WO1992019254A1 - α-SUBSTITUTED POLYPEPTIDES HAVING THERAPEUTIC ACTIVITY - Google Patents

α-SUBSTITUTED POLYPEPTIDES HAVING THERAPEUTIC ACTIVITY Download PDF

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Publication number
WO1992019254A1
WO1992019254A1 PCT/US1992/003119 US9203119W WO9219254A1 WO 1992019254 A1 WO1992019254 A1 WO 1992019254A1 US 9203119 W US9203119 W US 9203119W WO 9219254 A1 WO9219254 A1 WO 9219254A1
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Prior art keywords
gly
leu
tyr
phe
trp
Prior art date
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PCT/US1992/003119
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English (en)
French (fr)
Inventor
David Christopher Horwell
John Hughes
Reginald Stewart Richardson
William Howson
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Warner-Lambert Company
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Publication date
Application filed by Warner-Lambert Company filed Critical Warner-Lambert Company
Priority to CA002106764A priority Critical patent/CA2106764A1/en
Priority to JP4511401A priority patent/JPH06507402A/ja
Priority to EP92911434A priority patent/EP0668770A1/en
Publication of WO1992019254A1 publication Critical patent/WO1992019254A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/26—Psychostimulants, e.g. nicotine, cocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • 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]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/575—Hormones
    • C07K14/66—Thymopoietins
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/665—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans derived from pro-opiomelanocortin, pro-enkephalin or pro-dynorphin
    • C07K14/70—Enkephalins
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
    • C07K5/06034—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms
    • C07K5/06043—Leu-amino acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06078—Dipeptides 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
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06139—Dipeptides with the first amino acid being heterocyclic
    • C07K5/06156—Dipeptides with the first amino acid being heterocyclic and Trp-amino acid; Derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C07K5/0815—Tripeptides with the first amino acid being basic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C07K5/0821—Tripeptides with the first amino acid being heterocyclic, e.g. His, Pro, Trp
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C07K5/0821—Tripeptides with the first amino acid being heterocyclic, e.g. His, Pro, Trp
    • C07K5/0825—Tripeptides with the first amino acid being heterocyclic, e.g. His, Pro, Trp and Glp-amino acid; Derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—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
    • 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
    • C07K5/1021—Tetrapeptides with the first amino acid being acidic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • Peptides form the main messenger systems within and between cells and they number more than a
  • modified peptides offer significant opportunities.
  • the ⁇ , ⁇ -disubstituted amino acids are non-genetically coded synthetic analogues of natural mammalian ⁇ -amino acids and are incorporated at least once into the neuropeptides of this patent.
  • Tachykinins ANT Antipsychotic SP, NKA, NKB Analgesic
  • tranquilizers block central dopaminergic function indiscriminately.
  • CCK-neuropeptide/Dopamine system may be considerably more selective. An improvement in quality through the ability to modify drug resistant characteristics is also expected. In psychosis the blunting of affect leading to general impoverishment of social interactions with schizophrenics is expected to be susceptible to alternate modified peptide therapies.
  • the highly selective behavioral responses elicited by individual neuropeptides is shown in the Table II below.
  • the invention relates to novel compounds of formula
  • R 1 , R 2 , R 3 , and R 4 are as defined
  • the invention also relates to a pharmaceutical composition containing an effective amount of a compound according to formula I in combination with a pharmaceutically acceptable carrier in unit dosage form for appetite suppression.
  • the invention also relates to a method for suppressing appetite in a mammal.
  • the compounds of the invention are also useful for blocking the reaction caused by withdrawal from drug or alcohol use.
  • the compounds of the invention are also useful in reducing gastric acid secretion, in treating gastrointestinal ulcers, in treating pain, treating and/or preventing stroke, treating inflammation, and in treating anxiety.
  • the compounds of the invention are also useful in treating cognitive deficits, small cell lung cancer, colonic cancer, peptic ulcers, and are useful in contraception.
  • the invention also relates to a pharmaceutical composition for reducing gastric acid secretion containing an effective amount of a compound of formula I in combination with a pharmaceutically acceptable carrier in unit dosage form effective for reducing gastric acid secretion.
  • the invention also relates to a method for reducing anxiety in mammals which comprises
  • the invention further relates to a method for treating gastrointestinal ulcers in mammals which comprises administering an amount effective for gastrointestinal ulcer treatment of the composition as described above to a mammal in need of such treatment.
  • the invention also relates to a pharmaceutical composition containing an effective amount of a compound of formula I in combination with a pharmaceutical composition containing an effective amount of a compound of formula I in combination with a pharmaceutical composition containing an effective amount of a compound of formula I in combination with a pharmaceutical composition containing an effective amount of a compound of formula I in combination with a pharmaceutical composition containing an effective amount of a compound of formula I in combination with a pharmaceutical composition containing an effective amount of a compound of formula I in combination with a
  • the invention also relates to a pharmaceutical composition for preventing the withdrawal response produced by chronic treatment or abuse of drugs or alcohol.
  • the invention further relates to a method for treating the withdrawal response produced by
  • drugs include benzodiazepines, especially diazepam, cocaine, caffeine, opioids, alcohol, and nicotine. Withdrawal symptoms are treated by administration of an benzodiazepines, especially diazepam, cocaine, caffeine, opioids, alcohol, and nicotine. Withdrawal symptoms are treated by administration of an benzodiazepines, especially diazepam, cocaine, caffeine, opioids, alcohol, and nicotine. Withdrawal symptoms are treated by administration of an benzodiazepines, especially diazepam, cocaine, caffeine, opioids, alcohol, and nicotine. Withdrawal symptoms are treated by administration of an benzodiazepines, especially diazepam, cocaine, caffeine, opioids, alcohol, and nicotine. Withdrawal symptoms are treated by administration of an benzodiazepines, especially diazepam, cocaine, caffeine, opioids, alcohol, and nicotine. Withdrawal symptoms are treated by administration of an benzodiazepines, especially diazepam, cocaine, caffeine, opioids, alcohol, and nicotine. Withdrawal symptoms are treated by administration of an
  • This invention also relates to a pharmaceutical composition containing a therapeutically effective amount of a compound according to formula I in combination with a pharmaceutically acceptable carrier in unit dosage form for treating psychosis.
  • the invention also relates to a method for treating psychosis in mammals which comprises
  • This invention also relates to a pharmaceutical composition containing a therapeutically effective amount of a compound according to formula I in combination with a pharmaceutically acceptable carrier in unit dosage form for treating asthma.
  • the invention also relates to a method for treating asthma in mammals which comprises
  • This invention also relates to a pharmaceutical composition containing a therapeutically effective amount of a compound according to formula I in combination with a pharmaceutically acceptable carrier in unit dosage form for treating bladder dysfunction.
  • the invention also relates to a method for treating bladder dysfunction in mammals which
  • This invention also relates to a pharmaceutical composition containing a therapeutically effective amount of a compound according to formula I in combination with a pharmaceutically acceptable carrier in unit dosage form for treating arthritis and/or inflammatory pain.
  • the invention also relates to a method for treating arthritis and/or inflammatory pain in mammals which comprises administering an amount effective for treatment of the composition described above to a mammal in need of such treatment.
  • the invention further relates to methods of treating hypertension, heart failure, stroke,
  • the invention further provides processes for the preparation of compounds of formula I.
  • the invention further provides novel
  • the invention also relates to a pharmaceutical composition for treating pain and to a method of using a compound of formula I for treating pain.
  • the invention also relates to a pharmaceutical composition for treating and/or preventing stroke and to a method of using a compound of formula I for treating and/or preventing stroke.
  • N-terminal protecting refers to those groups known to the art intended to protect the N-terminus of an amino acid or peptide or to protect an amino group against undesirable
  • C-terminal protecting group refers to those groups known to the art intended to protect the C-terminus of an amino acid or peptide, these include but are not limited to an amide, methyl ester, benzyl ester/ether, tert-butyl ester/ether. Other examples of side chains and protecting groups are those known in the art. Any of those could be used.
  • R 1 is an N-terminal blocking group or from 0 to 4 amino acid residues or hydrogen
  • R 2 is a si.dechai.n of a genetically coded amino acid except glycine
  • R 3 is a C-terminal blocking group or from 0 to
  • R 4 is a sidecham of a genetically coded amino acid, except glycine, or
  • n is an integer of from
  • R is hydrogen or lower alkyl
  • Ar is a mono- or polycyclic
  • R 1 plus R 3 cannot be greater than 4 amino acid residues in total.
  • Preferred compounds of the invention are those rmula I selected from:
  • More preferred compounds of the invention are those of formula I selected from:
  • the compounds include solvates, hydrates, and pharmaceutically acceptable salts of the compounds of formula I above.
  • the compounds of the present invention may exist as diastereomers, mixtures of diastereomers, or as the mixed or the individual optical enantiomers.
  • the present invention contemplates all such forms of the compounds.
  • the mixtures of diastereomers are
  • the compounds of the present invention may be formed by coupling individual substituted ⁇ -amino acids by methods well known in the art. (See, for example, standard synthetic methods discussed in the multi-volume treatise The Peptides, Analysis,
  • substituted alpha amino acid starting materials are synthesized by methods within the skill of the art. (Synthesized racemic [DL]- ⁇ -methyl tryptophan methyl ester - see Brana, M. F., et al, J. Hetero ⁇ yclic Chem., 1980.
  • Solid form preparations include powders, tablets, dispersible granules, capsules, cachets, and suppositories.
  • a solid carrier can be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, or tablet disintegrating agents; it can also be an encapsulating material.
  • the carrier is a finely divided solid which is in a mixture with the finely divided active component.
  • the active component is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.
  • a low-melting wax such as a mixture of fatty acid glycerides and cocoa butter is first melted and the active ingredient is dispersed therein by, for example, stirring. The molten homogeneous mixture is then poured into convenient sized molds and allowed to cool and solidify.
  • the powders and tablets preferably contain 5% to about 70% of the active component.
  • Suitable carriers are magnesium carbonate, magnesium stearate, talc, lactose, sugar, pectin, dextrin, starch, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, a low-melting wax, cocoa butter, and the like.
  • preparation is intended to include the formulation of the active component with
  • encapsulating material as a carrier providing a capsule in which the active component (with or without other carriers) is surrounded by a carrier which is thus in association with it.
  • cachets are included.
  • Tablets, powders, cachets, and capsules can be used as solid dosage forms suitable for oral
  • Liquid form preparations include solutions, suspensions, and emulsions. Sterile water or
  • liquid preparations suitable for parenteral administration may be mentioned as an example of liquid preparations suitable for parenteral administration.
  • Liquid preparations can also be formulated in
  • Aqueous solutions for oral administration can be prepared by dissolving the active component in water and adding suitable colorants, flavoring agents, stabilizers, and thickening agents as desired.
  • Aqueous suspensions for oral use can be made by dispersing the finely divided active component in water together with a viscous material such as natural synthetic gums, resins, methyl cellulose, sodium carboxymethyl cellulose, and other suspending agents known to the pharmaceutical formulation art.
  • a viscous material such as natural synthetic gums, resins, methyl cellulose, sodium carboxymethyl cellulose, and other suspending agents known to the pharmaceutical formulation art.
  • the pharmaceutical preparation is in unit dosage form.
  • the preparation is in unit dosage form.
  • the preparation is divided into unit doses containing appropriate quantities of the active component.
  • the unit dosage form can be a packaged preparation, the package containing discrete quantities of the preparation, for example, packeted tablets, capsules, and powders in vials or ampoules.
  • the unit dosage form can also be a capsules, cachet, or tablet itself, or it can be the appropriate number of any of these packaged forms.
  • peptides of the invention were constructed on solid-phase resins designed to produce C-terminal amides either by treatment of the resin with ammonia in methanol or by direct cleavage of an appropriately substituted resin using trifluoroacetic acid, with the required scavengers, giving the amides directly.
  • the latter protocol was used with DuPont RapidAmide ® or Nova Biochem Ultrasyn C ® resins either in a simple bubbler apparatus (DuPont resin) or automated synthesizer (Nova Biochem resin).
  • peptides of the invention can be made by the above method. Although any compatible resin may be used or, alternatively, solution phase synthesis may be used.
  • Such peptides include but are not limited to the short chemotactic peptides, for example,
  • Preferred compounds are:
  • LTyr-Gly-Gly- ⁇ -MePhe-LLeu (isomer 2) whose full chemical names are N-[ ⁇ -methyl-N-[N-(N-L-tyrosylglycyl)glycyl]-L-phenylalanyl]-L-leucinetrifluoroacetate (1:1 salt) and N-[ ⁇ -methyl-N-[N-(N-L-tyrosylglycyl)glycyl]-D-phenylalanyl]-L-leucine trifluoroacetate (1:1 salt).
  • the data in Table III show that the compounds are selective NK2 receptor ligands.
  • the compounds of Examples 18 and 19 illustrate NK 2 receptor
  • L659,874 3 ⁇ M 41 7.1 a L659, 874 is a standard NK 2 antagonist . Its
  • the peptide was prepared and separated as described above, using solid-phase methodology.
  • N-(t-Butyloxycarbonyl)-DL- ⁇ -methylphenylalanine (1) DL- ⁇ -Methylphenylalanine (5.0 g, 28 mmol) was dissolved in warm 10% Na 2 CO 3 solution (60 mL) and then cooled to 0°C. t-Butyloxycarbonyl anhydride (6.39 g, 29.3 mmol) in dioxan (50 mL) was added dropwise and the mixture stirred at 0°C for 1 hour. The mixture was then allowed to warm to room
  • 1,3-Dicyclohexylcarbodiimide (4.95 g, 24 mmol) was added to a solution of 1 (6.70 g, 24 mmol) in THF (100 mL) at -15°C and allowed to stir for 5 minutes.3-Hydroxy-1,2,3-benzotriazine-4-(3H)-one (3.91 g, 24 mmol) and an additional volume of THF (20 mL) were added and the mixture stirred at -10°C for 1 hour and at 0°C for 4 hours. After leaving overnight at 5°C a white solid precipitated.
  • hexachlorophosphate (0.19 g, 0.5 mmol) was added to a solution of Z-(L)-Trp (0.15 g, 0.5 mmol), 16 (0.17 g, 0.5 mmol), and N,N-diisopropylethylamine (0.26 mL, 1.5 mmol) in DMF (3 mL) and stirred at room temperature for 45 minutes. Water was added and the mixture extracted with EtOAc. The organic layer was washed with 10% citric acid solution, saturated

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PCT/US1992/003119 1991-03-20 1992-04-15 α-SUBSTITUTED POLYPEPTIDES HAVING THERAPEUTIC ACTIVITY WO1992019254A1 (en)

Priority Applications (3)

Application Number Priority Date Filing Date Title
CA002106764A CA2106764A1 (en) 1991-04-24 1992-04-15 Ó-substituted polypeptides having therapeutic activity
JP4511401A JPH06507402A (ja) 1991-03-20 1992-04-15 治療活性を有するα−置換ポリペプチド
EP92911434A EP0668770A1 (en) 1991-04-24 1992-04-15 $g(a)-SUBSTITUTED POLYPEPTIDES HAVING THERAPEUTIC ACTIVITY

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US690,755 1976-05-27
US852,086 1977-11-16
US69075591A 1991-04-24 1991-04-24
US85208692A 1992-03-20 1992-03-20

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JP (1) JPH06507402A (enrdf_load_stackoverflow)
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Cited By (14)

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WO1994009031A1 (en) * 1992-10-19 1994-04-28 Warner-Lambert Company Analogues of cholecystokinin (30-33) containing an alpha-substituted aminoacid
WO1994016697A1 (fr) 1993-01-19 1994-08-04 Rhone-Poulenc Rorer S.A. Association synergisante ayant un effet antagoniste des recepteurs nk1 et nk2
WO1995028418A3 (en) * 1994-04-15 1995-11-16 Warner Lambert Co Tachykinin antagonists
US5554644A (en) * 1994-06-08 1996-09-10 Warner-Lambert Company Tachykinin (NK2) antagonists
FR2735687A1 (fr) * 1995-06-21 1996-12-27 Sederma Sa Nouvelles compositions cosmetiques amincissantes
WO1998007744A1 (fr) * 1996-08-23 1998-02-26 Sederma S.A. Peptides synthetiques et leur utilisation dans les compositions cosmetiques ou dermopharmaceutiques
US5780498A (en) * 1993-11-01 1998-07-14 Ciba-Geigy Japan Limited Endothelin receptor antagonists
US6593362B2 (en) 2001-05-21 2003-07-15 Guilford Pharmaceuticals Inc. Non-peptidic cyclophilin binding compounds and their use
WO2006049681A3 (en) * 2004-08-30 2006-07-27 Bayer Pharmaceuticals Corp Selective neuropeptide y2 receptor agonists
US7220725B2 (en) 2000-08-10 2007-05-22 S.I.S. Shulov Institute For Science Ltd. Pharmaceutical composition comprising an analgesic peptide and method for treating pain
WO2009071957A3 (en) * 2007-12-05 2009-08-27 Biostatin Gyógyszerkutató-Fejlesztö Kft. Novel peptides and amino acid derivatives, pharmaceutical compositions containing same and the use of these compounds
US20100190717A1 (en) * 2007-09-11 2010-07-29 Dorian Bevec Use of melanin concentrating hormone and met-enkephalin as therapeutic agents
WO2012131676A1 (en) 2011-03-28 2012-10-04 S.I.S. Shulov Innovative Science Ltd. Method for treating disorders of the skin
WO2025049670A1 (en) * 2023-08-31 2025-03-06 Northwestern University Compounds and methods for treating central nervous system disorders

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AU674525B2 (en) * 1992-06-01 1997-01-02 Magainin Pharmaceuticals, Inc. Biologically active peptides having N-terminal substitutions

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Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994009031A1 (en) * 1992-10-19 1994-04-28 Warner-Lambert Company Analogues of cholecystokinin (30-33) containing an alpha-substituted aminoacid
WO1994016697A1 (fr) 1993-01-19 1994-08-04 Rhone-Poulenc Rorer S.A. Association synergisante ayant un effet antagoniste des recepteurs nk1 et nk2
US6177450B1 (en) 1993-01-19 2001-01-23 Aventis Pharma S.A. Synergizing combination having an antagonist effect on NKI and NK2 receptors
US5780498A (en) * 1993-11-01 1998-07-14 Ciba-Geigy Japan Limited Endothelin receptor antagonists
WO1995028418A3 (en) * 1994-04-15 1995-11-16 Warner Lambert Co Tachykinin antagonists
US5610145A (en) * 1994-04-15 1997-03-11 Warner-Lambert Company Tachykinin antagonists
US5554644A (en) * 1994-06-08 1996-09-10 Warner-Lambert Company Tachykinin (NK2) antagonists
FR2735687A1 (fr) * 1995-06-21 1996-12-27 Sederma Sa Nouvelles compositions cosmetiques amincissantes
WO1998007744A1 (fr) * 1996-08-23 1998-02-26 Sederma S.A. Peptides synthetiques et leur utilisation dans les compositions cosmetiques ou dermopharmaceutiques
US7220725B2 (en) 2000-08-10 2007-05-22 S.I.S. Shulov Institute For Science Ltd. Pharmaceutical composition comprising an analgesic peptide and method for treating pain
US6593362B2 (en) 2001-05-21 2003-07-15 Guilford Pharmaceuticals Inc. Non-peptidic cyclophilin binding compounds and their use
WO2006049681A3 (en) * 2004-08-30 2006-07-27 Bayer Pharmaceuticals Corp Selective neuropeptide y2 receptor agonists
US20100190717A1 (en) * 2007-09-11 2010-07-29 Dorian Bevec Use of melanin concentrating hormone and met-enkephalin as therapeutic agents
WO2009071957A3 (en) * 2007-12-05 2009-08-27 Biostatin Gyógyszerkutató-Fejlesztö Kft. Novel peptides and amino acid derivatives, pharmaceutical compositions containing same and the use of these compounds
WO2012131676A1 (en) 2011-03-28 2012-10-04 S.I.S. Shulov Innovative Science Ltd. Method for treating disorders of the skin
US9012397B2 (en) 2011-03-28 2015-04-21 S.I.S. Shulov Innovative Science Ltd. Method for treating disorders of the skin
WO2025049670A1 (en) * 2023-08-31 2025-03-06 Northwestern University Compounds and methods for treating central nervous system disorders

Also Published As

Publication number Publication date
EP0668770A4 (enrdf_load_stackoverflow) 1995-09-27
IE921321A1 (en) 1992-11-04
CA2106764A1 (en) 1992-10-25
PT100422A (pt) 1993-09-30
JPH06507402A (ja) 1994-08-25
EP0668770A1 (en) 1995-08-30
NZ242441A (en) 1995-02-24
AU1907292A (en) 1992-12-21

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