MXPA00008966A

MXPA00008966A - New compounds

Info

Publication number: MXPA00008966A
Application number: MXPA/A/2000/008966A
Authority: MX
Inventors: Hakan Bergstrand; Jan Dahmen; Bengt Sarnstrand
Original assignee: Astra Ab
Priority date: 1998-03-20
Filing date: 2000-09-13
Publication date: 2001-07-09

Abstract

Compounds of general formula (I), wherein R represents a straight or branched chain alkyl group containing from 1 to 16 carbon atoms, pharmaceutically acceptable salts thereof and/or optical isomers thereof have an immunostimulating effect, and are useful in the treatment of artheriosclerosis.

Description

N UVOS TRISU LFURES AND SALTS THEREOF, PROCESSES FOR PREPARATION, COMPOSITION IS THAT THEY CONTAIN THEM AND METHODS FOR THEIR USE Field of / to Invention The invention provides new compounds, specifically new trisulfides and salts thereof, processes for their preparation, compositions that contain them and methods for their use.

Background of the Invention N-acetyl-L-cysteine is a well-known compound that is routinely used as a therapeutic agent against chronic obstructive pulmonary diseases, particularly chronic bronchitis. The mode of action of the compound is not clear, but the compound is considered to act as a mycolytic agent or an antioxidant. The reduction in the degree of exacerbations in patients suffering from chronic bronchitis has been reported for N-acetyl-L-cysteine. A possible explanation for this effect may be that the compound reinforces host defense in these patents (see Bergstrand, H. et al., J. Free Radie, Biol. Med. 2, 119-127, 1986). The corresponding disulfide of N-acetyl-L-cysteine, N, N'-diacetylcystin (DiNAC), is a potent stimulator of the immune system, as revealed by its REF, 122923 ability to reinforce a contact sensitivity reaction in mice.

Description of the Invention In accordance with the invention, a compound of the general formula is provided: where R represents a branched straight chain alkyl group containing from 1 to 6 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 group , n-tetradecyl, n-pentadecyl, n-hexadecyl, isopropyl, 1-methylpropyl, tertbutyl, 2-methylbutyl or 3-methyl-1-butyl. Examples of pharmaceutically acceptable salts of the compounds according to the invention include the sodium, potassium, calcium magnesium or ammonium salt (s) of the mono- or di-protonated organic amines, such as lysine, ethylenediamine, N, N'-dibenzylethylenediamine, adamantanamine, N-benzyl-2-phenylethylamine, benzathine, chloroprocaine, ine, diethanolamine, meglumine, procaine, benetamine, clemizole, tromethamine, ethanolamine, 2-amino-2-methyl-1,3-propane I, tert-buty I amine, triethanolamine, pyridoxine, nicotinamide, methyl nicotinate, arginine, histidine, morpholine, N-methylpiperidine, spermine, spermidine, cysteamine, cystamine, methenamine, piperazine. The compound, according to the invention, can optionally be in the form of a racemic mixture or of the D, D- or L, L-isomers or in the meso form. It is preferably found 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 the formula (I), which comprises reacting a compound of the formula (II): (II) where R is as defined above, with a sulfur transfer coupling agent and, optionally, reacting the obtained product with a suitable base to obtain a pharmaceutically acceptable salt, and / or isolating an optical isomer. Suitable sulfur transfer agents, which are used in the process according to the invention, include N, N'-1-bis (phthalimide), N, N'-dibenzimidacyl sulfide, thiobis (imidazole), sulfur dichloride, sulfur monochloride, sulfur elementa l, preferably N, N '- 1 io-bis (phta limida). 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, butanol, acetone, tetrahydrofuran and / or acetonitrile. A mixture of water and isopropanol is particularly preferred. The isolation of the optical isomers can be carried out using conventional methods. The compound of the formula (II) can be prepared from commercially available raw materials, using methods known to those trained in the art. According to the invention, it also provides a pharmaceutical composition comprising a compound of the formula (I) in association with a pharmaceutically acceptable carrier and / or excipient. The composition, according to the invention, is optionally formulated, suitably by administration by inhalation, or by oral, topical or parenteral administration. The composition may optionally be in the form of, for example, an aerosol, tablet, coated tablet, gelatin capsule or a solution, as appropriate. For the preparation of a tablet, a coated tablet or a gelatin capsule, a compound, according to the invention, is combined with a pharmaceutically acceptable vehicle such as lactose starch, dicalcium phosphate, microcrystalline cellulose polyvinylpyrrolidone, gelatin, derivatives of cellulose, colloidal silicon dioxide, talc and / or stearic acid and / or a salt thereof. For the preparation of a solution, or compound, according to the invention, it is combined with a pharmaceutically acceptable excipient, such as water, sucrose, glucose, sorbitol, fructose and / xylitol. The pharmaceutical composition, according to the invention, may further comprise, optionally, a condom, a stabilizer, a viscosity regulating agent, an emulsifier, a sweetening agent, a coloring agent, a flavoring agent, an agent for regulating tonicity, or buffer and / or an oxidant. Optionally, it may also comprise another active therapeutic 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 defense of the host is suspected. These diseases include chronic bronchitis, where a reduction in the rate of exacerbations has been previously reported as modifiers of the immune response such as Biostim (Radermecker, M, et al., Int 3, Immunopharmac, 10 913-917, 19.88).; Scheffer, J. et al. Arzneim Forsch / Dru Res. 41, 815-820, 1991), Ribomunyl® and Broncho Vaxo (Paupe, J. Respiration 58, 150-154, 1991) as well as with N-acetylcysteine (Bergstrand, H. et al., J Fre Radie, Biol. Med. 2, 119-127, 1986). Diseases wherein the compounds of the invention can be used for treatment include certain forms of malarial diseases. There are numerous reviews in the literature that address ways to stimulate the response of patients with various forms of malignancy (Stevenson, FK FASEB J 5: 2250-2257, 1991, Melief, C. J M. Advances in Cancer Research 58: 143-75, 1992; Chen, J. Et al., Immunology Toda 14: 10, 483-86, 1993). For example, patients with intracranial tumors (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 in these patients ( Roszman, T. et al., Immunolog Today 12, 370-374, 1991). A significant adjuvant effect in the immunotherapy of melanoma and carcinoma of the colon has been documented for the stimulator of the inm une Levamisol system (Va n Wauwe, 3. and Janssen, PA J: Int. J. Imm unopha rmac., 13, 3 -9, 1991). Also, immunotherapy with IL-2 in vivo or treatment with IL-2 of the killer cells, which activate with lymphokines, of the patients, ex vivo, h originated the regression of the cancer (Rosenberg, SA Immunology Today 9, 58- 62, 1988). Malignant diseases for which the compounds of the invention are expected to have advantageous effects include tumors or mesenchymal orige, such as sarcomas, such as fibrosarcoma, and mixosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcomas, orthosarcoma, sarcomas such as angiosarcoma, endotheliosarcoma, lymphaniosarcoma, synoviosarcomamesote Iosarcoma, leukemias lymphomas such as granulocytic leukemia, monocytic leukemia, malignant lymphoma, plasmacytoma, sarcoma of the reticulum cell or Hodgkins disease, sarcomas such as leiomisarcoma or rhabdomysarcoma, tumors of epithelial origin (carcinomas) such as carcinoma of the squamous cell, carcinoma of the base cell, carcinoma of the sweat gland, carcinoma of the sebaceous gland, adenocarcinoma, papillary carcinoma, adenocarcinoma papillary, cystadenocarcinoma, medullary carcinoma, undifferentiated carcinoma, bronchogenic carcinoma, melanoma, carc Inoma of the cell rena l, carcinoma of the hepatoma cell of the liver, carcinoma-cholangiocarcinoma of the biliary duct, papillary carcinoma r, transition cell carcinoma d, squamous cell carcinoma, choriocarcinoma, semonoma or embryonal carcinoma, tumors of the central nervous system such as glioma, meningoma, medulloblastoma, schwa noma or ependymoma. In addition, the compounds, according to the present invention, also have advantageous properties for the treatment of chronic infections such as herpes, aphthous stomatitis and minimal change syndrome, where previously clinical improvements had been reported by treatment with a stimulator. of the immune system such as Levamisole, other chronic inflammatory diseases in the urinary tract or in the ear, nose or throat, which benefit from treatment with the stimulators of the in mune system, such as Biostim®, Bronco-Vaxom and Ribomunyl® and the infection for HIV, or AIDS. In addition, the existence of a worsening, a defect or an imbalance of the immune response in atopic diseases, such as atopic dermatitis, rhinitis and asthma has also been postulated (Katz, DH Immunology Reviews 41, 77-108, 1977). Because theoretical considerations suggest that the stimulation of an immune response would possibly be the best way to restore imbalances and autoimmunity (Varela, FJ Coutinho, A. Immunology Today 12, 159-166, 1991) it is also expected that compounds of the invention have advantageous properties for the treatment of asthma, rhinitis, atopic dermatitis and autoimmune diseases such as non-obese diabetes, systemic lupus erythematosus, scleroderma, Sjórgen syndrome, multiple sclerosis, rheumatoid arthritis and psoriasis. In addition, the compounds, according to the present invention, due to their properties for stimulating the immune system, are thought to have advantageous properties as adjuvants in various forms of vaccine preparations. Due to their stimulating properties of the immune system, the compounds according to the present invention are also expected to possess favorable properties to inhibit the rejection of the transplanted organs. Finally, it is expected that the compounds according to the present invention have advantageous properties for the treatment of arteriosclerosis (Hansson, G. K. et al., Proc. Nat. Acad. Sci. USA 88 10530, 1991). 1 The compounds, according to the present invention, are particularly suitable for the treatment of diseases such as melanoma, mammary carcinoma, gastrointestinal carcinoma, glioma, carcinoma of the bladder and squamous cell carcinoma of the neck. and from the region of the head; diseases in the respiratory tract, such as chronic bronchitis, asthma, rhinitis; atopic diseases such as atopic dermatitis; infections such as hepatitis, post-infectious anergy and acquired immune deficiencies, such as AIDS; the post-traumatic immunological anergy; and significant autoimmune diseases such as rheumatoid arthritis, multiple sclerosis, arteriosclerosis and psoriasis. A further object of the invention is the use of the compounds of the present invention for the manufacture of a medicament with the effect of stimulating the immune system and especially drug for the treatment of arteriosclerosis. Another object of the invention is a method for the stimulation of the immune system, which comprises administration to a host, in need of treatment, of an effective amount of the compound of the present invention. Another object of the invention is a method for the treatment of a c r e r i s i s, comprising the administration, to a host in need of treatment, of an effective amount of the compound of the present invention. The invention is illustrated by the following example, which should not be construed as limiting the scope of the invention.

Acid (R, R ') - 3,3'-trithio is-2-acetamidopropanoic acid [N, N'-diacetyl-L-cystine trisulfide (acid form)]. N-acetyl cis cis (5 g, 30.6 mmol) was suspended in a mixture of sodium propane and water (1: 1, 3.0 L) and N, N '- 1 io-bis (phtha I imide) was added. (5 g, 15.4 mmol). The mixture was stirred at room temperature for 24 hours, after which the clear solution was evaporated to liberate it from isopropanol. Filtration of the precipitated material, followed by freeze drying gave the crude trisulfide product, contaminated. by the phthalimide, as the main impurity.

Preparative HPLC [Kromasil K100-10 C18 column (2"x 250 mm) using acetonitrile / water (19/81) containing 0.1% trifluoroacetic acid, eluent at a flow rate of 40 mL / min. Detection at 220 nm] gave, after drying by freezing, the pure title compound, with a quantitative yield, M + H: 357.

Pharmacological Test The ability of the compounds of the invention to modulate the immune responses was confirmed using the following hyper-sensitivity test d delayed type (DTH), animal, in the mouse. Male and female Balb / c mice, weighing from 18 to 20 grams, obtained from Bomholtsgaard (Denmark) were used. As antigen s used in this test 4 - e t o x i m e t i I n - 2 - f e n i I x a z o I i n 5-ona (OXA, acquired from BDH, England). The mice were sensitized, Day 0, mediant epicutaneous application of 150 mL of a solution of absolute ethanol: acetone (3: 1) containing 3% of OXA, in the shaved abdomen. The treatment with a compound, according to the present invention, vehicle (0.9% NaCl) was initiated by oral feeding immediately after sensitization and continued once daily until Day 6. Seven days (Day 6) after the first treatment. sensitization, the ears of all the mice were subjected to the stimulus on both sides by the topical application of 20 mL of dissolved OXA 1% and peanut oil. The thickness of the ear was measured before and 24 or 48 hours after stimulation using an Oditest spring gauge. The stimuli and measurements were made under a pentobarbital anesthetic. The intensity of the DTH reactions was expressed according to the formula: Tt24 / 48-Tt0 units d mm; where tO, t24 and t48 represent the thickness of the ear before and 24 or 28 hours after stimulation, respectively, in the individual tests (T). The results were expressed as the average S. E. M. The level of significance between the averages of the groups was obtained by means of the two-tailed Student t test. The potency of the compound for the stimulation of the immune system was measured by comparing the increase in the thickness of the ear with that obtained in the control.

It is noted that, in relation to this date, the best method known to the applicant for carrying out said invention is that which is clear from the present description of the invention.

Claims

REVIVAL DICTIONS Having described the invention as above, the contents of the following indications are claimed as property. 1. A compound of the general formula:

Characterized in that 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.
2. The compound according to claim 1, characterized in that R represents a methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl group, n -decyl, n-undecyl, n-dodecyl, n-tridecyl, n-tetradecyl, n -pentadecyl, n-hexadecyl, isopropyl, 1-methylpropyl, tert-butyl, 2-methyl I butyl or 3-methyl I butyl or
3. A process for the preparation of a compound according to claim 1 or 2, characterized in that it comprises reacting a compound of the formula (II): where R is as defined in claim 1, with a sulfur-transfer coupling agent; and, optionally, reacting the product obtained with a suitable base to obtain a pharmaceutically acceptable salt, and / or isolating the optical isomer.
4. The process, according to claim 3, characterized in that the coupling agent, sulfur transfer, is N, N 'thio-bis (phta limida).
5. The compound, according to claim 1 or 2, characterized in that it is for use in medical therapy.
6. The compound, according to claim 5, characterized in that the medical therapy is for the stimulation of the immune system.
7. The compound, according to claim 5, characterized in that the medical therapy is arteriosclerosis.
8. A pharmaceutical composition characterized in that it comprises a compound, according to claim 1 or 2, associated with a pharmaceutically acceptable carrier and / or excipient.
9. The use of a compound, according to claim 1 or 2, characterized in that it is for the manufacture of a drug with effect d stimulation of the immune system.
10. The use of a compound, according to claim 1 or 2, or of a composition, according to claim 8, characterized in that it is for the manufacture of a medicament which is used for the treatment of arteriosclerosis.
11. A method for stimulating the immune system, characterized in that it comprises administering to a host in need of stimulation of the immune system, an effective amount of a compound, as defined in claim 1 or 2 or of a composition, as defined in claim 8.
12. A method for the treatment of arteriosclerosis, characterized in that it comprises administering, to a host in need of treatment, an effective amount of a compound according to claim 1 or 2, or a composition , according to claim 8. SUMMARY OF THE INVENTION Compounds of the general formula (I) are described, where R represents a straight or branched chain alkyl group, containing from 1 to 1 carbon atoms, pharmaceutically acceptable salts thereof and / or optical isomers of the same. They have a stimulating effect on the immune system, and they are useful for the treatment of arteriosclerosis. (I)