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WO2010093191A2 - Nouveaux composés efficaces en tant qu'inhibiteurs de xanthine oxydase, leur procédé de préparation et composition pharmaceutique les contenant - Google Patents

Nouveaux composés efficaces en tant qu'inhibiteurs de xanthine oxydase, leur procédé de préparation et composition pharmaceutique les contenant Download PDF

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WO2010093191A2
WO2010093191A2 PCT/KR2010/000893 KR2010000893W WO2010093191A2 WO 2010093191 A2 WO2010093191 A2 WO 2010093191A2 KR 2010000893 W KR2010000893 W KR 2010000893W WO 2010093191 A2 WO2010093191 A2 WO 2010093191A2
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methyl
thiazole
carboxylic acid
indol
cyano
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WO2010093191A3 (fr
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Sung Pil Choi
Geun Tae Kim
Jeong Uk Song
Tae Hun Kim
Dong Chul Lim
Seung Wan Kang
Hyung Jin Kim
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LG Chem Ltd
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LG Life Sciences Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention relates to novel compounds of formula (1):
  • A, D, E, G, Y, Q, Wi, W 2 , W 3 and W 4 are as defined below, which are effective as an inhibitor for xanthine oxidase, a process for preparing the same, and a pharmaceutical composition comprising a therapeutically effective amount of the same.
  • Xanthine oxidase is known as an enzyme which converts hypozanthine to xanthine and further converts thus-formed zanthine to uric acid. Although most mammals have uricase, humans and chimpanzees do not, thereby uric acid is known to be the final product of purine metabolism (S. P. Bruce, Ann. Pharm., 2006, 40, 2187-2194). Sustained elevation of blood concentration of uric acid can cause various diseases, representatively including gout.
  • gout is caused by an elevated level of uric acid in the body, indicating the condition in which uric acid crystals accumulated in cartilage, ligament and surrounding tissue induce severe inflammation and pain. Gout is a kind of inflammatory articular disease, and its incidence rate has steadily increased during past 40 years (N. L. Edwards, Arthritis & Rheumatism, 2008, 58, 2587-2590).
  • gout patients in the West exhibited an astonishing increase of about 200-300%, mainly in males.
  • the increased rate of gout patients can be traced to obesity, aging, kidney function decline, hypertension, etc.
  • the incidence rate of gout appears to be a level of about 1.4/1,000 persons, but it also depends on the uric acid level. That is, while the incidence rate of gout is 0.5% in a patient group with a blood uric acid level of 7.0 mg/dl or more, the incidence rate of gout is 5.5% in a patient group with a uric acid level of 9.0 mg/dl or more (G. Nuki, Medicine, 2006, 34, 417-423).
  • Allopurinol was a unique drug for the treatment of gout for 40 years, until febuxostat was approved as an arthrifuge in Europe in 2008 (Brain Tomlinson, Current Opin. Invest. Drugs, 2005, 6, 1168-1178). Allopurinol is known to be a non-specific inhibitor for various enzymes that are involved in purine and pyrimidine metabolism, and it has a Ki of 700 nM for xanthine oxidase (Y. Takano et al., Life Sciences, 2005, 76, 1835-1847). Allopurinol is immediately oxidized to oxypurinol by xanthine oxidase, and this metabolite is known to act as a potent inhibitor for xanthine oxidase.
  • One object of the present invention is to provide novel compounds of formula (1) which exhibit very excellent inhibitory effect against xanthine oxidase.
  • Another object of the present invention is to provide a novel process for the preparation of the compounds of formula (1).
  • Still another object of the present invention is to provide a pharmaceutical composition for the inhibition of xanthine oxidase, which comprises a therapeutically effective amount of the compounds of formula (1) as an active ingredient.
  • Still another object of the present invention is to provide a method for the treatment and/or prevention of the diseases associated with xanthine oxidase such as hyperuricemia, gout, heart failure, cardiovascular disease, hypertension, diabetes, kidney disease, inflammation and articular disease, and inflammatory bowel disease, which comprises using the compounds of formula (1) as an active ingredient.
  • diseases associated with xanthine oxidase such as hyperuricemia, gout, heart failure, cardiovascular disease, hypertension, diabetes, kidney disease, inflammation and articular disease, and inflammatory bowel disease
  • Wi, W 2 , W 3 and W 4 represent N or C, provided that only one is N when Wi, W 2 , W 3 or W 4 represents N,
  • A represents the following A-i or A-ii: [35] (A-i)
  • J represents hydrogen; halogen; d-C 6 -alkyl which is unsubstituted or substituted by halogen; or substituted or unsubstituted d-C 6 -alkoxy, and X represents O or S
  • A is linked to only C when A is linked to Wi, W 2 , W 3 or W 4 ,
  • E represents hydrogen; halogen; nitro; cyano; amino; substituted or unsubstituted Ci -
  • D represents hydrogen; halogen; cyano; nitro; Ci-C 6 -alkyl which is unsubstituted or substituted by halogen; or-CHO,
  • Q is selected form the following Q-i, Q-ii, Q-iii-1 to Q-iii-14:
  • RlO and RI l independently of one another represent hydrogen; halogen; lower alkoxy; or lower alkyl, and m denotes an integer of 1-3
  • R12 represents substituted or unsubstituted lower alkyl or aryl, and n denotes an integer of 0-3)
  • Rl 3 and R14 independently of one another represent substituted or unsubstituted lower alkyl, or together with the nitrogen atom to which they are attached may form a 3-7 membered heterocycle containing N as the hetero atom, and n denotes an integer of 0-3)
  • N R15 0 (wherein R15 represents substituted or unsubstituted lower alkyl, and m denotes an integer of 1-3), [60] [61] (Q-iii-8)
  • Rl 6 and R17 independently of one another represent hydrogen or substituted or unsubstituted lower alkyl, or together with the atoms to which they are attached may form a 3-7 membered heterocycle containing N as the hetero atom, and m denotes an integer of 1-3
  • Wi, W 2 , W 3 , W 4 and W 5 represent N or C, provided that only one is N when Wi, W 2 , W 3 , W 4 or W 5 represents N, R24 and R25 independently of one another represent hydrogen; halogen; lower alkoxy; or lower alkyl, and m denotes an integer of 1 ⁇ 3),
  • Y represents hydrogen; halogen; substituted or unsubstituted, saturated or unsaturated, and straight-chain, branched or cyclic alkyl; substituted or unsubstituted Ci - C 6 -alkoxy; C 6 -Ci 0 -aryl; substituted or unsubstituted 3-7 membered heteroaryl which contains N as the hetero atom; substituted or unsubstituted 3-7 membered heterocycle which contains N as the hetero atom, or
  • G represents hydrogen; or substituted or unsubstituted, saturated or unsaturated, and straight-chain, branched or cyclic alkyl, pharmaceutically acceptable salts, or isomers thereof.
  • the compounds of formula (1) as an active in- gredient of the therapeutic agent include all their pharmaceutically acceptable salts and isomers, and they should be instrued to fall under the scope of the present invention.
  • they are simply referred to as 'compounds of formula (I)' in the present specification.
  • the above compounds of formula (1) according to the present invention have a quite different chemical structure from the earlier known xanthine oxidase inhibitors. As shown in the following experiments, they exhibit an excellent inhibitory effect against xanthine oxidase associated with gout. Thus, they can be used for the prevention and treatment of diseases associated with xanthine oxidase, such as, for example, hyperuricemia, heart failure, cardiovascular disease, hypertension, diabetes, kidney disease, inflammation, articular disease, etc.
  • diseases associated with xanthine oxidase such as, for example, hyperuricemia, heart failure, cardiovascular disease, hypertension, diabetes, kidney disease, inflammation, articular disease, etc.
  • substituted or un- substituted means to include both the cases of being substituted and unsubstituted.
  • the radical may be substituted by one or more groups individually and independently selected from alkyl, cycloalkyl, hydroxy, alkoxy, mercapto, alkylthio, cyano, halogen, carbonyl, thiocarbonyl, sulfonyl, nitro, aryl and their protective derivatives. If appropriate, these groups may be furthermore substituted.
  • pharmaceutically acceptable salts means the salt forms of a compound, which neither give any serious irritation to the organism to which the compound is administered nor damage the biological activities and properties of the compound.
  • a pharmaceutically acceptable salt includes a non-toxic acid addition salt containing a pharmaceutically acceptable anion, for example, a salt with inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, hydriodic acid, etc.; a salt with organic carboxylic acids such as tartaric acid, formic acid, citric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, maleic acid, salicylic acid, etc.; or a salt with sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-to
  • the compounds of formula (1) can also form a pharmaceutically acceptable base addition salt, for example, a salt with alkali metals or alkaline earth metals such as lithium, sodium, potassium, calcium, magnesium, etc.; a salt with amino acids such as lysine, arginine, guanidine, etc.; or an organic salt with dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, diethanolamine, choline, triethylamine, etc.
  • the compounds of formula (1) of the present invention may be converted to their salts according to any of the conventional methods.
  • “isomer” means those having the same chemical or molecular formula as, but optically or sterically different from, the compounds of formula (1), or salts thereof.
  • the compounds of formula (1) of the present invention may have an oxime structure, and so may exist in the form of geometrical isomers, trans and cis. All the isomers, their salts, and their mixtures (including racemic mixture) are also covered by the present invention.
  • aryl means a carbocyclic group (e.g., phenyl) having a covalent ⁇ electronic system and at least one ring. This term also includes monocyclic or fused- ring polycyclic (i.e., rings share the adjacent carbon pairs) groups.
  • heteroaryl means a heterocyclic aryl group having a covalent ⁇ electronic system and at least one ring. It includes but is not limited to furan, thiophene, pyrrole, oxazole, thiazole, imidazole, pyrazole, isothiazole, triazole, thiadiazole, pyridine, pyridazine, pyrimidine, pyrazine, triazine, etc.
  • alkyl means an aliphatic hydrocarbon group.
  • the alkyl group may be "a saturated alkyl” not containing alkene or alkine moiety at all, or "an unsaturated alkyl” containing at least one alkene or alkine moiety.
  • alkene means a group having at least one carbon-carbon double bond
  • alkine means a group having at least one carbon-carbon triple bond. Regardless of being saturated or unsaturated, the alkyl group may be branched, linear or cyclic.
  • the alkyl group may contain 1 to 20 carbon atoms, and the lower alkyl group may contain 1 to 7 carbon atoms.
  • the alkyl group may be substituted or unsubstituted.
  • heterocycle means a group wherein the ring carbon atom is replaced by oxygen, nitrogen, sulfur, etc. It may optionally include a double bond.
  • the typical examples thereof may include but are not limited to pyrroline, pyrrolidine, imidazoline, imidazolidine, pyrazoline, pyrazolidine, pyran, piperidine, morpholine, thiomorpholine, piperazine, etc.
  • halogen means F (or-F), Cl (or-Cl), Br (or-Br) and I (or-I).
  • W 1 , W 2 , W 3 and W 4 represent N or C, provided that only one is N when W 1 , W 2 , W 3 or W 4 represents N,
  • A represents the following A-i or A-ii:
  • J represents hydrogen; Q-Ce-alkyl which is unsubstituted or substituted by halogen; or substituted or unsubstituted Q-Ce-alkoxy, and X represents O or S
  • A is linked to only C when A is linked to W 1 , W 2 , W 3 or W 4 ,
  • E represents hydrogen; halogen; nitro; cyano; amino; or Q-Ce-alkyl, provided that E is linked to only C when E is linked to W 1 , W 2 , W 3 or W 4 ,
  • D represents hydrogen; halogen; cyano; or nitro
  • Q is selected form the following Q-i, Q-ii, Q-iii- 1 to Q-iii- 14:
  • %S-R12 0 (wherein R 12 represents lower alkyl, and n denotes an integer of 0-3)
  • Rl 6 and R17 independently of one another represent hydrogen or lower alkyl, or together with the atoms to which they are attached may form a 5-6 membered heterocycle containing one (1) N as the hetero atom, and m denotes an integer of 1-3
  • Wi, W 2 , W 3 , W 4 and W 5 represent N or C, provided that only one is N when Wi, W 2 , W 3 , W 4 or W 5 represents N, R24 and R25 independently of one another represent hydrogen or lower alkyl, and m denotes an integer of 1-3),
  • Y represents hydrogen; saturated or unsaturated and straight-chain, branched or cyclic alkyl which is unsubstituted or substituted by lower alkoxy or C 3 -C 6 -cycloalkyl; C 6 -Ci 0 - aryl; 5-6 membered heteroaryl which contains 1-2 N as the hetero atom and which is unsubstituted or substituted by lower alkyl; 5-6 membered heterocycle which contains 1-2 N as the hetero atom and which is unsubstituted or substituted by lower alkoxycarbonyl, lower alkyl or lower alkylsulfonyl, or [153] [154] Q and Y together with the atoms to which they are attached may form a 5-6 membered heterocycle which contains 1 N as the hetero atom, and [155] [156] G represents hydrogen; or saturated or unsaturated and straight-chain, branched or cyclic lower alkyl. [157] [158] Particularly preferred compounds among the preferred compounds are: are
  • A represents
  • J represents hydrogen; d-C 6 -alkyl which is unsubstituted or substituted by halogen; or substituted or unsubstituted d-C 6 -alkoxy, preferably represents Ci-C 4 - alkyl which is unsubstituted or substituted by halogen).
  • D represents halogen, cyano or nitro.
  • the present invention also provides processes for preparing the compounds of formula (1).
  • One of ordinary skill in the art to which the present invention pertains (“a skilled artisan") may prepare the compounds of formula (1) via various routes according to their structures, and such processes should be construed to fall under the scope of the present invention.
  • the compounds of formula (1) may be prepared by optionally combining various synthetic methods which are described in the present specification or disclosed in the prior arts.
  • the processes for preparing the compounds of formula (1) cover even such processes and are not limited to those explained below.
  • the compounds of formula (1) wherein Q is not hydrogen may be prepared by reacting compounds of formula (2) with compounds of formula (3) in the presence of a base, as depicted in the following Reaction Scheme (1):
  • L 1 is a leaving group in the substitution reaction, for example, halogen, methanesul- fonyloxy, p-toluenesulfonyloxy, or trifluoromethanesulfonyloxy, etc.
  • the above reaction may be carried out in an organic solvent such as dimethyl- formamide, dimethylacetamide, acetonitrile, etc., and in some cases a mixture of two or more organic solvents may be used.
  • organic solvent such as dimethyl- formamide, dimethylacetamide, acetonitrile, etc.
  • Typical examples for the base used in the reaction include sodium hydride, sodium hydroxide, potassium t-butoxide, cesium carbonate, potassium carbonate, sodium carbonate, potassium bis(trimethylsilyl)amide, etc., and in some cases a mixture of two or more bases may be used.
  • W 1 , W 2 , W 3 , W 4 , A, D, E, G and Y are as defined in formula (1), provided that D is not hydrogen.
  • Compound (4) and N-chlorosuccinimide may be reacted in an organic solvent such as methanol, ethanol, dimethylformamide, dimethylacetamide, acetonitrile, etc. to give the desired Compound (2). If appropriate, a mixture of two or more organic solvents may be used.
  • the substituent Q may be first introduced to Compound (4) in the same manner as the above Reaction Scheme (1), and the chloro group may be introduced later as explained above.
  • [317] a is NaSH, MgCl 2 , DMF,
  • [318] b is pyridine, ethanol,
  • W 1 , W 2 , W 3 , W 4 , A, E, G and Y are as defined in formula (1), and
  • Rn is lower alkyl
  • the present invention further provides a pharmaceutical composition for the in- hibition of xanthine oxidase, which comprises (a) a therapeutically effective amount of the compounds of formula (1), pharmaceutically acceptable salts or isomers thereof and (b) pharmaceutically acceptable carriers, diluents, excipients or their combinations.
  • pharmaceutical composition means compositions comprising the compounds of the present invention and other chemical components such as carriers, diluents, excipients, etc.
  • a pharmaceutical composition facilitates the administration of the compound into a living organism.
  • techniques to administer the compound include but are not limited to oral, injectable, aerosol, parenteral and topical administration.
  • the therapeutically active ingredients to be contained in the pharmaceutical composition may be converted to their salts by reacting acid compounds such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, p-toluenesulfonic acid, salicylic acid, etc. with the compounds of formula (1).
  • therapeutically effective amount means the amount of active ingredient effective to alleviate or remove one or more symptoms of the disorder to be treated, or to delay clinical markers or the initiation of symptoms of the disease to be prevented.
  • therapeutically effective amount means the amount having the effect of (1) reversing the rate of progress of the disease, (2) prohibiting further progress of the disease and/or (3) alleviating (preferably, removing) one or more symptoms associated with the disease.
  • the therapeutically effective amount can be determined on the basis of experience by testing compounds in the in vivo and invitro model systems known for the disease to be treated.
  • carrier means a substance that facilitates the incorporation of the compound into cells or tissues.
  • DMSO dimethylsulfoxide
  • carrier facilitates the introduction of various organic compounds into cells or tissues of living organisms.
  • diluent is defined as a substance that is diluted in water which dissolves the compound, as well as stabilizes the biologically active form of the subject compound.
  • the salts dissolved in a buffer solution are utilized as diluents in the art.
  • a typically used buffer solution is phosphate-buffered saline which mimics the salt form of human solution. Buffer diluents rarely alter the biological activities of the compound, as the buffer salts can control the pH of solution at a low concentration.
  • the compound used herein may be administered as the compound per se or as a pharmaceutical composition comprising the compound with other active ingredients in the combination therapy or with other suitable carriers or excipients, to the human patient.
  • Techniques for formulations and administrations of a compound can be found in "Remington's Pharmaceutical Sciences” (Mack Publishing Co., Easton, PA, 18 th edition, 1990).
  • composition of the present invention may be prepared by known methods, such as, for example, conventional mixing, dissolving, granulating, dragee- preparing, powdering, emulsifying, capsulating, trapping or freeze-drying, etc.
  • the pharmaceutical composition of the present invention may be prepared by the conventional methods of using one or more pharmaceutically acceptable carriers.
  • the carriers include excipients or adjuvants by which the active compound can be easily converted to pharmaceutically acceptable formulations. Suitable formulations may depend on the selected administration route. Techniques, carriers and excipients, and means known in the art, for example, in "Remington's Pharmaceutical Sciences,” as explained above may be appropriately selected.
  • the compounds of formula (1) of the present invention can be formulated as an injectable preparation, oral preparation, etc., depending on the purpose intended.
  • the active compounds of the present invention can be formulated to a liquid preparation by using pharmaceutically suitable buffers, preferably Hank solution, Ringer solution, physiological saline, etc.
  • pharmaceutically suitable buffers preferably Hank solution, Ringer solution, physiological saline, etc.
  • penetration promoters suitable for the barrier to be penetrated are used for the formulation. Such penetration promoters are conventionally known in the art.
  • the active compounds of the present invention can be easily formulated as solid dosage forms for oral administration by combining the compounds with pharmaceutically acceptable carriers known in the art. With the use of such carriers, the compounds of the present invention can be formulated to tablets, pills, powders, granules, dragees, capsules, liquids, gels, syrups, slurries, suspensions, etc. Capsules, tablets, pills, powders and granules are advantageous, and capsules and tablets are particularly advantageous. Preferably, tablets and pills are prepared as enteric coated forms.
  • the solid dosage forms for oral administration can be obtained as follows. [349]
  • One or more compounds of the present invention are mixed with one or more ex- cipients, and the mixture is pulverized, if appropriate. Suitable adjuvants are added if necessary, and tablets or dragee cores can be obtained from the granule mixtures.
  • suitable excipients fillers such as lactose, sucrose, mannitol or sorbitol; cellulose substances such as corn starch, wheat, starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethyl cellulose and/or polyvinylpyrrolidone (PVP); etc. can be mentioned.
  • disintegrating agents such as cross-linked polyvinylpyrrolidone, agar-agar, alginic acid or its salts like sodium alginate, lubricating agents such as magnesium stearate and binding agents may be added as a carrier.
  • the oral preparations may include sealed soft capsules that are made from gelatin and plastic agents such as glycol or sorbitol, and hard gelatin capsules that are made from gelatin.
  • the hard gelatin capsules may contain the active compound as a mixture with fillers such as lactose, binding agents such as starch, and/or lubricating agents such as talc or magnesium stearate.
  • the active compound may be dissolved or dispersed in a suitable medium such as fatty acid, liquid paraffin or liquid polyethyleneglycol.
  • a stabilizing agent may be included. All formulations for oral administration may contain a suitable amount of the active compound for such administration.
  • the active compound can also be formulated as an injection preparation, such as, for example, a large pill-type injection or continuous -type injection, for parenteral administration.
  • the injection preparation may be provided in the form of an ampoule having a preservative or a unit dosage form charged in a multi-dose container.
  • the compositions may take such forms as suspensions in oily or liquefied vehicles, solutions or emulsions and may contain such components for formulations as suspending agents, stabilizing agents and/or dispersing agents.
  • the active ingredient can be a form of dry powder which is intended to be reconstructed by dissolving in sterile, pyrogen-free water prior to use.
  • the compounds of the present invention can also be formulated into suppository forms utilizing typical suppository bases such as cocoa butter or other glycerides.
  • compositions according to the present invention contain the active ingredient in an amount effective to achieve its intended purpose. More specifically, the therapeutically effective amount means the amount of the active compound effective to prolong the survival of the subject to be treated, or to prevent, alleviate or ameliorate the symptoms of the disease. A skilled artisan would be able to determine the therapeutically effective amount, particularly in light of the detailed description provided herein.
  • the active compounds of formula (1) are preferably contained in an amount of about 0.1 to 1,000 mg per unit dosage.
  • the dosage of the compounds of formula (1) depends on the prescription of a physician, taking into account such factors as body weight or age of a patient, specific nature of the disease, severity of the disease, etc. However, dosage needed for the treatment of an adult is typically from about 1 to 1,000 mg per day, depending on the intensity and frequency of the administration. When administered to an adult via intramuscular or intravenous routes, total dosage typically from about 1 to 500 mg per day will be sufficient when separately administered in a single dosage, but for some patients a higher daily dosage may be desirable.
  • the present invention further provides a method for the prevention or treatment of diseases associated with human xanthine oxidase, using a therapeutically effective amount of the compounds of formula (1), pharmaceutically acceptable salts or isomers thereof.
  • diseases associated with human xanthine oxidase mean such diseases that can be treated or prevented by inhibiting human xanthine oxidase, and they include but are not limited to hyperuricemia, gout, heart failure, cardiovascular disease, hypertension, diabetes, complications of diabetes, kidney disease, inflammation and articular disease, inflammatory bowel disease, etc.
  • hyperlipidemia, atherosclerosis, obesity, hypertension, retinosis, renal failure, etc. may be mentioned.
  • treatment means the interruption or delay of the progress of the disease when applied to a subject showing the onset of disease symptoms
  • prevention means the interruption or delay of the sign of the onset of disease when applied to a subject who does not show, but is at risk of, the onset of disease symptoms.
  • Figure 1 is a graph showing the result of measuring the uric acid concentration (mg/dl) in the plasma according to the procedure of Experiment 2 ( ** P ⁇ 0.01, *** P ⁇ 0.001: ANOVA and post Dunnet's test).
  • Figure 2 is a graph showing the result of measuring the inhibitory rate (%) for uric acid in the plasma according to the procedure of Experiment 2.
  • Figure 3 is a graph showing the result of measuring the inhibitory ability for uric acid in the liver according to the procedure of Experiment 2 (LC-MS/MS peak area).
  • Step (1) (1.23g, 3.9mmol) obtained in Step (1) was dissolved in 2OmL of pyridine, hydroxyam- moniumchloride (406mg, 5.85mmol) was added, and the mixture was stirred while being heated to reflux for 5 h. After completion of the reaction, the solvent was removed by concentration under reduced pressure, and ethyl acetate was added thereto. The mixture was washed with lN-aqueous hydrochloric acid solution. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting solid compound was washed with ethyl acetate, and dried to give 1.15g (3.51mmol, Yield 90%) of the title compound.
  • Step (1) (202mg, 0.59mmol) obtained in Step (1) was reacted according to the same procedures as Steps (1), (2), (3) of Preparation 18 to give the title compound (177mg, Yield 82%).
  • N,N-dimethylformamide, magnesium chloride 6 hydrate 14.03g, 69mmol was added, and the mixture was stirred for 10 min at room temperature.
  • reaction solution was poured to 0.1 N hydrochloric acid, which was then controlled to basic using aqueous sodium bicarbonate solution, and extracted with ethyl acetate. The organic layer was collected, and distilled under reduced pressure. The remaining substance was purified by column chromatography to give 2.06g (8mmol, Yield 94%) of the title compound.
  • Preparation 108 was added 7OmL of dichloromethane, and the mixture was cooled to O 0 C. 3-chloroperoxybenzoic acid (70%, 3.94g, l ⁇ mmol) was slowly added, and the mixture was warmed to room temperature and stirred for 48 h. After completion of the reaction, dichloromethane was added, and the mixture was washed with aqueous sodium bicarbonate solution. The organic layer was distilled under reduced pressure, and the remaining substance was purified by column chromatography to give 1.98g (7.22mmol, Yield 90%) of the title compound.

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Abstract

La présente invention concerne de nouveaux composés qui sont efficaces en tant qu'inhibiteur de la xanthine oxydase, leur procédé de préparation et une composition pharmaceutique comportant une quantité efficace desdits composés.
PCT/KR2010/000893 2009-02-13 2010-02-12 Nouveaux composés efficaces en tant qu'inhibiteurs de xanthine oxydase, leur procédé de préparation et composition pharmaceutique les contenant Ceased WO2010093191A2 (fr)

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