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  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D335/00—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom
  • C07D335/04—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
  • C07D335/06—Benzothiopyrans; Hydrogenated benzothiopyrans
• • 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
  • A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory 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
  • A61P13/12—Drugs for disorders of the urinary system of the kidneys
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
  • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • 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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
  • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• • 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
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
  • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
  • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
  • C07D311/06—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2
  • C07D311/08—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring
  • C07D311/14—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring substituted in position 6 and unsubstituted in position 7
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
  • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

• the subject of the invention is new coumarin derivatives, their preparation methods and their use as medicaments which can inhibit serine proteases and cysteine proteases.
• serine or cysteine proteases such as leukocyte elastase, thrombin, coagulation factors (IXa, Xa, Xla, Xlla and Vlla for example), complement factors, plasmin , plasminogen activators (u-PA and t-PA), cathepsin G, acrosin, chymases, tryptases, chymotrypsin, trypsin, cathepsin B.
• Serine or cysteine proteases are involved in many physiological processes. Pathological conditions can arise when an imbalance between the protease and its natural inhibitor (s) macromolecular (s) is observed. Low molecular weight synthetic inhibitors can then be used to counter an excess of proteolysis and can therefore be of great interest in therapy in the following pathologies: pulmonary emphysema, rheumatoid arthritis, skin aging and inflammation (involvement of leukocyte elastase and cathepsin G); pancreatitis (involvement of pancreatic elastase, chymotrypsin and trypsin); tumor invasion and metastasis (plasmin, plasminogen activators, cathepsin B); thrombosis, cerebral and coronary infarction (involvement of thrombin and coagulation factors); thrombolysis and fertility disorders (plasmin and plasminogen activators); parasite and virus attacks (some of these organisms produce serine and cyst
• halogenomethylated dihydrocoumarins particularly attracted attention. They have shown good inhibitory activity with respect to a large number of serine proteases including in particular ⁇ -chymotrypsin, porcine pancreatic elastase, human leukocyte elastase 0, urokinase and thrombin (Béchet et al. 1973, Eur. J.
• protease inhibitors which are specific for a given protease in order to inhibit this enzyme without acting on nearby proteases.
• the present invention relates to the preparation of new coumarin derivatives 0 making it possible to achieve this goal since they combine activity and specificity.
• the subject of the invention is also the preparation of new coumarin derivatives, the synthesis of which is easily accessible.
• the subject of the invention is compounds corresponding to the general formula
• - Y represents O, S, NH or NHS
• a cycloalkyl group in particular from 3 to 12 carbon atoms and optionally comprising at least one heteroatom chosen from O, S or N, optionally substituted by one or more linear or branched alkyl group (s) from 1 to 6 atoms of carbon,
• - R3 advantageously representing -CgH5, -C6H4CH3, -C6H4I, -C6H4NO2,
• R, R7 and Rg identical or different from each other, represent hydrogen; a halogen atom; a linear or branched alkyl group of 1 to 6 carbon atoms; a linear or branched haloalkyl group of 1 to 6 carbon atoms, in particular halomethyl and in particular -CH2Cl; a perhaloalkyl group of 1 to 2 carbon atoms, in particular -CF3; a linear or branched alkyl group of 1 to 6 carbon atoms carrying an amine, amidine, guanidine function or a sulfonium function carrying two linear or branched alkyl substituents of 1 to 6 carbon atoms, aryl or aralkyl in which the alkyl group contains 1 to 6 carbon atoms; a carboxylic or carboxamide radical; a linear or branched alkoxy carbonyl group of 1 to 6 carbon atoms; a linear or branched alkoxy group of 1 to 6 carbon atoms
• R3 is different from -C6H5, -C6H 4 CH, -C6H C1, -C 6 H 4 I, -C 6 H 4 mNO 2 , -C 6 H3 /? Cl / nCH 3 , -C 6 H 4 rnBr, -C 6 H 4 rnF, C6H 4 rnOCH3,
• (-) R3 is different from -H, -CH3, -NO 2 , -Cl, Br when R 5 , R 7 , and Rg represent -H,
• (-) R7 is different from -Br, -N (CH2CH3) 2, when R 5 , R 6 , and Rg represent -H,
• Rg is different from -OCH3, -NO2 when R5, Rg, and R7 represent -H.
• Rg is different from -NO2, -NH2, -NHCOCH3, when R 5 , R 7 , and Rg represent -H,
• R7 is different from -NO2, -NH2 when Rg represents -H, OH or OCH3, and R5, R, represent H,
• Preferred salts according to the invention are physiologically acceptable salts.
• salts of hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, toluenesulfonic, lactic, citric, tartaric, succinic acids and the salts of mineral bases such as sodium hydroxide. , potash, ammonia and organic bases such as triethylamine, L-lysine.
• a subject of the invention is also compounds corresponding to the following formula:
• R3, X and Y have the meanings indicated above
• R and R ' have the same meanings as R5, R, R7 and Rg as defined above and in particular R and R' correspond respectively to R and Rg.
• a subject of the invention is also compounds corresponding to the following formula:
• a subject of the invention is also compounds corresponding to the following formula:
• R3 and Y have the meaning indicated above and R has the meaning indicated above with the exception of CICH2-.
• a subject of the invention is also compounds corresponding to the following formula:
• a subject of the invention is also compounds corresponding to the following formula:
• R represents CICH2-, and R3 is chosen from
• a subject of the invention is also compounds corresponding to the following formula:
• R3 is chosen from
• R3 is chosen from
• a subject of the invention is also compounds corresponding to the iormule
• a subject of the invention is also compounds corresponding to the formula
• a subject of the invention is also compounds corresponding to the following formula:
• R3 is chosen from:
• a subject of the invention is also compounds corresponding to one of the following formulas:
• a subject of the invention is also compounds corresponding to the following formula:
• Rl l CH 3 -, C 2 H 5 -, C3H7-, (CH 3 ) 3 C-, (CH 3 ) 2 CH-, or to the following formula:
• the invention also relates to a pharmaceutical composition characterized in that it comprises, as active substances, at least one of the compounds described above, in combination with a pharmaceutically acceptable vehicle.
• the invention also relates to a cosmetic composition characterized in that it comprises, as active substances, at least one of the compounds described above.
• the invention also relates to the use of one of the compounds described above, for the preparation of a medicament intended for the treatment of pathologies involving serine proteases such as thrombin, chymotrypsin, elastases, cathepsin G , plasminogen activators (u-PA and t-PA), plasmin, tryptases, chymases, cysteine proteases, coagulation factors, complement factors, acrosin or kallikrein.
• serine proteases such as thrombin, chymotrypsin, elastases, cathepsin G , plasminogen activators (u-PA and t-PA), plasmin, tryptases, chymases, cysteine proteases, coagulation factors, complement factors, acrosin or kallikrein.
• - Y represents O, S, NH or NHS
• a cycloalkyl group in particular from 3 to 12 carbon atoms and optionally comprising at least one heteroatom chosen from O, S or N, optionally substituted by one or more linear or branched alkyl groups of 1 to 6 carbon atoms,
• - R3 advantageously representing -C6H5, -C6H 4 CH3, -C6H 4 I, -C6H4.NO2, -C 6 H 4 F, -C 6 H 4 Br, -C 6 H C1, -C 6 H CF 3 , - C 6 H 4 OCH 3 , -C 6 H 3 C1 2 , -C 6 H 3 C1CH 3 , -C 6 H 3 ClOCH 3 ,
• R, R7 and Rg identical or different from each other, represent hydrogen; a halogen atom; a linear or branched alkyl group of 1 to 6 carbon atoms; a linear or branched haloalkyl group of 1 to 6 carbon atoms, in particular halogenomethyl and in particular -CH2Cl; a perhaloalkyl group of 1 to 2 carbon atoms, in particular -CF3; a linear or branched alkyl group of 1 to 6 carbon atoms carrying an amine, amidine, guanidine function or a sulfonium function carrying two linear or branched alkyl substituents of 1 to 6 carbon atoms, aryl or aralkyl in which the alkyl group contains 1 to 6 carbon atoms; a carboxylic or carboxamide radical; a linear or branched alkoxy carbonyl group of 1 to 6 carbon atoms; a linear or branched alkoxy group of 1 to 6 carbon atom
• O representing a linear or branched alkyl group of 1 to 6 carbon atoms, optionally mono or poly halogen, and in particular -CF3; a group -CH2-S-R9 in which R9 has the meaning indicated above; a group -CH2NR12R13, in which R12 and R13, identical or different, have the meanings indicated above with respect to R9; - R5, R ⁇ , R7 and Rg advantageously representing H-, CICH2-, CH 3 -CO-CH 2 -, C 2 H 5 -CO-CH 2 -, (CH 3 ) 3C-CO-CH 2 -, OOO
• R3 representing an aryl group substituted by one or more halogens, NO2, an alkyl radical of 1 to 6 carbon atoms or alkoxy of 1 to 6 carbon atoms, for the preparation of a medicament intended for the treatment of pathologies involving thrombin.
• a general method for the synthesis of esters, thiolesters, amides and N- [aryl / alkyl] sulfanylamides of substituted 2-oxo-2H-1-benzopyran-3-carboxylic acids is as follows.
• ethyl esters of 2-oxo-2H-1-benzopyran-3-carboxylic acids can be obtained from the appropriate salicylaldehyde by following the methods described in L. Pochet et al. , J. Med. Chem. 1996, 39: 2579-2585 and in the examples of this application (see below).
• R ' OR ", SR”, NHR ", NHSR"
• R “representing R3, defined previously and R representing R5, R ⁇ , R7 and / or Rg described above, i: ethyl malonate; ii: HCl / H2 ⁇ / EtOH; (iii) SOCI2; (iv) R "OH or R” SH or R "NH2 or R” SNH2 / pyridine / dioxane
• a method for the synthesis of esters, thiolesters and amides of substituted 2-oxo-2H-1-benzothiopyran-3-carboxylic acids is as follows.
• the ethyl esters of 2-oxo-2H-1-benzothiopyran 3-carboxylic acids can be prepared according to the method described in O. Meth Cohn and Tarnowski B., Synthesis, 1978, 1: 56-58 (i - iii below) ). The following steps are based on the methods described in L. Pochet et al. , J. Med. Chem. 1996, 39: 2579-2585, and in the examples of the present application (iv - vi below).
• R “representing R3, defined above and R representing R5, R ⁇ , R ⁇ and / or Rg described above, i: tC 4 H9SH / DMF; ii ethyl yanoacetate; iii: polyphoshoric ac; iv:
• a method for the synthesis of esters, thiolesters and amides of substituted 2-oxo-2H-1-benzopyran-3-carbothioic acids is as follows.
• the oethyl esters of 2-oxo-2H-1-benzopyran-3-carbothioic acids can be prepared according to the method described in B. S. Kirkiacharian and A. Danan, Synthesis, 1986, 5: 383-5 and in G. Barnikow and Stickmann G., Chem. Ber., 1967, 100: 1428-1435 (step i).
• the following steps are based on the methods described in L. Pochet et al., J. Med. Chem. 1996, 39: 2579-2585 and in the examples of this application.
• R “representing R3, defined above and R representing R5, R ⁇ , R7 and / or Rg described above, i: ethyl monothiomalonate; ii: HCl / H2 ⁇ / EtOH; (iii) SOCI2; (iv) R" OH or R "SH or R" NH2 / pyridine / dioxane;
• the ethyl esters of 2-thioxo-2H-1-benzopyran-3-carboxylic acids can be prepared according to the method described in Shishido Tadao and Okada ⁇ isashi, Jpn. Kokai Tokkyo Koho JP 02,172,916. The following steps are based on the methods described in L. Pochet et al., J. Med. Chem. 1996, 39: 2579-2585 and in the examples of this application.
• a method for the synthesis of esters, thiolesters and amides of substituted 2-thioxo-2H-1-benzopyran-3-carbothioic acids is as follows.
• o-ethyl esters of 2-thioxo-2H-1-benzopyran-3-carbothioic acids can be prepared according to the method described in A.
• the coumarin derivatives of the invention can enter into the preparation of pharmaceutical compositions.
• These pharmaceutical compositions can be in the form of solutions, suspensions, powders or soluble granules, syrups or elixirs, ear drops, nasal or ophthalmic, tablets, gelatin capsules, aerosols, ointments, transcutaneous applications or suppositories, in metered presentations containing non-toxic carriers, adjuvants and excipients.
• the injections can be, for example, intravenous, intramuscular, subcutaneous, intradermal, intrasternal, intraperitoneal or intra-articular. It is also possible to use infusion or instillation methods (for example intratracheal).
• solutions containing albumin microspheres to which the coumarin derivatives are covalently attached can be produced.
• Preparations for oral use may contain one or more sweetening agents, colors, flavors and preservatives.
• the tablets contain the active coumarin derivative molecule according to the invention mixed with non-toxic excipients which are acceptable from a pharmaceutical point of view.
• excipients examples include inert diluents, such as calcium or sodium carbonate, calcium or sodium phosphate and lactose; agents for granulation and disintegration, for example corn starch; fixing agents, for example gelatin, starch and gum arabic; and lubricating agents, for example talc or stearate magnesium.
• the tablets can be coated or not (for example with the help of glycerol monostearate or distearate) in order to delay disintegration and absorption.
• the preparation can be contained in a solid gelatin capsule containing the active molecule mixed with an inert solid (for example calcium carbonate or phosphate, or kaolin), or in a flexible gelatin capsule in which the coumarin derivative is mixed with water or fatty substances (for example liquid paraffin, olive or peanut oil).
• an inert solid for example calcium carbonate or phosphate, or kaolin
• water or fatty substances for example liquid paraffin, olive or peanut oil
• Aerosols of three types can be envisaged in particular: (a) aqueous aerosols (administered using atomizers) for which better solubilization of the coumarin derivative can be obtained by adding a co-solvent or the formation of micelles; (b) pressurized aerosols having for example as carrier gases chlorinated or fluorinated hydrocarbons of different formulas (or a replacement product) in which the coumarin derivative can be dissolved or in suspension; (c) powder aerosols with the coumarin derivative in fine particles, for example in a gelatin capsule.
• Aqueous suspensions containing the coumarin derivative and the appropriate excipients can be produced with optionally one or more preservatives (for example ethyl p-hydroxybenzoate), coloring agents, sweetening agents and flavors.
• preservatives for example ethyl p-hydroxybenzoate
• coloring agents for example methyl cellulose and gum arabic
• dispersing and wetting agents such as natural phosphatides (for example lecithin) or products for condensing ethylene oxide with various partially esterified fatty acids or aliphatic alcohols.
• Oily suspensions of the active molecule can be prepared using a vegetable oil (e.g. olive, peanut, sesame, coconut or soybean oil) or mineral oil (e.g. liquid paraffin ), possibly in the presence of sweetening agents and flavors such as those mentioned above as well as preservatives (in particular an antioxidant such as ascorbic acid).
• Syrups or elixirs could contain sweetening agents (for example sucrose or sorbitol), one or more preservatives as well as flavorings.
• Granules or powders which can be suspended in water are capable of being obtained by mixing the coumarin derivative with a wetting or dispersing agent, one or more preservatives and various excipients.
• Emulsions of the coumarin derivative in water can be produced using a mineral oil (liquid paraffin for example) or vegetable oil (olive oil or peanut) and various emulsifying agents, such as natural gums (gum arabic), natural phosphatides (lecithin) and various ester fatty acids, partially or not, or condensation products of these partial esters with the oxide of 'ethylene.
• Emulsions may also contain flavorings and sweetening agents.
• the coumarin derivative according to the invention can also be in the form of sterile injectable suspensions, aqueous or oily using wetting or suspending agents such as those described above.
• the solvents, diluents or excipients can be, for example, 1,3-butanediol, an isotonic solution of sodium chloride, a Ringer's solution, water, aqueous solutions of dextrose and related sugars, ethanol or glycols etc.
• Suppositories containing the active ingredient can be prepared with conventional excipients such as polyethylene glycol or for example cocoa butter.
• DMSO dimethyl sulfoxide
• Doses of 0.01 to 50 mg / kg / day are appropriate. However, the dose for a given patient may depend on a number of factors such as, for example, the efficacy of the coumarin derivative in question, age, weight, route and frequency of administration, diet, drug interactions and the severity of the disease.
• compositions can in particular be used for the treatment of very numerous pathologies in which an excess of protease is involved.
• coumarin derivatives behaving like inhibitors of leukocyte elastase and cathepsin G. They can be used in the treatment of acute or chronic inflammatory processes or the treatment of degenerative processes, whatever the organ involved, such as pulmonary emphysema, inflammation of the bronchi, rheumatoid arthritis, infectious arthritis, osteoarthritis, spondylitis, rheumatic fever, periodontitis, gingivitis, arterial sclerosis, glomerulonephritis , respiratory distress syndrome, septic shock, Crohn's disease, gout, pancreatitis, microvascular hemorrhage, cystic fibrosis, lupus erythematosus, psoriasis, respiratory failure, idiopathic pulmonary fibrosis, chronic respiratory infections, isperemia reperfusion syndrome , the phenomena of invasion and spread of malignant cells and similar diseases.
• Thrombin inhibitors can be useful as anticoagulants or antithrombotics, in particular in the treatment of stable and unstable angina, diseases of thrombotic origin and / or giving rise to thrombotic complications (thrombophlebitis for example) and in the treatment and prevention of myocardial infarction and venous and arterial thrombosis.
• Inhibitors of plasminogen or plasmin activators can be used in particular in the treatment of tumor invasion and metastases, the control of thrombolysis and fertility, in various coagulation disorders (deep vein thrombosis, coronary heart disease ), in various inflammatory processes (rheumatoid arthritis, psoriasis, leprosy, transplant rejection), in scarring, liver disorders and various infections.
• Mast cell tryptase and chymase inhibitors may be used to treat allergic responses and psoriasis.
• cysteine proteases eg cathepsin B
• coumarin derivatives can lead to applications in tumor invasion and the metastatic process.
• the active ingredient coumarin can also enter into the composition of cosmetic preparations such as creams, ointments, lotions, gels, milks, etc ... It can therefore be continuous systems (aqueous, oily or solid solutions) or dispersed systems (emulsions or suspensions).
• the coumarin derivative may be contained in liposomes.
• Hylanes derivatives of hyaluronans
• various polymer systems polyol-prepolymers, microsphere systems, etc.
• the anti-elastase action of coumarin derivatives can also lead to applications in cosmetology, in particular in the field of solar erythema, topical treatment of inflammations and skin aging.
• the active principle can be included for example in creams, lotions, tonics, body milks, etc.
• R3 cycloalkyle
• R3 phenyl mono-, polysubstituted
• R3 pyridyle mono-, polysubstituted
• Ic "8 Ic” 9 Ic “10 Ic” ll Ic "8: 6-chloromethyl-2-oxo-2H-1-benzopyran-3-carboxylate of 2,5-difluorophenyl; mp 137-140 ° C; IR (KBr): 3067, 1782, 1765, 1720, 1622 , 1574,
• 6-methylpyrid-2-yle m.p. 160-162 ° C; r.m.n. (CDCL3 / TMS): ⁇ (p.p.m.) 2.60 (s, 3 ⁇ , -CH3),
• 6-chloropyrid-2-yle m.p. 172-173 ° C; r.m.n. (CDCL3 / TMS): ⁇ (p.p.m.) 4.60 (s, 2 ⁇ ,
• Idll Idl2 Idl3 Idl4 Idl5 Idl6 Idll: 2,5-dichlorophenyl 6-acetoxymethyl-2-oxo-2H-1-benzopyran-3-carboxylate; mp 168-171 ° C; IR (KBr): 3068, 3027, 1775, 1728, 1624, 1576,
• the inactivating or inhibiting properties of coumarin derivatives have been tested against a certain number of enzymes: human leukocyte elastase, bovine ⁇ -chymotrypsin, human thrombin and bovine trypsin.
• Kinetic measurements were carried out at 25 ° C in the following buffers: ⁇ epes 0.1 M, NaCl 0.5 M, Tween 80 0.01%, p ⁇ 8.0 (elastase human leukocyte); H2P ⁇ 4Na 0.025 M, KC1 0.05 M, pH 7.5 ( ⁇ -chymotrypsin); 0.01 M Tris, 0.01 M Hepes, 0.1 M NaCl, 0.1% PEGOOO, pH 7.5 (human thrombin); 0.1 M Tris, 0.01 M CaCl2, pH 7.5 (bovine trypsin).
• the chromogenic substrates used to determine the activity of the enzymes are: MeOSuc-Ala2-Pro-Val-NA (human leukocyte e
• Suc-Ala2-Pro-Phe-pNA ( ⁇ -chymotrypsin); H-D-Phe-Pip-Arg-pNA (human thrombin); N-benzoyl-Arg-pNA (bovine trypsin) (pNA: ⁇ ra-nitroaniline).
• equation 1 [Daniels et al., 1983, J. Biol. Chem., 258: 15046-15053]):
• E * I represents both the El and E-I species (a kind of kinetic chimera).
• the kinetic constants characterizing the inactivation of enzymes by coumarin derivatives were determined using either the conventional method of sampling (or discontinuous method), or a method competing between the inhibitor and the substrate (or continuous method); these methods are described by Pochet et al. [Pochet et al. , 1996, J. Med. Chem. , 29: 2579-2585].
• the inactivation of serine proteases by coumarin derivatives is thus characterized by the following constants (see eq. 2):
• Other phenyl esters effectively inactivate ⁇ -CT or thrombin. Their efficiencies are presented in Table 5. For the derivatives do having no chloromethyl substituent in position 6, a transient inactivation of ⁇ -CT can be observed, contrary to what is noted for the pyridyl esters, in which case the parameters kj / Ki correspond to the inactivation phase.

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