JPS6346079B2 - - Google Patents
Info
- Publication number
- JPS6346079B2 JPS6346079B2 JP60098449A JP9844985A JPS6346079B2 JP S6346079 B2 JPS6346079 B2 JP S6346079B2 JP 60098449 A JP60098449 A JP 60098449A JP 9844985 A JP9844985 A JP 9844985A JP S6346079 B2 JPS6346079 B2 JP S6346079B2
- Authority
- JP
- Japan
- Prior art keywords
- ome
- phe
- arg
- met
- mts
- 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.)
- Expired
Links
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 8
- 102000004196 processed proteins & peptides Human genes 0.000 claims description 4
- PYOHODCEOHCZBM-RYUDHWBXSA-N Phe-Met Chemical compound CSCC[C@@H](C(O)=O)NC(=O)[C@@H](N)CC1=CC=CC=C1 PYOHODCEOHCZBM-RYUDHWBXSA-N 0.000 claims description 2
- 125000003275 alpha amino acid group Chemical group 0.000 claims 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 40
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 24
- 238000000034 method Methods 0.000 description 22
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 16
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- 238000000921 elemental analysis Methods 0.000 description 15
- 238000002844 melting Methods 0.000 description 15
- 230000008018 melting Effects 0.000 description 15
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- 150000001540 azides Chemical class 0.000 description 8
- 229940098779 methanesulfonic acid Drugs 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 7
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 150000001413 amino acids Chemical group 0.000 description 6
- 150000008065 acid anhydrides Chemical class 0.000 description 5
- 230000000202 analgesic effect Effects 0.000 description 5
- 239000012043 crude product Substances 0.000 description 5
- URLZCHNOLZSCCA-VABKMULXSA-N Leu-enkephalin Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(O)=O)NC(=O)CNC(=O)CNC(=O)[C@@H](N)CC=1C=CC(O)=CC=1)C1=CC=CC=C1 URLZCHNOLZSCCA-VABKMULXSA-N 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 4
- 238000009833 condensation Methods 0.000 description 4
- 230000005494 condensation Effects 0.000 description 4
- 230000007062 hydrolysis Effects 0.000 description 4
- 238000006460 hydrolysis reaction Methods 0.000 description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 238000011084 recovery Methods 0.000 description 4
- 238000001226 reprecipitation Methods 0.000 description 4
- 230000003472 neutralizing effect Effects 0.000 description 3
- 125000006239 protecting group Chemical group 0.000 description 3
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 2
- XJOQRTJDYAHKPY-MWSMAVIUSA-N (2s)-2-[[(2s)-2-[[(2s)-2-[[2-[[2-[[(2s)-2-amino-3-(4-hydroxyphenyl)propanoyl]amino]acetyl]amino]acetyl]amino]-3-phenylpropanoyl]amino]-4-methylsulfanylbutanoyl]amino]-n-[(2s)-1-[[(2s)-1-amino-3-methyl-1-oxobutan-2-yl]amino]-5-(diaminomethylideneamino)-1-o Chemical compound C([C@@H](C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](C(C)C)C(N)=O)NC(=O)CNC(=O)CNC(=O)[C@@H](N)CC=1C=CC(O)=CC=1)C1=CC=CC=C1 XJOQRTJDYAHKPY-MWSMAVIUSA-N 0.000 description 2
- WFIYPADYPQQLNN-UHFFFAOYSA-N 2-[2-(4-bromopyrazol-1-yl)ethyl]isoindole-1,3-dione Chemical compound C1=C(Br)C=NN1CCN1C(=O)C2=CC=CC=C2C1=O WFIYPADYPQQLNN-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- -1 Benzyl ester Chemical class 0.000 description 2
- 108010092674 Enkephalins Proteins 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- ODKSFYDXXFIFQN-BYPYZUCNSA-N L-arginine Chemical compound OC(=O)[C@@H](N)CCCN=C(N)N ODKSFYDXXFIFQN-BYPYZUCNSA-N 0.000 description 2
- 241000699666 Mus <mouse, genus> Species 0.000 description 2
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 2
- RLSSMJSEOOYNOY-UHFFFAOYSA-N m-cresol Chemical compound CC1=CC=CC(O)=C1 RLSSMJSEOOYNOY-UHFFFAOYSA-N 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 125000000896 monocarboxylic acid group Chemical group 0.000 description 2
- BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 description 2
- CZFNISFYDPIDNM-UHFFFAOYSA-N n,n-dimethylformamide;oxolane Chemical compound CN(C)C=O.C1CCOC1 CZFNISFYDPIDNM-UHFFFAOYSA-N 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- QTWJRLJHJPIABL-UHFFFAOYSA-N 2-methylphenol;3-methylphenol;4-methylphenol Chemical compound CC1=CC=C(O)C=C1.CC1=CC=CC(O)=C1.CC1=CC=CC=C1O QTWJRLJHJPIABL-UHFFFAOYSA-N 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- QNAYBMKLOCPYGJ-UWTATZPHSA-N D-alanine Chemical compound C[C@@H](N)C(O)=O QNAYBMKLOCPYGJ-UWTATZPHSA-N 0.000 description 1
- FFEARJCKVFRZRR-SCSAIBSYSA-N D-methionine Chemical compound CSCC[C@@H](N)C(O)=O FFEARJCKVFRZRR-SCSAIBSYSA-N 0.000 description 1
- SENJXOPIZNYLHU-UHFFFAOYSA-N L-leucyl-L-arginine Natural products CC(C)CC(N)C(=O)NC(C(O)=O)CCCN=C(N)N SENJXOPIZNYLHU-UHFFFAOYSA-N 0.000 description 1
- QEFRNWWLZKMPFJ-YGVKFDHGSA-N L-methionine S-oxide Chemical compound CS(=O)CC[C@H](N)C(O)=O QEFRNWWLZKMPFJ-YGVKFDHGSA-N 0.000 description 1
- SENJXOPIZNYLHU-IUCAKERBSA-N Leu-Arg Chemical compound CC(C)C[C@H](N)C(=O)N[C@H](C(O)=O)CCCN=C(N)N SENJXOPIZNYLHU-IUCAKERBSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 241000872931 Myoporum sandwicense Species 0.000 description 1
- 102100038931 Proenkephalin-A Human genes 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- MHLMRBVCMNDOCW-UHFFFAOYSA-N acetic acid;butan-1-ol;hydrate Chemical compound O.CC(O)=O.CCCCO MHLMRBVCMNDOCW-UHFFFAOYSA-N 0.000 description 1
- 108700003635 adrenorphin Proteins 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 229940035676 analgesics Drugs 0.000 description 1
- 239000000730 antalgic agent Substances 0.000 description 1
- FPRSPUHXEPWUBZ-HNNXBMFYSA-N benzyl (2s)-2-amino-3-phenylpropanoate Chemical compound C([C@H](N)C(=O)OCC=1C=CC=CC=1)C1=CC=CC=C1 FPRSPUHXEPWUBZ-HNNXBMFYSA-N 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 229930003836 cresol Natural products 0.000 description 1
- 239000012351 deprotecting agent Substances 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 230000007515 enzymatic degradation Effects 0.000 description 1
- MDKXBBPLEGPIRI-UHFFFAOYSA-N ethoxyethane;methanol Chemical compound OC.CCOCC MDKXBBPLEGPIRI-UHFFFAOYSA-N 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 125000000717 hydrazino group Chemical group [H]N([*])N([H])[H] 0.000 description 1
- 108010000761 leucylarginine Proteins 0.000 description 1
- 229960005181 morphine Drugs 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 238000004810 partition chromatography Methods 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 108010041071 proenkephalin Proteins 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
Description
この発明は新規な合成ペプタイドで強力な鎮痛
活性に関するものである。
この発明による新規な合成ペプタイドとは次の
構造式を有する化合物である。
Ｈ−Tyr−Ｄ−Met（Ｏ）−Gly−Ｘ
：Ｘ＝Phe−Met（Ｏ）−Arg−Arg−Val−
NH2
：Ｘ＝Phe−Leu−Arg−Phe−OH
〔経 緯〕
この発明に至るまでの経緯については、次のご
とくである。1975年にHughesらはウシの脳内よ
り鎮痛活性を有するペプタイド（Ｈ−Tyr−Gly
−Gly−Phe−Met（Leu）−OH：Met（Leu）−エ
ンケフアリン）二種を単離して以来、
Proenkephalinの発見と相まつて、多数のエンケ
フアリン類似体が合成され、その内でエンケフア
リンの２位のアミノ酸がＤ−AlaあるいはＤ−
Metに変えることにより、酵素的分解を阻害で
き、その結果、鎮痛活性が高くなることが判明し
た。そこで、２位にＤ−Met（Ｏ）を入れ、Ｃ端
部をおよびで示すアミノ酸配列を有するペプ
タイドを合成した。ちなみに、は天然に存在す
るadrenorphin（Tyr−Gly−Gly−Phe−Met−
Arg−Arg−Val−NH2）の、はArg6−Phe7−
エンケフアリンの類似体とみなし得る。
〔合 成〕
これらの合成法については、Ｃ端部より順次合
成を行なつたが、説明を簡単にするため、図１、
図２で示した。これらの合成図で用いた略号は次
のものを示す。
保護基
Ｚ（OMe）：ｐ−メトキシベルジルオキシカ
ルボニル
OBzl：ベンジルエステル
Mts：メシチレン−２−スルホニル
縮合法
azide：アジド法（Rudingerの変法）
Mix.：混合酸無水物法
DCC：ジシクロヘキシルカルボジイミド法
脱保護剤
TFA：トリフロロ酢酸
MSA：メタンスルホン酸
This invention relates to a novel synthetic peptide with potent analgesic activity. The novel synthetic peptide according to this invention is a compound having the following structural formula. H-Tyr-D-Met(O)-Gly-X: X=Phe-Met(O)-Arg-Arg-Val-
NH 2 :X=Phe-Leu-Arg-Phe-OH [Backstory] The story leading up to this invention is as follows. In 1975, Hughes et al. discovered a peptide with analgesic activity (H-Tyr-Gly) in the brain of cows.
-Gly-Phe-Met(Leu)-OH:Met(Leu)-enkephalin)
Coupled with the discovery of proenkephalin, a large number of enkephalin analogues were synthesized, among which the amino acid at position 2 of enkephalin was D-Ala or D-
It was found that by changing to Met, enzymatic degradation could be inhibited, resulting in increased analgesic activity. Therefore, a peptide was synthesized in which D-Met(O) was inserted at the 2nd position and the C-terminus had an amino acid sequence indicated by and. By the way, is naturally occurring adrenorphin (Tyr-Gly-Gly-Phe-Met-
Arg−Arg−Val−NH 2 ) is Arg 6 −Phe 7 −
It can be considered an analog of enkephalin. [Synthesis] For these synthesis methods, synthesis was performed sequentially starting from the C end, but for the sake of simplicity, Figure 1,
It is shown in Figure 2. The abbreviations used in these composite figures indicate the following. Protecting group Z (OMe): p-methoxyberzyloxycarbonyl OBzl: Benzyl ester Mts: Mesitylene-2-sulfonyl condensation method azide: Azide method (Rudinger's modified method) Mix.: Mixed acid anhydride method DCC: Dicyclohexylcarbodiimide method Deprotecting agent TFA: Trifluoroacetic acid MSA: Methanesulfonic acid
【表】
まず、を合成するために、Ｚ（OMe）−Arg
（Mts）−Arg−（Mts）−Val−NH2、Ｚ（OMe）−
Phe−Met（Ｏ）−NHNH2そしてＺ（OMe）−Tyr
−Ｄ−Met（Ｏ）−Gly−NHNH2を従来のアミド
形成反応（上記縮合法）によつて合成し、そして
それらをazide法により順次縮合させる。つづい
て得られる保護オクタペプチドをメタンスルホン
酸（MSA）で処理することにより全保護基を除
去し、目的物を得る（図１）。
次にを合成するために、Ｈ−Phe−OBzlを
出発物質とし、図１に示すように、従来の縮合法
とTFA（アミノ保護基の除去剤）を組合せること
により、ペプタイド鎖を延長し、得られる保護ヘ
プタペプタイドをメタンスルホン酸（MSA）で
処理し、全保護基を除去した。[Table] First, in order to synthesize Z(OMe)−Arg
(Mts)−Arg−(Mts)−Val−NH 2 , Z(OMe)−
Phe−Met(O) −NHNH2 and Z(OMe)−Tyr
-D-Met(O)-Gly-NHNH 2 is synthesized by a conventional amide forming reaction (condensation method described above), and they are sequentially condensed by the azide method. Subsequently, the resulting protected octapeptide is treated with methanesulfonic acid (MSA) to remove all protecting groups and obtain the desired product (Figure 1). In order to synthesize the , the resulting protected heptapeptide was treated with methanesulfonic acid (MSA) to remove all protecting groups.
以上合成した二種のペプタイドの鎮痛活性は、
tail−pinch法によつて測定した。即ち、使用し
た動物はddk系雄性マウス（18−22ｇ）を用い、
肛門筋を含むマウスの尾根を500ｇの一定圧に調
整したクレンメによつて挟み、挟んだ後１秒以内
にクレンメを噛まなかつたときに有効とした。結
果を表１に示した。
The analgesic activity of the two types of peptides synthesized above is
It was measured by the tail-pinch method. That is, the animals used were ddk male mice (18-22 g),
The ridge of the mouse, including the anal muscles, was pinched with a strainer adjusted to a constant pressure of 500 g, and the test was considered effective if the mouse did not bite the strainer within 1 second after being pinched. The results are shown in Table 1.
【表】
合成ペプタイドおよびを大槽内投与する場
合、標準品としたモルヒネよりも強い鎮痛効果を
示すことから、有効な鎮痛薬になることは明白で
ある。
実施例
以下、実施例を挙げて、本発明を更に具体的に
説明する。
実施例 １
Ｚ（OMe）−Val−NH2（5mmole）を氷冷下、
アニソール（７ml）存在下、TFA（28ml）で60分
間処理し、Ｚ（OMe）基を除去し、得られるＨ−
Val−NH2とＺ（OMe）−Arg−（Mts）−OHを混
合酸無水物法により縮合させ、粗生成物をメタノ
ール−エーテルから再結晶し、Ｚ（OMe）−Arg
（Mts）−Val−NH2を得る。収率65.8％、融点139
−142℃、〔α〕15 D＋8.5゜（in MeOH）。
元素分析：C29H42N6O7S.1/2H2Oとして
(C) (H) （Ｎ）
理論値：55.48 6.90 13.39
測定値：55.34 6.99 13.15
実施例 ２
Ｚ（OMe）−Arg（Mts）−Val−NH2（5mmol）
を実施例１に準じ、TFA処理し、得られるＨ−
Arg（Mts）−Val−NH2とＺ（OMe）−Arg（Mts）
−OHを混合酸無水物法で縮合させ、粗生成物を
メタノールとエーテルで再沈殿し、Ｚ（OMe）−
Arg（Mts）−Arg（Mts）−Val−NH2を得る。収
率83.9％、融点119−123℃、〔α〕15 D−5.7゜（in
MeOH）。
元素分析：C44H64N10S2・1/2H2Oとして
(C) (H) （Ｎ）
理論値：54.69 6.78 14.50
測定値：54.69 6.79 14.27
実施例 ３
Ｚ（OMe）−Phe−OH（10mmol）とＨ−Met−
OMe（塩酸塩をトリエチルアミノで中和して調
製）をジメチルホルムアミド−テトラヒドロフラ
ン（DMF−THF）混液中、ジシクロヘキシルカ
ルボジイミド法（DCC法）によつて縮合させ、
Ｚ（OMe）−Phe−Met−OMeを得る。収率63.0
％、融点111−113℃、〔α〕20 D−16.0゜（in DMF）。
元素分析：C24H30N2O6Sとして
(C) (H) （Ｎ）
理論値：60.74 6.37 5.90
測定値：60.69 6.52 6.11
実施例 ４
Ｚ（OMe）−Phe−Met−OMe（7mmol）の
DMF溶液に酸化剤としてNaBO3（1.1eq）及び
NaIO4（1.0eq）を作用させ、得られるＺ（OMe）
−Phe−Met（Ｏ）−OMe〔融点129−131℃、〔α〕
15 D−10.6゜（in MeOH）〕を抱水ヒドラジンで処理
する。得られる粗ヒドラジドをDMFとエタノー
ルで再沈殿し、Ｚ（OMe）−Phe−Met−（Ｏ）−
NHNH2を得る。収率31.0％、融点197−200℃
〔α〕15 D−17.2°（in DMF）。
元素分析：C23H30N4O6Sとして
(C) (H) （Ｎ）
理論値：56.31 6.16 11.42
測定値：56.04 5.99 11.33
実施例 ５
Ｚ（OMe）−Ｄ−Met（Ｏ）−OH（6mmol）とＨ
−Gly−OMe（6mmol）（塩酸塩をトリエチルア
ミンで中和して調製）をTHF（100ml）中DCC法
により縮合して、Ｚ（OMe）−Ｄ−Met（Ｏ）−Gly
−OMeを得る。収率81.0％、融点100−103℃、
〔α〕15 D＋27.0゜（in MeOH）。
元素分析：C16H24N2O7Sとして
(C) (H) （Ｎ）
理論値：50.99 6.04 7.00
測定値：50.81 6.05 7.23
実施例 ６
Ｚ（OMe）−Ｄ−Met（Ｏ）−Gly−OMe
（4mmol）を実施１に準じ、TFA処理し、得られ
るＨ−Ｄ−Met（Ｏ）−Gly−OMeとＺ（OMe）−
Tyr−NHNH2をアジド法（Rudingerの変法）で
縮合し、得られるＺ（OMe）−Tyr−Ｄ−Met（Ｏ）
−Gly−OMe（融点172−174℃、〔α〕15 D＋2.0（in
DMF））を10eqの抱水ヒドラジンで処理し、対応
するヒドラジド、Ｚ（OMe）−Tyr−Ｄ−Met（Ｏ）
−Gly−NHNH2を得る。収率63.4％、融点164−
166℃、〔α〕15 D0゜（in DMF）。
元素分析：C25H33N5O8S・1/2H2Oとして
(C) (H) （Ｎ）
理論値：52.44 5.99 12.23
測定値：52.44 6.01 12.17
実施例 ７
Ｚ（OMe）−Arg（Mts）−Arg（Mts）−Val−
NH2（2.92mmol）を実施例１に準じ、処理して
得られるＨ−Arg（Mts）−Arg（Mts）−Val−
NH2とＺ（OMe）−Phe−Met（Ｏ）−NHNH2
（3.5mmol）をDMF中でアジド法により縮合さ
せ、粗生成物をMeOHと酢酸エチルで再沈殿し
てＺ（OMe）−Phe−Met（Ｏ）−Arg（Mts）−Arg
（Mts）−Val−NH2（）を得る。収率56.2％、融
点133−136℃、〔α〕15 D−1.1゜（in DMF）。
6N−HCI加水分解後のアミノ酸分析値（モル
比）：Phe0.98、Met0.77、Arg2.28、Val1.00（Val
の回収率：83.0％）。
元素分析：C58H82N12O13S・H2Oとして
(C) (H) （Ｎ）
理論値：54.87 6.67 13.24
測定値：54.73 6.66 13.26
実施例 ８
実施例７で得たを実施例１に準じ、処理して
得られるＨ−Phe−Met（Ｏ）−Arg（Mts）−Arg
（Mts）−Val−NH2（0.32mmol）とＺ（OMe）−
Tyr−Ｄ−Met（Ｏ）−Gly−NHNH2（0.38mmol）
ごアジド法で縮合し、粗生成物をMeOHとエー
テルで再沈殿したのち、Ｚ（OMe）−Tyr−Ｄ−
Met（Ｏ）−Gly−Phe−Met（Ｏ）−Arg（Mts）−
Arg（Mts）−Val−NH2（）を得る。収率36.1
％、融点166−169℃、〔α〕20 D＋6.6゜（in DMF）。
6N−HCI加水分解後のアミノ酸分析値（モル
比）：Try0.96、Met＋Met（Ｏ）1.54、Gly1.05、
Phe1.05、Arg2.04、Val1.00（Valの回収率：89.0
％）。
元素分析：C74H103N15O18S4.3/2H2Oとして
(C) (H) （Ｎ）
理論値：54.00 6.49 12.77
測定値：53.92 6.38 15.56
実施例 ９
実施例８で得た（100mg、62μmol）をｍ−
cresol（20eq）存在下MSA（1.3ml）で氷冷下30分
間、さらに室温で60分間処理する。ｎ−ヘキサン
を加え、生じる沈殿物を水（30ml）にとかし、
AmberliteCG−4B（酢酸型、1.0ｇ）を加え、30
分間撹伴、ろ過し、ろ液を凍結乾燥。残渣を少量
の水にとかし、SephadexG−10（1.8×100cm）の
カラムにかけ、0.5NAcOHで溶出させ主ピーク
（tube No.11〜15：275nｍでの吸光度を測定）を
集め、凍結乾燥する。得られる粉末をCM−
Cellulose（1.8×10cm）のカラムにかけ、水（240
ml）で溶出ののち、0.01MAcCNH4（PH6.0）から
0.1MAcONH4（PH7.0）へのグラジエント溶出を
行ない、主ピーク（tube No.66−91）を集め、凍
結乾燥して白色不定形粉末としてＨ−Tyr−Ｄ−
Met（Ｏ）−Gly−Phe−Met（Ｏ）−Arg−Arg−
Val−NH2（）を得る。収率62.0％、〔α〕30 D＋
4.7゜（in H2O）。
6N−HCI加水分解後のアミノ酸分析値（モル
比）：Tyr0.97、Met1.67、Gly1.00、Phe1.02、
Arg1.88、Val0.86（Glyの回収率：73％）。
元素分析：C47H75N15O11S2・3CH3COOH・
2H2Oとして
(C) (H) （Ｎ）
理論値：48.72 7.02 16.08
測定値：48.55 7.03 16.01
実施例 10
Ｚ（OMe）−Arg（Mts）−OH（6mmol）とＨ−
Phe−OBzl（Ｈ−Phe−OBzl・Tos−OH
（6.6mmol）をトリエチルアミンで中和して調製）
を混合酸無水物法で縮合し、粗生成物を酢酸エチ
ルと石油エーテルから再沈殿して精製し、Ｚ
（OMe）−Arg（Mts）−Phe−OBzlを得る。収率97
％、融点133−134℃、〔α〕15 D−9.0゜（in MeOH）。
元素分析：C40H47N5O8Sとして
(C) (H) （Ｎ）
理論値：63.39 6.25 9.24
測定値：63.48 6.14 9.18
実施例 11
Ｚ（OMe）−Arg（Mts）−Phe−OBzl（5mmol）
を実施例１に準じ、TFAで処理し、得られるＨ
−Arg（Mts）−Phe−OBzlとＺ（OMe）−Leu−
OH（5mmol）を混合酸無水物法により縮合し実
施例10に準じて、得られるＺ（OMe）−Leu−Arg
（Mts）−Phe−OBzlを精製する。収率92.0％、融
点143−144℃、〔α〕15 D−19.1゜（in DMF）。
元素分析：C46H58N6O9Sとして
(C) (H) （Ｎ）
理論値：63.43 6.71 9.65
測定値：63.45 6.53 9.41
実施例 12
Ｚ（OMe）−Leu−Arg（Mts）−Phe−OBzl
（4mmol）を実施例１に準じTFA処理して、得ら
れるＨ−Leu−Arg（Mts）−Phe−OBzlとＺ
（OMe）−Gly−Phe−NHNH2（4.4mmol）をアジ
ド法で縮合し、得られるＺ（OMe）−Gly−Phe−
Leu−Arg（Mts）−Phe−OBzlをDMFと酢酸エチ
ルで再沈殿することにより精製する。収率88.0
％、融点169−170℃、〔α〕28 D−11.0℃（in
DMF）。
元素分析：C57H70N8O11S・H2Oとして
(C) (H) （Ｎ）
理論値：62.62 6.64 10.25
測定値：62.83 6.48 10.28
実施例 13
Ｚ（OMe）−Gly−Phe−Leu−Arg（Mts）−Phe
−OBzl（3mmol）を実施例１に準じ、Ｚ（OMe）
基を除去し、得られるＨ−Gly−Phe−Leu−Arg
（Mts）−Phe−OBzlとＺ（OMe）−Ｄ−Met（Ｏ）
−OH（3mmol）をDCC法によつて縮合した。得
られるＺ（OMe）−Ｄ−Met−Gly−Phe−Leu−
Arg（Mts）−Phe−OBzlをDMFと酢酸エチルで
再沈殿し、精製する。収率80.0％、融点201−202
℃、〔α〕26 D＋2.0℃（in DMF）。
元素分析：C62H79N9O13S2として
(C) (H) （Ｎ）
理論値：60.92 6.51 10.31
測定値：60.62 6.57 10.21
実施例 14
Ｚ（OMe）−Ｄ−Met（Ｏ）−Gly−Phe−Leu−
Arg（Mts）−Phe−OBzl（2mmol）を実施例１に
準じ、処理し、得られるＨ−Ｄ−Met（Ｏ）−Gly
−Phe−Leu−Arg（Mts）−Phe−OBzlとＺ
（OMe）−Tyr−NHNH2（2.0mmol）とアジド法
で縮合し、得られるＺ（OMe）−Tyr−Ｄ−Met
（Ｏ）−Gly−Phe−Leu−Arg−（Mts）−Phe−
OBzlをDMFと酢酸エチルで再沈殿して精製す
る。収率75.0％、融点150−151℃、〔α〕26 D−8.9°
（in DMF）。
元素分析：C71H88N10O15S2として
(C) (H) （Ｎ）
理論値：61.54 6.40 10.11
測定値：61.49 6.41 10.10
実施例 15
Ｚ（OMe）−Tyr−Ｄ−Met（Ｏ）−Gly−Phe−
Leu−Arg（Mts）−Phe−OBzl（144μｍmol）を氷
浴中ｍ−cresol存在下、MSA（3.0ml）で60分間、
さらに室温で60分間処理し、ｎ−ヘキサンを加え
る。生成する沈殿物をエーテルで洗浄後、2N−
AcOH（15ml）に溶かし、AmberliteCG−4B（酢
酸型、約２ｇ）を加え室温で30分間撹伴し、ろ過
後ろ液を凍結乾燥する。得られる粉末を、ｎ−
BuOH−AcOH−H2O（４：１：5v／ｖ）の上層
を溶出液とするSephadexG−10（3.0×58cm：下層
で了め置換している）での分配クロマトグラフイ
ーによつて精製する。目的物を含む分画（275n
ｍで溶出液をモニターする）を集め、減圧下溶媒
を留去し残渣を少量の水に溶かしたのち、凍結乾
燥する。白色不定形粉末としてＨ−Tyr−Ｄ−
Met（Ｏ）−Gly−Phe−Leu−Arg−Phe−OH
（）を得る。収率78.0％、〔α〕18 D＋7.3゜（in
2NAcOH）。6N−HCI加水分解後のアミノ酸析
値（モル比）：Tyr0.94、Met0.92、Gly1.03、
Phe2.00、Leu1.00、Arg1.01（Pheの回収率：80
％）
元素分析：C46H64N10O10S・CH3COOH・
2.5H2Oとして
(C) (H) （Ｎ）
理論値：54.68 6.98 13.29
測定値：54.64 6.90 13.23
以上により特許請求の範囲で述べた２種類の合
成ペプタイドはいずれも新規化合物である。[Table] When administered intracisternally, synthetic peptides exhibit stronger analgesic effects than the standard morphine, so it is clear that they are effective analgesics. Examples Hereinafter, the present invention will be explained in more detail with reference to Examples. Example 1 Z(OMe)-Val-NH 2 (5 mmole) was cooled on ice,
The resulting H-
Val-NH 2 and Z(OMe)-Arg-(Mts)-OH were condensed by mixed acid anhydride method, and the crude product was recrystallized from methanol-ether to form Z(OMe)-Arg
(Mts)-Val- NH2 is obtained. Yield 65.8%, melting point 139
−142°C, [α] 15 D +8.5° (in MeOH). Elemental analysis: C 29 H 42 N 6 O 7 S.1/2H 2 O (C) (H) (N) Theoretical value: 55.48 6.90 13.39 Measured value: 55.34 6.99 13.15 Example 2 Z (OMe) − Arg ( Mts)−Val− NH2 (5mmol)
was treated with TFA according to Example 1, and the obtained H-
Arg (Mts) − Val − NH 2 and Z (OMe) − Arg (Mts)
-OH was condensed by mixed acid anhydride method, and the crude product was reprecipitated with methanol and ether to form Z(OMe)-
Obtain Arg(Mts)-Arg(Mts)-Val- NH2 . Yield 83.9%, melting point 119-123°C, [α] 15 D -5.7° (in
MeOH). Elemental analysis: C 44 H 64 N 10 S 2・1/2H 2 O (C) (H) (N) Theoretical value: 54.69 6.78 14.50 Measured value: 54.69 6.79 14.27 Example 3 Z(OMe)−Phe−OH (10mmol) and H-Met-
OMe (prepared by neutralizing hydrochloride with triethylamino) is condensed in a dimethylformamide-tetrahydrofuran (DMF-THF) mixture by the dicyclohexylcarbodiimide method (DCC method),
Z(OMe)-Phe-Met-OMe is obtained. Yield 63.0
%, melting point 111-113°C, [α] 20 D -16.0° (in DMF). Elemental analysis: as C 24 H 30 N 2 O 6 S (C) (H) (N) Theoretical value: 60.74 6.37 5.90 Measured value: 60.69 6.52 6.11 Example 4 Z(OMe)-Phe-Met-OMe (7 mmol) of
NaBO 3 (1.1eq) and as oxidizing agent in DMF solution
Z(OMe) obtained by acting NaIO 4 (1.0eq)
-Phe-Met(O)-OMe [melting point 129-131℃, [α]
15 D −10.6° (in MeOH)] with hydrazine hydrate. The resulting crude hydrazide was reprecipitated with DMF and ethanol to form Z(OMe)-Phe-Met-(O)-
Obtain NHNH2 . Yield 31.0%, melting point 197-200℃
[α] 15 D −17.2° (in DMF). Elemental analysis: as C 23 H 30 N 4 O 6 S (C) (H) (N) Theoretical value: 56.31 6.16 11.42 Measured value: 56.04 5.99 11.33 Example 5 Z(OMe)-D-Met(O)-OH (6 mmol) and H
-Gly-OMe (6 mmol) (prepared by neutralizing the hydrochloride with triethylamine) was condensed by DCC method in THF (100 ml) to give Z(OMe)-D-Met(O)-Gly
- Obtain OMe. Yield 81.0%, melting point 100-103℃,
[α] 15 D +27.0° (in MeOH). Elemental analysis: as C 16 H 24 N 2 O 7 S (C) (H) (N) Theoretical value: 50.99 6.04 7.00 Measured value: 50.81 6.05 7.23 Example 6 Z(OMe)-D-Met(O)-Gly −OMe
(4 mmol) was treated with TFA according to Example 1 to obtain HD-Met(O)-Gly-OMe and Z(OMe)-
Z(OMe)-Tyr-D-Met(O) obtained by condensing Tyr- NHNH2 by the azide method (Rudinger's modified method)
-Gly-OMe (melting point 172-174℃, [α] 15 D +2.0 (in
DMF)) was treated with 10 eq of hydrazine hydrate to produce the corresponding hydrazide, Z(OMe)-Tyr-D-Met(O).
-Gly- NHNH2 is obtained. Yield 63.4%, melting point 164−
166℃, [α] 15 D 0゜ (in DMF). Elemental analysis: C 25 H 33 N 5 O 8 S・1/2H 2 O (C) (H) (N) Theoretical value: 52.44 5.99 12.23 Measured value: 52.44 6.01 12.17 Example 7 Z(OMe)−Arg( Mts)−Arg(Mts)−Val−
H-Arg(Mts)-Arg(Mts)-Val- obtained by treating NH 2 (2.92 mmol) according to Example 1
NH2 and Z(OMe)-Phe-Met(O) -NHNH2
(3.5 mmol) was condensed in DMF by the azide method, and the crude product was reprecipitated with MeOH and ethyl acetate to give Z(OMe)-Phe-Met(O)-Arg(Mts)-Arg.
(Mts)−Val−NH 2 () is obtained. Yield 56.2%, melting point 133-136°C, [α] 15 D -1.1° (in DMF). Amino acid analysis values (molar ratio) after 6N-HCI hydrolysis: Phe0.98, Met0.77, Arg2.28, Val1.00 (Val
Recovery rate: 83.0%). Elemental analysis: C 58 H 82 N 12 O 13 S・H 2 O (C) (H) (N) Theoretical value: 54.87 6.67 13.24 Measured value: 54.73 6.66 13.26 Example 8 An example of the sample obtained in Example 7 H-Phe-Met(O)-Arg(Mts)-Arg obtained by processing according to 1.
(Mts)-Val- NH2 (0.32mmol) and Z(OMe)-
Tyr-D-Met(O)-Gly- NHNH2 (0.38mmol)
After condensation using the azide method and reprecipitation of the crude product with MeOH and ether, Z(OMe)-Tyr-D-
Met(O)-Gly-Phe-Met(O)-Arg(Mts)-
Arg(Mts)-Val- NH2 () is obtained. Yield 36.1
%, melting point 166-169°C, [α] 20 D +6.6° (in DMF).
Amino acid analysis values (molar ratio) after 6N-HCI hydrolysis: Try0.96, Met+Met(O)1.54, Gly1.05,
Phe1.05, Arg2.04, Val1.00 (Val recovery rate: 89.0
%). Elemental analysis: C 74 H 103 N 15 O 18 S 4 .3/2H 2 O (C) (H) (N) Theoretical value: 54.00 6.49 12.77 Measured value: 53.92 6.38 15.56 Example 9 Obtained in Example 8 (100mg, 62μmol) m-
Treat with MSA (1.3 ml) in the presence of cresol (20 eq) for 30 minutes under ice cooling, and then for 60 minutes at room temperature. Add n-hexane, dissolve the resulting precipitate in water (30 ml),
Add AmberliteCG-4B (acetic acid form, 1.0g) and
Stir for a minute, filter, and lyophilize the filtrate. The residue is dissolved in a small amount of water, applied to a column of Sephadex G-10 (1.8 x 100 cm), eluted with 0.5NAcOH, and the main peak (tube No. 11 to 15: absorbance measured at 275 nm) is collected and freeze-dried. The obtained powder is CM−
Column of Cellulose (1.8 x 10 cm), water (240
ml) and then from 0.01 MAcCNH 4 (PH6.0).
Perform gradient elution to 0.1 MAcONH 4 (PH7.0), collect the main peak (tube No. 66-91), and freeze-dry to obtain H-Tyr-D- as a white amorphous powder.
Met(O)-Gly-Phe-Met(O)-Arg-Arg-
Obtain Val−NH 2 (). Yield 62.0%, [α] 30 D +
4.7° (in H2O ). Amino acid analysis values (molar ratio) after 6N-HCI hydrolysis: Tyr0.97, Met1.67, Gly1.00, Phe1.02,
Arg1.88, Val0.86 (Gly recovery rate: 73%). Elemental analysis: C 47 H 75 N 15 O 11 S 2・3CH 3 COOH・
As 2H 2 O (C) (H) (N) Theoretical value: 48.72 7.02 16.08 Measured value: 48.55 7.03 16.01 Example 10 Z (OMe) − Arg (Mts) − OH (6 mmol) and H −
Phe−OBzl (H−Phe−OBzl・Tos−OH
(Prepared by neutralizing (6.6 mmol) with triethylamine)
was condensed by a mixed acid anhydride method, and the crude product was purified by reprecipitation from ethyl acetate and petroleum ether to give Z
(OMe)-Arg(Mts)-Phe-OBzl is obtained. Yield 97
%, melting point 133-134°C, [α] 15 D -9.0° (in MeOH). Elemental analysis: as C 40 H 47 N 5 O 8 S (C) (H) (N) Theoretical value: 63.39 6.25 9.24 Measured value: 63.48 6.14 9.18 Example 11 Z (OMe) − Arg (Mts) − Phe − OBzl (5mmol)
was treated with TFA according to Example 1, and the obtained H
−Arg(Mts)−Phe−OBzl and Z(OMe)−Leu−
Z(OMe)-Leu-Arg obtained by condensing OH (5 mmol) by the mixed acid anhydride method according to Example 10
Purify (Mts)-Phe-OBzl. Yield 92.0%, melting point 143-144°C, [α] 15 D -19.1° (in DMF). Elemental analysis: as C 46 H 58 N 6 O 9 S (C) (H) (N) Theoretical value: 63.43 6.71 9.65 Measured value: 63.45 6.53 9.41 Example 12 Z(OMe)−Leu−Arg(Mts)−Phe −OBzl
(4 mmol) was treated with TFA according to Example 1 to obtain H-Leu-Arg(Mts)-Phe-OBzl and Z
Z(OMe)-Gly-Phe- obtained by condensing (OMe)-Gly-Phe- NHNH2 (4.4 mmol) by the azide method
Leu-Arg(Mts)-Phe-OBzl is purified by reprecipitation with DMF and ethyl acetate. Yield 88.0
%, melting point 169-170℃, [α] 28 D −11.0℃ (in
DMF). Elemental analysis: C 57 H 70 N 8 O 11 S・H 2 O (C) (H) (N) Theoretical value: 62.62 6.64 10.25 Measured value: 62.83 6.48 10.28 Example 13 Z(OMe)−Gly−Phe− Leu−Arg(Mts)−Phe
-OBzl (3 mmol) according to Example 1, Z (OMe)
By removing the group, the obtained H-Gly-Phe-Leu-Arg
(Mts)-Phe-OBzl and Z(OMe)-D-Met(O)
-OH (3 mmol) was condensed by DCC method. Obtained Z(OMe)-D-Met-Gly-Phe-Leu-
Arg(Mts)-Phe-OBzl is reprecipitated with DMF and ethyl acetate and purified. Yield 80.0%, melting point 201-202
°C, [α] 26 D +2.0 °C (in DMF). Elemental analysis: C 62 H 79 N 9 O 13 S as 2 (C) (H) (N) Theoretical value: 60.92 6.51 10.31 Measured value: 60.62 6.57 10.21 Example 14 Z(OMe)-D-Met(O)- Gly−Phe−Leu−
Arg(Mts)-Phe-OBzl (2 mmol) was treated according to Example 1, and the obtained H-D-Met(O)-Gly
-Phe-Leu-Arg(Mts)-Phe-OBzl and Z
Z(OMe)-Tyr-D-Met obtained by condensation with (OMe)-Tyr- NHNH2 (2.0 mmol) by the azide method
(O)-Gly-Phe-Leu-Arg-(Mts)-Phe-
Purify OBzl by reprecipitation with DMF and ethyl acetate. Yield 75.0%, melting point 150-151℃, [α] 26 D −8.9°
(in DMF). Elemental analysis: C 71 H 88 N 10 O 15 S as 2 (C) (H) (N) Theoretical value: 61.54 6.40 10.11 Measured value: 61.49 6.41 10.10 Example 15 Z(OMe)-Tyr-D-Met(O )−Gly−Phe−
Leu-Arg(Mts)-Phe-OBzl (144 μmmol) was added to MSA (3.0 ml) in the presence of m-cresol in an ice bath for 60 min.
After further treatment at room temperature for 60 minutes, n-hexane is added. After washing the formed precipitate with ether, 2N−
Dissolve in AcOH (15 ml), add AmberliteCG-4B (acetic acid form, about 2 g), stir at room temperature for 30 minutes, and freeze-dry the filtered solution. The obtained powder was
Purification by partition chromatography on Sephadex G-10 (3.0 x 58 cm: replaced with the lower layer) using the upper layer of BuOH-AcOH-H 2 O (4:1:5 v/v) as the eluent. do. Fraction containing the target product (275n
The eluate was collected (monitor the eluate at m), the solvent was distilled off under reduced pressure, the residue was dissolved in a small amount of water, and then freeze-dried. H-Tyr-D- as a white amorphous powder
Met(O)-Gly-Phe-Leu-Arg-Phe-OH
get (). Yield 78.0%, [α] 18 D +7.3° (in
2NAcOH). Amino acid analysis values (molar ratio) after 6N-HCI hydrolysis: Tyr0.94, Met0.92, Gly1.03,
Phe2.00, Leu1.00, Arg1.01 (Phe recovery rate: 80
%) Elemental analysis: C 46 H 64 N 10 O 10 S・CH 3 COOH・
As 2.5H 2 O (C) (H) (N) Theoretical value: 54.68 6.98 13.29 Measured value: 54.64 6.90 13.23 According to the above, both of the two synthetic peptides described in the claims are new compounds.
Claims (1)
）の合成ペプタイド。 Ｈ−Tyr−Ｄ−Met（Ｏ）−Gly−Ｘ ：Ｘ＝Phe−Met（Ｏ）−Arg−Arg−Val−
NH2 ：Ｘ＝Phe−Leu−Arg−Phe−OH[Claims] 1. Two types having the following amino acid sequences (
) synthetic peptides. H-Tyr-D-Met(O)-Gly-X: X=Phe-Met(O)-Arg-Arg-Val-
NH2 :X=Phe-Leu-Arg-Phe-OH
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP60098449A JPS61257997A (en) | 1985-05-08 | 1985-05-08 | Synthetic peptide having strong analgeisc activity |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP60098449A JPS61257997A (en) | 1985-05-08 | 1985-05-08 | Synthetic peptide having strong analgeisc activity |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP63014040A Division JPS63313799A (en) | 1988-01-25 | 1988-01-25 | Synthetic peptide having powerful analgesic activity |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS61257997A JPS61257997A (en) | 1986-11-15 |
| JPS6346079B2 true JPS6346079B2 (en) | 1988-09-13 |
Family
ID=14220035
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP60098449A Granted JPS61257997A (en) | 1985-05-08 | 1985-05-08 | Synthetic peptide having strong analgeisc activity |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS61257997A (en) |
-
1985
- 1985-05-08 JP JP60098449A patent/JPS61257997A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| JPS61257997A (en) | 1986-11-15 |
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