WO1996018627A1 - Derive tripeptidique contenant de l'ahpba - Google Patents

Derive tripeptidique contenant de l'ahpba Download PDF

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Publication number
WO1996018627A1
WO1996018627A1 PCT/JP1995/002546 JP9502546W WO9618627A1 WO 1996018627 A1 WO1996018627 A1 WO 1996018627A1 JP 9502546 W JP9502546 W JP 9502546W WO 9618627 A1 WO9618627 A1 WO 9618627A1
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group
compound
acid
amino
carbonyl
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PCT/JP1995/002546
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English (en)
Japanese (ja)
Inventor
Yuichiro Yabe
Takashi Watanabe
Takashi Nishigaki
Yuji Ozawa
Tomoaki Komai
Akihiko Nakagawa
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Sankyo Company, Limited
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Priority to AU41880/96A priority Critical patent/AU4188096A/en
Publication of WO1996018627A1 publication Critical patent/WO1996018627A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
    • C07K5/0202—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -NH-X-X-C(=0)-, X being an optionally substituted carbon atom or a heteroatom, e.g. beta-amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention relates to a novel human protease having an inhibitory activity on a human derived immunodeficiency syndrome onset virus (hereinafter referred to as HIV) -derived protease (hereinafter referred to as HIV protease).
  • HIV protease a human derived immunodeficiency syndrome onset virus
  • HIV protease a human derived immunodeficiency syndrome onset virus
  • HIV protease a tripeptide derivative containing amino-2-hydroxy-4-phenylbutanoic acid
  • AIDS is a disease caused by a retrovirus called HIV, one of the lentiviruses. According to WHO estimates, about 1 million people worldwide are affected by the disease today, and the number of patients is ever increasing. The disease is fatal and there is currently no effective cure for cure.
  • a general feature of retrovirus replication is that the viral protease processes the viral precursor protein to produce the viral protein required for virus composition and function. Inhibiting this processing usually prevents the production of infectious virus.
  • Kohl, NE et al., Proc. Natl. Acad. Sci. 85, 4686 (1988) report that mature infectious virions when HIV-encoded proteases are genetically inactive. Has not been produced. This indicates that that force 5 to inhibit HIV protease Ichize ', prevention of HIV infection properly is effective in the treatment of treatment and AIDS Things.
  • HIV protease inhibitors are administered in vivo or parenterally to a living body, it is difficult to maintain a blood concentration sufficient to suppress virus replication in infected cells in the body. In fact, few HIV protease inhibitors are in clinical trials.
  • the present invention includes a transition-state analog that is not cleaved by HIV protease, is specific for HIV protease, has excellent enzyme inhibitory activity, is effective at low levels on infected cells, and is useful in vivo.
  • a low-molecular-weight HIV protease inhibitor that achieves a blood level that can be expected to be effective by oral or parenteral administration.
  • Rl represents a quinolin-12-carbonyl group or a quinoxaline-12-carbonyl group
  • R2 represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, an acetyl group, a methoxymethyl group, Represents a methylthiomethyl group, an acetyloxymethyl group, a bivaloyloxymethyl group, a HOOC (CH 2 ) n CO— group (n represents an integer of 2 to 4) or a HOOCCH 20 CH 2 CO— group And a salt thereof.
  • BEST MODE FOR CARRYING OUT THE INVENTION In the above general formula (I):
  • alkyl group having 1 to 4 carbon atoms of R 2 examples include a methyl, ethyl, n- propyl, isopropyl, n-butyl, isobutyl, s-butyl and t-butyl group. Is a methyl or t-butyl group.
  • the compound (I) of the present invention may be converted into a salt in some cases.
  • the compound (I) is an alkali metal salt such as a sodium salt or a potassium salt, or a calcium salt.
  • Metal salts such as alkaline earth metal salts such as magnesium and magnesium salts; hydrohalides such as hydrochloride, hydrobromide and hydroiodide, nitrate, perchlorate and sulfuric acid Inorganic acid salts such as salts and phosphates; lower alkane sulfonates such as methanesulfonate, trifluormethanesulfonate and ethanesulfonate, benzenesulfonate, p_toluenesulfonate Organic acid salts such as arylsulfonate, fumarate, succinate, citrate, tartrate, oxalate, maleate, etc.
  • the compounds (I) of the present invention also include stereoisomers having an asymmetric carbon in the molecule and each having an R configuration or an S configuration, and each of them or a mixture thereof of Both are included in the present invention.
  • R2 is a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, an acetyl group, a methoxymethyl group, a HO OC (C H2) ⁇ CO— group (n represents an integer of 2 to 4) or H 00
  • R2 is a hydrogen atom or an alkyl group having 1 to 4 carbon atoms
  • Me represents a methyl group
  • ⁇ Bu represents a t-butyl group
  • M0M represents a methoxymethyl group
  • Ac represents an acetyl group
  • Suc represents a succinyl group (H 00 C (CH 2) 2 CO—)
  • Dig indicates a diglycolyl group (H00 CC H2 0 C H2 CO—)
  • Glt indicates a glutaryl group (H 00 C (C H2) 3 C-one).
  • M SM represents a methylthiomethyl group
  • a OM represents an acetomethyl group
  • Q xa represents a quinoxaline 12-carbonyl group
  • Q oa represents a quinolinyl 12-carbonyl group.
  • PM represents a pinoloyloxymethyl group.
  • R2 have the same meanings as above, and R3 and R4 are the same and represent a arylmethyl group which may be substituted with lower alkyl, lower alkoxy or hydroxyl group, or Represents a hydrogen atom, the other represents an amino group-protecting group other than arylmethyl group, and R5 represents a normal amino-protecting group.
  • R 3 and R 4 are substituted with lower alkyl, lower alkoxy or hydroxyl group
  • benzyl and arylmethyl groups include benzyl, 4-methylbenzyl, 4-methoxybenzyl, 4-ethylbenzyl, 4-ethoxybenzyl and 4-hydroxybenzyl. .
  • protecting group for amino groups other than arylmethyl group for R 3 or R 4 and the usual protecting group for the amino group for R 5 are not limited as long as they are commonly used.
  • said "aliphatic acyl group” benzoyl, o-naphthoyl.
  • Aryl carbonyl groups such as 1-naphthyl, 2-bromobenzoyl, halogenylarylcarbonyl groups, such as 4-cyclobenzoyl, 2,4,6—trimethylbenzoyl, 4-toluoyl
  • Lower alkylated aryls such as lower carbonyl groups, lower alkoxylated aryls such as 4-anisole, and lower alkoxylated aryls such as 4-anisole.
  • Aromatic carbonyl groups lower alkoxycarbonylated arylcarbonyl groups such as 2- (methoxycarbonyl) benzoyl, and arylated aryloxy groups such as 4-phenylbenzyl Acyl group; lower alkoxy such as methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, and isobutoxycarbonyl Lower alkoxycarbonyl substituted by halogen or tri-lower alkylsilyl groups such as cyclocarbonyl group, 2,2,21-triethoxy carbonyl, 2-trimethylsilylethoxycarbonyl An alkoxycarbonyl group such as a group; an alkenyloxycarbonyl group such as vinyloxycarbonyl and aryloxycarbonyl; benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, and 3,4-dimethoxybenzylo
  • the aryl ring is substituted with one or two lower alkoxy or nitro groups,
  • Compound (VI) used as a starting material is known or can be synthesized according to a known method.
  • the 4-chloroproline of compound (VI) can be obtained by using 4-hydroxyproline as a raw material, using hydrochloric acid, using phosphorus trichloride, or using an acid halide such as thionyl chloride or oxychlorine.
  • an acid halide such as thionyl chloride or oxychlorine.
  • AK Bose et al. [Tetrahedron Letters, 40, 3937 (1973), a method using N-chlorosuccinic acid imide and trialkyl phosphate, JG Calzada S (0rg. Syn. 634), a method of reacting carbon tetrachloride with triphenylphosphine is used.
  • Compound (V) used as a starting material is known or is easily synthesized according to a known method. For example, it is synthesized according to the method of R. Horanz et al. (Synthes is, 703, 1989) and the method of MT Reets et al. (Tetraheron Lett., 29.3295, 1988).
  • the first step is a step of reacting the compound (V) or a reactive derivative of the carboxylic acid thereof with the amino compound (VI) to produce the compound (VII).
  • the reaction is carried out according to a general peptide synthesis method, for example, an azide method, an active esterification method, a mixed acid anhydride method or a condensation method.
  • amino acid hydrazine produced by reacting an amino acid or its ester with hydrazide in an inert solvent at around room temperature was reacted with a nitrite compound to convert it to an azide compound. Later, it is carried out by treating with an amine compound.
  • a nitrite compound used include an alkali metal nitrite such as sodium nitrite or an alkyl nitrite compound such as isonitrite.
  • inert solvent used examples include amides such as dimethylformamide and dimethyl acetate, sulfoxides such as dimethyl sulfoxide, and pyrrolidone such as N-methylpyrrolidone. Can be mentioned.
  • the two reactions in this step are usually performed in one reaction solution, and the reaction temperature is 150 to 0 in the first stage, 110 to 10 in the second stage, and the reaction time is Is 5 minutes to 1 hour, and the latter is 10 hours to 5 days.
  • the active esterification method is carried out by reacting an amino acid with an active esterifying agent in a solvent to produce an active ester, and then reacting the active ester with an amide compound.
  • the solvent used is not particularly limited as long as it is inert.
  • examples thereof include halogenated hydrocarbons such as methylene chloride and chloroform, ethers, and tetrahydrofuran.
  • ethers include amides such as dimethylformamide and dimethylacetamide.
  • the active esterifying agents used include, for example, N-hydroxysuccinimide, n-hydroxybenzotriazole, N-hydroxy-5-norbornene-2,3-dicarboximide.
  • N-hydroxy compounds can be mentioned, and the active esterification reaction is suitably carried out in the presence of a condensing agent such as dicyclohexylcarbodiimide (DCC).
  • DCC dicyclohexylcarbodiimide
  • the reaction temperature is between 10 and 25 c in the active esterification reaction, around room temperature in the reaction between the active ester compound and the amine, and the reaction time is between 30 min and 10 h for both reactions. is there.
  • the mixed acid anhydride method is carried out by producing a mixed acid anhydride of an amino acid and then reacting it with an amine.
  • the reaction to produce the mixed anhydride is carried out in an inert solvent (for example, ethers such as ether and tetrahydrofuran, amides such as dimethylformamide and dimethylacetamide), and ethyl ethyl carbonate.
  • an inert solvent for example, ethers such as ether and tetrahydrofuran, amides such as dimethylformamide and dimethylacetamide
  • Lower alkyl carbonates such as sodium butyl carbonate, di-lower alkyl cyanophosphoric acid such as getyl cyanophosphoric acid (DEPC), or diphenyluric acid azide (DP PA) This is achieved by reacting the acid.
  • the reaction is suitably carried out in the presence of an organic amine such as triethylamine, N-methylmorpholine, the reaction temperature is between 110 and 25 "C, and the reaction time is 3 minutes. 0 minutes to 5 hours.
  • an organic amine such as triethylamine, N-methylmorpholine
  • the reaction of the mixed anhydride with the amine is preferably carried out in an inert solvent (eg, ethers such as ether, tetrahydrofuran, amides such as dimethylformamide, dimethylacetamide).
  • an inert solvent eg, ethers such as ether, tetrahydrofuran, amides such as dimethylformamide, dimethylacetamide.
  • the reaction is carried out in the presence of the above-mentioned organic amine, the reaction temperature is from 0 to room temperature, and the reaction time is from 1 hour to 24 hours.
  • the condensation method is carried out by directly reacting an amino acid and an amine in the presence of a condensing agent such as dicyclohexylcarbodiimide or carbonyldimidazole to produce the above-mentioned active ester.
  • the reaction is performed in the same manner as in the reaction.
  • the second step is a step of removing the protecting group for the amino group of the compound (VI
  • a silyl group When a silyl group is used as a protecting group for an amino group, it is usually treated with a compound that generates fluorine anion such as tetrabutylammonium fluoride or potassium fluoride. Removed.
  • the reaction solvent is not particularly limited as long as it does not inhibit the reaction, but ethers such as tetrahydrofuran and dioxane are preferable.
  • the reaction temperature and reaction time are not particularly limited, but the reaction is usually carried out at room temperature for 10 to 18 hours.
  • an alkoxycarbonyl group such as t-butyloxycarbonyl group
  • it is removed by treating with an acid in an inert solvent.
  • the reaction solvent is not particularly limited as long as it does not inhibit the reaction.
  • Amides such as dimethylformamide and dimethylacetamide; getyl ether, diisopropyl ether, and tetrahydrofuran Ethers such as dioxane, dimethoxetane, diethylene glycol dimethyl ether; methanol, ethanol, n-prono. Nor, Isoprono ,.
  • the acid to be used is not particularly limited as long as it is an acid, but is preferably an inorganic acid such as hydrochloric acid, an organic acid such as trifluoroacetic acid, or a trifluoroboronate ester. It is such a Lewis acid.
  • the reaction temperature and reaction time are not particularly limited, but are usually 0 to 30 and the reaction is carried out by treating for 20 minutes to 1 hour.
  • the protecting group for the amino group is an aliphatic acyl group, an aromatic acyl group, or a substituted methylene group forming a Schiff base
  • treatment with an acid or a saturated group in the presence of an aqueous solvent. Can be removed.
  • the acid used is not particularly limited as long as it is usually used as an acid.
  • an inorganic acid such as hydrochloric acid, sulfuric acid, phosphoric acid, or hydrobromic acid is used.
  • the base used is not particularly limited as long as it does not affect the other parts of the compound, but is preferably a metal alkoxide such as sodium methoxide, or carbonate.
  • isomerization may occur in hydrolysis with a base.
  • the solvent used is not particularly limited as long as it is one used in a usual hydrolysis reaction.
  • Water alcohols such as methanol, ethanol, n-propanol, tetrahydrofuran, and dioxane;
  • Organic solvents such as ethers or mixed solvents of water and the above organic solvents are preferred.
  • the reaction temperature and reaction time vary depending on the starting material, the base used, and the like, and are not particularly limited. However, in order to suppress a side reaction, the reaction is usually performed at 0 to 150 for 1 to 10 hours.
  • the protecting group for the amino group is an aralkyloxycarbonyl group
  • it is removed by reduction in an inert solvent in the presence of a catalytic reduction catalyst.
  • the solvent to be used is not particularly limited as long as it is one used in a usual reduction reaction.
  • it is dimethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxeta.
  • Ethers such as dimethyl ether; methanol, ethanol, n -Prono, 'Nol, Isoprono ⁇ ', n-butanol, isobutanol, toluene, isoamyl alcohol, diethyl glycol, glycoline, octanol , Alcohols such as cyclohexanol and methyl sorb.
  • Examples of the catalytic reduction catalyst to be used include palladium carbon, palladium black and the like.
  • reaction temperature and reaction time vary depending on the starting materials and the like, and are not particularly limited. Usually, the reaction is carried out by reacting hydrogen at normal pressure to 10 atm near room temperature for 1 hour to 8 hours.
  • the protecting group of the amino group is an arylmethyl group
  • it is usually removed by contacting with a reducing agent in a solvent, and preferably, the catalytic reduction is carried out at room temperature under a catalyst. It is preferable to use a removing method or a removing method using an oxidizing agent.
  • the solvent used in the removal by catalytic reduction is not particularly limited as long as it does not participate in the reaction.
  • Alcohols such as ethanol, methanol, ethanol, and isopropanol; ethers such as getyl ether, tetrahydrofuran, and dioxane; and aromatics such as toluene, benzene, and xylene.
  • Aliphatic hydrocarbons such as aromatic hydrocarbons, hexane and cyclohexane, esters such as ethyl acetate and propyl acetate, fatty acids such as formic acid and acetic acid, or a mixed solvent of these organic solvents and water Alternatively, a mixed solvent of a fatty acid and an alcohol is preferable.
  • the catalyst to be used is not particularly limited as long as it is usually used in a catalytic reduction reaction, but is preferably palladium black, palladium carbon, Raney-nickel, platinum oxide, platinum oxide Black, rhodium aluminum monoxide, triphenylphosphine rhodium monochloride, no. Radium monosulfate barrier is used.
  • the pressure is not particularly limited, it is usually carried out at a pressure of 1 to 0 atm.
  • reaction temperature and reaction time vary depending on the starting material and catalyst type, etc. It is usually carried out at 0 to 100 hours for 5 minutes to 24 hours.
  • the solvent used in the removal by oxidation is not particularly limited as long as it does not participate in this reaction, but is preferably a water-containing organic solvent.
  • organic solvents include ketones such as acetone, halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, and acetonitrile.
  • Ethers such as nitriles, getyl ether, tetrahydrofuran, and dioxane; and amines such as dimethylformamide, dimethylacetamide, and hexamethylphosphorotriamide
  • sulphoxides such as dimethylsulphoxide.
  • the oxidizing agent to be used is not particularly limited as long as it is a compound usually used for oxidation, but preferably, potassium persulfate, sodium persulfate, or ammonium silicate is used.
  • CAN potassium persulfate, sodium persulfate, or ammonium silicate is used.
  • CAN potassium persulfate, sodium persulfate, or ammonium silicate is used.
  • CAN 2,3-dichloro-5,6-dicyano- p- benzoquinone (DDQ) are used.
  • reaction temperature and reaction time vary depending on the starting material and the type of catalyst, etc., but are usually 0 to 150, and are usually from 10 minutes to 24 hours.
  • the protecting group of the amino group is a diarylmethyl group
  • it can be achieved by performing the treatment in the same manner as in the above-mentioned conditions for the removal reaction of the arylmethyl group.
  • the amino-protecting group is an alkenyloxycarbonyl group
  • the amino-protecting group usually forms the above-mentioned aliphatic acyl group, aromatic acyl group, alkoxycarbonyl group or Schiff base. This can be achieved by treating with a base in the same manner as the conditions for the removal reaction in the case of a substituted methylene group.
  • the method of removing it using palladium and triphenylphosphine or nickel tetrapropyl is particularly simple and can be carried out with few side reactions.
  • the third step is a step of producing the compound (X) by reacting the compound (IX) or a reactive derivative of the carboxylic acid thereof with the compound (VIII) in the same manner as in the first step.
  • the fourth step is a step of producing the compound (XI) by removing the protective period of the amino group of the compound (X) in the same manner as in the second step.
  • the fifth step is a step of reacting the compound (XII) or a reactive derivative of the carboxylic acid thereof with the compound (XI) in the same manner as in the first step to produce the compound (I) of the present invention.
  • R1, R2 , R3 , R4 and R5 have the same meanings as described above, and R6 represents a hydroxyl-protecting group.
  • the sixth step is a step of producing a compound (XIV) by protecting the hydroxyl group of the compound (VII) by a usual method.
  • the seventh step is a step of producing a compound (XV) by removing the amino group of the compound (XIV) in the same manner as in the second step of the method A.
  • the eighth step is a step of reacting the compound (XVI) or a reactive derivative of the carboxylic acid thereof with the amino compound (XV) in the same manner as in the first step of Method A to produce the compound (XVII). is there.
  • the ninth step is a step of producing a compound (XVIII) by removing the protective period of the amino group of the compound (XVIII) in the same manner as in the second step of Method A.
  • the compound (XII) or a reactive derivative of the carboxylic acid thereof and the amino compound (XVIII) are reacted in the same manner as in the first step of the method A to produce a conjugate (XIX). It is a process.
  • the first step is a step of reacting compound (X) with compound (XIX) to produce compound (XXI).
  • the 12th step is a step for producing the compound (I) of the present invention by selectively removing the hydroxyl-protecting group (R 6 ) of the compound (XXI).
  • each target compound is collected from the reaction mixture according to a conventional method.
  • the reaction mixture is appropriately neutralized, and if insolubles are present, they are removed by filtration, an organic solvent immiscible with water is added, and after washing with water, the solvent is distilled off. can get.
  • the obtained target compound can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or chromatography.
  • the administration form of the compound (I) of the present invention includes, for example, oral administration by tablets, capsules, granules, powders or syrups, or parenteral administration by injections or suppositories.
  • These preparations may include excipients (eg, lactose, sucrose, dextrose, mannite, saccharides such as sorbite; corn starch, starch starch, starch, Dextrin, power Starch derivatives such as ropoxymethyl starch; cellulose derivatives such as crystalline cellulose, low-substituted hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, carboxymethylcellulose calcium, and internally-carboxylated methylcarboxymethylcellulose sodium.
  • excipients eg, lactose, sucrose, dextrose, mannite, saccharides such as sorbite
  • corn starch, starch starch, starch, Dextrin power Starch derivatives such as ropoxymethyl starch
  • Arabic gum dextran
  • organic excipients such as burlan: and silicate derivatives such as light silicic anhydride, synthetic aluminum silicate, and magnesium metasilicate magnesium
  • silicate derivatives such as light silicic anhydride, synthetic aluminum silicate, and magnesium metasilicate magnesium
  • Inorganic excipients such as phosphates, carbonates such as calcium carbonate, and sulfates such as calcium sulfate.
  • Lubricants eg, stearic acid, calcium stearate, metal stearate such as magnesium stearate; talc; colloid silica; veegum; Cousins; boric acid; adipic acid; sulfates such as sodium sulfate; glycol; fumaric acid; sodium benzoate; DL leucine; sodium fatty acid salt; sodium lauryl sulfate; Lauryl sulfates such as magnesium lauryl sulfate; silicic acids such as silicic anhydride and silicic acid hydrate; and the above-mentioned starch derivatives.), Binders (for example, polyvinylpyrrolidone) Don, Macrogol, and the same compounds as the excipients can be mentioned.), Disintegrants (for example, the same compounds as the excipients, and Chemically modified starches such as croscarmellose sodium, carboxymethyl starch sodium, and cross-linked polyvinyl pyr
  • the amount used depends on the symptoms, age, administration method, etc.For example, in the case of oral administration, the lower limit is 0.1 mg / kg and the upper limit is 20 mg / kg. In the case of intravenous administration, it is preferable to administer once or less, 0.01 mg / kg as the lower limit and 2 mg / kg as the upper limit, once or several times a day depending on the symptoms.
  • the present invention will be described in more detail with reference to examples.
  • reaction mixture solvent was evaporated under reduced pressure, acetic Echiru 2 0 m 1 was added 5% Kuen acid, washed with 5 0 / oN a HC O3 solution and saturated brine, and dried over anhydrous N a 2 S 0 4 .
  • Anti ⁇ compound solvent was evaporated under reduced pressure, acetic Echiru 3 0 m 1 was added 5% Kuen acid, 5% N a HC 03 solution and saturated brine in washing ⁇ , dried over anhydrous N a 2 S 0 4 did.
  • the solvent was evaporated under reduced pressure, and the oily residue was purified by silica gel chromatography (methylene chloride-methanol-methanol-10 :). Crystallization from hexane gave 1.56 g of the title compound as a white crystalline solid.
  • reaction mixture solvent was evaporated under reduced pressure, acetic Echiru 2 0 ml was added, 5% Kuen acid, 5% N a HC 03 solution and saturated brine in washing ⁇ and Drying over anhydrous N a 2 S 0 4 .
  • the solvent is decompressed and the oily residue is purified by silica gel chromatography.
  • reaction mixture solvent was evaporated under reduced pressure, acetic Echiru 2 0 m 1 was added 596 Kuen acid, 5 6 N a HC O3 solution and a saturated saline wash ⁇ , and dried over anhydrous N a 2 S 0 4.
  • the reaction mixture was evaporated reduced pressure solvent, acetic Echiru 2 0 m 1 was added 5% Kuen acid, 5% N a HC O3 solution and a saturated saline wash ⁇ , and dried over anhydrous N a 2 S 0 4.
  • reaction mixture was washed with 5% citrate, 5% NaHCl3 aqueous solution and brine, and dried over anhydrous Na2S04.
  • each of the standard bisected hard gelatin capsules by filling each of the standard bisected hard gelatin capsules with 100 mg of the powdered compound of Example 1, 150 mg of lactose, 50 mg of cellulose and 6 mg of magnesium stearate, Manufacture unit capsules, wash and dry.
  • a mixture of the compound of Example 1 in a digestible oil for example, soybean oil, cottonseed oil, or olive oil, is prepared and injected into gelatin with a positive displacement pump to give a soft powder containing 100 mg of active ingredient.
  • a digestible oil for example, soybean oil, cottonseed oil, or olive oil
  • the HIV protease inhibitory activity of the peptide derivative of the present invention was determined using the IC 50 value as an index as follows.
  • Escherichia coli BL-21 containing the T7 polymerase gene [(DE-3) Barbar a A. Mofiatt et al., J. Mol. Biol., 189, 113-130, 1986] describes: After transfection of pT7HIV.GP (-), the resulting transformants were transformed into 600% of M9CA—10% LB medium containing 200 ⁇ gZml of ampicillin. Culture at 37 until the absorbance at nm reaches 2.
  • the obtained cells were collected and stored as pellets at 18.
  • the polyprotein synthesized from the expression vector is degraded in the cells by autolysis, and the HIV protease itself is produced.
  • DNaseI 0.1 mg
  • 10 mM magnesium chloride were added to decompose DNA in the suspension.
  • the supernatant obtained by centrifuging this suspension was applied to DEAE Sephade XA25 column (5 cm inner diameter X 20 cm) to fractionate.
  • the column is a buffer B [5 O mMHE PES (pH 7.8),] mM dithiol. Plate, lO ⁇ gZmI aprotinin, 5 mM ethylenediaminetetraacetic acid, 1 OgZml benzamide, 1 mM fluormethylsulfonic acid, 10% glycerin] Using.
  • the obtained active fraction was concentrated twice by using an ultrafiltration membrane having a molecular weight cut off of 10,000 daltons, and stored at 180 as an enzyme solution.
  • the measurement of the HIV protease inhibitory activity was carried out based on the method of E.D.Matey0shhi et al. (Science 247,954 (1990)).
  • EDAN S I-sulfonic acid
  • a reaction solution of 50 mM sodium acetate (pH 5.5) -11 M saline containing the inhibitor at each concentration was prepared.
  • a partially purified recombinant HIV protease was added thereto, the reaction was started at room temperature, and the reaction product was measured by a fluorescence spectrophotometer. The amount of reaction produced per unit time in the presence of each concentration of the inhibitor was calculated, and the 509 inhibition degree (IC 50 ) was determined.
  • the compounds of the present invention showed strong inhibitory activity.
  • Mo1t4 cells (Mo1t4ZHTLVIIIB) persistently infected cells
  • Mo1t4 cells (Mo1t4ZHTLVIIIB) were transformed twice using RPMI1640 medium (containing 1096 non-immobilized fetal calf serum). After washing, the cells were inoculated into the same medium at a concentration of ixi 05 cells, and cultured at 37 under 5% carbon dioxide gas. After 2 hours, the culture supernatant was obtained by centrifugation and used as virus stock: C ⁇ cells were grown in R ⁇ I 1640 medium (containing 10% non-immobilized fetal calf serum) for 2 hours. xi 0 was adjusted to 5 cells / / ml, were added to the virus scan bets get diluted to a suitable concentration.
  • the compounds of the present invention exhibited strong virus release inhibitory activity.
  • the compounds of the present invention exhibit pharmacodynamic properties which are expected to exert the above inhibitory effects in vivo.
  • 1 OmgZkg of the compound of the present invention is intravenously administered to a rat
  • the blood level at 1 hour after the administration is almost the same as or higher than the ED go value in the cell test.
  • the concentration detected in the blood of the rat 30 minutes after administration is higher than the ED90 value in the cell test, preferably the cell concentration. It is about 6 times the ED 90 value in the test.
  • a solution for administration as follows.
  • 1 Omg of the test compound is dissolved in 0.3 ml of dimethylacetamide (DMA), and a solution is prepared by adding 0.4 ml of PEG 400 ml and 0.3 ml of water I do.
  • DMA dimethylacetamide
  • 30 m of the test compound was dissolved in 0.6 ml of DMA, then 0.8 ml of PEG and 0.8 ml of water.
  • blood is collected over time, and the blood is centrifuged (300 rpm, 10 minutes) to obtain plasma. Analyze by HPLC using the column switching method to determine the plasma concentration.

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un nouveau tripeptide contenant de l'AHPBA représenté par la formule générale (I). Ce produit a une excellente activité inhibitrice de la protéase du VIH et il est utile comme médicament préventif ou thérapeutique contre l'infection par le VIH. Dans la formule (I), R1 représente un groupe quinoléine-2-carbonyle ou quinoxaline-2-carbonyle; et R2 représente H, un alkyle, un acétyle, un méthoxyméthyle, un méthylthiométhyle, un acétoxyméthyle, un pivaloyloxyméthyle, un HOOC(CH¿2?)nCO- (où n représente un nombre entier de 2 à 4) ou un HOOCCH2OCH2CO-.
PCT/JP1995/002546 1994-12-14 1995-12-13 Derive tripeptidique contenant de l'ahpba WO1996018627A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU41880/96A AU4188096A (en) 1994-12-14 1995-12-13 Ahpba-containing tripeptide derivative

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP6/310419 1994-12-14
JP31041994 1994-12-14

Publications (1)

Publication Number Publication Date
WO1996018627A1 true WO1996018627A1 (fr) 1996-06-20

Family

ID=18005036

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP1995/002546 WO1996018627A1 (fr) 1994-12-14 1995-12-13 Derive tripeptidique contenant de l'ahpba

Country Status (2)

Country Link
AU (1) AU4188096A (fr)
WO (1) WO1996018627A1 (fr)

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0578311A (ja) * 1991-02-08 1993-03-30 Sankyo Co Ltd β−アミノ−α−ヒドロキシカルボン酸誘導体
WO1993013066A1 (fr) * 1991-12-20 1993-07-08 Syntex (U.S.A.) Inc. Amides cycliques d'acides 3-amino-2-hydroxy-carboxyliques utilises comme inhibiteurs de la protease du vih
JPH05170722A (ja) * 1990-12-11 1993-07-09 Nikko Kyodo Co Ltd Ｈｉｖプロテアーゼ阻害剤
JPH05178824A (ja) * 1991-08-05 1993-07-20 Takeda Chem Ind Ltd アスパラギン誘導体およびその用途
JPH06100533A (ja) * 1992-08-07 1994-04-12 Sankyo Co Ltd Ｈｉｖプロテアーゼ阻害活性を有するペプチド誘導体

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH05170722A (ja) * 1990-12-11 1993-07-09 Nikko Kyodo Co Ltd Ｈｉｖプロテアーゼ阻害剤
JPH0578311A (ja) * 1991-02-08 1993-03-30 Sankyo Co Ltd β−アミノ−α−ヒドロキシカルボン酸誘導体
JPH05178824A (ja) * 1991-08-05 1993-07-20 Takeda Chem Ind Ltd アスパラギン誘導体およびその用途
WO1993013066A1 (fr) * 1991-12-20 1993-07-08 Syntex (U.S.A.) Inc. Amides cycliques d'acides 3-amino-2-hydroxy-carboxyliques utilises comme inhibiteurs de la protease du vih
JPH06100533A (ja) * 1992-08-07 1994-04-12 Sankyo Co Ltd Ｈｉｖプロテアーゼ阻害活性を有するペプチド誘導体

Also Published As

Publication number Publication date
AU4188096A (en) 1996-07-03

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