Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
  • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
  • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
  • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
• • 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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P13/00—Drugs for disorders of the urinary system
• • 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
  • A61P27/00—Drugs for disorders of the senses
  • A61P27/16—Otologicals
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

• A represents either a hydrogen atom, a hydroxyl, a C ⁇ 6 hydroxyalkyl group, a thiol, a C xs alkylsulfanyl group, an amino group, a C x 6 alkylammo group, a di (C x 6 alkyl) amino group, a group C ⁇ 6 alkyl hydroxylamine, a group C ,. 6 alkoxy, a hydroxylamine group, a Cj 6 N group, 0-d ⁇ alkyl hydroxylamine, an azido, a halogen such as fluorine, chlorine or bromine, B represents a hydrogen atom, a C : s alkyl group, linear or branched, a group C 2 .
• X represents an oxygen or sulfur atom
• R 2 represent, independently of one another, a hydrogen atom, a halogen such as fluorine, chlorine or bromine, a cyano, a carboxamide, a C l 6 alkyl group, linear or branched, a group C 2 .
• R 3 and R 4 represent, independently of one another, a hydrogen atom, a C 1- ⁇ alkyl group, a C 2 6 alkenyl group, C 3-6 cycloalkyl, C 3 6 cycloalkenyl, a group C 16 fluoroalkyle, a group C l 2 perfluoroalkyle or R 3 and R 4 together form a group C 2 6 alkylene, C 2 6 alkenylene, to give for example a piperidyle, azURIdinyle or pyrrolidyl, or R 3 and R 4 together, with the nitrogen to which they are attached, a heterocycle, saturated or unsaturated, comprising 3 to 6 carbon atoms and a second nitrogen atom, this nitrogen atom being optionally substituted by a C ⁇ ,, alkyl group, to give for example a piperazyl or imidazyl, or an oxygen atom, to give for example a morpholinyl; and
• R 5 represents a hydrogen atom or a halogen, such as fluorine, chlorine or bromine.
• the compounds of general formula (I) may contain 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 are 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 compounds of the invention can be prepared by methods illustrated by the schemes which follow.
• an ethenyl derivative of formula IV is reacted with an oxidant such as sodium periodate, osmium tetroxide or metachloroperbenzoic acid in basic or acidic medium so as to form a diol of formula III.
• an oxidant such as sodium periodate, osmium tetroxide or metachloroperbenzoic acid in basic or acidic medium so as to form a diol of formula III.
• the hydroxyl group twinned with group B is selectively protected by a protective group P, in a manner known to a person skilled in the art, for example by formation of a silylated ether, so as to obtain the compound of formula II.
• the hydroxyl group carried by the alpha carbon of the heterocyle of the compound thus obtained can then optionally be activated, in a manner known to those skilled in the art, so as to obtain a nucleophuge group, such as a mesyl, tosyle group or a bromine atom.
• the compound of formula (I) according to the invention is then prepared from this compound by reacting it with an amine HR 3 R 4 , followed by deprotection by methods known to those skilled in the art.
• the meanings of X, R lt R 2 , R 3 , R 4 , R 5 and B in each of the compounds of formulas II, III and of the amine NHR 3 R 4 are those indicated for formula (I).
• the ethenyl derivative of formula IV can itself be prepared from a bro derivative of formula V as defined above, by palladic coupling of Stille with a compound of formula X, under the conditions defined by Me Kean, DR; Parinello, G. Renaldo, AF; Stille, JK, J. Org. Chem. , 52, 1987, 492.
• the ethenyl derivative of formula IV can be prepared from an aldehyde derivative of formula XI, by a Wittig reaction under conditions standard for a person skilled in the art.
• the compounds of formula XI can themselves be prepared by formylation of a bro derivative of formula V in the presence of N, N-dimethylformamide and butyl lithium.
• the formylation reaction can be carried out in an organic solvent such as tetrahydrofuran, N, N-dimethylformamide or a mixture of these solvents, according to the following reaction scheme (2):
• the compounds of formula V can themselves be prepared from ⁇ -phenoxyketones or ⁇ -thiophenoxyketones of formula
• the compounds of formula VI can be obtained directly from the corresponding phenols or thiophenols of formula
• the compounds of formula VI can also be prepared in two stages, by reaction of a compound of formula VII as defined above, with an ⁇ -haloester of formula VIII, where R j has the meaning indicated for formula I , in an organic solvent such as N, N-dimethylformamide, in the presence of potassium carbonate and an iodide such as potassium iodide followed, after saponification, by the transformation of intermediate IX thus obtained into said compound of formula VI.
• This transformation is effected by the action of thionyl chloride followed or not by the amine of einreb (SO 2 C1 2 / NH (CH 3 ) (OCH 3 )), under the conditions described by Nahm and Weinreb, Tet.
• organometallic of formula R 2 MY for which R 2 has the meaning indicated for formula I, M represents a metal and Y represents a halogen such as chlorine or bromine .
• This organometallic is preferably an organomagnesium.
• a compound of formula VII is reacted as defined above, with propargyl bromide.
• This reaction can be carried out in an organic solvent such as N, N-dimethylformamide, in the presence of potassium carbonate and an iodide such as potassium iodide.
• the phenoxypropargyl derivative of formula XII thus obtained is then reacted with diethylaniline in the presence of cesium fluoride, this under the conditions described by Ishi, H. et al., Chem. Pharm. Bull., 40, 1992, 1148.
• a 2,3-dihydrobenzofuran or 2,3-dihydrobenzothiophene of formula XIII is reacted with n-butyl lithium in an organic solvent such as N, N-dimethylformamide, tetramethylene diamine (TMEDA) or their mixtures .
• An aldehyde derivative of formula XIV is then obtained which is treated with 2, 3-dichloro-5, 6-d ⁇ cyanocyclohexa- 2, 5-diene-1,4-dione (DDQ).
• DDQ 2, 3-dichloro-5, 6-d ⁇ cyanocyclohexa- 2, 5-diene-1,4-dione
• the compound of formula XI obtained is then recovered which can be used to prepare the compound of formula (I) according to the process described above.
• the compound of formula (I) is prepared by reacting an oxirane derivative of formula XV with an amine NHR 3 R 4 .
• the meanings of X, Rj, R 2 , R 3 , R 2, R 5 and B of the oxirane derivative of formula XV and of said amine, are those indicated for formula (I).
• the oxirane derivative of formula XV can be prepared either by reaction of trimethylsulfonium iodide on the aldehyde of formula XI described above, or by the action of a peracid such as metachloroperbenzoic acid on the ethenyl derivative of formula IV in conventional conditions for those skilled in the art.
• the ketone is halogenated in the ⁇ position, and reduced to halohydrin which, treated with a base, is converted into oxirane XV.
• a metallation of a bromine derivative of formula V as defined above is carried out, for example by means of butyl lithium or preferably by action of magnesium, by forming the corresponding G ⁇ gnard reagent, then reacting this produced with alkyl glyoxylate of formula XVII.
• the reaction can be carried out in an organic solvent such as tetrahydrofuran.
• the hydroxyl group of the compound of formula XVIII can be activated by methods known to those skilled in the art, so as to obtain a nucleophuge group, such as a mesyl, tosyl group or a bromine atom, and it is then reacted with a amine NHR 3 R 4 , as defined above.
• the compounds of formula (I), in which A is a C x 6 alkoxy group and B an oxo group according to the invention can be prepared by reaction of an organozmic or an organomagnesium compound of the bromine derivative of formula V with a compound obtained by reaction of a secondary amine of formula HNR 3 R 4 , for which the meanings R 3 and R 4 are those indicated for the formula (I) except the hydrogen atom, the benzotriazole and the alkyl glyoxylate of formula XVII or the monoacetal of glyoxale according to the process described by Katrizky et al. (Synthesis 1989, 323; synthesis 1990, 1173).
• the compound of formula (I), in which A is a C x 6 alkoxy group and B an oxo group, can be reduced, by conventional methods known to those skilled in the art, to give the compounds of formula (I) in which A is a hydroxyl group and B is a hydrogen.
• the compound of formula (I) according to the invention for which A is not a hydroxyl group, can also be prepared from the compound of formula I, where A is a hydroxyl group, by activating this group, so known to a person skilled in the art, so as to obtain a nucleophuge group W, such as a mesyl, tosyle group or a bromine atom and from this compound by reacting it with a nucleophilic group A according to the reaction scheme ( 7) following:
• the compounds of formula (I) according to the invention for which A is a hydrogen atom, can also be prepared by dehydroxylation of a corresponding compound of formula (I), where A is a hydroxyl group.
• the dehydroxylation reaction can be carried out, in a manner known to those skilled in the art, by reaction with triethylsilane and trifluroacetic acid.
• the compound of formula (I) is prepared by reacting a nucleophilic derivative of formula B-CH 2 MY for which M represents a metal, Y represents a halogen and B has the meaning indicated for formula (I), such as for example an organomagnesium or an organolithium, with an imine derivative of formula XX obtained by reaction of a secondary ine of formula NHR 3 R 4 , for which the meanings of R 3 and R 4 are those indicated for the formula ( I) except the hydrogen atom, with an aldehyde of formula XI.
• the meanings of X, R 1f R 2 , R 5 and B are those indicated for formula (I).
• Example 1 2, 3 -Dimethyl -7- (ld ethylam ⁇ no-2 -hvdroxyethyl) - benzofuran. hydrochloride
• This compound is prepared from 2 -ethyl -3 -methyl -7- bromobenzofuran according to the procedure of Katrizky, A.R .; Urogdi, L.; Mainz, A. Synthesis 1989, 323.
• the in vi o activity of the compounds of the invention has been studied on the urethral and arterial smooth muscles. These tests were carried out on female New Zealand rabbits weighing 3 to 3.5 kg. The animals were killed by vertebral dislocation, and then rings of tissue from the mesenteric arteries and urethra were removed. These tissue rings were immersed in a modified Krebs solution, oxygenated by a mixture of 95% of 0 2 and 5% of CO 2 . Each tissue sample was subjected to a tension of 1 g and then phenylephrine was introduced at cumulative doses and the dose / response curve was established. After rinsing the samples, the compound to be studied was introduced at cumulative doses and the dose / response curve established.
• the contractile effect of each compound is evaluated by calculating the pD 2 (negative logarithm of the agonist concentration which induces 50% of the maximum contraction) as well as by the maximum effect representing the percentage of the maximum contraction obtained with the phenylephrine (% E max ).
• the in vitro activity of the compounds of the invention was studied on the saphenous veins of Yucatan micro-pigs.
• the tissue is cut in a helix and is mounted in a tank with organs isolated in an oxygenated modified Krebs solution by a mixture of 95% 0 2 and 5% C0 2 maintained at 37 ° C.
• the vessel is connected to an isometric sensor at a basal voltage of 1 g and is connected to a polygraph allowing the recording of blood pressure variations.
• the viability of each preparation is tested by pre-stimulation with noradrenaline 3 ⁇ M.
• the compound to be studied is introduced and its concentration-response curve constructed cumulatively until a maximum response is obtained.
• the contractile effect of each compound is evaluated by calculating the EC S0 (concentration producing 50% of the maximum response).
• the compounds of the invention have made it possible to obtain a vemoconstrictor activity with an EC 50 value usually between 1 ⁇ M and 100 ⁇ M.
• the compounds of the invention can be used in the treatment of venous insufficiency and venous ulcer.
• Wistar rats are anesthetized and demedulated (according to the technique described by Gillespie, MacLaren A. and Polock D., A method of stimulatmg different segments of the autonomy outflow from the spinal column to va ⁇ ous organs m the pithed cat and rat; Br. J Pharmacol., 1970, 40: 257-267).
• the catheters are introduced through the femoral artery and a jugular vein. Another catheter is introduced into the urethra through an incision made in the bladder.
• the test compounds are administered in increasing doses by intravenous infusion.
• the results are expressed in doses ( ⁇ g / kg) necessary to increase the urethral pressure by 10 cm of water (PU 10 ) or the blood pressure of 10 mm Hg (PA l0 ) or 50 mm Hg (PA 50 ).
• the experiments are carried out on female New Zealand rabbits weighing between 3 and 4 kg, anesthetized with a mixture of Ketamine and Xylazine.
• the catheters are introduced for the descending aorta into the femoral artery, into a jugular vein and into the urethra (1.5 cm below the neck of the bladder).
• test compounds are administered 5 to 15 days after the operation, by intravenous (i.v.) administration in 5 minutes, and in a single dose (10 or 100 ⁇ g / kg).
• i.v. intravenous
• the compounds to be tested orally are administered by gavage at a single dose (10, 30, 100, 300 or 1000 ⁇ g / kg).
• PU urethral pressure
• PA blood pressure
• the compounds of the invention thus tested, allowed an increase in the PU greater than 50%, usually between 50 and 350% after intravenous administration. venous, and usually between 50 and 200% after force-feeding. The increase in BP was always less than 10%, usually it is 0%.
• the compounds according to the invention can be used as a medicament, in particular as a contracting agent for smooth muscles, and more particularly still, in the treatment of stress urinary incontinence.
• the compounds according to the invention have good efficacy and, usually, less side effects than the drugs conventionally used for such treatment, in particular as regards the side effects affecting the cardiovascular system, in particular the arterial beds.
• the compounds according to the invention can also be used for the treatment of venous insufficiency, migraine, gastrointestinal disorders and as a vasoconstrictor of the nasal mucosa.
• the compounds according to the invention can be presented in different pharmaceutical forms suitable for administration by the digestive or parenteral route, if necessary by combining with at least one pharmaceutical excipient.
• suitable pharmaceutical forms are for example tablets, capsules, dragees, capsules, oral or injectable solutions, syrups, suppositories.
• These pharmaceutical forms can be dosed to allow a daily dose of 0.1 ⁇ g / kg to 50 mg / kg.

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• 1996
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