JPH11505515A - ペプチドと、その製造方法 - Google Patents
ペプチドと、その製造方法Info
- Publication number
- JPH11505515A JPH11505515A JP8526185A JP52618596A JPH11505515A JP H11505515 A JPH11505515 A JP H11505515A JP 8526185 A JP8526185 A JP 8526185A JP 52618596 A JP52618596 A JP 52618596A JP H11505515 A JPH11505515 A JP H11505515A
- Authority
- JP
- Japan
- Prior art keywords
- trp
- ile
- nval
- tyr
- phe
- Prior art date
- Legal status (The legal status 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 status listed.)
- Granted
Links
- 108090000765 processed proteins & peptides Proteins 0.000 title claims abstract description 26
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 8
- AGPKZVBTJJNPAG-RFZPGFLSSA-N D-Isoleucine Chemical compound CC[C@@H](C)[C@@H](N)C(O)=O AGPKZVBTJJNPAG-RFZPGFLSSA-N 0.000 claims abstract description 8
- ONIBWKKTOPOVIA-SCSAIBSYSA-N D-Proline Chemical compound OC(=O)[C@H]1CCCN1 ONIBWKKTOPOVIA-SCSAIBSYSA-N 0.000 claims abstract description 8
- COLNVLDHVKWLRT-MRVPVSSYSA-N D-phenylalanine Chemical compound OC(=O)[C@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-MRVPVSSYSA-N 0.000 claims abstract description 8
- QIVBCDIJIAJPQS-SECBINFHSA-N D-tryptophane Chemical compound C1=CC=C2C(C[C@@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-SECBINFHSA-N 0.000 claims abstract description 8
- OUYCCCASQSFEME-MRVPVSSYSA-N D-tyrosine Chemical compound OC(=O)[C@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-MRVPVSSYSA-N 0.000 claims abstract description 8
- KZSNJWFQEVHDMF-SCSAIBSYSA-N D-valine Chemical compound CC(C)[C@@H](N)C(O)=O KZSNJWFQEVHDMF-SCSAIBSYSA-N 0.000 claims abstract description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims abstract description 8
- SNDPXSYFESPGGJ-UHFFFAOYSA-N L-norVal-OH Natural products CCCC(N)C(O)=O SNDPXSYFESPGGJ-UHFFFAOYSA-N 0.000 claims abstract description 8
- 229960002684 aminocaproic acid Drugs 0.000 claims abstract description 8
- -1 D-NVal Chemical compound 0.000 claims abstract description 7
- QNAYBMKLOCPYGJ-UWTATZPHSA-N D-alanine Chemical compound C[C@@H](N)C(O)=O QNAYBMKLOCPYGJ-UWTATZPHSA-N 0.000 claims abstract description 7
- BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 claims abstract description 7
- ROHFNLRQFUQHCH-RXMQYKEDSA-N D-leucine Chemical compound CC(C)C[C@@H](N)C(O)=O ROHFNLRQFUQHCH-RXMQYKEDSA-N 0.000 claims abstract description 5
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 claims abstract description 5
- 125000000174 L-prolyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])([H])[C@@]1([H])C(*)=O 0.000 claims abstract description 5
- 125000000510 L-tryptophano group Chemical group [H]C1=C([H])C([H])=C2N([H])C([H])=C(C([H])([H])[C@@]([H])(C(O[H])=O)N([H])[*])C2=C1[H] 0.000 claims abstract description 5
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 claims abstract description 5
- 150000001413 amino acids Chemical class 0.000 claims abstract description 3
- 125000000524 functional group Chemical group 0.000 claims abstract description 3
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 4
- 150000001408 amides Chemical class 0.000 claims description 3
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 2
- 235000019253 formic acid Nutrition 0.000 claims description 2
- 238000004366 reverse phase liquid chromatography Methods 0.000 claims description 2
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 claims 2
- 238000000746 purification Methods 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 10
- 102000004196 processed proteins & peptides Human genes 0.000 abstract description 8
- 230000002519 immonomodulatory effect Effects 0.000 abstract description 5
- 230000004071 biological effect Effects 0.000 abstract description 4
- 238000000034 method Methods 0.000 abstract description 4
- 150000008064 anhydrides Chemical class 0.000 abstract description 2
- 230000000903 blocking effect Effects 0.000 abstract description 2
- 230000004913 activation Effects 0.000 abstract 1
- 229940088623 biologically active substance Drugs 0.000 abstract 1
- 229940079593 drug Drugs 0.000 abstract 1
- 238000010647 peptide synthesis reaction Methods 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 241000700199 Cavia porcellus Species 0.000 description 3
- LEHPJMKVGFPSSP-ZQINRCPSSA-N Ile-Glu-Trp Chemical compound C1=CC=C2C(C[C@H](NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](N)[C@@H](C)CC)C(O)=O)=CNC2=C1 LEHPJMKVGFPSSP-ZQINRCPSSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 229920001184 polypeptide Polymers 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 231100000041 toxicology testing Toxicity 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- QJCNLJWUIOIMMF-YUMQZZPRSA-N (2s,3s)-3-methyl-2-[(2-methylpropan-2-yl)oxycarbonylamino]pentanoic acid Chemical compound CC[C@H](C)[C@@H](C(O)=O)NC(=O)OC(C)(C)C QJCNLJWUIOIMMF-YUMQZZPRSA-N 0.000 description 1
- NVSXSBBVEDNGPY-UHFFFAOYSA-N 1,1,1,2,2-pentafluorobutane Chemical compound CCC(F)(F)C(F)(F)F NVSXSBBVEDNGPY-UHFFFAOYSA-N 0.000 description 1
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- LLEUXCDZPQOJMY-AAEUAGOBSA-N Glu-Trp Chemical compound C1=CC=C2C(C[C@H](NC(=O)[C@H](CCC(O)=O)N)C(O)=O)=CNC2=C1 LLEUXCDZPQOJMY-AAEUAGOBSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical class [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 102000004142 Trypsin Human genes 0.000 description 1
- 108090000631 Trypsin Proteins 0.000 description 1
- LUTSRLYCMSCGCS-BWOMAWGNSA-N [(3s,8r,9s,10r,13s)-10,13-dimethyl-17-oxo-1,2,3,4,7,8,9,11,12,16-decahydrocyclopenta[a]phenanthren-3-yl] acetate Chemical compound C([C@@H]12)C[C@]3(C)C(=O)CC=C3[C@@H]1CC=C1[C@]2(C)CC[C@H](OC(=O)C)C1 LUTSRLYCMSCGCS-BWOMAWGNSA-N 0.000 description 1
- 108010050025 alpha-glutamyltryptophan Proteins 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- RPFRANTWLFOUSQ-UHFFFAOYSA-N butan-1-ol;2-pyridin-2-ylacetic acid Chemical compound CCCCO.OC(=O)CC1=CC=CC=N1 RPFRANTWLFOUSQ-UHFFFAOYSA-N 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 239000002955 immunomodulating agent Substances 0.000 description 1
- 229940121354 immunomodulator Drugs 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 210000004698 lymphocyte Anatomy 0.000 description 1
- 231100000957 no side effect Toxicity 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 229940034252 thymus extracts Drugs 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
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
- C07K5/08—Tripeptides
- C07K5/0821—Tripeptides with the first amino acid being heterocyclic, e.g. His, Pro, Trp
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
-
- 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
- C07K5/0205—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)3-C(=0)-, e.g. statine or derivatives thereof
-
- 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
- C07K5/021—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)n-C(=0)-, n being 5 or 6; for n > 6, classification in C07K5/06 - C07K5/10, according to the moiety having normal peptide bonds
-
- 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
- C07K5/06104—Dipeptides with the first amino acid being acidic
-
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- 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
- C07K5/0802—Tripeptides with the first amino acid being neutral
- C07K5/0804—Tripeptides with the first amino acid being neutral and aliphatic
-
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- 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
- C07K5/0802—Tripeptides with the first amino acid being neutral
- C07K5/0812—Tripeptides with the first amino acid being neutral and aromatic or cycloaliphatic
-
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- 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
- C07K5/0815—Tripeptides with the first amino acid being basic
-
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- 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
-
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- 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
- C07K5/0821—Tripeptides with the first amino acid being heterocyclic, e.g. His, Pro, Trp
- C07K5/0823—Tripeptides with the first amino acid being heterocyclic, e.g. His, Pro, Trp and Pro-amino acid; Derivatives thereof
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- C07K5/10—Tetrapeptides
- C07K5/1002—Tetrapeptides with the first amino acid being neutral
- C07K5/1005—Tetrapeptides with the first amino acid being neutral and aliphatic
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- C07K5/10—Tetrapeptides
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- C07K5/1016—Tetrapeptides with the first amino acid being neutral and aromatic or cycloaliphatic
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- C07K5/10—Tetrapeptides
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- C07K5/10—Tetrapeptides
- C07K5/1024—Tetrapeptides with the first amino acid being heterocyclic
-
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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Abstract
(57)【要約】
本発明は医薬、特に免疫調節特性を有する生物活性な物質の製造方法に関するものである。本発明は医薬、獣医薬および実験生化学で用いることができる。本発明の主要な課題は免疫調節特性を有する生物活性を有する新規な合成ペプチドの製造にある。本発明ペプチドは下記配列を有する：X-Glu-Trp-Y（ここで、XはHまたはGly，Ala，Leu，Ile，Val，NVal，Pro，Tyr，Phe，Trp，D-Ala，D-Leu，D-Ile，D-Val，D-NVal，D-Pro，D-Tyr，D-Phe，D-Trp，y-アミノ酪酸，ζ-アミノカプロン酸; YはGla，Ala，Leu，Ile，Val，NVal，Pro，Tyr，Phe，Trp，D-Ala，D-Leu，D-Ile，D-Val，D-NVal，D-Pro，D-Tyr，D-Phe，D-Trp，y-アミノ酪酸，ζ-アミノカプロン酸，-OH，モノ-またはジ-置換アミド（C1-C3））。ペプチド合成では溶液中で分子のC末端から鎖を徐々に成長させ、官能基を最大限ブロッキングする戦略を用い、アミノ酸アルキルエーテルから開始し、エーテル活性法およびトリブチルオキシカルボニルアミノ酸を用いた混合無水物法を用いる。
Description
【発明の詳細な説明】
ペプチドと、その製造方法
技術分野
本発明は医薬に関するものであり、特に医薬、獣医薬および生化学実験で利用
可能な免疫調節特性を有する生物活性物質の製造方法に関するものである。
必要な知識および技術
胸腺抽出物(thymus extracts)，特にサイモシン画分(thymozine fraction)５
／ゴールドスタイン(Goldstein)A.L.,ギュナ(Guna)A.,ラッツ(Latz)M．M.,ハー
ディ(H.A).,ホワイト(White)A.／Thymolyn／CH.N659586／は応用医薬で免疫調節
剤として広く用いられている。
この抽出物はポリペプチド培養物で構成され、その製造は複雑である。従って
、天然資源からの収量は限られるだけでなく、物理化学的および生物学的特性が
一定しない。また、天然資源から得られたポリペプチドを使用した患者には副作
用が見られている。そのためペプチドを合成で得る必要性がある。現在では免疫
調節特性を有する合成されたペプチド株が利用可能である：PCT WO 089/06134，
欧州特許第230052号，米国特許第5008246号，米国特許第5013723号。主要成分に
絞ったこれらの各合成ペプチドは高活性で、毒性が低く、副作用が無いため、医
薬での利用に適している。
本発明
本発明は免疫調節特性を備えた生物活性を有する新規なペプチドを単離したこ
とによって得られたものである。
本発明の対象は下記配列を有するペプチドにある：
X-Glu-Trp-Y
［ここで、
XはHまたはGly，Ala，Leu，Ile，Val，NVal，Pro，Tyr，Phe，Trp，D-Ala，D-Le
u，
D-Ile，D-Val，D-NVal，D-Pro，D-Tyr，D-Phe，D-Trp，Y-アミノ酪酸，ζ-アミ
ノカプロン酸;
YはGla，Ala，Leu，Ile，Val，NVal，Pro，Tyr，Phe，Trp，D-Ala，D-Leu，D-Il
e，D-Val，D-NVal，D-Pro，D-Tyr，D-Phe，D-Trp，Y-アミノ酪酸，ζ-アミノカ
プロン酸，-OH，モノ-またはジ-置換アミド（C1-C3）］
本発明の他の目標はペプチドの新規な生成方法を提供することにある。このペ
プチド製造方法はペプチドを高い品質と収量で容易に製造できなければならない
。本発明の新規なプチド製造方法は溶液中で分子のC末端から鎖を徐々に成長さ
せ、官能基を最大限ブロッキングする戦略を用い、アミノ酸アルキルエーテルか
ら開始してエーテルを活性化する方法を用い、トリブチルオキシカルボニルアミ
ノ酸を用いる混合無水物法を用いる。
ペプチド鎖の概略は下記の表に示す。ここで、Rf1は（クロロホルム-メタノー
ル-32％酢酸＝60:45:20）中、Rf2は（ブタノール-ピリジン-酢酸＝5:5:4:1）中
上記の配列によって得られたペプチドは白色粉末組織を有し、この粉末は水溶
性で、アルコールにはあまり溶けず、クロロホルムには全く溶けない。
本発明を得るための最良の方法
以下、本発明の実施例を説明する。
本発明の実施例をH-Ile-Glu-Trp-OHで表されるペプチドを得る方法で説明する
。
1. Boc-Ile-OPFP の合成
46.0g(0.2mol)のBoc-Ile-OHと、40.5g(0.22mol)のペンタフルオラインフェノ
ー
ルとを100mlのエチルアセテートに溶解した混合液を、−５℃に冷却し、45.3g(0
.22mle)のN,N-ジシクロヘキシルカルボジイミドを添加する。次いで、混合物を
室温で３時間攪拌し、ジシクロヘキシルカルバミドを濾別し、溶媒を減圧留去す
る。残留物を酢酸エチル-ヘキサン混合物で結晶化し、残渣を濾過する。収量＝7
1.3g(90％)。
2. Boc-Ile-Glu-Trp-OH の合成
19.8g(0.05mol)のBoc-Ile-OPFPを100mlのジメチルホルムアミドに溶解し、得
られた溶液に、攪拌しながら、20g(0.06mol)のGlu-Trpと、5.0g(0.06mol)のNaHC
O3水溶液を添加する。この溶液を室温で20時間攪拌する。溶媒は減圧留去する。
残留物に200mlの酢酸エチルと、200mlの2％硫酸を攪拌しながら添加する。有機
層を硫酸(２×100ml)で洗浄し、NaCl溶液を添加してpH=7にする。次いで、脱水
した硫酸ナトリウムで乾燥し、溶媒を減圧留去する。残留物を酢酸エチル−ヘキ
サンで結晶化し、残渣を濾過し，減圧乾燥する。
収量＝20.5g(75％)。
3. H-Ile-Glu-Trp-OH の合成
20.5gのBoc-Ile-Glu-Trp-OHを150mlのギ酸に溶解し、得られた溶液を45℃で3.
5時間攪拌し、溶媒を減圧留去する。この残留物に200mlの水を加え、減圧留去を
繰り返す。残留物に300mlのイソプロピルと、200mlのエーテルとを添加して10時
間放置する。残留物を濾過し、減圧乾燥する。
収量＝15.3g(75％)。
このペプチドをトリフルオロ酢酸の0.1％アセトニトリル溶液を用いた逆相ク
ロマトグラフィーで精製した。
収量＝13g(85％)。
ペプチドの物理化学特性は下記の通り：
初期構造： H-Ile-Glu-Trp-OH
グロス配列： C24-H30-N4-O4
分子量： BEC-446.5DA
外観組織： 黄色がかった白色粉末または灰色粉末。
溶解性 水に溶解するが、クロロホルムには全く溶解しない。
Y，F 250〜300mmの境界のスペクトルは最大280±2mm、
287±2mm
この新規なペプチドの生物活性をモルモット(guinea pig)を用い、トリプシン
で処置したモルモットのリンパ球のE-収量を公知の試験法を用いて調べた。
上記ペプチドは他の公知化合物より103倍活性であることは"in vitro" の使
用で分かっている。
ペプチドの安全性を確立するために毒性試験を実施した。毒性試験は薬物学委
員会PFの指針「新規な物理学化合物の一般的毒性の臨床前研究指針」、M.,1985
年に従って実施した。
実験の結果、1/1000量を体内注入してもペプチドは全く毒性が無く、LD50は検
出されないことが分かった。
商業的使用
生物活性を有する上記ペプチドは医薬および獣医薬で使用できる。
─────────────────────────────────────────────────────
フロントページの続き
(72)発明者 ディーギン，ブラディスラブ イサコビィ
ッチ
ロシア国 121609 モスクワ ウリ．オー
セナヤ デ．４ コルプ．１ カヴェ.
276
(72)発明者 コロツコフ，アンドレ マルコビィッチ
ロシア国 121609 モスクワ ウリ．オー
セナヤ デ．４ コルプ．１ カヴェ.
135
Claims (1)
- 【特許請求の範囲】 １．下記配列を有するペプチド： X-Glu-Trp-Y ［ここで、 XはHまたはGly，Ala，Leu，Ile，Val，NVal，Pro，Tyr，Phe，Trp，D-Ala，D-Le u，D-Ile，D-Val，D-NVal，D-Pro，D-Tyr，D-Phe，D-Trp，Y-アミノ酪酸，ζ-ア ミノカプロン酸； YはGla，Ala，Leu，Ile，Val，NVal，Pro，Tyr，Phe，Trp，D-Ala，D-Leu，D-Il e，D-Val，D-NVal，D-Pro，D-Tyr，D-Phe，D-Trp，Y-アミノ酪酸，ζ-アミノカ プロン酸，-OH，モノ-またはジ-置換アミド（C1-C3）］ ２．溶液中で分子のC末端から鎖を徐々に成長させ、アミノ酸アルキルエーテル から始まる官能基を最大ブロッキングし、エーテルを活性化し、トリブチルオキ シカルボニルアミノ酸を用いて無水混合とし、ギ酸で処理し、さらに結晶化で精 製し、X-Glu-Trp-Yの形で得られた生成物を逆相クロマトグラフィで洗浄するこ とを特徴とする下記配列を有するペプチドの製造方法： X-Glu-Trp-Y ［ここで、 XはHまたはGly，Ala，Leu，Ile，Val，NVal，Pro，Tyr，Phe，Trp，D-Ala，D-Le u，D-Ile，D-Val，D-NVal，D-Pro，D-Tyr，D-Phe，D-Trp，Y-アミノ酪酸，ζ-ア ミノカプロン酸; YはGla，Ala，Leu，Ile，Val，NVal，Pro，Tyr，Phe，Trp，D-Ala，D-Leu，D-Il e，D-Val，D-NVal，D-Pro，D-Tyr，D-Phe，D-Trp，Y-アミノ酪酸，ζ-アミノカ プロン酸，-OH，モノ-またはジ-置換アミド（C1-C3）］
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| RU95102461 | 1995-03-02 | ||
| RU95102461A RU2107691C1 (ru) | 1995-03-02 | 1995-03-02 | Пептид и способ его получения |
| PCT/RU1996/000046 WO1996026955A1 (fr) | 1995-03-02 | 1996-02-28 | Peptide et son procede d'obtention |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH11505515A true JPH11505515A (ja) | 1999-05-21 |
| JP3902226B2 JP3902226B2 (ja) | 2007-04-04 |
Family
ID=20164981
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP52618596A Expired - Fee Related JP3902226B2 (ja) | 1995-03-02 | 1996-02-28 | ペプチドと、その製造方法 |
Country Status (20)
| Country | Link |
|---|---|
| US (1) | US6051683A (ja) |
| EP (1) | EP0818462B1 (ja) |
| JP (1) | JP3902226B2 (ja) |
| CN (1) | CN1161373C (ja) |
| AT (1) | ATE306495T1 (ja) |
| AU (1) | AU708084B2 (ja) |
| BR (1) | BR9607901A (ja) |
| CA (1) | CA2214410C (ja) |
| CZ (1) | CZ288418B6 (ja) |
| DE (1) | DE69635272T2 (ja) |
| DK (1) | DK0818462T3 (ja) |
| ES (1) | ES2250984T3 (ja) |
| HK (1) | HK1012859A1 (ja) |
| HU (1) | HUP0000320A3 (ja) |
| LT (1) | LT4393B (ja) |
| LV (1) | LV11993B (ja) |
| RU (1) | RU2107691C1 (ja) |
| SK (1) | SK282604B6 (ja) |
| UA (1) | UA51647C2 (ja) |
| WO (1) | WO1996026955A1 (ja) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2011503215A (ja) * | 2007-11-20 | 2011-01-27 | イミュノテック ディベロップメンツ インコーポレイテッド | 新規の免疫調節ペプチド、その組成物およびその使用 |
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| US6159940A (en) * | 1996-02-28 | 2000-12-12 | Immunotech Developments Inc. | Method for modulating hemopoiesis |
| DE19712633A1 (de) * | 1997-03-26 | 1998-10-08 | Laves Arzneimittel | Verwendung von gamma-Aminobuttersäure als Interleukinbildungsstimulans |
| IL137820A (en) * | 2000-08-10 | 2009-06-15 | S I S Shulov Inst For Science | Pharmaceutical composition for topical administration comprising an analgesic peptide |
| US20020098999A1 (en) * | 2000-10-06 | 2002-07-25 | Gallop Mark A. | Compounds for sustained release of orally delivered drugs |
| WO2002028881A1 (en) * | 2000-10-06 | 2002-04-11 | Xenoport, Inc. | Bile-acid derived compounds for providing sustained systemic concentrations of drugs after oral administration |
| WO2002042414A2 (en) * | 2000-11-17 | 2002-05-30 | Xenoport, Inc. | Amino acid conjugates providing for sustained systemic concentrations of gaba analogues |
| WO2002100344A2 (en) * | 2001-06-11 | 2002-12-19 | Xenoport, Inc. | Amino acid conjugates providing for sustained systemic concentrations of gaba analogues |
| WO2006105811A1 (en) | 2005-04-07 | 2006-10-12 | Centre National De La Recherche Scientifique | Compounds useful as modulators of the proteasome activity |
| CA2571645A1 (en) | 2006-12-19 | 2008-06-19 | Apotex Technologies Inc. | Pharmaceutically acceptable salts of thymodepressin and processes for their manufacture |
| US20120231025A1 (en) | 2009-08-10 | 2012-09-13 | Immunotech Developments Inc. | Vaccine Having a Peptide Adjuvant for Eliciting a Specific Immune Response to Treat Viral Infection and Other Conditions |
| RU2458935C1 (ru) * | 2011-02-18 | 2012-08-20 | Общество с ограниченной ответственностью "ЦитоНИР" (ООО "ЦитоНИР") | Средство для коррекции метаболического синдрома |
| WO2013172728A1 (ru) * | 2012-05-18 | 2013-11-21 | Общество С Ограниченной Ответственностью "Цитонир" | Средство для коррекции метаболического синдрома |
| RU2540496C1 (ru) * | 2014-01-20 | 2015-02-10 | Общество с ограниченной ответственностью "ПРОМОМЕД" | Композиция для назального применения, лекарственное средство на его основе и способ его пременения |
| EA025690B1 (ru) * | 2014-07-15 | 2017-01-30 | Государственное бюджетное образовательное учреждение высшего профессионального образования "Курский государственный медицинский университет" Министерства здравоохранения Российской Федерации | Ранозаживляющее средство, обладающее иммуностимулирующим и антиоксидантным эффектами |
| RU2672888C1 (ru) | 2018-04-18 | 2018-11-20 | Пивипи Лабс Пте. Лтд. | Противовирусное иммунотропное средство для лечения ОРВИ |
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| HU185263B (en) * | 1981-06-12 | 1984-12-28 | Richter Gedeon Vegyeszet | Process for producing peptides effective on the immuncontroll analogous with the tp5 |
| JPS609182Y2 (ja) * | 1981-06-18 | 1985-04-02 | アルファレコ−ド株式会社 | カセツトテ−プケ−スマガジン |
| HU184481B (en) * | 1981-10-02 | 1984-08-28 | Richter Gedeon Vegyeszet | Process for producing tripeptides for diminishing appetite |
| US4699897A (en) * | 1983-06-04 | 1987-10-13 | Amgen | Biologically active peptides structurally related to regions within growth hormones |
| US4603121A (en) * | 1983-10-06 | 1986-07-29 | G. D. Searle & Co. | Enkephalin analogs |
| IT1172391B (it) * | 1983-12-23 | 1987-06-18 | Polifarma Spa | Composti tirpeptidici contenenti acido piroglutaminico e triptofano,procedimentio di produzione ed applicazioni terapeutiche |
| CH659586A5 (de) | 1985-07-02 | 1987-02-13 | Le G Ped I | Arzneimittel aus dem thymus und verfahren zu dessen herstellung. |
| US5070076A (en) * | 1985-07-02 | 1991-12-03 | Leningradsky Gosudarstvenny Pedagogichesky Institut | Thymus-gland preparation and method for producing same |
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| CA1286989C (en) | 1985-12-26 | 1991-07-30 | A. Arthur Gottlieb | Immunoamplifiers and related compositions |
| IT1216908B (it) * | 1987-03-19 | 1990-03-14 | Eniricerche Spa | Analoghi retro-inversi della timopentina e dei suoi frammenti, il metodo per la loro sintesi ed il loro impiego per la preparazionedi composizioni farmaceutiche. |
| WO1989006134A1 (en) | 1987-12-30 | 1989-07-13 | Vsesojuzny Kardiologichesky Nauchny Tsentr Akademi | Pharmaceutical preparation for treating immunodeficiency conditions |
| HU201095B (en) * | 1988-06-14 | 1990-09-28 | Richter Gedeon Vegyeszet | New peptides inhibiting the activity of the immune system and pharmaceutical compositions comprising same, as well as process for producing these peptides and compositions |
| GB2231051B (en) * | 1989-05-05 | 1992-12-16 | Erba Carlo Spa | Bombesin antagonists |
| WO1992009628A1 (en) * | 1990-11-23 | 1992-06-11 | Immunodynamics, Inc. | Synthetic immunoactive peptides having immunomodulating and therapeutic activities |
| JPH07503456A (ja) * | 1991-10-28 | 1995-04-13 | サイトラン・リミテッド | 医薬的ジペプチド組成物およびその使用法 |
| IT1264129B1 (it) * | 1993-04-09 | 1996-09-16 | Codev S A | Peptidi ad attivita' immunomodulatoria derivati da frammenti di leucochinina |
| WO1995003067A1 (en) * | 1993-07-21 | 1995-02-02 | Khavinson Vladimir Khatskelevi | Pharmaceutical with immunomodulating activity |
| RU2067000C1 (ru) * | 1994-06-29 | 1996-09-27 | Владислав Исакович Дейгин | Пептид и способ его получения |
| RU2107692C1 (ru) * | 1995-06-07 | 1998-03-27 | Дейгин Владислав Исакович | Пептид и способ его получения |
-
1995
- 1995-03-02 RU RU95102461A patent/RU2107691C1/ru active
-
1996
- 1996-02-28 CZ CZ19972703A patent/CZ288418B6/cs not_active IP Right Cessation
- 1996-02-28 DK DK96906117T patent/DK0818462T3/da active
- 1996-02-28 AT AT96906117T patent/ATE306495T1/de active
- 1996-02-28 EP EP96906117A patent/EP0818462B1/en not_active Expired - Lifetime
- 1996-02-28 DE DE69635272T patent/DE69635272T2/de not_active Expired - Lifetime
- 1996-02-28 SK SK1180-97A patent/SK282604B6/sk not_active IP Right Cessation
- 1996-02-28 WO PCT/RU1996/000046 patent/WO1996026955A1/ru active IP Right Grant
- 1996-02-28 US US08/894,963 patent/US6051683A/en not_active Expired - Lifetime
- 1996-02-28 UA UA97104869A patent/UA51647C2/uk unknown
- 1996-02-28 CN CNB961923172A patent/CN1161373C/zh not_active Expired - Fee Related
- 1996-02-28 AU AU49594/96A patent/AU708084B2/en not_active Ceased
- 1996-02-28 JP JP52618596A patent/JP3902226B2/ja not_active Expired - Fee Related
- 1996-02-28 ES ES96906117T patent/ES2250984T3/es not_active Expired - Lifetime
- 1996-02-28 BR BR9607901-0A patent/BR9607901A/pt not_active Application Discontinuation
- 1996-02-28 HU HU0000320A patent/HUP0000320A3/hu unknown
- 1996-02-28 CA CA002214410A patent/CA2214410C/en not_active Expired - Fee Related
-
1997
- 1997-10-02 LV LVP-97-186A patent/LV11993B/lv unknown
- 1997-10-02 LT LT97-158A patent/LT4393B/lt not_active IP Right Cessation
-
1998
- 1998-12-10 HK HK98113125A patent/HK1012859A1/xx not_active IP Right Cessation
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2011503215A (ja) * | 2007-11-20 | 2011-01-27 | イミュノテック ディベロップメンツ インコーポレイテッド | 新規の免疫調節ペプチド、その組成物およびその使用 |
Also Published As
| Publication number | Publication date |
|---|---|
| LV11993B (lv) | 1998-05-20 |
| UA51647C2 (uk) | 2002-12-16 |
| EP0818462A1 (en) | 1998-01-14 |
| DE69635272T2 (de) | 2006-07-20 |
| HUP0000320A2 (hu) | 2000-08-28 |
| DE69635272D1 (de) | 2006-02-23 |
| EP0818462B1 (en) | 2005-10-12 |
| CZ270397A3 (cs) | 1998-05-13 |
| CN1185160A (zh) | 1998-06-17 |
| DK0818462T3 (da) | 2006-02-27 |
| CN1161373C (zh) | 2004-08-11 |
| BR9607901A (pt) | 1999-09-08 |
| ATE306495T1 (de) | 2005-10-15 |
| LT4393B (lt) | 1998-10-26 |
| EP0818462A4 (en) | 2000-05-31 |
| US6051683A (en) | 2000-04-18 |
| HUP0000320A3 (en) | 2000-10-30 |
| AU708084B2 (en) | 1999-07-29 |
| SK118097A3 (en) | 1998-04-08 |
| CA2214410A1 (en) | 1996-09-06 |
| CA2214410C (en) | 2001-05-29 |
| RU95102461A (ru) | 1996-12-20 |
| LT97158A (en) | 1998-05-25 |
| RU2107691C1 (ru) | 1998-03-27 |
| JP3902226B2 (ja) | 2007-04-04 |
| HK1012859A1 (en) | 1999-08-13 |
| ES2250984T3 (es) | 2006-04-16 |
| AU4959496A (en) | 1996-09-18 |
| SK282604B6 (sk) | 2002-10-08 |
| LV11993A (lv) | 1998-03-20 |
| WO1996026955A1 (fr) | 1996-09-06 |
| CZ288418B6 (en) | 2001-06-13 |
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