TH68046B - Mixtures of cyclosporine-like substances And use as an immune modulator - Google Patents

Abstract

DC60 (13/01/46) This invention relates to a mixture of isomers of a cyclosporin-like substance with a structure similar to cyclosporin A. This mixture exhibits a combination of enhancement and toxicity superior to each individual isomer and to naturally occurring and currently known cyclosporin and its derivatives. The composition of this invention is directly related to the cis and trans-isomers of the cyclosporin-like substance A, denotes cyclosporin ISATX247, and its derivatives. The mixture of ISATX247 isomers exhibits a combination of enhancement and toxicity superior to naturally occurring and currently known cyclosporin and its derivatives. The ISATX247 isomer and its derivatives, alkylated, arylated, and deuterated, were synthesized by stereoselective methods, with each reaction condition indicating a degree of stereoselectiveity. The stereoselective method could be a vitric reaction, or an organometallic agent, which is incorporated. Inorganic elements such as boron civil, titanium, and lithium, the ratio of isomers in the mixture may range from approximately 10 to 90 percent by weight of (E)-isomers to approximately 90 to 10 percent by weight of (Z)-isomers on the basis of the total weight of the mixture. This invention relates to a mixture comprising isomers of a cyclosporin-like substance with a structure similar to cyclosporin A. This mixture exhibits better enhancement and detoxicity than each individual isomer and better than naturally occurring and currently known cyclosporin and cyclosporin derivatives. The composition of this invention is directly related to the cis and trans-isomers of the cyclosporin-like substance A, denoting cyclosporin ISATX247, and its derivatives. The mixture of ISATX247 isomers exhibits a combination of enhancement and detoxicity. ISATX247 isomers and derivatives that are adelateted, arylated, and deuterated are more toxic than naturally occurring and well-known cyclosporin and cyclosporin derivatives. These isomers are synthesized by stereoselective methods, with each reaction condition indicating the degree of stereoselectiveity. Stereoselective methods can be vittic reactions or organometallic agents incorporating inorganic elements such as boron civiloid, titanium, and lithium. The isomer ratios in the mixture can range from approximately 10 to 90 percent by weight of (E)-isomers to approximately 90 to 10 percent by weight of (Z)-isomers on a basis of the total weight of the mixture.

Claims (69)

------27/09/2561------(OCR) Page 1 of 3 pages. Claims. 1. A composition consisting of a mixture of isomers of cyclosporin-like substances modified at the 1-amino acid residue with a 1,3-diene substituent, where the isomer mixture contains 75% to 90% by weight of E-isomers and 25% to 10% by weight of Z-isomers, where the sum of the weight percentages of the (E) isomers and (Z) isomers is 100% by weight. The isomers are E- and Z-isomers as shown below (chemical structure). (Chemical structure) E-isomer Z-isomer 2. Composition of Claim 1, whereby the isomer mixture consists of 75% to 85% E-isomer and 15% to 25% Z-isomer. 3. Composition of Claim 1, whereby the isomer mixture consists of 85% to 90% E-isomer and 10% to 15% Z-isomer. 4. The elements claimed under any one of the claims 1 through 3 are considered therapeutic elements. 5. Any of the components claimed under claims 1 through 3 is a pharmaceutical component consisting of a mixture of isomers of cyclosporine-like substances as described in any of claims 1 through 3 and a pharmaceutically acceptable vehicle, dine. 6. The pharmaceutical composition of claim 5 consists of a liquid solution containing a surfactant, ethanol, a fatty solvent, and/or a fatty filament. 7. The pharmaceutical composition of claim 6, which includes d-alpha-tocopheryl polyethylene glycol 1000 succinate (vitamin E TPGS), medium-chain triglyceride (MCT) oil, Twin 40 and ethanol. Page 2 of 3. 8. The pharmaceutical composition of claim 5 consists of a gelatin capsule containing a mixture of isomers of a cyclosporine-like substance, a liquid solution containing a surfactant, ethanol, a lipid-loving solvent, and/or a lipid-loving vaporizer. 9. The pharmaceutical component of one of the claims in clauses 7 or 8, which is in the form of an active unit. 10. The pharmaceutical composition of claim 9, which contains an active ingredient ranging from 5 milligrams to 500 milligrams. 11. The pharmaceutical component of claim 8, which contains a 50 mg isomer mixture. 12. The pharmaceutical component of claim 6 or 7, where the solution contains 50 mg/ml of the isomer of the mixture. 13. The pharmaceutical components of claim 5, which have been modified for oral use. 14. A pharmaceutical component of any of the claims 5 through 13 whereby the mixture of cyclosporine-like isomers is present in an effective therapeutic concentration for the production of immunosuppression when administered to animals. 15. The pharmaceutical component of claim 14, whereby the animal in question is the human being. 16. The pharmaceutical component of claim 14 or 15 where such immunosuppression is intended to treat or alleviate acute organ or tissue transplant rejection. 17. The pharmaceutical components of claim 16, whereby the said transplantation continuation is selected from a group comprising continuation of heart, lung, heart-lung, liver, kidney, pancreas, skin, ligament, and lens transplants. 18. A pharmaceutical component of either claim 14 or 15 where the reduction of such immune response is for therapeutic or alleviative effect on T-cell resistance. 19. A pharmaceutical component of either claim 14 or 15 where such immunoreduction is for the treatment or alleviation of disease resulting from transplant resistance. 20. Pharmaceutical component of claim 19 where the disease occurs following bone marrow transplantation. 21. A pharmaceutical component of either claim 14 or 15 where such immunoreduction is for the treatment or alleviation of chronic adverse reactions of the transplanted organ. 22. The pharmaceutical component of claim 21, whereby the said chronic vascular disease is a vascular transplant disease. 23. A pharmaceutical component of either claim 14 or 15 where such immunoreduction is for the treatment or alleviation of organ transplant failure. (Page 3 of 3) 24. The pharmaceutical component of claim 23, whereby rejection of an organ transplant from another person is selected from a group comprising acute, severe, and chronic organ rejection that occurs when the donor is of a different genetic type than the recipient. 25. A pharmaceutical component of claim 24 where the rejection of an organ transplant from another person is an rejection caused by B-cell or antibody reactions. 26. A pharmaceutical component of any of claim 14 or 15 where the reduction of such immune response is for the treatment or alleviation of an autoimmune disease or condition, or an inflammatory disease or condition. 27. A pharmaceutical component of claim 26 where the disease or condition is selected from a group comprising arthritis, rheumatoid arthritis, progridentoid arthritis, deforman arthritis, and rheumatic disease. 28. A pharmaceutical component of claim 27 where the disease or condition is selected. From the group comprising hematological disorders, hemolytic anemia, apoptosis, erythropoietic anemia, thrombocytopenia, thrombocytopenia of unknown etiology, congestive erythema, osteomyelitis, scleroderma, ventureiate granuloma, myositis and dermatitis, chronic inflammatory bowel disease, severe myasthenia gravis, psoriasis, Stevens-Johnson syndrome, idiopathic spruce, autoimmune colitis, intestinal ulcers, Crohn's disease, endocrine glandular diseases, Graves' disease, Scharcoid disease, Twig's scleroderma, biliary inflammatory bowel disease, adolescent diabetes mellitus (type 1 diabetes), anterior and posterior ocular septitis, corneal and conjunctival diseases. Dry inflammation, spring keratitis and conjunctivitis, pulmonary fibrosis, psoriatic arthritis, glomerular nephritis, spontaneous nephritis, minimally altered renal dysfunction, and adolescent myositis and dermatitis. 29. Pharmaceutical composition of claim 27 where such disease or condition is selected from the group comprising psoriasis, contact dermatitis, hereditary atopic dermatitis, alopecia areata, disseminated rash, shingles, scleroderma, vitiligo, hypersensitivity vasculitis, urticaria, blistering skin, ulcerative erythema, vesicular nephritis, ruptured epidermal blistering, inflammatory or atopic conditions of the skin, inflammatory conditions of the lungs and respiratory tract, asthma, allergic and pulmonary thrush. ------------ 1. Composition consisting of an isomer mixture of cyclosporine-like substances modified at the acid residue. 1-amino with 1,3-diene substituents, where the isomer mixture contains 75% to 90% by weight of E-isomers and 25% to 10% by weight of z-isomers, where the sum of the weight percentages of (E) isomers and (Z) isomers is 100% by weight. 1. A mixture of claim 1 where the non-deuterized isomers are E- and Z-isomers as specified below. 2. A mixture of claim 1 where the non-deuterized isomers are E and Z-isomers as specified below: (chemical formulas). 3. A mixture of claim 1 or 2 where this isomer mixture contains approximately 55 to 65% E-isomers and approximately 35 to 45% Z-isomers. 4. A mixture of claim 1 or 2 where this isomer mixture contains approximately 65 to 75% E-isomers and approximately 25 to 35% Z-isomers. 5. A mixture of claim 1 or 2 where this isomer mixture contains approximately 75 to 85% E-isomers and approximately 15 to 25% Z-isomers. 6. A mixture of claims 1 or 2 where such isomer mixture contains approximately 85% to 90% E-isomers and approximately 10% to 15% Z-isomers. 7. A mixture of claims 1 or 2 where such isomer mixture contains approximately 90% to 95% E-isomers and approximately 10% to 5% Z-isomers. 8. A mixture of claims 1 or 2 where such isomer mixture contains greater than or equal to 95% E-isomers and less than or equal to 5% Z-isomers. 9. A mixture containing isomers of a cyclosporin-like substance modified at amino acid-1 with a 1,3-diene substituent, where such isomer mixture contains... 10. A mixture of claim 9 where the non-deuterized isomers are E- and Z-isomers as defined below (chemical formulas). 11. A mixture according to claim 9 or 10 where such isomer mixture contains approximately 75 to 65% Z-isomers and approximately 25 to 35% E-isomers. 12. A mixture according to claim 9 or 10 where such isomer mixture contains approximately 65 to 55% Z-isomers and approximately 35 to 45% E-isomers. 13. A pharmaceutical mixture containing an isomer mixture of cyclosporine-like substances according to one of the claims 1 through 12 and an acceptable vehicle. 14. A pharmaceutical mixture of claim 13 consisting of a liquid solution containing a surfactant, ethanol, a fat-loving and/or semi-fat-loving solvent. 15. A pharmaceutical mixture of claim 14 consisting of d-alpha-tocopheryl polyethylene glycol 1000 succinate (vitamin E TPGS), medium-chain triglyceride (MCT) oil, Tween 40, and ethanol. 16. A pharmaceutical mixture of claim 13 consisting of gelatin capsules containing an isomer mixture of cyclosporine-like substances, a liquid solution containing... 17. A pharmaceutical mixture of any one of the claims in claims 15 to 16 in an active unit form. 18. A pharmaceutical mixture of claim 17 containing between approximately 50 mg and approximately 500 mg of active ingredient. 19. A pharmaceutical mixture of claim 16 containing approximately 50 mg of isomer. 20. A pharmaceutical mixture of claim 14 or 15 where the solution contains 50 mg/ml of isomer. 21. A pharmaceutical mixture of claim 13 modified for oral administration. 22. A pharmaceutical mixture intended to induce immunosuppression. When used in animals, it consists of a mixture of isomers of cyclosporin-like substances as per any of the patent claims 1 through 12, or a pharmaceutical mixture as per any of the patent claims 13 through 21, in a therapeutic dose; 23. A pharmaceutical mixture as per patent claim 22, where the animal is a human; 24. A pharmaceutical mixture for immunosuppression, consisting of a mixture of isomers of cyclosporin-like substances that reduce the immunosuppression in a therapeutic dose, where the preparation of such isomer mixture reduces the toxicity of the cyclosporin-like substance; 25. A pharmaceutical mixture as per patent claim 29, where such isomer mixture contains a mixture as per any of the patent claims 1 through 12. 26. Pharmaceutical mixtures for immunosuppression comprising a mixture of immunosuppressant isomers of cycloporin-like substances in therapeutic concentrations, where the preparation of such isomer mixtures enhances the efficacy of cycloporin-like substances. 27. Pharmaceutical mixtures under claim 29, whereby such isomer mixtures consist of any one of the mixtures under claims 1 through 12. 28. Pharmaceutical mixtures under any of the claims in clauses 22 through 27 where such immunoreduction is for the treatment or alleviation of acute organ or tissue transplant rejection. 29. Pharmaceutical mixtures pursuant to claim 28, whereby such transplant rejection is selected from a group comprising rejection of heart, lung, heart-lung, liver, kidney, pancreas, skin, intestine, and lens transplants. 30. Pharmaceutical mixtures pursuant to any one of the claims under clauses 22 through 27 where such immunoreduction is for the treatment or alleviation of T-cell-induced rejection. 31. Pharmaceutical mixtures under any of the claims 22 through 27 where such immunoreduction is for the treatment or alleviation of transplant rejection disease. 32. Pharmaceutical mixture pursuant to claim 31, where the disease occurred following bone marrow transplantation. 33. Pharmaceutical mixtures under any of the claims 22 through 27 where such immunoreduction is for the treatment or alleviation of chronic rejection of transplanted organs. 34. Pharmaceutical mixture under claim 33, where the chronic resistance is a vascular disease. 35. Pharmaceutical mixtures under any of the claims 22 through 27 where such immunoreduction is for the treatment or alleviation of rejection of organ transplants from another person. 36. Pharmaceutical mixtures pursuant to claim 35, whereby organ transplant rejection from another donor is selected from a group comprising acute, acute, severe, and chronic organ rejection that occurs when the organ donor is of a different species from the recipient. 37. Pharmaceutical mixtures under claim 36 where the rejection of an organ transplant from another person is an rejection caused by B-cell or antibody reactions. 38. Pharmaceutical mixtures under any of the claims from clauses 22 to 27 where such immunoreduction is for the treatment or alleviation of an autoimmune disease or condition, or an inflammatory disease or condition. 39. Pharmaceutical mixtures pursuant to claim 38, whereby the disease or condition is selected from a group comprising arthritis, rheumatoid arthritis, prograde inflammatory arthritis, deforman arthritis, and other rheumatic diseases. 40. Pharmaceutical mixtures pursuant to claim 38, whereby the disease or condition is selected from a group comprising hematological disorders, hemolytic anemia, anemia-atrophy, erythropoietic anemia, thrombocytopenia, generalized hemorrhagic erysipelas, osteomyelitis, scleroderma, venturei granuloma, myositis and dermatitis, chronic hepatitis, severe myasthenia gravis, psoriasis, Stevens-Johnson syndrome, idiopathic sprue, autoimmune inflammatory bowel disease, intestinal ulcers, Crohn's disease, endocrine sclerosis, Graves' disease, sarcoidosis, progressive scleroderma, biliary hepatitis, adolescent diabetes mellitus (type 1 diabetes), and ocular sclerosis. (Both anterior and posterior), dry conjunctivitis, spring keratitis and conjunctivitis, pulmonary fibrosis, psoriatic arthritis, glomerular nephritis, spontaneous nephritis, minimally altered renal dysfunction, and adolescent myositis and dermatitis. 41. Pharmaceutical mixtures according to claim 38, whereby the disease or condition is selected from a group comprising psoriasis, contact dermatitis, atopic dermatitis, alopecia areata, disseminated eczema, shingles, scleroderma, vitiligo, hypersensitivity vasculitis, urticaria, blistering skin, ulcerative erythema, vesicular necrosis, epidermal blistering, other inflammatory or allergic skin conditions, pulmonary and respiratory tract infections, asthma, allergies, and purpura. 42. Any mixture as described in any of the claims in Claims 1 through 12 is used as a therapeutic mixture. 43. Any combination of any one of the claims in Claims 1 through 12 shall be used as a compound for the preparation of pharmaceuticals for immunodeficiency in the prevention of homologous or heterogeneous transplantation of kidney, heart, or liver, or for the prevention or treatment of autoimmune disorders, particularly rheumatoid arthritis or psoriasis. 44. Pharmaceutical mixtures pursuant to any one of the claims under clauses 22 through 27, where such immunosuppression is intended to prevent acute rejection of organ or tissue transplants. 45. Pharmaceutical mixtures pursuant to any one of the claims from clauses 22 to 27, where such immunosuppression is for the prevention of an autoimmune disease or condition, or an inflammatory disease or condition. 46. A method for preparing a mixture of isomers of cyclosporin-like substances modified at the amino acid-1 portion with a 1,3-diene substituent, which includes the following steps: a) beta-alcoholization of the amino acid-1 portion of cyclosporin to form the protected cyclosporin; b) oxidation of the protected cyclosporin to form the aldehyde of the protected cyclosporin; c) conversion of the aldehyde of the protected cyclosporin to a mixture of E- and Z- isomers of the protected 1,3-diene cyclosporin by phosphorus-lyzed aldehyde reaction of the protected cyclosporin via a vitric reaction; d) de-protection of the mixture of E- and Z- isomers of the protected 1,3-diene cyclosporin to obtain the mixture of isomers of cyclosporin-like substances modified at the amino acid-1 portion. With a 1,3-diene substituent group. 47. A method pursuant to claim 46 where an isomer mixture of cyclosporine-like substances contains 90% or more E-isomers. 48. The method pursuant to claim 46, whereby the beta-alcohol of amino acid-1 of cyclosporin is protected by reaction of the cyclosporin with a reagent to obtain a protected cyclosporin selected from a group of compounds consisting of acetate esters, benzoate esters, structurally substituted benzoate esters, ethers, and xylyl ethers. 49. The procedure pursuant to claim 46, whereby the beta-alcohol of amino acid-1 of cyclosporine is protected by an acetate ester, resulting in acetylcyclosporine, whereby the protection procedure involves the mixing of acetic anhydride with cyclosporine in the presence of dimethylaminopyridine (DMAP) at room temperature under a nitrogen atmosphere. 50. The method under claim 46, whereby the oxidation step is performed with an oxidizing agent selected from a group of agents consisting of ozone, potassium permanganate, ruthenium tetroxide, osmium tetroxide, osmium tetroxide on a polymer support, and ruthenium chloride. 51. Method under claim 50, where the oxidizing agent is ozone. 52. The procedure under claim 51, whereby the conversion procedure of the aggregate compound by aldehyde reaction of phosphorus-soluble cyclosporine with the presence of a base. 53. Method according to claim 52, where phosphorus lyide is tributyl allyl phosphonium bromide. 54. The method under claim 52, where the base is selected from a group of compounds consisting of sodium hydroxide, sodium carbonate, butyllithium, hexyllithium, sodium amide, lithium hinder base, and alkali metal alkoxides. 55. Method according to claim 54, where the base is potassium tertiary-butoxide. 56. The procedure pursuant to claim 46, whereby the de-protection procedure involves exposing the mixture of the E- and Z- isomers of the protected cyclosporin 1,3-diene to the base. 57. The procedure pursuant to claim 56, whereby the deprotection procedure consists of dissolving a mixture of E- and Z- isomers of the protected cyclosporin 1,3-diene in methanol and water, and adding a base to obtain a mixture of cyclosporin-like isomers modified at the amino acid-1 portion with a 1,3-diene substituent. 58. A method for preparing a mixture of isomers of cyclosporin-like compounds modified at the amino acid-1 portion with a 1,3-diene substituent, which includes the following steps: a) Beta-alcohol protection of the amino acid-1 portion of cyclosporin to form acetylcyclosporin by mixing acetic anhydride with cyclosporin in the presence of dimethylaminopyridine (DMAP) at room temperature under a nitrogen atmosphere; b) Oxidation of acetylcyclosporin by reacting acetylcyclosporin with ozone to form the acetylcyclosporin aldehyde; c) Conversion of the acetylcyclosporin aldehyde to a mixture of E- and Z- isomers of acetyl 1,3-diene cyclosporin by mixing the acetylcyclosporin aldehyde with tributylallyl phosphonium bromide. with the presence of potassium tertiary butoxide, and d) the release of the protective coating of the mixture of E- and Z-isomers of acetyl 1,3-diene cyclosporin by dissolving the mixture of E- and Z-isomers of acetyl 1,3-diene in methanol and water and by adding potassium carbonate to form a mixture of cyclosporin-like isomers modified at the amino acid-1 portion with a 1,3-diene substituent. 59. A method for preparing a mixture of isomers of cyclosporin-like substances modified at the amino acid-1 portion with a 1,3-diene substituent, which includes the following steps: a) protection of the amino acid-1 beta-alcohol of cyclosporin to form the protected cyclosporin; b) oxidation of the protected cyclosporin to form the protected cyclosporin aldehyde; c) reaction of the protected cyclosporin aldehyde with gamma-trimethylxylyl dialkylborane or with gamma-trimethylxylylallyboronic asdiester to form the modified beta-trimethylxylyl alcohol; d) conversion of the modified beta-trimethylxylyl alcohol cyclosporin into a mixture of E- and Z-isomers of 1,3-diene cyclosporin. This was protected by Peterson olefination and e) the de-protection of the mixture of E- and Z-isomers of the protected 1,3-diene cycloporin to obtain a mixture of cycloporin-like isomers modified at the amino acid-1 portion with a 1,3-diene substituent. 60. The method pursuant to claim 59, whereby Peterson olefination is performed under acidic conditions and a mixture of cyclosporine-like isomers comprising 90% or more E-isomers. 61. The method pursuant to claim 59, whereby the beta-alcohol of amino acid-1 of cyclosporin is protected by reaction of the cyclosporin with reagents to obtain a protected cyclosporin, which is selected from a group of compounds consisting of acetate esters, benzoate esters, structurally substituted benzoate esters, ethers and xylyl ethers. 62. The method pursuant to claim 59, whereby the beta-alcohol of amino acid-1 of cyclosporin is protected by an acetate ester, resulting in acetylene cyclosporin at the protection step, consists of the mixing of acetic anhydride with cyclosporin in the presence of dimethylaminopyridine (DMAP) at room temperature under a nitrogen atmosphere. 63. The method under claim 59, whereby the oxidation step is performed with an oxidizing agent selected from a group of agents consisting of ozone, potassium permanganate, ruthenium tetroxide, osmium tetroxide, osmium tetroxide on a polymer support, and ruthenium chloride. 64. Method according to claim 63, where the oxidizing agent is zone. 65. The method under claim 59, where Peterson olefination is performed under acidic conditions, where the acid is chosen from a group consisting of acetic acid, sulfuric acid, and Lewis acid. 66. The procedure pursuant to claim 59, whereby the Peterson olefination consists of (i) dissolution of the protected cyclosporin beta-trimethylxylyl alcohol in tetrahydrofuran (THF) and (ii) addition of sulfuric acid to obtain a mixture of E- and Z- isomers of the protected 1,3-diene cyclosporin. 67. The procedure pursuant to claim 59, whereby the release procedure involves the exposure of a mixture of E- and Z- isomers of the protected 1,3-diene cyclosporine to the base. 68. The method pursuant to claim 67, whereby the deprotection procedure comprises the dissolution of a mixture of E- and Z-isomers of the protected 1,3-diene cyclosporine in methanol and water, and the addition of a base to obtain a mixture of cyclosporine-like isomers modified at amino acid-1 with a 1,3-diene substituent. 69. A method for preparing isomer mixtures of cyclosporin-like compounds modified at the amino acid-1 portion with a 1,3-diene substituent, where the following steps are involved: a) Protection of the amino acid-1 beta-alcohol of cyclosporin to form acetylcyclosporin by mixing acetic anhydride with cyclosporin in the presence of dimethylaminopyridine (DMAP) at room temperature under a nitrogen atmosphere; b) Oxidation of acetylcyclosporin by reacting it with ozone to form the acetylcyclosporin aldehyde; c) Reaction of the acetylcyclosporin aldehyde with beta-(gamma-trimethylxylyl-allyl)-diethylborane to form acetylcyclosporin beta-trimethylxylyl alcohol; d) Conversion of acetylcyclosporin to beta-trimethylxylyl alcohol. A mixture of E- and Z- isomers of acetyl 1,3-diene cyclosporine was formed by Peterson olefination under acidic conditions. Peterson olefination comprises the following steps: i) dissolving acetyl cyclosporine in beta-trimethylxyl alcohol in tetrahydrofuran (THF), and ii) adding sulfuric acid to obtain the mixture of E- and Z- isomers of acetyl 1,3-diene cyclosporine, and e) releasing the protective barrier of the mixture of E- and Z- isomers of acetyl 1,3-diene in methanol and water, and adding potassium carbonate to form the mixture of isomers of 1,3-diene cyclosporine. This is modified at the amino acid-1 portion with a 1,3-diene substituent.