WO1997046229A1 - New use of derivatives of cystine - Google Patents
New use of derivatives of cystine Download PDFInfo
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- 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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- cystine
- derivative
- diacetylcystine
- organic base
- diacetyl
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- 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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Abstract
The use of a derivative of cystine, or physiologically acceptable salts thereof, for the preparation of a medicament for the treatment of chronic hepatitis B and/or C infections.
Description
NEW USE OF DERIVATIVES OF CYSTINE
Field of the Invention 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.
Background of the Invention
At present 6 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.
Currently, the only treatment of chronic hepatitis B and C infections of proven benefit is α- interferon. Influenza-like symptoms, which appear after administration, and an increased risk of auto-immune diseases are associated with such treatment. As administration is by injection and frequent administration is required, it is desirable that the patients inject themselves, which many patients find very unpleasant. The treatment is expensive.
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.
We have now found that cystine derivatives such as are described in EP 0532595 and EP 0621862 are indicated in the treatment of chronic hepatitis B and C infections.
Disclosure of the Invention Accordingly, 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.
Most preferably, the cystine derivative is selected from N,N'-diacetylcystine and crystalline organic salts thereof, having the general formula
or
.2+ wherein 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.
Also included in the scope of suitable compounds for the purpose of the present invention are hydrated and solvated forms of the salts.
In another aspect of the invention there is provided 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.
The utility of the 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.
Methods of preparation
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. For examples of 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. Alternatively, 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. For specific examples of the preparation of salts included in the present invention, reference may be made to EP 621862.
Pharmaceutical formulations
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.
The 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.
For the preparation of a formulation for inhalation from a dry powder inhaler, the 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.
For the preparation of a formulation for inhalation from a pMDI the 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.
For the preparation of tablets, coated tablets and gelatine capsules the 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.
For the preparation of oral solutions suitable 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.
The invention will now be described in more detail with reference to the accompanying drawings and the following experimental part.
In the drawings:
Fig. 1 shows the development of lesion diameter in CBA mice infected with Leishmania major and treated with 0.03 or 3 μmol/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 μmol/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 μmol/kg di-L-lysinium- N,N'-diacetyl-L-cystinate.
Experiment
There is no reliable animal model for indicating effect against chronic hepatitis B and/or C infection. However, the Leishmania model, when used in CBA and BALB/c mice is thought to reflect THl- and TH2 -types of immunity, respectively, and a strengthening of the THl -type response is thought to be desirable for the treatment of chronic hepatitis B and/or C. For these reasons, an indication of increased THl -type response in the
Leishmania model may be correlated with utility in the treatment of chronic hepatitis B and or C.
Materials and Methods
In the study, 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.
Challenge with Leishmania was conducted and monitored as described by Connell et al (N. Connell, E. Medina- Acosta, W. McMaster, B. Bloom and D. Russell, 1993, Effective immunisation against cutaneous leishmaniasis with recombinant bacilli Calmette-Guerin expressing the Leishmania surface proteinase p63, Proc. Natl. Acad. Sci. USA, 90:1 1473). L. major (Friedlin strain, clone VI) was maintained in SDM79 medium. Parasites were replenished from frozen isolates transformed from amastigotes isolated from infected mice to ensure infectivity. The mice were challenged by injection in their shaven rumps with 5x104 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.
The 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 μmol/kg and 3.00 μmol/kg respectively, based on the assumption that the mice were drinking 3 ml daily.
Results
L. major induces a progressive disease in BALB/c mice that has been shown to correlate with an unbalanced TH2 type cellular immune response. In contrast, 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.
In both the preliminary and follow-up experiments on CBA mice, the lesions developed and resolved with time (Figs 1 A and IB). In mice treated with di-L-lysinium-N,N'-diace- tyl-L-cystinate prior to and throughout the course of infection, there was an extremely rapid development of the curative response.
In BALB/c mice in the preliminary (Fig. 2A) and follow-up (Fig. 2B) experiments, the groups that had been treated with the drug showed a constantly lower lesion development (more marked and consistent effect in the follow-up experiment) although the disease progression was observed in both treated and untreated groups.
Conclusion The results indicate that treatment with di-L-lysinium-N,N'-diacetyl-L-cystinate induced an improvement of the host defence, resulting in a clear acceleration of the curative response due to an increased expansion of THl type response.
Claims
1. Use of a derivative of cystine, or a physiologically acceptable salt thereof, in its individual stereoisomeric forms, or in a mixture of steroisomers, for the preparation of a medicament for the treatment of chronic hepatitis B and/or C infections.
2. Use according to claim 1, wherein the derivative of cystine is chosen from the group consisting essentially of N,N'-diacetylcystine, N,N'-dibutyrylcystine, N,N'-diiso- valerylcystine, N,N'-dicaprylylcystine, N,N'-diacetylcystine dimethyl ester, N,N'- diacetylcystine diethyl ester and N,N'-diisovalerylcystine dimethyl ester.
3. Use according to claim 1, wherein the derivative of cystine is N,N'-diacetylcystine.
4. Use according to claim 1, wherein the derivative of cystine is a salt of an organic base and N,N'-diacetyl cystine, having the general formula
or
wherein R""" and 
i•s the cation of the organic base lysine, ethylenediamine, N,N'- dibenzylethylenediamme, adamantanamine, N-benzyl-2-phenylethylamine, piperazine or ammonium.
5. Use according to claim 1, wherein the derivative of cystine is a salt of an organic base and N,N'-diacetyl cystine, having the general formula
or
wherein R and R is the cation of the organic base lysine, ethylenediamine, N,N'- dibenzylethylenediamine, adamantanamine, N-benzyl-2-phenylethylamine or piperazine.
6. Use according to any one of claims 1-5, wherein the derivative of cystine is in the form of a mixture of D- and L-stereoisomers containing at least 50% of the L-stereoisomer.
7. Use according to any one of claims 1-5, wherein the derivative of cystine consists of the L-stereoisomer.
8. Use according to any of claims 4-7, wherein the derivative of cystine is di-L-lysinium- N,N'-diacetyl-L-cystinate.
9. A method for the treatment of chronic hepatitis B and/or C infections in mammals including man, characterised by administration to a host, in need of such treatment, of an effective amount of a derivative of cystine or a physiologically acceptable salt thereof, in its individual stereoisomeric forms, or in a mixture of steroisomers.
10. A method according to claim 9, wherein the derivative of cystine is chosen from the group consisting of N,N'-diacetylcystine, N,N '-dibutyrylcystine, N,N'-diisovalerylcystine, N,N'-dicapryIylcystine, N,N'-diacetylcystine dimethyl ester, N,N'-diacetylcystine diethyl ester, N,N'-diisovaleryicystine dimethyl ester.
11. A method according to claim 10, wherein the derivative of cystine is N,N'- diacetylcystine.
12. A method according to claim 9, wherein the derivative of cystine is a salt of an organic base and N,N'-diacetyl cystine, having the general formula
or
wherein R+ and-R + is the cation of the organic base lysine, ethylenediamine, N,N'- dibenzylethylenediamine, adamantanamine, N-benzyl-2-phenylethylamine, piperazine or ammonium.
13. A method according to claim 9, wherein the derivative of cystine is a salt of an organic base and N,N'-diacetyl cystine, having the general formula 
or
wherein R and R is the cation of the organic base lysine, ethylenediamine, N,N'- dibenzylethylenediamine, adamantanamine, N-benzyl-2-phenylethylamine or piperazine.
14. A method according to any one of claims 9-13, wherein the derivative of cystine is in the form of a mixture of D- and L-stereoisomers containing at least 50% of the L- stereoisomer.
15. A method according to any one of claims 9-13, wherein the derivative of cystine consists of the L-stereoisomer.
16. A method according to any one of claims 12-15, wherein the derivative of cystine is di- L-lysinium-N,N'-diacetyl-L-cystinate.
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 |
|---|---|---|---|
| SE9602262-9 | 1996-06-06 | ||
| SE9602262A SE9602262D0 (en) | 1996-06-06 | 1996-06-06 | New use of cystine derivatives |
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| Publication Number | Publication Date |
|---|---|
| WO1997046229A1 true WO1997046229A1 (en) | 1997-12-11 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/SE1997/000990 Ceased WO1997046229A1 (en) | 1996-06-06 | 1997-06-05 | New use of derivatives of cystine |
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|---|---|
| AR (1) | AR007294A1 (en) |
| AU (1) | AU3114197A (en) |
| ID (1) | ID17383A (en) |
| SE (1) | SE9602262D0 (en) |
| WO (1) | WO1997046229A1 (en) |
| ZA (1) | ZA974679B (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001056561A1 (en) * | 2000-02-02 | 2001-08-09 | Ajinomoto Co., Inc. | Preventives for viral infection |
| WO2009100431A1 (en) * | 2008-02-07 | 2009-08-13 | Marquette University | Cysteine and cystine prodrugs to treat schizophrenia and reduce drug cravings |
| US7829709B1 (en) | 2007-08-10 | 2010-11-09 | Marquette University | Cysteine prodrugs to treat schizophrenia and drug addiction |
| JP6814312B1 (en) * | 2020-02-05 | 2021-01-13 | 株式会社タイショーテクノス | How to impart antiviral properties to antiviral agents and articles |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0051682A1 (en) * | 1980-05-13 | 1982-05-19 | Mitsubishi Kasei Corporation | Cysteine derivatives and process for their preparation |
| WO1991018594A1 (en) * | 1990-06-08 | 1991-12-12 | Aktiebolaget Astra | The pharmacological use of certain cystine derivatives |
| WO1993011104A1 (en) * | 1991-11-29 | 1993-06-10 | Ab Astra | Organic salts of n, n'-diacetyl cystine |
-
1996
- 1996-06-06 SE SE9602262A patent/SE9602262D0/en unknown
-
1997
- 1997-05-26 AR ARP970102236A patent/AR007294A1/en unknown
- 1997-05-28 ZA ZA9704679A patent/ZA974679B/en unknown
- 1997-06-02 ID IDP971863A patent/ID17383A/en unknown
- 1997-06-05 AU AU31141/97A patent/AU3114197A/en not_active Abandoned
- 1997-06-05 WO PCT/SE1997/000990 patent/WO1997046229A1/en not_active Ceased
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0051682A1 (en) * | 1980-05-13 | 1982-05-19 | Mitsubishi Kasei Corporation | Cysteine derivatives and process for their preparation |
| WO1991018594A1 (en) * | 1990-06-08 | 1991-12-12 | Aktiebolaget Astra | The pharmacological use of certain cystine derivatives |
| WO1993011104A1 (en) * | 1991-11-29 | 1993-06-10 | Ab Astra | Organic salts of n, n'-diacetyl cystine |
Non-Patent Citations (2)
| 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 (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001056561A1 (en) * | 2000-02-02 | 2001-08-09 | Ajinomoto Co., Inc. | Preventives for viral infection |
| 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 (en) * | 2008-02-07 | 2009-08-13 | Marquette University | Cysteine and cystine prodrugs to treat schizophrenia and reduce drug cravings |
| US8173809B2 (en) | 2008-02-07 | 2012-05-08 | Marquette University | Cysteine and cystine prodrugs to treat schizophrenia and reduce drug cravings |
| JP6814312B1 (en) * | 2020-02-05 | 2021-01-13 | 株式会社タイショーテクノス | How to impart antiviral properties to antiviral agents and articles |
| JP2021123556A (en) * | 2020-02-05 | 2021-08-30 | 株式会社タイショーテクノス | Antiviral agent and method of imparting antiviral property to article |
Also Published As
| Publication number | Publication date |
|---|---|
| AU3114197A (en) | 1998-01-05 |
| AR007294A1 (en) | 1999-10-27 |
| SE9602262D0 (en) | 1996-06-06 |
| ZA974679B (en) | 1997-12-08 |
| ID17383A (en) | 1997-12-24 |
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