Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/06—Anti-spasmodics, e.g. drugs for colics, esophagic dyskinesia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/12—Antidiarrhoeals
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/04—Centrally acting analgesics, e.g. opioids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/06—Antimigraine agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
  • A61P25/16—Anti-Parkinson drugs
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

• the subject of the present invention is benzoxazine derivatives, their preparation and their therapeutic application, more particularly as antagonists of the 5-HT 3 /5-HT 4 receptors.
• 5-HT 3 receptor antagonists are well known and have a specificity as antiemetics, more particularly as antiemetics when using highly emetic anticancer drugs.
• Such compounds are for example those of the class of setons, such as Ondansetron or Granisetron.
• the benzoxasine derivatives according to the invention exhibit a balanced mixed activity as antagonists of the 5-HT 3 and 5-HT receptors.
• the term “balanced mixed activity” is understood to mean a compound which has an equivalent affinity for both the 5-HT 3 receptor and the 5-HT 4 receptor, that is to say a 5-HT 4 /5-HT affinity ratio. 3 on the order of 0.5 to 5 and preferably 0.5 to 2.5.
• This new and unexpected pharmacological profile leads to powerful inhibitors of visceral hypersensitivity and regulators of colonic motility, major symptoms of functional intestinal disorders (IBS).
• IBS functional intestinal disorders
• the compounds demonstrate specific antisecretory activities of the intestine extended to powerful antidiarrhoeal properties in the absence of a slowdown in colonic transit (in non-pathological conditions).
• R x represents a hydrogen atom, a halogen, a group
• R 2 and R 3 identical or different, represent a hydrogen atom, a C- ⁇ alkyl group, a phenyl or a benzyl,
• X represents an oxygen atom, a group -NH- or -N (C 1.4 alkyl) -, and A is a group of formula B or C
• Y represents a nitrogen atom or a methylene group
• R 4 represents a hydrogen atom, a C x _ 4 alkyl group, or a benzyl
• n is equal to 0 or 1
• m is equal to 0 or 1.
• C _ represents a carbon chain which may have from 1 to 4 carbon atoms, such as for example methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl,
• alkyl or alkoxy represents respectively an alkyl or alkoxy with a linear or branched carbon chain
• - halogen represents an iodine, bromine, chlorine or fluorine atom.
• the compounds of general formula (I) have one or more asymmetric carbon atoms. They can therefore exist in the form of enantiomers or diastereoisomers. These enantiomers, diastereoisomers, as well as their mixtures, including racemic mixtures, form part of the invention.
• the compounds of general formula (I) can be in the form of a free base or of addition salts with pharmaceutically acceptable acids, which also form part of the invention.
• the preferred compounds according to the invention are the compounds for which:
• R 2 and R 3 identical or different, represent a hydrogen atom or a group C 1 . i alkyl, more particularly methyl.
• the compounds of the invention can be prepared by methods illustrated in the schemes which follow.
• the compounds of formula (I) can be prepared, according to scheme 1, by reaction of a compound of formula (II), in which R ⁇ , R 2 and R 3 are as defined in formula (I) and W represents a halogen, in particular a chlorine atom, with a compound of formula (III), in which X and A are defined as in formula (I).
• a compound of formula (II) in which R ⁇ , R 2 and R 3 are as defined in formula (I) and W represents a halogen, in particular a chlorine atom
• a compound of formula (III) in which X and A are defined as in formula (I).
• X represents an oxygen atom
• the reaction can be carried out by prior formation of the corresponding alcoholate by means of butyllithium in tetrahydrofuran.
• reaction can be carried out in an organic solvent, such as chloroform or dichloromethane, in the presence of a base such as triethylamine.
• organic solvent such as chloroform or dichloromethane
• esterification or amidification reactions well known to those skilled in the art, can be carried out at a temperature between -10 ° C and + 50 ° C.
• the compounds of formula (II) described in scheme 1, in which W is a chlorine atom and R x , R 2 and R 3 are as defined in formula (I), can be prepared from a compound of formula (XIII) by activation of the carboxylic acid to acid chloride by means of thionyl chloride or oxalyl chloride according to methods known to those skilled in the art.
• the compounds of formula (XIII) can be prepared according to the general process described in scheme 2, from derivatives of formula (IV), in which R ⁇ , R 2 and R 3 are as defined in formula (I).
• the compounds of formula (IV) can be treated using boron trichloride and acetonitrile under the conditions described by T. Sugasawa et al., J “ . Am. Chem. Soc. (1980) 100 1357 , to give the compounds of formula (V), in which R ⁇ , R 2 and R 3 are as defined in formula (I), followed by N-nitrosation with sodium nitrite in acid medium, in the conditions known to those skilled in the art (Jerry March, Advanced Organic Chemistry, ed. John Wiley & Sons, 3 rd ed., pp 572), to give the compounds of formula (VI).
• the compounds of formula (VI) can then be treated under the Knoevenagel reaction conditions, known to those skilled in the art (Jerry March, Advanced Organic chemistry, ed. John Wiley & Sons, 3 rd ed., 835-841), to give the compounds of formula ( VII), in which R x , R 2 and R 3 are as defined in formula (I).
• the N-nitroso function of the compounds of formula (VII) can be reduced using zinc powder in the presence of acetic acid and immediately cyclized to give the compounds of formula (VIII), in which R 1f R 2 and R 3 are as defined in formula (I).
• the compounds of formula (IX) can be prepared by oxidation of the compounds of formula (VIII), in the presence of ozone or by treatment with sodium periodate and osmium tetroxide to give the compound of formula (IX).
• the latter can then be oxidized using silver nitrate in the presence of potassium hydroxide to yield the compounds of formula (XIII), in which R 1 # R 2 and R 3 are as defined in formula (I).
• the compounds of formula (X) can be prepared from the derivatives of formula (IV) by reaction of 2-cyanofuran and boron trichloride under reaction conditions described by Sugasa a, above referenced.
• the compounds of formula (XII) can then be obtained by N-nitrosation of the compounds of formula (X) followed by the reduction of the compounds resulting from formula (XI) using zinc and by subsequent cyclization of the intermediate.
• the compounds of formula (XII) are oxidized by treatment with a mixture of potassium permanganate and carbonate of potassium in acetonitrile or alternatively in a mixture of benzene and acetone (Chem. Abs. 55, p.16518, 1961) to give the compounds of formula (XIII), in which R 1 # R 2 and R 3 are as defined in formula (I).
• the compounds of formula (IV) can be prepared according to methods known to those skilled in the art.
• the compounds of formula (IV), in which R 2 and R 3 represent a hydrogen atom can be prepared by reaction of a 2-aminophenol derivative with chloroacetyl chloride under phase transfer conditions (X Huang et al., Synthesis (1984) 10 851), followed by a reduction reaction using lithium aluminum hydride or a borane complex, generally in an ethereal solvent such as tetrahydrofuran or diethyl ether.
• the compounds of formula (IV), in which R 2 and / or R 3 represent a group C 1 . 4 alkyl, phenyl or benzyl can be directly prepared by reaction of a 2-nitrophenol derivative with chloracetone or 2-chloro or 2-bromoacetophenone respectively in the presence of Raney nickel, in ethanol (Melloni et al. J. Het. Chem. (1983) 20 259).
• Example 1 Hydrochloride of 7, 8-dihydropyrazolo [1, 5, 4- del [1, 4] benzoxazine-2-carboxylate of endo-8-methyl-8-azabicyclo [3.2.1] oct-3-yl.
• the reaction medium is poured onto ice water and the product is extracted with chloroform, the organic phase is washed with water until the pH is neutral, it is dried and the solvent is evaporated.
• the product is purified by chromatography on silica gel, eluting with a mixture of chloroform and methanol (90:10), 2.77 g of product are obtained in the form of the free base.
• Example 2 N- hydrochloride (exo-8-methyl-8- azabicyclo [3.2.1] oct-3 -yl) -7, 8-dihydropyrazolo [1,5,4- del [1,4] benzoxazine-2 -carboxamide.
• the product is purified by chromatography on silica gel, eluting with a mixture of chloroform, methanol and ammonia (95: 5: 0.5), 0.120 g of product is obtained in the form of the free base.
• a hydrochloric ether solution to the product as a free base and after trituration in ethanol, the hydrochloride is obtained. Melting point> 270 ° C.
• Example 3 N- (endo-9-methyl-9-azabicyclo [3.3.1] non-3-yl) -7,8-dihydropyrazolo hydrochloride [1,5,4- de] [1,4] benzoxazine- 2-carboxamide.
• Example 4 N- [[8- (phenylmethyl) -8- azabicyclo [3.2.1] oct-3-yl] methyl] -7,8-dihydropyrazolo hydrochloride [1,5,4- de] [1,4 ] benzoxazine-2 -carboxamide.
• Example 5 7, 8-Dihydropyrazolo [1, 5, 4-de] [1, 4] benzoxazine-2-carboxylate of endo- 9- (phenylmethyl) -9-azabicyclo [3.3.1] non 3-yl.
• Example 6 4-fluoro-7,8-dihydropyrazolo hydrochloride [1,5,4-de] [1,4] benzoxazine-2-carboxylate of endo- 8-methyl- 8 -azabicyclo [3.2.1] oct- 3-yle.
• Example 7 4-Fluoro-8-methyl-7,8-dihydropyrazolo hydrochloride [1, 5, 4-de] [1, 4] Benzoxazine-2-carboxylate of endo-8-methyl-8-azabicyclo [3.2. 1] oct-3-yle.
• Example 8 7,7-dimethyl-7,8-dihydropyrazolo hydrochloride [1,5,4-de] [1,4] benzoxazine-2-carboxylate of endo-8-methyl -8 -azabicyclo [3.2.1] Oct-3-yle.
• Example 10 Ethanedioate of 7, 8-dihydropyrazolo [1, 5, 4- del fi, 41 benzoxazine-2-carboxylate of 1-azabicyclo [2.2.2] oct-3-yl.
• the product is purified by chromatography on silica gel, eluting with a mixture of chloroform, methanol and ammonia (95: 5: 0.5), 0.280 g of product is obtained in the form of the free base.
• Example 11 (S) -N- (1-azabicyclo [2.2.2] oct-3 - yl) -7, 8 -dihydropyrazolo hydrochloride [1, 5,4-de] [1, 4] benzoxazine-2- carboxamide.
• Example 12 7,8-Dihydropyrazolo hydrochloride [1,5,5,4 del [1,4] benzoxazine-2-1-azabicyclo [2.2.2] oct-3-ylmethylcarboxylate.
• Example 13 (R) -N- (1,4-diazabicyclo [2.2.2] oct-3-ylmethyl) -7,8-dihydropyrazolo hydrochloride [1, 5,4- de] [1, 4] benzoxazine- 2 -carboxamide (2: 1).
• Example 14 Acid 7, 8 -dihydropyrazolo [1,5,4-de] [1,4] benzoxazine-2 -carboxylic.
• the reaction medium is cooled in an ice-water bath, 500 ml of 3M hydrochloric acid are added thereto, the temperature being maintained between 5 and 8 ° C., then it is brought to at reflux for 45 min.
• the mixture is again cooled and made alkaline to pH 11 by adding 30% concentrated sodium hydroxide.
• the product is extracted with dichloromethane, the organic phase is washed with a saturated aqueous solution of sodium chloride, it is dried and the solvent is evaporated off under reduced pressure.
• the product is purified by chromatography on silica gel, eluting with dichloromethane.
• the product is extracted with dichloromethane, the organic phase is washed with water, dried over sodium sulfate and the solvent is evaporated to dryness.
• the precipitate is filtered and then washed with acetonitrile.
• Example 15 Acid 7, 8 -dihydropyrazolo [1,5, 4-de] [1,4] - benzoxazine-2 -carboxylic.
• reaction mixture is brought to reflux for 3 hours and then left overnight at room temperature.
• reaction medium is cooled in an ice-water bath and 500 ml of 3M hydrochloric acid are added, the temperature being maintained between 5 and 8 ° C, then brought to reflux for 45 min.
• the mixture is again cooled and made alkaline to pH 11 with 30% concentrated sodium hydroxide.
• We extract the product with dichloromethane the organic phase is washed with a saturated aqueous sodium chloride solution, dried and the solvent is evaporated off under reduced pressure.
• the product is purified by chromatography on silica gel, eluting with dichloromethane.
• the product is purified by chromatography on silica gel, eluting with dichloromethane. 5.5 g of product are obtained in the form of an oil.
• This compound is obtained according to two processes:
• Acid 7, 8 -dihydropyrazolo [1,5, 4-de] [1, 4] benzoxazine- 2 -carboxylic A solution of 0.64 g (0.00163 mole) of silver nitrate in 1 ml of water and a solution of 0.5 g of potassium hydroxide in 10 ml of water are successively added at room temperature to a solution of 0.3 g (0.00163 mole) of 7,8-dihydropyrazolo [1,5,4-de] [1, 4] benzoxazine-2 -carboxaldehyde in 10 ml of ethanol. The mixture is stirred for 22 hours at room temperature, filtered through celite and washed with water.
• the filtrate is taken up in dichloromethane, the aqueous phase is separated and acidified to pH 4 with acetic acid.
• the desired product is extracted from the acid mixture with dichloromethane.
• the homogenate is centrifuged for 10 min at 45000xg (in a SORVALL centrifuge fitted with a rotor
• the pellet is resuspended in 10 volumes of Tris buffer and incubated at 37 ° C for 10 min with shaking.
• the suspension is then diluted to 20 volumes using Tris buffer and centrifuged under the same conditions as above.
• the pellet obtained is resuspended in 5 volumes of Tris buffer and then distributed into aliquots of 5 ml which are frozen at -80 ° C.
• the membrane suspension (100 ⁇ l, 1 mg of proteins) is incubated at 25 ° C for 25 min in the presence of 0.5 nM of [ 3 H] - (S) -zacopride (specific activity: 75-85 Ci / mmol, Amersham, Little Chalfont, United Kingdom) in a final volume of 500 ⁇ l of Tris-NaCl buffer, in the absence or in the presence of the compound to be tested.
• the filters are precut before drying in the oven (120 ° C, 5 min).
• the radioactivity retained on the filters is measured by liquid scintigraphy. Nonspecific binding is determined in the presence of 10 ⁇ M of MDL 72222 (ligand described in the article NM Barnes et al. referenced above).
• the concentration of the compound inhibiting 50% of the specific binding of [3H] - (S) -zacopride is between 0.5 nM and 2 ⁇ M, preferably between 1 nM and 10 nM and more particularly between 1 nM and 5 nM.
• the compounds of the invention were studied as to their antagonistic effects with respect to the 5-HT 3 receptors of the smooth muscle of the descending colon isolated from guinea pigs, according to the method described by Grossman et al. in Br. J. Pharmacol. (1989) 97,451.
• Serotonin (0.1-100 ⁇ M), after blocking of receptors of 5-HT x and 5-HT 2 types (Methysergide 0.1 ⁇ M) and desensitization of 5-HT 4 receptors (5-methoxytryptamine 10 ⁇ M) concentration-dependent contraction of the smooth muscle part of the guinea pig's descending colon by stimulation of 5-HT 3 receptors. Contractions are recorded in isometry.
• the antagonistic effect of a compound on the 5-HT 3 serotonergic receptors is quantified by measuring the displacement of a control effect-concentration curve of serotonin (successive increasing concentrations not accumulated), at concentrations between 1 nM and 0 , 1 ⁇ M, with an incubation of 30 min.
• the compounds of the invention have also been studied as to their affinity for 5-HT 4 receptors in the guinea pig striatu, according to the method described by Grossman et al., In Br. J. Pharmacol. , 109, 618-624 (1993).
• Guinea pigs (Hartley, Charles River) weighing 300 to 400 g are euthanized and their brains removed.
• the striata are excised and frozen at -80 ° C.
• the homogenate is centrifuged for 10 min at 48000 ⁇ g, the pellet is recovered, it is resuspended and it is again centrifuged under the same conditions.
• the final pellet is suspended in Hepes-NaOH buffer (30 mg of fresh tissue / ml). This membrane suspension is used as it is.
• the IC 50 values of the compounds of the invention are between 1 nM and 2 ⁇ M, preferably between 1 nM and 50 nM and more particularly between 1 nM and 12.5 nM.
• the compounds of the invention were studied as to their agonist or antagonist effects with respect to the 5-HT 4 receptors in the rat esophagus according to the method described by Baxter et al., In Naunyn Schmied Arch. Pharmacol. (1991), 343, 439.
• Compounds that induce relaxation are characterized as 5-HT 4 agonists.
• the preparation is exposed to serotonin in increasing cumulative concentrations, from 0.1 nM up to a concentration inducing maximum relaxation, and the relaxation curve due to serotonin, in the presence of the compound to be studied, is then compared to a control curve established in the absence of said compound. If its presence induces a shift of the curve to the right, the compound studied is characterized as a 5-HT 4 antagonist.
• the pK b of the compounds according to the invention are between 5 and 10, preferably between 7.5 and 9.
• the compounds of the invention of formula (I) are particularly useful for the treatment and / or prevention of functional intestinal disorders such as intestinal motor and secretory disorders, disorders of intestinal secretion, of irritable bowel, viscerosensitivity, intestinal pain, diarrhea, but also esophageal reflux; cystic fibrosis of the pancreas, carcinoid syndrome; urinary or intestinal incontinence, megacolon.
• functional intestinal disorders such as intestinal motor and secretory disorders, disorders of intestinal secretion, of irritable bowel, viscerosensitivity, intestinal pain, diarrhea, but also esophageal reflux; cystic fibrosis of the pancreas, carcinoid syndrome; urinary or intestinal incontinence, megacolon.
• the compounds of the invention due to their affinity for 5-HT 3 receptors can also be used for the treatment and / or prevention of nausea and vomiting, for example consecutive to treatment antitumor or administration of an anesthetic; esophageal spasm; central nervous system disorders such as schizophrenia, mania, anxiety and depression; cognitive disorders such as senile dementia of the Alzheimer's type or age-related dementias, memory and attention deficits, cerebrovascular deficiencies, Parkinson's disease; psychoses; dyskinesia, pain, migraines and headaches; alcohol or drug dependence or withdrawal disorders; gastrointestinal function disorders such as dyspepsia, peptic ulcer, heartburn, flatulence; disorders of the cardiovascular system and respiratory disorders.
• central nervous system disorders such as schizophrenia, mania, anxiety and depression
• cognitive disorders such as senile dementia of the Alzheimer's type or age-related dementias, memory and attention deficits, cerebrovascular deficiencies, Parkinson's disease
• psychoses dyskinesia, pain, migraines and headaches
• alcohol or drug dependence or withdrawal disorders
• the compounds of the invention in combination with appropriate excipients, can be presented in all forms suitable for oral or parenteral administration, such as tablets, dragees, capsules, capsules, suspensions or solutions for oral or injectable injection, and dosed to allow administration of 0.005 to 5 mg / kg, 1 to 4 times a day.

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