Compounds

Details Compounds Compounds

1999-09-30

2001-09-11

Richter, Johann (Department: 1621)

Organic compounds -- part of the class 532-570 series

Organic compounds

Fatty compounds having an acid moiety which contains the...

C554S046000, C554S047000, C514S885000, C514S824000

Reexamination Certificate

active

06288250

ABSTRACT:

FIELD OF THE INVENTION
The invention provides new compounds, specifically novel trisulphides and salts thereof, processes for their preparation, compositions containing them and methods for their use.
BACKGROUND OF THE INVENTION
N-acetyl-L-cysteine is a well known compound which is routinely used as a therapeutic agent against chronic obstructive pulmonary diseases, particularly chronic bronchitis. The mode of action of the compound is not fully clarified but it is considered that the compound acts as a mycolytic agent or an antioxidant. Reduction of the degree of exacerbations in patients suffering from chronic bronchitis has been reported for N-acetyl-L-cysteine. A possible explanation for this effect could be that the compound enhances the host defence in these patents (see Bergstrand, H. et al J. Free Radic. Biol. Med. 2, 119-127, 1986).
The corresponding disulphide of N-acetyl-L-cysteine, N,N′-diacetylcystine (DiNAC), is a potent immunostimulator as revealed by its capacity to enhance a contact sensitivity reaction in mice.
DESCRIPTION OF THE INVENTION
According to the invention there is provided a compound of the general formula
wherein R represents a straight or branched chain alkyl group containing from 1 to 16 carbon atoms, a pharmaceutically acceptable salt thereof and/or an optical isomer thereof.
Preferably R represents a methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl, n-tridecyl, n-tetradecyl, n-pentadecyl, n-hexadecyl, iso-propyl, 1-methylpropyl, tert-butyl, 2-methylbutyl or 3-methylbutyl group.
Examples of pharmaceutically acceptable salts of compounds according to the invention include the sodium, potassium, calcium, magnesium or ammonium salt or salts of mono- or di-protonated organic amines such as lysine, ethylenediamine, N,N′-dibenzyl ethylenediamine, adamantanamine, N-benzyl-2-phenylethylamine, benzathine, chloroprocaine, choline, diethanolamine, meglumine, procaine, benethamine, clemizole, tromethamine, ethanolamine, 2-amino-2-methyl-1,3-propanediol, tert. butylamine, triethanolamine, pyridoxine, nicotineamide, methyl nicotinate, arginine, histidine, morpholine, N-methylpiperidine, spermine, sperimidine, cysteamine, cystamine, metheneamine, piperazine.
The compound according to the invention may optionally be in the form of a racemic mixture or of the D,D- or L,L- isomer or meso form. It is preferably in the form of its L,L-isomer.
According to the invention there is further provided a process for the preparation of a compound of formula (I) which comprises reacting a compound of formula (II)
wherein R is as defined above, with a sulphur transferring coupling agent, and, optionally, reacting the product obtained with a suitable base to obtain a pharmaceutically acceptable salt, and/or isolating an optical isomer.
Suitable sulphur transferring coupling agents used in the process according to the invention include N,N′-thio-bis(phthalimide), N,N′-dibenzimidazyl sulphide, thiobis(imidazole), sulphur dichloride, sulphur momochloride, elemental sulphur, preferably, N,N′-thio-bis(phthalimide).
The process according to the invention is preferably carried out in a polar solvent, more preferably in a mixture of water and a polar organic solvent. Examples of suitable polar organic solvents include n-propanol, isopropanol, ethanol, buthanol, aceton, tetrahydrofuran and/or acetonitrile. A mixture of water and isopropanol is particularly preferred.
The isolation of optical isomers can be carried out using conventional methods.
The compound of formula (II) can be prepared from commercially available starting materials using methods known to a person of skill in the art.
According to the invention there is also provided a pharmaceutical composition comprising a compound of formula (I) in association with a pharmaceutically acceptable carrier and/or excipient. The composition according to the invention is optionally formulated in a manner suitable for administration by inhalation, or for oral, topical or parenteral administration. The composition may optionally be in the form of, for example, an aerosol, tablet, coated tablet, gelatine capsule or a solution, as appropriate.
For the preparation of a tablet, coated tablet or gelatine capsule, a compound according to the invention is combined with a suitable pharmaceutically acceptable carrier such as lactose, starch, dicalcium phosphate, microcrystalline cellulose, polyvinylpyrrolidone, gelatine, cellulose derivatives, colloidal silicone dioxide, talc and/or stearic acid and/or a salt thereof.
For the preparation of a solution, a compound according to the invention is combined with a pharmaceutically acceptable excipient such as water, saccharose, glucose, sorbitol, fructose and/or xylitol.
The pharmaceutical composition according to the invention may optionally further comprise a preservative, stabiliser, viscosity regulating agent, emulsifier, sweetening agent, colouring agent, flavouring agent, tonicity regulating agent, buffer and/or an oxidant. It may optionally also comprise another therapeutically active substance.
The invention provides compounds for use in medical therapy, especially compounds with advantageous properties for the treatment of diseases, particularly diseases where an anergy of the immune response or an aberrant immune response or an ineffective host defence is expected. Such diseases include chronic bronchitis, where a reduction of the rate of exacerbations has previously been reported with immune response modifiers such as Biostim® (Radermecker, M. et al. Int. J. Immunopharmac. 10, 913-917, 1988; Scheffer, J. et al. Arzneim Forsch/Drug Res. 41, 815-820, 1991), Ribomunyl® and BronchoVaxom (Paupe, J. Respiration 58, 150-154, 1991) as well as with N-acetylcysteine (Bergstrand, H. et al J. Free Radic. Biol. Med. 2, 119-127, 1986).
Diseases which the compounds of the invention can be used to treat include certain forms of malignant diseases. There are numerous reviews in the literature concerning ways of stimulating the immune response in patients with various forms of malignant diseases (Stevenson, F. K. FASEB J 5: 2250-2257, 1991; Melief, C. J. M. Advances in Cancer Research 58: 143-75, 1992; Chen, J. et al., Immunology Today 14:10, 483-86, 1993). For example patients with intracranial tumours (gliomas) exhibit a profound decrease in immunity possibly due to a defect in the secretion of IL-2 as well as the expression of IL-2 receptors in T cells from these patients (Roszman, T. et al. Immunology Today 12, 370-374, 1991). A significant adjuvant effect in immunotherapy of melanoma and colon carcinoma has been documented for the immunostimulator Levamisole (Van Wauwe, J. and Janssen, P. A. J: Int J. Immunopharmac. 13, 3-9, 1991). Also immunotherapy with IL-2 in vivo or treatment of patients' lymphokine activated killer cells with IL-2 ex vivo has caused the regression of cancer (Rosenberg, S. A. Immunology Today 9, 58-62, 1988).
The malignant diseases for which the compounds of the invention are expected to have advantageous effects include tumours of mesenchymal origin such as sarcomas like fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma or chordosarcoma, sarcomas like angiosarcoma, endotheliosarcoma, lymphangiosarcoma, synoviosarcoma or mesotheliosarcoma, leukemias and lymphomas like granulocytic leukemia, monocytic leukemia, lymphocytic leukemia, malignant lymphoma, plasmocytoma, reticulum cell sarcoma or Hodgkins disease, sarcomas like leiomysarcoma or rhabdomysarcoma, tumours of epithelial origin (carcinomas) like squamous cell carcinoma, basal cell carcinoma, sweat gland carcinoma, sebaceous gland carcinoma, adenocarcinoma, papillary carcinoma, papillary adenocarcinoma, cystadenocarcinoma, medullary carcinoma, undifferentiated carcinoma, bronchogenic carcinoma, melanoma, renal cell carcinoma, hepatoma-liver cell carcinoma, bile duct carcinoma-cholangiocarcinoma, papillary carcinoma, transitional cell carcinoma, squamous cell carcinoma, choriocarcinoma, semonoma or embryo

Affiliated with

Also associated with

Rating

Compounds does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Compounds, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Compounds will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-2488392