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WO2000047201A1 - Utilisation pharmacologique de certains derives de la cystine - Google Patents

Utilisation pharmacologique de certains derives de la cystine Download PDF

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Publication number
WO2000047201A1
WO2000047201A1 PCT/SE2000/000238 SE0000238W WO0047201A1 WO 2000047201 A1 WO2000047201 A1 WO 2000047201A1 SE 0000238 W SE0000238 W SE 0000238W WO 0047201 A1 WO0047201 A1 WO 0047201A1
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WO
WIPO (PCT)
Prior art keywords
butyl
methylpropyl
propyl
methylbutyl
ethyl
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/SE2000/000238
Other languages
English (en)
Inventor
Tommy Abrahamsson
Harriet BJÖRK-SKANTZE
Knut Pettersson
Göran WALLDIUS
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.)
AstraZeneca AB
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 AU29540/00A priority Critical patent/AU2954000A/en
Publication of WO2000047201A1 publication Critical patent/WO2000047201A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • 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

Definitions

  • the present invention relates to a new medical use of certain cystine derivatives.
  • the invention relates to the use of such cystine derivatives for the preparation of medicaments with effect against diseases related to endothelial dysfunction.
  • cystine derivatives as to which the present invention has found a new pharmacological use are known from EP 532 595 and EP 463 514 to have immunomodulating activity and from WO 96/28149 to have effect against restenosis. None is reported or generally known concerning the pharmacological and/or therapeutic properties of these compounds with respect to effects on diseases related to endothelial dysfunction.
  • R is a straight or branched alkyl
  • R is hydrogen or a moiety which provides an ester hydrolysablc in body fluids to release the active compound in free acid form, or a physiologically acceptable salt and/or a stereochemical isomer thereof.
  • R is hydrogen or a moiety -CO-R wherein R is methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n- nonyl, n-decyl, n-undecyl, isopropyl, 1-methylpropyl, 2-methylpropyl, tert.
  • R is methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n- heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, isopropyl, 1-methylpropyl, 2-methylpropyl,
  • tert. butyl, 3-methylbutyl or 2-methylbutyl and R is hydrogen, methyl, ethyl, propyl, isopropyl, butyl or isobutyl, or a physiologically acceptable salt and/or a stereochemical isomer thereof, are preferred.
  • the compounds of formula I are used in racemic form as well as stereoisomers (enantiomers, diastereomers). Of particular interest are the compounds having the L configuration, particularly interesting is N-N'-diacetyl-L-cystine.
  • the invention also involves the compounds of formula I in the form of its physiologically acceptable salts, such as the salts of sodium, potassium, ammonium, calcium or magnesium. Also included are salts of the unesterified compounds with pharmaceutically acceptable organic bases, such as arginine, lysine, ethylenediamine, N,N'- dibenzylethylenediamine, adamantanamine, N-benzyl-2-phenylethylamine and piperazine.
  • physiologically acceptable salts such as the salts of sodium, potassium, ammonium, calcium or magnesium.
  • pharmaceutically acceptable organic bases such as arginine, lysine, ethylenediamine, N,N'- dibenzylethylenediamine, adamantanamine, N-benzyl-2-phenylethylamine and piperazine.
  • Lysine and arginine can be used in its D- or L- forms. Most preferred is the L-form.
  • the most preferred compound is di-L-lysinium-N,N'-diacetyl-L-cystinate (compound A).
  • the compounds of the general formula I may be prepared by any of the processes disclosed in EP 463 514. Salts of such compounds with organic bases are prepared according to any conventional method or any method disclosed in EP 621 862. Prior art
  • the vascular endothelium has a major role in controlling the tone of the vascular musculature, provide a non-thrombogenic surface to avoid the formation of blood clots in the undisturbed blood vessel, and exert control over growth processes in the vessel wall.
  • One of the most important mechanism by which the endothelium can exert its control processes is by synthesis and release of nitric oxide (NO).
  • NO nitric oxide
  • Coronary heart disease is a condition well known to be associated with loss of endothelium mediated relaxation. This disease is common in hypercholesterolemia. Upon reducing the plasma cholesterol concentration by lipid lowering drug therapy, an improvement of endothelial function can be obtained, and the addition of probucol to lipid lowering could further improve endothelial function (Anderson TJ. Meredith IT. Yeung AC. Frei B. Selwyn AP. Ganz P. The effect of cholesterol-lowering and antioxidant therapy on endothelium-dependent coronary vasomotion. New England Journal of Medicine. 332(8):488-93, 1995). There are, however, no treatments available that can restore endothelial function in coronary heart disease patients. The need for such treatment is obvious, not only for coronary heart disease patients, but also for other patients with endothelial dysfunction.
  • R is hydrogen, methyl, ethyl, n-propyl or a moiety -COR , wherein R is straight
  • R is a straight or branched alkyl
  • R is hydrogen or a moiety which provides an ester hydrolysable in body fluids to release the active compound in free acid form, or a physiologically acceptable salt and/or a stereochemical isomer thereof can improve endothelial dysfunction.
  • diseases are coronary heart disease, hyperlipidemia, hypertension, diabetes, insulin resistance, peripheral arterial disease, Raynaud's disease.
  • R is hydrogen or a moiety -CO-R wherein R is methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n- nonyl, n-decyl, n-undecyl, isopropyl, 1-methylpropyl, 2-methylpropyl, tert. butyl, 3-
  • R is methyl, ethyl, n-propyl, n-butyl, n-petnyl, n-hexyl, n- heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, isopropyl, 1-methylpropyl, 2-methylpropyl,
  • the compounds of the general formula I, their stereoisomers (enantiomers, diastereomers) and salts thereof may be used for the prophylaxis and/or treatment of endothelium dysfunction related diseases.
  • the invention includes the use of these compounds for the preparation of a medicament for prophylaxis and/or treatment of endothelium dysfunction related diseases.
  • the invention also includes a method for the prophylaxis and/or treatment of endothelial dysfunction using compounds of formula I.
  • Severe hypercholesterolemia is commonly used as an experimental model of endothelial dysfunction.
  • rabbits homozygous for a mutation in the LDL-receptor gene (WHHL rabbits) were used.
  • the mutation leads to the development of hypercholesterolemia and, subsequently, atherosclerosis.
  • segments of the aorta were removed for studies of endothelial function in vitro and for extent of atherosclerosis.
  • Endothelial function was studied in 2 mm wide rings of the aorta that were mounted in organ baths.
  • the vascular smooth muscle cells were contracted with either phenylephrine or 5-hydroxytryptamine.
  • Endothelial function was then assessed as the capacity of the endothelium to dilate the smooth muscle cells by the release of NO induced by the addition of either acetylcholine or by the calcium ionophore A23187.
  • These agents stimulate NO release from the endothelium through a receptor-mediated and a non-receptor-mediated mechanism, respectively.
  • the active compound was administered as a solution in the drinking water in doses corresponding to 3.0 ⁇ moles/kg/day for 3 weeks before the investigation of endothelial dysfunction.
  • the aortic rings were fixed in neutral buffered formaline, embedded in paraffin, and the amount of atherosclerotic lesions in each aortic ring was investigated microscopically.
  • the cross-section areas of the atherosclerotic lesions and of the musclular layer were obtained through morphometric procedures.
  • Table 1 summarizes the findings, and shows that the capacity of the endothelium stimulated with acetylcholin to reduce phenylephrine-induced smooth muscle cell tension was reduced in WHHL compared to aged matched controls, and that active treatment restored endothelial function in WHHL rabbits to an extent similar to that in non- atherosclerotic vessels. Similar results were obtained independently of the agent used to induce smooth muscle cell contraction, and NO release from the endothelium.
  • the described active substances for human use can be prepared in different dosage forms e.g. tablets, coated tablets, gelatin capsules, oral solutions, solutions for injection, and aerosols and dry powder for inhalation.
  • the active substances can be combined with pharmaceutically acceptable carriers or diluents, e.g. lactose, starch, dicalcium phosphate, microcrystalline cellulose, polyvinylpyrrolidone, gelatin, cellulose derivatives, colloidal silicone dioxide, talc and stearic acid or its salts.
  • pharmaceutically acceptable carriers or diluents e.g. lactose, starch, dicalcium phosphate, microcrystalline cellulose, polyvinylpyrrolidone, gelatin, cellulose derivatives, colloidal silicone dioxide, talc and stearic acid or its salts.
  • suitable excipients are water or solutions of saccharose, glucose, sorbitol, fructose or xylitol.
  • Solutions for parenteral administration may be prepared as a solution of a compound of the invention in a pharmaceutically acceptable solvent, preferably in a concentration from 0.1% to 10% by weight. These solutions may also contain stabilizing ingredients and/or buffering ingredients and are conveniently dispensed into unit doses in the form of ampoules or vials. Solutions for parenteral administration may also be prepared as a dry preparation to be reconstituted with a suitable solvent extemporaneously before use.
  • the substance can be inhaled from a pressurized metered dose inhaler, from a dry powder inhaler, e.g. a Turbuhaler® or from a dry powder inhaler utilizing gelatine, plastic or other capsules.
  • a dry powder inhaler e.g. a Turbuhaler®
  • Non-toxic and chemically inert substances e.g. lactose, trehalose, mannitol or glucose can be added to the powdered substance for inhalation therapy.
  • Pressurized aerosols are intended for oral or nasal inhalation.
  • the aerosol system is generally designed in such a way that each delivered dose contains 10-1000 ⁇ g, preferably 20-250 ⁇ g of the active compound.
  • the most active compounds are administered in the lower part of the dose range.
  • micronized compound are used and these consists of particles substantially smaller than 5 ⁇ m, which are suspended in a propellent mixture with the assistance of a dispersant, such as sorbitan trioleate, oleic acid, lecithin or sodium salt of dioctylsulphosuccinic acid.
  • the dosage forms can contain in addition to mentioned excipients preservatives, stabilizers, viscosity regulating agents, emulsifiers, sweetening agents, colouring agents, flavouring agents, tonicity regulating agents, buffers or antioxidants. They can also contain other therapeutically valuable substances.
  • the compounds of the formula I will normally be administered orally, rectally, by injection or inhalation, in the form of pharmaceutical preparations comprising the active ingredient either as the compound per se or as a pharmaceutically acceptable non-toxic, acid addition salt.
  • the dosage form may be a solid, semisolid or liquid preparation.
  • the active substance will constitute between 0.1 and 99 % by weight of the preparation, more usually between 0.5 and 20 % by weight for preparations for injection and between 0.2 and 50 % by weight for preparations for oral administration.
  • Effective amounts of the compounds of the formula I for use in the prophylaxis and treatment of endothelial dysfuncion are in the range 0.5 - 500 mg, preferably 1 - 100 mg for a daily dose.
  • Example 1 illustrate medicaments for prophylaxis or treatment of endothelial dysfunction.
  • the obtained tablets can be film coated with e.g. hydroxypropyl methylcellulose, hydroxypropyl cellulose or dimethylaminoethyl methacrylate methacrylic acid ester copolymer.
  • Each tablet contains:
  • a single dose of 10 mL contains 10 - 100 mg.
  • 1 mL in a single dose contains 1.0 - 10.0 mg

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  • Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Diabetes (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Epidemiology (AREA)
  • Hematology (AREA)
  • Endocrinology (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L'invention concerne une méthode de traitement et/ou de prévention de maladies liées à un dysfonctionnement de l'endothélium, à l'aide de certains dérivés de la cystine représentés par la formule générale (I). L'invention concerne également une préparation pharmaceutique comprenant ces dérivés.
PCT/SE2000/000238 1999-02-10 2000-02-07 Utilisation pharmacologique de certains derives de la cystine Ceased WO2000047201A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU29540/00A AU2954000A (en) 1999-02-10 2000-02-07 The pharmacological use of certain cystine derivatives

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
SE9900438-4 1999-02-10
SE9900438A SE9900438D0 (sv) 1999-02-10 1999-02-10 The pharmacological use of certian cystine derivatives

Publications (1)

Publication Number Publication Date
WO2000047201A1 true WO2000047201A1 (fr) 2000-08-17

Family

ID=20414412

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/SE2000/000238 Ceased WO2000047201A1 (fr) 1999-02-10 2000-02-07 Utilisation pharmacologique de certains derives de la cystine

Country Status (3)

Country Link
AU (1) AU2954000A (fr)
SE (1) SE9900438D0 (fr)
WO (1) WO2000047201A1 (fr)

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1991018594A1 (fr) * 1990-06-08 1991-12-12 Aktiebolaget Astra Utilisation pharmacologique de certains derives de cystine
EP0463514A1 (fr) * 1990-06-28 1992-01-02 Astra Aktiebolag 3.3'-Dithiobis (acides propioniques) et leurs esters
WO1993011104A1 (fr) * 1991-11-29 1993-06-10 Ab Astra Sels organiques de cystine de n, n'-diacetyle
WO1996028149A1 (fr) * 1995-03-14 1996-09-19 Astra Aktiebolag Utilisation pharmacologique de certains derives de la cystine
WO1997048679A1 (fr) * 1996-06-18 1997-12-24 Astra Aktiebolag (Publ) Nouvelles formes d'un sel organique de n'n-diacetylcystine

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1991018594A1 (fr) * 1990-06-08 1991-12-12 Aktiebolaget Astra Utilisation pharmacologique de certains derives de cystine
EP0463514A1 (fr) * 1990-06-28 1992-01-02 Astra Aktiebolag 3.3'-Dithiobis (acides propioniques) et leurs esters
WO1993011104A1 (fr) * 1991-11-29 1993-06-10 Ab Astra Sels organiques de cystine de n, n'-diacetyle
WO1996028149A1 (fr) * 1995-03-14 1996-09-19 Astra Aktiebolag Utilisation pharmacologique de certains derives de la cystine
WO1997048679A1 (fr) * 1996-06-18 1997-12-24 Astra Aktiebolag (Publ) Nouvelles formes d'un sel organique de n'n-diacetylcystine

Also Published As

Publication number Publication date
SE9900438D0 (sv) 1999-02-10
AU2954000A (en) 2000-08-29

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