Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
  • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
  • C07H15/20—Carbocyclic rings
  • C07H15/203—Monocyclic carbocyclic rings other than cyclohexane rings; Bicyclic carbocyclic ring systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
  • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
  • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
• • 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
• • 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
  • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
  • C07H1/00—Processes for the preparation of sugar derivatives

Definitions

• the present invention relates, as new industrial products, to 4-cyano-4'-hydroxybenzophenone derivatives of formula I below which are benzophenone glycopyranosides. It also relates to their preparation process as well as their use in therapy, in particular in the form of compositions containing them as active principles.
• EP-A-0051023 compounds having a hydroxybenzophenone residue substituted with a ⁇ -D-xylosyl group, and having an advantageous pharmacological activity for treating or preventing venous thrombosis.
• EP-A-0133103 Also known from EP-A-0133103 are derivatives of the benzylphenyl ⁇ -D-xyloside type endowed with cholesterol-lowering and lipid-lowering properties. It is also known that in EP-A-0365397, EP-A-0290321, derivatives have been described in which the ⁇ -D-xylosyl radical has been replaced by a ⁇ -D-thioxylosyl radical, said compounds being useful because of their antithrombotic activity.
• This mode of action obtained after administration of the product by the oral route, is very probably responsible for the antithrombotic activity and only the derivatives of the ⁇ configuration of D-xylose exhibit activity in this therapeutic field. There is therefore a correlation between the action on the synthesis GAGs and the antithrombotic activity which made the compounds other than those derived from ⁇ -D-xylose irrelevant in this therapeutic area.
• new products are recommended, which are characterized in that they are chosen from the group consisting of:
• glycopyranosyl group R represents a ⁇ -D-arabinopyranosyl, ⁇ -D-lyxopyranosyl, ⁇ -D-ribopyranosyl, ⁇ -D- galactopyranosyl, ⁇ -D-mannopyranosyl, ⁇ -L-arabinopyranosyl, ⁇ - L-xylopyranosyl group , ⁇ -L-arabinopyranosyle, ⁇ -L-xylopyranosyle or ⁇ - L-rhamnopyranosyle; and, (ii) their esters resulting from the esterification of at least one OH function of each glycopyranosyl group with a C 2 -C alkanoic or cycloalkanoic acid.
• a process for preparing the compounds of formula I above and their esters there is provided a process for preparing the compounds of formula I above and their esters.
• a therapeutic composition is provided, characterized in that it contains, in association with a physiologically acceptable excipient, an amount therapeutically effective of at least one compound of formula I or of one of its esters.
• the use of a compound of formula I or of one of its esters is also recommended as an active principle for obtaining a medicament intended for use in therapeutic vis -in relation to the atheroma plaque, in particular for the prevention or treatment thereof.
• the new compounds according to the invention include the products of formula I and their esters; they are pyranoside derivatives of 4-cyano-4 '-hydroxybenzophenone [or 4- (4-hydroxybenzoyl) benzonitrile].
• the preferred products, in which the glycoside radical is in pyranose form correspond to the following formulas given as a function of the structure of the glycopyranosyl group R: (a) ⁇ -D-arabinose structure ( ⁇ -D-Ara):
• R 1 represents a hydrogen atom or a COR 2 group, R 2 being a C 1 -C 3 alkyl group chosen from methyl, ethyl, propyl, isopropyl and cyclopropyl groups.
• the process for the preparation of a compound of formula I or of one of its esters according to the invention is characterized in that it comprises: (1 °) the reaction of a peracetylated pentose or hexose of pyranosyl structure, corresponding in formula II:
• Z is H, CH 3 or CH 2 OAc, and chosen from the group consisting of 1,2,3,4-tetraacetyl-D-arabinose, 1,2,3,4-tetraacetyl-D-lyxose, 1 , 2,3,4-tetraacetyl-D-ribose, 1,2,3,4,6-pentaacetyl-D-galactose, 1,2,3,4,6-pentaacetyl-D-mannose, 1,2,3 , 4-tetraacetyl-L-arabinose, 1,2,3,4-tetraacetyl-L-xylose and 1,2,3,4-tetraacetyl-L-rhamnose, with 4- (4-hydroxybenzoyl) benzonitrile of formula III
• reaction II + III of step (1 °) is carried out in an organic solvent, (in particular dichloromethane), in the presence of a Lewis acid (such as for example tin tetrachloride), at a temperature between 25 ° C and the boiling point of the solvent, for 10 to 30 hours.
• organic solvent in particular dichloromethane
• Lewis acid such as for example tin tetrachloride
• step (2 °) the replacement of the Ac groups by hydrogen atoms is advantageously carried out as follows.
• the compound of formula IN is reacted with ⁇ H 3 in solution in an anhydrous alcohol (in particular methanol) to displace the Ac groups and replace them with H.
• an anhydrous alcohol in particular methanol
• step (1 °) becomes the following step (1 '), namely:
• X is a halogen atom (ie F, Cl, Br or I, the preferred halogen atom being Br) and Z is H, CH 3 or CH 2 OAc, and chosen from the group consisting of l -bromo-2,3,4-triacetyl-D- arabinose, 1 -bromo-2,3, 4-triacetyl-D-lyxose, 1 -bromo-2,3, 4-triacetyl- D-ribose, l-bromo -2,3,4,6-tetraacetyl-D-galactose, 1-bromo-2,3,4,6- tetraacetyl-D-mannose, 1 -bromo-2,3,4-triacetyl-L-arabinose, 1 -bromo-2,3,4-triacetyl-L-xylose, and l-bromo-2,3,4-triacetyl-L-rhamnose, with 4- (4-hydroxybenzo
• the N + III - IN reaction is carried out in an anhydrous solvent such as dichloromethane, 1-2-dichloroethane or acetonitrile, in the presence of a coupling agent such as silver trifluoromethanesulfonate or the silver oxide, at a temperature of the order of -10 to + 10 ° C, for 5 to 40 hours.
• anhydrous solvent such as dichloromethane, 1-2-dichloroethane or acetonitrile
• a coupling agent such as silver trifluoromethanesulfonate or the silver oxide
• Example 1 [4- [4-cyanobenzoyl) phenyl] 2,3,4-tri-O-acetyl- ⁇ -D-arabinopyranoside
• a solution of 0.8 g (2.52 ⁇ 10 ⁇ 3 mole) of 1.2 is prepared , 3,4-tetra-O-acetyl-D-arabinopyranose and 0.567 g (2.52.10 "3 mole) of 4- (4-hydroxybenzoyl) benzonitrile in 15 ml of anhydrous dichloromethane.
• a mixture of 90 mg (0.19 ⁇ 10 ⁇ 3 mole) of the compound obtained according to Example 1 is prepared in 20 ml of a solution of 2M ammonia in methanol and the mixture is stirred for 20 hours at room temperature The solvent is then removed under reduced pressure and the residue is purified by chromatography on silica gel, eluting with the aid of a methanol / dichlorornethane mixture (4/96; v / v).
• HMPA hexamethylphosphotriamide
• Example 12 By following a procedure analogous to Example 2, starting from the compound obtained according to Example 12, the expected product is obtained in the form of a white solid with a yield of 88%.
• Example 16 By following a procedure analogous to Example 2, starting from the compound obtained according to Example 16, the expected product is obtained in the form of a white solid with a yield of 76%.
• the anti-atheromatous activity of the compounds according to the invention was evaluated as a function of their ability to lower the serum cholesterol level in mice subjected to a fatty diet. It has indeed been shown in several publications a close correlation between a lipid overload and a marked increase in the atheromatous risk (cf. Lancet 1996, 348 pages 1339-1342; Lancet 1990, 335 pages 1233-1235). This correlation makes it possible to implement a faster test than direct tests on the atheroma plate, said tests requiring a long treatment of animals and a heavy histological study of the walls of the aortic arch.
• the test used consists in administering a single dose of the compound to female mice of strain C57BL / 6J.
• the protocol is as follows: the first day (D0), the mice are fasted from 9 am to 5 pm, a blood sample being taken at 2 pm. At 5 p.m., a determined quantity of food (fatty diet comprising 1.25% cholesterol and 0.5% cholic acid) is distributed. On the second day (Jl), at 9 am, the food remains are weighed and the mice fasted from 9 am to 2 pm. At 2 p.m., a blood sample is taken. For groups of treated mice, the compound is administered by tubing, in suspension in a gummy water solution, at 3%, the second day (Jl) at 9 am. Control groups receive only gummy water.
• the compounds were tested at a dose of 100 mg / kg.
• the total serum cholesterol is assayed and the results are expressed as a percentage of inhibition of the increase in cholesterolemia compared to the control group.
• the results obtained are reported in the "Activity" column of Table I.
• the analysis of the cholesterol content of the various classes of serum lipoproteins shows a favorable effect of the product on the HDL-cholesterol / total cholesterol ratio. .
• the products of formula I and their esters according to the invention can be administered, preferably orally, in the form of tablets or capsules, each containing 20 to 500 mg of a compound of formula I or one of its esters as an active ingredient, in combination with excipients.
• the dosage will be approximately 1 to 4 taken per day.
• the products according to the invention are advantageously prescribed vis-à-vis the atheroma plaque, and in particular for the prevention or treatment of atheromatous risk.

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• Vascular Medicine (AREA)
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• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

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• 1999
  • 1999-12-23 FR FR9916389A patent/FR2802930B1/fr not_active Expired - Fee Related
• 2000
  • 2000-12-06 BR BR0016533-6A patent/BR0016533A/pt not_active Application Discontinuation
  • 2000-12-06 IL IL15023700A patent/IL150237A0/xx unknown
  • 2000-12-06 JP JP2001549410A patent/JP2003519157A/ja active Pending
  • 2000-12-06 WO PCT/FR2000/003419 patent/WO2001047940A1/fr active IP Right Grant
  • 2000-12-06 CA CA002395561A patent/CA2395561A1/en not_active Abandoned
  • 2000-12-06 US US10/168,251 patent/US20030100515A1/en not_active Abandoned
  • 2000-12-06 EP EP00988884A patent/EP1240176A1/de not_active Withdrawn
  • 2000-12-06 MX MXPA02006339A patent/MXPA02006339A/es unknown
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  • 2000-12-06 KR KR1020027007993A patent/KR20020071000A/ko not_active Application Discontinuation
  • 2000-12-06 RU RU2002116676/04A patent/RU2002116676A/ru unknown
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  • 2000-12-06 NZ NZ519719A patent/NZ519719A/en unknown
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• 2002
  • 2002-06-21 NO NO20023003A patent/NO20023003D0/no not_active Application Discontinuation

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