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WO1997046229A1 - Nouvelle utilisation de derives de cystine - Google Patents

Nouvelle utilisation de derives de cystine Download PDF

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Publication number
WO1997046229A1
WO1997046229A1 PCT/SE1997/000990 SE9700990W WO9746229A1 WO 1997046229 A1 WO1997046229 A1 WO 1997046229A1 SE 9700990 W SE9700990 W SE 9700990W WO 9746229 A1 WO9746229 A1 WO 9746229A1
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WO
WIPO (PCT)
Prior art keywords
cystine
derivative
diacetylcystine
organic base
diacetyl
Prior art date
Application number
PCT/SE1997/000990
Other languages
English (en)
Inventor
Håkan BERGSTRAND
Jan Rollof
Original Assignee
Astra Aktiebolag
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 Astra Aktiebolag filed Critical Astra Aktiebolag
Priority to AU31141/97A priority Critical patent/AU3114197A/en
Publication of WO1997046229A1 publication Critical patent/WO1997046229A1/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]

Definitions

  • the present invention relates to the use of derivatives of cystine for the preparation of a medicament for the treatment of hepatitis B and/or C infections, and to a method for the treatment of chronic hepatitis B and/or C infections in mammals including man by administration of an effective dose of said derivatives.
  • hepatitis A, B, C, D, E and F types of viral hepatitis are known, namely hepatitis A, B, C, D, E and F.
  • Hepatitis B and C each have an acute phase which sometimes develops into a chronic phase, leading in a percentage of cases to cirrhosis of the liver and ultimately liver cancer.
  • Hepatitis B is caused by a DNA virus. Most of the patients suffering from hepatitis B will recover completely, but about 5% of the patients develop the chronic condition. Hepatitis B is transmitted parenterally or by intimate contact. The infection may be transmitted from mother to child, or through kissing, sharing of utensils (e.g. toothbrushes and razors), or by sexual contact. Blood transfusion continues to cause hepatitis B in countries where donor blood is not screened for hepatitis B surface antigen. Opportunities for transmission include the use of non-sterile instruments for dental treatment, ear piercing and manicures, neurological examination, prophylactic inoculations, subcutaneous injections, acupuncture and tattooing. The very young and the very old are at particular risk of developing the chronic condition, which is found predominantly in males.
  • Hepatitis C is caused by a small, enveloped RNA virus, and develops into a chronic phase in about a high proportion of patients.
  • the infection is acquired in various ways, for example as the result of an infected blood transfusion and intravenous drug abuse. However, for a substantial part of the infections the route of transmission is unknown. Perinatal spread is unusual. Chronic hepatitis C ranks as one of the most important causes of chronic liver disease, and may lead to cirrhosis and hepatocellular carcinoma.
  • Cystine derivatives are described for example in EP 0532595 and EP 0621862, in which they are indicated in the treatment of diseases where an anergy of the immune response or an aberrant immune response or an ineffective host defence can be expected; for example in the treatment of chronic bronchitis, certain forms of malignant diseases, and chronic infections.
  • cystine derivatives such as are described in EP 0532595 and EP 0621862 are indicated in the treatment of chronic hepatitis B and C infections.
  • the present invention provides the use of a derivative of cystine for the manufacture of a medicament for the treatment of chronic hepatitis B and/or C infections.
  • the said derivative of cystine is particularly selected from those disclosed in EP 532595 and, preferably, EP 621862.
  • the cystine derivative is preferably selected from N,N'-diacetylcystine (DiNAC), N,N'- dibutyrylcystine (DiBUT), N,N ' -diisovalerylcystine (DiVAL), N,N'-dicaprylylcystine (DiCAP), N,N'-diacetylcystine dimethyl ester (DiMeNAC), N,N'-diacetylcystine diethyl ester (DiEtNAC), N,N'-diisovalerylcystine dimethyl ester (DiMeVAL) and salts thereof.
  • N,N'-Diacetylcystine (DiNAC) is especially preferred.
  • cystine derivative is selected from N,N'-diacetylcystine and crystalline organic salts thereof, having the general formula
  • R and R individually represent the cation of the organic base lysine, ethylenediamine, N,N'-dibenzylethyIenediamine, adamantaneamine, N-benzyl-2- phenylethylamine, piperazine or ammonium.
  • Di-L-lysinium,N,N'diacetyl-L-cystinate is especially preferred.
  • the derivatives..of cystine may be used in their individual stereoisiomeric forms (D- and In ⁇ forms), and in mixtures of the stereoisomers.
  • the L-stereoisomers are preferred over the D- stereoisomers so mixtures of stereoisomers containing at least 50% of the particular L-form are preferred. Mixtures containing even higher proportions of the L-stereoisomer are more preferred, and the L-stereoisomer itself is most preferred.
  • Suitable compounds for the purpose of the present invention are hydrated and solvated forms of the salts.
  • a method for the treatment of chronic hepatitis B and/or C infections in mammals including man comprising administration to a host, in need of such treatment, of an effective amount of the above cystine derivative.
  • cystine derivatives of the present invention in the treatment of chronic hepatitis B and/or C is indicated in the Leishmania model, described elsewhere herein.
  • the compounds DiNAC, DiBUT, DiVAL and DiCAP may be prepared, for example, from L-cystine via acetylation (see US 4827016; EP 300100; US 4724239; US 4708965; DE 2326444; Marshall, R., Winitz, M., Birnbaum, S.M. and Greenstein, J.P., J. Am. Chem. Soc. 1957, 79, 4538-4544; and Cecil, R., McPhee, J.B., Biochem. J. 1957, 66, 538-543) or through oxidative dimerisation of the appropriate acylcysteines (see Snow, J.T., Finley, J.W., Friedman, M., Biochem. Biophys. Res. Commun. 1975, 64, 441-447).
  • the esters DiMeNAC, DiEtNAC and DiMeVAL may be synthesised analogously, i.e. by acylation of the cystine methyl or ethyl esters as appropriate or by oxidative dimerisation of the respective N-acetyl cystine methyl or ethyl esters or N-isovalerylcystine methyl ester.
  • preparations see Bonnett, R., Nicolaidow, P., J. Chem. Soc. Perkin Trans. I 1979, 1069-1077, Schaad, L.J., Werner, R.M., Dillon, L., Field, L., Tate, C.E., J. Med. Chem. 1969, 12, 950-953.
  • the organic salts of an organic base and N,N-diacetyl cystine (DiNAC) are generally prepared by ixing DiNAC and the organic base, as defined above, each dissolved or dispersed in solvent or solvent mixture.
  • Solvents such as water, alcohols, glycols, ketones, amides, sulphoxides or other polar solvents or solvent mixtures may be used.
  • the salt either precipitates directly from the reaction mixture, or is obtained by the addition of a less polar solvent or by evaporation or lyophihsation.
  • the reaction is performed at elevated temperature or room temperature, depending on the solubility in the medium.
  • the salt can be prepared by oxidation of the appropriate N-acetyl cysteine salt in aqueous or alcoholic solution, followed by precipitation as above.
  • the oxidation may be effected either chemically, using e.g. hydrogen peroxide or halogen, or electrochemically.
  • the cystine derivatives can be formulated for administration by inhalation, for example from a dry powder inhaler or from a pressurised metered dose inhaler (pMDI); alternatively, they can be formulated for oral, topical, or parenteral use.
  • the formulations may include a pharmaceutically acceptable carrier.
  • cystine derivatives of the present invention can be included in different dosage forms, e.g., dry powders, aerosols, tablets, coated tablets, gelatine capsules and solutions.
  • cystine derivatives of the present invention may be combined with for example a pharmaceutically acceptable diluent or carrier and provided in the form of inhalable particles.
  • cystine derivatives of the present invention may be dissolved or suspended in a suitable propellant optionally together with a co-solvent and/or one or more pharmaceutically acceptable surfactants or other excipients.
  • cystine derivatives can be combined with pharmaceutically acceptable materials, e.g. lactose, starch, dicalcium phosphate, microcrystalline cellulose, polyvinylpyrrolidone, gelatine, cellulose derivatives, colloidal silicone dioxide, talc and stearic acid or its salts.
  • pharmaceutically acceptable materials e.g. lactose, starch, dicalcium phosphate, microcrystalline cellulose, polyvinylpyrrolidone, gelatine, cellulose derivatives, colloidal silicone dioxide, talc and stearic acid or its salts.
  • excipients are water, saccharose, glucose, sorbitol, fructose and xylitol.
  • the dosage forms can besides mentioned excipients contain preservatives, stabilisers, viscosity regulating agents, emulsifiers, sweetening agents, colouring agents, flavouring agents, tonicity regulating agents, buffers or antioxidants. They can also contain other therapeutically valuable substances.
  • Fig. 1 shows the development of lesion diameter in CBA mice infected with Leishmania major and treated with 0.03 or 3 ⁇ mol/kg di-L-lysinium-N,N'-diacetyl-L-cystinate.
  • the data are from the initial experiment (frame A) and from the follow-up experiment (frame B).
  • Fig. 2 shows the development of lesion diameter in BALB/c mice infected with Leishmania major and treated with 0.03 or 3 ⁇ mol/kg di-L-lysinium-N,N'-diacetyl-L- cystinate.
  • the data are from the initial experiment (frame A) and from the follow-up experiment (frame B), where treatment was performed with 0.03 ⁇ mol/kg di-L-lysinium- N,N'-diacetyl-L-cystinate.
  • Leishmania model may be correlated with utility in the treatment of chronic hepatitis B and or C.
  • mice Female BALB/c and CBA mice of 6-10 weeks of age were used. The mice were held under P2 biohazard barrier conditions for the duration of the experiments. Each experimental group consisted of five animals.
  • mice were challenged by injection in their shaven rumps with 5x10 4 L.major metacyclic promastigotes, selected by lectin agglutination of the developmentally-regulated alterations in the structure of lipophosphoglycan (d.L. Sacks, T.N. Brodin and SJ. Turco, 1990, Developmental modification of the lipophosphoglycan from Leishmania major promastigotes during metacyclogenesis, Mol. Biochem. Parasitol. 42:225).
  • the progression of lesions was assayed by measuring the diameter of the lesion in two directions and the average diameter was recorded for each mouse.
  • the figures show means and standard deviations.
  • mice were given di-L-lysinium-N,N'-diacetyl-L-cystinate ("Compound A") dissolved in autoclaved drinking water replenished daily from frozen 1000X aliquots.
  • the drug concentrations were calculated to provide daily doses of 0.03 ⁇ mol/kg and 3.00 ⁇ mol/kg respectively, based on the assumption that the mice were drinking 3 ml daily.
  • L. major induces a progressive disease in BALB/c mice that has been shown to correlate with an unbalanced TH2 type cellular immune response.
  • L. major causes a self- healing disease in CBA mice reminiscent of the course of this disease in humans.
  • the curative response has been shown to be due to an increased expansion of THl type response.

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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)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

L'invention concerne l'utilisation d'un dérivé de cystine, ou de sels physiologiquement acceptables de celui-ci, dans la préparation d'un médicament destiné au traitement d'infections chroniques du type hépatite B et/ou C.
PCT/SE1997/000990 1996-06-06 1997-06-05 Nouvelle utilisation de derives de cystine WO1997046229A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU31141/97A AU3114197A (en) 1996-06-06 1997-06-05 New use of derivatives of cystine

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
SE9602262A SE9602262D0 (sv) 1996-06-06 1996-06-06 New use of derivatives of cystine
SE9602262-9 1996-06-06

Publications (1)

Publication Number Publication Date
WO1997046229A1 true WO1997046229A1 (fr) 1997-12-11

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ID=20402927

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/SE1997/000990 WO1997046229A1 (fr) 1996-06-06 1997-06-05 Nouvelle utilisation de derives de cystine

Country Status (6)

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AR (1) AR007294A1 (fr)
AU (1) AU3114197A (fr)
ID (1) ID17383A (fr)
SE (1) SE9602262D0 (fr)
WO (1) WO1997046229A1 (fr)
ZA (1) ZA974679B (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001056561A1 (fr) * 2000-02-02 2001-08-09 Ajinomoto Co., Inc. Agents preventifs diriges contre l'infection virale
WO2009100431A1 (fr) * 2008-02-07 2009-08-13 Marquette University Pro-médicaments de cystéine et de cystine pour traiter la schizophrénie et réduire les addictions aux médicaments
US7829709B1 (en) 2007-08-10 2010-11-09 Marquette University Cysteine prodrugs to treat schizophrenia and drug addiction
JP6814312B1 (ja) * 2020-02-05 2021-01-13 株式会社タイショーテクノス 抗ウイルス剤及び物品に抗ウイルス性を付与する方法

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0051682A1 (fr) * 1980-05-13 1982-05-19 Mitsubishi Kasei Corporation Derives de la cysteine et procede pour leur preparation
WO1991018594A1 (fr) * 1990-06-08 1991-12-12 Aktiebolaget Astra Utilisation pharmacologique de certains derives de cystine
WO1993011104A1 (fr) * 1991-11-29 1993-06-10 Ab Astra Sels organiques de cystine de n, n'-diacetyle

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0051682A1 (fr) * 1980-05-13 1982-05-19 Mitsubishi Kasei Corporation Derives de la cysteine et procede pour leur preparation
WO1991018594A1 (fr) * 1990-06-08 1991-12-12 Aktiebolaget Astra Utilisation pharmacologique de certains derives de cystine
WO1993011104A1 (fr) * 1991-11-29 1993-06-10 Ab Astra Sels organiques de cystine de n, n'-diacetyle

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
PATENT ABSTRACTS OF JAPAN, Vol. 6, No. 3, C-86; & JP,A,56 127 312 (KATSUJI NAGAI), 6 October 1981. *
PEDIATRIC RESEARCH/AN INTERNATIONAL JOURNAL OF CLINICAL, LABORATORY AND DEVELOPMENTAL INVESTIGATION, BALTIMORE Md WILLIAMS, Editor, Volume 13 (4 Part 2), No. 484, 1979, ROBERT G. PETERSON et al., "N,N'Diacetylcystine (DAC) a New Antagonist of Acetaminophen (APAP) Hepatic Toxicity in Mice", page 406. *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001056561A1 (fr) * 2000-02-02 2001-08-09 Ajinomoto Co., Inc. Agents preventifs diriges contre l'infection virale
US7829709B1 (en) 2007-08-10 2010-11-09 Marquette University Cysteine prodrugs to treat schizophrenia and drug addiction
US8435997B2 (en) 2007-08-10 2013-05-07 Marquette University Cysteine prodrugs to treat schizophrenia and drug addiction
WO2009100431A1 (fr) * 2008-02-07 2009-08-13 Marquette University Pro-médicaments de cystéine et de cystine pour traiter la schizophrénie et réduire les addictions aux médicaments
US8173809B2 (en) 2008-02-07 2012-05-08 Marquette University Cysteine and cystine prodrugs to treat schizophrenia and reduce drug cravings
JP6814312B1 (ja) * 2020-02-05 2021-01-13 株式会社タイショーテクノス 抗ウイルス剤及び物品に抗ウイルス性を付与する方法

Also Published As

Publication number Publication date
ID17383A (id) 1997-12-24
AU3114197A (en) 1998-01-05
AR007294A1 (es) 1999-10-27
SE9602262D0 (sv) 1996-06-06
ZA974679B (en) 1997-12-08

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