WO1997010262A1 - Derives peptidiques - Google Patents
Derives peptidiques Download PDFInfo
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- WO1997010262A1 WO1997010262A1 PCT/JP1996/002573 JP9602573W WO9710262A1 WO 1997010262 A1 WO1997010262 A1 WO 1997010262A1 JP 9602573 W JP9602573 W JP 9602573W WO 9710262 A1 WO9710262 A1 WO 9710262A1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
- C07K5/0202—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -NH-X-X-C(=0)-, X being an optionally substituted carbon atom or a heteroatom, e.g. beta-amino acids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- 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
- C07K5/10—Tetrapeptides
- C07K5/1002—Tetrapeptides with the first amino acid being neutral
- C07K5/1016—Tetrapeptides with the first amino acid being neutral and aromatic or cycloaliphatic
-
- 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 peptide derivative which exerts a pharmacological action such as analgesia through an action on an obioid receptor or the like.
- Obioid receptors to which morphine and other obioids bind, were proven to exist in the early 1970s. Obioid receptors are currently roughly classified into ⁇ 5 and / or 3. Morphine mainly acts as an agonist on the receptor and exerts pharmacological effects such as analgesia, intestinal motility suppression and respiratory depression.
- obioid peptides The pharmacological effect of obioid peptide is considered to be basically the same as that of morphine, and since it is a substance that originally exists in the living body, it is expected that it may be a drug that is safer than morphine. You. However, natural opioid peptides have problems in pharmacokinetics and are not yet used as pharmaceuticals.
- the present inventors have diligently searched for an obioid peptide derivative having an excellent analgesic effect and oral absorption to solve the above-mentioned problems. As a result, they have found that an oligopeptide derivative having L-Tyr- (L or!))-Arg-Phe as the basic skeleton and having an amidino group at the N-terminus and a salt thereof retain such properties, and these inventions (Japanese Patent Application No. 40989 and 1995 Patent Application No. 49894). The present inventor has further conducted intensive studies and has found that novel peptides in which the basic skeleton is variously modified have desired properties. The present invention has been completed based on these findings.
- the peptide derivative of the present invention has the following formula I:
- HN C (R 1 ) -XY-NH-CH (R £ ') -CO-Q
- a medicine comprising the above compound or a salt thereof, and an analgesic pharmaceutical composition comprising the compound or a salt thereof as an active ingredient.
- the present invention also provides a method of preventing and / or treating pain, which comprises the use of the compound or a salt thereof for the production of the pharmaceutical composition, and a step of administering an effective amount of the compound or a salt thereof to a mammal.
- R 1 represents an amino group or an alkyl group which may have a substituent.
- the number of substituents may be either one or two, and when it has two substituents, they may be the same or different.
- the substituent include an alkyl group, a hydroxyl group, a substituted or unsubstituted amino group Etc. can be used. In the present specification, when alkyl is used, they may be linear or branched.
- R 1 is preferably an unsubstituted amino group or a methyl group.
- ⁇ Denotes the also ⁇ Li Ichiru group or may have a substituent substituted with c 3 _ 6 consequent opening alkyl group an alkyl group which may be substituted. 6 position of the alkyl group Ariru group or a cycloalkyl group you substituted on is not particularly limited, C ⁇ - 6 is preferred arbitrarily be substituted at the terminal alkyl group.
- the aryl group or the alkyl group having a substituent has a substituent
- the aryl group or the alkyl group may have one or more substituents at an arbitrary substitution position.
- Examples of the substituent on the aryl group or the cycloalkyl ring include a hydroxyl group, an amino group which may have a substituent, a guanidino group which may have a substituent, an alkyl group, and a 6- alkyloxy group.
- An (alkoxy) group, a halogen atom in the present specification, a halogen atom may be any of a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom) can be used.
- ⁇ for example, a p-hydroxybenzyl group, a phenethyl group, a cyclohexylmethyl group, a parachlorobenzyl group, a parafluorobenzyl group, or the like is preferable.
- the absolute configuration of the carbon atom bonded to R 2 is not particularly limited, but those having the S configuration are preferred compounds of the present invention.
- X represents a proline (Pro) residue which may have a substituent.
- the proline residue may be either a reproline residue or a D-proline residue, but is preferably a D-proline residue.
- the proline residue may have one or more substituents at any position, and when it has two or more substituents, the substituents may be the same. It may be different.
- a proline residue having a substituent for example, 4-hydroxyproline can be suitably used.
- X is the following formula:
- R 3, R 4, and R 5 independently represent hydrogen atom, arsenic Dorokishiru group, (: Bok 6 alkyl group, ( ⁇ - shows the 0s0 3 H - 6 alkoxyl group, a halogen atom, or.
- R 3, R 4, and R 5 may be the same or different for example, R 3, R 4, and iT chart Re compound of which hydrogen atom;.
- R 3 is 4-arsenide Dorokishiru group, R 4 And compounds wherein IT is a methyl group at the 2-position and 6-position, respectively; compounds wherein R 3 is a 4-hydroxyl group and R 4 and R 5 are hydrogen atoms; IT is a 4-methoxy group A compound wherein R 4 and R 5 are hydrogen atoms; a compound wherein R 3 and R 4 are 3- and 4-position hydroxy groups, respectively, and R 3 is a hydrogen atom; and R 3 There -. OS0 is 3 H, and compounds wherein R 4 and is a hydrogen atom is preferred among these, X or tyrosine (Thy) residues, in particular L-Tyr residues Compounds that are groups are a particularly preferred embodiment of the present invention.
- Y represents a D-proline (Pro) residue or an L-proline (Pro) residue, or a group represented by the following formula:
- Bok 6 alkyl), alkylsulfonyl group indicates Ashiruokishi group, a carboxyl group, or alkoxycarbonyl two Le group, n is an integer of 1-4.
- R 14 if a hydrogen atom or an alkyl group.
- R G represents a hydrogen atom, the The formula preferably represents a D-alanine (Ala) residue, an L-alanine residue, a D-norparin (Nva) residue, a renorvaline (Nva) residue, or the like. When it has a substituent, the substituent may be either 1 or 2.
- substituent on the amino group examples include, for example, imidazolinyl group, alkyl group, triaminoethyl group and the like.
- Mi Roh _ 6 alkyl group such as Asechiru the group -.
- Arukanoi group also It may have use a halogenated _ 6 Al force Noiru group such Bok re Furuoroasechiru group, for example, one methyl group respectively, Echiru group, ⁇ having an isopropyl group, Bokui Mi Noechiru group, or Asechiru group Mino groups can be suitably used.
- the guanidino group When the guanidino group has a substituent, it can have one or more substituents on the nitrogen atom constituting the guanidino group, and when it has two or more substituents, they are the same or different. May be.
- substituents on the nitrogen atom constituting the guanidino group, and when it has two or more substituents, they are the same or different. May be.
- a methyl group or the like can be used.
- the substituent When RD is a mercapto group having a substituent, the substituent may be an alkyl group, preferably a methyl group.
- R 6 When R 6 is a phenyl group having a substituent, it may have one or more substituents at any position on the phenyl ring.
- the substituent for example, an amino group which may have the substituent described above or a guanidino group which may have the substituent can be used.
- a P-aminophenyl group or a p-guanidinophenyl group can be preferably used.
- RG is a substituted peridode group, a substituted permebamoyl group, or a substituted thioperido group
- substituents include ( ⁇ _ such as a 6 alkyl group and an acetyl group).
- R 6 is ( ⁇ _ 6 alkylsulfinyl group or an alkylsulfonyl group, substituted sulfinyl group or a sulfonyl group - 6 alkyl group as e.g. arbitrary preferable to use the methyl group.
- the Ashiruokishi group R 6 represents, it is possible to use a halogenated aralkyl force Noiru Okishi groups such as _ 6 Al force Roh Iruokishi group and Bok Li Full O b acetyl O alkoxy groups such Asechiruokishi group.
- R 6 an aryl-substituted carboxy group which may have a substituent on the ring, such as a benzoyloxy group, can be used.
- the substituent on the phenyl ring of the benzoyl group for example, an alkyl group, a halogen atom, or an amino group which may have the above-described substituent can be used.
- R 6 represents a carboxyl group
- the above formula preferably represents a D-glutamic acid (Glu) residue or an L-glutamic acid residue.
- R 6 is (: is an example of a case showing a Bok 6 alkoxy force Lupo two group, and the like main Tokishikarubo alkenyl group Ya et Tokishikarubo two Le group.
- R 14 is a hydrogen atom
- R D is a substituted or unsubstituted Guanijino group
- R Q is alkyl group, for example a methyl group I prefer that there be.
- the configuration of the ⁇ -carbon of the residue represented by Y is not particularly limited, or it may be preferable to use a D-amino acid residue from the viewpoint of stability in the body.
- D A compound which is a residue selected from -methionine sulfoxide residue is a preferable compound of the present invention.
- Q is - 0R ', - N (R 8) (R 9), or - NR 10 -C (R U) (R 1 2) indicates one of (R lj).
- R 8 represents a hydrogen atom or a ( ⁇ alkyl group;
- R 9 represents a ( ⁇ _ 6 hydroxyalkyl group or a sulfonic acid-substituted alkyl group; a hydroxyl group or a sulfonic acid)
- the group may be substituted at any position of the alkyl group, or a terminally substituted alkyl group is preferred, and R ° and ⁇ together form a 5- or 6-membered nitrogen atom with which R 8 and R 9 substitute.
- heterocyclic group may indicate nitrogen saturated heterocyclic group, the heterocyclic ring may contain two or more nitrogen atoms such as -.
- 1-piperazinyl group as NR ° R 9, Bok pyro Li Jiniru group, or Bokupi A peridinyl group or the like can be used.
- R 10 is a hydrogen atom, - 6 alkyl group, or Fuweniru Ariru group such groups are substituted ( ⁇ alkyl group (
- the aralkyl group includes, for example, a benzyl group, etc.
- R 10 is a methyl group
- R 11 is a hydrogen atom, a carboxyl group, methoxy carbonyl, and ethoxy.
- carbonyl - 6-carbonyl group an alkoxy group substituted; substituted or unsubstituted force Rubamoiru group; a carboxyl group-substituted ( ⁇ -6 alkyl group; an alkyl group substituted or unsubstituted force Rubamoiru group is substituted; or - 6 alkoxy
- R 11 is preferably —CH 2 —C00H.
- R 1 2 is hydrogen; _ 6 alkyl group; ⁇ Mi Roh (: Bok 6 alkyl group; the alkyl group which Guanijino group is substituted, human Dorokishi al Kill group; an alkyl group ⁇ Mi Gino group is substituted with a carboxyl group substituted ( ⁇ _ 6 alkyl group, or a substituted or unsubstituted Cal Pa 'carbamoyl-substituted ( ⁇ -.!?
- a 5- or 6-membered nitrogen-containing saturated heterocyclic group having a carboxyl group on the ring may be formed together with the nitrogen atom, such as a 2-carboxy-1-pyrrolidinyl group (-Pro-0H ) and 3-carboxy -..
- R 1 3 represents a hydrogen atom or a ( ⁇ _ 6 alkyl group e.g., R 1 1 is a carboxymethyl ethyl group or Scarpa 'Moirumechiru group, A combination wherein R 1 and R 13 are hydrogen atoms
- R 10 is a methyl group (when Q is —NCH; —CH 2 —CH 2 —COOH) is preferable.
- R 2 is an unsubstituted benzyl group
- X is an L-tyrosine (L-Tyr) residue
- R 3 is a P-hydroxyl group
- R 4 and R 5 are hydrogen An atom whose configuration corresponds to L-amino acid
- Y is an L- or D-arginine (Arg) residue
- the asymmetric carbon present in the compounds of the invention represented by the above formula I may have any S- or R- configuration except as defined above.
- a sulfur atom such as a sulfoxide
- the configuration may be any of those.
- Y is D-methyl
- RS D-methionine-
- R D-methionine-
- S D-methionine-
- the compound represented by the formula I of the present invention includes all optically active or racemic forms, diastereoisomers or any mixtures thereof.
- the compounds of the present invention include acid addition salts such as hydrochloride, acetate, and para-toluenesulfonic acid, and base addition salts such as ammonium salts and organic amine salts. Any hydrates and solvates of the compounds in the form are also included in the scope of the present invention. Further, in addition to the compounds represented by the above general formula, compounds which are dimers or multimers of the above compounds, and cyclic compounds in which the C-terminal and the N-terminal of these compounds are bound are included.
- the peptide of the present invention has an analgesic effect exceeding morphine.
- the histamine release effect and heart rate lowering effect associated with the analgesic effect are relatively weak compared to morphine, and the degree of cross-resistance with morphine is low, so that it is expected to be suitable for use in the treatment of cancer pain.
- the present invention provides a medicine comprising the above compound.
- Administration routes include intravenous administration, subcutaneous administration, and oral administration. Mucosal absorption preparations including nasal absorption and transdermal absorption preparations are also expected to be useful.
- the dose is not particularly limited.For example, in the case of transdermal administration, the single dose is 0.1 to 10 mg, and in the case of oral administration, the single dose is 1 to 100 mg. It can be administered 2-3 times per dose.
- the peptide derivative of the present invention can be synthesized by a solid phase method and a liquid phase method usually used for peptide synthesis.
- a solid phase method for example, it is possible to produce a peptide derivative of interest by synthesizing a peptide chain having no amidino group by a solid phase method, and further introducing an amidino group to the amino group of tyrosine at the N-terminal. It is also possible to modify the C-terminal after introducing an amidino group in advance.
- the present invention will be described more specifically with reference to Examples, but the present invention is not limited to these Examples.
- the desired present invention of the present invention encompassed by the general formula I is obtained.
- the peptide derivative can be easily produced.
- the meaning of the amino acid group is the same as that usually used.
- the amino acid means an amino acid.
- the following abbreviations may be used, and similar abbreviations may be used unless otherwise indicated.
- H 0 NC (NH) - Phe - notation such as Boc-Phe- or BZA-Phe- may, N- terminal nitrogen atom of Fuyunirua alanine respectively H 0 NC (NH) -, is modified by the Boc or BZA
- amino acids indicate amino acid residues.
- AGHX 2-amino-6-guanidinohexanoic acid
- Alko resin p-alkoxybenzyl alcohol resin [4-hydroxymethylphenyloxymethylcopolystyrene divinylbenzene resin, J. Am. Chem. So, 95, 1328 (1974)], Watanabe Chemical Industry
- BPBA 2-amino-3-phenylbutyric acid
- BZA ⁇ , ⁇ '-bis (benzyloxycarbonyl) amidino group
- D1PEA N, N-diisopropyrethylamine
- D1PC1 N-diisopropylcarbodiimide
- Fmoc-NH-SAL resin 4- (2 ', 4'-dimethoxyphenyl-1-9-fluorenylmethoxylponylaminomethyl) phenyloxy resin: Watanabe Chemical Industry
- IPPE 2-amino-5-isopropylaluminopentanoic acid
- eTyr N-methyltyrosine GPE or Arg (CH 3 ): 2-amino-5_methylguanidinopentanoic acid
- the resulting Fmoc-S MeAla-Alko resin is washed three times with 6 ml of DMF, then three times with 6 ml of methanol and then three times with 6 ml of DCM, and unreacted hydroxymethyl groups are removed in 6 ml of DCM. Then, 0.0891 ml of benzoyl chloride and 0.0847 nil of pyridine were added, and the mixture was shaken for 1 hour to benzoylate.
- the amino acid resin is further washed three times with 6 ml of DCM, three times with 6 ml of DMF, and three times with 6 ml of methanol, and vacuumed in a calcium hydroxide desiccator. Dried.
- the Fmoc group was removed from the Fmoc-Phe- / S MeAla-Alko resin by the same operation as above, and Fmoc-D-Arg (Pmc) -OH 0.557 g, HOBt 0.121 g, HBTU 0.299 g, 0.274 ml of DI PEA was added and shaken for 1 hour to produce Fmoc-D-Arg (Pmc) -Phe- / 3 MeAla-Alko resin. Then, after filtration and washing as in the previous section, unreacted amino groups were removed.
- the Fmoc group was removed from Fmoc-D-Arg (Pmc) -Phe- ⁇ MeAla-Alko resin by the same operation as above, and Fmoc-Tyr (t-Bu) -0H 0.310 g, HOBt 0.103 g, 0.25 g of HBTU and 0.235 ml of DI PEA were added and shaken for 1 hour to produce Fmoc_Tyr (t-Bu) -D-Arg (Pmc) -Phe- / S MeAla-Alko resin. After filtration and washing as in the previous section, unreacted amino groups were capped. In the same manner as in (1) above, the peptide was separated from the resin, and at the same time, the protecting group was removed.
- the resulting Fmoc- ⁇ EtAla-Alko resin was washed three times with 12 ml of NMP, then three times with 12 ml of methanol and three times with 12 ml of DCM, and the unreacted hydroxymethyl groups were removed in 12 ml of DCM. 0.178 ml and 0.170 ml of pyridine were added and shaken for 1 hour to benzoylate. Further, the amic acid resin was washed three times with 12 ml of DCM, three times with 12 ml of DMF, and three times with 12 ml of methanol, and dried in a potassium hydroxide desiccator under vacuum.
- the Fmoc group was removed by treating 3 times with 12 ml of DMF and 6 times with 12 ml of DMF, and added 0.387 g of Fmoc-Phe-OH, 0.466 g of PyBrop, 12 ml of NMP, and 0.523 ral of DIPEA, and added for 24 hours. Shaking produced the Fmoc-Phe-ySEtAla-Alko resin.
- the precipitate was washed with 12 ml of NMP, and unreacted amino groups were treated with 12 ml of DMF containing 0.551 g of triacetyl imidazole and 0.174 ml of DIPEA for 1 hour and capped. Then, the obtained resin was washed again with 12 ml of NMP.
- the Fmoc group was removed from the Fmoc-Phe- / SEtAla-Alko resin by the same operation as described above. Add 0.707 g of Fmoc-D-Arg (Pmc) -OH, 0-153 g of HOBt, 0.379 g of HBTU, 0.348 ml of DIPEA to the resin, shake for 1 hour and shake Fmoc- D-Arg (Pmc) -Phe-/ SEtAla- Alko A resin was formed. After filtration and washing as in the previous section, unreacted amino groups were capped.
- the Fmoc group is removed from Fmoc-D Arg (Pmc) -Phe-ySEtAla-Alko resin by the same operation as above, and Fmoc-Tyr (t-Bu) -0H 0.460 g, HOBt 0.153 g, HBTU 0.399 g, DIPEA 0.348 ml was added, and the mixture was shaken for 1 hour to produce Fmoc-Tyr (t-Bu) -D-Arg (Pmc) -Phe-SEtAla-Alko resin. After filtration and washing as described above, unreacted amino groups were capped. By the same method as in (1) above, the peptide was separated from the resin, and at the same time, the protecting group was removed.
- Z- Phe- OTCE 254 25 hydrobromic acid 900 ml The starting material was dissolved in CH 2 C1 2 1000 ml in an ice bath. To this solution was added Boc-D-Arg (Z. OH 288 g, HOBt 85 g), neutralized with TEA 77 ml, and then condensed with EDC HC1 121 to condense Boc-D-Arg (Z 2 ) -Phe- Then, 241 g of Boc-D-Arg (Z 2 ) -Phe-OTce was treated with 1000 ml of 4N HC1-ethyl acetate to remove the Boc group, and dissolved in 1300 ml of DMF in an ice bath.
- Boc-Tyr (Bzl) -0H and 46 g of HOBt neutralized with 42 ml of TEA, and then condensed with 65 g of EDC / HC1 to obtain a protected peptide represented by the following formula: Boc-Tyr (Bzl) -D-Arg (Z 2 ) -Phe-OTce Boc Tyr (Bzl)-D-Arg (Z 2 ) _Phe-OTce 48 g was treated with 4N HC1-ethyl acetate 250 ml to obtain Boc The group was removed.
- TosOH ⁇ Me ⁇ Ala- OBzl was used as a starting material, and was produced sequentially from the C-terminal by the liquid phase method.
- Example 1 H 2 NC (NH) -Phe-D-Arg-Phe—Me / 3Ala-0H ⁇ 2 acetate
- Boc- Phe- D - Arg (Z 2 ) - Phe- MeSAla- OBzl (0.51 g, 0.5 mmol) was dissolved in 4N HC1 acetic E chill solution (20 ml), and stirred for 1 hour at room temperature. Crystals precipitated by adding getyl ether to the reaction solution were collected by filtration. The crystals were dissolved in dimethylformamide (20 ml), and 1- ( ⁇ , ⁇ '-bis (benzyloxycarbonyl) amidino) pyrazole (0.18 g, 0.48 mmol) and triethylamine (0.08 ml, 0.6 mmol) were dissolved. ) was dissolved. The solution was stirred at room temperature for 18 hours.
- the protective peptide (0.36 g, 0.29 mmol) obtained in (1) above was dissolved in acetic acid (10 ml), and 0.2% of 5% Pd-C (water content: 50 ⁇ ⁇ ⁇ ) was added as a catalyst, followed by catalytic reduction for 4 hours. To remove the protecting group. After filtering off the catalyst, the solvent was concentrated under reduced pressure, and the residue was dissolved in 0.1N acetic acid. The solution was lyophilized to give 200 mg of the title compound as a white powder (
- Boc-DMT-D-Arg (Z 2 ) -Phe-e ⁇ Ala-OBzl (0.74 g, 0.7 mmol) was dissolved in a 4N HC1 ethyl acetate solution (20 ml) and stirred at room temperature for 0.5 hour. Crystals precipitated by adding getyl ether to the reaction solution were collected by filtration. The crystals were dissolved in dimethylformamide (20 ml), and 1- (N, ⁇ '-bis (benzyloxycarbonyl) amidino) pyrazole (0.25 g, 0.67 mmol) and triethylamine (0.12 ml, 0.84). The solution was stirred at room temperature for 18 hours.
- the protective peptide (0.06 g, 0.05 mmol) obtained in (1) above was dissolved in acetic acid (10 ml), and 5% Pd-C (water content: 50 «0.2 g) was added as a catalyst, followed by catalytic reduction for 4 hours. After filtering off the catalyst, the solvent was concentrated under reduced pressure, the residue was dissolved in 0.1N acetic acid, and the solution was lyophilized to give 30 mg of the title compound as a white powder (yield: 833 ⁇ 4).
- Boc-PPA-D-Arg (Z 2 ) -Phe-Me ⁇ Ala-OBzl (0.5 g, 0.48 mmol) was dissolved in 4N HC1 ethyl acetate solution (20 ml) and stirred at room temperature for 1 hour. Crystals precipitated by adding getyl ether to the reaction solution were collected by filtration. The crystals were dissolved in dimethylformamide (20 ml), and 1- ( ⁇ , ⁇ '-bis (benzyloxycarbonyl) amidino) pyrazole (0.17 g, 0.46 mmol) and triethylamine (0.08 ml, 0.57 mrnol). The solution was stirred at room temperature for 18 hours.
- the protective peptide (0.20 g, 0.16 mmol) obtained in (1) above was dissolved in acetic acid (10 ml), and 5% Pd-C (0.20 g of 50W water content) was added as a catalyst, followed by catalytic reduction for 4 hours. After removing the catalyst by filtration, the solvent was concentrated under reduced pressure, the residue obtained was dissolved in 0.1 N acetic acid, and the solution was lyophilized to give 80 mg of the title compound as a white powder.
- Boc-DOPA-D-Arg (Z 2 ) -Phe-Me ⁇ Ala-OBzl (0.32 g, 0.3 mmol) was dissolved in 4N HC1 ethyl acetate solution (20 ml) and stirred at room temperature for 1 hour. Crystals precipitated by adding getyl ether to the reaction solution were collected by filtration. The crystals were dissolved in dimethylformamide (20 ml), and 1- ( ⁇ , ⁇ '-bis (benzyloxycarbonyl) amidino) pyrazole (0.10 g, 0.26 mmol) and triethylamine (0.05 ml) were dissolved in dimethylformamide (20 ml).
- the solution was stirred at room temperature for 18 hours.
- the reaction solution was concentrated under reduced pressure, and ethyl acetate (50 ml) was added to the residue, and the mixture was washed with 1N hydrochloric acid and then with a saturated aqueous solution of sodium hydrogencarbonate.
- the protective peptide (0.19 g, 0.15 mmol) obtained in (1) above was dissolved in acetic acid (10 ml), and 0.20 g of 53 ⁇ 4 Pd-C (water content 50%) was added as a catalyst, followed by catalytic reduction for 4 hours. To remove the protecting group. After the catalyst was separated by filtration, the solvent was concentrated under reduced pressure, and the obtained residue was dissolved in 0.1N acetic acid. The solution was freeze-dried to obtain 70 mg of the title compound as a white powder.
- N- BZA- Tyr (Bzl) - D- Arg (Z 9) - Phe- / SAla- OBzl was synthesized by the liquid phase method or solid phase method used in the normal base peptide synthesized, Example 4 (2)
- the protected peptide was dissolved in acetic acid in the same manner as described above, and 53 ⁇ 4 Pd-C (water content: 503 ⁇ 4) was added as a catalyst, followed by catalytic reduction for 4 hours to remove the protecting group. After the catalyst was filtered off, the solvent was concentrated under reduced pressure, and the obtained residue was dissolved in 0.1N acetic acid. The solution was lyophilized to give the title compound as a white powder.
- Boc-Hyp-D-Arg (Z 2 ) -Phe-Me ⁇ Ala-OBzl (0.49 g, 0.5 mmol) was dissolved in a 4N HC1 ethyl acetate solution (20 ml) and stirred at room temperature for 1 hour. Crystals precipitated by adding getyl ether to the reaction solution were collected by filtration. The crystals were dissolved in dimethylformamide (20 ml), and 1- (N, ⁇ '-bis (benzyloxycarbonyl) amidino) pyrazole (0.23 g, 0.61 mmol) and triethylamine (0.07 ral, 0.50 mmol) was dissolved. The solution was stirred at room temperature for 18 hours.
- Boc-Tyr (Bzl) -D-Lys (Z) -Phe-Me ⁇ Ala-OBzl (7.65 g, 8.00 mmol) was dissolved in a 4N HC1 ethyl acetate solution (20 ml) and stirred at room temperature for 1 hour. Getyl ether was added to the reaction solution, and the precipitated crystals were collected by filtration. The crystals were dissolved in dimethylformamide (20 ml), and 1- ( ⁇ , ⁇ '-bis (benzyloxycarbonyl) amidino) pyrazole (3.33 g, 8.80 mmol) and triethylamine (1.112) ml, 8.00 mmol).
- Example 7 H 2 NC (NH) -Tyr-D-Lys-Phe-Me / 3Ala-0H ⁇ 2 acetate (500 mg, 0.71 I IOI) obtained in (2) was added to dimethylformamide (4 ml). ) And water (3 ml), and 1H-virazole-tricarboxyamidine hydrochloride (1.08 g, 0.74 mmol) and triethylamine (0.35 ml, 2.5 mmol) were dissolved. The solution was stirred at room temperature for 20 hours.
- the crude product is charged to 0DS column chromatography (Fuji Siricia DM 1020T, 100 g), and stepwise gradient elution is performed with a 1 to 8% acetate nitrile / 0.1N acetic acid solution. did. Collect the fractions containing the target compound and freeze-dry to obtain the title compound as a white powder.
- the solution was charged to 190 g) and eluted stepwise with a 6-acetonitrile Z0.1N acetic acid solution.
- the fractions containing the target compound were collected and lyophilized to give 1.36 g of the title compound as a white powder.
- Example 13 N-H 2 NC (NH) -Tyr- (R) -PAPA-Phe-MeSAla-OH ⁇ diacetate (0.60 g, 0.80 mmol), 1H-pyrazole-tricarboxyamidine hydrochloride obtained in Example 13
- the reaction was carried out in the same manner as in Example 8 using a salt (0.75 g, 3.98 mmol) and triethylamine (0.78 ml, 0.70 alcohol).
- the crude product was charged on a 0DS force column chromatograph (Fuji Silica DM 1020T, 75 g) and eluted stepwise with a 3 to 9-acetonitrile Z0.1N acetic acid solution. The fractions containing the target compound were collected and lyophilized to give 208 mg (26.0%) of the title compound as a white powder.
- the BZA-Tyr (Bzl) -D-Orn (Troc) -Phe-Me / 3Ala-OBzl obtained in (1) was dissolved in 903 ⁇ 4 acetic acid (100 ml), and zinc dust (6.70 g, 103 mmol) was added. And stirred at room temperature for 2 hours. After filtering off the zinc dust, 6.15 g of 53 ⁇ 4 Pd-C (water content: 503 ⁇ 4) was added as a catalyst and subjected to catalytic reduction for 5 hours.
- Example 15 (2) BZA-Tyr (Bzl)-(R) -MGPE (Z) -Phe-Me SAla-OBzl -BZA-Tyr (Bzl) -D-Orn (Troc) -Phe-Me ⁇ Ala-OBzl (3.40 g, 2.85 iraiol) obtained in Example 15 (1) was dissolved in 903 ⁇ 4 acetic acid (50 ml), Zinc powder (3.75 g, 57.3 mmol) was added, and the mixture was stirred at room temperature for 2 hours. After filtering off the zinc dust, the filtrate was concentrated under reduced pressure. To the residue was added chloroform (50 ml), and the mixture was washed with saturated aqueous sodium hydrogen carbonate.
- Example 15 The BZA-Tyr (Bzl) -D-Orn (Troc) -Phe-e / SAla-OBzl (3.20 g, 2.68 mmol) obtained in Example 15 (1) was dissolved in acetic acid (50 ml), and zinc powder (3.53 g, 54.0 mmol) and stirred at room temperature for 2 hours. After filtering off the zinc dust, the filtrate was concentrated under reduced pressure. To the residue was added chloroform (50 ml), and the mixture was washed with saturated aqueous sodium hydrogen carbonate. After evaporating the solvent under reduced pressure, dissolve it in methanol (10 ml), and stir with ice-cooled acetone (181 ⁇ , 2.46 ramol) and sodium cyanoborohydride
- This protective peptide is dissolved in acetic acid (30 ⁇ ) and used as a catalyst in 5% Pd-C (water content 503 ⁇ 4)
- Boc-Tyr (Bzl) -D-Lys (Z) -Phe-Me / SAla-OBzl (1.00 g, 1.05 mmol) was dissolved in 4N HC1 ethyl acetate solution (3 ml) and stirred at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure, dissolved in dimethylformamide (4 ml), and dissolved in ethyl acetate ethyl hydrochloride (0.26 g, 2.09 tmol) and triethylamine (0.28 ml, 2.00 ramol). This solution Stirred at room temperature for 20 hours.
- reaction solution was dissolved in ethyl acetate (50 ml), and washed with a 10% aqueous solution of citric acid and a saturated aqueous solution of sodium bicarbonate.
- the protective peptide (248 mg, 0.76 mmol) obtained in (1) above was dissolved in acetic acid (4 ml), and 0.13 g of 53 ⁇ 4 Pd-C (water content 503 ⁇ 4) was added as a catalyst, followed by catalytic reduction for 4 hours and 30 minutes. Was performed to remove the protecting group. After the catalyst was separated by filtration, the solvent was concentrated under reduced pressure, and the residue obtained was collected on a 0DS column chromatography (Fuji Siricia DM 1020T, 20 g) to obtain 1 to 7-acetonitrile / 0.1 g. Stepwise gradient elution was performed with an N acetic acid solution. The fractions containing the desired compound were collected and lyophilized to give 95 mg of the title compound as a white powder.
- Boc-Tyr (Bzl) -D-Ala-Phe-Me ⁇ Ala-OBzl (0.39 g, 0.5 excitation 1) was dissolved in 4N HC1 ethyl acetate solution (30 ml) and stirred at room temperature for 30 minutes. Crystals precipitated by adding getyl ether to the reaction solution were collected by filtration. The crystals were dissolved in dimethylformamide (25 ml), and 1- ( ⁇ , ⁇ '-bis (benzyloxycarbonyl) amidino) pyrazole (0.18 g,
- the protected peptide (0.4 g, 0.41 mmol) obtained in (1) above was dissolved in acetic acid (10 ml), and 0.4 g of 5 Pd-C (water content 50%) was added as a catalyst, followed by catalytic reduction for 4 hours. Go to the protecting group Removed. After removing the catalyst by filtration, the solvent was concentrated under reduced pressure, and the obtained residue was dissolved in 0.1N acetic acid. The solution was lyophilized to give 210 ni of the title compound as a white powder.
- Boc-Tyr (Bzl) -D-Glu (Bzl) -Phe-Me ⁇ Ala-OBzl (0.46 g, 0.50 fraction 1) was dissolved in 4N HC1 ethyl acetate solution (30 ml) and stirred at room temperature for 1 hour. Crystals precipitated by adding getyl ether to the reaction solution were collected by filtration. The crystals were dissolved in dimethylformamide (5 ml), and tri ( ⁇ , ⁇ '-bis (benzyloxycarbonyl) amidino) pyrazole (0.23 g, 0.6 mmol) and triethylamine (0.07 ml, 0.5 mmol) was dissolved. The solution was stirred at room temperature for 18 hours.
- Boc-Tyr (Bzl) -D-Nva-Phe-Me ⁇ Ala-OBzl (0.56 g, 0.7 mmol) was added to 4N HC1 acetic acid. The residue was dissolved in ethyl acetate (30 ml) and stirred at room temperature for 1 hour and 30 minutes. Crystals precipitated by adding getyl ether to the reaction solution were collected by filtration. The crystals were dissolved in dimethylformamide (25 ml), and 1- ( ⁇ , ⁇ '-bis (benzyloxycarbonyl) amidino) pyrazole (0.23 g, 0.6 mmol) and triethylamine (0.12 ml, 0.84 mmol).
- the protective peptide (0.42 g, 0.42 mmol) obtained in (1) above was dissolved in acetic acid (30 ml), and catalytic reduction was performed for 4 hours by adding 0.2% of Pd-C (water content: 50%) as a catalyst. To remove the protecting group. After the catalyst was filtered off, the solvent was concentrated under reduced pressure, and the obtained residue was dissolved in 0.1N acetic acid. The solution was lyophilized to give 220 mg of the title compound as a white powder.
- Boc-Tyr (Bzl) -D-Pro-Phe-Me ⁇ Ala-OBzl (0.4 g, 0.5 cited ol) was dissolved in 4N HC1 ethyl acetate solution (20 ml) and stirred at room temperature for 1 hour and 30 minutes. Hexane was added to the reaction solution to wash it, and an oil was obtained. This oil was dissolved in dimethylformamide (5 ml), and 1- (N, ⁇ '-bis (benzyloxycarbonyl) amidino) pyrazole (0.23 g, 0.6 mmol) and triethylamine (0.07 ml, 0.23 o) was dissolved. The solution was stirred at room temperature for 18 hours.
- Boc- Tyr (Bzl) - D- Arg (Z 9) - Tyr (Bzl) - Me / SAla- OBzl (0.61 g, 0.50 mmol) was dissolved in 4N HC1 acetate Wechiru solution (20 ml), 1 hour at room temperature Stirred. Crystals precipitated by adding getyl ether to the reaction solution were collected by filtration. The crystals were dissolved in dimethylformamide (10 ml), and tri (N, ⁇ '-bis (benzyloxycarbonyl) amidino) pyrazole (0.23 g, 0.6 mmol) and triethylamine (0.07 ml, 0.5 mraol) was dissolved.
- Boc-Tyr (Bzl) -D- Arg (Z o) -APBA- e / 3Ala-0Bzl (0.34 g, 0.3 mmol) was dissolved in 4N HC1 acetate Echiru solution (20 ml), and stirred 0.5 hours at room temperature. Getyl ether was added to the reaction solution to obtain a washed oil. This oil was dissolved in dimethylformamide (20 ml) Then, tri ( ⁇ , ⁇ '-bis (benzyloxycarbonyl) amidino) birazol (0.10 g, 0.27 mmol) and triethylamine (0.05 ml, 0.36 ramol) were dissolved.
- the protective peptide (0.3 g, 0.22 ramol) obtained in the above was dissolved in acetic acid (20 ml), and 0.2 g of 5% Pd-C (water content 503 ⁇ 4) was added as a catalyst, followed by catalytic reduction for 4 hours. The protecting group was removed. After the catalyst was filtered off, the solvent was concentrated under reduced pressure, and the obtained residue was dissolved in 0.1N acetic acid. The solution was lyophilized to give 130 mg of the title compound as a white powder.
- Boc-Tyr (Bzl) -D-Arg (Z 2 ) -Cha-Me ⁇ Ala-OBzl (0.56 g, 0.5 mmol) was dissolved in a 4N HC1 ethyl acetate solution (20 ml) and stirred at room temperature for 1 hour. Crystals precipitated by adding getyl ether to the reaction solution were collected by filtration. The crystals were dissolved in dimethylformamide (5 ml), and tri ( ⁇ , ⁇ '-bis (benzyloxycarbonyl) amidino) pyrazol (0.2 g, 0.53 mmol) and triethylamine (0.06 ml) were dissolved. , 0.2 mmol) was dissolved.
- the protective peptide (0.2 g, 0.15 mmol) obtained in (1) above was dissolved in acetic acid (20 ml), and the mixture was catalytically reduced for 3 hours by adding 0.2% of 53 ⁇ 4 Pd-C (water content: 503 ⁇ 4) as a catalyst. The protecting group was removed. After filtering off the catalyst, the solvent was concentrated under reduced pressure, and the resulting residue was dissolved in 0.1N acetic acid. The solution was lyophilized to give 96 mg of the title compound as a white powder.
- Boc-D-AMSB-Phe-Me ⁇ Ala-OMe (0.86 g, 1.68 mmol) was dissolved in a 4N HC1 ethyl acetate solution (30 ml) and stirred at room temperature for 30 minutes. After the reaction solution was concentrated under reduced pressure, dimethyl ether was added to the residue for washing. Then, the oil obtained by concentrating the solvent under reduced pressure was dissolved in methylene chloride (25 ml), and trihydroxybenzotriazole (0.27 g, 2.02 mmol) and triethylamine (0.28 ml) were dissolved. , 2.02 mmol) were dissolved. The solution was stirred at room temperature for 18 hours.
- the protective peptide (0, 11 g, 0.17 mmol) obtained in the above (2) was dissolved in 4N HC1 ethyl acetate (30 ml) and stirred at room temperature for 30 minutes. Crystals precipitated by adding getyl ether to the reaction solution were collected by filtration. The crystals were dissolved in dimethylformamide (25 ml), and the amidinating reagent (1H-pyrazole-1-carboxamidine 'hydrochloride, 0.03 g, 0.19 mmol) and Triethylamine (0.10 ml, 0.72 cellulose) was dissolved. This solution was stirred at room temperature for 18 hours.
- the amidinating reagent (1H-pyrazol-1-carboxamidine 'hydrochloride, 0.015 g, 0.09 mmol) and triethylamine (0.05 ml, 0.36 mmol) were added to the reaction solution, and the solution was stirred at room temperature for 18 hours. did. Getyl ether was added to the reaction solution, and decanting and washing were performed twice to obtain an oily substance.
- the obtained oil was dissolved in water, adjusted to pH 4 with acetic acid, and purified by 0DS column chromatography (acetonitrile: eluted with 0.1N acetic acid) to obtain a colorless oil.
- the oil was dissolved in 0.1N acetic acid, and the solution was freeze-dried to give 30 of the title compound as a white powder.
- Boc-Tyr-D-Met-Phe-Me ⁇ Ala-OMe (9.45 g, 14.3 mmol) was suspended in 673 ⁇ 4methanol (110 ml), and IN NaOH (28.6 ml) was added. Stirred. To the reaction solution After water (50 ml) was added and methanol was distilled off under reduced pressure, the residue was washed with ethyl acetate. The aqueous phase was adjusted to pH 3 with 6N HCl under ice cooling. The precipitated oil was extracted with ethyl acetate and washed with saturated saline. The solution was dried over magnesium sulfate and concentrated under reduced pressure.
- the Boc-Tyr-D-AMSB-Phe-Me ⁇ Ala-OH (9, 37 g, 14.2 fractions) obtained in the above (1) was dissolved in 4N HC1 dioxane (100 ml) and stirred at room temperature for 30 minutes. . Crystals precipitated by adding getyl ether to the reaction solution were collected by filtration. The crystals were dissolved in dimethylformamide (70 ml), and ethyl acetate ethyl hydrochloride (3.51 g, 28.4 ol) and triethylamine (8.4 ml, 60 irnnol) were dissolved. The solution was stirred at room temperature for 3 hours.
- Getyl ether was added to the reaction solution, and the supernatant was removed with decantation.
- the obtained oily substance was charged into a 0DS column chromatography (Fuji Siricia DM 1020 T, 200 g) and eluted stepwise with a 2 to 11-acetonitrile / 0.1 N acetic acid solution. .
- the fractions containing the target compound were collected and freeze-dried to obtain 2.57 g of the title compound as a white powder.
- Boc-Tyr (Bzl) -D-DAPR (Z) -Phe-Me SAla-OBzl (1.00 g, 1.08 fraction) was dissolved in acetic acid (10 ml), and 5! 3 ⁇ 4 Pd-C (water content 50V) was used as a catalyst. ) 0.4 was added and contact reduction was carried out for 4 hours and 30 minutes to remove the protecting group. After filtering off the catalyst, the solvent was concentrated under reduced pressure. The residue obtained was dissolved in dimethylformamide (9 ml), and 1H-pyrazole-tolcarboxamidine 'hydrochloride (341 mg, 2.33 mmol) and triethylethyl The min (0.56 ml, 4.0 ramol) was dissolved. The solution was stirred at room temperature for 48 hours. Getyl ether was added to the reaction solution, and the supernatant was removed with decantation to obtain 609 mg of an oil.
- the Boc-Tyr-D-AGPR-Phe-Me ⁇ Ala-OH (609 rag, 0.87 mmol) obtained in the above was dissolved in 4N HC1 dioxane (10 ml) and stirred at room temperature for 30 minutes. Getyl ether was added to the reaction solution, and the solvent was removed by decantation. The residual oil was dissolved in dimethylformamide (10 ml), and ethyl imidoethyl acetate hydrochloride (2 mg, 1.74 mmol) and triethylamine (0.42 ml, 3.0 mmol) were dissolved. . This solution was stirred at room temperature for 1 hour and 30 minutes. The reaction solution was concentrated under reduced pressure, and the obtained oil was purified by 0DS column chromatography.
- Boc-Tyr (Bzl) -D-Cit-Phe-Me ⁇ Ala-OBzKO (77 g, 0.90 ramol) was dissolved in 4N HC1 dioxane (10 ml) and stirred at room temperature for 30 minutes. Crystals precipitated by adding geethylether to the reaction solution were collected by filtration. The crystals were dissolved in DMF (10 ml), and 1- ( ⁇ , ⁇ '-bis (benzyloxycarbonyl) amidino) birazol (323 mg, 0.86 mmol) and triethylamine (0.15 ml, 1.08 mmol). The solution was stirred at room temperature for 20 hours.
- Boc-Tyr (Bzl) -D-Cit-Phe-Me / 3 Ala-OBzl (8.75 g, 10.3 mmol) was dissolved in 4N HCl ethyl acetate (50 ml) and stirred at room temperature for 30 minutes. After the reaction solution was concentrated under reduced pressure, getyl ether was added and the precipitated crystals were collected by filtration. The crystals were dissolved in acetic acid (100 ml), and 3.0 g of 5-Pd-C (water content: 50%) was added as a catalyst, followed by catalytic reduction for 3 hours and 30 minutes to remove protective groups. After the catalyst was filtered off, the solvent was concentrated under reduced pressure, and the obtained residue was dissolved in 0.1N acetic acid. The solution was freeze-dried to obtain a white powder.
- the obtained crude product was charged to 0DS column chromatography (Fuji Siricia M 1020 T, 50 g), and eluted stepwise with a 20-milliliter / 1N acetic acid solution to 10. The fractions containing the target compound were collected and freeze-dried to obtain 527 mg of the title compound as a white powder.
- Stepwise gradient elution was carried out with a methanol / 0.1% acetic acid solution. Including object The fractions were collected and freeze-dried to obtain 115 mg of the title compound as a white powder.
- the analgesic effect of the peptide derivative of the present invention was evaluated by a pressure stimulation method as follows. A pressure stimulus was applied to the ridge of the mouse at a rate of 10 inmHg seconds, and the pressure indicating a struggling action such as striking and stimulating the stimulation site was measured, and this was used as a pain response threshold. Mice that responded to the pressure of 40 to 50 ramHg in advance were used in the experiment. The maximum stimulation pressure was 100 strokes Hg.
- the analgesic effect is:
- the peptide derivative of the present invention is useful because it can be used for treating cancer pain and the like.
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Description
Claims
Priority Applications (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EA199800289A EA001001B1 (ru) | 1995-09-11 | 1996-09-10 | Производные пептидов |
AU68906/96A AU718320B2 (en) | 1995-09-11 | 1996-09-10 | Peptide derivatives |
BR9610085-0A BR9610085A (pt) | 1995-09-11 | 1996-09-10 | Derivados de peptìdios |
EP96929576A EP0850950A4 (en) | 1995-09-11 | 1996-09-10 | PEPTIDE DERIVATIVES |
NO981052A NO981052L (no) | 1995-09-11 | 1998-03-10 | Peptidderivater |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP7/232162 | 1995-09-11 | ||
JP23216295 | 1995-09-11 | ||
JP8/100081 | 1996-04-22 | ||
JP10008196 | 1996-04-22 |
Publications (1)
Publication Number | Publication Date |
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WO1997010262A1 true WO1997010262A1 (fr) | 1997-03-20 |
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ID=26441170
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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PCT/JP1996/002573 WO1997010262A1 (fr) | 1995-09-11 | 1996-09-10 | Derives peptidiques |
Country Status (8)
Country | Link |
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EP (1) | EP0850950A4 (ja) |
KR (1) | KR19990044554A (ja) |
CN (1) | CN1202174A (ja) |
AU (1) | AU718320B2 (ja) |
CA (1) | CA2231220A1 (ja) |
EA (1) | EA001001B1 (ja) |
NO (1) | NO981052L (ja) |
WO (1) | WO1997010262A1 (ja) |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1999033864A1 (fr) * | 1997-12-26 | 1999-07-08 | Daiichi Pharmaceutical Co., Ltd. | Derives peptidiques |
WO2000012539A1 (fr) * | 1998-08-31 | 2000-03-09 | Fuji Chemical Industries, Ltd. | Composes de peptides |
WO2007145208A1 (ja) | 2006-06-12 | 2007-12-21 | Vexon, Inc. | ペプチド誘導体 |
JP2009519942A (ja) * | 2005-12-14 | 2009-05-21 | アンブルックス,インコーポレイテッド | 非天然アミノ酸およびポリペプチドを含んでいる組成物、それらに関する方法、ならびに、それらの使用 |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6593466B1 (en) | 1999-07-07 | 2003-07-15 | Isis Pharmaceuticals, Inc. | Guanidinium functionalized nucleotides and precursors thereof |
WO2007144979A1 (ja) * | 2006-06-12 | 2007-12-21 | Vexon, Inc. | ペプチド誘導体 |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS61103898A (ja) * | 1984-10-25 | 1986-05-22 | フアルムイタリア・カルロ・エルバ・ソシエタ・ペル・アチオーニ | 生物学的に活性なペンタペプチド類及びヘプタペプチド類 |
WO1995024421A1 (fr) * | 1994-03-11 | 1995-09-14 | Daiichi Pharmaceutical Co., Ltd. | Derive peptidique |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
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ATE235911T1 (de) * | 1992-11-12 | 2003-04-15 | Sod Conseils Rech Applic | Opioidpeptide |
-
1996
- 1996-09-10 KR KR1019980701803A patent/KR19990044554A/ko not_active Application Discontinuation
- 1996-09-10 WO PCT/JP1996/002573 patent/WO1997010262A1/ja not_active Application Discontinuation
- 1996-09-10 CA CA002231220A patent/CA2231220A1/en not_active Abandoned
- 1996-09-10 CN CN96198006A patent/CN1202174A/zh active Pending
- 1996-09-10 EA EA199800289A patent/EA001001B1/ru not_active IP Right Cessation
- 1996-09-10 AU AU68906/96A patent/AU718320B2/en not_active Ceased
- 1996-09-10 EP EP96929576A patent/EP0850950A4/en not_active Withdrawn
-
1998
- 1998-03-10 NO NO981052A patent/NO981052L/no not_active Application Discontinuation
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS61103898A (ja) * | 1984-10-25 | 1986-05-22 | フアルムイタリア・カルロ・エルバ・ソシエタ・ペル・アチオーニ | 生物学的に活性なペンタペプチド類及びヘプタペプチド類 |
WO1995024421A1 (fr) * | 1994-03-11 | 1995-09-14 | Daiichi Pharmaceutical Co., Ltd. | Derive peptidique |
Non-Patent Citations (6)
Title |
---|
EUR. J. MED. CHEM. - CHIM. THER., 1983, Vol. 18, No. 6, SALVADORI, S. et al., "Synthesis and Pharmacological Activity of Dermorphin Tetrapeptide-Analogs", p. 489-493. * |
FARMACO, ED. SCI., 1982, Vol. 37, No. 8, SALVADORI, S. et al., "Opioid Peptides. Structure-Activity Relationships in Dermorphin Tetrapeptides I", p. 514-518. * |
HOPPE-SEYLER'S Z. PHYSIOL. CHEM., 1984, Vol. 365, No. 10, SALVADORI, S. et al., "Synthesis and Opioid Activity of (Sar4) Dermorphintetrapeptide Analogs", p. 1199-1206. * |
J. MED. CHEM., 1987, Vol. 30, No. 11, CASTIGLIONE-MORELLI, M.A. et al., "A 500-MHz Proton Nuclear Magnetic Resonance Study of mu Opioid Peptides in a Simulated Receptor Environment", p. 2067-2073. * |
J. MED. CHEM., 1987, Vol. 30, No. 9, MARASTONI, M. et al., "Synthesis and Activity Profiles of New Dermorphin-(1-4) Peptide Analogs", p. 1538-1542. * |
See also references of EP0850950A4 * |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1999033864A1 (fr) * | 1997-12-26 | 1999-07-08 | Daiichi Pharmaceutical Co., Ltd. | Derives peptidiques |
WO2000012539A1 (fr) * | 1998-08-31 | 2000-03-09 | Fuji Chemical Industries, Ltd. | Composes de peptides |
JP2009519942A (ja) * | 2005-12-14 | 2009-05-21 | アンブルックス,インコーポレイテッド | 非天然アミノ酸およびポリペプチドを含んでいる組成物、それらに関する方法、ならびに、それらの使用 |
WO2007145208A1 (ja) | 2006-06-12 | 2007-12-21 | Vexon, Inc. | ペプチド誘導体 |
Also Published As
Publication number | Publication date |
---|---|
CA2231220A1 (en) | 1997-03-20 |
EP0850950A1 (en) | 1998-07-01 |
NO981052L (no) | 1998-05-11 |
EP0850950A4 (en) | 1999-05-19 |
AU718320B2 (en) | 2000-04-13 |
AU6890696A (en) | 1997-04-01 |
CN1202174A (zh) | 1998-12-16 |
EA001001B1 (ru) | 2000-08-28 |
NO981052D0 (no) | 1998-03-10 |
KR19990044554A (ko) | 1999-06-25 |
EA199800289A1 (ru) | 1998-08-27 |
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