,4R)-1-[5-Chloro-1-[(2,4-dimethoxyphenyl)-sulphonyl]-3-(2,4-dimethoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl)-4-hydroxy-N,N-dimethyl-2-pyrrolidinecarboxamide, laevorotatory isomer;- (2S,4R)-1-[5-Chloro-1-[(2,4-dimethoxyphenyl)-sulphonyl]-3-(1,3-benzodioxol-4-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-N,N-dimethyl-2-pyrrolidinecarboxamide, laevorotatory isomer;- (2S,4R)-1-[5,6-Dichloro-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;- tert-Butyl ester of 2-[[(3R,5S)-1-[5-chloro-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-5-[(dimethylamino)carbonyl]-3-pyrrolidinyl]oxy]-acetic acid, laevorotatory isomer;- 2-[[(3R,5S)-1-[5-Chloro-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-5-[(dimethylamino)-carbonyl]-3-pyrrolidinyl]oxy]acetic acid, laevorotatory isomer;- (2S,4R)-1-[5-Chloro-1-[(2,4-dimethoxyphenyl)-sulphonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-[2-[[2-hydroxy-1-(hydroxymethyl)-1-methylethyl]amino]-2-oxoethoxy]-N,N-dimethyl-2-pyrrolidinecarboxamide, laevorotatory isomer;- (2S,4R)-1-[5-Chloro-1-[(2,4-dimethoxyphenyl)-sulphonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethyl-4-[2-oxo-2-(1-piperazinyl)ethoxy]-2-pyrrolidinecarboxamide, laevorotatory isomer;- (2S,4R)-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethyl-4-[2-oxo-2-(4-morpholinyl)ethoxy]-2-pyrrolidinecarboxamide, laevorotatory isomer;- (3R,5S)-1-[5-Chloro-1-[(2,4-dimethoxyphenyl)-sulphonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-5-[(dimethylamino)carbonyl]-3-pyrrolidinyl 3-(4-morpholinyl)propanoate, laevorotatory isomer;and its possible salts with inorganic or organic acids, its solvates and/or hydrates.
- Compound according to Claim 2, which is:- (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.
- Method for preparing the compounds of formula (Ia), laevorotatory isomer, according to Claim 1, their possible salts with inorganic or organic acids, their solvates and/or hydrates, characterized in that: a compound of formula: in which the carbon atom carrying the substituent OR6 has the (R) configuration and R1, R2, R3, R4, R5 and R6 are as defined for a compound of formula (Ia), laevorotatory isomer, in Claim 1, is reacted, in the presence of a base, with a halide of formula: in which R7 and R8 are as defined for a compound of formula (Ia), laevorotatory isomer, in Claim 1 and Hal represents a halogen atom.
- Compound of formula: in which:- the carbon atom carrying the substituent -OR6 has the (R) configuration;- R1, R2, R3, R4, R5 and R6 are as defined for a compound of formula (Ia), laevorotatory isomer, in Claim 1;and its salts with inorganic or organic acids, in the form of an optically pure isomer or in the form of the mixture of diastereoisomers.
- Pharmaceutical composition comprising, as active ingredient, a compound according to any one of Claims 1 to 3, its salts with inorganic or organic acids, its solvates and/or hydrates which are pharmaceutically acceptable.
- Use of a compound according to any one of Claims 1 to 3, of its salts with inorganic or organic acids, of its solvates and/or hydrates which are pharmaceutically acceptable, for the preparation of medicaments intended for treating any pathology where arginine-vasopressin and/or its V1b receptors or both its V1b receptors and its V1a receptors are involved.
- Medicament, characterized in that it consists of a compound according to any one of Claims 1 to 3.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR0000957 | 2000-01-25 | ||
| FR0000957A FR2804114B1 (en) | 2000-01-25 | 2000-01-25 | NOVEL 1,3-DIHYDRO-2H-INDOL-2-ONE DERIVATIVES, A PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM |
| PCT/FR2001/000226 WO2001055130A2 (en) | 2000-01-25 | 2001-01-24 | Novel 1,3-dihydro-2h-indol-2-one derivatives and their use as ligands for v1b and v1a arginine-vasopressin receptors |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| HK1050900A1 HK1050900A1 (en) | 2003-07-11 |
| HK1050900B true HK1050900B (en) | 2005-02-04 |
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