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WO1996017623A1 - Medicament contre le sida - Google Patents

Medicament contre le sida Download PDF

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Publication number
WO1996017623A1
WO1996017623A1 PCT/JP1995/002489 JP9502489W WO9617623A1 WO 1996017623 A1 WO1996017623 A1 WO 1996017623A1 JP 9502489 W JP9502489 W JP 9502489W WO 9617623 A1 WO9617623 A1 WO 9617623A1
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Prior art keywords
group
lower alkyl
alkyl group
hydrogen atom
atom
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PCT/JP1995/002489
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English (en)
Japanese (ja)
Inventor
Naomi Wakasugi
Yoshiaki Monden
Yoshikazu Iwasawa
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MSD KK
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Banyu Phamaceutical Co Ltd
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Publication of WO1996017623A1 publication Critical patent/WO1996017623A1/fr
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/662—Phosphorus acids or esters thereof having P—C bonds, e.g. foscarnet, trichlorfon
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/548—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame having two or more sulfur atoms in the same ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/005—Enzyme inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/07—Tetrapeptides

Definitions

  • the present invention is useful in the field of medicine. More specifically, the present invention relates to a novel anti-HIV
  • PFT protein-farnesyltransferase
  • Anti-AIDS drugs actually used in AIDS patients so far include the reverse transcriptase inhibitors AZT, ddl and ddC. These drugs have problems such as being highly toxic, acquiring resistance to the drugs, and having no effect of suppressing the growth of HIV already integrated into host genes.
  • soluble CD4 and low-molecular-weight dextran sulfate that inhibit the binding and entry of HIV into cells, and various HIV protease inhibitors that inhibit the formation of viral constituent proteins after transcription of HIV have been studied. It has entered clinical trials but is not yet in a practical stage.
  • protein-farnesyltransferase inhibitor suppresses cell carcinogenesis by Ras and is useful as an antitumor agent.
  • An object of the present invention is to provide a novel anti-HIV agent which suppresses the expression of mature Ras and thereby inhibits the process of virus reactivation from an asymptomatic stage to provide an anti-AIDS effect.
  • the present inventors have found that various protein-farnesyltransferase inhibitors suppress the expression of mature Ras, and as a result, have found that they are useful as anti-HIV agents, and have completed the present invention.
  • the present invention relates to an anti-HIV agent containing a protein-farnesyltransferase inhibitor as an active ingredient.
  • the protein-farnesyltransferase inhibitor is not particularly limited as long as it has the action and is a pharmaceutically acceptable drug.
  • the general formula [I-a] is not particularly limited as long as it has the action and is a pharmaceutically acceptable drug.
  • the general formula [I-a] is a pharmaceutically acceptable drug.
  • R ′ a is a hydrogen atom, a lower alkyl group, An aralkyl group, an acyl group, a lower alkylsulfonyl group, an aralkylsulfonyl group or an arylsulfonyl group:
  • R 2a is a lower alkyl group: "is a lower alkyl group or an aralkyl group:
  • R ' 3 is a mercapto lower alkyl group
  • R 5a represents a hydrogen atom or a lower alkyl group
  • R 5a is a hydrogen atom or
  • Cys represents a cystinel group
  • X ′ b represents methionine, serine or leucine which is bonded to an adjacent carbonyl group on a nitrogen atom, wherein the carboxyl group of methionine, serine and leucine is a lower alkyl group
  • FT represents a hydrogen atom or a lower alkyl group, or a pharmaceutically acceptable salt thereof, which may form an ester with the group or a lipoxamide with the amino group
  • a Ariru group or a heteroaromatic ring group consisting Alpha 'epsilon is a lower alkyl group, a hydroxyl group, human Dorokin lower alkyl group, a lower alkoxy group, a carboxyl group, carboxy lower alkyl group, a Ariru group and Ararukiru group A saturated or unsaturated aliphatic hydrocarbon group having 2 to 8 carbon atoms which may have a substituent selected from the group: Q ′ c is — (CH 2 ) contend-(where n Represents an integer of 1 to 6) or one (CH 2 ) p -W ' c- (CH 2 ) q- (where W "represents an oxygen atom, a sulfur atom, a vinylene group or an ethynylene group: P and q represents the same or different and represents an integer of 0 to 3): R "represents a hydrogen atom, haloke A hydrogen atom, haloke
  • X ' is d and Y ia the same or different, an oxygen atom, a sulfur atom, a force Lupo alkenyl group, - CHR 1M - (wherein, R' M Represents a hydrogen atom or a lower alkyl group) or one NR ′ ′′.
  • R represents a hydrogen atom or a lower Al Kill group
  • Y and Y 'd are the vinylene Motowaka properly is Echiniren groups become Ichi ⁇ :
  • R la , R 2 R M , IT and R M are the same or different and each represents a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkyl group or a lower alkoxy group:
  • R ′ ′ One o one o one
  • R 53 are the same or different and are a hydrogen atom, a halogen atom, a hydroxyl group, an amino group, a nitro group, a cyano group, a carboxyl group, a lower alkoxycarbonyl group, a carbamoyl group, a lower alkyl group, a lower alkyl group, a lower alkyl group, and a hydroxy group.
  • lower alkyl group, a Furuoro lower alkyl group or a lower alkoxy group R M is a lower alkyl group: means a hydrogen atom or a lower alkyl group.
  • X "and ⁇ ' is an oxygen atom, a sulfur atom or -NR".
  • R ′ ld has the above-mentioned meaning
  • the other group is a carbonyl group or a group represented by one CHR ′ ° d — (where R ′ M has the above-mentioned meaning)
  • a pharmaceutically acceptable salt or ester thereof a pharmaceutically acceptable salt or ester thereof.
  • the aryl group means a fuunyl group, a naphthyl group or an anthryl group, and a phenyl group and a naphthyl group are preferable.
  • a heteroaromatic group is a group consisting of an oxygen atom, a nitrogen atom and a sulfur atom.
  • a condensed cyclic aromatic heterocyclic group in which the different monocyclic aromatic heterocyclic groups are fused to each other for example, a pyrrolyl group, an imidazolyl group, a pyrazolyl group, a pyridyl group, a virazinyl group, a pyrimidinyl group, a pyrita 'group.
  • the lower alkyl group means a linear or branched alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, and phenyl.
  • the aralkyl group means the lower alkyl group having the aryl group, for example, benzyl, phenyl, 3-phenylpropyl, 11-naphthylmethyl, 2-naphthylmethyl, 1- (2-naphthyl) And a benzyl group, a phenethyl group, a 2-naphthylmethyl group and the like.
  • the acyl group means an alkanoyl group having the lower alkyl group, an aracil group having the aralkyl group or an aroyl group having the aryl group, for example, an acetyl group, a propionyl group, a butyryl group, an isobutyryl group.
  • alkanoyl groups such as pivaloyl groups: aracil groups such as benzylcarbonyl group and phenethylcarbonyl group: aroyl groups such as benzoyl group, 11-naphthyl group and 2-naphthyl group, among which acetyl group and benzoyl group. Groups and the like are preferred.
  • the lower alkylsulfonyl group means an alkylsulfonyl group having the lower alkyl group, for example, a methylsulfonyl group, an ethylsulfonyl group, a pyrsulfonyl group, a butylsulfonyl group, and the like.
  • a tylsulfonyl group and the like are preferred.
  • the aralkylsulfonyl group means an aralkylsulfonyl group having the aralkyl group, for example, a benzylsulfonyl group, a phenylsulfonyl group, a phenylpropylsulfonyl group, a 1-naphthylmethylsulfonyl group, a 2-naphthyl group. And a benzylsulfonyl group. Among them, a benzylsulfonyl group and the like are preferable.
  • the arylsulfonyl group means an arylsulfonyl group having the aryl group, and examples thereof include a fuynylsulfonyl group, a 1-naphthylsulfonyl group, and a 2-naphthylsulfonyl group.
  • a phenylsulfonyl group is preferred.
  • the mercapto lower alkyl group means the lower alkyl group having a mercapto group, for example, a mercaptomethyl group, a mercaptoethyl group, a mercaptopropyl group, a mercaptobutyl group, etc., among which a mercaptomethyl group, a mercaptoethyl group And a mercaptopropyl group.
  • the lower alkylthio lower alkyl group means the lower alkyl group substituted by the alkylthio group having the lower alkyl group, such as a methylthiomethyl group, a methylthioethyl group, a methylthiopropyl group, a methylthiobutyl group, and an ethylthiomethyl group. And ethylthioethyl group, ethylthiopropyl group and the like. Among them, methylthiomethyl group, methylthioethyl group, methylthiopropyl group and the like are preferable.
  • the lower alkylsulfinyl lower alkyl group means the lower alkyl group substituted by the alkylsulfinyl group having the lower alkyl group, for example, methylsulfinylmethyl group, methylsulfinylethyl group, methylsulfinylpropyl group, methyl Examples include a sulfinylbutyl group, an ethylsulfinyl'methyl group, an ethylsulfinylethyl group, an ethylsulfinylpropyl group and the like, and among them, a methylsulfinylmethyl group, a methylsulfinylethyl group, a methylsulfinylpropyl group and the like are preferable. .
  • the lower alkylsulfonyl lower alkyl group means the lower alkyl group substituted by the alkylsulfonyl group having the lower alkyl group, for example, a methylsulfonylmethyl group, a methylsulfonylethyl group, a methylsulfonyl group.
  • Pill group methylsulfonylbutyl group, ethylsulfonylmethyl group, ethylsulfonylethyl group, ethylsulfonylpropyl group, etc., among which methylsulfonylmethyl group, methylsulfonylethyl group, methylsulfonylpropyl group, etc. Is preferred.
  • the hydroxy lower alkyl group means the above lower alkyl group having a hydroxyl group, that is, a hydroxyalkyl group having 1 to 6 carbon atoms, such as a hydroxymethyl group, a hydroxyxethyl group, a hydroxyquinpropyl group, and the like.
  • a hydroquinyl butyl group and the like are mentioned, and among them, a hydroxymethyl group, a hydroquinethyl group, a hydroxypropyl group and the like are preferable.
  • the lower alkoxy group means an alkoxy group having 1 to 6 carbon atoms or an alkylene dioxy group, such as a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, a tert-butoxy group, and a methylene dioxy group.
  • An ethylenedioxy group, a trimethylenedioxy group and the like, and among them, a methoxy group, an ethoxy group, a methylenedioxy group and the like are preferable.
  • the carboxy lower alkyl group means the lower alkyl group having a carboxyl group, that is, a carboxyalkyl group having 1 to 7 carbon atoms, such as a carboxymethyl group, a carboxyethyl group, a carboxypropyl group, and a carboxybutyl group. Among them, a carboxymethyl group, a carboquinethyl group and the like are preferable.
  • saturated aliphatic hydrocarbon group examples include an ethylene group, a trimethylene group, a tetramethylene group, a pentamethylene group, a hexamethylene group, a heptamethylene group, and an octamethylene group.
  • a trimethylene group, a tetramethylene group, a pen Tamethylene groups and the like are preferred.
  • An unsaturated aliphatic hydrocarbon group refers to an unsaturated aliphatic hydrocarbon group having one or more, preferably: one or two double bonds at any position on the carbon chain.
  • halogen atom examples include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.
  • a fluorine atom and a chlorine atom are preferable.
  • a lower alkoxyl propyl group is an alkoxycarbonyl group having 1 to 7 carbon atoms.
  • lower alkyl group refers to a mono- or di-substituted group formed by the lower alkyl group, such as a methylcarbamoyl group, an ethylcarbamoyl group, a dimethylcarbamoyl group, and a getylcarbamoyl group.
  • fluoro lower alkyl group means a lower alkyl group having a fluorine atom, that is, a fluoroalkyl group having 1 to 6 carbon atoms, for example, a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a 1-fluoroethyl group, a 2 —Fluoroethyl group, 2,2,2— Trifluoroethyl group, pentafluoroethyl group and the like.
  • the salt of the compound represented by the general formula [I-a], [I-b], [I-c] or [I-d] means a conventional pharmaceutically acceptable salt. Examples thereof include salts of a base addition salt at a carboxy group or an acid addition salt at a basic nitrogen atom.
  • the base addition salt examples include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt: for example, ammonium salt: such as trimethylamine salt, triethylamine salt, and disium salt.
  • Organic amine salts such as chlorhexylamine salt, ethanolamine salt, diethanolamine salt, triethanolamine salt, procaine salt, N .'- dibenzylethylenediamine salt and the like can be mentioned.
  • the acid addition salts include inorganic salts such as hydrochloride, sulfate, nitrate, phosphate, and perchlorate: for example, maleate, fumarate, tartrate, citrate, ascorbate, and the like.
  • Organic acid salts such as trifluoroacetate; sulfonates such as methanesulfonate, isethionate, benzenesulfonate and p-toluenesulfonate.
  • the ester of the compound represented by the general formula [I-c] or [I-d] means a conventional pharmaceutically acceptable ester such as a methyl group, an ethyl group, or a methyl group.
  • Esters with lower alkyl groups such as pill group, isopropyl group, butyl group, sec-butyl group, tert-butyl group, cyclopropyl group and cyclopentyl group; esters with aralkyl groups such as benzyl group and phenyl group; Esters with lower alkoxy lower alkyl groups such as esters with alkenyl groups, 2-butenyl groups and other lower alkenyl groups, methoxymethyl groups, 2-methoxyethyl groups, 2-ethoxyhexyl groups, etc., acetoxmethyl groups, vivaloyl Esters with lower alkanoyloxy lower alkyl groups such as methoxymethyl group and 1-bivaloyloxyethyl group; est
  • a hydroxyl group is present at the 7-position or 5-position of the carboxyl group.
  • an intramolecular ester that is, a 5- or 6-membered lactone ring may be formed between the hydroxyl group and the carboxyl group.
  • the compound according to the present invention may have stereoisomers such as optical isomers, diastereoisomers, and geometric isomers depending on the mode of the substituents. And mixtures thereof.
  • R 3a for example, benzyl group
  • R 4a for example, 2-methylsulfonylethyl group
  • R 53 for example, hydrogen atom, methyl group, ethyl group, isopropyl group
  • Etc. are preferred.
  • the compound represented by the general formula [I-b] is, for example, a compound described in Science (SCIENCE), vol. 260, p. 1937 (1993), and the compound is described in the above-mentioned publication. It can be manufactured and obtained by a method or an equivalent method.
  • the compound represented by the general formula [I-c] or [I-d] exists in a stereoisomer such as an optical isomer, a diastereoisomer, and a geometric isomer depending on the form of the substituent.
  • the present invention also includes all of these stereoisomers and mixtures thereof.
  • a 'QRRRR ", R 5 ⁇ RR 7c and R 8c have the above-mentioned meanings, or a general formula [ ⁇ -1 d-1]
  • a '",X' ⁇ Y 'd, R'., R 2d, R M, R 'R 5d, R M, R 7d, compound R 8d and R 9d are represented by have the meanings of the can preferable.
  • W ′ e represents a vinylene group
  • a force E isomer in which an E isomer (trans isomer) and a Z isomer (cis isomer) exist is more preferable.
  • X ′ d and Y ia are the same or different and each represent an oxygen atom, a sulfur atom, a carbonyl group, —CHR ′. .
  • a group represented by one here, R ′ ° represents a hydrogen atom or a lower alkyl group) or one NR ′′ d ⁇ (here, R ′′ d represents a hydrogen atom or a lower alkyl group), Or X ld and ⁇ ⁇ - It means a len group or an ethynylene group.
  • a ' c A lower alkyl group represented by A 'a, hydroxyl group, human Dorokin lower alkyl group, a lower alkoxy group, a carboxyl group, a carboxy lower alkyl group, optionally having a substituent selected Ri by the group consisting of Ariru group and Ararukiru group
  • the saturated or unsaturated aliphatic hydrocarbon group having 2 to 8 carbon atoms may be the unsubstituted saturated aliphatic hydrocarbon group or the unsaturated aliphatic hydrocarbon group or any substitutable position.
  • the substituent means the saturated aliphatic hydrocarbon group or the unsaturated aliphatic hydrocarbon group having a substituent, and the substituent is a lower alkyl group, a hydroxyl group, a hydroxy lower alkyl group, a lower alkoxy group, a sulfoxyl group, a carboxy lower group.
  • One or two or more, preferably one to three, identical or different groups can be selected from the group consisting of an alkyl group, an aryl group and an aralkyl group. You.
  • a ' c or A' a is the formula [a]
  • R ' is a hydrogen atom, a hydroxyl group, a hydroxy lower alkyl group, a lower alkoxy group or a carboxyl group:
  • R 1 ' is a hydrogen atom, a hydroxyl group, a lower alkoxy group, a carboxyl group or a carboxine lower alkyl group:
  • R '2 is a hydrogen atom, a human Dorokin lower alkyl group or a carboxyl group:
  • R 13 is a hydrogen atom, a hydroxyl group or a carboxyl certain; t and u are the same or different, it means an integer of 0 to 2
  • the compound represented by the formula and Ale or Ald are represented by the formula [b]
  • R '2 is a hydrogen atom, a human Dorokin lower alkyl group or a carboxyl group: R' 3 represents a hydrogen atom, a hydroxyl group or a carboxyl group; V is 0 or 1: w ⁇ beauty X are the same or different And an integer of 0 to 2).
  • a or A ' d is represented by the formula [a], represents a hydrogen atom, a hydroxyl group, a carboxyl group and the like, and R 1 ′′ represents a carboxy lower alkyl group such as a carboxyl group and a carboxymethyl group.
  • R 12 and R 13 a hydrogen atom, a carboxyl group and the like are preferable, and t and u are the same or different, and 0 or 1 is preferable.
  • R' 2 is a hydroxy lower alkyl group such as a hydroquinmethyl group, a carboxyl group, etc.
  • R 13 is a hydrogen atom
  • v, w and X is preferably 0.
  • Ar - ⁇ - is a naphthyl group, a benzofuranyl group or a benzozoenyl group.
  • R ′ c represents an aryl group or a heteroaromatic group which may have a substituent selected from the group consisting of a halogen atom, a lower alkyl group and a lower alkoxy group; Means the unsubstituted aryl group or the heteroaromatic ring group, or the aryl group or the heteroaromatic ring group having a substituent at any substitutable position, wherein the substituent is a halogen atom, One or two or more same or different groups may be selected from the group consisting of lower alkyl group and lower alkoxy group. Among them, the unsubstituted aryl group or heteroaromatic ring group is preferable.
  • R 1 represents a hydrogen atom, a halogen atom, a lower alkyl group or a lower alkoxy group
  • R 2 represents a hydrogen atom, a halogen atom or a lower alkyl group
  • a naphthyl group Benzofuranyl group, benzochenyl group, benzothiazolyl group, benzoxazolyl group and benzoimidazolyl group, and more specifically, phenyl group, 2-benzo [b] furanyl group, 2 —Benzo [b] thenyl, 2-naphthyl, 2-benzoxazolyl, etc. are preferred.
  • a naphthyl group and a pyridyl group, a furyl group or a phenyl group having R 3C on the ring and more specifically, 4-fluorophenyl group, 4-chlorophenyl group, 4-methylphenyl group, 3-fluoro-4-methylphenyl group, 4-fluoro-3-methylphenyl group, 3-chloro-4-methylphenyl group, 4-chloro-3-methylphenyl group , 3,4-dichlorophenyl group, 3,4-dimethylphenyl group, 4-methoxyphenyl group, 3,4 dimethoxyphenyl group, 212-trophenyl group, 4-aminophenyl group, 4-hydroxyphenyl group, 4l-lubamoylphenyl Group, 4-methylcarbamoylphenyl group, 4-hydroxymethylphenyl group, 4-trifluoromethylphenyl group 4-Cyanophenyl group
  • R 3c or R 6d a methyl group, an ethyl group, a propyl group and the like are preferable, and a methyl group, an ethyl group and the like are particularly preferable.
  • R “or R 7d, a hydrogen atom, a methyl group, Echiru group, an a propyl group virtuous suitable, especially hydrogen, methyl group is preferred.
  • R 7 "and R e " are the same or different and each represent a hydrogen atom, a halogen atom, a lower alkyl group or a lower alkoxy group), a naphthyl group, a quinolyl group, a benzoxazolyl And benzofuranyl group and benzothienyl group, and more specifically, 3.4-dichlorophenyl group, 3,4-difluorophenyl group, 3,4-dimethylphenyl group, 2-naphthyl group, and 2-benzyl group.
  • Zoxazolyl, 2-benzo [b] furanyl, 2-benzo [b] thenyl, 5-benzo [b] thenyl and the like are preferred.
  • the protein-phenylsulfonyltransferase inhibitor of the present invention includes, for example,
  • the protein-farnesyl transfusylase (PFT) inhibitor according to the present invention suppresses the expression of mature Ras and inhibits the reactivation of HIV genes integrated into host cells. Since it can be suppressed without cytotoxicity, it is useful as an anti-HIV agent.
  • PFT protein-farnesyl transfusylase
  • the protein-Pharnesyltransferase (PFT) inhibitor according to the present invention can be classified into two types according to the mode of inhibition of the enzyme. One antagonizes the Ras protein, a substrate, and the other antagonizes pharmacophoric acid, another substrate.
  • PFT protein-phenylsulfuryltransferase
  • a PFT inhibitor that antagonizes the Ras protein and a PFT inhibitor that antagonizes phenylnesyl pyrophosphate can be used in combination.
  • a PFT inhibitor that antagonizes funesyl pyrophosphate when used as an anti-HIV agent, a compound that can reduce the concentration of funesyl pyrophosphate in cells, such as simvastatin, lovastatin, pravastatin, or fluvastatin An HMG-CoA reductase inhibitor such as vastatin can be used in combination.
  • the compound of the present invention can be administered orally or parenterally, and can be provided as an anti-HIV agent by being formulated into a form suitable for such administration. When the compound according to the present invention is used clinically, it can be administered after formulating various preparations by adding pharmaceutically acceptable additives according to the administration form.
  • additives various additives commonly used in the field of pharmaceutical preparations can be used, such as gelatin, lactose, sucrose, titanium oxide, starch, crystalline cellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, and corn starch.
  • Microcrystalline wax Microcrystalline wax, White petrolatum, Magnesium aluminate metasilicate, Calcium phosphate anhydrous, Cuenoic acid, Trisodium citrate, Hydroquinine propyl cellulose, Sorbitol, Sorbitan fatty acid ester, Polysorbate, Sucrose fatty acid ester, Polyoxyethylene ethylene hydrogenated castor oil, polyvinyl virion, magnesium stearate, light gay anhydride, talc, vegetable oil, benzyl alcohol, gum arabic, propylene glycol Le, polyethylene alkylene glycol, cyclodextrin or hydroxypropyl professional building cycloalkyl de Kiss Bok phosphorus, and the like.
  • Dosage forms formulated as a mixture with these additives include, for example, solid preparations such as tablets, capsules, granules, powders and suppositories: or liquid preparations such as syrups, elixirs and injections, etc. These can be prepared according to a usual method in the pharmaceutical field. In the case of liquid preparations, they may be dissolved or suspended in water or other appropriate medium before use. In particular, in the case of an injection, it may be dissolved or suspended in a physiological saline solution or a glucose solution as necessary, and a buffer or a preservative may be added.
  • the compounds according to the present invention all the drug from 1.0 to 100 wt%, preferably be in a proportion of 1.0 to 60 weight 0/0. These preparations may also contain other therapeutically effective compounds.
  • the dose and frequency of administration vary depending on the sex, age, weight, degree of symptoms and the type and range of the intended therapeutic effect of the patient, but generally,
  • 0.1 to 100 mg kg is divided into 1 to several doses per adult, and for parenteral administration, 0.01 to 100 mgZ It is preferred to administer the kg in one or several divided doses.
  • FIG. 1 is a graph showing the degree of viable cell survival and luciferase activity at each concentration of compound 1.
  • FIG. 2 is a graph showing the degree of survival of living cells and luciferase activity at each concentration of compound 2.
  • a vector in which luciferase is linked to the long terminal repeat (LTR) of the HIV gene is introduced into PC12Zras, 24 hours later, a PFT inhibitor is added, and the cells are solubilized 24 hours later, and the luciferase activity is measured.
  • the luciferase activity reflects the activity of the HIV gene, and when dexamethasone was added to cells to express ras in PC12 / ras, luciferase activity increased 4 to 5 times compared to when dexamethasone was not added. I do.
  • the PFT inhibitor of the present invention suppressed the ras-dependent increase in HIV luciferase activity in a dose-dependent manner.
  • microscopic examination at a concentration that suppressed HIV activity revealed no cytotoxicity, but prevented neurite outgrowth of cells due to ras expression. Further measurement of the extent to which the number of remaining viable cells reduced Alamar Blue did not show a decrease.
  • the protein-farnesyltransferase (PFT) inhibitory ij according to the present invention is useful as an anti-HIV agent because it inhibits the activation of the HIV gene by ras.

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Abstract

L'invention concerne un agent anti-VIH comprenant comme principe actif un inhibiteur de la protéine farnésyle transférase, par exemple un composé représenté par la formule générale [I-a]. Dans cette formule, X1a représente -O-, -S(O)¿m?-, où m est un nombre entier de 0 à 2, -NR?6a, où R6a¿ représente un alkyle inférieur éventuellement substitué par un aryle ou un hétéroaryle, -CH¿2?CH2- ou -CH=CH-; R?1a¿ représente un hydrogène, un alkyle inférieur, un aralkyle, un acyle, un alkylsulfonyle inférieur, un aralkylsulfonyle ou un arylsulfonyle; R2a représente un alkyle inférieur; R3a représente un alkyle inférieur ou un aralkyle; R4a représente un mercapto alkyle inférieur, un alkyl(inférieur)thioalkyle inférieur, un alkyl(inférieur)sulfinylalkyle inférieur, un alkyl(inférieur)sulfonylalkyle inférieur ou un hydroxyalkyle inférieur; R5a représente un hydrogène ou un alkyle inférieur; ou R?4a et R5a¿ peuvent former ensemble un alkylène C¿2?-C4.
PCT/JP1995/002489 1994-12-09 1995-12-05 Medicament contre le sida Ceased WO1996017623A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP33169194 1994-12-09
JP6/331691 1994-12-09

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WO1996017623A1 true WO1996017623A1 (fr) 1996-06-13

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6271197B1 (en) 1996-04-11 2001-08-07 Gpc-Biotech Inc. Assays and reagents for identifying anti-fungal agents, and uses related thereto
US6455281B1 (en) 1996-04-11 2002-09-24 Gpc Biotech Inc. Nucleic acids for identifying anti-fungal agents, and uses related thereto
US6696280B2 (en) 1996-04-11 2004-02-24 Gpc Biotech, Inc. Candida geranylgeranyl-protein transferase polypetide, compositions and methods related thereto

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
BIOMED. PHARMACOTHER., Vol. 48, No. 2, (1994), pages 63-67. *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6271197B1 (en) 1996-04-11 2001-08-07 Gpc-Biotech Inc. Assays and reagents for identifying anti-fungal agents, and uses related thereto
US6277564B1 (en) 1996-04-11 2001-08-21 Gpc Biotech Inc. Assays and reagents for identifying anti-fungal agents, and uses related thereto
US6455281B1 (en) 1996-04-11 2002-09-24 Gpc Biotech Inc. Nucleic acids for identifying anti-fungal agents, and uses related thereto
US6696280B2 (en) 1996-04-11 2004-02-24 Gpc Biotech, Inc. Candida geranylgeranyl-protein transferase polypetide, compositions and methods related thereto
US6727082B1 (en) 1996-04-11 2004-04-27 Gpc Biotech Inc. Assays and reagents for identifying anti-fungal agents, and uses related thereto

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