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WO1999033787A1 - Derives d'acides amines - Google Patents

Derives d'acides amines Download PDF

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Publication number
WO1999033787A1
WO1999033787A1 PCT/JP1998/005742 JP9805742W WO9933787A1 WO 1999033787 A1 WO1999033787 A1 WO 1999033787A1 JP 9805742 W JP9805742 W JP 9805742W WO 9933787 A1 WO9933787 A1 WO 9933787A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl group
group
amino acid
branched
alkenyl group
Prior art date
Application number
PCT/JP1998/005742
Other languages
English (en)
Japanese (ja)
Inventor
Hiroshi Maruoka
Shigeru Suzuki
Kunitaka Hirose
Mikiro Yanaka
Michinori Hakozaki
Toru Yamazaki
Toshikazu Dewa
Yoshiyuki Takemura
Eiji Inoguchi
Takeo Edamatsu
Original Assignee
Kureha Chemical Industry Co., Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from JP9368042A external-priority patent/JPH11193264A/ja
Priority claimed from JP10092306A external-priority patent/JPH11269195A/ja
Priority claimed from JP10092307A external-priority patent/JPH11269134A/ja
Application filed by Kureha Chemical Industry Co., Ltd. filed Critical Kureha Chemical Industry Co., Ltd.
Priority to AU16840/99A priority Critical patent/AU1684099A/en
Publication of WO1999033787A1 publication Critical patent/WO1999033787A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
    • C07K5/06026—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atom, i.e. Gly or Ala
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
    • C07K5/06034—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms
    • C07K5/06043—Leu-amino acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C07K5/0819—Tripeptides with the first amino acid being acidic
    • 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 amino acid derivative and a salt thereof. Furthermore, the present invention relates to a chemokine receptor antagonist comprising this compound as an active ingredient.
  • the compound of the present invention is used as a chemokine receptor antagonist for treating or preventing AIDS, allergic diseases, inflammatory diseases and the like. n landscape technology
  • Chemokine (short for chemokine, cheraotactic cytokine) is a group of proteins having chemotactic activity on leukocytes, and is a CXC chemokine with one amino acid inserted between the first and second cystine. There is a chemokine subfamily and a CC chemokine subfamily with the first and second cysteines adjacent. The CXC chemokine has enabled the entry of T-cell lin- tropic HIV (T-HIV) into CD4-positive cells.
  • the CC chemokine family includes RANTES, MIP-1 MCP-1, MCP-2, MCP-3, 1-309, and so on.
  • CCR5 the second receptor of macrophage-1 ropic HIV (M-HIV)
  • M-HIV macrophage-1 ropic HIV
  • CC chemokines act alone, act on lymphocytes, eosinophils, basophils, and mast cells to migrate these cells, and also act to degranulate and release various inflammatory mediators.
  • Interleukin 8 (lL-8) is also known as a chemokine.
  • CXCR4 had already been found and cloned by the Matsushima group at Kanazawa University (now Tokyo University), and SDF-1 had already been cloned by the Honjo group at Kyoto University and the Kishimoto group at Osaka University.
  • CC chemokines ⁇ chemokines such as RANTES, MIP-1 and others
  • chemokine receptor antagonist a peptide consisting of 6 to 14 amino acids of Arg Arg Trp Trp Cys Xaa is used as an interleukin 8 antagonist (wo95 / 16702), and an indole derivative is used.
  • interleukin 8 antagonists JP-A-9-169729
  • chemokine receptor antagonists containing piperidine derivatives JP-A-9-249566
  • the present inventors have conducted intensive studies to develop drugs that inhibit diseases caused by chemokines such as interleukin 8, RANTES, MIP-1 and SDF-1, and found that a novel amino acid derivative was obtained. On the other hand, they have found that they have an antagonistic effect on receptors such as RANTES, MIP-1 and SDF-1. Further, as a result of further study based on this finding, the present invention was completed.
  • chemokines such as interleukin 8, RANTES, MIP-1 and SDF-1
  • an object of the present invention is to provide a novel amino acid derivative and a chemokine receptor antagonist comprising the amino acid derivative as an active ingredient.c
  • the amino acid derivative is one or more amino acid residues Means an amino acid derivative containing one amino acid residue and an amino acid derivative containing a peptide consisting of two or three amino acid residues together with a derivative consisting of two or three amino acid residues.
  • the present invention relates to an amino acid derivative represented by the following formula (1) or a salt thereof.
  • A is arginine containing at least one amino acid residue selected from the group consisting of arginine, lysine, and ordinine, or A or arginine, lysine, and ordinine;
  • a peptide consisting of two or three amino acid residues selected from the group consisting of, lysine, ordinine, leucine, alanine, quinoline, isoleucine, glycine, glumic acid and aspartic acid Is shown.
  • Y is absent, or - 0 -, - S -, - NH- or - NR 3 - shows the.
  • RR 2 independently represents a straight-chain alkyl group having 12 to 30 carbon atoms, a branched alkyl group, a cyclic alkyl group, a cholesteryl group, a straight-chain alkenyl group having 1 to 5 double bonds or a branched alkenyl group.
  • R 1 and!? 2 represents a hydrogen atom, a linear alkyl group having 1-8 carbon atoms, a branched alkyl group, a straight-chain alkenyl group, a branched alkenyl group or a cyclic alkyl group.
  • R 3 represents a hydrogen atom, a linear alkyl group having 1 to 8 carbon atoms, a branched alkyl group, a linear alkenyl group, a branched alkenyl group or a cyclic alkyl group.
  • the present invention also relates to an amino acid derivative represented by the following formula (I) or a salt thereof.
  • R 1 -X is ph-X 2 -A-YR 2 (I)
  • A represents an amino acid residue selected from D or L arginine, lysine and orditin.
  • Y is absent, or - 0 -, - S-, -NH- or - NR 3 - shows the.
  • R′R 2 is independently a straight-chain alkyl group having 12 to 30 carbon atoms, a branched alkyl group, a cyclic alkyl group, a cholesteryl group, a straight-chain alkenyl group having 1 to 5 double bonds or a branched alkenyl group.
  • R 1 !? 2 represents a hydrogen atom, a straight-chain alkyl group having 1-8 carbon atoms, a branched alkyl group, a straight-chain alkenyl group, a branched alkenyl group or a cyclic alkyl group.
  • R represents a hydrogen atom, a linear alkyl group having 1 to 8 carbon atoms, a branched alkyl group, a linear alkenyl group, a branched alkenyl group or a cyclic alkyl group.
  • substitution position for the ph group may be any of ortho, meta and para.
  • the present invention also relates to an amino acid derivative having no ph group or X 2 in the formula (I), that is, an amino acid derivative represented by the following general formula (I) or a salt thereof.
  • A represents an amino acid residue selected from the group consisting of arginine, lysine and ordinine;
  • Y is absent or represents -0-, -S- or -NR 3- .
  • R 1 and R 2 are each independently a straight-chain alkyl group having 12 to 30 carbon atoms, a branched alkyl group, a cyclic alkyl group, a cholesteryl group, a straight-chain alkenyl group having 1 to 5 double bonds or a branched alkenyl group.
  • one of R 1 and R 2 represents a hydrogen atom, a linear alkyl group having 1 to 8 carbon atoms, a branched alkyl group, a cyclic alkyl group, a linear alkenyl group or a branched alkenyl group.
  • R 2 may have an acyloxy group at the terminal.
  • R 3 represents a hydrogen atom, a linear alkyl group having 1 to 8 carbon atoms, a branched alkyl group, a cyclic alkyl group, a linear alkenyl group or a branched alkenyl group.
  • the present invention relates to an amino acid derivative in which the ph group and X 2 are not present in the formula (1) and two to three amino acids are peptide-bonded, that is, an amino acid derivative represented by the following general formula (3) Or its salts.
  • A contains at least one amino acid residue selected from the group consisting of arginine, lysine and orditin, arginine, lysine, orditin, leucine, alanine, nokurin, isoleucine , Glycine, glutamic acid and aspartic acid, and a peptide consisting of two or three amino acid residues.
  • Y is absent, - 0- '-S- or - NR 3 - shows the.
  • R 1 and R 2 are each independently a straight-chain alkyl group having 12 to 30 carbon atoms, a branched alkyl group, a cyclic alkyl group, a cholesteryl group, a straight-chain alkenyl group containing 1 to 5 double bonds, and a branched alkenyl group.
  • one of R 1 and R 2 is a hydrogen atom, a straight-chain alkyl group having 1 to 8 carbon atoms, a branched alkyl group, a cyclic alkyl group, a straight-chain alkenyl group, or a branched alkenyl group.
  • R 2 May have an acyloxy group at the terminal.
  • R 3 represents a hydrogen atom, a linear alkyl group having 1 to 8 carbon atoms, a branched alkyl group, a cyclic alkyl group, a direct alkenyl group or a branched alkenyl group.
  • the present invention relates to a caffeine receptor antagonist comprising an amino acid derivative represented by the above general formula (1) or a salt thereof as an active ingredient.
  • amino acid derivative of the present invention is represented by the following general formula.
  • A is an arginine containing at least one amino acid residue selected from D or L arginine, lysine and orditin, or an amino acid residue selected from the group consisting of arginine, lysine and orditin.
  • a peptide consisting of two or three amino acid residues selected from the group consisting of lysine, orthine, leucine, alanine, quinoline, isoleucine, glycine, glutamic acid and aspartic acid.
  • Y is absent, or - 0 -, - S- NH- or - NR 3 - shows the.
  • RR 2 independently represents a straight-chain alkyl group having 12 to 30 carbon atoms, a branched alkyl group, a cyclic alkyl group, a cholesteryl group, a straight-chain alkenyl group containing 1 to 5 double bonds or a branched alkenyl group.
  • R 1 and!? 2 represents a hydrogen atom, a linear alkyl group having 1-8 carbon atoms, a branched alkyl group, a straight-chain alkenyl group, a branched alkenyl group or a cyclic alkyl group.
  • R 3 is a hydrogen atom, a linear alkyl group having 1-8 carbon atoms, a branched alkyl group, a linear It represents an alkenyl group, a branched alkenyl group or a cyclic alkyl group.
  • substitution position of the ph group may be any of ortho, meta and para.
  • R 1 is a linear alkyl having 4-8 carbon atoms.
  • R 2 is an amino acid derivative that is a linear alkyl group, branched alkyl group, cyclic alkyl group, cholesteryl group, or linear alkenyl group or branched alkenyl group containing 1-5 double bonds, having 12-30 carbon atoms.
  • Y is -0- or -NH-, or a salt thereof.
  • no ph group and X 2 may be prepared by synthetic methods known peptide.
  • amino acid residue is one of the present invention, and, as the ⁇ amino acid derivative ph group and X 2 is absent can be exemplified the following compounds.
  • Acetyl-shi-arginine-n-octadecyl ester (Compound No. 2) acetyl-L-arginine-n-hexadecyl amide (Compound No. 3) Compound No. 4) n-Hexadecanoyl-shi-arginine -n-hexadecylamide (Compound No. 5)
  • Acetyl-L-lysine-n-octadecyl ester (Compound No. 6)
  • A is an amino acid residue selected from arginine, lysine, and olunichi
  • R is a linear alkyl group having 4 to 8 carbon atoms, a branched alkyl group, a cyclic alkyl group, a linear alkenyl group, or a branched alkylene group
  • R 2 may be a compound having a linear alkyl group having 12 to 30 carbon atoms, a branched alkyl group, a cyclic alkyl group, a cholesteryl group, a linear alkenyl group having 1 to 5 double bonds, or a branched alkenyl group. Good. ⁇ ⁇ ⁇
  • no ph group and X 2 may be prepared by known methods. For example, 1) an amino acid with a protected N-terminal of a predetermined ⁇ amino acid, by condensation of the R 2 -Y- H (step 1), 2) removing the amino acid N-terminal protecting group (step 2), 3) Condensation of R i -X 1 -Z and X 1 -p -X 2 -0R 4 (Step 3) (where R 4 represents a protecting group such as a methyl group); 4) Deprotection of R 4 If there is, activate (Step 4), 5)! ?
  • Step 5 (wherein, Z is a halogen atom or a hydroxyl group, A' represents an amino acid side chain is protected), 6) It can be produced by removing the amino acid side chain protecting group (Step 6).
  • the following compounds can be exemplified as the amino acid derivative of the present invention having a Ph group and one amino acid residue.
  • the amino acid residue has 2 to 3 amino acids, and the ph group and X 2 are When not present, R 1 represents a straight-chain alkyl group, branched alkyl group, cyclic alkyl group, straight-chain alkenyl group or branched alkenyl group having 1 to 8 carbon atoms, and R 2 has 12 to 30 carbon atoms.
  • A is composed of A 1 and A 2
  • a 1 is D or L mouth prestige, Aranin, Nokuri down, isoleucine
  • a 2 is preferably be peptides binding with Amino acid residue selected from the group consisting of D or L of ⁇ arginine, lysine and ol two Chin
  • X 1 in the case the general formula (1) is It is desirable that it does not exist or that-(C 0)-and Y be -0- or -NH-.
  • the compound of the present invention having 2 to 3 amino acid residues and having no ph group and X 2 can be produced by a known peptide synthesis method.
  • the protected amino acid whose terminal is protected is condensed with R 2 -Y-H (step 1), and 2) the amino acid N-terminal protecting group is removed (step 2), 3) If necessary, amino acids are sequentially condensed (Step 3), 4) Condensed with Ri-X-Z (Step 4), where Z represents a halogen atom, a hydrogen atom or a hydroxyl group. 5) Amino acid It can be produced by removing the side chain protecting group (Step 5).
  • the following compounds can be exemplified as amino acid derivatives (peptide derivatives) of the present invention having 2 to 3 amino acid residues and having no ph group and X 2 .
  • salts include trifluoroacetate, hydrochloride, acetate, sulfate, lactate, maleate, methanesulfonate, oxalate, malonate, succinate, and fumarate. , Propionate, butyrate and the like.
  • the present invention also relates to a chemokine receptor antagonist comprising the amino acid derivative or a salt thereof as an active ingredient.
  • the amino acid derivative or a salt thereof according to the present invention is used for treating or preventing diseases caused by chemokines such as IL-8, RANTES, MIP-1 and SDF-1, such as AIDS, allergic diseases, and inflammatory diseases.
  • chemokines such as IL-8, RANTES, MIP-1 and SDF-1
  • Can be The amino acid derivative of the present invention or a salt thereof was administered to an ICR mouse in a single oral administration (dose of 500 mg / kg), and no deaths were observed after 6 days, indicating no acute toxicity. Is determined.
  • the dosage can be 0.1 to 150 mg, preferably 1 to 100 mg, per 1 kg of body weight per day, which can be administered once or in several divided doses. Oral administration is desirable, but not limited to. Parenteral administration can be appropriately selected, for example, injection, transdermal, enteral administration and the like. In addition, the dose can be appropriately changed according to the patient's condition.
  • the dosage form is such that powder or tablet, granule, capsule, suppository is obtained by adding one or more pharmaceutically acceptable additives to the amino acid derivative of the present invention or a salt thereof. , Injection, or oral liquid.
  • Additives include, for example, magnesium stearate, sugar, lactose, dextrin, starches, methylcellulose, fatty acid glycerides, water, propylene glycol, macrogol, alcohol, crystalline cellulose, hydroxypropylcellulose, low degree of substitution Hydroxypropyl cellulose, carmelloses, povidone, polyvinyl alcohol, calcium stearate and the like can be mentioned.
  • coloring agents if necessary
  • stabilizers, antioxidants, preservatives, pH regulators, tonicity agents, solubilizing agents, and / or soothing agents can be added.
  • Granules, tablets or capsules can also be coated with a coating base such as hydroxypropylmethylcellulose, hydroxypropylmethylcellulose phthalate and the like. It is desirable that the amino acid derivative of the present invention be contained in a single dose in an amount of 0.1 to 500 mg, preferably 1 to 100 mg.
  • G is Gly
  • P is Pro
  • A is Ala
  • L is Leu
  • R is Arg
  • T represents 3 ⁇ 4r
  • V represents Val
  • K represents ys
  • E represents Glu
  • Arg synthesized by the method of Example 1 (Pmc) - 0C 18 H 37 17. was dissolved lm in pyridine lmg, acetic anhydride was added 5 ⁇ , and 2:00 ⁇ at room temperature. Water was added to the reaction solution, which was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product obtained was purified by silica gel column chromatography (chloroform / methanol-15 / 1) to obtain 16.7 mg of the title compound as a white solid. .
  • the Finoc-Arg (Pmc) NHCi S H 33 38.2mg synthesized by the method of Example 1 was dissolved in DMF0,16m 1, added Jechiru completion Min 16 i, and ⁇ 15 minutes at room temperature.
  • the crude product obtained by concentrating the reaction solution under reduced pressure was dissolved in 0.6 ml of methylene chloride, triethylamine 121 and hexadecanoyl chloride 261 were added, and the mixture was stirred at room temperature for 1.5 hours. Water was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure.
  • the crude product obtained by concentrating the reaction solution under reduced pressure was purified by silica gel column chromatography (form: methanol 5: 1) to obtain 9.0 mg of the title compound as a white solid.
  • the resulting solution was dissolved in 8 ml, digylamine (0.08 ml) was added, and the mixture was stirred at room temperature for 1 hour.
  • the crude product obtained by concentrating the reaction solution under reduced pressure was dissolved in pyridine (0.55 ml), acetic anhydride 101 was added, and the mixture was stirred at room temperature for 15 hours.
  • To the crude product obtained by concentrating the reaction solution under reduced pressure was added 0.28 ml of trifluoroacetic acid, and the mixture was stirred at room temperature for 20 minutes.
  • the reaction mixture was diluted with 1N hydrochloric acid, extracted with chloroform, and concentrated under reduced pressure.
  • the crude product obtained was purified by silica gel column chromatography (chloroform / methanol-30 / 1) to give the title compound 34. 7nig was obtained as a white solid.
  • Example 9 N-9-fluorenyl methoxycarbonyl obtained in (2) - 2, 2, 5, 7, 8-pentamethyl chroman - 6-sulphonyl -L- arginine - Kisadeshiruami de to n--CFmoc Arg (N G Pmc ) -NH-n-Ci S H 33) 81.5oig the DMF After dissolving in 1.63 Oml, 0.163 ml of getylamine was added under stirring at room temperature, followed by stirring at the same temperature for 0.25 hours. The reaction solution is concentrated under reduced pressure, distilled water is added, and the mixture is separated and extracted with ethyl acetate.
  • the organic layer is dried over anhydrous sodium sulfate and concentrated, and then N ° -2,2,5,7,8-pentamethylchroman-6-sulfo cycloalkenyl - crude product of L- Aruginin to -n- Kisadeshiru Ami de [Arg (N s Pmc) -NH- nC 18 H 3 3) as a yellow sticky solid.
  • Step 1 isopropyl force Rubamoiru) - Benzoiru -N G -2, 2, 5, 7, 8- pentamethyl chroman - 6-sulphonyl -L- arginine - black and Kisadeshiruami de 35.2mg to n-
  • the solution was dissolved in 0.352 ml of mouth form, and 0.352 ml of trifluoroacetic acid was added thereto with stirring at room temperature, followed by stirring for 3 hours.
  • Example 9 obtained in Furuorenirume Tokishikarubo nil - ⁇ ⁇ -2, 1, 5 , ⁇ , 8- pentamethyl chroman - 6-sulphonyl -L- arginine - .eta. to hexa Deshiruami de [Fmoc-Arg ( ⁇ Pm -NH-nd 8 ⁇ 33 ) 57.2mg to DMF1.145ml After dissolving, 0.115 ml of getylamine was added under stirring at room temperature, and the mixture was stirred at the same temperature for 0.25 hours. The reaction mixture was concentrated under reduced pressure, distilled water was added, and the mixture was separated and extracted with ethyl acetate.
  • Example 9 (3) Arg obtained in step 1 (N Pmc.) -.
  • the S H 33 15. Ryo mg was dissolved in pyridine 0.3 ml, Benzoiruku chloride de 3.3 l was added, stirred for 1 hour at room temperature did. Water was added to the reaction solution, which was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (form: methanol 20: 1) to give 12.5 mg of the title compound as a colorless syrup Obtained.
  • the Ac-Leu-Arg (Pmc) -NHC 1 3H 2 7 150mg was dissolved in black port Holm L 5 ml, the door Rifuruoro acetate 1.5mi was added, and allowed to stand overnight at room temperature.
  • n-dodecyl alcohol 50 mg was dissolved in 1.5 ml of methylene chloride, and triethylamine 51 and methanesulfonyl chloride 421 were added, followed by stirring at room temperature for 1.5 hours.
  • a saturated aqueous solution of sodium hydrogen carbonate Extracted with Holm.
  • the organic layer was dried over anhydrous sodium sulfate to give the crude product 3 ⁇ 4'isO-C 1 2 H 2 5 and concentrated in vacuo.
  • Fmoc-Leu-Arg (Pmc) -0Me50nig synthesized by the method of Example 30 was dissolved in 3 ml of DMF, 0.3 ml of getylamine was added, and the mixture was stirred at room temperature for 20 minutes.
  • the crude product obtained by concentrating the reaction solution under reduced pressure was dissolved in 1 ml of methylene chloride, triethylamine and tetradecanoyl chloride 261-1 were added, and the mixture was stirred at room temperature for 30 minutes. Water was added to the reaction solution, which was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure.
  • the crude product obtained by concentrating the reaction solution under reduced pressure was dissolved in 3.6 ml of pyridine, 30 I of acetic anhydride was added, and the mixture was stirred at room temperature for 1.5 hours. Water was added to the reaction solution, which was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure.
  • the crude product obtained by depressurizing and concentrating the reaction solution was dissolved in pyridine (0.45 ml), acetic anhydride 41 was added, and the mixture was stirred at room temperature for 1.5 hours. Water was added to the reaction solution, which was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • test examples are shown for the results of measuring the IL-8, SDF-1 and RANTES antagonistic activities of the amino acids of the present invention.
  • Human THP-1 (monocyte-derived cell line) cells were tested for the affinity of the IL-8 amino acid derivative of the present invention for the receptor by the following method by a binding test using ( 125 I) iL-8. .
  • THP-1 cells were passaged at RPM Bok 1640 medium containing 10% FCS (FBS), suspended the cells in logarithmic growth phase 5xiO s cell / 400 ul in R ⁇ -1640 medium containing 0.1% ⁇ shea serum albumin It became cloudy.
  • FBS FCS
  • THP-1 specific binding of cells to (I25 DlL-8 (THP- 1 bound to other than IL-1 receptor on the cell (125 I) IL- 8) is die Amino acid derivatives of the present invention of the operation
  • THP-1 to cells (125 ⁇ ) ⁇ Mr - specific binding of 8 was determined by subtracting the non-semi-specific binding amount from the total binding.
  • the inhibition rate (%) of the amino acid derivative of the present invention at a 100 M dose for the specific binding of ⁇ -1 cells to IL-8 was determined by the following formula. Inhibition rate (%) 2 [(total binding amount-non-specific binding amount) 1 (binding amount when the amino acid derivative of the present invention is added-non-specific binding amount)] ⁇ (total binding amount-non-specific binding amount) ) X100
  • the amino acid derivative of the present invention exhibits an antagonistic activity against IL-8, SDF-1 or RAiYTES, and It has been found that diseases caused by chemokines can be prevented.
  • the acute toxicity of the amino acid derivative was examined. That is, 5-week-old ICR mice (male) were divided into 5 mice in each group. After acclimation and rearing for 1 week, the amino acid derivative of the example was dissolved or dispersed in a 0.5% methylcellulose aqueous solution, and a single oral administration ( The dose was 500 rag / kg), and the number of deaths after 6 days was examined. Table 3 shows the results.
  • a novel amino acid derivative or a salt thereof can be provided.
  • the novel amino acid derivative of the present invention or a salt thereof has CXC and CC chemokine receptor antagonism, and exhibits excellent effects as a therapeutic or preventive agent for AIDS, allergic diseases, inflammatory diseases and the like.

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Abstract

L'invention se rapporte à de nouveaux dérivés d'acides aminés représentés par la formule générale: R?1-X1-ph-X2-A-Y-R2¿ ainsi qu'à des sels de ces dérivés et à des antagonistes de récepteurs de chimiokine contenant de tels dérivés en tant qu'ingrédient actif. Dans cette formule générale, A représente un reste d'acide aminé sélectionné parmi Arg, Lys et Orn ou un peptide constitué de 2 ou 3 restes d'acides aminés sélectionnés parmi Arg, Lys, Orn, Leu, Ala, Val, Ile, Gly, Glu et Asp, qui contient au moins soit Arg, soit Lys, soit Orn; R1 et R2 représentent chacun indépendamment alkyle, alcényle, cholestéryle ou hydrogène, à condition qu'au moins R1 ou R2 représente alkyle C¿12-30?, alcényle ou cholestéryle; X?1¿ est absent ou représente -(C=O)-, -(C=O)-NH-, -(C=O)-O-, -NH-(C=O)-, -NH-(C=O)-NH-, -(S=O)-, -SO¿2?-, -NH-, -O-, -S-, etc.; X?2¿ est absent ou représente -(C=O)-, -(S=O)-, -SO¿2?-, -NH-(C=O)-, etc.; Y est absent ou représente -O-, -S-, -NH- ou -NR?3¿; et ph est absent ou présent au niveau d'un site de substitution arbitraire de o-, m- ou p-.
PCT/JP1998/005742 1997-12-26 1998-12-18 Derives d'acides amines WO1999033787A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU16840/99A AU1684099A (en) 1997-12-26 1998-12-18 Amino acid derivatives

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
JP9/368042 1997-12-26
JP9368042A JPH11193264A (ja) 1997-12-26 1997-12-26 新規アミノ酸誘導体
JP10092306A JPH11269195A (ja) 1998-03-20 1998-03-20 ペプチド誘導体
JP10/92307 1998-03-20
JP10/92306 1998-03-20
JP10092307A JPH11269134A (ja) 1998-03-20 1998-03-20 アミノ酸誘導体

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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WO2001055098A1 (fr) * 2000-01-28 2001-08-02 The Procter & Gamble Company Composes d'arginine d'un gout agreable et leurs utilisations pour la sante cardio-vasculaire
WO2002094261A1 (fr) * 2001-05-24 2002-11-28 Kureha Chemical Industry Company, Limited Medicaments antagonistes de cxcr4 comprenant un compose contenant de l'azote
WO2001098362A3 (fr) * 2000-06-16 2002-12-05 Hercules Inc Peptides modifies chimiquement, compositions et leur procede de production et d'utilisation
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WO2001041808A1 (fr) * 1999-12-10 2001-06-14 Takeda Chemical Industries, Ltd. Compositions medicinales a usage par voie orale
WO2001055098A1 (fr) * 2000-01-28 2001-08-02 The Procter & Gamble Company Composes d'arginine d'un gout agreable et leurs utilisations pour la sante cardio-vasculaire
US7098215B2 (en) 2000-04-14 2006-08-29 Kureha Chemical Industry Co., Ltd. Nitrogenous compounds and antiviral drugs containing the same
WO2001098362A3 (fr) * 2000-06-16 2002-12-05 Hercules Inc Peptides modifies chimiquement, compositions et leur procede de production et d'utilisation
WO2002094261A1 (fr) * 2001-05-24 2002-11-28 Kureha Chemical Industry Company, Limited Medicaments antagonistes de cxcr4 comprenant un compose contenant de l'azote
US7176227B2 (en) 2002-09-11 2007-02-13 Kureha Corporation Amine compounds and use thereof
US7833991B2 (en) 2002-09-11 2010-11-16 Kureha Corporation Amine compound and use thereof
US7932281B2 (en) 2004-03-10 2011-04-26 Kureha Corporation Amine-based compound and use thereof
JP2010528985A (ja) * 2007-05-04 2010-08-26 エムディーアールエヌエー，インコーポレイテッド アミノ酸脂質およびその使用
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US8501824B2 (en) 2007-05-04 2013-08-06 Marina Biotech, Inc. Amino acid lipids and uses thereof
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US9731016B2 (en) 2007-05-04 2017-08-15 Marina Biotech, Inc. Tyrosine-based lipids for delivery of therapeutics

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