TW200522975A - Pharmaceutical composition for use in the treatment of an inflammatory autoimmune disease or condition - Google Patents

Abstract

A pharmaceutical composition comprising a non-immunosuppressive, cyclophilin-binding cyclosporin, in particular [Melle]4 -Ciclosporin, and a Sanglifehrin is useful in the treatment and prevention of inflammatory autoimmune diseases, such rheumatoid arthritis.

Description

200522975. IX. Description of the invention: [Technical field to which the invention belongs] The present invention relates to new uses of cyclosporine, in particular new pharmaceutical uses of cyclosporin that are not immunosuppressive and can be combined with cyclophilin. [Prior art] Non-immunosuppressive cyclosporine that can be combined with cyclophilin and its use in the treatment and prevention of AIDS and AIDS-related diseases can be found in European Patent No. 484281, which includes a general description of cyclosporin compounds , Its nomenclature, and its mode of action. The disclosures in EP 0,484,281 B, in particular the general descriptions related to the above, and other descriptions related to the present invention, are incorporated herein by reference. [Summary of the Invention] It has been surprisingly found that cyclosporine, which can bind cyclophilin but does not have immunosuppressive properties, has an inhibitory effect on inflammatory autoimmune diseases. [Embodiment] The competitive ELISA test described in Quesniaux in Eur · J · Immunol. 1987, 1_7_, 1359-1365, if cyclosporin has one fifth of Cicclosporin (also known as cyclosporin A) binding to humans The ability to reconstitute cyclophilin, cyclosporine is considered to bind cyclophilin. In this test, the cyclosporine to be tested was added during the cultivation of cyclophilin and coated BSA-cyclosporine A. At the same time, the required amount of 50% inhibition of the control group in the absence of competitors Concentration (IC5G). Results are expressed as a binding ratio (BR), which is the ratio of IC50 of the test compound to IC50 of the same test in which cyclosporine A was used instead of cyclosporine. Therefore, BR of 1.0 refers to the test compound C: \ WINDOWS \ TEMPORARY INTERNET FILES \ OLK2153 \ 100808.DOC -5- 200522975 has a tenth of the ability of cyclosporin A to bind to cyclophilin, and a negative value means that it The binding force is greater than that of cyclosporine A. Cyclosporine, which can effectively inhibit inflammatory autoimmune diseases, has a BR value of less than 0.7 (because l0gi05 is approximately equal to 0.7), preferably equal to or lower than zero. Cyclosporine has less than 5 ° C of cyclosporine a in mixed lymphosphere reaction (MLR). , Preferably a binding force of less than 2%, the cyclosporine is considered to be non-immunosuppressive. Mixed lymphocytic reactions are described in T. Meo in "Immunoassays", l. Lefkovits and B.

Peris, Eds ·, Academic Press, N · Υ · pp. 227-239 (1979). Spleen cells (0.5 × 0.6) from Balb / C mice (female, 8 to 10 weeks of age) and radiation treatment (2000 raids) from CB A mice (female, 8 to 10 weeks of age) or Plasmamycin C-treated 0.5 × 106 spleen cells were cultured together for five days. The same tissue cells treated with radiation could induce a thinning response in Balb / C cells. The reaction could be tested by incorporating the pre-labeled region into DNA. measuring. Because the elicitor cells have been treated with radiation (or plasmamycin C), they will not be induced to proliferate by Balb / C cells, but still retain their antigenic properties. The IC5G of the test compound found in the MLR can be compared with the value of cyclosporine a @ found in parallel experiments. It has been found that the non-immunosuppressive compounds identified by the above MLR are often inactive in IL_2 Reporter Gene Assay. Therefore, IL-2 Reporter Gene Assay can be used as a method for preliminary screening to screen for the present invention. Cyclin binds a cyclosporine compound. Cyclosporine, which is a non-immunosuppressive agent which can inhibit inflammatory autoimmune diseases and which can bind cyclophilin, is considered as the active compound here and hereinafter. Active compounds are particularly useful in the treatment, prevention, or improvement of autoimmune diseases C: \ WINDOWS \ TEMPORARY INTERNET FILES \ OLK2153 \ 100808.DOC · 0 · 200522975 Diseases and inflammatory reactions, especially those with autoimmune components, Such as arthritis (such as rheumatoid arthritis, chronic progressive arthritis, and deformity arthritis) and rheumatic diseases. Specific autoimmune diseases in which the active compound can be used include autoimmune hematopoietic diseases (including, for example, hemolytic anemia, aplastic anemia, pure red blood cell anemia, and primary thrombocytopenia), systemic lupus erythematosus, polychondral Inflammation, scleroderma, Wegener's granulomatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, Stephen Johnson syndrome, primary tropical aphtha, autoimmune inflammatory bowel disease (including, for example, ulcerative colon • Inflammation and local ileitis), pancreatitis, endocrine eye disease, exophthalmic goiter, sarcomatoid disease, multiple sclerosis, primary biliary sclerosis, diabetes, such as juvenile diabetes (type 1 diabetes), Uveitis retinitis (Bescher's disease), uveitis (anterior uveitis and posterior uveitis), dry keratoconjunctivitis, spring keratoconjunctivitis, interstitial pulmonary fibrosis, psoriasis arthritis, and silky nephritis (With or without concomitant nephropathy syndromes, including primary nephropathy syndrome or minimally altered nephropathy), asthma and others Respiratory inflammatory immune ingredient, Han thyroiditis (chronic thyroiditis), encephalomyelitis, inflammatory CNS disease, and autoimmune diseases similarities. The activity of% porin as an inflammatory immune response inhibitor can be demonstrated by the following test system: ΑΑϋχΜ cancer-free uveal membrane

The right leg of a twelve-week-old female Lewis rat (brl, Basel) / primarily injected 50 mg of pure retinal s antigen. The antigen was diluted with acid-buffered physiological salt water ’, and was completely adjuvanted with Freund ’s and Bacto M AWINDOTOTEMPORARYINTEKNE ^^ m See circle DQc · η · 200522975

Tuberculosis H37 RA (Difco) was emulsified at 50:50 (v / v). The injection volume was 0.1 ml, containing 50 microliters of complete adjuvant and 1.14 mg of tuberculosis. From the tenth day after the injection, the eyes were examined daily with a slit lamp. Score the inflammation of the eye with a semi-quantitative method ranging from 0 to 4: ○ No change in vision 1 Small changes in blood vessel distribution, partial iris and conjunctival vasodilation 2 Moderate changes, loss of blood vessel clarity, iris and vasodilation The foggy medium φ 3 was significantly changed, the eye protrusions, the pupils were blurred, the blood vessel structure was obviously lost, and some bleeding 4 was severely changed. The eye protrusions were completely lost, and the structure was diffusely bleeding. References: Wacker WB ·, Donoso LA ·, Kalsow CM ·, Yakeelov JA Jr., Organisciak DT.-Experimental Allergic Uveitis. Isolation, Characterisation and Localization of a soluble Uveitopathogenic antigen from bovine retina. J. Immunol. 119 (1977) 1949-1958 Rats were called for experimental autologous encephalomyelitis (EAE). Inject the fetal bovine spinal cord and Freund's complete adjuvant mixture into the feet of male Winston rats (Wistar). Symptoms of the disease (paralysis of the tail and hind legs) usually occur within sixteen days. Record the number of diseased animals and the time of onset. Inhibition of disease occurrence in the above test mode can be used as an indicator for medical use. References · Levine et al ·, Am. JL Path · 47 (1965) 61; McFarlin et al ·, J · Immunol. 113 (1974) 712; Borel,

Transplant. &Amp; Clin. Immunol. 13 (1981) 3] o

C: \ WINDOWS \ TEMPORARY INTERNET FILES \ OLK2153 \ 100808.DOC 200522975 Florent's adjuvant-induced arthritis is injected into the bottom of the tail or hind paw of OA and Winston rats (male or female, 150 grams) 0.1 ml of mineral oil containing 0.6 mg of heat killed Mycobacterium smegmatis. In the developing arthritis model, the treatment is started immediately after the adjuvant injection (days 1 to 18); in the established arthritis model, the treatment starts on the fourteenth day, at which time the The second stage inflammation is complete (days 14 to 20). At the end of the test, the swelling of the joint was measured with a micro-bend ruler. Prevention or suppression of disease processes in the development or establishment of experimental models can be used as indicators of medical use. Reference: Winter & Nuss, Arthritis and Rheumatism 9 (1996) 394: Billingham & Davies, Handbook of

Experimental Pharmacology (Vane & Ferreira Eds, Springer Verlag, Berlin), 50/11 · (1979) 108-144] Collagen-induced f-state is administered intradermally to rats with type II collagen at the base of the tail to stimulate immunity reaction. Ten to twelve days later, the onset of arthritis is characterized by redness of the skin, swelling and swelling of the patient. Oral treatment of experimental animals ' with test compounds twice a day generally begins treatment at the beginning of swelling at two different doses and lasts up to ten days. The trial also included arthritis animals and rats treated with a patented COX inhibitor. Routine assessment of swelling of the hind feet. At the end of the study, experimental animals were sacrificed and their joints were processed for histological evaluation. A test compound that has a good swelling suppression effect, that is, about 50% of the effect of the patented Cox inhibitor, can be selected for further testing. You can also use in vitro chemotaxis tests (such as Boy den Chamber), and ring

C: \ WINDOWS \ TEMPORARY INTERNET FILES \ OLK2153 \ 100808.DOC 200522975 Avidin-induced neutrophil infiltration test and similar tests. It has been found that the structural difference between the active compound of the present invention and cyclosporine is at positions 4 and / or 5. Other possible differences are at 6 and 7. One group of active compounds is the replacement of methyl leucine at position 4 with N-methyl amino acid, such as r-hydroxy-methyl leucine, methyl isoleucine, methyl 2-amino Isovaleric acid, methylthreonine, methylaminopropionic acid, methyltyrosine or methyltyrosine (0-P0 (OH) 2), or proline. In addition to methisoleucine and methylthreonine, Mea leucine and Mea • threonine in the allotropic form can also be used. In the allotropic form, its spatial configuration is opposite to that of the natural amino acid at the / 3 position, so the amino acid in the natural form and the allotropic form are diastereomeric shopping. Another group of active compounds are those in which 2-aminoisovaleric acid is substituted at position 5 with cylamyl ', preferably N-methyl amino acid. The N-alkylated amino acid is preferably 2-aminoisovaleric acid or leucine. The hydrogen on the imino group of [2-aminoisovaleric acid] 5 is preferably substituted by unbranched (^ -6 alkyl, preferably methyl, ethyl, or n-propyl. The last group of preferred active compounds They are all novel compounds. In addition, some active compounds may differ from cyclosporine at positions 1, 2, 3, and / or 6. A particular group of active compounds used in the present invention are cyclosporine derivatives of formula A -MeBmt-ocAbu-BC-Val-MeLeu-AJa- (D) Ala-MeLeu-MeLeu-MeVal

1 2 3 4 5 6 7 8 9 10 n A C: \ WINDOWS \ TEMPORARY INTERNET FILES \ OLK2153 \ 100808.DOC-10-200522975 where B is the amino acid residue of formula B

NI CH S-AIk-R into CII 0

B wherein a represents a bond to a Abu residue at position 2; b represents a bond to a C residue at position 4;

Aik represents a straight or branched chain of olefins containing 2 to 6 carbon atoms or a fine class of 3 to 6 carbon atoms' and R represents a carboxyl or alkoxycarbonyl radical; the radical -NRiR2, where 1 ^ and 1 ^ 2 may be the same or different, and is hydrogen, alkyl, C: 2.4 alkenyl, C3-6 cycloalkyl, phenyl (optionally halogen, alkyl, oxycarbonyl, amino, Amine or diamine amino substitution), or benzyl, or saturated or unsaturated heterocyclic radicals containing 5 to 6 membered rings and 1 to 3 heteroatoms, or the heart of them! ^ Forms a saturated or unsaturated heterocyclic ring of 4 to 6 members with a nitrogen atom, and optionally contains other heteroatoms selected from nitrogen, oxygen, or sulfur, and optionally substituted with alkyl, phenyl, or benzyl; Free radicals of the following formula, n), R1 I ^ R3 R, /, where Ri and R2 are as defined above, R3 represents hydrogen or alkyl, and n is an integer from 2 to 4, and the alkyl group represents Straight or branched chain alkyl groups containing 丨 to 4 carbon atoms; C is methylleucine or 4_hydroxy_methylleucine; and its pharmacologically acceptable bribery _ 1 丨 _ 200522975

Salt.

This group of cyclosporine derivatives can be found in published International Patent Nos. WO 98/28328, WO 98/283 29, and WO 98/2833 0. Particularly preferred compounds in this group are compounds of formula A, where B is the amino acid residue Bf s-ch3

And C is the amino acid residue 4-hydroxy-methylleucine. A group of particularly good active compounds are composed of compounds of formula I -W-X-R-Y-Z-Q-AJa-(D) Ala-MeLeu-MeLeu-MeVal

I 2 3 4 5 6 7 8 9 10 11 I where W is methyl Bmt, dihydromethyl Bmt, or 8f-hydroxy-fluorenyl Bmt; X is a Abu, 2-aminoisovaleric acid, threonine, Nva, or O-methylthreonine (methyl 0 threonine); R is Sar or (D) -methylaminopropionic acid; Y is fluorenyl leucine, T-meryl-methyl white Amino acid, methyl isoleucine, methyl 2-aminoisovaleric acid, fluorenylthreonine, fluorenylaminopropionic acid, methyl tyrosine, methyltyrosine (OPO (OH) 2) , Mea isoleucine or Mea threonine, or proline; Z is 2-aminoisovaleric acid, leucine, N-Alk-2-aminoisovaleric acid, or N-Aik-leucine, Where Aik represents methyl, or methyl is substituted with ethyl, the ethyl may be optionally substituted by phenyl, or nitrogen or sulfur containing 6 members, C: \ WINDOWS \ TEMPORARY INTERNET FILES \ OLK2153 \ 100808.DOC -12- 200522975 Oxycyclyl substitution, or phenyl substitution, optionally the phenyl may be substituted by halogen; and Q is methylleucine, 7-mercapto-methylleucine, or methylaminopropionic acid and its Pharmaceutically acceptable salts. W, X, Y, Z, and Q groups have the following independent characteristics: W is preferably W1, and F is methyl Bmt or dihydromethyl Bmt;

X is preferably X '' and X 'is aAbu or Nva, more preferably X ", and X, is cl Abu J

Y is preferably Y '' and γι is T-hydroxy-methylleucine, methyl 2-aminoisovaleric acid, methylthreonine, methylaminopropionic acid, or methylglycine ( Po (OΗ) 2); Z is preferably Z ', and Z' is 2-aminoisovaleric acid or methyl 2-aminoisophosphonic acid; and Q is preferably Qf, and Q 'is fluorenyl leucine acid. Wherein W is w, X is a particularly preferred group of active compounds are compounds of formula I, Y is Y ', Z is Z', and Q is Q '. Particularly preferred active compounds of the formula I are: a) [Dihydromethyl Bmt] 1- !; hydroxy-methylleucine cycycline ab) [methyl 2-aminoisovalerate] 4-cyclosporine A , 0 [fluorenylisoleucine] 4-cyclosporine A, d) [methylthreonine] cyclosporine A, e) [r -hydroxy-fluorenylleucine] cyclosporine A, f ) [Nva] 2- [r-Hydroxy-methylleucine] 4-cyclosporine A, Amino] cyclosporine g) [T-Cycloyl-methylleucine] 4- [7-Cyclosyl -Methyl white C: \ WINDOWS \ TEMPORARY INTERNET FBLES \ OLK2153 \ 100808.doc-13-200522975-Element A, h) [Methyl 2-aminoisovaleric acid] 5_Cyclolinin a, 1) [Methyl oxygen Threonine] 2-[(D) methylaminopropionic acid] 3- [methyl 2-aminoisovaleric acid] 5-cyclosporine A, j) [8, mesityl-methyl Bmt] 1-cyclo Sporin A, k) [methylaminopropionic acid] 6-cyclosporine a, U [(D) methylaminopropionic acid] 3- [methyltyrosine (〇p〇 (〇H) 2) ] t Cyclosporine A, # m) [N_benzyl-2-aminoisovaleric acid] 5-Cyclosporin a, n) [N-5-fluoro-benzyl-2-aminoisovaleric acid ] 5_Cyclosporine a, o) [N-allyl-2-aminoisovaleric acid] Cyclosporine a, p) [N_3_phenyl-allyl_2_aminoisovaleric acid] L ring Spores a

q) [Proline] 4-Cyclosporine A The best active compounds are [methylisoleucine] 4-cyclosporin A and [r -hydroxy-methylleucine] 4-cyclosporine A , The best is [methylisoleucine] 4-cyclosporine A. In addition to the compound of formula 1, preferred active compounds include, for example, 0 [r_hydroxy-methylleucine] 9_cyclosporin A. The active compound can be obtained by the following methods: l) hair growth method 2) biological transformation method 3) derivatization 4) partial synthesis 5) total synthesis. C: \ WINDOWS \ TEMPORARY INTERNET FILES \ OLK2153 \ 100808.DOC -14- 200522975 A general and specific description of these methods can be found in Examples 1 to 10 of EP 0484281 B. This general description and example teachings are incorporated as reference material for the present invention. Example 11 in EP 0484281 B describes the non-immunosuppressive activity of the active compound relative to cyclosporine A and can be combined with cyclophilin activity measurement 'and the teaching of this example is also incorporated in the present invention. The active compound can be used in patients to prevent or treat inflammatory autoimmune diseases. Therefore, the present invention provides a non-immunosuppressive and cyclosporine-combined cyclosporine for use in the manufacture of a medicament for treating or preventing an inflammatory autoimmune disease. The invention further provides a method for treating or preventing a patient suffering from or at risk of an inflammatory autoimmune disease, which comprises administering to the patient an effective amount of an active compound of the invention. The active compound can be administered by any of the conventional routes, particularly orally, such as orally, in the form of a drinkable solution, lozenge or capsule, or parenterally, such as in the form of an injectable solution or suspension. If taken intravenously, the daily dose may be 1 to 20 mg / kg, preferably 3 to 10 mg / kg, and if taken orally, 1 to 50 mg / kg, preferably 丨0 to 30 mg / kg. This active compound is believed to be less toxic than cyclosporin A. Because the active compound is non-immunosuppressive, the side effects of cyclosporin A in immunosuppression can be avoided. In terms of side effects of other cyclosporine A, especially the nephrotoxicity and central nervous system toxicity during long-term use, the toxicity of the active compound is less than that of cyclosporine A. The active compound can be used alone or with other drugs to treat or prevent hair C: \ WINDOWS \ TEMPORARY INTERNET FELES \ OLK21S3 \ 100808.DOC -15- 200522975 inflammatory autoimmune diseases, such as with anti-inflammatory compounds and / or immunosuppression Compounds are used in combination. In a particularly preferred embodiment, the active compound is used in combination with Sanglifehrins, a recently discovered immunosuppressive compound that can bind cyclophilin, which does not inhibit Cassie Calcineurin activity. Sangrifax and its preparation are described in WO 9702285 and WO 9807743. The best grades of Sangri-Frui used with active compounds are Sangri-Fu Rui A to L, especially Sanri-Fu Rui A, B, C, and D.

Therefore, in a preferred embodiment, the present invention provides a method for treating or preventing a patient suffering from or at risk of an inflammatory autoimmune disease, comprising administering to the patient an effective amount of a combination drug containing the Active compound and a Sangri-Fruit. The present invention also provides a medical composition for treating or preventing an inflammatory autoimmune disease, which contains the active compound of the present invention and a sagrelide. The form of the pharmaceutical composition of the present invention is suitable for simultaneous, separate, or sequential treatment. Therefore, the active compound and sangriafel may be administered as a fixed composition, or they may be administered separately at different times. In general, the composition may be in the form of a unit dose having an effective amount of the preparation. Preferred active compound legal formulations include micro-emulsifiers based on those described in British Patent Case No. 2 222 770A, which include topical and oral forms; and oral and injectable forms obtained from solid solutions, as described in the British Patent Case Fatty acid monosaccharides in 2 209 671A, such as lauric monoenzyme. Unit dosage forms suitable for oral administration include, for example, 25 to 200 mg of active compound per dose. May 200522975 EP 0484281 B The formulation examples A, b, C, and all are included in the reference material of the present invention. The various ingredients of the formula and its preparation method are fully described in British Patent Case No. 2 222 770A, and its inner valley is also included in the reference material of the present invention. When the active compound is used in combination with other compounds such as Sangrifax, similar formulations can be used at appropriate active compound to other compound ratios. Therefore, when using the active compound and sagrel, the preferred weight ratio range is about 5: 1 to 50: 1 (active compound: sagrel), where the active compound dose is about 10 to 100 mg. /kg. The activity of the active compound of the present invention has been tested in animal model biological activity tests A, B, and C, see the accompanying drawings, in which: Biological activity test A. Damei experimental autologous moxibustion beer myelitis (EAR) An active compound, [methylisoleucine] 4-cyclosporine A, was tested at a dose of 30 mg / kg in the acute eaE test as described above, and was found to significantly inhibit the onset of disease. The results obtained are shown in Fig. 1, which shows the condition of the control group animals and the active compound-treated animals on the 9th to the 8th days after the immune stimulation. Animals in the control group scored more than 0.05 on day U, and approached 2.0 on days 15 and 16; and [methylisoleucine] 4-Cs treated animals did not measure scores until day 12, and scored on day 12. It reached a maximum score of about 0.5 from 15 to 17 days and then declined. Β. Body gas glucosphingitis (EAU) i) [Methylisoleucine] Cyclosporine A and Sangali Furui A were also tested separately in the EAU test as described above. Used in combination with tests. C: \ WINDOWS \ TEMPORARY INTERNET FILES \ 〇LK2153 \ 1〇〇〇〇〇〇〇〇〇〇〇〇〇〇〇〇〇〇 08〇 200522975 The results obtained are shown in Table i below.

Table I

[Methylisoleucine] 4-Cyclosporin A and Sangali Furui A in experimental autoimmune uveitis The lowest dose in the group (4 = highest) Days Control group-3.3 17.2 [ Methyl isoleucine] 4-Cyclosporin A 25 1.9 29.5 Sangali suit Rui A 1 2.5 17.7 Sangali suit Rui A 3 2.5 23.9 [Methyl isoleucine] 4-Cyclosporin A + Sangri Rui A 25 + 1 1.0 33.8 [methyl isoleucine] 4-cyclosporine A + Sangriflex Rui A 25 + 3 0 37 ii) [methyl isoleucine] 4-cyclosporine A, [ 7_Hydroxy-methylleucine] 4-cyclosporine A, and [N-benzyl-2-aminoisovaleric acid] 5-cyclosporine A, and ethanol plus corn oil placebo are also described above Tested in EAU test. The results obtained are shown in Table II below.

Table II Compounds are administered via ethanol / corn oil Compound dose mg / kg Number of eyes affected by uveitis on the twelfth day / Total number of eyes versus high score (0-4) 〇 = No uveitis 4 = Very severe Days of placebo acetic acid / corn oil 5ml / kg 4/10 4 14 NIM811 25 0/10 2 18.4 211-110 25 2/10 3.66 16.7 224-602 25 5/10 4 13.5 [methylisoleucine] 4-Cyclosporin A and Sangali Fu Rui A were also tested separately and in combination in the adjuvant arthritis test in development as described above. The results obtained are shown in FIG. 2, which shows treatment with 5 animals at 30 mg / kg [methylisoleucine] 4-cyclosporine A, 1 mg / kg Sangali Fu Rui A, or a combination of 30 mg / kg Kg [methylisoleucine] 4-cyclosporine A and 1 mg / kg sangria C: \ WINDOWS \ TEMPORARY INTERNET FELES \ OLK2153 \ 100808.DOC -18 · 200522975 The average swelling inhibition figure obtained by taking Rui A. C. Induced arthritis In the collagen-induced arthritis model of rats, the study of non-immunosuppressive cyclosporine, [methylisoleucine 4] -cyclosporine A (also known as NIM 811) for therapeutic use method. Rats were given intradermal collagen type II from the base of the tail for immunostimulation. After ten to twelve days, arthritis can occur, which can be determined by joint swelling. Immediately after swelling, animals were treated with [methylisowhite gas] -cyclosporin A (in ethanol 10% / corn oil vehicle, two different agents in private) for two days . Animals and rats in the control group Guan Lingyan treated with cox-inhibitors were also included in this study. Routine assessment of swelling of the hind feet. At the end of the study, the animals were sacrificed and their joints were taken to study their histology. [Methylisoleucine 4] _Cyclosporine A exhibited a good swelling suppressive effect on both doses (12.5 and 25 mg / kg, twice a day) on the ninth day (Figure 3) COX inhibitors were 60% effective on day 9 (dose 2.5 mg / kg, two-person a day, intraperitoneally). And Cyclosporin A data (CyA, effective ed5G is about 10-15 mg / kg, see SmithR j andslyL M ·, 'J · Pharmacol. Exp · Ther ·, June 1996; 277 (3): 1801-1813) The comparison shows that [methylisoleucine 4] _cyclosporine A has similar efficacy in the rheumatoid arthritis model. [Schematic description] Figure 1 shows control group animals (A ,, black bars) and (χ • axis) of [methylisoleucine] 4-Cs treated animals (B ,, 9 to 18 days after immune challenge). Gray bars) Disease scores (y-axis) in the EAE test; Figure 2 shows the animals in the adjuvant arthritis test at the exhibition. Α · _ 3 〇 C: \ WINDOWS \ TEMPORARY INTERNET FILES \ OLK2153 \ 100808 .DOC-19 200522975 g / kg [methylisoleucine] -Csp.o ·, β · -1 mg / kg shangri force sc, and C. 30¾g / kg [methylisoleucine wide cs ρ · 0 · + 1 mg / kg Sangali Fu Rui A treatment after inhibition of swelling percentage chart, in addition to Figure 3 is a collagen-induced arthritis test, rats were treated with a vehicle (• 匚 1-; ethanol 10 % / Corn oil / 5ml / kg, 6 animals), [methylisoleucine] _Cs 2x12.5 gram / kg / day, 7 animals), [methylisoleucine] 4-Cs ; 25 mg / kg / day, 7 animals), and patented COX inhibitors; 2 × 2.5 mg / kg / day, 4 animals), immune stimulation on the 11th day of the younger brother and on the 0th to the 9th Days (X-axis) treatment, Paw swelling clothing (in mm, y-axis) FIG. [Explanation of Symbols of Main Components] A A bar graph showing the disease score of the animals in the EAE test for the known group B A bar graph showing the disease score of the animals in the eae test treated with [methylisoleucine] 4_Cs A A bar chart showing the percentage of swelling of animals treated with 30 mg / kg [methylisoleucine] 4-Cs ρ · ο · in a developing adjuvant arthritis test B showing a developing adjuvant In the arthritic test, the animals were given i mg / kg of sangria-Fresh A sc. The percentage of swelling after treatment was shown. C shows that in the developing adjuvant arthritis test, the animals used 30 mg / kg [methyl Isoleucine] 4_Cs p〇 + 1 mg / kg

Claims (1)

200522975 10. Scope of patent application: 1. A pharmaceutical composition for treating an inflammatory autoimmune disease or disorder, which comprises an effective amount of a cyclin of formula I that is non-immunosuppressive and can be combined with cyclophilin:- W-X. R. Γ. Z-Q-AJa-(D) A] a-MeLeu ^ MeLeu-iMeVal-1 2 3 4 5 6 7 8 9] 〇 11 where W is methyl Bmt Bxnt, or 8, -hydroxy-methyl Bmt; X is a Abu, 2-aminoisovaleric acid, threonine, Nva, or 0-methylthreonine (methyl 0 threonine); R is Sar or (D) -methylaminopropionic acid; Y is methylleucine, hydroxy-methylleucine, methylisoleucine, methyl2-aminoisovaleric acid, methylthreonine , Methylaminopropionic acid, methyltyrosine, methyltyrosine (0P0 (0H) 2), Mea isoleucine or Mea threonine, or proline; Z is 2-aminoisopentyl Acid, leucine, N-Alk-2-aminoisovaleric acid, or N-Alk-leucine, where Aik represents methyl, or methyl is substituted with ethyl, which may be optionally substituted by phenyl, or Contains 6-membered ring nitrogen, sulfur, oxetanyl substitution, or benzyl substitution, as appropriate Group may be substituted by i; and Q is methylleucine, hydroxy-methylleucine, or methylaminopropionic acid, and an effective amount of Sanglifehrin, and pharmacologically O: \ 10O \ lO08O8.DOC 200522975 Acceptable diluent, excipient, or carrier. 2. The pharmaceutical composition according to item VII of the scope of the patent application, wherein the non-immunosuppressive cyclosporin-binding cyclosporine is selected from the group consisting of: and [7 Technical Group. Methyl Leucine] 4 -Cyclosporine A, [Methylisoleucine] 4 · Cyclosporine A '[Methyl 2-aminoisovalerate wide cyclosporine A, [Methyl isothreonine wide cyclosporine A, [曱Aminoaminopropionic acid] 4-cyclosporine a, [methyltyrosine], cyclosporin A '[methyltyrosine (0-P0 (0H) 2)] 4-cyclosporine A, [preserved [Mea isoleucine] aerocycline A, and [Mea threonine] 4-cyclosporine A. 3 _ The pharmaceutical composition according to item 2 of the scope of the patent application, wherein the non-immunosuppressive cyclosporine-binding cyclosporine is [methylisoleucine wide cyclosporine A or [r-hydroxy-methyl Leucine] 4-cyclosporine a. O: \ 100U00808.DOC