WO2004024685A1 - Nouveaux composes dipeptidiques et utilisation de ces derniers a des fins medicales - Google Patents

Nouveaux composes dipeptidiques et utilisation de ces derniers a des fins medicales Download PDF

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Publication number
WO2004024685A1
WO2004024685A1 PCT/JP2003/011672 JP0311672W WO2004024685A1 WO 2004024685 A1 WO2004024685 A1 WO 2004024685A1 JP 0311672 W JP0311672 W JP 0311672W WO 2004024685 A1 WO2004024685 A1 WO 2004024685A1
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group
amino
hydroxy
compound
pharmaceutically acceptable
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PCT/JP2003/011672
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English (en)
Japanese (ja)
Inventor
Tsutomu Mimoto
Keisuke Terashima
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Sumitomo Pharmaceuticals Co., Ltd.
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Priority to AU2003262091A priority Critical patent/AU2003262091A1/en
Publication of WO2004024685A1 publication Critical patent/WO2004024685A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom 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
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom 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 hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to a novel peptide compound that inhibits the enzyme activity of HIV protease, and an anti-AIDS drug that suppresses HIV growth in the body by utilizing the inhibitory effect of the peptide compound on HIV protease.
  • HIV Human immunodeficiency virus
  • proproteins are only cut to a specific size by a virus-derived protease (HIV protease), and each function can be achieved only when it is cut.
  • HIV protease virus-derived protease
  • HIV protease inhibitors that inhibit the activity of the above HIV proteases and block the formation and maturation of infectious virions can be used as antiviral agents, and some HIV protease inhibitors have already been used clinically. I have.
  • the present inventor has also shown that a dipeptide derivative containing 3-amino-2-hydroxy-4-phenylbutanoic acid (AHPBA, hydroxymethylcarboxamide derivative) in its basic structure strongly inhibits the activity of HIV protease. It was found to exhibit antiviral activity and was proposed as an anti-AIDS drug (JP-A-10-25242).
  • AHPBA 3-amino-2-hydroxy-4-phenylbutanoic acid
  • JP-A-10-25242 JP-A-10-25242
  • a dipeptide derivative having a substituent on the aromatic ring of AHPBA has the property of maintaining a strong antiviral activity even in the presence of plasma protein, and has proposed it as a novel HIV protease inhibitor (W001 / 47948 A1).
  • HIV protease inhibitors have shown sufficient efficacy in the clinic, but their use requires frequent use of large amounts of drugs, and this is necessary from the viewpoint of compliance, side effects, and induction of resistance. There is still a problem, and there is a need for pharmacokinetic drugs that are effective at low doses and infrequent doses. Disclosure of the invention
  • the present invention has been made in view of the above situation, and is a novel dipeptide compound having excellent pharmacokinetics as compared with a conventional HIV protease inhibitor comprising a substrate transition state derivative proposed as an anti-AIDS drug. And an anti-AIDS drug.
  • the present inventors have conducted various studies in order to solve the above-mentioned problems, and as a result, among the peptide derivatives having a substituted AHPBA described in WO 01/47948, in particular, the 3,3-dimethylpyrrolidine-2-carbonyl structure Have been found to have excellent effects on metabolism by human liver microsomal enzyme-derived enzymes, and also maintain high blood levels in pharmacokinetic studies, leading to the completion of the present invention.
  • the present invention is as follows.
  • R 1 represents a hydroxyl group or an amino group
  • R 2 represents a lower alkyl group or a halogeno group
  • R 3 , R 4 and R 5 each independently represent a lower alkoxy group or a lower alkoxy group.
  • R 3 and R 4 are R 6 and R 7 may be independently bonded to each other to represent a methylenedioxy group or an ethylenedioxy group
  • R 6 and R 7 each independently represent a lower alkyl group, a halogeno group or a hydrogen atom.
  • R 1 R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 have the same meanings as in the above (1).
  • a pharmaceutically acceptable salt thereof
  • R 2 represents a methyl group or a chloro group
  • R 6 and R 7 each independently represent a methyl group, a chloro group or a hydrogen atom.
  • An anti-AIDS drug comprising, as an active ingredient, the dipeptide compound or the pharmaceutically acceptable salt thereof described in (1) Kiki et al. (5).
  • FIG. 1 is a graph showing the change over time in the concentration of a compound in plasma of Test Example 4. The best way to implement
  • R 1 in the general formulas (I) and (II) of the present invention represents a hydroxyl group or an amino group.
  • the lower alkyl group in R 2 for example 1 to 4 carbon atoms having a straight-chain or branched, halogeno methyl group, Echiru group, propyl group, heptyl group, an isopropyl group, sec Petit Le group, also in R 2
  • the group include a fluoro group, a chloro group, and a bromo group.
  • R 2 a methyl group, Echiru group, black port group, and a bromo group, more preferably methyl group, black port group.
  • a linear or branched C 1-4 alkoxy group such as methoxy group, ethoxy group, propoxy group, butoxy group, isopropoxy group, sec butoxy group, tert-butoxy group and the like.
  • a linear or branched C 2-4 alkyl group such as a vinyloxy group, an aryloxy group, an isopropenyloxy group, a 1-propenyloxy group, etc. Is mentioned.
  • Examples of the lower alkoxy group in R 3 , R 4 and R 5 include a straight-chain or branched C 2-8 alkoxy group, for example, a methoxy methoxy group, an ethoxy methoxy group, and a methoxy ethoxy group. No.
  • R 3 , R 4 and R 5 include a methoxy group and an ethoxy group.
  • R 3 and R 4 may be bonded to each other to represent a methylenedioxy group or an ethylenedioxy group, more preferably a methylenedioxy group.
  • Examples of the lower alkyl group for R 6 and R 7 include a linear or branched C 1 to C 4 alkyl group such as a methyl group, an ethyl group, a propyl group, a butyl group, an isopropyl group and a sec butyl group.
  • Examples of the halogeno group for R 6 and R 7 include a fluoro group, a chloro group, and a bromo group.
  • R 6 and R 7 include a methyl group, an ethyl group, a chloro group, a bromo group, and a hydrogen atom, and more preferably a methinole group.
  • the pharmaceutically acceptable salts of the dipeptide compounds of the present invention specifically include hydrochloride, acetate, methanesulfonate, oxalate, citrate, succinate and the like. Can be.
  • a series of dipeptide compounds represented by the above general formulas (I) and (II) can be prepared by a known method for synthesizing a hydroxy-] 3-amino acid (R. Nishizawa et al., J ". Med. Chem., 20, 510 (1977), Umezawa et al., JP-A-56-90050, W. Yuan et al., J. Med. Chem., 36, 211 (1993), Matsumoto et al., JP-A-10-59909, or Suzuki et al. , Japanese Patent Laid-Open No.
  • N-protected-hydroxy- / 3-amino acid derivatives synthesized by known methods and known synthetic methods (Morgan, Barry Arnold et al., DE 2609154, R. Sharma et al. J. Org. Chera., 61, 202-9) (1996)), using N-protected-3,3-dimethylpyrrolidine-2-carboxylic acid, a method for synthesizing a known hydroxymethy / recarboxamide HIV protease inhibitor (T. Mimoto et al. J. Med. Chem., 42, 1789 (1999)).
  • a cyanohydrin derivative obtained by reacting a hydrogen cyanide equivalent with a ⁇ -protected aminoaldehyde prepared by a conventional method is hydrolyzed under acidic conditions such as hydrochloric acid to obtain the desired hydroxy-] 3 -Can lead to amino acids.
  • N-protected-3,3-dimethylpyrrolidine-2-carboxylic acid can be added to N-benzyloxycarbonylaminomalonic acid getyl ester in the presence of a base such as sodium methoxide.
  • a base such as sodium methoxide.
  • -Methyl-2-butenal, followed by catalytic hydrogen reduction in the presence of palladium, alkali saponification, and then decarboxylation by heating under acidic conditions, and Boc 20 and Z-C1 are widely used.
  • the reaction with N-protected reagent can lead to N-protected-3,3-dimethylpyrrolidine-2-carboxylic acid.
  • the racemic mixture thus obtained can be split into only the S-isomer, which has a more preferred configuration, by forming a salt with the optically active form.
  • the diastereomer after the diastereomer is formed in the subsequent steps, it can be converted to a compound containing only the S-isomer, which is a more preferable configuration, by column chromatography or recrystallization.
  • hydroxymethylcarboxamide-type compounds can be performed, for example, by using a phenyl-aminocarboxamide derivative with a benzyl substitution at the carbamoyl nitrogen atom and an N-protected (2S, 3S) -3-amino-2-hydroxy-phenylbutanoic acid derivative.
  • HOBt N-hydroxybenzotriazo
  • HOSu N-hydroxysuccinimide
  • DCC ⁇ , ⁇ '-dicyclohexylcarbodiimide
  • EDC 1-ethyl-3- (3- ⁇ , ⁇ Amide bond is formed by the action of carbodiimide reagents such as' -dimethylaminopropyl pill) carbodiimide), followed by the action of an acid such as hydrochloric acid or catalytic hydrogenolysis using palladium as a catalyst. Deprotection of the amino group.
  • the desired amino-modifying group is condensed to the obtained dipeptide amine derivative by a method such as the above-mentioned carpoimide method, acid chloride method or mixed acid anhydride method, whereby the peptide of the present invention is obtained. Can be obtained.
  • the desired synthesis can be carried out as a nitro group, and a final reduction can lead to an amino group.
  • the chemical structure of the dipeptide compound of the present invention can be easily determined by a spectroscopic method such as a nuclear magnetic resonance method or an infrared absorption method, and mass spectrometry.
  • the dipeptide compound of the present invention When the dipeptide compound of the present invention is clinically applied as an anti-AIDS drug, it can be administered in the form of a pharmaceutical according to a conventional method using a pharmaceutical carrier or excipient for f penetration.
  • they can be injected intravenously or intramuscularly as injections, or parenterally administered as sprays, suppositories, etc., orally administered as granules, capsules, liquids, tablets and the like.
  • the dipeptide compound of the present invention is a low-molecular compound having excellent in vivo stability and excellent gastrointestinal absorption, so that it can be orally administered as granules, capsules, liquids, tablets and the like. Is the purpose.
  • the dose is determined as appropriate according to the age of the patient, the gender, etc., depending on the symptoms of the subject, or the therapeutic purpose, such as suppression of the onset of AIDS and suppression of the progression of AIDS. It is administered 1 to 4 times a day in the range of 10 mg to 2 g.
  • Penzinoleoxycarboni / leaminomalonic acid getyl ester (16.7 g, 54 mmol) was dissolved in a solution of sodium ethoxide in ethanol (0.34 M, 40 ml), and 3 -methyl-2-butenal (5. 7 ml, 59 mmol) and stirred at room temperature for 2 days.
  • Solution A was added to solution B at an internal temperature of about 5 ° C, and the reaction was further performed at 40 ° C for 6 hours.
  • reaction solution was added to a solution consisting of 1N hydrochloric acid (150 ml) and ethyl acetate (150 ml).
  • the organic layer was washed with water and 5% brine, and dried over anhydrous magnesium sulfate. After filtration and concentration, the residue was purified by silica gel chromatography and recrystallized from a mixed solvent of ethyl acetate and n-hexane to obtain the title compound (6.3 g, 70%).
  • reaction solution was washed with a 5% aqueous sodium carbonate solution, 1N hydrochloric acid, and 5% saline, and then dried over anhydrous magnesium sulfate. After filtration and concentration, 4N hydrochloric acid / ethyl acetate (20 ml) was added, and the mixture was stirred for 3 hours.
  • the reaction solution was ice-cooled, neutralized with a 2N aqueous sodium hydroxide solution, and the organic layer was washed with 5% brine and dried over anhydrous magnesium sulfate. Dried.
  • Example 1 using (2S, 3S) _3- (N-tert-butoxycarbo-nore) amino-2-hydroxy_4- (4-methoxyphenyl) butanoic acid obtained in the same manner as in Reference Example 2.
  • the title compound was obtained according to the same method as described above.
  • HIV protease inhibitory activity was prepared by a genetic recombination method using Escherichia coli. It was measured under the following conditions using HIV protease (NY5 type).
  • Table 1 shows an example of the evaluation results of the HIV protease inhibitory activity and the anti-HIV activity.
  • the compounds of the examples are inferior in the HIV-1 protease inhibitory activity as compared with the corresponding compounds of the comparative examples, and are equivalent to the compounds of the comparative examples because of their excellent cell membrane permeability. It is evident that it exhibits anti-HIV activity.
  • Test example 3
  • Human and dog microsomes were prepared by thawing a frozen product and diluting it with 0.1 N (Na + ) phosphate buffer (pH 7.4) to a concentration of 5 mg / ml.
  • the reaction was started by adding a microsomal solution.
  • the reaction was performed at 37 ° C for 30 minutes, and the reaction was stopped by adding 400 ⁇ l of cold methanol containing 1.5 ng / ml of biphenyl as an internal standard substance.
  • This sample was mixed well, left standing on ice for 10 minutes, and then centrifuged at 10,000 X g for 10 minutes.
  • the obtained sample was passed through a PTFE membrane (Mill ex LG 0.22 ⁇ ) to obtain a sample for analysis.
  • Table 2 shows the results of metabolic experiments using liver microsomes.
  • Drugs (compound of Example 1, compound of Comparative Example 1 and Atazanavir) were dissolved in 50% polyethylene glycol # 400 (PEG # 400), adjusted to a concentration of 3 mg / ml, and administered at a volume of 5 ml / kg. (3 dogs were used for each treatment group).
  • PEG # 400 polyethylene glycol # 400
  • Administration was performed by oral gavage using a tube, and blood was collected at 30 minutes, 1, 2, 3, 4, 6, 12, 24 hours after administration into a heparin-treated syringe via the external jugular vein. One mL was collected and performed. The collected blood was immediately centrifuged (1,870 X g for 10 minutes), and the supernatant was obtained as a blood clot.
  • tert-heptyl have rows deproteinized plasma by extraction using methyl ether (MTBE), 40 ° and the organic layer obtained by centrifugation C, solidified centrifugal drying under reduced pressure, re-residue 50% methanol
  • the lysate was loaded onto an HPLC, eluted with a linear gradient of water / acetonitrile containing 0.1% TFA, and monitored by measuring the UV absorbance at 210 nm.
  • Compound concentration in plasma sample The quantification of was calculated based on a calibration curve obtained by analyzing a standard plasma sample containing known concentrations of the compounds, and the results are shown in FIG.
  • the compounds shown in the examples were compared with the compounds of the comparative examples in liver micromixing. It can be seen that it has excellent stability against metabolism by rosomes and, as a result, has the property of maintaining high blood levels.
  • Example 1 100 mg of Example 1, 0.2 mg of colloidal silicon dioxide, 5 mg of magnesium stearate, 275 mg of microcrystalline cellulose, 11 mg of starch, and 98.8 mg of ratatose It is manufactured using
  • novel compounds of the present invention have HIV protease inhibitory activity and use this property to exhibit antiviral activity by blocking the formation and maturation of infectious virions in HIV T-cell lymphocytes. It becomes a compound.
  • the compound of the present invention exhibits high stability against metabolic enzymes derived from human liver microsomes, a novel drug capable of maintaining a high drug concentration in blood for a long period of time when administered to a living body. It will have pharmaceutical use as an anti-AIDS drug.

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  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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  • AIDS & HIV (AREA)
  • Tropical Medicine & Parasitology (AREA)
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  • Bioinformatics & Cheminformatics (AREA)
  • Communicable Diseases (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pyrrole Compounds (AREA)

Abstract

L'invention concerne un composé dipeptidique de formule générale (I), dans laquelle R1 représente hydroxyle ou amino, R2 représente alkyle inférieur ou halogéno, chaque radical R3, R4 et R5 représente indépendamment l'un de l'autre alcoxy inférieur, alcényloxy inférieur ou hydrogène (à condition que R3, R4 et R5 ne représentent pas simultanément hydrogène) à condition que R3 et R4 puissent être liés l'un à l'autre pour former ainsi méthylènedioxy ou éthylènedioxy, et chaque radical R6 et R7 représente indépendamment l'un de l'autre alkyle inférieur, halogéno ou hydrogène ; ou un sel pharmaceutiquement acceptable dudit composé ; et un médicament anti-SIDA contenant ledit composé en tant que principe actif. Comparé aux inhibiteurs de la protéase du VIH classiques, ce nouveau composé dipeptidique présente d'excellentes propriétés sur le plan de la cinétique du médicament.
PCT/JP2003/011672 2002-09-13 2003-09-11 Nouveaux composes dipeptidiques et utilisation de ces derniers a des fins medicales WO2004024685A1 (fr)

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JP2002-269031 2002-09-13
JP2002269031A JP2006076882A (ja) 2002-09-13 2002-09-13 新規なジペプチド化合物及びその医薬用途

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001047948A1 (fr) * 1999-12-28 2001-07-05 Japan Energy Corporation Nouveau composé dipeptidique et ses applications en médecine
WO2002100844A2 (fr) * 2001-06-11 2002-12-19 Agouron Pharmaceuticals, Inc. Inhibiteurs de la protease vih, compositions les contenant, leurs utilisations pharmaceutiques et materiaux utilises pour leur synthese

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001047948A1 (fr) * 1999-12-28 2001-07-05 Japan Energy Corporation Nouveau composé dipeptidique et ses applications en médecine
WO2002100844A2 (fr) * 2001-06-11 2002-12-19 Agouron Pharmaceuticals, Inc. Inhibiteurs de la protease vih, compositions les contenant, leurs utilisations pharmaceutiques et materiaux utilises pour leur synthese

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AU2003262091A1 (en) 2004-04-30

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