NZ238306A

NZ238306A - Pharmaceutical compositions containing certain cystine derivatives.

Info

Publication number: NZ238306A
Application number: NZ23830691A
Authority: NZ
Inventors: Carl-Magnus Alexande Andersson; Sten Haken Axel Bergstrand; Anders Rudolf Hallberg
Original assignee: Astra Ab
Priority date: 1990-06-28
Filing date: 1991-05-29
Publication date: 1994-02-25
Also published as: DZ1511A1; SE9002275D0

Description

<div class="application article clearfix" id="description"> New Zealand Paient Spedficaiion for Paient Number £38306 m 23 8 3 0 5 Priority Dates;;)'. . ?rf>r%>;T\S>... Corriplats Specification Filed: .T-r*?: K'fii Class: Pte) *w\w£, 2*. ' 5 f £'S" 1994 Publication Date: ..... .\.... .7.7, P.O., Journal, No: ..... HA f\ ?■ \ •>? * : ..'1 *1 NEW ZEALAND PATENTS ACT 1953 COMPLETE SPECIFICATION N-Z. PATfiWT QFM^r 29 MAY 1991 ftECErv*:*) "THE PHARMACOLOGICAL USE OF CERTAIN CYSTINE DERIVATIVES" We, AKTIEBOLAGET ASTRA, a Swedish Company, of S-151 85 Sodertalje, Sweden, hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statements: ,1 (followed by 1A) v. - 1A Field of the Invention The present invention provides a method for the preparation of a pharmaceutical composition containing a medicament with immunomodulating action, which comprises formulating at least one compound selected from racemic N,N'-diacetylcystine, N, N1 -dibutyrylcystine, N, N' -diisovalerylcystine, N,N'-dicaprylylcystine, N,N'-diacetylcystine dimethyl ester, N,N1-diacetylcystine diethyl ester, N,N'-diisovalerylcystine dimethyl ester, the D or L optical isomers, or a 10 physiologically acceptable salt thereof, into unit dosage form with a pharmaceutically acceptable .carrier to deliver said at least one compound to a patient in an amount in the range of 0.5-500 mg daily dose, suitable for effecting immunomodulating action, particularly immunostimulating 15 action. Background of the Invention N-Acetyl-L-cysteine is a compound widely used for treating chronic obstructive airway diseases/chronic bronchitis (for further references see Multicentre Study Group. 20 Long-term oral acetylcysteine in chronic bronchitis. A double-blind controlled, study. Eur. J. Respir. Dis. 1980, 61 (suppl. Ill), 93-108; Boman, G., Backer, U., Larsson, S., Melander, B., and Wahlander, L. Oral acetylcysteine reduces exacerbation rate in chronic bronchitis. Report of 25 a trial organized by the Swedish Society for Pulmonary Disease. Eur. J. Respir. Dis. 1983, 64, 405-415; and British Thoracic Society Research Committee. Oral N-acetylcysteine and exacerbation rates in patients with •^ chronic bronchitis and severe airway obstruction. Thorax'. 30 1985, 40, 832-835). The mechanism of action of the ^2® compound is not disclosed; its effect has been attribute^v^ . to mucolytic properties (see Multicentre Study Group. £ t; V..-—" 2 238306 Long-term oral acetylcysteine in chronic bronchitis. A double-blind controlled study. Eur. J. Respir. Dis. 1980, 61 (suppl. Ill), 93-108; Boman, G., Backer, U., Larsson, S., Melander, B., and Wahlander, L. Oral acetylcysteine 5 reduces exacerbation rate in chronic bronchitis. Report of a trial organized by the Swedish Society for Pulmonary Disease. Eur. J. Respir. Dis. 1983, 64, 405-415; and British Thoracic Society Research Committee. Oral N-acetylcysteine and exacerbation rates in patients with 10 chronic bronchitis and severe airway obstruction. Thorax 1985, 40, 832-835), antioxidant properties (see Aruoma, . O.I., Halliwell, B., Hoey, B.M., and Butler, J. Free Radical Biol. Med. 1989, 6, 593-597), and also immunomodulating properties (see Bergstrand, H., Bjornson, 15 A., Eklund, A., Hernbrand, R., Eklund, A., Larsson, K., Linden M., and Nilsson, A. Stimuli-induced superoxide radical generation in vitro by human alveolar macrophages from smokers: Modulation by N-Acetylcysteine treatment in vivo. J. Free Radicals Biol. & Med. 2, 1986, 119-127). 20 The present invention deals with the disulfide of N-acetylcysteine, that is N,N'-diacetylcystine (in the following referred to as DiNAC), i.e. the compound of the formula: 25 COOH I s-ch2-ch-nh-coch3 I 30 s-ch2-ch-nh-coch3 I COOH N,N' - dibutyrylcystine (in the following referred to as diBUT), i.e. the compound of the formula: 35 3 238306 COOH I S-CH2-CH-NH-COCH2CH2CH3 S-CH2-CH-NH-COCH2CH2CH3 I COOH N,N'-diisovalerylcystine (in the following reffered to as 10 diVAL), i.e. the compound of the formula COOH CH3 I s-ch2- 15 S-CH2-CH-NH-COCH2CHCH3 S-CH2-CH-NH-COCH2CHCH3 1 I COOH CH~ 20 N,N'-dicaprylylcystine (in the following referred to as diCAP), i.e. the compound of the formula COOH I 25 S-CH2-CH-NH-CO-(CH2)6CH3 I S-CH2-CH-NH-CO-(CH2)6CH3 I COOH 30 N,N'-diacetylcystine dimethyl ester (in the following referred to as diMeNAC), i.e. the compound of the formula: 10 15 COOCH3 I s-ch2-ch-nh-coch3 s-ch2-ch-nh-coch3 I coocha N,N'-diacetylcystine diethyl ester (in the following referred to as diEtNAC), i.e. the compound of the formula: cooc2h5 s-ch2-ch-nh-coch3 I s-ch2-ch-nh-coch3 cooc2h. and N,N'-diisovalerylcystine dimethyl ester (in the following referred to as diMeVAL), i.e. the compound of 20 the formula: COOCH3 CH3 I 1 S-CH2-CH-NH-COCH2-CHCH3 I 25 S-CH2-CH-NH-COCH2-CHCH3 I I COOCHa CHa The invention deals with the above mentioned compounds in 30 racemic form as well as the isomeric D and L forms of the compounds, of particular interest are the compounds having the L configuration, particularly interesting is N,N'-diacetyl-L-cystine. 35 The invention also deals with the compounds in the form of their physiologically acceptable salts such as the salts 23 8 5 of sodium, potassium, ammonium, calcium or magnesium. Also included are salts of the compounds diNAC, diBUT, diVAL and diCAP with pharmaceutically acceptable organic bases. 5 The above mentioned compounds have previously been described in the patent literature as well as in the scientific literature. DiNAC in the following publications: US 4827016; EP 300100; US 4724239; US 10 4708965; DE 2326444; Wilson, I.D., and Nicholson, J.K. i Analysis of thiols and disulfides in Sulphur-containing1 drugs and related organic compounds. Chemistry, Biochemistry an Toxicology (ed L.A. Damani) Vol. 2A. Analytical, biochemical and toxicological aspects of 15 sulphur xenobiochemistry. Ellis Horwood Series in Biochemical Pharmacology (Halstred Press: a division of John Wiley & Sons) Chichester 1989, p. 45; and Sjodin K., Nilsson E., Hallberg, A., and Tunek, A. Metabolism of N-Acetyl-L-cysteine. Some structural reguirements for the 20 deacetylation and consequences for the oral biovailability. Biochem. Pharmacol. 1989, 38, 3981-3985). In US 4827016 the compound is claimed to be effective for topical treatment of dermal inflammations which are induced and propagated by leukotrienes. The remaining compounds have also been described in the literature. (See for instance, for diMeNAC: Bowman, W.R. Richardson, G.D. Tetrahedron Lett. 1981, 22, 1551-1554; for diEtNAC: Damico, R.A. Boggs, R.W. US 3952115 (1976); 30 for diVAL, diMeVAL: Martin, T.A. J. Med. Chem 1969, 12, 950-953), for diCAP: FR 8205 M (a copy of which is available on request), for diBUT: FR 2503151). Nothing is reported or generally known concerning the pharmacological and/or therapeutic properties of these 35 compounds with respect to immunological systems or inflammatory diseases of the lung such as chronic bronchitis. 25 25 ^ 7 A 0 y - rj 1 ni .^closure of the Invention It has unexpectedly been found that the hereinbefore mentioned compounds diNAC, diBUT, diVAL, diCAP, diMeNAC, diEtNAC and diMeVAL in an experimental animal model for assessing a T-cell reactivity in vivo, i.e. the delayed type hypersensitivity (DTH) reaction in the mouse ear, are highly potent and efficient immunostimulating agents, some being in the order of 100-1000 times more effective than the .thiol NAC. Thus, in this model the compounds are highly effective immunostimulators with a potency and efficacy superior or equal to known immunostimulants such as diethyl dithiocarbamate (DTC) or hydroxyethyl disulfide (HEDS; see St Georgiev, V. New synthetic immunomodulating agents. Trends in Pharmacological Science 1988, 446-451). Therefore, the compounds DiNAC, diBUT, diVAL, diCAP, diMeNAC, diEtNAC, diMeVAL and their D and L optical isomers may be used for treatment of diseases where a defect in the immune system and/or an ineffective host defence is at hand or can be suspected. Examples of such diseases are chronic bronchitis and other inflammatory diseases of the airways such as asthma and rhinitis but also certain forms of autoimmune diseases like diabetes and rheumatoid arthritis and/or various malignant diseases. HIV infection or AIDS may be treated with the compounds. Also atherosclerotic disease may be treated with the compounds. Effective amounts of the compounds diNAC, diBUT, diVAL, diCAP, diMeNAC, diEtNAC, diMeVAL and their D and L optical isomers for use in the treatment of the above mentioned diseases are in the range. 0.5-500 mg, preferably 5-50 mg, daily dose. Synthesis of compounds The compounds diNAC, diBUT, diVAL and diCAP may be prepared, for example, from L-cystine via acylation (see US 4827016; EP 300100; US 4724239; US 4708965; DE 2326444; 5 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, 665, 538-543) or through oxidative dimerization of the appropriate acylcysteines (see Snow, J.T., Finley, J.W. Friedman, M. Biochem. 10 Biophys. Res. Commun. 1975, 64, 441-447). The esters diMeNAC, diEtNAC and diMeVAL may be synthesized 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 15 or N-isovalerylcysteine 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. 1975, 18, 344-351, and Martin, T.A. J. Med. Chem. 20 1969, 12, 950-953. Effects of compounds in a model of delayed type hypersensitivity in the mouse The property of the compounds diNAC, diBUT, diVAL, diCAP, diMeNAC, diEtNAC and diMeVAL to stimulate immune responses 25 is illustrated by their efficacy in a model of the delayed type hypersensitivity (DTH) reaction in the mouse. 8 23 8 3 Both male and female Balb/c mice obtained from Bomholtsgaard (Denmark) and Charlie Rivers (England), were used at the weight of 18-20 gram. 4-ethoxymethylene-2-phenyloxazolone (OXA) was purchased from BDH (England) and served as an antigen in this test. The mice were sensitized, Day 0, by epicutaneous application of 150 y.1 absolute ethanol-acetone (3:1) solution containing 3% OXA on the shaved thorax and abdomen. Treatment with the L-form of diNAC, diMeNAC, diEtNAC, diMeVAL, or vehicle (phosphate buffer, pH 7.0) was initiated by oral feeding immediately after sensitization and continued once daily to Day 6. Seven days (Day 6) after the sensitization both ears of all mice were challenged on both sides by topical application of 20 y.1 1% OXA dissolved in peanut oil. Ear thickness was measured prior to and 24 or 48 hours after challenge using an Oditest spring calliper. Challenges and measurements were performed under light pentobarbital anasthesia. The intensity of the DTH reactions was expressed according to the formula: Tt24/4S-Tt0 um units, where to, t24 and t48 represent the ear thickness before and 24 or 48 hours after challenge, respectively, in an individual test (T) . The results were expressed as the mean +/-S.E.M. The level of significance between means of the groups was obtained by Student's two-tailed t-test. Tables 1 and 2 show the results from 24 and 48 hours measurements, respectively, from a representative experiment with the L-form of diNAC. The results show that L-diNAC, after oral administration, caused a significant increase of the ear thickness in a concentration-response manner. 2 O U 0 0;\ Table 1 Ear thickness 24 hours after challenge of animals treated with the indicated doses of L-diNAC or vehicle. 5 Cone, yjnol/kg N Diff. T-fc2.4~T.fcO S.E.M. Sign. Buffer 13 7.85 0.32 NaCl 10 7.90 0.30 n.s. 0.03 10 13.75 0.47 *** 0.30 10 15.70 0.48 *** 3.0 10 18.30 1.02 *** 30.0 15 20.67 0.67 *** 20 ***: p < 0.001 10 Table 2 5 Ear thickness 48 hours after challenge of animals treated with the indicated doses of L-diNAC or vehicle. Cone. Uitiol/kg N Diff T-t.4a~T.to S.E.M. Sign Buffer 14 9.64 0.35 NaCl 10 9.85 0.54 n.s. 0.03 10 11.65 0.27 *** 0.30 10 12.65 0.48 *** 3.0 10 14.95 0.55 *** 30.0 15 13.63 0.30 *** 20 ***: p < 0.001 25 Table 3 gives the correponding figures for ear thickness 24 and 48 hours after challenge of animals treated with diMeNAC and diEtNAC. 238306 11 Table 3 5 Ear thickness 24 and 48 hours after challenge of animals treated with the L-forms of diMeNAC and diEtNAC. 10 Cone N Diff S.E.M. Sign. umol/kg Tt24-Tto 24 h 15 Buffer 10 8.70 0.34 diMeNAC 0.03 10 18.00 0.84 *** 3.0 10 12.55 0.88 ** 20 diEtNAC 0.03 10 11.75 0.62 *** 3.0 10 13.05 0.59 *** 25 (to continue...) 12 f) ,fj y ^ ^ 0 0 U y ) ( ...table 3) 15 Cone N ymol/kg Diff Tt48"T-tO S.E.M. Sign. 48 h 10 diMeNAC 0.03 3.0 10 10 12.85 13.35 0.67 0.67 ** *** diEtNAC 0.03 3.0 10 10 13.15 13.20 0.53 0.66 *** *** **: p < 0.01 20 ***: p < 0.001 J J 13 Pharmaceutical formulations The described active substances can be included in 5 different dosage forms e.g. tablets, coated tablets, gelatin capsules, solutions and aerosols. For the preparation of tablets, coated tablets and gelatin capsules the active substances can be combined with 10 pharmaceutically acceptable materials, e.g. lactose, starch, dicalcium phosphate, microcrystalline cellulose, polyvinylpyrrolidone, gelatin, cellulose derivatives, colloidal silicone dioxide, talc and stearic acid or its salts. 15 For the preparation of oral solutions suitable excipients are water, saccharose, glucose, sorbitol, fructose and xylitol. 20 The dosage forms can besides mentioned excipients contain preservatives, stabilizers, viscosity regulating agents, emulsifiers, sweetening agents, colouring agents, flavouring agents, tonicity regulating agents, buffers or antioxidants. They can also contain other therapeutically 25 valuable substances. 14 238306 Example 1 Tablet containing 10 mg of active substance per tablet: 5 Active substance 10 mg Lactose 100 mg Potato starch 50 mg Polyvinylpyrrolidone 5 mg Microcrystalline cellulose 15 mg Magnesium stearate 1 mg Example 2 15 Direct compression tablet containing 5 mg of active substance per tablet: Active substance 5 mg Lactose, anhydrous 150 mg Microcrystalline cellulose 50 mg Colloidal silicon dioxide 1 mg Magnesium stearate 2 mg If desired, the obtained tablets can be film coated with 25 e.g. hydroxypropyl methylcellulose, hydroxypropyl cellulose or dimethylaminoethyl methacrylate methacrylic acid ester copolymer. Example 3 30 Solution for injection containing active substance 1 mg/ml 35 Active substance Sodium chloride Water for injection 1.0 mg 8.8 mg to 1 ml </div>

Claims

<div class="application article clearfix printTableText" id="claims"> If9*';I 3 ij 0 f j 0;® 15;Example 4;Oral solution containing active substance 1 mg/ml;5 Active substance 1.0 mg;Sorbitol 150 mg;Glycerin 100 mg;Disodium edetate 0.5 mg;Preservative q.s.;10 Flavour q.s.;Water, purified to 1 ml;Example 5;15 Powder aerosol giving 1 mg per dose;The micronized active substance can be filled into a;R;powder inhaler device e.g. Turbuhaler giving 1 mg/dose.;20;The matter contained in each of the following claims is to be read as part of the general description of the present invention.;WHAT WE CLAIM IS:;1. Method for the preparation of a pharmaceutical composition containing a medicament with immunomodulating action, which comprises formulating at least one compound 5 selected from racemic N,N'-diacetylcystine,;N,N'-dibutyrylcystine, N,N'-diisovalerylcystine, N,N1 -dicaprylylcystine, N,N'-diacetylcystine dimethyl ester, N,N1-diacetylcystine diethyl ester, N,N'-diisovalerylcystine dimethyl ester, and the D or L optical isomers thereof, or a 10 physiologically acceptable salt thereof, into unit dosage form with a pharmaceutically acceptable carrier to deliver said at least one compound to a patient in an amount in the range 0.5 - 500 mg daily dose, suitable for effecting immunomodulating action.;15 2. Method for the preparation of a pharmaceutical composition containing a medicament with immunomodulating action, which comprises formulating at least one compound selected from the L optical isomers of N,N'-diacetylcystine, N,N'-dibutyrylcystine, N,N'-diisovalerylcystine, 20 N,N'-dicaprylylcystine, N,N'-diacetylcystine dimethyl ester, N,N'-diacetylcystine diethyl ester, and N,N'-diisovalerylcystine dimethyl ester, or a physiologically acceptable salt thereof, into unit dosage form with a pharmaceutically acceptable carrier to deliver said at least one compound to a 25 patient in an amount in the range 0.5 - 500 mg daily dose, suitable for effecting immunomodulating action.;3. Method for the preparation of a pharmaceutical composition containing a medicament with effect against chronic bronchitis, which comprises formulating at least one 3 0 compound selected from racemic N,N'-diacetylcystine, N,N'-dibutyrylcystine, N,N'-diisovalerylcystine, N,N'-dicaprylylcystine, N,N'-diacetylcystine dimethyl ester,;23;7 A;3 M;- n -;N,N1-diacetylcystine diethyl ester, N,N'-diisovalerylcystine dimethyl ester, and the D or L optical isomers thereof, or a physiologically acceptable salt thereof, into unit dosage form with a pharmaceutically acceptable carrier to deliver 5 said at least one compound to a patient in an amount in the range 0.5 - 500 mg daily dose, suitable for treating chronic bronchitis.;4. Method for the preparation of a pharmaceutical composition containing a medicament with effect against;10 chronic bronchitis, which comprises formulating at least one compound selected from the L optical isomers of N,N'-diacetylcystine, N,N1-dibutyrylcystine, N,N'-diisovalerylcystine, N,N1-dicaprylylcystine, N,N' -diacetylcystine dimethyl ester, N,N'-diacetylcystine diethyl 15 ester, and N,N'-diisovalerylcystine dimethyl ester, or a physiologically acceptable salt thereof, into dosage unit form with a pharmaceutically acceptable carrier to deliver said at least one compound to a patient in an amount in the range 0.5 - 500 mg daily dose, suitable for treating chronic 20 bronchitis.;5. Method for the preparation of a pharmaceutical composition containing a medicament with effect against asthma, which comprises formulating at least one compound selected from racemic N,N'-diacetylcystine, N,Nf-;25 dibutyrylcystine, N,N'-diisovalerylcystine, N,N'-;dicaprylylcystine, N,N'-diacetylcystine dimethyl ester, N,N'-diacetylcystine diethyl ester, N,N'-diisovalerylcystine dimethyl ester, and the D or L optical isomers thereof, or a physiologically acceptable salt thereof, into unit dosage 30 form with a pharmaceutically acceptable carrier to deliver said at least one compound to a patient in an amount in the range 0.5 - 500 mg daily dose, suitable for treating asthma.;- 18 -;6. Method for the preparation of a pharmaceutical composition containing a medicament with effect against asthma, which comprises formulating at least one compound selected from the L optical isomers of N,N1-diacetylcystine,;5 N,N!-dibutyrylcystine, N,N1-diisovalerylcystine,;N,N'-dicaprylylcystine, N,N'-diacetylcystine dimethyl ester, N,N'-diacetylcystine diethyl ester, and N,N'-diisovalerylcystine dimethyl ester, or a physiologically acceptable salt thereof, into unit dosage form with a pharmaceutically 10 acceptable carrier to deliver said at least one compound to a patient in an amount in the range 0.5 - 500 mg daily dose, suitable for treating asthma.;7. Method for the preparation of a pharmaceutical composition containing a medicament with effect against;15 rhinitis, which comprises formulating at least one compound selected from racemic N,N'-diacetylcystine, N,N1-dibutyrylcystine, N,N'-diisovalerylcystine, N,N1-dicaprylylcystine, N,N'-diacetylcystine dimethyl ester, N,N1-diacetylcystine diethyl ester, N,N'-diisovalerylcystine 20 dimethyl ester, and the D or L optical isomers thereof, or a physiologically acceptable salt thereof, into unit dosage form with a pharmaceutically acceptable carrier to deliver said at least one compound to a patient in an amount in the range 0.5 - 500 mg daily dose, suitable for treating 25 rhinitis.;8. Method for the preparation of a pharmaceutical composition containing a medicament with effect against rhinitis, which comprises formulating at least one compound selected from the L optical isomers of N,N1 - diacetylcystine,;30 N,N1-dibutyrylcystine, N,N'- diisovalerylcystine,;N,N'-dicaprylylcystine, N,N'-diacetylcystine dimethyl ester, N,N'-diacetylcystine diethyl ester, and N,N'-diisovalerylcystine dimethyl ester, or a physiologically acceptable salt;- 19 -;thereof, into unit dosage form with a pharmaceutically acceptable carrier to deliver said at least one compound to a patient in an amount in the range 0.5 - 500 mg daily dose, suitable for treating rhinitis.;9. Method for the preparation of a pharmaceutical composition containing a medicament with effect against diabetes, which comprises formulating at least one compound selected from racemic N,N'-diacetylcystine,;N,N'-dibutyrylcystine, N,N'-diisovalerylcystine, N,N'-dicaprylylcystine, N,N'-diacetylcystine dimethyl ester, N,N'-diacetylcystine diethyl ester, N,N1-diisovalerylcystine dimethyl ester, and the D or L optical isomers thereof, or a physiologically acceptable salt thereof, into unit, dosage form with a pharmaceutically acceptable carrier to deliver said at least one compound to a patient in an amount in. the range 0.5 - 500 mg daily dose, suitable for treating diabetes.;10. Method for the preparation of a pharmaceutical composition containing a medicament with effect against diabetes, which comprises formulating at least one compound selected from the L optical isomers of N,N'-diacetylcystine, N,N'-dibutyrylcystine, N,N'-diisovalerylcystine, N,N'-dicaprylylcystine, N,N1-diacetylcystine . dimethyl ester, N,N'-diacetylcystine diethyl ester, and N,N'-diisovalerylcystine dimethyl ester, or a physiologically acceptable salt thereof, into unit dosage form with a pharmaceutically acceptable carrier to deliver said at least one compound to a patient in an amount in the range 0.5 - 500 mg daily dose, suitable for treating diabetes.;11. Method for the preparation of a pharmaceutical composition containing a medicament with effect against;P M-Z. P£rE.^T OFFICE 1;I 12 AUG 1993;- 20 -;3030;rheumatoid arthritis, which comprises formulating at least one compound selected from racemic N,N'-diacetylcystine, NfN'-dibutyrylcystine, N,N'-diisovalerylcystine, N,N'-dicaprylylcystine, N,N'-diacetylcystine dimethyl ester, N,N'-diacetylcystine diethyl ester, .,N,N' -diisovalerylcystine dimethyl ester, and the D or L optical isomers thereof, or a physiologically acceptable salt thereof, into unit dosage form with a pharmaceutically acceptable carrier to deliver said at least one compound to a patient'in an amount in the range 0.5 - 500 mg daily dose, .suitable for treating rheumatoid arthritis.;12. Method for the preparation of a pharmaceutical composition containing a medicament with effect against rheumatoid arthritis, which comprises formulating at least one compound selected from the L optical isomers of;-diacetylcystine, N,N'-dibutyrylcystine, N,N'-diisovalerylcystine, N,N'-dicaprylylcystine, . If,N'-diacetylcystine dimethyl ester, N,N'-diacetylcystine diethyl ester, and N,N'-diisovalerylcystine dimethyl ester, or a physiologically acceptable salt thereof, into-unit dosage form with a pharmaceutically acceptable carrier to deliver said at least one compound to a patient in-, an amount in the range 0.5 - 500 mg daily dose, suitable for treating rheumatoid arthritis.;13, Method for the preparation of a pharmaceutical composition containing a medicament with effect against malignant diseases, which comprises formulating at least one compound selected from racemic N,N'-diacetylcystine, N,N'-dibutyrylcystine, N,N'-diisovalerylcystine, N>N'-dicaprylylcystine, N,N*-diacetylcystine dimethyl e&ter, N,N'-diacetylcystine diethyl ester, N",N'-diisovalerylcystine dimethyl ester, and the D or L optical isomers thereof, or a physiologically acceptable salt thereof, into N.Z. PATENT Of hce 30 NOV 1993 REIVED - 21 - dosage unit form with a pharmaceutically acceptable carrier to deliver said at least one compound to a patient in an amount in the range 0.5 - 500 mg daily dose, suitable for treating malignant diseases. 14. Method for the preparation of a pharmaceutical composition containing a medicament with effect against malignant diseases, which comprises formulating at least one compound selected from the L optical isomers of N,N'-diacetylcystine, N,N'-dibutyrylcystine, N,N'-diisovalerylcystine, N,N1-dicaprylylcystine, N,N1-diacetylcystine dimethyl ester, N,N'-diacetylcystine diethyl ester, and N,N'-diisovalerylcystine dimethyl ester, or a physiologically acceptable salt thereof, into unit dosage form with a pharmaceutically acceptable carrier to deliver said at least one compound to a patient in an amount in the range 0.5 - 500 mg daily dose, suitable for treating malignant diseases. 15. Method for the preparation of a pharmaceutical composition containing a medicament with effect against HIV infections/AIDS, which comprises formulating at least one compound selected from racemic N,N1-diacetylcystine, N,N'-dibutyrylcystine, N,N'-diisovalerylcystine, N,N'-dicaprylylcystine, N,N1-diacetylcystine dimethyl ester, N,N1-diacetylcystine diethyl ester, N,N'-diisovalerylcystine dimethyl ester, and the D or L optical isomers thereof, or a physiologically acceptable salt thereof, into unit dosage form with a pharmaceutically acceptable carrier to deliver said at least one compound to a patient in an amount in the range 0.5 - 500 mg daily dose, suitable for treating HIV infections/AIDS. 16. Method for the preparation of a pharmaceutical composition containing a medicament with effect against HIV - 22 - infections/AIDS, which comprises formulating at least one compound selected from the L optical isomers of N,N1-diacetylcystine, N,N1-dibutyrylcystine, N, N1 -diisovalerylcystine, N,N'-dicaprylylcystine, N,N1 -diacetylcystine dimethyl' ester, N,N'-diacetylcystine diethyl ester, and N,N'-diisovalerylcystine dimethyl ester, or a physiologically acceptable salt thereof, into unit dosage form with a pharmaceutically acceptable carrier to deliver said at least one compound to a patient in an amount in the range 0.5 - 500 mg daily dose, suitable for treating HIV infections/AIDS. 17. Method for the preparation of a pharmaceutical composition containing a medicament with effect against atherosclerotic disease, which comprises formulating at least one compound selected from racemic N,N'-diacetylcystine, N,N1-dibutyrylcystine, N,N'-diisovalerylcystine, N,N1-dicaprylylcystine, N,N1 -diacetylcystine dimethyl ester, N,N'-diacetylcystine diethyl ester, N,N'-diisovalerylcystine dimethyl ester, and the D or L optical isomers thereof, or a physiologically acceptable salt thereof, into unit dosage form with a pharmaceutically acceptable carrier to deliver said at least one compound to a patient in an amount in the range 0.5 - 500 mg daily dose, suitable for treating atherosclerotic disease. 18. Method for the preparation of a pharmaceutical composition containing a medicament with effect against atherosclerotic disease, which comprises formulating at least one compound selected from the L optical isomers of N,N'-diacetylcystine, N,N'-dibutyrylcystine, N,N'~ diisovalerylcystine, N,N'-dicaprylylcystine, N,N'~ diacetylcystine dimethyl ester, N,N'-diacetylcystine diethyl ester, and N,N1-diisovalerylcystine dimethyl ester, % f - 23 - or a physiologically acceptable salt thereof, into unit dosage form with a pharmaceutically acceptable carrier to deliver said at least one compound to a patient in an amount in the range 0.5 - 500 mg daily dose, suitable for 5 treating atherosclerotic disease. IS. Method for the preparation of a pharmaceutical composition containing a medicament with immunomodulating action, which comprises formulating the compound N,N1-diacetyl-L-cystine into unit dosage form with a 10 pharmaceutically acceptable carrier to deliver said compound to a patient in an amount in the range 0.5 - 500 mg daily dose, suitable for effecting immunomodulating action. 20. Method according to any one of claims 1 to 19 wherein 15 said compound is formulated with the pharmaceutically acceptable carrier into unit dosage form to deliver such compound to the patient in an amount in the range of 5-50 mg daily dose. 21. A pharmaceutical composition when prepared by the 20 method according to any one of claims 1 to 20. AKTIEBOLAGET ASTRA By Their Attorneys HENRY HUGHES LTD </div>