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WO1999063990A1 - Utilisation nouvelle - Google Patents

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Publication number
WO1999063990A1
WO1999063990A1 PCT/SE1999/001033 SE9901033W WO9963990A1 WO 1999063990 A1 WO1999063990 A1 WO 1999063990A1 SE 9901033 W SE9901033 W SE 9901033W WO 9963990 A1 WO9963990 A1 WO 9963990A1
Authority
WO
WIPO (PCT)
Prior art keywords
npy
treatment
antagonist
antagonists
peptic ulcer
Prior art date
Application number
PCT/SE1999/001033
Other languages
English (en)
Inventor
Bengt ÅBLAD
Original Assignee
Astrazeneca Ab
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 Astrazeneca Ab filed Critical Astrazeneca Ab
Priority to AU48121/99A priority Critical patent/AU4812199A/en
Publication of WO1999063990A1 publication Critical patent/WO1999063990A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide

Definitions

  • This invention relates to a new use of NPY antagonists.
  • Neuropeptide Y is a peptide consisting of 36 amino acids. In recent years it has been established that NPY is an important co-transmitter in the peripheral sympathetic nerve system.
  • NPY neuropeptide
  • NPY receptor sub-types have been identified, namely the Y 3 , Y 4 , Y 5 and Y 6 sub-types. The precise function of these sub-receptors has not been elucidated in any detail, but it has been widely postulated that the Y 5 subtype is involved in the regulation of feeding and eating (see, for example, Exp. Opin. Invest. Drugs, vol. 6, pp. 437-445 (1997)).
  • Antagonists of NPY have been indicated as being of potential use in the treatment of many different conditions, including cardiovascular diseases such as hypertension, myocardial ischaemia, myocardial infarction, cardiac failure, vasospasm and arrhythmia, as well as in the treatment of kidney failure, cerebral haemorrhage, pain, migraine, anxiety, depression, ⁇ flammation, Alzheimer's disease, asthma, epilepsy, diabetes, sleeping disorders, obesity and eating disorders.
  • Dyspepsia is a very common medical condition. It has been estimated that up to 40% of the western population experience dyspeptic symptoms, many of which result from peptic ulcer disease.
  • antacids and inhibitors of gastric secretion e.g. H 2 -antagonists and proton pump inhibitors.
  • gastric secretion e.g. H 2 -antagonists and proton pump inhibitors.
  • Inhibitors of gastric secretion have the disadvantage that they are expensive and may have an impact on gut physiology, thus increasing the risk of intestinal and/or systemic infections.
  • Prokinetic drugs e.g. cisapride
  • anticholinergic compounds are often administered for the treatment of dyspeptic symptoms, usually with variable effect and high incidence of side effects.
  • Haemorrhage and/or trauma elicit a vasoconstrictive response that preferentially reduces blood flow to mesenteric organs. If severe, haemorrhage may result in circulatory shock, a condition in which oxygen delivery becomes insufficient to maintain tissue integrity and function.
  • Manifestations of circulatory shock on mesenteric organs include collapse of the gut permeability barrier, which enables gut pathogens to cross the intestinal mucosa and eventually spread to systemic compartments via lymphatic or blood vessels.
  • the barrier dysfunction with microbial translocation together with the initially comprised systemic circulation, leads to disruption of haemostasis and functional failure of various organ systems (kidneys, heart, lungs, etc.). Such a sequential development of devastating sequels is defined as multiple organ failure (MOF).
  • MOF mesenteric blood flow and oxygen delivery
  • NPY antagonists including benextramine, CC2137, arpromidine, BIBP3226, NGD 95-1, SR120819A, SR120107A, 1229U91 and PD160170, are described in DDT, vol. 2 pages 19-24 (1997), which provides a general review of patents and patent applications in the NPY area.
  • NPY antagonists are also provided in Peptides vol. 18, No. 3, pages 445-57 (1997).
  • Non-peptide based (which term includes amino acid-based) antagonists of NPY have been disclosed in European patent applications EP 614 911, EP 747 357, EP 747 356 and EP 747 378; international patent applications
  • European patent application EP 614 911 (which discloses sulphamoyl substituted derivatives of phenylalanine amidine) and international patent application WO 94/17035, do not mention the receptor sub-type upon which the disclosed compounds act.
  • EP 747 357, EP 747 356 and EP 747 378 disclose dihydropyridine derivatives as sub-receptor Y, antagonists.
  • Japanese patent application JP 09157253 discloses amino acid derivatives as NPY antagonists.
  • the compounds disclosed in international patent application WO 96/22305 are described as having Y 2 sub-receptor antagonist activity and are indicated for use in the treatment of eating disorders.
  • the compounds specifically disclosed are phenylalanine amide derivatives of N-(diphenylpropionyl)arginine .
  • Peptide derivatives as NPY antagonists are disclosed in international patent applications WO 94/00486, WO 93/12139, WO 95/00161, US Patent No. 5,328,899, German patent application DE 393 97 97, European patent applications EP 355 794 and EP 355 793 and Japanese patent applications JP 06116284 and JP 07267988. None of the aforementioned prior art documents mention or suggest that the NPY antagonists disclosed therein may be useful in the treatment of peptic ulcer diseases, or of MOF.
  • NPY antagonists reduce vascular constriction in the gastrointestinal tract, and may thus be used to reduce the symptoms of, and to treat, peptic ulcer disease, as well as MOF (for example, as demonstrated in the Examples described below).
  • NPY antagonist for the manufacture of a medicament for the treatment of peptic ulcer disease, or of MOF.
  • NPY antagonists may be used to treat such conditions in preferably mammalian, and especially human, patients.
  • peptic ulcer disease will be understood to include all classes of peptic ulcer (i.e. ulceration of the mucous membrane of a relevant part of the gastrointestinal tract, e.g. the oesophagus, stomach, duodenum, etc.) as well as the symptoms which are associated with such a condition, such as pain and dyspepsia (i.e. impairment of the power or function of digestion in the gastrointestinal tract, before, during or after the intake of food or drink).
  • peptic ulcer i.e. ulceration of the mucous membrane of a relevant part of the gastrointestinal tract, e.g. the oesophagus, stomach, duodenum, etc.
  • symptoms which are associated with such a condition such as pain and dyspepsia (i.e. impairment of the power or function of digestion in the gastrointestinal tract, before, during or after the intake of food or drink).
  • NPY antagonist will be well understood by those skilled in the art to include all those compounds which inhibit the activity of NPY to an experimentally determinable degree, i.e. those compounds which bind to a NPY receptor without eliciting a biological response, for example those compounds which, by binding to NPY receptors, inhibit the functional activity of NPY with an IC 50 (as measured in, for example, rat-brain cortex membranes) of less than 10 ⁇ M.
  • the term thus includes antagonists of all NPY receptor sub-types including the Y l 5 Y 2 , Y 3 , Y 4 , Y 5 and Y 6 sub-types.
  • the NPY antagonist is a NPY Y, sub-receptor antagonist.
  • NPY antagonists which may be mentioned include those disclosed in European patent applications EP 614 911, EP 747 357, EP 747 356 and EP 747 378; international patent applications WO 94/17035, WO 97/19911, WO 97/19913, WO 96/12489, WO 97/19914, WO 96/22305, WO 96/40660, WO 96/12490, WO 97/09308, WO 97/20820, WO 97/20821, WO 97/20822, WO 97/20823, WO 97/19682, WO 97/25041, WO 97/34843, WO 97/46250, WO 98/03492, WO 98/03493, WO 98/03494 and WO 98/07420; US patents Nos.
  • NPY antagonists include those compounds that are specifically disclosed in these patent documents. More preferred compounds include amino acid and non-peptide-based NPY antagonists.
  • Amino acid and non-peptide-based NPY antagonists which may be mentioned include those disclosed in European patent applications EP 614 911 , EP 747 357, EP 747 356 and EP 747 378; international patent applications WO 94/17035, WO 97/19911 , WO 97/19913, WO 96/12489, WO 97/19914, WO 96/22305, WO 96/40660, WO 96/12490, WO 97/09308, WO 97/20820, WO 97/20821 , WO 97/20822, WO 97/20823, WO 97/19682, WO 97/25041 , WO 97/34843, WO 97/46250, WO 98/03492, WO 98/03493, WO 98/03494, WO 98/07420 and WO 99/15498; US patents Nos. 5,552,411 , 5,663, 192 and 5,567,
  • Particularly preferred compounds include amino acid-based NPY antagonists.
  • Amino acid-based compounds which may be mentioned include those disclosed in international patent applications WO 94/17035, WO 97/19911 , WO 97/19913, WO 97/19914 or, preferably, WO 99/15498.
  • Preferred amino acid-based NPY antagonists include those that are specifically disclosed in these patent documents, for example BIBP3226 and, especially, (R)-N 2 -(diphenylacetyl)-(R)-N-[l-(4-hydroxy- phenyl)ethyl]arginine amide (Example 4 of international patent application WO 99/15498).
  • the NPY antagonists may be administered orally, intravenously, subcutaneously, buccally, rectally, dermally, nasally, tracheally, bronchially, by any other parenteral route, or via inhalation, in the form of a pharmaceutical preparation comprising the active ingredient either as a free base, or a pharmaceutical acceptable non-toxic organic or inorganic acid addition salt, in a pharmaceutically acceptable dosage form.
  • the compositions may be administered at varying doses (see below) .
  • the NPY antagonists may be given as a pharmaceutical formulation in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.
  • NPY antagonists in the formulation will depend on the condition, and patient, to be treated, as well as the compound(s) which is/are employed.
  • a pharmaceutical formulation for use in the treatment of peptic ulcer disease, or of MOF comprising an effective amount of a NPY antagonist and a pharmaceutically-acceptable adjuvant, diluent or carrier.
  • the NPY antagonists may also be combined with other therapeutic agents that are useful in the treatment of peptic ulcer disease (e.g. antacids, proton pump inhibitors, etc.), or of MOF (e.g. angiotensin II antagonists, volume supplementation, dopaminergic agents, vasodilators, etc).
  • other therapeutic agents e.g. antacids, proton pump inhibitors, etc.
  • MOF e.g. angiotensin II antagonists, volume supplementation, dopaminergic agents, vasodilators, etc.
  • Suitable doses of the NPY antagonists in the therapeutic and/or prophylactic treatment of mammalian, especially human, patients are 0.01 to 10 mg/kg body weight per day at peroral administration and 0.001 to 1.0 mg/kg body weight per minute at parenteral administration.
  • a method of treatment of peptic ulcer disease, or of MOF which comprises administering a therapeutically effective amount of a NPY antagonist to a patient in need of such treatment.
  • treatment we include the therapeutic treatment, as well as the prophylaxis, of a condition.
  • the use and method described herein may have the advantage that, in the treatment of peptic ulcer disease, or of MOF, NPY antagonists do not possess the disadvantages of known drugs presently used in the treatment of such indications, such as those discussed hereinbefore.
  • NPY antagonists The effect of NPY antagonists on MOF in pigs was evaluated as follows.
  • Anaesthetised pigs were exposed to haemorrhage by withdrawal of blood (25 mL/kg body weight, corresponding to about 30% of the total blood volume) for 30 minutes.
  • the haemodynamic and metabolic consequences in the intestines were studied by recording arterial pressure, portal vein blood flow, pH and oxygen saturation in arterial and portal venous blood before and after bleeding. Basal values were recorded for one hour (0 to 60 minutes). Following this, blood was withdrawn for 30 minutes (60 to 90 minutes) and the responses to bleeding were recorded for the next 40 minutes (90 to 130 minutes).
  • the NPY r antagonist (_.)-N -(diphenylacetyl)-(R)-N-[l-(4-hydroxyphenyl)- ethyl] arginine amide (Compound I, disclosed in international patent application WO 99/15498 as Example 4) by i.v. infusion in a dose of 0.06 ⁇ mol/kg per minute during the experimental time 20 to 140 minutes.
  • the other two pigs were given a corresponding infusion of the vehicle.
  • the two pigs given Compound I were still surviving after 140 minutes.
  • the two pigs given control vehicle however, died due to severe hypotension, one at 109 minutes, the other at 133 minutes.
  • results obtained are tabulated below, at the following times: 20 minutes (before start of drug/vehicle infusion), 60 minutes (before start of bleeding), 90 minutes (at end of bleeding) and 130 minutes (40 minutes after end of bleeding). The results are given as means of the two drug and the two control experiments respectively.
  • NPY antagonists especially Y, sub-receptor antagonists
  • NPY antagonists The effect of NPY antagonists on stress induced ulcers in the rat was evaluated as follows.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L'invention concerne l'utilisation d'un antagoniste NPY pour la fabrication d'un médicament destiné au traitement en cas d'ulcère gastro-duodénal ou de défaillance polyviscérale.
PCT/SE1999/001033 1998-06-11 1999-06-10 Utilisation nouvelle WO1999063990A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU48121/99A AU4812199A (en) 1998-06-11 1999-06-10 New use

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
SE9802075-3 1998-06-11
SE9802075A SE9802075D0 (sv) 1998-06-11 1998-06-11 New use

Publications (1)

Publication Number Publication Date
WO1999063990A1 true WO1999063990A1 (fr) 1999-12-16

Family

ID=20411660

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/SE1999/001033 WO1999063990A1 (fr) 1998-06-11 1999-06-10 Utilisation nouvelle

Country Status (3)

Country Link
AU (1) AU4812199A (fr)
SE (1) SE9802075D0 (fr)
WO (1) WO1999063990A1 (fr)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994017035A1 (fr) * 1993-01-20 1994-08-04 Dr. Karl Thomae Gmbh Derives d'amino-acides, medicaments contenant ces composes et procede permettant de les preparer
WO1997019911A1 (fr) * 1995-11-30 1997-06-05 Dr. Karl Thomae Gmbh Derives d'acides amines, compositions pharmaceutiques contenant ces composes et procedes de preparation de ceux-ci
WO1997019914A1 (fr) * 1995-11-30 1997-06-05 Dr. Karl Thomae Gmbh Derives d'acides amines, medicaments contenant ces composes et procede de production correspondant
WO1999015498A1 (fr) * 1997-09-23 1999-04-01 Astrazeneca Ab Nouveaux antagonistes de npy

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994017035A1 (fr) * 1993-01-20 1994-08-04 Dr. Karl Thomae Gmbh Derives d'amino-acides, medicaments contenant ces composes et procede permettant de les preparer
WO1997019911A1 (fr) * 1995-11-30 1997-06-05 Dr. Karl Thomae Gmbh Derives d'acides amines, compositions pharmaceutiques contenant ces composes et procedes de preparation de ceux-ci
WO1997019914A1 (fr) * 1995-11-30 1997-06-05 Dr. Karl Thomae Gmbh Derives d'acides amines, medicaments contenant ces composes et procede de production correspondant
WO1999015498A1 (fr) * 1997-09-23 1999-04-01 Astrazeneca Ab Nouveaux antagonistes de npy

Also Published As

Publication number Publication date
SE9802075D0 (sv) 1998-06-11
AU4812199A (en) 1999-12-30

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