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WO1994009031A1 - Analogues de cholecystokinine (30-33) contenant un acide amine a substitution alpha - Google Patents

Analogues de cholecystokinine (30-33) contenant un acide amine a substitution alpha Download PDF

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Publication number
WO1994009031A1
WO1994009031A1 PCT/US1993/009809 US9309809W WO9409031A1 WO 1994009031 A1 WO1994009031 A1 WO 1994009031A1 US 9309809 W US9309809 W US 9309809W WO 9409031 A1 WO9409031 A1 WO 9409031A1
Authority
WO
WIPO (PCT)
Prior art keywords
methyl
gly
tryptophyl
carbonyl
leu
Prior art date
Application number
PCT/US1993/009809
Other languages
English (en)
Inventor
David Christopher Horwell
William Howson
John Hugues
Reginald Stewart Richardson
Original Assignee
Warner-Lambert Company
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
Application filed by Warner-Lambert Company filed Critical Warner-Lambert Company
Priority to AU53596/94A priority Critical patent/AU5359694A/en
Publication of WO1994009031A1 publication Critical patent/WO1994009031A1/fr

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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
    • C07K5/06—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
    • C07K5/02—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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C07K5/0821—Tripeptides with the first amino acid being heterocyclic, e.g. His, Pro, Trp
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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 thousand. Over a hundred peptides are known to act as hormone, neurohormones, or neurotransmitters, and this number is growing rapidly. The potential for drug development is therefore vast. However, the great majority of peptide messengers are not suitable for use as pharmaceuticals in their natural state.
  • the problems of natural peptides as drugs are lack of oral activity, failure to penetrate the blood-brain barrier, rapidly metabolized, no selectivity for receptor subclasses, antigenic properties, and
  • 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
  • the invention relates to novel compounds of formula
  • 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
  • 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 gastric acid secretion in mammals which comprises administering an amount effective for gastric acid secretion reduction of the composition described above to a mammal in need of such treatment.
  • the invention also relates to a method for
  • the invention further relates to a method for treating inflammation in mammals which comprises administering an amount effective of a composition as described above to a mammal in need of such treatment.
  • 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 withdrawal from chronic treatment or withdrawal from abuse of drugs or alcohol.
  • drugs include benzodiazepines, especially diazepam, cocaine, caffeine, opioids, alcohol, and nicotine. Withdrawal symptoms are treated by administration of an effective withdrawal treating amount of a compound of the instant invention.
  • the invention also relates to a method for
  • the invention also relates to a method for
  • the invention also relates to a method for
  • treating bladder dysfunction 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 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 intermediates useful in the preparation of compounds of Formula I and also provides processes for the preparation of the intermediates.
  • 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 reactions during a synthetic procedure or to prevent the attack of exopeptidases on the compounds or to increase the solubility of the compounds and includes, but is not limited to, sulfonyl, acetyl, pivaloyl,
  • 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.
  • 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
  • R is a sidechain of a genetically coded ammo
  • R is a C-terminal blocking group or from 0 to
  • R n is straight or branched alkyl or cycloalkyl of 1 to 6 carbon atoms
  • R 4 is a sidechain of a genetically coded ammo
  • n is an integer of from 0 to 3
  • R is hydrogen or lower alkyl
  • Ar is a mono- or polycyclic unsubstituted or substituted carbo- or heterocyclic aromatic or hydroaromatic moiety
  • Preferred compounds of the invention are those of Formula 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 typically obtained as a result of the reactions described more fully below.
  • Individual diastereomers may be separated from mixtures of the diastereomers by conventional techniques such as column chromatography or repetitive recrystallizations.
  • Individual enantiomers may be separated by conventional methods well known in the art such as conversion to a salt with an optically active compound, followed by separation by chromatography or recrystallization and reconversion to the nonsalt form.
  • 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
  • inert, pharmaceutically acceptable carriers can be either solid or liquid.
  • Solid form preparations include powders, tablets, dispersible granules, capsules, cachets, and
  • 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
  • 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.
  • 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.
  • Liquid preparations can also be formulated in solution in aqueous polyethylene glycol solution.
  • 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
  • the pharmaceutical preparation is in unit dosage form.
  • the preparation is in unit dosage form.
  • the preparation is divided into unit doses containing appropriate
  • the unit dosage form can be a packaged preparation, the package
  • 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.
  • RapidAmide ® or Nova Bi.ochem Ultrasyn C ® resins either in a simple bubbler apparatus (DuPont resin) or automated synthesizer (Nova Biochem resin).
  • 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-leucine trifluoroacetate (1:1 salt) and N-[ ⁇ -methyl-N-[N-(N-L-tyrosylglycyl)glycyl]-D-phenylalanyl]-L-leucine trifluoroacetate (1:1 salt).
  • NK 1 receptor - measurement of the binding of [ 125 I]-Bolton Hunter labeled substance P (0.1 nM) to guinea pig cerebral cortex membranes and for the NK 3 receptor - measurement of the binding of [ 3 H]-senktide (2 nM) to guinea pig cerebral cortex membranes. See Lee, C. M., et al, Eur. J. Pharmacol. 130:209 (1986), and Guard, S., et al, Brit. J. Pharmacol. 99:767
  • Examples 18 and 19 illustrate NK 2 receptor antagonism. See Table IV below. Therefore, they are expected to be useful in treating disorders mediated by tachykinins, eg, respiratory disorders, inflammation, gastrointestinal disorders, ophthalmic diseases, allergies, pain, circulatory insufficiency, diseases of the central nervous system, and migraine. TABLE IV. NK 2 Functional Data Summary
  • L659,874 3 ⁇ M 41 7.1 a L659,874 is a standard NK 2 antagonist. Its structure is
  • the peptide was prepared and separated as
  • Citric acid was added to the filtrate to pH 3 and washed with EtOAc (3x).
  • the aqueous layer was made alkaline (pH 9) with solid Na 2 CO 3 and extracted with
  • 1,3-Dicyclohexylcarbodiimide (4.95 g, 24 mmol) was added to a solution of 1 (6.70 g, 24 mmol) in THF
  • hexachlorophosphate (0.19 g, 0.5 mmol) was added to a solution of Z-(L)-Trp (0.15 g, 0.5 mmol), 16
  • Trp- ⁇ -H 4.84-5.06 (2H, m, CH 2 OCO) , 6.88-7.45 (16H, m, Ar, OCONH, CONH 2 ) , 7.55-7.75 (2H, m, Ar) , 7.80
  • Step 4 To a solution of the acid (Step 4) (216 mg) in DMF (4 mL) was added the HCl-GlyNH 2 (41 mg) followed by BOP reagent (164 mg) and DIPEA (144 mg). The reaction mixture was stirred overnight at room temperature and then evaporated to dryness. The residue was taken up in EtOAc and the organic layer washed with aqueous 0.1 M HCl solution. The organic layer was then
  • Acid (14) was prepared as a crude sample without purification and was a white amorphous solid (90 mg, 93%); IR (film) 3340, 1721, 1715, and 1667 cm -1 .
  • Example 7 white solid (0.100 g, 58%); MS (FAB) m/e 603 [M+H]; 1 H NMR (DMSO-d 6 ) ⁇ 1.39 (3H, s, ⁇ -CH 3 ), 2.89-3.38 (4H, m, CH 2 indole, CH 2 Ph), 4.02 (1H, m, Trp ⁇ H), 5.07 (2H, m, Ar CH 2 O 2 CNH) , 6.97-7.85 (23H, m, Ar, NH, NH 2 , OCONH), 10.84 (1H, s, indole NH); Anal.
  • Example 7 yellow foam (0.37 g, 68%); MS (FAB) m/e 544 [M+H]; 1 H NMR (DMSO-d 6 ) ⁇ 1.39 (0.5 ⁇ 3H, S, ⁇ -CH 3 ), 1.42 (0.5 ⁇ 3H, s, ⁇ -CH 3 ), 3.16-3.40 (4H, m,
  • 1,3-Dicyclohexyxcarbondiimide (4.95 g, 24 mmol) was added to a solution of ⁇ -methyl-L-phenylalanine (obtained by the method of Turk, et al) (6.70 g,
  • N-BOC- ⁇ -Me-(L)Phe(H)-DCHA (4.6 g, 10 mmol) was taken up in CH 2 Cl 2 and washed with 1N HCl, H 2 O, dried (MgSO 4 ), and the solvent was removed in vacuo to give the acid as a solid.
  • the solid was taken up in DMF (50 mL) and stirred with HBTU (3.80 g, 10 mmol) and diisopropylethyl amine (2.58 g, 20 mmol) at room temperature for 30 minutes.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Genetics & Genomics (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • General Health & Medical Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Crystallography & Structural Chemistry (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Peptides Or Proteins (AREA)

Abstract

Les composés de la présente invention sont des mono-, di-, tri-, tétra- et pentapeptides à substitution α utiles pour traiter l'obésité, l'anxiété, les ulcères gastro-intestinaux, la douleur, les accidents vasculaires cérébraux et les inflammations. Ils sont également utiles pour bloquer les réactions causées par le sevrage de drogues ou d'alchool et pour réduire les secrétions acides gastriques. Ils sont en outre utiles commme agents thérapeutiques dans l'hypertension, l'insuffisance cardiaque, les accidents vasculaires cérébraux, la cognition, la stimulation de la mémoire, la spasticité, la dépression, le diabète, le cancer, l'asthme, le dysfonctionnement de la vessie, la psychose et l'arthrite et/ou les douleurs inflammatoires. Des compositions pharmaceutiques, de nouveaux intermédiaires et des procédés sont également décrits.
PCT/US1993/009809 1992-10-19 1993-10-14 Analogues de cholecystokinine (30-33) contenant un acide amine a substitution alpha WO1994009031A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU53596/94A AU5359694A (en) 1992-10-19 1993-10-14 Analogues of cholecystokinin (30-33) containing an alpha-substituted aminoacid

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US96316992A 1992-10-19 1992-10-19
US07/963,169 1992-10-19
US13169393A 1993-10-08 1993-10-08
US08/131,693 1993-10-08

Publications (1)

Publication Number Publication Date
WO1994009031A1 true WO1994009031A1 (fr) 1994-04-28

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PCT/US1993/009809 WO1994009031A1 (fr) 1992-10-19 1993-10-14 Analogues de cholecystokinine (30-33) contenant un acide amine a substitution alpha

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AU (1) AU5359694A (fr)
MX (1) MX9306494A (fr)
WO (1) WO1994009031A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2735687A1 (fr) * 1995-06-21 1996-12-27 Sederma Sa Nouvelles compositions cosmetiques amincissantes
US8362068B2 (en) 2009-12-18 2013-01-29 Idenix Pharmaceuticals, Inc. 5,5-fused arylene or heteroarylene hepatitis C virus inhibitors
WO2015083816A1 (fr) * 2013-12-06 2015-06-11 国立大学法人京都大学 Nouvel agoniste des récepteurs nk3

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992011284A1 (fr) * 1990-12-17 1992-07-09 The James Black Foundation Limited Derives de tetrapeptides et analogues
WO1992019254A1 (fr) * 1991-04-24 1992-11-12 Warner-Lambert Company POLYPEPTIDES α SUBSTITUES AYANT DES PROPRIETES THERAPEUTIQUES

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992011284A1 (fr) * 1990-12-17 1992-07-09 The James Black Foundation Limited Derives de tetrapeptides et analogues
WO1992019254A1 (fr) * 1991-04-24 1992-11-12 Warner-Lambert Company POLYPEPTIDES α SUBSTITUES AYANT DES PROPRIETES THERAPEUTIQUES

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
D C HORWELL ET AL.: "alpha-methyl tryptophanylphenylalanines and their arylethylamine "dipeptoid" analogues of the tetrapeptide cholecystokinin (30-33)", EUR J MED CHEM, vol. 25, no. 1, February 1990 (1990-02-01), ELSEVIER, PARIS, pages 53 - 60, XP023870633, DOI: doi:10.1016/0223-5234(90)90164-X *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2735687A1 (fr) * 1995-06-21 1996-12-27 Sederma Sa Nouvelles compositions cosmetiques amincissantes
US8362068B2 (en) 2009-12-18 2013-01-29 Idenix Pharmaceuticals, Inc. 5,5-fused arylene or heteroarylene hepatitis C virus inhibitors
US9187496B2 (en) 2009-12-18 2015-11-17 Idenix Pharmaceuticals Llc 5,5-fused arylene or heteroarylene hepatitis C virus inhibitors
WO2015083816A1 (fr) * 2013-12-06 2015-06-11 国立大学法人京都大学 Nouvel agoniste des récepteurs nk3

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MX9306494A (es) 1994-06-30
AU5359694A (en) 1994-05-09

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