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WO1982000640A1 - Derives de tripeptides alkylamide - Google Patents

Derives de tripeptides alkylamide Download PDF

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Publication number
WO1982000640A1
WO1982000640A1 PCT/JP1981/000175 JP8100175W WO8200640A1 WO 1982000640 A1 WO1982000640 A1 WO 1982000640A1 JP 8100175 W JP8100175 W JP 8100175W WO 8200640 A1 WO8200640 A1 WO 8200640A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
residue
dissolved
value
distilled
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.)
Ceased
Application number
PCT/JP1981/000175
Other languages
English (en)
Japanese (ja)
Inventor
Chem Co Ltd Earth
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Earth Corp
Original Assignee
Earth Chemical Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from JP11365680A external-priority patent/JPS5738756A/ja
Priority claimed from JP55161127A external-priority patent/JPS5785349A/ja
Application filed by Earth Chemical Co Ltd filed Critical Earth Chemical Co Ltd
Priority to AU74557/81A priority Critical patent/AU7455781A/en
Publication of WO1982000640A1 publication Critical patent/WO1982000640A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

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
    • C07K5/0802—Tripeptides with the first amino acid being neutral
    • C07K5/0812—Tripeptides with the first amino acid being neutral and aromatic or cycloaliphatic

Definitions

  • the present invention relates to a triadal derivative and a pharmacological composition containing the derivative, as well as an analgesic and an anesthetic.
  • tripetide derivative of the present invention is a novel compound not described in the text, and is represented by the following one-kill formula [I].
  • ⁇ E and ⁇ 2 2 is a hydrogen atom, a lower A Le thousand group, low grade A Le Quai two group or full e d group, as well as 3 and the hydrogen atom Further, ⁇ t Chi le radical ]
  • the main narcotics induction salary expressed by the above general formula [I] and its 5 pharmacologically permissible narcotics are added to the narcotics.
  • analgesics and narcotics, and other drug antagonists, antidiarrheal drugs, etc. are available.
  • the above-mentioned induction method is used to relieve gastrointestinal motility, and is used as a therapeutic agent for gastrointestinal disorders, and also as a therapeutic agent for psychiatric disorders such as schizophrenia and schizophrenia. And it can also be a sickness.
  • the derivatives of the present invention are toxic and have a long duration: 3 ⁇ 4.
  • the compound of the present invention should be appropriately protected and activated according to the usual peptide synthesis method, for example, solution synthesis method, solid peptide synthesis method, etc., c — It can be combined sequentially from the end, or it can be formed by cutting an appropriate unit of the compound containing the desired ⁇ -noic acid.
  • jL is the same as above, is the protecting group of the ⁇ no group, and ⁇ is the protecting group of the hydroxyl group or the hydroxyl group]
  • the £ pedal represented by is manufactured in the same manner as in the above 15 according to the unusual peptide bond formation reaction, and then this is appropriately reduced.
  • OMPI The compounds in which ⁇ 3 is a hydrogen atom in the tripedal derivative of the present invention are the above ⁇ Pezuchi ⁇ '[v] and Pezuchidoaru ⁇ ! Do [W] and the conventional compound bond formation reaction, for example, the reaction according to the ad method, the general formula CH OR
  • the combination of the present invention represented by the above general formula [I] can be used as a pharmacologically acceptable ⁇ addition salt using a suitable ⁇ , and such a salt is also clarified.
  • a suitable ⁇ for example, hydrogen chloride, hydrogen bromide, etc.
  • ⁇ -log / Inorganic water, such as hydrogen chloride, sulfuric acid, glass, and phosphorus, and acid, male, etc. It is possible to mention the prohibition of hydrogen chloride, hydrogen chloride, hydrogen chloride, hydrogen chloride, hydrogen bromide, and hydrogen bromide.
  • the combination of the present invention includes both an optical variant and a laser.
  • the compound of the present invention can be used together with the conventional formulation carrier in the form of the formulation composition and can be applied to the man and the person.
  • the administration method and administration unit form are not particularly limited and are appropriately selected according to need.
  • Orally administered by parenteral administration such as injection (including lyophilized solution), etc.
  • It can be administered subcutaneously or intraperitoneally, or directly in the form of a drug, and locally given in the form of a sedative.
  • the above-mentioned administration unit coloration is prepared by a conventional method, and the carrier used at that time is usually used to prepare a drug according to the usage pattern.
  • the carrier used at that time is usually used to prepare a drug according to the usage pattern.
  • rare agents or excipients such as fillers, bulking agents, binders, wetting agents, disintegrants, surface activators, and lubricants.
  • zinc preparations are made by mixing the compound of the present invention with ordinary zinc and shaping it.
  • carriers are known in this field, for example, lactose, sucrose, sodium chloride. Calu ⁇ , power. Ori!
  • lubricants such as stones, powdered shavings, and macro solid polycarbonate reels.
  • the above-mentioned zinc preparations should be the usual — coated preparations, such as zinc, zinc lock, enteric-coated, film-coy zinc, or two. It is possible to use a heavy key and multiple layers.
  • Liquid preparations such as injections are manufactured by dissolving or suspending the compound of the present invention in a sterilized liquid carrier.
  • a sterilized liquid carrier all the usual rare agents that are used in this field can be used, for example, water, etc.
  • the above injections be isotonic with the liquid.
  • OMPI In addition to the usual dissolving aids, buffers, soothing agents, preservatives, etc., colorants, preservatives, fragrances, flavors, sweeteners, etc. and other medicines may be added as needed. It may be contained in the formulation.
  • the drug agent is prepared by mixing the compound of the present invention with the above-mentioned pharmaceutical carrier (excipient or dilute agent) and filling it into a sequel, a product, or a product. Prepared. Suppositories are manufactured in a conventional manner. When molding into the form of the suppository, a widely known carrier can be widely used, for example, polite liquor, cacao butter, high.
  • the swelling agent is molded into the form of a pace, a crystal and a gel containing the compound of the present invention according to a conventionally known method.
  • the rare agents are white washeri, paraffin, lyseri, t lb 0-s derivatives, and police, which are known in this field. You can use white, paraffin, paraffin, etc.
  • the amount of the compound of the present invention to be contained in the above-mentioned administration unit form is not particularly limited and may be appropriately selected within the IS range, but it is usually 1 to 70% by weight in the total composition.
  • the compound of the present invention or a salt thereof is usually 1 to 70% by weight in the total composition.
  • O PI " It is a good idea to set the value to about 1 to 20/1.
  • the amount of this compound to be absorbed can be appropriately returned from a wide range, not particularly limited, depending on the method of administration, the form of the formulation, the intended symptoms, etc.
  • this compound or salt thereof is applied once a day from 0.0 0 7 to i QQ / ⁇ , preferably Q.
  • the award is good, and the award is divided into four times.
  • ⁇ Trif j Leolo Alcohol intoxication value is Syricagel [Merck, r-Zerger]
  • the upper thin layer chroma ⁇ ruffy (a C) was measured using the following mixed solvent.
  • Dissolve compound 1.99 in MF 50 add lower (about 130 ° C) -2.6 C, medium san 7 and oxalic acid solution 0.6, and stir for about 20 minutes before trimming. Neutralized by adding Echirua ⁇ 2.6.
  • Crystall 1 Fenylalan (Compound ⁇ ) Compound --0 Anisole 0.3 is dissolved in 0 and stirred for 1 hour under ice-cooling to reduce the amount of precipitation. Distilled off, ice was added to the residue, and the precipitated crystals were collected. Dissolved in ⁇ ⁇ 20 and applied
  • OMPI It was dissolved in the mouth hole 30 a and neutralized by adding a triech. Combine both solutions, and after 24 hours of S worship, separate the analyzed urine-inducing iron, and wash with 0% queic acid, 5% charcoal liquor, and saturated saline solution in sequence. After drying, reduce the amount of the extract a and distill off the residue, and remove the residual residue from the silicon chrome traffy (dissolved in the color ⁇ 3.2 ⁇ 40, kuhol ⁇ ). It was refined to obtain 5.6 da.
  • Moto ⁇ analysis [ ⁇ ⁇ 3 ⁇ 0 5 ⁇ ⁇ CIi 3 C0 2 as two 0) physical 'theory value [%) 54. ⁇ 9; - ⁇ 7 21;. ⁇ 8, 72
  • Elemental analysis value (as C 27. CH 3 C0 2 H ⁇ 2) Theoretical value (%) C53. 04; ⁇ . 75; ⁇ 8,
  • N-me ⁇ ⁇ be: ⁇ ) Leo medium ⁇ / force ruponiru ⁇ ruru ⁇ —
  • OMPI WIP ⁇ rum, ⁇ Japanese salt solution was used for scavenging. After drying with ⁇ , reduce the amount of effluent, remove the residue, and remove the residue. Elution with oral methano lb 0) was purified to obtain 900 ⁇ .
  • Elemental analysis value (as C ⁇ S. CH ⁇ CO ⁇ H. 20) Theoretical value [) 19; ⁇ 7. 21; ⁇ 8. 72
  • OMPI WIPO Neutralized After combining the two solutions and pruriting for 24 hours, the urinary derivative that was analyzed was separated, and 0% quenoic acid? ⁇ Charcoal liquor was washed sequentially with saturated saline solution. Na ⁇ SO ⁇ After drying, the amount of extraction ⁇ is reduced and the residue is removed. By elution), the target product 5.7 ⁇ was obtained.
  • Elemental analysis value (as C. 0 S. CH 3 C0 2 H ⁇ 2) Theoretical value () ⁇ 54. 86; ⁇ 7. 37; ⁇ 8. 53 Analysis value (%) C 54. 65; 7.1 ⁇ ⁇ 8. 57? Analysis results
  • Elemental analysis value (as a C ⁇ 3 f 52 O s NS )
  • Elemental analysis value (( 29. 0 ma. CH ⁇ CO ⁇ H ⁇ 2 as 0) theoretical value) C54. 37; ⁇ 7.06; ⁇ 8.1 8
  • Table 1 shows the same manner as in any of the above examples.
  • Table 1 also shows the S / value of each compound.
  • Table 2 shows the elemental analysis values of each compound. The elemental analysis value was measured in the form of ⁇ acid salt ⁇ dihydrate.
  • Table 3 shows the analysis results for several more compounds.
  • the main tripetal ⁇ rua ⁇ de induction (test compound) was given to the cone 3 ⁇ 4 mouse with a body weight of 25 to 30 ⁇ in a static manner and subcutaneously.
  • the value of the poisonous cormorant ( ⁇ 50 ) is shown in the table below. Table 8
  • Distilled water for injection The total amount is 10. Dissolve each of the above components in distilled water for injection and sterilize at 100 for 30 minutes to obtain an injection with the above composition.
  • Amount of distilled water for injection to be 100 «Injectable preparation having the above composition is obtained in the same manner as in Production Example 1.
  • Amount of distilled water for injection to be 1003 ⁇ 4

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Medicinal Chemistry (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Derives de tripeptides alkylamide representes par la formule generale: (FORMULE) (ou R1 et R2 representent chacun un atome d'hydrogene, un groupe alkyle inferieur, un groupe alkenyle inferieur ou un groupe phenyle et R3 et R4 representent chacun un atome d'hydrogene ou un groupe acetyle), leurs sels acides pharmaceutiquement acceptables, et compositions pharmaceutiques les contenant.
PCT/JP1981/000175 1980-08-18 1981-08-13 Derives de tripeptides alkylamide Ceased WO1982000640A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU74557/81A AU7455781A (en) 1980-08-18 1981-08-13 Tripeptide alkylamide derivatives

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
JP11365680A JPS5738756A (en) 1980-08-18 1980-08-18 Tripeptide alkylamide derivative
JP80/113656 1980-08-18
JP55161127A JPS5785349A (en) 1980-11-14 1980-11-14 Tripeptide alkylamide derivative
JP80/161127801114 1980-11-14

Publications (1)

Publication Number Publication Date
WO1982000640A1 true WO1982000640A1 (fr) 1982-03-04

Family

ID=26452603

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP1981/000175 Ceased WO1982000640A1 (fr) 1980-08-18 1981-08-13 Derives de tripeptides alkylamide

Country Status (2)

Country Link
IT (1) IT1205447B (fr)
WO (1) WO1982000640A1 (fr)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5340735A (en) * 1976-09-16 1978-04-13 Richter Gedeon Vegyeszet Production of pentaapeptide
JPS5490142A (en) * 1977-12-15 1979-07-17 Reckitt & Colmann Prod Ltd Compound
JPS5697255A (en) * 1979-12-17 1981-08-05 Lilly Co Eli Pharmacutically active peptides

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5340735A (en) * 1976-09-16 1978-04-13 Richter Gedeon Vegyeszet Production of pentaapeptide
JPS5490142A (en) * 1977-12-15 1979-07-17 Reckitt & Colmann Prod Ltd Compound
JPS5697255A (en) * 1979-12-17 1981-08-05 Lilly Co Eli Pharmacutically active peptides

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, Vol. 93, No. 15, 1980-10-13, (Columbus, Ohio, USA), KISO YOSHIAKI et al., "Synthesis and Activity of Enkephalin Analogs", page 756, left columnm Abstract No. 93:150630q, Prep. Chem. 1979 (pub. 1980), 17th, 199-204 (Eng). *

Also Published As

Publication number Publication date
IT8105201A0 (it) 1981-08-17
IT1205447B (it) 1989-03-23

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