WO2004026832A1 - Compose d'uree et utilisation de celui-ci - Google Patents

Compose d'uree et utilisation de celui-ci Download PDF

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WO2004026832A1
WO2004026832A1 PCT/JP2003/011907 JP0311907W WO2004026832A1 WO 2004026832 A1 WO2004026832 A1 WO 2004026832A1 JP 0311907 W JP0311907 W JP 0311907W WO 2004026832 A1 WO2004026832 A1 WO 2004026832A1
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amino
group
phenyl
compound
methyl
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PCT/JP2003/011907
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English (en)
Japanese (ja)
Inventor
Yoshihiro Sugihara
Shinichi Imamura
Naoyuki Kanzaki
Yuji Iizawa
Masanori Baba
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Takeda Pharmaceutical Company Limited
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Priority to AU2003266529A priority Critical patent/AU2003266529A1/en
Publication of WO2004026832A1 publication Critical patent/WO2004026832A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
    • C07D211/24—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by sulfur atoms to which a second hetero atom is attached
    • 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
    • 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
    • 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
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic 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
    • 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
    • A61P7/08—Plasma substitutes; Perfusion solutions; Dialytics or haemodialytics; Drugs for electrolytic or acid-base disorders, e.g. hypovolemic shock
    • 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
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms

Definitions

  • the present invention relates to a urea compound useful for treating acquired immunodeficiency syndrome and its use.
  • HIV human immunodeficiency virus
  • protease inhibitors have been developed as a treatment for AIDS (acquired immunodeficiency syndrome), and combined with two previously used HIV reverse transcriptase inhibitors, Although treatment for DS has progressed significantly, it is still not enough to eradicate AIDS, and the development of new anti-AIDS drugs based on another mechanism of action is desired.
  • CD4 has long been known as a receptor for HIV entry into target cells, but recently a macrophage-directed HIV second receptor, called CCR5, has a seven-transmembrane form.
  • CCR5 macrophage-directed HIV second receptor
  • a G-protein-coupled chemokine receptor, Yuichi has been discovered, and it is thought that this chemokine receptor plays an essential role in the establishment and transmission of HIV infection.
  • CCR5 antagonists are expected to be new anti-HIV drugs.
  • chemokine receptor antagonists include piperidine derivatives (see, for example, Patent Document 1, Patent Document 2, Patent Document 3, Patent Document 4, and Patent Document 5), ureidoalkyl piperidine derivatives (for example, Patent Document 6, Patent Document 7), cyclic amide derivatives (for example, see Patent Document 8), cyclic amine derivatives (for example, see Patent Document 9), and urea derivatives (for example, see Patent Document 10) are known.
  • CCR5 antagonists being launched as a treatment for AIDS.
  • Prior art document information related to the invention of this application includes the following.
  • Patent Document 1 International Publication No. WO 99/04794 pamphlet
  • Patent Document 2 WO 99/38514 pamphlet
  • Patent Document 3 WO 00/39125 pamphlet
  • Patent Document 4 WO 00/66558 pamphlet
  • Patent Document 5 WO 00/66559 pamphlet
  • Patent Document 6 WO 00/35451 pamphlet
  • Patent Document 7 International Publication No. 01/98269 pamphlet
  • Patent Document 8 International Publication No. 00/66551 pamphlet
  • Patent Document 9 International Publication No. 01/25200 pamphlet
  • Patent Document 10 WO 01/25199 pamphlet Disclosure of the invention
  • the CCR5 gene is cloned from a human tissue-derived cDNA library, ligated to an animal cell expression vector, and introduced into animal cells to express CCR5. You need to obtain a cell line. This transformed cell line must then be used to screen for compounds that strongly inhibit the binding of the natural ligand CC chemokine RANTES to CCR5.
  • the present inventors have conducted intensive studies on compounds having CCR5 antagonistic activity, particularly urea derivatives and their structural analogs described in WO01 / 25199, and as a result, a compound represented by the following general formula (I) or a salt thereof was It has excellent CCR 5 antagonism, is useful as a preventive and therapeutic agent for HIV infection of human peripheral blood mononuclear cells, especially AIDS, and is metabolically stable and has excellent oral absorption.
  • the present invention was completed based on this.
  • R 1 represents halogen, one may be substituted by halogen alkyl, a Shiano or a 4 good phenylene Le group optionally having a Arukiruokishi as _ 8 alkyl group or a substituted group
  • R 2 the formula: - S0 2 NR 3 R 4 (wherein, R 3 is hydrogen atom or - C'i having 6 alkyl group, R 4 is a hydroxyl group as a substituent, any force Rupokishiru group or force Rubamoiru group May represent an alkyl group, or R 3 and R 4 may combine with each other to form a nitrogen-containing heterocyclic group having a hydroxyl group, a sulfoxyl group or a sulfamoyl group as a substituent together with a nitrogen atom; .) a group represented by or the formula: a s (o) m - W- Y ( wherein, Y represents a hydroxyl group, a carboxyl group
  • a halogen as R 1 is a substituted group
  • a halogen-substituted _ 4 may ⁇ alkyl
  • Shiano or a 4 Arukiruokishi Ru good phenyl group der may have the (1) compound according
  • R 2 has the formula: - S0 2 NR 3 R 4 ( provided that, R 3 is a hydrogen atom or - a 4 ⁇ alkyl group, R 4 is a hydroxyl group as a substituent, any force Rupokishiru group or force Rubamoiru group _ 4 represents an alkyl group having, or R 3 and R 4 hydroxyl group as a substituent together with the bond to the nitrogen atom, may form a nitrogen-containing heterocyclic group having any force Rupokishiru group or force Rubamoiru group the compounds of the group represented by good O) above (1), wherein,
  • R 2 has the formula: _S— W, — Y (where W ′ is optionally substituted with methyl C
  • composition according to the above (7) which is a CC chemokine receptor antagonist
  • composition according to the above (7) which is a CCR 5 antagonist
  • composition according to the above (7) which is a therapeutic agent for HIV infection.
  • composition according to the above ( ⁇ ), which is an agent for preventing or treating AIDS is an agent for preventing or treating AIDS.
  • composition according to the above (7) which is an AIDS disease progression inhibitor
  • composition according to the above (7) which is a blood or a blood product for transfusion
  • composition according to (7) which is an agent for preventing or treating graft-versus-host disease and Z or rejection during organ or bone marrow transplantation.
  • composition according to the above (7) which is a preventive / therapeutic agent for rheumatoid arthritis, an autoimmune disease, an allergic disease, ischemic brain cell injury, myocardial infarction, nephritis, nephropathy or arteriosclerosis.
  • HIV infection treatment HIV prevention and treatment, AIDS disease progression inhibitor, graft-versus-host disease during organ or bone marrow transplantation and prevention or treatment of Z or rejection, or chronic Rheumatoid arthritis, autoimmune disease, allergic disease, ischemia
  • the ⁇ E _ 8 alkyl group represented by R 1 for example methyl, E Ji Le, n- propyl, i one propyl, n- butyl, i- butyl, s- butyl, t-Bed chill, n-pentyl, i-pentyl, t-pentyl, neopentyl, n-hexyl, i-hexyl, n-heptyl and n-octyl, among which methyl, ethyl, propyl, etc. Four are preferred.
  • halogen optionally substituted by _ 4 alkyl, Shiano or 4 a phenyl group which may have a Arukiruokishi", with substituents phenylene Le group there the halogen such as fluorine, chlorine, bromine, and iodine, as the _ 4 alkyl optionally substituted by halogen, for example fluorine, chlorine, bromine, optionally substituted with a halogen such as iodine _ 4- alkyl (eg, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, etc.), and the like.
  • 4- alkyloxy include methyloxy, ethyloxy, n-propyloxy, i monopropyloxy, n-butyloxy, i-butyloxy and the like.
  • the —6 alkyl group represented by R 3 includes, for example, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, i-pentyl, t one pentyl, neopentyl, hexyl n-, like key sill can be mentioned to i one, represented by R 4 "hydroxyl group as a substituent, or force Rupokishiru group has any force Rubamoiru group - 6 alkyl group" in _ 6 alkyl groups include, for example, methyl, ethyl, n-propyl, i-propyl, n-butyl.
  • N-containing heterocyclic group in the ⁇ nitrogen-containing heterocyclic group having any one of a hydroxyl group, a carboxyl group, and a carbamoyl group as a substituent together with a nitrogen atom '' include, for example, azetidinyl, pyrrolidinyl, piberidinyl, homopiperidinyl, 3- to 8-membered (preferably 4- to 6-membered) saturated or unsaturated (preferably saturated) non-aromatic heterocyclic groups (aliphatic heterocyclic groups) such as heptamethyleneimino, morpholinyl, thiomorpholinyl, piperaziny
  • (E _ 4 alkyl-substituted _ 4 may be an alkylene group with a group" -
  • the salt of the compound represented by the formula (I) of the present invention is preferably a pharmacologically acceptable salt, for example, a salt with an inorganic base, a salt with an organic base, a salt with an inorganic acid, or an organic compound.
  • a salt with an inorganic base examples include salts with acids, salts with basic or acidic amino acids, and the like.
  • the salt with an inorganic base include, for example, alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; and aluminum salt, ammonium salt and the like.
  • Preferred examples of the salt with an organic base include, for example, salts with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, ⁇ , ⁇ '-dibenzylethylenediamine and the like.
  • Preferable examples of the salt with an inorganic acid include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, and the like.
  • salts with organic acids include, for example, formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, ⁇ ⁇ ⁇ ⁇ - Salts with toluenesulfonic acid and the like can be mentioned.
  • Preferable examples of the salt with a basic amino acid include, for example, salts with arginine, lysine, orditin and the like.
  • Preferred examples of the salt with the acidic amino acid include, for example, aspartic acid, glutamic acid, and the like. And salts thereof.
  • the compound represented by the formula (I) of the present invention may be a hydrate or a non-hydrate.
  • Compound (I) is an isotope (eg, 3 H, 1 4 C, 3 5 S, 1 such as 2 5 I) may be labeled with a.
  • each can be isolated by a separation / purification means known per se, if desired.
  • the compound (I) may have one or more asymmetric carbon atoms in the molecule, but when these compounds are in a racemic form, the (S) form can be obtained by ordinary optical resolution.
  • And (R) -isomers, and each of the optically active isomers and racemic isomers is included in the present invention.
  • the compound represented by the formula (I) or a salt thereof, which is used in the present invention [hereinafter, may be referred to as compound (I).
  • I a compound that is converted into compound (I) by a reaction with an enzyme or stomach acid under physiological conditions in vivo, that is, Originally, a compound which undergoes hydrolysis or the like to change to the compound (I), or a compound which undergoes hydrolysis or the like due to stomach acid or the like to change to the compound (I).
  • Examples of the prodrug of compound (I) include compounds in which the amino group of compound (I) is acylated, alkylated, or phosphorylated (eg, the amino group of compound (I) is eicosanoylated, alanylated, pentylamino).
  • the prodrug of compound (I) is compounded under physiological conditions as described in Hirokawa Shoten, 1990, “Development of Drugs,” Volume 7, Molecular Design, pp. 163-198. It may change to the object (I).
  • the prodrug of compound (I) may be itself or a pharmacologically acceptable salt.
  • salts include inorganic bases (eg, alkali metals such as sodium and potassium, alkaline earth metals such as calcium and magnesium, zinc) when the prodrug of compound (I) has an acidic group such as a carboxy group. , Iron, copper and other transition metals) and organic bases (eg, trimethylamine, triethylamine, pyridine, picolin, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N, N'— And salts with organic amines such as dibenzylethylenediamine, and basic amino acids such as arginine, lysine and ordinine.
  • inorganic bases eg, alkali metals such as sodium and potassium, alkaline earth metals such as calcium and magnesium, zinc
  • iron, copper and other transition metals eg, copper and other transition metals
  • organic bases eg, trimethylamine, triethy
  • the prodrug of compound (I) has a basic group such as an amino group, an inorganic acid or an organic acid (eg, hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, carbonic acid, bicarbonate, formic acid, acetic acid, propionic acid, trifluoroacetic acid) , Fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc.), and salts with acidic amino acids such as aspartic acid, glutamic acid, etc. Is mentioned. Further, the prodrug of compound (I) may be either a hydrate or a non-hydrate.
  • an inorganic acid or an organic acid eg, hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, carbonic acid, bicarbonate, formic acid
  • Compound (I) can be produced, for example, by the method shown below.
  • the compound used in each of the following production methods may form a salt similar to compound (I) as long as the reaction is not hindered.
  • a protecting group generally used in peptide chemistry or the like is introduced into these groups.
  • the target compound can be obtained by removing the protecting group as necessary after the reaction.
  • the protecting group of the Amino group may have a substituent _ 6 alkyl Karuponiru (e.g., Asechiru, propionyl, etc.), formyl, phenylene Rukarupo nil. ⁇ 6- alkyloxycarbonyl (eg, methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, etc.), phenyloxycarbonyl (eg, benzoxycarbonyl, etc.), C 7 _! 0 Aralkyloxycarbonyl (for example, benzyloxycarbonyl), triter, phthaloyl and the like are used.
  • a substituent _ 6 alkyl Karuponiru e.g., Asechiru, propionyl, etc.
  • formyl e.g., Asechiru, propionyl, etc.
  • phenylene Rukarupo nil. ⁇ 6- alkyloxycarbonyl eg, meth
  • substituents examples include halogen atom (e.g., fluorine, chlorine, bromine, etc. iodine), - 6 alkyl Cal Poni Le (e.g., Asechiru, propionyl, etc. Puchiriru) and nitro groups, the number of substituents About 1 to 3 pieces.
  • halogen atom e.g., fluorine, chlorine, bromine, etc. iodine
  • - 6 alkyl Cal Poni Le e.g., Asechiru, propionyl, etc. Puchiriru
  • nitro groups the number of substituents About 1 to 3 pieces.
  • an optionally substituted substituent such as 6- alkyl (eg, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl), phenyl, trityl, silyl, etc. are used.
  • substituents include halogen atom (e.g., fluorine, chlorine, bromine, iodine), (: E _ 6 alkylene Rukaruponiru (e.g., Asechiru, propionyl, etc. Puchiriru), formyl, such as a secondary preparative port group is used
  • the number of substituents is about 1 to 3.
  • Examples of the protecting group for the hydroxy group include, for example, an optionally substituted substituent such as 6 -alkyl (for example, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, etc.), phenyl, and C 7 -phenyl.
  • 6 -alkyl for example, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, etc.
  • phenyl and C 7 -phenyl.
  • Ararukiru e.g., benzyl, etc.
  • Rukirukaruponiru e.g., Asechiru, propionyl, etc.
  • formyl phenyl O alkoxycarbonyl, C 7 _!
  • Aralkyloxycarponyl eg, benzyl xycarponyl, etc.
  • pyranyl fluel, silyl and the like are used.
  • substituents include a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), C
  • the removal method is, for example, acid, base, reduction, ultraviolet light, hydrazine, phenylhydrazine, N-methyldithiocarpamine
  • a method of treating with sodium acid, tetrabutylammonium fluoride, palladium acetate or the like is used.
  • the compounds represented by the formulas (I), (II), (V), (VII) and (VIII) include the compounds (I), ( ⁇ ), Compound (V), compound (VII) and compound (VIII).
  • the compounds represented by the formulas (III), (IV), (VI) and (IX) may be simply referred to as compound (III), compound (IV), compound (VI) and compound (IX), respectively. .
  • compound (I) can be produced by reacting compound (II) with compound (III).
  • This reaction is usually performed in a solvent inert to the reaction.
  • the solvent include ether solvents (eg, ethyl ether, diisopropyl ether, dimethoxy ether). , Tetrahydrofuran, dioxane, etc.), halogenated solvents (eg, dichloromethane, dichloroethane, chloroform, etc.), aromatic solvents (eg, toluene, benzene, xylene, etc.), acetonitrile, NN-dimethylformamide (eg, DMF), acetone, methyl ethyl ketone, dimethyl sulfoxide (DMSO), water, etc. can be used alone or in combination.
  • ether solvents eg, ethyl ether, diisopropyl ether, dimethoxy ether
  • halogenated solvents eg, dichloromethane,
  • This reaction is generally carried out by reacting compound (III) with 1 to 5 equivalents, preferably 1 to 3 equivalents, of compound (II).
  • the reaction temperature is from ⁇ 20 ° C. to 50 ° C., preferably from 0 ° C. to room temperature, and the reaction time is usually from 5 minutes to 100 hours.
  • the reaction may proceed more smoothly by coexisting a base.
  • the base both inorganic bases and organic bases are effective.
  • inorganic bases include hydroxides, hydrides, carbonates, hydrogencarbonates of alkali metal alkali earth metals, among which potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide Preferred are sodium hydrogen carbonate and potassium hydrogen oxy.
  • Tertiary amines such as triethylamine are preferred as the organic base.
  • the compound (II) used in this method can be produced, for example, by the method described in Synthetic Comm., 1991 20, 3167-3180. That is, it can be produced by the following method utilizing an addition reaction of an amine to an unsaturated bond.
  • the base examples include 1) a strong base, for example, a hydride of an alkali metal or an alkaline earth metal (eg, lithium hydride, sodium hydride, potassium hydride, calcium hydride, etc.), an alkali metal or an alkaline earth metal Amides (eg, lithium amide, sodium amide, lithium diisopropylamide, lithium dicyclohexylamide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide, etc.) Or lower alkoxides of alkaline earth metals (eg, sodium methoxide, sodium ethoxide, potassium t-butoxide, etc.) 2) Inorganic salts such as water of alkaline metal or alkaline earth metal Oxides (eg, sodium hydroxide, potassium hydroxide, hydroxide Titanium, ⁇ -barium oxide, etc.), alkali metal or alkaline earth metal carbonates (eg
  • a reducing agent can be used or a catalytic reduction method can be used.
  • the reducing agent include sodium borohydride, lithium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride and the like.
  • the amount of these reducing agents to be used is generally 1 to 10 equivalents, preferably 1 to 4 equivalents, relative to compound (VII).
  • the reaction temperature is from 120 to 50 ° (: preferably from 0 ° C to room temperature, and the reaction time is from 0.5 to 24 hours.
  • the catalytic reduction method uses a catalytic amount of a metal catalyst such as Raney nickel, platinum oxide, metallic palladium, palladium monocarbon and an inert solvent (eg, methanol, ethanol, It can be obtained by reacting at room temperature to 100, hydrogen pressure of 1 to 100 atm and room temperature to 100 atm for 1 to 48 hours.
  • a metal catalyst such as Raney nickel, platinum oxide, metallic palladium, palladium monocarbon and an inert solvent (eg, methanol, ethanol, It can be obtained by reacting at room temperature to 100, hydrogen pressure of 1 to 100 atm and room temperature to 100 atm for 1 to 48 hours.
  • the compound (V) used in this method can be synthesized by a known general method.
  • compound (I) can be produced by reacting compound (IV) with compound (V).
  • This reaction is usually performed in a solvent inert to the reaction.
  • a solvent an alcohol solvent, an ether solvent, a halogen solvent, an aromatic solvent, acetonitrile, ⁇ , ⁇ -dimethylformamide (DMF), acetone, methyl ethyl ketone, dimethyl sulfoxide (DMS0) or the like may be used alone or in combination. Can be used in combination. Of these, acetonitrile, dimethylformamide, acetone, ethanol and the like are preferable.
  • the reaction temperature is usually from room temperature to 10Ot: preferably from room temperature to 50 ° C, and the reaction time is usually from 0.5 to 1 day. This reaction is usually, but not always, required to add 1 to 3 equivalents of the base to the compound (IV).
  • the base the base used in the reaction between compound (II) and compound (III) can be used.
  • Compound (IV) used as a starting material in this reaction can be synthesized by a known general method using compound (III) as a starting material.
  • Compound (I) can be produced by reacting a compound represented by formula (IX) with a compound represented by formula (V) under reducing conditions as shown in the following formula.
  • compound (IX) and compound (V) are usually required in an appropriate solvent (eg, water, alcohol, ether, halogen, acetonitrile, a mixed solvent of two or more of these).
  • an appropriate solvent eg, water, alcohol, ether, halogen, acetonitrile, a mixed solvent of two or more of these.
  • the reaction is carried out in the presence of 1 to 5 equivalents, preferably 1 to 1.5 equivalents of a reducing agent by adding an acidic substance such as acetic acid or trifluoroacetic acid.
  • the method described in Production Method 1 can be used for the reducing agent and other conditions.
  • Compound (IX) used as a raw material in this reaction can be produced by a known general method using compound (III) as a raw material.
  • the compounds produced by the methods analogous thereto or the above-mentioned production method 1-3 as a starting material, producing a compound (I) Te cowpea its substituent conversion can do.
  • a known general method is used for the substituent conversion. Conversion of groups.
  • the compound (I) having a hydroxy group in the substituent R 2 the compound is produced by the above production method 1 to 3 or a method analogous thereto in a form in which the hydroxy group is protected, and then the protective group is added.
  • the compound (I) can be produced by removing.
  • a known general protecting group can be used, and a method for removing the protecting group can be performed by a known general method.
  • the compound (I) of the present invention has an excellent CCR antagonism, particularly a strong CCR5 antagonism, the compound (I) is a prophylactic / therapeutic agent for HIV infections in humans, such as AIDS.
  • the compound (I) of the present invention has low toxicity and can be used safely.
  • the above compound (I) can be used alone or in a pharmaceutical composition in combination with a pharmaceutically acceptable carrier, for example, a solid preparation such as tablets, capsules, granules and powders; or a liquid preparation such as syrups and injections. It can be administered orally or parenterally as a formulation.
  • a pharmaceutically acceptable carrier for example, a solid preparation such as tablets, capsules, granules and powders; or a liquid preparation such as syrups and injections. It can be administered orally or parenterally as a formulation.
  • Parenteral administration forms include injections, infusions, suppositories, vaginal suppositories, and the like. In particular, vaginal suppositories are useful for prevention of HIV infection.
  • Pharmaceutically acceptable carriers include various organic or inorganic carrier substances commonly used as pharmaceutical materials, such as excipients, lubricants, binders, and disintegrants in solid preparations; solvents and dissolution aids in liquid preparations. Formulation, suspending agent, tonicity agent, buffering agent, soothing agent, etc. If necessary, pharmaceutical additives such as preservatives, antioxidants, coloring agents and sweeteners can be used.
  • the excipient include lactose, sucrose, D-mannitol, starch, crystalline cellulose, light caffeic anhydride and the like.
  • Preferred examples of the lubricant include, for example, magnesium stearate, calcium stearate, talc, colloidal silica and the like.
  • Preferred examples of the binder include crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone and the like.
  • Preferred examples of the disintegrant include starch, carboxymethylcellulose, carboxymethylcellulose calcium, croscarmellose sodium, sodium carboxymethylsulfate and the like.
  • Preferable examples of the solvent include water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil and the like.
  • solubilizing agent examples include, for example, polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate and the like. Is mentioned.
  • Preferred examples of the suspending agent include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, and glycerin monostearate; Examples include hydrophilic polymers such as polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, and hydroxypropylcellulose. Suitable examples of the tonicity agent include, for example, sodium chloride, glycerin, D-mannitol and the like.
  • Preferred examples of the buffer include buffer solutions such as phosphate, acetate, carbonate, and citrate.
  • Preferred examples of the soothing agent include, for example, benzyl alcohol And the like.
  • Preferred examples of preservatives include, for example, esters of paraoxybenzoic acid, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, and sorbic acid.
  • Suitable examples of the antioxidant include, for example, sulfite, ascorbic acid and the like.
  • a pharmaceutical composition containing the compound (I) of the present invention can be used as a CCR5 antagonist, for example, an AIDS prophylactic or therapeutic agent and an AIDS disease progression inhibitor.
  • the compound (I) of the present invention may be used in combination with other prophylactic / therapeutic agents for HIV infectious diseases (in particular, prophylactic / therapeutic agents for AIDS).
  • these drugs can be formulated separately or simultaneously and mixed with pharmacologically acceptable carriers, excipients, binders, diluents, etc., to prevent or treat HIV infection. It can be administered orally or parenterally as a pharmaceutical composition.
  • the separately formulated ones can be mixed and administered using a diluent at the time of use, but the separately formulated individual products can be administered simultaneously or with a time lag. And may be administered separately to the same subject.
  • kits product for administering separately formulated products using a diluent or the like at the time of use for example, an ampoule containing a powdered individual drug and two or more drugs mixed at the time of use and dissolved Kit products for administration of the same formulation to the same subject at the same time or separately at different times, such as injection kits containing diluents for Tablets in the same or separate bags and, if necessary, a column for the time of drug administration is provided.
  • kits for administering two or more tablets simultaneously or separately with a time lag. Kits are also included in the pharmaceutical composition of the present invention.
  • prophylactic / therapeutic agents for HIV infection used in combination with the compound (I) of the present invention include zidovudine, didanosine, and zalci tabine.
  • Lamivudine Lamivudine (l amivudine), stavudine (s tavudine), abavirvir (abacavir), adefovir (adefovir), adefovir dipipoxyle adefovir dipivoxil
  • Nucleic acid reverse transcriptase inhibitors such as: nevirapine (nevi rapine), delahiriresino (delavi rdine), efavirenz (efavi renz),
  • Antioxidant activity such as non-nucleic acid reverse transcriptase inhibitors such as oral viride (loviride), imnocal (istitute Un
  • zidovudine zidovudine
  • didanosine didanosine
  • zalcitabine zalcitabine
  • lamivudine lamivudine
  • stavudine stavudine
  • nevirapine nevirapine
  • aravirirezine delavirdine
  • efavirenz efavirenz efavirenz
  • the compound (I) of the present invention may be, for example, an antagonist of CXCR4, which is a second receptor for T cell-directed HIV-1, in addition to the above-mentioned protease inhibitor, nucleic acid reverse transcriptase inhibitor and the like (eg, AMD — 3100), can be used in combination with antibodies against HIV-1 surface antigens and HIV-1 vaccines.
  • the daily dose of Compound (I) varies depending on the condition and weight of the patient, and the method of administration.
  • the dose of the reverse transcriptase inhibitor or the protease inhibitor is, for example, about 1 / It is appropriately selected within the range of 200 to 1/2 or more and about 2 to 3 times or less.
  • the dose of each drug is appropriately adjusted. The dose at the time of single drug administration is used. Typical dosages of typical reverse transcriptase inhibitors and protease inhibitors are eg It is as shown below.
  • a pharmaceutical composition containing the compound (I) of the present invention can be used as a preventive or therapeutic agent for graft-versus-host disease and Z or rejection, rheumatoid arthritis, autoimmune disease, allergic disease, ischemic brain. It can be used as a preventive / therapeutic agent for various disorders such as cell damage, myocardial infarction, chronic nephritis and arteriosclerosis.
  • the diseases targeted by the above preventive and therapeutic agents of the present invention include, for example, graft rejection (rejection after transplantation, erythrocytosis after transplantation, hypertension, organ disorders, vascular hypertrophy, graft versus host disease, etc. ), Arthritis bone diseases such as meningitis, etc.
  • the dose of the pharmaceutical composition of the present invention can be appropriately selected depending on the administration subject, age and weight of the administration subject, symptoms, administration time, administration method, dosage form, and the like.
  • the dosage for a particular patient will depend on age, weight, general health, gender, diet, time of administration, mode of administration, rate of excretion, and the extent of the condition the patient is treating at the time. The decision is made in consideration of these and other factors.
  • the pharmaceutical composition containing the compound (I) of the present invention varies depending on the kind of the target disease, but may be used in combination with another drug.
  • other drugs include, for example, HDL enhancers [squalene synthase inhibitors, CETP inhibitors, LPL activators, etc.], NMG-CoA reductase inhibitors: seribas-utin, Atoguchi bath Evening Chin, Prabas Evening Chin, Simbas Evening Chin, Itabasu Evening Chin, Mouth Bath Evening Chin, Full Bath Evening Chin, (+)-3R, 5S-7- [4- (4-Fluorophenyl) -6f 2- (N-methyl N-methanesulfonylamino) pyrimidine-5-yl] _3,5-dihydroxy-6 (E) monoheptenoic acid, etc.
  • Atopic dermatitis drug [Sodium cromoglycate] And allergic rhinitis treatment [sodium cromoglycate, chlorpheniramine maleate, alimemazine tartrate, clemastine fumarate, homochlor cyclidine hydrochloride, terfenadine, mequitazine, etc.], imidenem shirasu Evening sodium, endotoxin antagonist or antibody, oxidized squalene-lanosterol cyclase [eg decalin derivative, azaderic phosphorus derivative and indane derivative], calcium antagonist (diltiazem etc.), glycerol, cholinesterase inhibitor (eg, Alicebut (donebezil), a compound that suppresses cholesterol absorption [eg, sitosterol and neomycin, etc.], a compound that inhibits cholesterol biosynthesis [eg, oral bath, simbas, pravas HM G—Co A reducing enzyme inhibitors], cyclohexoxy
  • liver diseases include glycyrrhizin preparations [eg, strong minophagen, etc.], liver hydrolyzate, SH compounds [eg, daltathione, etc.], special amino acid preparations [eg, aminolevan, etc.], phospholipids [eg, PO Lin phosphatidylcholine, etc.], vitamins [e.g., vitamin, B 2, B 6, 2 , C , etc.], Adrenocortical hormones [eg, dexamezozone, betamethasone, etc.], interferon [eg, interferon, etc.] 3, etc., drugs for treating hepatic encephalopathy [eg, lactu
  • vasodilators [oxifedrin, diltiazem, tolazoline, hexobendine, bamethane, clonidine, methyldopa, guanabenz, etc.], vasoconstrictors [dopamine, doptamine denopamine, etc.], platelet aggregation Inhibitors (such as ozadarrel), Antithrombotic and therapeutic agents: anticoagulants [eg, heparin sodium, heparin calcium, perhalin calcium (perfurin), Xa inhibitor], thrombolytics [eg, tPA, perokinase], anti- Platelet drug [eg, ass Pilin, sulfinpyrazone (anlan), dipyridamole (persantin), ticlovidine (panaldine), cilostazol (pletal), GPII b / II
  • Ia antagonist (Leopro)]
  • antidepressant [imipramine, clomipramine, noxiptilin, phenelzine, amitriptyline hydrochloride, nortriptyline hydrochloride, amoxapine, mianserin hydrochloride, maprotiline hydrochloride, sulpiride, alpoxamine maleate, trazodone hydrochloride, etc.
  • Antiepileptic drugs [Gyabapentin, phenytoin, ethosuximide, acesuximide, chlorezazepoxide, trimetadione, kylarva mazepine, phenovalpital, primidone, sultiam, sodium parbroate, clonazepam, diazepam, nitrazepam, etc.]
  • Allergic drugs [diphenhydramine, chlorpheniramine, triberenamine, methdilamine, clemizole, diphenylpyralin, methoxyphenamine, cromoglycic acid Thorium, tranilast, repirinast, amlexanox, ibudilast, ketotifen, terfenadine, mequitazine,fugstine, epinastine, ozadarrel hydrochloride, pranlukast hydrate, seratrodust, fexofenadine,
  • Antifungals [(i) polyethylene antibiotics (eg, amphotericin 8, nice quintin, tricomycin), (ii) glycemic (Iii) cytosine antimetabolites (eg, flucytosine, (iv) imidazole derivatives (eg, econazole, clotrimazole, miconazole nitrate, pifonazole, croconazole) such as fluvin and pyrrole ditolin; (V) Triazole derivatives (eg, fluconazole, itraconazole, azole compounds [2-[(1R, 2R) -2- (2,4-difluorophenyl) -1-2-hydroxy-1-methyl-3- ( 1 H _ 1, 2,4 _triazol-1-yl) propyl] 1 4— [4 1 (2,2,3,3-tetrafluoropropoxy) phenyl— 3— (2H, 4 H) -1,2,4-triazolone
  • Antipsychotics [chlorpromazi hydrochloride , Prochlorperazine, trifluoroperazine, thioridazine hydrochloride, perphenazine maleate, fluphenazine enanthate, prochlorperazine maleate, lepomepromazine maleate, promethazine hydrochloride, haloperidol, properidol, spiperone, reserpine, chlorcapramine Sulpiride, zotepine, etc.), anti-ulcer drugs [metaclopromide, histidine hydrochloride, lansoprazole, metoclopramide, pirenzepine, cimetidine, ranitidine, famotidine, ⁇ rogastrine, oxesazein, proglumide, omebrazole, sucralphate sulphate sulphate sulphate sulpharthur sulphate sulphate sulphate
  • Anti-asthmatic drugs [Isoprenaline hydrochloride, salbutamol sulfate, propotanol hydrochloride, terbutaline sulfate, trimethoxynol hydrochloride, rlobbuterol hydrochloride, orciprenaline sulfate, phenothrol hydrobromide, efuedrine hydrochloride, iprotropium bromide , Platinum fluodium, Fium fluodium bromide, Theophylline, Aminophylline, Sodium cromoglycate, Tranilast, Repirinast, Amlexanox, Ibudilast, Ketotiff , Terfenadine, mexidin, alastin, epinastine, ozadarel hydrochloride, pranlukast hydrate, serratrodast, dexamethasone, prednisolone, hydrocortisone, veclo
  • vasodilators [calcium channel antagonists (e.g., manidipine, Two Karujipin, Two Rubajipin, Two Sorujipin, nitrendipine, Beni adipic, amlodipine, etc.
  • phthalazine derivatives e.g., Budoraraji Iii
  • ACE inhibitors [alasepril, captopril, cilazapril, delapril, enalapril, lisinopril, temocapril, trandolapril, quinapril, imidabril, benlabril ⁇ ⁇ , etc.
  • AII antagonists oral sultan, force desartan, valsartan, telmisartan, irbesartan, forasartan, etc.]
  • diuretics for example, the above diuretics etc.
  • antihypertensive drugs diuretics [ For example, furosemide (Rasix), bumetaed (Lunetron), azosemide (Diaart)], antihypertensive drugs [eg, ACE inhibitors, (enalapril maleate (renipace), etc.)
  • calcium preparations eg, calcium carbonate etc.
  • calcitonin preparations the active vitamin D 3 preparations (e.g., such as alfacalcidol (Alfarol), calcitriol (mouth cull trawl), etc.)
  • sex hormones e.g., estrogens, Esutoranjio Ichiru etc.
  • hormones formulation example, conjugated estrogen (Premarin), etc. such Osten) Ivry flavone formulation, vitamin K 2, vitamin kappa 2 formulation example, Menate Bok Lennon (cod cable), etc.]
  • bisphosphonic acid-based formulations such as Echidoroneto; ), Prostaglandin ⁇ 2, fluorine compounds (eg, sodium fluoride, etc.), bone formation protein (BMP), wire Fibroblast growth factor (FGF), platelet-derived growth factor (PDGF), transforming follower one timing growth factor (TGF
  • Inotropic drugs eg digitoxin
  • Digoxin Digoxin
  • methyldigoxin methyldigoxin
  • lanatoside C prossilaridine, etc.
  • a stimulants eg, epinephrine, norlepinephrine, isoproterenol, dopamine, docarpamine, dobutamine, denopamine
  • phosphodiesterase inhibitors eg, , Amrinone, milrinone, olprinone hydrochloride, etc.
  • Calcium channel sensitivity enhancers eg, pimoventan, etc.
  • nitrates eg, nitroglycerin, isosorbide dinitrate, etc.
  • ACE inhibitors eg, the above ACE inhibitors, etc.
  • diuretics Formula example, the above diuretics
  • carperitide ubidecarenone, vesnarinone, aminophylline, etc.
  • neurotrophic factor eg.
  • Isujirin acid brain function enhancers (eg, Idebe non, Vinpocetine, etc.), Urinary and male genital disorders: [Examples: Prostate hypertrophy treatments (such as mucus mouth hydrochloride, prazosin hydrochloride, chrommadinone acetate), prostate cancer treatments (reuprorelin acetate, goserelin acetate, chlormadinone acetate)
  • Non-steroidal anti-inflammatory drugs [acetoaminophen, phenacetin, ethenzamide, sulpyrine, antipyrine, migrenine, aspirin, mefenamic acid, flufenamic acid, diclofenac sodium, loxoprofen sodium, fenilbutazone, indomestic evening Syn, ibuprofen, ketoprofen, ketoprofen, naproxen, oxaprozin, flurpiprofen, fenbufen, pranoprof
  • Hemp Intoxicants [a. Local anesthetics [cocaine hydrochloride, proforce hydrochloride, lidocaine, dibu hydrochloride power-in, te small labourin hydrochloride, mepiva-force hydrochloride, bupiva-force hydrochloride, oxybium hydrochloride pro-in, aminobenzoic acid Etc.], b.
  • Anesthetic antagonists [levalorphan, nalorphine, naloxone or a salt thereof], drugs for chronic heart failure: inotropic drugs [eg, cardiac glycosides (digoxin, etc.), jS receptor stimulants (denovamin, dobu yumin, etc.) Catecholamine preparations) and PDE inhibitors etc.), diuretics [eg, flosemid (Lasix), spironolactone (aldactone), bumeyumid (Luneto mouth), azosemide (diart), etc.], ACE inhibitors, [examples , Enala prill maleate (Renibeis) etc.], Ca antagonist [eg, amlodipine, ma Nisipin etc.) and immunomodulatory drugs such as jS receptor blockers [cyclosporine, evening crolimus, guslimus, azathioprine, anti-lymph serum, dried sulfonated immunoglobulin,
  • drugs can be formulated separately or simultaneously and mixed with pharmacologically acceptable carriers, excipients, binders, diluents and the like, and administered orally or parenterally.
  • the separately formulated ones can be mixed with a diluent at the time of use and administered, but the individually formulated separately can be administered simultaneously or with a time lag. And may be administered separately to the same subject.
  • Kit products for administering separately formulated products using a diluent or the like at the time of use for example, mixing an ampoule containing individual powdered drugs with two or more drugs at the time of use
  • Kit products for the administration of the same formulation to the same subject at the same time or separately at different times such as injection kits containing diluents for dissolution, etc.
  • injection kits containing diluents for dissolution, etc. Put the disintegrant containing the drug in the same or separate bags, Where necessary, a column for describing the time for administering the drug, a kit for tablets for administering two or more tablets simultaneously or separately with a time lag, etc.
  • a column for describing the time for administering the drug, a kit for tablets for administering two or more tablets simultaneously or separately with a time lag, etc. may be included in the pharmaceutical composition of the present invention. included.
  • a pharmaceutical composition containing the compound (I) of the present invention is used as a therapeutic agent for preventing graft-versus-host disease and / or rejection when transplanting an organ such as heart, kidney, liver, or bone marrow, It is administered 3 days before transplantation and continuously after transplantation.
  • the daily dose of the pharmaceutical composition of the present invention varies depending on the condition and weight of the patient and the method of administration.
  • the active ingredient per adult (body weight 50 kg) [Compound (I)] About 5 to 1000 mg, preferably about 10 to 60 Omg, more preferably about 10 to 30 Omg, particularly preferably about 15 to 150 mg, once or twice to three times a day. Is administered.
  • inhibitors of graft-versus-host disease and Z or rejection at the time of organ transplantation used in combination with the above compound (I) include cyclosporin, evening chlorimus, rapamycin, steroids, azathioprine, and Mico Mofethyl phenolate, mizoribine and the like.
  • the dose of each drug is adjusted appropriately, but generally, the dose of each drug as a single drug is The current dose is used.
  • a pharmaceutical composition containing the compound (I) of the present invention for a prophylactic / therapeutic agent for AIDS, an agent for suppressing the progression of AIDS pathology, a graft-versus-host disease at the time of organ transplantation, and a target disease other than an agent for suppressing Z or rejection.
  • the daily dose depends on the type of target disease, the condition and weight of the patient, and the method of administration.
  • an adult body weight of 5 O kg
  • the dose of the other drug is appropriately selected, for example, in the range of about 1/200 to 1/2 or more and about 2 to 3 times or less of the usual dose.
  • the dose of each drug is adjusted as appropriate, but generally, the dose of each drug at the time of single drug administration is used.
  • the compound (I) of the present invention can also be contained in or used in combination with blood for transfusion or blood products. Transfusion blood or blood products are usually produced by mixing blood from multiple people, which may contain cells infected with the HIV virus and cells not infected. Yes, in this case, it may infect uninfected cells.
  • compound (I) of the present invention By incorporating the compound (I) of the present invention, infection and proliferation of these viruses can be prevented or suppressed. In particular, it is effective to mix compound (I) when storing blood products in order to prevent or suppress viral infection and proliferation.
  • compound (I) when blood or blood products for transfusion contaminated with the HIV virus are administered, compound (I) can be added to the blood to give the body of the person who received the blood or blood products for transfusion. Can prevent HIV transmission and proliferation. For example, when administered orally to an adult (body weight of about 60 kg) to prevent HIV infection during transfusion and use of blood products, a single dose of about 0.02 to 5 Omg / kg as a CCR antagonist is usually given.
  • the dose is preferably about 0.05 to 30 mgZkg, more preferably about 0.1 to 1 OmgZkg, and it is desirable to administer these doses about once to three times a day.
  • these dose ranges can be adjusted on a unit basis needed to divide up the daily dose, but as noted above, the dose may vary depending on the nature and extent of the disease, the age of the patient, weight, general health, Gender, diet, time of administration, mode of administration, rate of excretion, and other factors may be considered. In this case, the administration method can also be appropriately selected.
  • the HIV infection preventive agent of the present invention described above may be directly added to the blood or blood product to be transfused before blood transfusion or before use of the blood product. It is desirable to mix immediately before to 24 hours, preferably immediately before to 12 hours, more preferably immediately before to 6 hours.
  • silica gel 60 70-230 or 230-400 mesh
  • Fuji Silica Chemical NH-silica gel 100-200 mesh
  • ⁇ NMR spectra were measured using Varian Gemini-200 (200 MHz) or Varian Mercury (300 MHz) with tetramethylsilane as the internal standard.
  • Example 4-1 The title compound was synthesized in the same manner as in Example 3-2, using the compound obtained in Example 4-1. Yield 99%.
  • Example 6-1 The title compound was synthesized in the same manner as in Example 3-2 using the compound obtained in Example 6-1. Yield 91%.
  • Example 7-1 1-( ⁇ 4- [ ⁇ - ⁇ 3-[ ⁇ [(4-Cyanophenyl) amino] carbonyl ⁇ (phenyl) amino] propyl ⁇ piperidine-4-yl) methyl] phenyl ⁇ sulfonyl) piperidine -4-Carboxylic acid Using the compound obtained in Example 7-1, the title compound was synthesized in the same manner as in Example 3-2. Yield 91%.
  • Example 5-3 Using the compound obtained in Reference Example 5-3, the title compound was synthesized in the same manner as in Example 3-1. Yield 41%.
  • Example 9-1 Using the compound obtained in Example 9-1, the title compound was synthesized in the same manner as in Example 3-2. 97% yield.
  • Example 10-1 Using the compound obtained in Example 10-1, the title compound was synthesized in the same manner as in Example 3-2. Yield 71%. ,
  • a colorless oil obtained by concentrating the target fraction was dissolved in ethyl acetate (lOmL), and a 4N hydrochloric acid / ethyl acetate solution (lmL) was added. The residue obtained by evaporation of the solvent was washed with diisopropyl ether to give the title compound (152 mg, 73%) as a colorless amorphous.
  • Example 14-II Using the compound obtained in Example 14-II, the title compound was synthesized in the same manner as in Example 13-2. Yield 75%.
  • Example 8-3 Using the compound obtained in Reference Example 8-3, the title compound was synthesized in the same manner as in Example 3-1. Yield 54%.
  • Example 18-1 Using the compound obtained in Example 18-1, the title compound was prepared in the same manner as in Example 3-2. Was synthesized. 82% yield.
  • Example 19-1 Using the compound obtained in Example 19-1, the title compound was synthesized in the same manner as in Example 3-2. Yield 72%.
  • Example 11-3 Using the compound obtained in Reference Example 11-3, the title compound was synthesized in the same manner as in Example 3-1. Yield 88%.
  • Example 22-1 Using the compound obtained in Example 22-1, the title compound was synthesized in the same manner as in Example 3-2. Yield 943 ⁇ 4.
  • N- (3-chloropropyl) aniline hydrochloride (1.18 g, 5.7 mmol), the compound obtained in Reference Example 5-2 (1.62 g, 4.8 ⁇ .1), and potassium iodide (0.95 g, 5.7).
  • a mixture of 1), sodium hydrogen carbonate (1.60 g, 19.0 marl) and acetonitrile (60 mL) was stirred at 100 ° C for 18 hours. After the reaction mixture was concentrated under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and concentrated under reduced pressure.
  • the CCR5 gene was cloned from human spleen cDNA by PCR. 0.5 ng of spleen cDNA (Toyobo, QUICK_Clone cDNA) was used as type III, and was prepared with reference to the CCR5 gene base sequence reported by Samson et al. (Biochemistry 35 (11), 3362-3367 (1996)). Primer set;
  • SEQ ID NO: 2 described in Experimental Example (1) of WO 99/32100 [Sequence length: 34; Sequence type: nucleic acid; number of strands: single-stranded; topology: linear; Nucleic acid synthetic DNA]
  • PCR reaction was carried out in DNA Thermal Cycler 480 (Pakinkin Elma) using TaKaRa EX Taq (Takara Shuzo) at 25 pmol each (reaction conditions: 95 ° C for 1 minute, 60 minutes). 30 cycles of 1 minute at ° C and 5 minutes at 75).
  • the PCR product was subjected to agarose gel electrophoresis, and a DNA fragment of about 1. Okb was recovered. Then, the CRC5 gene was cloned using the Original TA Cloning Kit (Funakoshi).
  • the plasmid obtained above was digested with restriction enzymes Xbal (Takara Shuzo) and BamHI (Takara Shuzo), and then agarose gel electrophoresis was performed to recover a DNA fragment of about 1. Okb.
  • the DNA fragment and the expression plasmid pcDNA3.1 (Funakoshi) for animal cells digested with Xbal and BamHI are mixed and ligated with DNA Ligation Kit Ver.
  • the plasmid pCKR5 was obtained by the conversion. (3) Introduction and expression of human CCR5 expression plasmid into CHO-K1 cells
  • the obtained dineticin-resistant strain was cultured in a 96-L plate (Becton Dickinson), and CCR5-expressing cells were selected from the resistant strains. That is, an assay buffer (ham F12 medium containing 0.5% BSA, 2 OmM HEPES (Wako Pure Chemicals, pH 7.2)) supplemented with 200 pM of 25 I] -R ANTES (Amersham) as a ligand. After binding for 40 minutes at room temperature, wash with ice-cold PBS, add 1M NaOH at 5 ⁇ / well, stir, and measure the radioactivity with a ⁇ -counter to identify the ligand. CCR5ZCHO strain was selected.
  • an assay buffer ham F12 medium containing 0.5% BSA, 2 OmM HEPES (Wako Pure Chemicals, pH 7.2)
  • 200 pM of 25 I] -R ANTES Amersham
  • test compound ( ⁇ ) inclusive mediation Si buffer to each Ueru is the ligand after addition C 1 2 5 I] -RANTES the ( ⁇ Ma one sham) so that 10 ⁇ , was reacted at room temperature for 40 minutes.
  • the Atsushi buffer was removed by suction and washed twice with cooled PBS.
  • 200 ⁇ of Micro Shin Chi 20 (Packard) was added to each well, and the radioactivity was measured with a top count (Packard).
  • MOLT-4 no CCR5 cell As a CCR5 expressing cell, MOLT-4 no CCR5 cell (AIDS Res. Hum. Retrovir. 16, 935-941 (2000)), which is a human lymphocyte-derived cell line reported by Baba et al. RPMI 1640 medium (Nikken Institute of Biomedical Research) containing 10% fetal bovine serum (FBS, GI BCO) and lmg / mL dieneticin (Lifetech Oriental) was used as the medium.
  • FBS fetal bovine serum
  • GI BCO fetal bovine serum
  • lmg / mL dieneticin Lifetech Oriental
  • test compound was dissolved in dimethylsunoxide (DMSO) and diluted to 200 nM in RPMI 1640 medium containing 1.0% FBS and lmg ZmL dieneticin (Lifetech Oriental).
  • DMSO dimethylsunoxide
  • the B a-L strain which is a laboratory strain of R 5 H I V-1, was used.
  • MOLT-4ZCCR5 cells (4 ⁇ 10 6 cells / lmL) were inoculated with R5HIV-1Ba-L strain at 1,000 CCID 5 Q / mL and incubated at 37 ° C for 6 hours. After incubation, suspended infected cells washing away unadsorbed virus to the cell in the medium of 2 mL, 96 well microphone port plate in infected cells 100 L, the test compound was dispensed 100 min, 5% C_ ⁇ 2 The cells were cultured at 37 ° C for 3 days. The concentration of the test compound was 100 nM. Three days after infection, the cells were diluted 5-fold with a medium containing the same concentration of the test compound, and cultured for another 2 days.
  • the amount of p24 in the supernatant after the culture was measured using a commercially available ELISA kit '(ZeptoMetrix).
  • the infection inhibition rate was calculated as the amount of P24 in the test compound-administered group relative to the amount of p24 in the control group.
  • the compound represented by the formula (I) of the present invention or a salt thereof has an extremely strong CCR5 antagonistic effect and has good metabolic stability, so that various HIV infections in humans, for example, AIDS It can be used advantageously for prevention as well as treatment.

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  • Tropical Medicine & Parasitology (AREA)
  • Transplantation (AREA)
  • Pulmonology (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • AIDS & HIV (AREA)
  • Hospice & Palliative Care (AREA)
  • Vascular Medicine (AREA)
  • Cardiology (AREA)
  • Psychiatry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Hydrogenated Pyridines (AREA)

Abstract

L'invention concerne un composé représenté par la formule (I) [dans cette formule, R1 représente phényle ou alkyle C1-8 pouvant comprendre un halogène, alkyle C1-4 éventuellement halogéné, cyano, ou alkyloxy C1-4 en tant que substituant; et R2 représente un groupe représenté par la formule SO2NR3R4 (R3 représentant hydrogène ou alkyle C1-6 et R4 représentant alkyle C1-6 comprenant, en tant que substituant, l'un des éléments parmi lesquels, hydroxy, carboxy, et carbamoyle, pour autant que R3 puisse être lié à R4 pour former, conjointement avec l'atome d'azote, un groupe hétérocyclique azoté, comprenant, en tant que substituant, l'un des éléments parmi lesquels, hydroxy, carboxy, et carbamoyle) ou un groupe représenté par la formule S(O)m-W-Y (Y représente hydroxy, carboxy ou carbamoyle; W représente alkylène C1-4 éventuellement substitué par alkyle C1-4; et m est 0, 1 ou 2] ou un sel de ce composé. De tels composés présentent une excellente activité antagoniste de CCR5 et ils sont utiles en tant qu'agent prophylactique/thérapeutique pour des maladies provoquées par une infection à VIH dans des cellules mononucléaires de sang humain périphérique, plus particulièrement, le SIDA.
PCT/JP2003/011907 2002-09-20 2003-09-18 Compose d'uree et utilisation de celui-ci WO2004026832A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2003266529A AU2003266529A1 (en) 2002-09-20 2003-09-18 Urea compound and use thereof

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2002-275551 2002-09-20
JP2002275551A JP2004107298A (ja) 2002-09-20 2002-09-20 ウレア化合物およびその用途

Publications (1)

Publication Number Publication Date
WO2004026832A1 true WO2004026832A1 (fr) 2004-04-01

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PCT/JP2003/011907 WO2004026832A1 (fr) 2002-09-20 2003-09-18 Compose d'uree et utilisation de celui-ci

Country Status (3)

Country Link
JP (1) JP2004107298A (fr)
AU (1) AU2003266529A1 (fr)
WO (1) WO2004026832A1 (fr)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000066559A1 (fr) * 1999-05-04 2000-11-09 Schering Corporation Derives de piperidine faisant office d'antagonistes ccr5
EP1219605A1 (fr) * 1999-10-05 2002-07-03 Takeda Chemical Industries, Ltd. Composes d'uree, procede de production et d'utilisation de ces derniers
EP1238970A1 (fr) * 1999-12-08 2002-09-11 Teijin Limited Antagonistes du recepteur ccr5 de la cycloamine

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000066559A1 (fr) * 1999-05-04 2000-11-09 Schering Corporation Derives de piperidine faisant office d'antagonistes ccr5
EP1219605A1 (fr) * 1999-10-05 2002-07-03 Takeda Chemical Industries, Ltd. Composes d'uree, procede de production et d'utilisation de ces derniers
EP1238970A1 (fr) * 1999-12-08 2002-09-11 Teijin Limited Antagonistes du recepteur ccr5 de la cycloamine

Also Published As

Publication number Publication date
AU2003266529A1 (en) 2004-04-08
JP2004107298A (ja) 2004-04-08

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