TW200410677A - Method of treating osteoarthritis - Google Patents

Abstract

This invention relates to combinations, compositions, and methods using or having a substituted dialkyl ether, substituted aryl-alkyl ether, substituted dialkyl thioether, substituted dialkyl ketone, or substituted-alkyl compound, or a pharmaceutically acceptable salt thereof, as an active component for preventing or treating osteoarthritis, preventing or inhibiting cartilage damage, preventing or treating rheumatoid arthritis, improving joint function, alleviating pain, including joint pain, and the like in a patient in need thereof.

Description

200410677 〇). Description of the invention [Technical field to which the invention belongs] The present invention relates to the use or use of a substituted dialkyl ether, a substituted aryl-alkyl ether, a substituted dialkyl sulfide, Methods, compositions, and combinations of substituted dialkyl ketones, or substituted-alkyl compounds, or pharmaceutically acceptable salts thereof, as active ingredients for administering to patients in need to prevent or treat bone Arthritis ("OA,"), prevention or suppression of cartilage damage, prevention or treatment of rheumatoid arthritis ("RA ,,), improvement of joint function, relief of pain, including: joint pain and the like. [Previous technology] • More than 100 million people around the world suffer from different forms of arthritis, resulting in diseases or conditions that cause disability, or even paralysis, in the joints or spine (rheumatoid spondylitis). Depending on the type of disease or condition, patients suffering from arthritis can withstand or not suffer from other symptoms, such as: psoriasis (psoriasis arthritis), autoimmune symptoms (such as systemic lupus erythematosus), gout, Muscle disorders (such as fibromyalgia), joint infections (infectious arthritis), scleroderma, or one or more of the following symptoms: urethritis, prostatitis, cervicitis, cystitis, eye disease, or skin disease (Lai Tel's Syndrome). Take the United States as an example, there are currently more than 42 million people with different forms of arthritis, including: 3,000,000 children (such as juvenile rheumatoid arthritis), the total number is expected to increase to 6 in 2020 Ten thousand people. Among various arthritis in the United States, OA is the most prevalent, with 21 million people suffering from -5- (2) (2) 200410677. OA patients suffer from cartilage damage, mainly due to joint pain and stiffness caused by joint deformities and joint function degradation or loss. In patients with RA, clinical diagnosis revealed progressive destruction of cartilage and bone. Chronic inflammation in the joints with RA and the proliferation of synovial fluid tissue invades the cartilage and bones of Bibilian, resulting in loss of joint function and disability. Aspirin and conventional non-steroidal anti-inflammatory drugs (NSAIDS), such as ibuprofen, diclofenac, and mepronyl, are typically used to treat RA-related inflammation or RA- or OA-related pain Pharmacy. NsaIDS inhibits the release of prostaglandins by blocking arachidonic acid via cyclooxygenase-1 (COX-1) and / or cyclooxygenase-2 (COX-2) modulation into cell membrane lipids. However, the traditional therapeutic uses of N S A I DS are limited by their associated drug and mechanism side effects, including fatal gastric ulcers and toxicity to the kidneys. In addition, these drugs can only treat secondary symptoms such as pain associated with cartilage damage, rheumatoid arthritis, or osteoarthritis. He cannot prevent or treat the factors that make up the symptoms of cartilage or bone pathological damage. Therefore, new and improved therapies are still needed for these diseases. It was found that the substituted mono-based alcohols, substituted aryl-sinyl ethers, substituted dialkyl sulfides, substituted dialkyl ketones, or substituted -alkyl A compound, or a pharmaceutically acceptable salt thereof, including a compound named 6- (5-carboxy-5-methyl-hexyloxy) -2,2-dimethyl-hexanoic acid (calcium salt), It can be used to prevent and suppress cartilage damage, prevent and treat rheumatoid arthritis, improve joint function, and alleviate pain, including: joint pain, bead prevention and treatment of osteoarthritis. All of the above diseases require the method (3) (3) 200410677 of the present invention to administer an effective amount of a substituted dialkyl ether, a substituted aryl-alkyl ether, a substituted dioxane to a patient in need of treatment. Sulfide, substituted dialkyl ketone, or substituted -alkyl compound, or a pharmaceutically acceptable salt thereof or comprising the compound and another therapeutically active agent (such as a COX-2 inhibitor ). [Summary of the Invention] The present invention intends that the present invention relates to the use or the presence of a substituted dialkyl ether, a substituted sulphonic acid, a substituted monobasic compound, or a substituted-carbon compound. Methods, compositions, and conjugates, in patients who need them, they use him as an active ingredient to prevent or treat osteoarthritis (" OA), prevent or inhibit cartilage damage, prevent or treat rheumatoid Arthritis ("RA"), improving joint function, alleviating pain, including ... joint pain and the like. One of the systems of the present invention is a method of inhibiting cartilage damage in mammals, comprising administering to the mammal an effective therapeutic amount of A substituted dialkyl ether, a substituted aryl-alkyl ether, a substituted dialkyl sulfide, a substituted dialkyl ketone 'or a substituted' alkyl compound, or a pharmaceutically acceptable Accepted salt. Another system of the present invention is a method for preventing mammalian cartilage damage, comprising administering to a mammal a therapeutically effective amount of a substituted dialkyl ether, a substituted aryl alkyl ether, and a substituted dialkyl sulfur. Ethers, substituted amphoteric ketones, or substituted -alkyl compounds, or pharmaceutically acceptable salts thereof-7- (4) (4) 200410677. Another system of the present invention is a method for preventing chondritis in mammals, which comprises administering to a mammal an effective amount of a substituted dialkyl ether, a substituted aryl-alkyl ether, a substituted A dialkyl sulfide, a substituted dialkyl ketone, or a substituted-alkyl compound, or a pharmaceutically acceptable salt thereof. Another system of the present invention is a method of treating mammalian osteoarthritis' comprising administering to a mammal an effective amount of a substituted monoalkyl ether, a substituted aryl-alkyl ether, a substituted Dialkyl sulfide, substituted dialkyl ketone, or substituted-alkyl compound, or a pharmaceutically acceptable salt thereof. Another system of the present invention is a method for preventing mammalian rheumatoid arthritis, which comprises administering to a mammal an effective amount of a substituted dialkyl ether, a substituted aryl-alkyl ether , Substituted dimeryl sulfide, substituted dimeryl ketone, or substituted -alkyl compound, or a pharmaceutically acceptable salt thereof. Another system of the present invention is a method of treating mammalian rheumatoid arthritis, which comprises administering to a mammal: an effective amount of a substituted diamino acid, a substituted aryl-alkane that can treat rheumatoid arthritis. Ethers, substituted dialkyl sulfides, substituted dialkyl ketones, or substituted compounds, or pharmaceutically acceptable salts thereof. Another system of the present invention is a formula for treating arthritis in mammals, which comprises a substituted ^ > — substituted aryl group, substituted aryl-alkane, which is effective for administering a therapeutic amount to mammals. Ether, substituted monoalkyl sulfide, substituted mono-8- (5) (5) 200410677 alkyl ketone, or substituted-alkyl compound, or a pharmaceutically acceptable salt thereof. In one of the systems of the present invention, the arthritis is rheumatoid arthritis. Another system of the present invention is a method for improving the function of mammalian joints' comprising administering to a mammal an effective amount of a substituted monoalkyl ether, a substituted aryl-alkyl ether, a substituted dialkyl Alkyl sulfide, a substituted dialkyl ketone, or a substituted-alkyl compound, or a pharmaceutically acceptable salt thereof. Another system of the present invention is a method for relieving pain in mammals' comprising administering to a mammal an effective amount of a reduced dialkyl ether, a substituted aryl-alkyl ether, a substituted dialkyl sulfur An ether, a substituted dialkyl ketone, or a substituted-alkyl compound, or a pharmaceutically acceptable salt thereof. Another system of the present invention is a method of treating mammalian systemic lupus erythematosus' comprising administering to a mammal a therapeutically effective amount of a substituted dialkyl ether, a substituted aryl-alkyl ether, a substituted dioxane Sulfide, substituted dimeryl ketone, or substituted-alkyl compound, or a pharmaceutically acceptable salt thereof. Another system of the present invention is a method of treating mixed connective tissue disease in mammals. 'Comprising administering to a mammal a therapeutically effective amount of a substituted dinosyl ether, a substituted aryl-alkyl ether, a substituted Alkyl sulfide, substituted diheranone, or substituted-alkyl compounds, or pharmaceutically acceptable salts thereof. Another system of the present invention is a method for treating mammalian disease regulated by IL-6. (6) (6) 200410677 disease 'comprises administering to a mammal a therapeutically effective amount of a substituted dialkyl ether, a substituted An aryl-alkyl ether, a substituted dialkyl sulfide, a substituted mono-j: ketyl ketone, or a substituted-nosyl compound, or a pharmaceutically acceptable salt thereof. Another system of the present invention is a method of treating mammalian IL-6 receptor-regulated diseases. Substituted dialkyl sulfide, substituted diheranone, or substituted-alkyl compounds, or pharmaceutically acceptable salts thereof. In another system of the invention, the disease regulated by IL-6 or the IL-6 receptor is sepsis. Another system of any one of the above methods of the present invention is that the substituted dialkyl ether is a compound of formula I

r2 R3 I or a pharmaceutically acceptable salt thereof, wherein: η and m are independently integers of 2 to 9; R1, R2, R3, and R4 are independently Cl-C6 alkyl, C2-C6 alkenyl Or C2-C6 alkynyl; or R1 and R2 attached to each other, or R3 and R4 attached to each other, or R1 and R2 attached to each other, and R3 and R4 attached to each other , Can form a carbocyclic ring having 3 to 6 carbons together; Y1 and Y2 are independently COOH, CHO, tetrafluorene, or COOR5, where R5 is C] -C6 alkyl, C2-C6 alkenyl, Or c2_C6 alkynyl; and -10- (7) (7) 200410677 wherein the alkyl, alkenyl, and alkynyl groups may be substituted by one or two groups, and the substituents are selected from the group consisting of: halogen, hydroxyl, and CrC6 alkoxy And phenyl; wherein halogen includes: chlorine, bromine, and iodine, and Ci-C6 alkoxy is a Ci-C6 alkyl group bonded through oxygen. Another system of any of the above methods of the invention is that the name of the substituted dialkyl ether compound is 6- (5-carboxy-5-methyl-hexyloxy) -2,2-dimethyl-hexanoic acid, Or a pharmaceutically acceptable salt thereof. Another system of any of the above-mentioned inventive methods is that the name of the substituted dialkyl ether compound is 6- (5-carboxy-5-methyl-hexyloxy) -2,2-dimethyl-hexanoic acid, Calcium salt. Another system of any of the above-mentioned inventive methods is that the name of the substituted dialkyl ether compound is 6- (5-carboxy-5-methyl-hexyloxy) -2,2-dimethyl-hexanoic acid, Brocade hydrated salt. Another system of any of the methods of the invention described above is the administration of a first crystalline form of a substituted dialkyl ether compound, the compound name is 6- (5-carboxy-5-methyl-hexyloxy)) -2,2-dimethyl-hexanoic acid, calcium salt. Another system of any of the methods of the invention described above is the administration of a second crystalline form of a substituted dialkyl ether compound whose name is 6- (5 · carboxy · 5-methyl-hexyloxy)) -2,2-dimethyl-hexanoic acid, calcium salt. Another system of any of the above methods of the invention is that the name of the substituted dialkyl ether compound is 6- (5-carboxy-5-methyl-hexyloxy) -2,2-dimethyl-hexanoic acid, Calcium salt ethanol solvate. Another system of any of the above methods of the invention is that the name of the substituted diethyl ether compound is 6- (5-carboxy-5-methyl-hexyloxy) -2,2-dimethyl-11-(8 ) (8) 200410677 Methyl-hexanoic acid, a calcium salt methanol solvate. Another system of any of the above methods of the invention is that the name of the substituted dipentyl ether compound is 6- (5-carboxy-5-methyl-hexyloxy) _2,2-dimethyl-hexanoic acid, Calcium salt propyl alcohol solvate. Another system of any of the above methods of the invention is that the name of the substituted diphenylenyl ether compound is 6- (5-carboxy-5-methyl-hexyloxy) -2,2-dimethyl-hexanoic acid, Calcium salt 2-propyl alcohol solvate. Another system of any of the methods of the invention described above is that the name of the substituted dialkyl acid compound is 6- (5 -endo:: 5-methyl-hexyloxy) _252 -dimethyl-hexanoic acid, calcium Salt 1-butanol solvate. Another system of the present invention is a method for inhibiting cartilage damage in mammals, comprising administering an effective inhibitory amount of a compound to mammals with cartilage damage, wherein α is called 6- (5-residue-5-methylhexyloxy) -2,2-dimethyl-hexanoic acid, Kim Jong. Another system of the present invention is a method for preventing mammalian cartilage damage, which comprises administering an effective preventive amount of the compound to mammals with cartilage damage, and the name is 6- ( 5 -residues. 5 -methylhexyloxy) -2,2-monomethyl-hexanoic acid, gold salt. Another system of the present invention is a method for preventing osteoarthritis in mammals, which comprises administering an effective preventive amount of a compound to a mammal with osteoarthritis, the name of which is 6- (5-carboxy-5-methylhexyloxy) _2_Dimethyl-hexanoic acid, Ming salt. Another system of the present invention is a method for treating osteoarthritis in mammals, comprising administering a therapeutically effective amount of a compound to a mammal with osteoarthritis, which is-12- 200410677 〇 The name is 6- (5-residue-5-methylhexyloxy) -2-monomethyl-hexanoic acid, | Bacium salt. Another system of the present invention is a method for preventing rheumatoid arthritis in mammals. Contains a compound that is effective in preventing osteoarthritis in mammals. Its name is 6- (5-carboxy-5-methylhexyloxy) -2,2-dimethyl-hexanoic acid, calcium salt. Another system of the present invention is a method for treating mammalian rheumatoid arthritis, which comprises administering an effective therapeutic amount of a compound to mammals with osteoarthritis, whose name is 6- (5-carboxy-5-methylhexyloxy Group) -2,2-dimethylhexanoic acid, calcium salt. Another system of the present invention is a method for relieving pain in mammals, which comprises administering an effective relieving amount of a compound to the mammal in pain, which is named 6- (5-carboxy-5-methylhexyloxy))-252- Dimethyl-hexanoic acid, calcium salt. In another system, the compound of formula I used in the method of the present invention is selected from the group consisting of: 7,7 ^ oxybis (2,2-dimethylheptanoic acid); 5,5'-oxybis ( 2,2-dimethylvaleric acid); 4,4'-oxybis (2,2-dimethylbutanoic acid); 8,8'-oxybis (2,2-dimethyloctanoic acid); Ethyl 2,2-dimethyl-5- (4-methyl-4-ethoxycarbonylpentyloxy) valerate; 2,2-dimethyl-6- (5-methyl-5-ethoxy Carbonylhexyloxy) hexanoic acid ethyl ester; 2,2-dimethyl-8- (7-methyl-7-methylyloctyloxy) octanoic acid methyl ester; and 7- (4-methyl-hydroxyl Carbonylpentyloxy >2; 2-dimethylheptanoic acid; or -13- (10) (10) 200410677 pharmaceutically acceptable salts thereof. In another system, it is used in the method of the present invention. A compound of formula I, which is selected from: 5- (3-carboxy-3-methyl-butoxy) -2., 2-dimethyl-valeric acid; 2.2-diethyl-5- (4-methyl Oxy-4-methyl-pentyloxy) -valeric acid; 6- (3-carboxy-3-ethyl-4-methyl-pentyloxy) -2,2-diethyl-hexanoic acid methyl ester ; 2- (3-chloro-propyl) -5- (5-methylfluorenyl-7-hydroxy-5-methyl-heptyloxy) -2-methyl-valeric acid, 6- (5-carboxyl -5-methyl-hexane Group) -2,2-dimethyl-hexanoic acid; 6- (5-carboxy-5-ethyl-heptyloxy) -2,2-diethyl-hexanoic acid, double sodium salt; 6- ( 5-butyl-5-methoxy-nonyloxy) -2-ethyl-2-methyl-hexanoic acid 6- (5-ethoxycarbonyl-6-hydroxy-5-hydroxymethyl-hexanoic acid ) -2,2-bis-hydroxymethyl-hexanoic acid ethyl ester; 2.2-dipropyl-6- [5-propyl-5- (111-tetrazolyl-5-yl) -octyloxy Group; l-hexanal; 1- {4- [4- (1-carboxycyclopropane-butyl) -butoxy] -butylbutycyclopropanecarboxylic acid; or [4- (5, 5-dimethylformate) 6-keto-hexyloxy) -butyl] -cyclopentanecarboxaldehyde 5 2-benzyl-6- (5,5-dimethyl-6-keto-hexyloxy) -2-methyl -Hexanoaldehyde; 6- (6-ethyl-6-methylamido-octyloxy) -2; 2-dimethyl-hexanoic acid; -14- (11) (11) 200410677 7- (5 -Carboxy-5-ethyl-6-methyl-heptyloxy) -2-ethyl-2-isobutyl-heptanoic acid, 2- [2- (6-carboxy-6-hexyl-dodecane (Oxy) -ethyl] -2-hexyl-octanoic acid; 8- (3-carboxy-3-isobutyl-5-methyl-hexyloxy) -2,2-dipropyl-octanoic acid, dipotassium Salt; 8- (4-carboxy-4-methyl-pentyloxy) -2,2-diethyl-octanoic acid; 2-bromomethyl-9- (4-carboxy-4-chloromethyl-5- Hydroxy-pentyloxy ) -2-iodomethyl-nonanoic acid; 9- (5-carboxy-5-pentyl-decyloxy) -2,2-bis-methoxymethyl-nonanoic acid, and triethylamine 1: 1 salt; 10- (5,5-dimethyl-6-keto-hexyloxyb, 2,2-dimethyl-decanoic acid; 11- (5-hexyloxycarbonyl-5-methyl-hexyl (Oxy) -2,2-dimethyl-undecanoate; 5- {3-ethyl-ll- [6-ethyl-6- (1 6-tetrazolyl-5-yl) -octa Alkane-n- 1-yloxy] -undecane-3 -ylbutrazole; and 11- (10-benzyl-10-carboxy-11-chloro-undecylalkyloxy) -2 , 2-diethyl · undecanoic acid; or a pharmaceutically acceptable salt thereof. Another system of any one of the above methods of the present invention is that the substituted alkyl compound is a compound of formula II. Ch3 ch3o II II,

RO—C-(CH2) n--c—OR1 II ch3 ch3 or a pharmaceutically acceptable salt thereof, wherein η is 6, 7, 8, 9, or 10; and -15- (12) 200410677 R and R1 are selected from: hydrogen and C8C8 alkyl. In another system, the compound of formula 11 used in the method of the present invention is selected from: 2,259,9-tetramethylsebacic acid; And · 2,2,12,12-tetramethyltridecanedicarboxylic acid; or a pharmaceutically acceptable salt thereof.

Another system of any one of the above methods of the present invention, the substituted nosyl compound is a compound of formula 111 ch3 ch3 R0-CH2 ——- (CH2) n--CHfOR1 m CH3 ch3 or a pharmaceutically acceptable compound thereof. Salts, where n is 6, 7, 8, 9, or 1 0;

R and R1 are selected from: hydrogen, (CrCI2-alkyl) -C (= 〇) ... H02C (CH2) mCH2-C (= 〇)-, phenyl-CH2-C (H) (NH2) .c ( = 〇)-, and (H0) 2-P (= 0)-; and m is an integer from 1 to 3; wherein the alkyl group is a linear or branched alkyl group. In another system, it is used in the method of the present invention. The compound of formula 111 is selected from the group consisting of: 2,2,9,9-tetramethyl-1,10-decanediol; or a pharmaceutically acceptable salt thereof. Another system of any one of the above methods of the present invention is that the substituted aryl-alkyl ether is a compound of formula IV -16-200410677

Or a pharmaceutically acceptable salt thereof, in which R1 is Ci-CiG radical, C3-C7i radical, phenyl- (Ci-C5), phenyl, thienyl, furanyl , Thiazolyl, pyridyl, or

r3r4n-; R3 and R4 may be the same or different G-C4 alkyl groups, or R3 and R4 may be directly combined with each other, or may be interrupted by a heteroatom selected from N, 0, and S and bonded to each other The nitrogen atom forms a 5- or 6-membered ring, wherein the 5- or 6-membered ring is hexahydropyridyl, morpholinyl, pyrrolidinyl, or piperazinyl; R2 is a bond or-(CH2) m; L1 and L2 may be the same or different alkyl groups, or L1 and L2 may be combined with each other to form-(CH2) P-;

P is an integer from 2 to 6; and when R1 is C3-C7 cycloalkyl, phenylalkyl)-, phenyl, thienyl, furanomethyl, thiazolyl, pyridyl, or R3R4N-, then L1 And L2 may further be hydrogen; wherein C3_C7 cycloalkyl, phenyl- (Cl-C5 alkyl)-, phenyl, thienyl, furanomethane, thiazolyl, pyridyl, hexahydropyridyl, morpholine Group, pyrrolidinyl group, and piperazine group may have 1 to 3 substituents as required, and the substituents are independently selected from the group consisting of: C1-C4, (C1-C4), -0, F, C1 , Br, I, OH, and a methylene dioxy group of the formula -0- (CH2) ni0-, wherein the oxygen atom of the methylene-17- (14) 200410677 dioxy group is bonded to an adjacent carbon atom To form a member ring of 5 to '; and each m is an integer of 1 to 3 independently. In another system, the compound of formula IV used in the method of the present invention is selected from: 5- [4- (1.methylcyclohexylmethyloxy) benzyl] thiazolidine-2,4-di Ketones Compounds of any one of Examples 1 to 8, 10, and 11 in U.S. Patent No. 4,287,200; Examples 1 to 5 of 4 compounds in U.S. Patent No. 4,2 8 7,200 Any one of the compounds; and U.S. Patent No. 4, 2 8 7 5 2 0 0: [any one of 2 to 7 compounds; or a pharmaceutically acceptable salt thereof. Another system of any of the above methods of the invention is that the compound substituted with a dialkyl ether, an aryl-alkyl ether, a dialkyl thioether, a dialkyl fluorene, or an alkyl compound is represented by the formula: V compound

X R1 R1 X

HOOC—— Y R2

Q

--- COOH R2 Y

V — ..... 丨 上-丨-丨 丨 A hydrolyzable functional derivative, which is selected from the group consisting of an ester, amidamine, or a 5 / methyl group) c 〇〇〇 anhydride, where R] and R2 Each independently represents an unsubstituted or

The hydrocarbon substituents of the 4th and 5th generations are selected from those which may be substituted as required: C ^ C6, _, too (15) (15) 200410677, OH, (C) -C6 alkyl) -〇_, ρ, ci , Or Br, C2-C6 alkenes, C2 C6 alkynyl, C ^ C: 7 cycloalkyl, phenyl can be optionally passed through 0H, (κ6 alkyl) -0-, Ci-Ce alkyl, F, Cl , Or Br, or heterocyclic group substitution; X and υ may each independently be: hydrogen, c] -c6 alkyl, F, C1, Br, COOH, (C-C6 alkyl) _0-C (= 0) · , Or (C ^ C6 alkyl group N (H) -C (= 0)-, and another X and γ may also be (Ci_C6 alkyl) _〇_, HO, or NC-; Q is a double radical, It consists of alkyl alkenyl diradicals containing 8 to 14 carbon atoms or from 8 to 14 carbon atoms and heteroatoms (which are selected from: S, S (O), S (0) 2, ν (Ii) Heterodenyl alkenyl diradical composition of N ((^-(: 6 alkyl), N (CH2-phenyl), and 0), in which alkylalkenyl or heteroalkylalkenyl can be seen Need to be substituted with keto (= 〇), F, Cl, Br, ΟΗ, or (C〗 -C 6 alkyl) -0, and any 1 to 4 adjacent atoms in the alkyl alkenyl or heteroalkyl alkenyl Can form C3-C7 cycloalkyl and alkane Any 2 to 4 adjacent atoms in the alkenyl or heteroalkyl alkenyl group may form a phenyl group. In another system, the compound of formula V used in the method of the present invention is selected from the group consisting of: 2,353, 14, 14, 15, -Hexamethyl-hexadecane-1,16-diacid; 2,15-di-aminomethylamido-3,3,14,14-tetramethyl-hexadecane-1,16-diacid; 3.14-diethyl-3,14-dimethyl-hexadecane-1,16-diacid; 3,3,14,14-tetrakis (2-propenyl l.hexadecane-1,16-di Acid; 3,3,1,4,1 4 -tetracyclohexyl-hexadecane-1,1 6 -diacid; 2.15-mona-3,3,14,14-tetrabenzyl-hexadecane-1 , 16-mono · acid, -19- (16) (16) 200410677 1.2- cyclopropylidene-bis- (3,3-dimethyl-7-yl-heptanoic acid); 9,9-pentyl -3,3-15,15 -tetramethyl-heptadecan-1,17-diacid; 1.2-cyclohexylene-bis- (3,3-dimethyl-7-yl-heptanoic acid); 1 , 2-benzyl- (3, 3 --methyl-7-yl · 'heptanoic acid),-3,3,15,15-tetramethyl-9-thio-heptadecan-1,17- Diacid; 9-oxa-3,3,1,5,1 -tetramethyl-heptadecan-1,1 7-diacid; 9-nitrogen-3,3,15,15 -tetramethyl -Heptadecan-1,17-diacid; 3,3,14,14 -tetramethyl-6,1 1-dithiahexadecane-1,16-diacid; Yilian 2,15-difluoro-3,3,14,14-tetramethyl-hexadecane-1,16-diacid; 2,2 , 15, 15 -tetrafluoro-3,3,14,14 -tetramethyl-hexadecane-1,16-diacid; 2,2,15,15 -tetrachloro-3,3,14,14- Tetramethyl-hexadecane-1,16-diacid; 3, 3,14,14-tetramethylol-hexadecane-1,16-diacid; 2.15-dichloro-3,14-di ( (Chloromethyl) -3,14-dimethyl-hexadecane-1,16-diacid; 2.15-dichloro-35351451, tetrakis (chloromethyl) -hexadecane-1,16-diacid; 3,3,14,14-tetra (4-hydroxyphenyl) -hexadecane-1,16-diacid; β 3,3,14,14-tetra (4-chlorophenyl) -hexadecane- 1,16-diacid; 3,3,14,14-tetra (4-methyl-phenyl) -hexadecane-1,16-diacid; and 3,3,14,14-tetra (4- Methoxy-phenyl) -hexadecane-1,16-diacid; or a pharmaceutically acceptable salt thereof. In another system, the compound of formula V used in the method of the invention is selected from the group consisting of: 1,1,14,14-tetrakis (ethoxycarbonyl) -2,2,13,13-tetramethyl-deca Tetraalkane; 1,1,16,16-tetrakis (ethoxycarbonyl) -2,2,15,15-tetramethyl-hexadecane; -20- (17) 200410677 151,12,12-tetrakis (ethyl (Oxycarbonyl) -252511511-tetramethyl-dodecane; 3,3,14,14-tetramethyl-hexadecane-1,16-diacid; 3,3,16,16-tetramethyl -Octadecane-1,1 8-diacid; 3,3,12,12-tetramethyl-tetradecanedioic acid; 1,14-bis- (ethoxycarbonyl) -1,14-dicyano -2,213,13-tetramethyl-tetradecane; 2,15-dicyano-3,3,14,14 -tetramethyl-hexadecane-1,16-diacid;

2.15 -dibromo-3,3,14,14-tetramethyl · hexadecane-1,16-diacid; 2,3,3,14,14,15-hexamethyl-hexadecane-1, 16-Diacid; 1.14-diethoxycarbonyl-2,2,13,13-tetramethyl-tetradecane; 1.14-bis- (ethoxycarbonyl) -1,14-dibromo-2,2,13 , 13-tetramethyl-tetradecinium; 1, M-bis-aminomethylmethyl-2,2,13,13-tetramethyl-tetradecane; 2.15 -dichloro-3,3,14,14 -Tetramethylhexadecane-1,16-diacid; 2.15 dibromo-3,3,14,14-tetramethylhexadecane-1,16-diacid;

2.15-dihydroxy-3,3,14,14-tetramethylhexadecane-1,16-diacid; 1,14-bis- (methylyl) -1,14-dibromo-2,2, 13,13-tetramethyltetradecane 5 1,14-di- (methyl ester) -1,14-dichloro-2,2,13,13-tetramethyltetradecane 2,15-dimethyl Oxy-3, 3,14,14-tetramethylhexadecane-1,16-diacid; 1,1,18518-tetrakis (ethyl) -2,2,17517-tetramethyloctadecane ; 3,3,18,18-tetramethyl eicosane-1,20-diacid; 3,3,14,14-tetramethyl-8-hexadecene-1,16-diacid; -21-(18) (18) 200410677 3, 3,14,14 -tetraphenyl-6, Π-diketohexadecane-1,16-diacid; 3,3,14,14-tetrabenzene Hexadecanedioic acid; 1,4-phenylene-bis-[(1,1-dimethyl-but-4-yl) -dipropionic acid dimethyl 1,4-phenylene-bis- [(1,1-dimethyl-but-4-yl) -dipropionic acid]; 1.4-phenylene-bis (3, 3-dimethyl-6-yl-5-hexenoic acid methyl Ester); 1,3-phenylene-bis (3,3-dimethyl-6-yl-5-hexenoic acid methyl ester); 1.4-phenylene-bis (3,3-dimethyl -6-yl-hexanoic acid methyl ester); Introduction 1.3- phenylene-bis (3, 3-dimethyl-6-yl-hexanoic acid methyl ester); 1.4- phenylene -Bis (3,3-dimethyl-6-yl-hexanoic acid); 1,3-phenylene-bis (3,3-dimethyl-6-yl-hexanoic acid); 1,4- (Cyclohexylene-bis- (3,3-dimethyl-6-yl-hexanoic acid methyl ester); 1,3- (cyclohexylene-bis- (3,3-dimethyl-6-yl -Methyl hexanoate); 1,4- (cyclohexylene-bis- (3,3-dimethyl-6-yl-hexanoic acid); 1,3 cyclohexylene-bis- (3,3 -Dimethyl-6-yl-hexanoic acid); 1,4-phenylene-bis (3,3-dimethyl-7-yl-5-heptenoic acid); 1.3-phenylene-bis ( 3,3-dimethyl-7-yl-5-heptenoic acid); 1,4-phenylene-bis (3,3-dimethyl-7-yl-heptanoic acid); Phenyl-bis (3 5 3 -dimethyl-7-yl-heptanoic acid); ^ 1.4- (cyclohexylene-bis- (3,3-dimethyl-7-yl-heptanoic acid); ♦ 1 , 3- (cyclohexylene-bis- (3,3-dimethyl-7-yl-heptanoic acid); and M- (cyclohexylene-bis- (3, 3-dimethyl-5-keto) -7-yl-heptanoic acid); or a pharmaceutically acceptable salt thereof. _ Another system of any of the above-mentioned methods of the invention is via a dialkyl ether-(22) (19) 200410677 square group ~ alkane Radicals, radicals, or radicals, or substituted by alkyl radicals, substituted by dialkyl sulfide, The dialkyl compound is a compound of formula VI

X R1 HOOC

γ R2

R1 X --- COOH R2 Y

VI or its pharmaceuticals μ > above accepted salts, or hydrolysable scavenger B derivatives in the body, Gan ΓΛ is selected from esters, amidines, or (c) -C5 alkyl )-〇〇Η anhydride; wherein R 1 and ρ 2 each independently represent an unsubstituted or substituted I 1, C 6 Y. The substituents are selected from the optionally substituted: 0 Η (C〗 -C 6 alkyl) -0 ... Fm C1, Br or phenyl, where phenyl may be passed through one ® or more as required,

B (scientific group) -0-, C] -C6 substituted with F, Cl, or, or heterocyclic group; 〇 X and γ are each independently: hydrogen, Ci_c6 alkyl, (Ci_c6 alkyl Η〇, NC_, F, ci, Br, COOH, (CrC6 courtyard)-0_ (〇)-, or (Cl'C6 alkyl) -N (H) -C (= 0) _; Q is a double radical 'system Alkyl alkenyl bis from 8 to 14 carbon atoms. Consists of radicals or from 8 to 14 carbon atoms and heteroatoms (selected from% Q, S (O), s (0) 2 , N (H), N (CrC6 alkyl), N (CH2-phenyl), and 0) heteroalkenyl diradical composition, in which alkyl alkenyl or wood alkenyl via keto (20), F, Cl, Br, OH, or (C ^ C6 alkyl) -0 substitution, and any 1 to 4 adjacent atoms in the alkylalkenyl or heteroalkylalkenyl group can form a C3_C7 cycloalkane And any 2 to 4 adjacent atoms in the alkylalkenyl or heteroalkenyl alkenyl group may form a phenyl group. -23- (20) 200410677 In another system, a compound of formula V1 used in the method of the invention ' It is selected from: 2,15-difluoro-3,3,14,14-tetramethyl-1,16-hexadecanedioic acid; 2,15-dichloro-3,3,14,14-tetra Methyl-hexadecane-1,1 6-diacid diisopropyl ester; and 2,2,15,15-tetrachloro-3,3,14,14-tetramethyl-hexadecane-1,16-diacid; or

Its pharmaceutically acceptable salts. Another system of any of the above methods of the invention is a compound substituted with a dialkyl ether, an aryl-alkyl ether, a dialkyl sulfide, a dialkyl ketone I, or an alkyl substituted compound Is a compound of formula VII R5 R3 R1 R5

I III HOOC—C—CH2 ~ C—Q—C—CH〇—C—COOH νπ

Or a pharmaceutically acceptable salt thereof, or a hydrolyzable end group functional group derivative, which is selected from the group consisting of C] -C6 alkyl esters, unsubstituted ammonium amines, CrC6 alkyl ammonium amines, A cyclic lactone formed by dehydration between a bis (Ci-C6 alkyl) fluorenamine, an anhydride having a Ci-C6 carboxylic acid, and a C00H group and any 0H group of R5 or R6, wherein:

Ri, R2, R3, and R4 are each independently: hydrogen, unsubstituted or substituted alkyl radical, which is selected from the group consisting of: alkyl, e-alkenyl, C2-C6 alkynyl, C3 -C7 cycloalkyl, phenyl, and phenyl VL 1-C: fluorenyl alkenyl), or heterocyclic radical; R5 and R6 are independently: hydrogen, hydroxyl, c] -c6 alkyl, -24 -(21) 200410677 bromo, cyano, nitro, C! -C 6 alkoxy, or c F 3; Q is an unsubstituted or substituted diradical of 2 to 14 carbon atoms, One or more carbon atoms may be heteroatom substituted atomic systems selected from: 0, S, S (0), S (0) 2, N (H), and N (CH2phenyl); wherein the substituents are selected From: keto (= 〇), F, Cl, Br (C! -C 6 alkyl) -〇-, and any 1 to 4 adjacent components in the straight chain C 3-C 7 cycloalkyl and in the straight chain Any 2 to 4 adjacent constituent phenyl groups. In another system, Formula VII used in the method of the present invention wherein each of R], R2, R3, R4, R5, and R6 are not hydrogen. In another system, Formula VII used in the method of the present invention is selected from: 4,4,1 1,1 tetramethyltetradecanedioic acid; 4; 4,13,13-tetramethyldeca Hexane-2,5,11,14-tetraenedi4,4,13513-tetramethylhexadecanedioic acid; 4,4,15,15 · tetramethyloctadecanedicarboxylic acid; 2,2, 1 5, 15-tetramethylhexadecane diacid; and 2,2,17,17-tetramethyloctadecanediacid. In another system, the compounds used in the method of the present invention may be benefited from Application No. 10 / 205,939; US Patent Nos. 6 ^ 6,4 5 9,003; and 6,5 06,799; US Patent Application No. 20 03/00 65 No. 1 95; and PCT international patent application straight-chain group, substituted -C 6 radical), OH, or atomic atomic compounds, compounds, diethyl acid

US Patent No. 10,802; US Case No. WO -25- (22) 200410677 0 0/5 9 8 5 5 5 Any single compound or a compound thereof, or a pharmaceutically acceptable salt thereof. In another system, the compound used in the method of the present invention may be U.S. Patent Application No. 10/20 5,9 39; U.S. Patent Nos. 6,4 1 0,802; 6,4 5 9,0 03; and 6 No. 5,06,799; U.S. Patent Application No. US 200 3/00 6 5 195; and PCT International Patent Application No. w〇

0 0/5 9 8 5 Any single compound or a compound thereof, or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of: 6- (6-hydroxy-5,5-dimethyl- Hexyloxy) -2,2-dimethyl-hexaane-1-ol phosphate mono- (1,1-dimethyl-5 (5-methyl-5 —phosphonooxyhexyloxy) _ Amyl) ester sodium salt; Dibenzyl phosphate 5- (5- (bis · benzyloxy-phosphoniumoxy) -5methyl-hexyloxy) -1,1-dimethyl-pentyl Ester; mono- (1,1-dimethyl-4- (4-methyl-4-phosphonooxypentyloxy) -butyl) phosphate sodium salt; dibenzyl phosphate 4- ( 4- (bis-benzyloxy-phosphoranyloxy) -4 methyl-pentyloxydimethyl-butyl ester; and 6- (5-hydroxy-5-methyl-hexyloxy) -2 -Methyl-hexadec-2-ol; or a pharmaceutically acceptable salt thereof. In another system, the compound used in the method of the present invention may be US Patent Application No. 09/97 6,8 67 ; US Patent Application No. US 2 0 3/0 0 1 8 0 1 3; and PCT International Patent Application No. W 0 00/3 0 863 for a single compound or a compound thereof, or a medicine thereof School -26-(23) 200410677 acceptable salt In another system, the compound used in the method of the present invention may be US Patent Application No. 09/9 7 6, 8 6 7; US Patent Application No. US 2 00 3/0 0 1 8 0 1 3 And any single compound or a compound thereof, or a pharmaceutically acceptable salt thereof, in PCT International Patent Application No. WO 0 0/3 0 8 3.

5- [2_ (5-hydroxy_4,4_dimethyl-pentyloxy) -ethoxy] dimethyl-pent-1-ol; and 3- {3- [3- (2-carboxy- 2-methyl-propylphenoxyphenylphenyl 2 52-dimethylpropanoic acid; or a pharmaceutically acceptable salt thereof.

In another system, the compounds used in the method of the present invention may be US Patent Application No. 09 / 976,93 8; US Patent Application No. US 2 03/0 0 7 82 3 9; and PCT International Patent Application No. WO 0 2/3 0 8 60 Any single compound or a compound thereof, or a pharmaceutically acceptable salt thereof. In another system, the compounds used in the method of the present invention may be U.S. Patent Application No. 09/9 7 659 3 8; U.S. Patent Application No. US 2003/000778239; and pCT International Patent Application No. WO 0 2/3 08 60, any single compound or a compound thereof, or a pharmaceutically acceptable salt thereof, which is selected from: 1,13-dihydroxy-2,2512,12 -Tetramethyl-tridecane-7__; 2,2,12,12 -tetramethylketo-tridecane diethyl ester; 1,11-dihydroxy-2,2,1051〇- Tetramethyl-alkane-6-one; -27- (24) (24) 200410677 2,12-dimethyl-7-keto-2,12-di-p-tolyl-tridecanedicarboxylic acid ; 1,13-dihydroxy-2,12-dimethyl-2,12-di-P-tolyl-tridecane-7-one; 2.12-bis- (4-isobutyl-phenyl)- 2,12-dimethyl-7-keto-tridecanedicarboxylic acid; 1.13-dihydroxy-2,12-bis- (4-isobutyl-phenyl) -2,12-dimethyl-deca Triane-7-one; 2.10-dimethyl-6-keto-2,10-diphenyl-undecane diacid; 1.11-dihydroxy-2,10-dimethyl-2,10-di Phenyl-undecane-6-one; 9-hydroxy-3 (6-hydroxy-5,5-dimethyl-hexyl) -8,8-di Nonan-2-one; bis [3- (3-hydroxy-2,2-dimethylpropyl) phenyl] methanone; 3- {3- [3- (2-carboxy-2-methyl -Propyl) -benzylidene] -phenylbenzene 2,2-dimethylpropanoic acid; 2,2J2,12-tetramethyl-7-keto-tridecanedicarboxylic acid bis-methylphosphonium amine ; 2,2J2,12-tetramethyl-7-keto-tridecanedioic acid bis-phenylphosphonium amine; and 7-keto-2; 12-dimethyl-2,12 ·· diphenyl -Tridecanedicarboxylic acid; or a pharmaceutically acceptable salt thereof. In another system, the compound used in the method of the present invention may be U.S. Patent Application No. 0 9/9 7 6, 8 9 8; U.S. Patent Application No. US 2 0 02/00 7 73 1 6; and PCT International Patent Application No. WO 02/3 0 8 84, any single compound or a compound thereof, or a pharmaceutically acceptable salt thereof. -28- (25) 200410677

In another system, the compound used in the method of the present invention may be U.S. Patent Application No. 0 9 / 976,8 98; U.S. Patent Application No. US 2 0 02/0 0 7 7 3 1 6 ·, and PCT International Patent Application No. WO 0 2/3 0 8 8 4 or any single compound or the like, or a pharmaceutically acceptable salt thereof, which is selected from: 5- [2- ( 4-carboxy-4-methyl-pentylthio) -ethylthio] -2,2-dimethylvaleric acid;

Bis- (5,5-dimethyl-6-tetrahydropiperanyloxy-hexyl) -sulfide; 6- (5,5-dimethyl-6-hydroxy-hexyl-thio) -2, 2-dimethyl-hexane-1 -alcohol; 5-hydrothio-2,2-dimethylvalerate ethyl ester; 2,2,12,12 -tetramethyl-6,8-dithiadeca Trioxane-1,13-diacid; 6- (6-hydroxy-5-methyl-5-phenylhexylthio) -2-methyl-2-phenylhexane-1-ol; 6- ( 5 -fluorenyl-5-phenylhexylthio) -2-methyl-2-phenyl-hexanoic acid;

Di- (6-hydroxy-5,5-dimethylpentyl) sulfide; 5- (5-hydroxy-4-methyl-4-phenylpentylthio) -2 · methyl-2phenyl Penta-butanol; and disodium salt of 2,2,12,12-tetramethyl-5,9-dithiatridecane diacid; or a pharmaceutically acceptable salt thereof. ‘

In another system, the compounds used in the method of the present invention may be US Patent Application No. 09/97 6,8 99; US Patent Application No. US 2 003/00228 65; and PCT International Patent Application WO 02/3 0 8 8 2 Any single compound or a compound thereof, or a pharmacologically acceptable salt thereof. In another system, the compound used in the method of the present invention may be U.S. Patent Application No. 0 9/9 7 6,8 99; U.S. Patent Application No. US 2 03/0 0 22 8 6 5; and PCT International Patent Application No. WO 0 0/3 0 8 82 Any single compound or a compound thereof, or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of: 6- (5,5-II Methyl-6-hydroxy-hexane-1-sulfinyl) -2,2-dimethyl-hexane-butanol; 6- (6-hydroxy-5-methyl-5-phenylhexylidene Sulfofluorenyl) -2-methyl-2-phenylhexyl-1-ol; 5- (5-hydroxy-4,4-dimethyl-pentyl-sulfenylsulfenyl) -2,2- Dimethyl-pentyl-butanol; and 5- (5-hydroxy-o-methyl-4-phenylpentylsulfinyl) -2-methyl-2-phenylpentane-ol; or pharmaceuticals thereof Academically acceptable salts. Another system of the present invention is a method for inhibiting mammalian cartilage damage, which comprises administering to a mammal an effective therapeutic amount of a mammalian cartilage damage and a pharmaceutically acceptable carrier, diluent, or agent. Tincture of tincture. Another system of the present invention is a method for preventing mammalian cartilage damage, which comprises administering to a mammal a therapeutically effective amount of a therapeutic agent capable of preventing mammalian cartilage damage, and a pharmaceutically acceptable carrier, dilute it, or Excipients and tinctures. Another system of the present invention is a method for preventing osteoarthritis in mammals, which comprises administering to a mammal an effective preventive agent for preventing osteoarthritis in mammals. (30) (27) (27) 200410677 Anti-dose therapeutic agent and medicine Academically acceptable carriers, diluents, or excipients. Another system of the present invention is a method for treating mammalian osteoarthritis, which comprises administering to a mammal a therapeutically effective amount of a therapeutic agent for treating mammalian osteoarthritis, and a pharmaceutically acceptable carrier, diluent, Or excipients. Another system of the present invention is a method for preventing mammalian rheumatoid arthritis, which comprises administering to a mammal an effective preventive amount of a therapeutic agent capable of preventing mammalian rheumatoid arthritis and a pharmaceutically acceptable carrier , Diluents, or excipients. Another system of the present invention is a method for treating mammalian rheumatoid arthritis, which comprises administering to a mammal an effective therapeutic amount of a therapeutic agent capable of treating mammalian rheumatoid arthritis and a pharmaceutically acceptable carrier , Diluents, or excipients. Another system of the present invention is a method for improving mammalian joint function, which comprises administering to a mammal an effective and improved amount of a therapeutic agent for improving mammalian joint function and a pharmaceutically acceptable carrier, diluent, or excipient.剂 之 搀和 剂。 The tincture and agent. Another system of the present invention is a method for treating mammalian systemic lupus erythematosus', which comprises administering to a mammal an effective therapeutic amount of a therapeutic systemic mammalian systemic lupus erythematosus, a pharmaceutically acceptable carrier, and a dilution Agents, or admixtures of excipients. Another system of the present invention is a method for treating mixed connective tissue disease in mammals, which comprises administering to a mammal an effective therapeutic amount of a therapeutic mixture of mammalian connective tissue diseases -31-(28) 200410677 And pharmaceutically acceptable carriers, diluents, or excipients. Another system of the present invention is a method for treating a regulated disease in mammals, which comprises administering to a mammal a therapeutically effective amount of a therapeutic agent capable of treating mammalian IL-6 regulated diseases, a pharmaceutically acceptable carrier, and a dilution Agents, or admixtures of excipients. Another system of the present invention is a method for treating a mammalian disease through the IL-6 receptor, which comprises administering to a mammal a therapeutically effective amount of a therapeutic agent and a medicine capable of treating mammalian disease through the IL-6 receptor. An acceptable carrier, diluent, or excipient. Another system of the present invention is a method for treating mammalian sepsis, comprising administering to a mammal an effective amount of a therapeutic agent for treating mammalian sepsis and a pharmaceutically acceptable carrier, diluent, or Tincture and agent. Another system of the present invention is a method for relieving pain in mammals, comprising administering to the mammal an effective relieving amount of a therapeutic agent and a pharmaceutically acceptable carrier, diluent, or excipient. In another system, the pain in any one of the methods for alleviating pain is osteoarthritis pain. In another system, the pain in any one of the methods for alleviating pain is rheumatoid arthritis pain. In another system, in any one of the above-mentioned methods for alleviating pain, the pain is joint pain. The received disease is regulated by animal medicine, its therapeutic agent is its treatment, and its, 苴 -32- (29) (29) 200410677. In another system, in any one of the methods for relieving pain described above , Its pain is joint pain of osteoarthritis. In another system, in any of the above-mentioned methods for alleviating pain, the pain is joint pain of rheumatoid arthritis. In another system, in any one of the above-mentioned methods for alleviating pain, the pain is acute pain. In another system, in any of the above-mentioned methods for alleviating pain, the pain is acute joint pain. In another system, in any of the above-mentioned methods for alleviating pain, the pain is chronic pain. In another system, in any of the above-mentioned methods for alleviating pain, the pain is chronic joint pain. In another system, in any of the above-mentioned methods for alleviating pain, the pain is inflammatory pain. In another system, in any of the above-mentioned methods for alleviating pain, the pain is inflammatory joint pain. In another system, in any of the above-mentioned methods for alleviating pain, the pain is mechanical pain. In another system, in any one of the methods for alleviating pain, the pain is mechanical joint pain. In another system, in any one of the above-mentioned methods for alleviating pain, 调节 pain is regulated by 1L-6, IL-6sR, or Π-6 receptors. First, in another system, in any one of the above-mentioned ways to relieve pain, the pain is in addition to joint pain, bones and joints _ ㈢ ㈢ 丨 Do not 卽 inflammation pain, rheumatoid _ arthritis pain -33 -(30) (30) 200410677 pain, and inflammatory joint pain, regulate pain via IL-6, IL-6sR, or IL-6 receptors. In another system, in any one of the methods for relieving pain, the pain is a protein or a protein and its receptor regulating pain, and the protein and its receptor system are selected from the group consisting of oncostatin, oncostatin-M, and tumorigenesis. Receptor, leukemia inhibitor factor (" LIF "), LIF and leukemia inhibitor factor receptor (LIF-R π), type 1 interleukin 1 (" IL-1 1 "), and IL _ JJ and type 1 interleukin 1 receptor ("IL-1 1 R "). In another system, in any of the above methods of pain relief, the pain is in addition to joint pain, osteoarthritis pain, rheumatoid arthritis In addition to arthritis pain and inflammatory joint pain, endothelin-1 regulates pain. In another system, any one of the above-mentioned methods of alleviating pain, the pain is bone cancer pain. In another system In any one of the methods for relieving pain, the pain is neuropathic pain. In another system, in any one of the methods for relieving pain, the pain is static touch pain. In another system, the pain relieving method is In one method, the pain is dynamic touch pain. In another system, in any of the above-mentioned methods for alleviating pain, the pain is headache. Another system of the present invention is a pharmaceutical composition comprising An effective dose of substituted dialkyl ether, substituted aryl-alkyl ether, substituted dialkyl sulfide, substituted -34- (31) (31) 200410677 dioxane Ketone, or substituted-alkyl compound, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, or excipient thereof. Another system of the present invention is a The use of pharmaceutical composition 'Lexue composition system contains an effective dose of substituted dialkyl ether, substituted aryl-alkyl ether, substituted dialkyl sulfide, applied in any of the above methods, A substituted dialkyl ketone, or a substituted -alkyl compound, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, or excipient thereof. Another aspect of the present invention One system is the use of substituted dioxane Ether, substituted aryl-alkyl ether, substituted dialkyl sulfide, substituted dialkyl ketone, or substituted -alkyl compound, or a pharmaceutically acceptable salt thereof Preparation of an agent that can be effectively applied to any of the above methods. Another system of the present invention is a composition comprising a selective COX-2 inhibitory hydrazone, or a pharmaceutically acceptable salt thereof, And substituted dialkyl ethers, substituted aryl-alkyl ethers, substituted dialkyl thioethers, substituted dialkyl ketones, or substituted -alkyl compounds, or a pharmaceutically acceptable compound thereof Acceptable salts. Another system of the present invention is a composition comprising a selective COX-2 inhibitory hydrazone, which is selected from the group consisting of xyloxane, val decoxib, and parecoxib, And the compound named 6- (5-residue-5-methyl-hexyloxy) -2,2-dimethyl-hexanoic acid, 15 salts. Another system of the present invention is a composition comprising methotrexate and a substituted dialkyl ether, a substituted aryl-alkyl ether, and a substituted -35- (32) 200410677 dialkyl A thioether, a substituted dialkyl ketone, or a substituted-endyl compound, or a pharmaceutically acceptable salt thereof. Another system of the present invention is a composition comprising a therapeutic biological agent and a substituted dialkyl ether, a substituted aryl-alkyl acid, a substituted dialkyl sulfide, a substituted dialkyl Alkyl ketones, or substituted-honoyl compounds, or pharmaceutically acceptable salts thereof.

Another system of the invention is any method of the invention, wherein a substituted dialkyl ether, a substituted aryl-alkyl ether, a substituted dialkyl sulfide, a substituted dialkyl ketone, or a substituted -Alkyl compounds are comprised of a substituted dialkyl ether, a substituted aryl alkyl ether, a substituted dialkyl sulfide, a substituted dialkyl ketone, or a substituted alkyl compound and another A therapeutically active compound or a therapeutic biological agent is replaced by a composition of the invention

Another system of the present invention is a pharmaceutical composition comprising an effective combination dose of a medicament for use in any of the above methods, and a pharmaceutically acceptable carrier, diluent, or excipient thereof. Another system of the present invention is the use of a pharmaceutical composition comprising an effective combination dose of a medicament used in any of the above methods, and a pharmaceutically acceptable carrier, diluent, or excipient thereof. Agent. [Embodiment] Formulation Example 1 Tablet formulation: -36- (33) 200410677

Ingredients __ Substituted dialkyl ethers, substituted aryl-alkyl ethers, substituted dialkyl sulfides,

Dialkyl ketones, substituted-alkyl compounds lactose ____ Intersex (for mixing) powder (paste sauce 3 magnesium stearate (1%) _ total will be used in the method of the present invention Alkyl acids, _, = and substituted aryl-alkyl ethers, substituted dialkyl sulfides, substituted ~ "monoalkyl ketones, or substituted -alkyl compounds with lactose, and corn Dian powder mix) blend until uniform. Corn starch (paste sauce) was suspended in 200 ml of water and heated with stirring to form a paste sauce. Granulated with this paste sauce and mixed powder. The wet granules were passed through a No. 8 hand screen and dried at 80 ° C. The dried granules were lubricated with 1% magnesium stearate and compressed into tablets. The tablet can be administered to humans one to four times daily to inhibit cartilage damage, improve joint function, treat rheumatoid arthritis, or treat osteoarthritis. Formulation Example 2 Coated Tablets: The tablets of Formulation Example 1 were coated with sucrose, potato starch, talcum powder, Tragarcons gum, and tinting agent-37- (34) (34) 200410677 Formulation Example 3 Injection bottle: 500 g of 6- (5-carboxy-5-methyl-hexyloxy) -2,2-dimethyl-hexanoic acid calcium salt, and 5 The pH of 3 liters of a double-distilled aqueous solution of gram of disodium hydrogen phosphate was adjusted to pH 6 · 5 with 2M hydrochloric acid. Filter the solution to sterilize, fill the filtrate into an injection bottle, freeze dry under sterile conditions, and seal under sterile conditions. Each syringe contains 25 mg of 6- (5-carboxy-5-methyl-hexyloxy) -2,2-dimethyl-hexanoic acid calcium salt. Formulation Example 4 Suppository: 25 g of 6- (5-carboxy-5 · methyl-hexyloxy) -2,2-dimethylhexanoate calcium salt, 1000 g of soybean lecithin, and 1 4 0,0 g of cocoa butter mixture is fused, poured into a mold and allowed to cool. Each suppository contains 2.5 mg of 6- (5-residue-5-methyl-hexyloxy) -2,2-dimethyl-hexanoic acid calcium salt. Formulation Example 5 Solution ... 1 g. 6- (5-carboxy-5-methyl-hexyloxy) -2,2-dimethyl-hexanoic acid calcium salt, 9.38 g NaH2P04. 1 2H20, 2 A solution was prepared from 8 · 4 8 g of N a2 Η Ρ Ο 4 · 1 2 Η 2 〇 and 0.1 g of benzyl ammonium chloride in 940 ml of double-distilled water. The pH of the solution was adjusted to 6.8 with 2M hydrochloric acid. The solution was diluted with double distilled water -38- (35) (35) 200410677 to 1.0 liter, and sterilized by radiation sterilization. 2 A 5 ml volume solution contains 25 mg of 6- (5-carboxy-5-methyl-hexyloxyb, 2,2-dimethyl-hexanoic acid calcium salt. Formulation Example 6 Ointment: In aseptic symptoms Next, 500 mg of 6- (5-carboxy-5-methyl-hexyloxy) -2,2-dimethyl-hexanoic acid calcium salt was mixed with 99.5 g of petroleum ointment. A 5 g portion of the ointment contained 25 mg 6- (5-carboxy-5-methyl-hexyloxy) -2,2-dimethyl-hexanoic acid phosphonium bow salt. Formulation Example 7 Capsule: 2 kg of 6- (5-carboxy-5 -Methyl-hexyloxy) -2,2-dimethyl_hexanoic acid calcium salt is filled into hard gelatin capsules by ordinary methods, each capsule contains .25 mg 6- (5-carboxy-5-methyl -Hexyloxy) -2,2-dimethylhexanoic acid calcium salt. Formulation Example 8 Ampoule: 2.5 kg of 6- (5-carboxy-5-methyl-hexyloxy) -2,2-di The methyl-caproate solution was dissolved in 60 liters of double distilled water. The solution was sterilized by filtration, and the filtrate was filled into ampoules. The ampoules were freeze-dried under sterile conditions and sealed under aseptic. Each ampule contained 25 Mg of 6- (5-Ceto-5-methyl-hexyloxy) -2,2-dimethyl-hexanoic acid calcium salt. -39- (36) 200410677 Formulation Example 9 tablets Formulation: Ingredient amount (mg) 6- (5-carboxy-5-methyl-hexyloxy) -2,2-dimethyl-hexanoic acid calcium salt 25 Valdecoxib 20 milk bran 50 corn Starch (for mixing) 10 Corn starch (paste) 10 Magnesium stearate (1%) 5 Total 120 6- (5-carboxy-5-methyl-hexyloxy) -2,2- Dimethyl-hexanoic acid calcium salt, val deco xib, lactose, and corn starch (for mixing) are blended until uniform. Corn starch (paste sauce) is suspended in 200 ml of water and heated with stirring To form a paste-like sauce. Granulate with this paste-like sauce and mixed powder. Pass the wet granules through a No. 8 hand screen and dry at 80 ° C. The dried granules are lubricated with 1% magnesium stearate And compressed into tablets. The tablets can be administered to humans one to four times a day to treat one of the above diseases, including rheumatoid arthritis. Formulation Example 10 Coated tablets: The tablets of Formulation Example 9 'Coating with sucrose, potato starch, talcum powder, Tragarcons gum tree' and pigment -40- (37) (37) 200410677 by general coating method Example 11 Injection bottle: 50 g of valdecoxib, 500 g of 6- (5-carboxy-5-methyl-hexyloxy) -2,2-dimethyl-hexanoic acid calcium salt, And the pH of 3 g of a double-distilled aqueous solution of 5 g of disodium hydrogen phosphate was adjusted to pH 6.5 with 2M hydrochloric acid. The solution was sterilized by filtration, the filtrate was filled into an injection bottle, freeze-dried under sterile conditions, and sealed under aseptic conditions. Each syringe contains 12.5 mg of valdecoxib and 25 mg of 6- (5-carboxy-5-methyl-hexyloxy) -2,2-dimethyl-hexanoic acid calcium salt. Formulation Example 1 2 Suppository: 50 grams of valdecoxib, 25 grams of 6- (5-carboxy-5-methyl-hexyloxy) -2,2-dimethylhexanoate, 100 A mixture of grams of soy lecithin and 1 400 grams of cocoa butter is fused, poured into a mold and allowed to cool. Each suppository contains 50 mg of valdecoxib and 25 mg of 6- (5-carboxy ~ 5-methyl-hexyloxy) -2,2-dimethyl-hexanoic acid calcium salt. Formulation Example 1 3 Solution: 0.5 g valdecoxib, [g 6- (5-carboxy-5-methyl-hexyloxy) -2,2-dimethyl-hexanoic acid calcium salt , 9.38 g of NaH2P0412H20, -41-(38) 200410677 2 8.4 8 g of Na2HP0412H2 0, and 0 1 g of benzalkonium chloride in 940 ml of bi-distilled water were used to prepare a solution. Adjust the pH of the solution to 6 · 8 with 2M hydrochloric acid. The solution was diluted to 1.0 liter with double distilled water and sterilized by radiation sterilization. A volume of 25 ml contains 12.5 mg of valdecoxib and 25 mg of 6- (5-carboxy-methyl-hexyloxy) -2,2-dimethyl-hexanoic acid calcium salt.

Formulation Example 1 4 Ointment = 100 mg of valdecoxib, 5000 mg of 6- (5-carboxy-5-methyl-hexyloxy) _2_dimethyl- Calcium hexanoate is mixed with 9 9.4 grams of petroleum paste. The 5 g portion of the ointment contains 5 mg of valdecoxib and 25 mg of 6- (5-carboxy-5-methyl-hexyloxy))-2,2-dimethyl-hexanoic acid calcium salt.

Formulation Example 15 Capsules: 2 kg of valdecoxib and 20 kg of 6- (5-carboxy-5-methyl-hexyloxy) -2,2-dimethyl-hexanoic acid calcium salt are generally The method is filled with hard gelatin capsules. Each capsule contains 25 mg of valdecoxib and 250 mg of 6- (5-carboxy-5-methyl-hexyloxy) _2,2-dimethyl-hexanoic acid. Calcium Formulation Example 16 -42- (39) 200410677 Anwa: 2.5 kg of valdecoxib, 2.5 kg of 6- (5-carboxy-5 -methyl-hexyloxy) -2,2- The dimethyl-hexanoic acid salt solution was dissolved in 60 liters of double distilled water. The solution was sterilized by filtration, and the filtrate was filled into ampoules. The female ampoules are freeze-dried under sterile conditions and sealed under sterile conditions. Each Ministry of Health: Contains 25 mg of valdecoxib and 25 mg of 6- (5-residue-5-methyl-hexyloxy) -2,2-dimethyl-hexanoic acid bromide.

Formulation Example 17 6- (5-Carboxy-5-methyl-hexyloxy) -2,2-dimethyl-hexanoic acid salt-consuming tablet Formulation: Ingredients-Amount (mg) -Miscellaneous- 5-methyl-hexyloxy) -2,2--hydrazone 1-yl-caproic acid calcium salt 25 lactose ------........ 50 corn starch (for mixing)-one by one .. .... 10 Corn starch (pastey sauce) _ .......... — 10 Magnesium stearate (1%) .........-..... ... 5 Total_ .. .......... 100

Blend 6- (5-residue-5-methyl-hexyloxy) -2,2-dimethyl-hexanoic acid, lactose, and corn starch (for mixing) until homogeneous. Corn starch (paste-like sauce) was suspended in 200 ml of water and heated with stirring to form a paste-like sauce. Granulate with this paste sauce and mixed powder. The wet granules were passed through a No. 8 hand screen and dried at 80 ° C. The dried granules are lubricated with 1% magnesium stearate -43- (40) 200410677 and compressed into tablets. Wadexi (v a 1 d e c ο X i b) syringe formulation: 3 liters of disodium. In the case of cold kvard calcium salt, you can use different water-soluble calcium salts. For coating and coloring, 500 g of valdecoxib and 5 g of hydrogen phosphate double-distilled aqueous solution can be adjusted to 2 The total volume of the filtered solution at pH 6.5 was sterilized. The filtrate was filled into injection bottles, lyophilized in sterile strips, and sealed under aseptic conditions. Each injection tube contains 25 millisieval (valdecoxib). 6- (5-carboxy-5-methyl-hexyloxy) -2,2-dimethylhexyl tablets can be administered to humans one to four daily To treat the above diseases, and the injection solution containing valdecoxib to humans 1 or 2 times a day, this injection treatment can be used simultaneously or with pills to treat one of the diseases mentioned above, including Wind festival inflammation. Formulation Example 1 8 Tablets containing a coating of 6- (5-carboxy-5-methyl-hexyloxy) -2,2-dimethyl-hexane: The tablets of Formulation Example 17 The general coating method is sucrose, potato starch, talcum powder, Tragacons gum tree, agent. Capsules containing valdecoxib: Fill 2 kg of valdecoxib with ordinary velveteen (41) 200410677 hard gelatin capsules, each capsule contains 25 mg of vadecoxib ). The tablets containing 6- (5-carboxy-5-methyl-hexyloxy) -2-dimethylhexanoic acid salt-consuming coating can be administered to humans one to four times a day to treat the above-mentioned diarrhea Diseases, and capsules containing valdecoxib can be administered to humans 1 or 2 times a day. The capsules can be taken at the same time or different pills as needed to treat one of the diseases mentioned above.

Other systems of the methods, compositions, and combinations of the invention considered by the inventors of the present case will be described in the detailed description of the invention below. DETAILED DESCRIPTION OF THE INVENTION In summary, the present invention relates to the use or the presence of substituted dialkyl ethers, substituted aryl-honoethers, substituted dihodothioethers, substituted dihonoketones, or Substituted-alkyl compounds, or methods, compositions, and combinations thereof that are pharmaceutically acceptable salts, are used in patients who require them as an active ingredient to prevent or treat osteoarthritis (" 〇A "), prevent or suppress cartilage damage, prevent or treat rheumatoid arthritis ("RA "), improve joint function, ease pain, including: joint pain. A substituted dialkyl ether, a substituted aryl-alkyl ether, a substituted dialkyl sulfide, a substituted dialkyl ketone, or a substituted dialkyl ketone used in the method, composition, or composition of the present invention Substituted-alkyl compounds include those described in U.S. Patent Nos. 35737,946; 3,930,024; 4,287,200;; 4,711,896; 5,648,387; 5,7 5 0,5 6 9; 5,756,544; 5,783,600; 6,41 〇, 802; 65459,003; and 6,506,799; U.S. Patent Application No. 09/9 76,8 6 7; 0 9/97 6,93 8; 0 9/9 76,8 9 8; -45- (42) (42) 200410677 09/9 7 6,899; and 10/2 05,93 9; US Patent Application Publication Number US 2002/0077316; US 2003/0018013; US 2003/0022865; US 2 003/0065 1 95; and US 2 003/007823 9; and PCT International Application Publication Number WO 96/30328; WO 98/30530; WO 00/5 9 8 5 5; WO 0 1/5 5 07 8; WO 02/3 0 8 60; WO 02/3 0 8 63; WO 02/3 08 82; and any system or specific embodiment of a therapeutic compound in WO 02/3 0 8 84 (herein incorporated by reference in its entirety). The substituted dialkyl ethers of formula I and their pharmaceutically acceptable salts include the compound name 6- (5-carboxy-5-methyl-hexyloxy) -2,2- Dimethyl hexanoate, and has been described in U.S. Patent Nos. 5,64 8,3 8 7 and 5,7 5 0,5 6 9; 5,7 5 6,5 4 4; and 5,783.600, and PCT International Application Publication No. WO 96/30328; WO 0 1/5 5 0 7 8. Substituted-alkyl compounds of formula II, and their pharmaceutically acceptable salts are described in U.S. Patent No. 3,7 7 3 J46. Substituted-alkyl compounds of formula III, and their pharmaceutically acceptable salts are described in U.S. Patent No. 359 3 0,024. Substituted aryl-alkyl ethers of formula IV and their pharmaceutically acceptable salts are described in U.S. Patent No. 4,28,200. A substituted dialkyl ether of formula V, a substituted aryl-co-based ether, a substituted dialkyl sulfide, a substituted dialkyl ketone, or a substituted alkyl compound, and a medicine thereof 'Scientifically acceptable salts' have been described in U.S. Patent Nos. 4,6 8 9, 3 4 4. A substituted dialkyl ether of formula VI, a substituted aryl-alkyl ether, -46- (43) (43) 200410677 substituted dialkyl sulfide, substituted dialkyl ketone, or Substituted-alkyl compounds, and pharmaceutically acceptable salts thereof, have been described in U.S. Patent No. 4,7 1 1,8 9 6. A substituted dialkyl ether of formula VII, a substituted aryl-alkyl ether, a substituted dialkyl sulfide, a substituted dialkyl ketone, or a substituted -alkyl compound, and a medicament thereof Academically acceptable salts have been described in PCT International Patent Application Publication WO 98/330530. Substituted dialkyl ethers, substituted aryl-alkyl ethers, substituted dialkyl sulfides, substituted dialkyl ketones, or substituted -alkyl compounds, and pharmaceutically acceptable Accepted salts have been described in U.S. Patent Application No. 10/2 0 5,9 3 9; U.S. Patent No. 6,4 1 0,802; 6,459,0〇3; and 6,506,799; U.S. Patent Application Publication No. US 2003 / 0065195; and PCT International Patent Application Publication WO00 / 59855 ° Substituted dialkyl ether, substituted aryl-alkyl ether, substituted dialkyl sulfide, substituted dialkyl ketone Or substituted-alkyl compounds, and their pharmaceutically acceptable salts, have been described in US Patent Application No. 09/97 6,8 67; US Patent Application Publication No. US 20 03/00 1 8 0 13; and PCT International Patent Application Publication WO 02/30863 °

Substituted dialkyl sulfides have been described in U.S. Patent Application Nos. 09 / 976,898; and 09 / 976,899; U.S. Patent Application Publication Nos. US 2002/00 7 7316; and US 2003/0022865; and PCT International Patents Application publication number wo 02/3 0 8 82 and WO-47- (44) 200410677 02/30884 ° Substituted dialkyl ketones have been described in U.S. Patent Application No. 09/97 6,93 8; U.S. Patent Application Publication No. US 2 03/0 07 8239 and PCT International Patent Application Publication WO 02/30860.

It should be recognized that the compounds used in the methods, compositions or compositions of the present invention are capable of further forming pharmaceutically acceptable salts, including (but not limited to) acid addition and / or basic salts. Acid addition salts form self-basic compounds, while basic addition salts form self-acidic compounds. All such forms are within the scope of the compounds used in the methods, compositions, or compositions of the present invention.

Substituted dialkyl ethers, substituted aryl-alkyl ethers, substituted dialkyl thioethers, substituted dialkyl ketones, or substituted > hospital compounds are pharmaceutically acceptable Acid addition salts include non-toxic salts derived from inorganic acids such as: hydrogen chloride, nitric acid, phosphoric acid, sulfuric acid, hydrogen bromide, hydrogen iodide, hydrofluoric acid, phosphorous acid, and the like Also, non-toxic salts can be derived from organic acids, such as: aliphatic mono- and dicarboxylic acids, phenyl substituted alkanoic acids, hydroxyalkanoic acids, paraffin diacids, aromatic acid acids, fats And aromatic sulfonic acids, etc., so that the salts include: sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monophosphate, dihydrogen phosphate, Metasalt, pyrophosphate, chloride, bromide, iodide, acetate, trifluoroacetate, propionate, caprylate, isobutyrate ', oxalate, malonate, No. Tallow salt, soft wood acid, sebacic acid, fumarate, maleate, phenyl glycolate Benzoate, chlorobenzoate, methylbenzoate, -48- (45) (45) 200410677 dinitrobenzoate, phthalate, benzenesulfonate, tosylate, Phenyl acetate, citrate, lactate, malate, tartrate, mesylate and the like. Non-toxic salts of amino acids may also be considered, such as: arginate and the like, as well as gluconate, galacturonic acid esters (see, for example, Berge SM · et al., "Pharmaceutical Salts, ' 'J. 〇f Phanna. Sci., 197 7; 6 6 · 1). Substituted dialkyl ethers, substituted aryl-alkyl ethers, substituted dialkyl sulfides, substituted dialkyl ketones, or acid addition salts of substituted -alkyl compounds, It is prepared by contacting a compound in a non-base form with a sufficient amount of the desired acid to produce non-toxic salts in a conventional manner. Contacting an acid addition salt with a base can regenerate compounds in a base-free form, and isolate compounds in a base-free form in a conventional manner. Compounds that do not contain the test form differ in their acid addition salt form in certain physical properties, such as solubility, crystal structure, hygroscopicity, etc. In addition, compounds that do not contain the base form exhibit acidity. The addition salt form of the formula can be equally used in the method, composition, or composition of the present invention. Substituted monoalkyl ethers, substituted aryl-alkyl ethers, substituted dialkyl sulfides, substituted dialkyl ketones, or substituted _hospital compounds that are pharmaceutically acceptable A basic addition salt is prepared by contacting a compound that does not contain an acid form with a metal cation, such as an alkali gold or alkaline earth metal cation, or an amine, especially an organic amine. Examples of suitable metal cations include: sodium cations (NO, potassium cations (κ +), magnesium cations (Mg 2 +), calcium cations (Ca 2 +), etc.) Examples of suitable amines are N, N, -di Benzylethylene monoamine, chloroprocaine, bile test, diethanolamine, dicyclohexylamine, ethyl-49- (46) (46) 200410677 diamine, N-methylamidamine, and procaine (see (Eg be OC. Supra, 1977). Substituted dialkyl ethers, substituted aryl-alkyl ethers, substituted dialkyl sulfides, substituted dialkyl ketones, or substituted -A basic addition salt of an alkyl compound, which is prepared by contacting a compound in an acid-free form with a sufficient amount of the required base to produce salts in a conventional manner. Basically, salt formation can be regenerated by contact with an acid Formation of acid-free compounds and isolation of acid-free compounds in a conventional manner. Acid-free compounds differ in some physical properties from their salt-addition salt forms. • Solubility, crystal structure, hygroscopicity, etc. In addition, the addition salt form can be equivalent Compounds used in the methods, compositions, or compositions of the present invention. Compounds used in the methods, compositions, or compositions of the present invention can be in insoluble and fused forms, including hydrated forms. Generally, this fused Forms (including hydrated forms) are inferior to insoluble forms. The method, composition or composition of the present invention may use compounds in any fused form (including hydrated form), and mixtures thereof. Used in the method, composition, or The compounds of the composition may possess one or more asymmetric centers, and each center may exist in the R or S configuration. The method, composition, or composition of the present invention may allow any substituted dialkyl ether, substituted aromatic Non-mirromeric, mirror-isomeric, or epi-isomeric forms of alkyl-alkyl ethers, substituted dialkyl sulfides, substituted dialkyl ketones, or substituted-alkyl compounds, Or a pharmaceutically acceptable salt thereof 'and mixtures thereof. Certain compounds used in the methods, compositions, or compositions of the present invention may have two or more tautomers in the range of -50 to (47) (47) 200410677. form Substituted dialkyl ethers, substituted aryl-alkyl ethers, substituted dialkyl sulfides, substituted dialkyl ketones, or tautomeric forms of substituted -alkyl compounds may Interchange ', for example, via enolization / deenolization, hydride, 1,3-hydride, or 154-hydroanion transfer, etc. The method, composition, or composition of the present invention can use any solvated form, including hydrated Form), and mixtures thereof. Some of the compounds used in the methods, compositions, or compositions of the present invention have fine groups that may exist in the entgegen or zusammen conformation, where all their geometric forms, entgegen and zusammen, cis, and Trans, and mixtures of the above, can be used in the method, composition, or composition of the present invention. Some compounds used in the method, composition, or composition of the present invention have cycloalkyl groups, and more than one carbon atom can be passed through. Instead, all of its geometric forms, cis and trans, and mixtures thereof, can be used in the methods, compositions, or compositions of the present invention. Some of the compounds used in the method, composition, or composition of the present invention may exist in an amorphous or crystalline form, and all their physical forms, including their crystal cages and mixtures thereof, can be used in the method, composition, Or composition. It is also possible to use isotopically-labeled chemical compounds in the methods, compositions, or combinations of the invention for the methods, compositions, or compositions of the invention, which are the same as the compounds described above, but in fact one or more atoms are used An atomic mass or mass number that is different from a natural atomic or mass number atom. -51-(48) (48) 200410677 Examples of isotopes that can be used in the method, composition, or composition of the present invention include examples of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine. Isotopes are, for example, 2H, 3H, 3C, MC, 15N, 180, 770, 3] p, 32p, 35S, 18] ρ, and 36C1. Compounds containing the above isotopes and / or other isotopes of other atoms and their pharmaceutically acceptable salts can be used in the methods, compositions, or compositions of the present invention. Certain isotope-labeled compounds used in the methods, compositions, or compositions of the present invention, for example, doped with a radioactive isotope such as 3 Η and 14 C, can be used to determine the distribution of drug and / or reactive tissues. Tritiated (ie, 3 η) and carbon — i 4 (ie, MC) isotopes are well known isotopes that are easy to prepare and detect. In addition, the use of heavier isotopes (such as deuterium, 2H) for metabolic stability has certain therapeutic advantages, such as increased half-life in vivo or reduced dose requirements, and can therefore be used in some situations. The above-mentioned isotope-labeled compounds in the methods, compositions, or compositions of the present invention can generally be prepared by the above and below references, or methods disclosed in the illustrations and / or examples and formulations. Reagents replace non-isotopically labeled reagents. As described above, the system of the present invention is a method for preventing or suppressing cartilage tissue damage. The ability of compounds used in the methods, compositions, or compositions of the present invention to prevent or inhibit cartilage damage can be attributed to the beneficial effects of the active compounds on changes in joint synovial fluid and tibial plateau damage, as well as evidence of reduced femoral condyle and tibial plateau damage. Explicit. Additional evidence that this active compound is beneficial includes a beneficial effect on joint proteoglycan content. The method, composition, or compounds of the composition of the present invention can also be used in combination with existing therapeutic agents for treating osteoarthritis or rheumatoid arthritis, or for alleviating pain. Suitable combination agents include standard non-steroidal anti-inflammatory agents (hereinafter referred to as NS AID'S) such as: piroxicam, diclofenac, propanoic acid such as: mepronaphthic acid, flurbiprofen, fenoxyfene, ketobenzene Propionic acid and ibuprofen, fenamates, such as · mefenamic acid, indomethacin, sulindac, azapropion, pyrazolinone, such as: batamicpine, salicylic acid Salts, such as: aspirin, C OX-2 inhibitors, such as: Celebrex® (trade name CELEBREX®, GD Searle & Co., Skokie, Illinois), valdecoxib (trade name BEXTRA) ® by Pharmacia & Upjohn Company, North Peapack, New Jersey), e tori coxib (trade name ARCOXIA® by Merck & Co., I nc., Whitehouse Station, New Jersey), In miracoxib (trade name PREXIGE® by Novartis AG, Basel, Switzerland) parecoxib, and rofecoxib (trade name VIOXX® by Merck & Co., Inc., Whitehouse Station, New Jersey), d eracoxib (trade name DERAMAXX ® by Novartis AG 5 Basel, S wit zer l and), and carprofen analgesics and intra-atrial therapies such as corticosteroids and hyaluronic acid, such as hyalinin and synvisc. Another system of the present invention is a method for treating the progress of inflammation and disease, and pharmacy A composition comprising administering an active compound, composition, or composition to mammals, including humans, cats, domestic animals, or dogs (wherein the inflammation and disease are as defined above), and the compound may be used in combination with one or more of the following to treat Other active agents of symptoms: -53- (50) 200410677 A ·) When the joint is severely inflamed and simultaneously infected with bacteria, fungi, protozoa and / or virus, the inhibitory combination is combined with one or more antibiotics, several fungi , Antiprotozoal and / or antiviral therapeutic agents; Β ·) When multiple pain and inflammation need to be treated, the inhibitory combination is administered in combination with other inflammation inhibitor modulators, which include one or more members , Which is independently selected from: (!) NSAIDS;

(2) H! -Receptor antagonists; (3) ketamine-B!-And B2-receptor antagonists; (4) prostaglandin inhibitors, which are selected from the group consisting of: PGD-, PGF-PG 12- PG E-receptor antagonists; (5) Thrombin flavin α2 (TXA2-) inhibitors; (6) 5 ... 1 2-and 1 5 -lipoxygenase inhibitors; (7) leukotrienes LTC4 · , Ltd4 / LTE4- and LTB4- inhibitors; (8) PAF-receptor antagonists;

(9) gold in a gold thio group and one or more hydrophilic groups; (10) an immunosuppressive agent selected from the group consisting of: cyclosporin, azathioprine, and methotrexate; (Π) Anti-inflammatory glucocorticoids; (12) penicillamine; (13) hydroxychloro D-quine; (1 4) anti-gout agents, including colchicine; xanthine oxidase inhibitors, including allopurinol; and uric acid excretion agents A medicament selected from the group consisting of probenecid, sulpyrazone and bromofurone; -54-(51) 200410677 c ·) When treating disease symptoms, symptoms and symptoms found in elderly mammals When the inhibitory combination is administered in combination with one or more members, it is independently selected from: (1) therapeutic agents that block memory loss and cognitive impairment: (2) can reduce atherosclerosis, hypertension, and myocardium Antihypertensive agents for ischemia, angina pectoris, congestive heart failure, and the consequences of myocardial infarction, as well as other cardiovascular drugs, are selected from:

a. Diuretics; b. Vasodilators; c. β-adrenergic receptor antagonists; d. Angiotensin-II conversion enzyme inhibitors (ACE-inhibitors), alone or as necessary Endopeptidase inhibitors; e. Angiotensin II receptor antagonists; f. Renal hormone inhibitors; g. Calcium channel blockers;

h · Sympathetic nerve cell lysing agent; i · α2-adrenergic agonist; j · α-adrenergic receptor antagonist; and k. HMG-CoA-reductase inhibitor (anti-hypercholesterol Anemia agents); (3) antitumor agents, which are selected from: a. Anti-mitotic drugs, which are selected from: i. Vinca alkaloids, which are selected from: [1] vinblastine and [2] Changchun new test; -55- (52) (52) 200410677 (4) growth hormone secretagogues; (5) strong painkillers; (6) local and general anesthetics; and (7) H2- Receptor antagonists, proton pump inhibitors, and other drugs that protect the stomach. Such compounds suitable for the method, composition, or composition administration of the present invention may be combined with inhibitors of other inflammation regulators, and one or more members contained therein are selected from the following main inhibitors and examples thereof, which Including, matrix metalloproteinase inhibitors, lectin inhibitors, TACE inhibitors, leukotriene receptor antagonists, IL-1 action and release inhibitors, iLra, Η! -Receptor antagonists; kalamine- bi_ and b 2 -receptor antagonists; prostaglandin inhibitors, such as PGD-, PGF-, PGI2-, and PGE-receptor antagonists' aflavin A2 (TXA2-) inhibitors; 5- and 12- Lipoxygenase inhibitors; leukotrienes LTC4-, LTD4 / LTE4- and LTB4- inhibitors; PAF-receptor antagonists; MEK inhibitors; κκ inhibitors; MKK inhibitors; Co-existing gold-thio forms; immunosuppressive agents' such as: cyclosporin, azathioprine, and methotrexate; anti-inflammatory glucocorticoids; penicillamine; hydroxychloro D-quine; anti-gout agents, such as: Colchicine, xanthine oxidase inhibitor, for example: allopurine And uricosuric agents to agents, e.g., probenecid, sulfinpyrazone and bromophenol pyrazolone furosemide ketone. Compounds suitable for use in the methods, compositions, or compositions of the present invention can also be used with anticancer agents such as: endostatin and angiostatin; or cytokine drugs, such as adria in vcin, daunorubicin, Cisplatin, -56- (53) 200410677 epipodophyllotoxin, glucopyranoside, paclitaxel, paclitaxel, and alkaloids, such as vincristine and antimetabolites (eg aminopterin) In conjunction with. Suitable for combination of the method, composition, or composition of the present invention with pressure medicines and other cardiovascular medicines used to overcome the consequences of atherosclerosis (including hypertension, myocardial blood including angina pectoris, congestive heart failure, and myocardial infarction) Use, which is selected from blood vessels such as hydrazine, beta-adrenergic receptor antagonists such as propranolol blockers such as nifedipine, α2-adrenergic properties such as clonidine, α-adrenergic Receptor antagonists such as prazosin with methylglutarate monocolyte CoA-reductase inhibitors (anti-high cholesterol such as lovastatin or atorvastatin. Suitable for use in combination of methods, compositions, or compositions of the present invention Administration of one or more antibiotics, antifungal, antiprotozoic or similar therapeutic agents. Combinations suitable for use in the methods, compositions, or compositions of the present invention and CNS agents such as antidepressants (eg sertraline) ), Anti-parkin medicines (such as levodopa, ricopic, mirapi, Μ Α Ο B such as cilazine and rasagiline, comp inhibitors such as tas | inhibitors, dopa Amine reuptake inhibitors, NMDA antagonists, nitinols, dopamine agonists, and neuronal nitric oxide synthase J and anti-Alzheimer's drugs such as donepezil, tacroline, inhibitors, pentylene tea It can be used in combination with alkaloid or medica. It is applicable to the method, composition, or composition of the present invention. Tysolte: For example, the formazan may also be partially deficient in local blood expansion agents, calcium general effect agents, and Symptomatic agent) can also be used, anti-disease can also be Sen's disease inhibitor b 'A-2 Gutin to promote P preparations) COX-2 can also be used -57- (54) (54) 200410677 and osteoporosis For example, roloxifene, lasofoxifene, droloxifene, or fosomax are used in combination with immunosuppressants such as FK-5 06 and rapamycin. Other mammalian diseases and conditions that can be treated with the inventive combination itself, or with a pharmaceutical composition as defined below, include: fever (including rheumatic fever and fever associated with influenza and other viral infections), common cold , Dysmenorrhea, menstrual pain, inflammatory bowel disease, local ileitis, emphysema, acute respiratory distress syndrome, asthma, bronchitis, chronic obstructive pulmonary disease, Alzheimer's disease, organ transplant toxicity, wood hole disease, allergic reactions Contact hypersensitivity, cancer (such as solid tumor cancers include colon, breast, lung, and prostate cancers; hematopoietic malignancies include leukemias and lymphomas; Hodgkin's disease; aplastic anemia, skin cancer, and familial gonadal Tumor-like polyposis), tissue ulcers, gastric ulcers, gastritis, local enteritis, ulcerative colitis, diverticulitis, recurrent gastrointestinal damage, gastrointestinal trauma, coagulation, anemia, synovitis, gout, rheumatoid spondylitis, Restenosis, periodontal disease, bullous epidermolysis, osteoporosis, loosening of artificial joint implants, atherosclerosis Sclerosis (including ruptured atherosclerotic plaques), aneurysms of the aorta (including aneurysms of the abdominal aorta and brain aortic aneurysms), nodular arteritis, congestive heart failure, myocardial infarction, stroke, Cerebral ischemia, head trauma, spinal cord injury, neuralgia, neurodegenerative disorders (acute and chronic), autoimmune disease, Huntington's disease, Parkinson's disease, periodic migraine, depression, Peripheral neuropathy, pain (including lower back and neck pain, headache, and toothache), gingivitis -58- (55) (55) 200410677, amyloid angiopathy of the brain, mental activation stimulation or cognitive enhancement, lateral sclerosis Muscular dystrophy, multiple sclerosis, ocular angiogenesis, corneal damage; injuries, macular degeneration of the retina, conjunctivitis, abnormal wound healing, muscle or joint sprains or strains, tendinitis, skin diseases (such as psoriasis, skin inflammation, scleroderma Disease and dermatitis), myasthenia gravis, polymyositis, myositis, mucocystitis, burns, diabetes (including diabetes type I and II Type, diabetic retinopathy, neuropathy, and kidney disease), tumor invasion, tumor growth, tumor metastasis, corneal scarring, scleroderma, immunotrophic diseases (such as human AIDS and FLV, FIV in cats), sepsis Disease, premature delivery, hypoprothrombin, hemophilia, thyroiditis, sarcoidosis, Behcet's syndrome, allergies, kidney disease, rickettsial infections (such as Lyme arthritis, Erlichiosis, protozoan 'protozoan diseases (such as malaria, Piridium, coccidia), reproductive disorders (such as livestock), epilepsy, cramps, and septic shock. Substituted as described in the text Dialkyl ethers, substituted aryl-alkyl ethers, substituted dialkyl sulfides, substituted dialkyl ketones, or substituted -alkyl compounds are useful human and veterinary medicines and are available To prevent and treat osteoarthritis, prevent and treat rheumatoid arthritis, improve joint function; relieve pain including (but not limited to) 0A pain, RA pain, joint pain, inflammatory pain, acute Pain, chronic pain, bone cancer pain; pain regulated by IL-6, IL-6sR, or a combination of IL-6 and IL-6sR, pain regulated by endothelin-1, static touch pain, dynamic touch pain, mechanical Pain, headache pain, and the like; and the prevention and suppression of cartilage damage in mammals; and the treatment of any other symptoms or repercussions of cartilage damage -59- (56) 200410677 Illness. The meaning of this article δ 我 和 片 §My meaning is as follows or otherwise defined in the explanatory text

"A substituted dialkyl ether, a substituted aryl-alkyl ether, a substituted dialkyl sulfide, a substituted dialkyl ketone, or a substituted -alkyl compound" is related to the `` activity "Compound" has the same meaning and means a substituted dialkyl ether, substituted aromatic compound which can be used in the method, composition, or composition of the present invention, or a pharmaceutically acceptable salt thereof, or any other form. -Alkyl ethers, substituted dialkyl sulfides, substituted dialkyl ketones, or substituted -alkyl compounds. Substituted dialkyl ethers, substituted aryl-alkyl ethers, A substituted dialkyl sulfide, a substituted dialkyl ketone, or a substituted-alkyl compound is any of the compounds described above, including cyclic ethers, which include keto-substituted ether compounds in which the oxygen atom of the ether Contains a functional group of the formula (Α): Ο

And keto-substituted thioether compounds, which are substituted dimeryl fluorene or substituted dialkyl fluorene. Any compound described herein as the active compound can be used in any method, composition, or composition of the invention. The substituted dialkyl ether 6-(5-carboxy-5 -methyl-hexyloxy))-2,2-dimethyl-hexanoic acid can be represented by the following structural formula: -60- (57) 200410677

HO

OH substituted dialkyl ether 6- (5-carboxy-5-methyl-hexyloxy) -2,2 ~ dimethyl-hexanoic acid calcium salt can be represented by the following structural formula:

H3c CH H3C ch3 2-

Ca2 +

〇

Other known names of substituted dialkyl ethers 6- (5-carboxy-5-methyl-hexyloxy) -2,2-dimethyl-hexanoic acid include π6- (5-carboxy-5 -Methyl_hexyloxy) -2,2-dimethyl-hexanoic acid monocalcium salt "," 6- (5-carboxy-5-methyl · hexyloxy) -2,2-dimethyl- Caproic acid monocalcium salt "," 6,6 ^ oxybis (2,2-dimethylhexanoic acid) ", " CI-1 02 7 " and gemcarbene calcium. CI has been clinically used -1 02 7 is used to treat dyslipidemia. Here CI-1 02 7 is a substituted dialkyl ether monocalcium salt. The substituted dialkyl ether 6- (5-carboxy-5-methyl-hexyloxy ) -2,2-dimethyl-hexanoic acid calcium salt can have many different physical forms, including crystalline form 1 and crystalline form 2. Substituted dialkyl ethers 6- (5-carboxy-5-methyl- Hexyloxy) -2,2-dimethyl-hexanoic acid calcium salt crystal form 1 and crystal form 2 have been disclosed in PCT International Patent Application Publication WO 0 1/5 5 07 8. The use of each crystal form is in Within the scope of the method of the present invention. -61-(58) 200410677 (58)

The X-ray diffraction pattern of Crystalline 1 essentially includes # 2-Theta d (A) Peak P% Area Area% FWHM 1 6.760 13.0648 5106 100.0 1497 100.0 0.234 2 8.183 10.7953 1743 34.1 435 29.1 0.200 3 8.560 10.3207 1866 36.5 543 36.3 0.233 4 9.239 9.5638 234 4.6 29 1.9 0.096 5 9.760 9.0546 972 19.0 220 14.7 0.181 6 10.569 8.3634 156 3.1 12 0.8 0.061 7 11.141 7.9353 178 3.5 29 1.9 0.130 8 13.760 6.4304 266 5.2 46 3.1 0.138 9 15.599 5.6761 338 6.6 63 4.2 0.148 10 16.740 5.2917 433 8.5 64 4.3 0.118 11 17.420 5.0866 1890 37.0 689 46.0 0.291 12 20.639 4.3000 523 10.2 128 8.5 0.196 13 21.391 4.1505 188 3.7 20 1.3 0.085 14 22.139 4.0119 445 8.7 74 4.9 0.132 15 31.559 2.8326 270 5.3 24 1.6 0.070

-62- (59) (59) 200410677 The X-ray diffraction mode of Crystal 2 essentially includes: # 2-Theta d (A) Peak P% Area Area% fwhm 1 7.259 12.1686 9283 100.0 2482 100.0 0.214 2 8.739 10.1100 4191 45.1 603 24.3 0.115 3 9.386 8.9628 967 10.4 161 6.5 0.133 4 11.659 7.5838 430 4.6 49 1.9 0.089 5 13.955 6.3408 305 3.3 58 2,3 0.151 6 14.220 6.2233 326 3.5 73 2.9 0.178 7 15.387 5.7537 278 3.0 19 0.7 0.053 8 16.461 5.3806 986 10.6 187 7.5 0.152 9 17.361 5.1039 1490 16.1 348 14.0 0.187 10 18.063 4.9069 1284 13.8 323 13.0 0.201 11 19.302 4.5947 871 9.4 166 6.7 0.152 12 19.862 4.4664 686 7.4 142 5.7 0.166 13 20.200 4.3923 457 4.9 103 4.1 0.179 14 21.178 4.1918 656 7.1 97 3.9 0.117 15 21.641 4.1031 167 1.8 6 0.2 0.029 16 22.300 3.9833 794 8.6 192 7.7 0.193 17 23.218 3.8278 247 2.7 23 0.9 0.071 18 24.100 3.6897 183 2.0 34 1.3 0.145 19 25.481 3.4928 487 5.2 141 5.7 0.231 20 28.800 3.0974 134 1.4 14 0.6 0.083 21 29.297 3.0459 259 2.8 28 1.1 0.084 22 30.700 2.9099 287 3.1 20 0.8 0-055 Substituted Alkyl ether 6- (5-carboxy-5-methyl-hexyloxy) -2,2-dimethyl-hexanoic acid calcium salt may further exist as a hydrate, published in PCT International Patent Application Publication WO 0 1 / 5 5 0 7 8 is a conventional 6- (5-carboxy-5-methyl-hexyloxy) -2,2-dimethyl-hexanoic acid monohydrate salt. Use of this hydrate or another form is within the scope of the method of the invention. -63- (60) (60) 200410677 substituted dialkyl ether 6- (5-carboxy-5-methyl-hexyloxy) -2,2-dimethyl-hexanoic acid calcium salt, further CrCn alcohol solvates, including ethanol, methanol, 1-propyl alcohol, 2-propyl alcohol, or 1-butanol solvates, the known names are PCT International Patent Application Publication WO 0 1/5 5 07 8 of 6- (5-carboxy-5-methyl-hexyloxy) -2J-dimethyl-hexanoic acid mono-calcium salt ethanol solvate, 6- (5-carboxy-5-methyl- Hexyloxy) -2,2-dimethyl-hexanoic acid mono-calcium salt methanol solvate, 6- (5-carboxy-5-methyl-hexyloxy) -2,2-dimethyl-hexane Acid monocalcium salt 1-propyl alcohol solvate, 6- (5-carboxy-5-methyl-hexyloxy) -2,2-dimethyl-hexanoic acid monocalcium salt 2-propyl alcohol Compound, 6- (5-carboxy-5-methyl-hexyloxy) -2,2-dimethyl-hexanoic acid monocalcium salt butyrate solvate. The use of such and other alcohol solvate forms is within the scope of the method of the present invention. "Therapeutic biological agents" include CP-8 70, etanercept (a tumor necrosis factor a ("TNF-alpha") receptor immunoglobulin molecule; trade names ENBREL® and ENBREL ENTANERCEPT®, Immunex Corporation, Seattle, Washington (Produced); infliximab (anti-TNF-alpha chimeric immunoglobulin 1K monoclonal antibody; trade name REMICADE®, C entocor, Inc., Malvern, Pennsylvania); methotrexate ( Trade name: RHEUMATREX®, manufactured by American Cyanamid Company, Wayne, New Jersey) 5 and adalimumab (anti-TNF-alpha human monoclonal antibody; trade name: HUMIRA®, Abbott Laboratories, manufactured by Abbott Park, Illinois). (Etanercept) refers to a dimer fusion protein comprising a human 75 kilodalton-64- (61) (61) 200410677 ("P7 5 ") tumor necrosis linked to the Fc segment of human immunoglobulin Gi The extracellular ligand-binding segment of the factor receptor (" TNFR "). The Fc component of Etanercept contains the CH2 structural region, CH3 structural region and pivotal region of immunoglobulin G1, but Non-CH1 structural region. Lydianis 01 & ^^ "〇 is made by recombinant DNA technology in the Chinese hamster ovary (" 〇] ^ 〇 '') mammalian cell expression system. It is made of 9 3 4 It has an amino acid composition and an apparent molecular weight of about 50 kilodaltons. Etanercept is a tumor necrosis factor a ("TNFan) that inhibits qi U. The brand names of Lebanese in the US market are ENBREL® and ENBREL ENTANERCEPT®, which are used to treat rheumatoid arthritis and psoriasis arthritis. 1ENBREL㊣ and ENBREL ENE T ANERCEP T® are registered by Immunex Corporation, Seattle, Washington. ENBREL® is a sterile, white, preservative-free, freeze-dried powder that has been reconstituted with 1 ml of Sterile Bacteriostatic Water for Injection, USP (containing 0.9% benzyl alcohol) for parenteral use. After reconstitution, ENBREL® solution is clear and colorless with a pH of 7.4 ± 0.3. Each single-use ENBREL (R) vial contained 25 mg of lenalixi, 40 mg of mannitol, 10 mg of sucrose, and 1.2 mg of tromethamine. As used herein, the term "infima (i n f 1 i X i m a b)" includes the product REMICADE® used in the United States market to treat rheumatoid arthritis. REMICADE⑧ is registered by Centocor, I n c.? Malvern, Pennsylvania. As used herein, the term "methotrexate" includes the compound name N- [4- [[(2,4-diamino-6-pyridinyl) methyl] methylamino] benzyl] -butan Amino acid, or a pharmaceutically acceptable salt thereof. Methotrexate is used to treat certain tumor diseases -65- (62) (62) 200410677 disease, severe psoriasis, and adult rheumatoid arthritis For example, there is a therapeutic packaging system for oral methotrexate sodium tablets called RHEUMATREX⑧ Methotrexate Sodium Dose Pack, which is designed to administer weekly doses of 5 mg, 7.5 mg, 10 mg, 12.5 mg, and 15 mg A Aminopterin and the following pharmaceutically acceptable excipients, diluents, or carriers: lactose, magnesium stearate, and pregelatinized starch. RHEUMATREX® is registered by the American Cy anamid Company, Wayne, New Jersey. The tablets may also contain corn starch. Methotrexate can also be injected intramuscularly, intravenously, intra-arterially, or in the cerebrospinal membrane. COX-2 is also known as prostaglandin synthase-2 and prostaglandin PG Η 2 synthase, and prostaglandin-Η 2 synthetase-2. C 〇 X-2 Selective inhibition! J means a compound that has a more selective inhibition of C OX-2 than COX-1, such that I c 5 〇 of a cox-!-Containing compound divided by c 〇 X-2 The I c 50 ratio of the compound is greater than or equal to 5 '. This ratio is determined by one or more determination methods. To test whether a compound is a selective COX-2 inhibitor, only a few of them need to be used in this technique. It can be tested by known test methods. There are currently two known forms of cyclooxygenase (" COX "). One is the cyclooxygenase-l (,, coxl, which is a basic isoform. ",") 'The other is inducible isoform cyclooxygenase _ 2 ("C0X2"), which will regulate the expression in the inflammation site. C OX-ΐ has physiological effects and is responsible for gastrointestinal and renal protection. CoX-2, on the other hand, has a pathological effect and is generally believed to be the main isoform when inflammation occurs. Xi-66-(63) 200410677 See the therapeutic use of C OX inhibitors (usually C OX-1 and C χ χ-2 non-selective inhibitors), limited by drug-related side effects, including lethality Ulcers and kidney toxicity. Compounds that selectively inhibit COX-2 will have anti-inflammatory effects without adverse side effects related to COX-1 inhibition. For the purposes of the present invention, selective CO OX-2 inhibitors include compounds, or pharmaceutically acceptable salts thereof, which are selected from the group consisting of: LAS-3 447 5; UR-8 8 8 0; ABT-963; Valdecoxib; BMS-347070; CELECOXIB; T i 1ac oxib; compound of formula (B)

(B) CS-502 [CheiTiical Abstracts Service Registry

Number (nCAS Reg. Number) 1 76429-82-6]; (6aR, 10aR) -3- (l, l-dimethylheptyl) -6a, 75l0,10a-tetrahydro-1- -6,6-monomethyl-611 · monobenzo [b, d] piperan · 9-xiangase (" CT-3 "); -67- (64) (64) 200410677 CV-247; 2 (5H) -furanone, 5,5-dimethyl-3- (1-methylethoxy) -4- [4- (methylsulfonyl) phenyl] _ (`` DFP "); Carprofen (trade name RIMADYL®, Pfizer, Inc., New York, New York);

Deracoxib (trade name DERAMAXX®, Novartis AG, Basel, Switzerland);

Etoricoxib (trade name ARCOXIA®, MERCK & CO., Inc., Whitehouse Station, New Jersey); GW-4063 8 1; T iracoxib; M e 1 oxicam; Nimesu 1 ide 2- (ethoxyloxy) Benzoic acid, 3 .- [(nitrooxy) methyl] phenyl ester (,, NCX4016 ,,);

Lumiracoxib (trade name PREXIGE® by Novartis AG, Basel, Switzerland);

Parecoxib (trade name application pending for DYNASTAT® by G. D. Searle & Co., Skokie, Illinois); P54 (CAS Reg. No. 1 3 0996-2 8-0)

Rofecoxib (trade name VIOXX® by MERCK & CO ·, Inc ·, W hitehouse Station, New Jersey);

ReviMiD; 2,6-bis (1,1-dimethylethyl) -4- [kg]-(2-ethyl-1,1-di: keto-68- (65) (65) 200410677 5-isothiazolidine-1-ylidene) methyl] phenol (nS-2474 "); 5 (11) -thio-6-sulfamin-3 (21 ^ benzofuranone (", "7 ^ 2〇16 ,,); and N- [3- (formamidine) -4-keto-6-phenoxy-4H-1-phenylsulfanyl] -methanesulfonamide ΓΤ-614 "); or its medicine Scientifically acceptable salts. The term "xyloroxine" as used herein means the name 4-(5-(4-tolyl 3 _ (trifluoromethyl) -1Η-pyrazol-1-yl)- A compound of benzsulfonamide. Hillard is a selective cyclooxygenase-2 ("COX-2") inhibitor currently approved by the US Food and Drug Administration for the treatment of osteoarthritis, rheumatoid arthritis, and Polyposis and familial adenoma. The market name of Xilean is "CELEBREX®". Currently, Xilean is currently used in clinical trials to treat bladder cancer, chemopreventive lung cancer, and postoperative pain, and it has been registered for treatment. Dysmenorrhea. The structure of Xilean is as follows:

The term "valdecoxib" herein means the name of the compound is 4- (5-methyl-3-phenyl-4-isohumazolyl) -benzenesulfonamide, which is described in US Patent No. 55633, 272; 5,8595257; and 5,985,902, the entire contents of which are incorporated herein by reference. Valdecoxib has been approved by the US Food and Drug Administration for the treatment of osteoarthritis, rheumatoid arthritis, dysmenorrhea, and general pain, and is marketed under the trade name `` BEXTRA® ''. -69- (66) ( 66) 200410677 λ / aide cox ib is currently undergoing clinical trials to treat periodic migraine. The structure of valdecoxib is as follows:

Carprofen and deracoxib have been shown to treat animal arthritis, especially dogs. The terms "use", "use", and "adoption", and derivatives thereof, can be used interchangeably to describe the method, composition, or composition of the present invention. The terms "including", "having π" and " 'Included', unless specifically stated otherwise, is open ended. "'Coupling" or' 'coupling agent' means that the ingredients to be mixed comprise a heterogeneous or homogeneous mixture. In some cases a homogeneous mixture is preferred. In other cases, a heterogeneous mixture is preferred. The term n ED 4 0 herein means a dosage of a drug sufficient to inhibit cartilage damage or treat at least 40% of the above-mentioned diseases or conditions to be treated, including the active compound, or a pharmaceutically acceptable salt thereof. The term "drug" herein has the same meaning as "therapeutic agent", "active ingredient", "active compound", and "active ingredient", and includes non-toxic therapeutic agents such as active compound, heroin, Or a pharmaceutically acceptable salt thereof, valdecoxib or a pharmaceutically acceptable salt thereof, and may further include one or two other therapeutic agents described above. -70- (67) (67) 200410677 The term "non-toxic" herein means that its effective dose is 10 times or more of the dose at which toxicity is observed at 10% or more of the number of patients. The term "patient" herein means a mammal, and the two terms are interchangeable. For the purposes of the present invention, the term "mammal" includes humans, dragons such as cats and dogs, domestic animals such as horses, cattle, Ogata, goats, and sheep, and experimental animals such as guinea pigs, rabbits, rats, mice, mice, and monkeys, as well as variants that introduce foreign genes. It is better for human patients. Dragons are also good, especially dogs , Cats, and horses. Also preferred are experimental animals, especially rabbits, mice, mice, and monkeys, as well as variants that introduce foreign genes. "Pets" include dogs, cats, rabbits, hamsters, monkeys, horses, and Other kinds of domestic or sakura pets. "Livestock" here means domesticated tetrapods, which includes Ichimichi breeders for meat and different by-products. For example, bovines include cattle and their daggers. Members, pigs including domestic, domestic, homemade pigs and other members of the family, pigs including sheep and other sheep, domestic, domestic, homemade Sheep and other members of the genus Goat; domesticated tetrapods raised for special tasks, such as for use as load animals, for example, equines include domestic, domestic, home-made horses and other equine scallops, or for Search and alert tasks, such as canines including domestic, domestic, homemade dogs, and other members of the canine family; and domesticated tetrapods that are raised primarily for recreational purposes, such as equine and canine members, And felines include domestic, domestic, homemade cats and -71-(68) (68) 200410677 other members of the feline family. For the purposes of the present invention, the term "arthritis" herein includes osteoarthritis, rheumatoid arthritis, degenerative joint disease, spinal arthropathy, gouty arthritis, systemic lupus erythematosus, juvenile, Juvenile arthritis' and psoriatic arthritis. The substituted dialkyl ethers, substituted aryl-honoethers, substituted dialkyl sulfides, and the like used in the methods, compositions, or compositions of the present invention, Substituted dialkyl ketones, or substituted-hospital compounds are also used in the treatment of degenerative joint disease, spondyloarthropathy, gout (sex) arthritis, systemic lupus erythematosus; juvenile, juvenile arthritis' And psoriatic arthritis. "Cartilage damage" means articular cartilage and subchondral bone disorders, which are characterized by hypertrophy of the joint site and surrounding tissues, which may or may not be accompanied by deterioration of the surface of the articular cartilage. Here cartilage damage refers to articular cartilage Damage. Cartilage is a multicellular tissue found in joint linings and other body parts, including the nose. Cartilage tissue moves in the joints. It provides a friction-free surface and forms the soft tissue of the body, such as the nostrils of the nose. When cartilage tissue is damaged by disease or trauma, it is a product of fracture, and the physiological function of the tissue is damaged. The main cartilage in the body is Three types, including articular cartilage. "Inhibiting cartilage damage" means a compound, or a combination of the above, for the pathological features or symptoms of any one or more of the cartilage damage phenomena of some diseases and disorders that include cartilage damage in the pathology of the disease or disorder. Partially or completely eliminates, alleviates, inhibits or prevents the initiation, inhibits development, prevents further development, or reverses the effect of treatment. For patients at risk of cartilage damage -72- (69) (69) 200410677 can be like cartilage damage The patients receive medical treatment for preventive treatment. The pathological characteristics of the disease or condition are related to changes in the body structure. This is the direct or indirect result of the body being afflicted with the disease or condition. The structural changes can be clinically observed and tissue sectioned. , Pathological examination or imaging techniques such as X-ray or magnetic resonance scanning The structure of the site is confirmed. Exemplary examples of pathological features include histopathological cartilage damage, bone thickening or loosening, muscle hypertrophy, fibrosis, ligament or tendon laceration, etc. The term "osteoarthritis" as used herein includes the main joint diseases It is characterized by pathological features of articular cartilage damage, and may also have joint pain symptoms. Osteoarthritis patients do not experience symptoms of joint inflammation, although they may sometimes experience transient inflammatory burning. The term "rheumatoid arthritis" as used herein includes articular rheumatism, which is mainly characterized by symptoms of arthritis and is visually accompanied by joint pain. Patients with rheumatoid arthritis also end up with articular cartilage damage. The term `` treatment '' herein refers to the administration of one or more compounds, or compositions as defined above in the methods of the invention, to one or more signs or symptoms of any one of the diseases and disorders to be treated, including (but not limited to) The pathological characteristics of cartilage damage and pain symptoms and inflammation, partially or completely eliminate, alleviate, inhibit or prevent initiation, inhibit development, prevent further development, or reverse progression. Patients at risk for a disease or condition can be treated as if they were medically treated for preventive treatment. As used herein, the term "prevention" means the prophylactic administration of one or more active compounds or combinations of the present invention to asymptomatic patients at risk of suffering from the disease or condition to be prevented according to the methods defined above in the present invention to inhibit the priming phase. -73- (70) (70) 200410677 related pathological features or symptoms, including (but not limited to) cartilage damage pathological features and pain symptoms and inflammation. In addition, once the onset of pathological features or symptoms begins, 'prevention means preventing further progress Or reverse the progression of some or all of the pathological features or symptoms. As described above, the 'active compound can be administered preventively to prevent or inhibit asymptomatic patients (mammals) from causing osteoarthritis, rheumatoid arthritis, loss of joint function, Cartilage damage, or any pain. Asymptomatic patients at risk for the disease or condition to be prevented can be analyzed for genetic effects (hereditary or spontaneous mutational diseases and conditions), family history, occupation, exercise habits, general medical screening, etc. Acknowledgement. The term "improved" herein means the use of a method in accordance with the above definition of the invention. Clinical evaluation of various compounds or conjugates, including, but not limited to, partial or complete elimination or prevention of loss, suppression of further loss, improvement of any one or more functions of patients with any ameliorable diseases and conditions, including (but not limited to) Rheumatoid arthritis and osteoarthritis. "Joint function" refers to the results of clinical evaluation of any one or more joint functions in patients with any ameliorable diseases and conditions, including (but not limited to) rheumatoid arthritis and osteoarthritis diseases, Includes stiffness, range of displacement, flexibility, and displacement-related symptoms (for example, gait changes, pain, fever, or inflammation). Western Ontario and McMaster Universities Osteoarthritis Index ("WOMAC") can be used clinically to assess joint function g. "Relieving pain" means that one or more compounds or conjugates as defined above according to the method of the present invention are effective in reducing, preventing, or inhibiting pain in a patient, including eliminating, or inhibiting, or initiating, inhibiting, reducing -74-(71) 200410677 (But not limited to) inhibiting, reducing, preventing, suppressing or removing pain symptoms caused by cartilage damage, acute pain, chronic pain, mechanical pain, static touch pain, dynamic touch pain, bone cancer pain, headache, osteoarthritis pain , Inflammatory pain, and the effects of pain associated with autoimmune disease or myofiberic pain. "Joint pain" means any joint pain. π Osteoarthritis pain, which means joint pain in the joint area of osteoarthritis. "Rheumatoid arthritis pain" means joint pain in the joint area of rheumatoid arthritis. "Inflammatory pain" means pain caused by edema or swelling of any tissue inflammation, including inflammatory joint pain. Inflammatory Joint pain includes rheumatoid arthritis pain. "Mechanical pain" means pain related to injury or damage to the body's structure, including osteoarthritis pain, surgical pain, burn pain, bone cancer pain, and the like. & Health pain means any pain, including (but not limited to) joint pain, osteoarthritis pain, rheumatoid arthritis pain, inflammatory pain, fever ^ pain ^ pain ^ pain, surgical pain, fibromyalgia, bone Cancer pain, menstrual pain, painful pain, static touch pain, and dynamic touch pain, if not treated, each time lasts from 1 minute to 9 丨 day minutes to 31 days, 1 minute to 7 days, 1 minute to 5 days, hours To 91 days, 1 hour to day, 1 hour to 3 days, 1 minute to 3 days, 1 minute to 2 days, 1 hour to 31 days, 1 hour to 7 days, 1 hour to 5 hours to 2 days, 1 Hours to 24 hours, 1 hour to 12 hours, or 1 hour to hours. Acute pain includes (but is not limited to -75- (72) (72) 200410677) joint pain, osteoarthritis pain, rheumatoid arthritis pain, pain, burn pain, cut pain, surgical pain, myofiberic pain, Bone cancer pain, menstrual pain, back pain, headache, static touch pain, dynamic touch pain, acute joint pain, acute osteoarthritis pain, acute rheumatoid arthritis pain, acute inflammatory pain, acute headache, Acute menstrual pain, acute back pain, and acute myofiberic pain. Acute pain may be selected from acute joint pain, acute osteoarthritis pain, acute rheumatoid arthritis pain, and acute inflammatory pain. Acute pain can be selected from acute joint pain, acute osteoarthritis pain, and acute rheumatoid arthritis pain. Acute pain can be selected from acute joint pain and acute osteoarthritis pain. Relieving acute pain means administering a first dose of an active compound or comprising a substituted monoalkyl ether, a substituted aryl-alkyl ether, a substituted dialkyl sulfide, a substituted dialkyl ketone, or The combination of the substituted alkyl compound and another active ingredient can be used in 91, 31, 7, 5, 3, or 2 days, or 24, 12, 6, 3, 2, 1, 0.5, 0.25, 0.20, 0.17, Or feel the pain relief effect within 0.10 hours. `` Chronic pain '' means any pain, including (but not limited to) joint pain, bone inflammation, rheumatoid arthritis pain, inflammatory pain, burn pain, cut pain, surgical pain, myofiberic pain, bone Cancer pain, menstrual pain, back pain, headache, static touch pain, dynamic touch pain, chronic joint pain, chronic osteoarthritis pain, chronic rheumatoid arthritis pain, chronic inflammatory pain, chronic headache, chronic Back pain, and chronic S-fibromyalgia, if not treated, each episode will last more than 91 days, 6 -76-(73) (73) 200410677, 1 year, 5 years, or 0 years. Chronic pain Can be selected from chronic joint pain, chronic osteoarthritis pain, chronic rheumatoid arthritis pain, inflammatory pain, chronic headache, chronic back pain, and chronic myofiberic pain. Chronic pain is optional From chronic joint pain, chronic osteoarthritis pain, chronic rheumatoid arthritis pain. Chronic pain can be selected from chronic joint pain and chronic osteoarthritis pain. Relieve chronic Pain means that after the first dose of the active compound or other active ingredients is administered, it can be on 91, 60, 31, 28, 21, 14, 14, 7, 2, 3, or 2 days, or 24, 12, 6, 3, 2, 1, 0.5 , 0.25, 0.20, 〇17, or 〇10 within 10 hours to feel the pain relief effect. '' Wherein the pain is regulated by IL-6, IL-6 s R, or IL-6 receptor, meaning the patient Of pain in the administration of cytokinin interleukin-6 (,, IL_6 "), its cell-bound receptor interleukin-6 receptor (,, IL-6 receptor"), or interleukin to patients The soluble receptor ("iL6sR", which is an unbound IL-6: fragment of fL-6 receptor) that can bind to IL-6 can be alleviated after being inhibited by iL_6, IL-6sR, or IL-6. Inhibitors that regulate body pain can also be confirmed by the following biological methods 5. Inhibitors of IL-6, IL-6sR, or IL-6 receptors include Ire6, IL-6sR, or IL-6 expression or biological Activity inhibitors and IL-6, IL-6sR, or IL-6 knockout promoters. Consistent pain (> 10%) caused by insufficient oxygen in organs (eg, brain, heart, or liver) does not belong to here No pain. "Effective therapeutic amount" and "effective amount" are synonymous and represent the amount of one of the above compounds or combinations, which is sufficient to make any particular disease or condition that the particular disease to be treated should or may occur. One or more pathological features or symptoms-77- (74) (74) 200410677 to alleviate, or alleviate, eliminate, inhibit or prevent initiation, or inhibit progression, prevent further progression, or reverse progression. A therapeutically effective amount or effective Amount means an amount sufficient to achieve the desired effect in the administered patient. For example, when reference is made to suppressing cartilage damage, an effective therapeutic amount includes an effective amount to suppress cartilage damage. When referring to the treatment of osteoarthritis, the effective therapeutic amount includes an effective amount for treating osteoarthritis. When referring to pain relief, an ' effective therapeutic amount includes a pain relief effective amount. When referring to the relief of osteoarthritis or rheumatoid arthritis pain, the effective therapeutic amount includes the effective amount of relief of osteoarthritis or rheumatoid arthritis pain, respectively. Endothelin-1 is one of the members of the 21 residues. Endothelin peptides are produced by a large number of cell types in response to different stimuli and are regulated by specific ETA and ETB receptors. The affinity of eta-type receptors for endothelin-1 is limited to that for endothelin-3 and can be selectively blocked by antagonists known in the art. An active compound having an anti-inflammatory, analgesic, anti-arthritis, or cartilage damage inhibitory effect or any combination of such effects can be immediately identified by one of the usual skills in medicine or medical technology, which is determined by measuring the Alkyl ethers, substituted aryl-alkyl ethers, substituted dialkyl sulfides, substituted dialkyl ketones, or substituted -alkyl compounds are determined by any well-known measurement method Dialkyl ether, substituted aryl-alkyl ether, substituted dialkyl sulfide, substituted dialkyl ketone, or substituted -alkyl compound for cartilage damage, arthritis, inflammation, Or the effect of pain. Such assays include ex vivo assays using cartilage samples and in vivo measurements of cartilage degradation, inhibition of inflammation, or alleviation of -78- (75) 200410677 and pain in whole animals. For example, with regard to the determination of cartilage damage in vitro, a certain number of compounds or a control vehicle and a cartilage damage agent can be administered to the cartilage, and the inhibitory effect of the cartilage damage to be tested is investigated by the overall examination or omics of the cartilage, Cartilage damage is measured with biomarkers, for example, polysaccharide content or hydroxyproline content. In addition, the measurement of in vivo damage can be performed as follows: a certain amount of active compound or vehicle and cartilage damage agent can be administered to animals, and the measured substituted ethers, substituted aryl alkyl ethers , Substituted dialkyl thioether-substituted one-based ketones, or substituted nosodium-based compounds on animal cartilage can be examined by cartilage overall or histopathological examination, observation of the affected joints caused by cartilage damage in the formula Impaired function measures cartilage damage assessment with biomarkers, such as, for example, protein or hydroxyproline content. Several active compounds confirmed to have the property of suppressing cartilage damage are as follows. The amount used at the time of analysis varies depending on the specific analysis used, and does not exceed the allowable compounds well known in the specific analysis. Similarly, substituted dialkyl-substituted aryl-alkyl ethers with pain-relieving properties A substituted dialkyl sulfide, a substituted alkyl ketone, or a substituted-alkyl compound can be used in a variety of animal pain modes, any of which are identified. Many of the pain patterns in vivo are technically known, and the regulation of endothelin d has been described in Piovezan, Anna P, et British quantities of two tissue pathologies such as the dioxin, Methods of taking acute effects, or sugar content methods, but regardless of the maximum amount of ether, the second generation of living body joint pain Journal-79-(76) 200410677 of Pharmacology, 2000; 129: 961-968 References are incorporated herein.

Similarly, substituted diethylenyl ethers, substituted aryl-honosyls, substituted dihonosyl sulfides, substituted dinosyl ketones, or substituted-alkyl compounds having anti-inflammatory properties Any of a number of anti-inflammatory modes in vivo animals can be used to confirm. For example, taking the pattern of inflammation as an example, see U.S. Patent No. 6,3 29,429, the entirety of which is incorporated herein by reference. Similarly, substituted dialkyl ethers having anti-arthritis properties, substituted aryl-honoyl ethers, substituted dihodothiols, substituted dihonoketones, or substituted -alkyl Compounds can be identified using any of a variety of anti-arthritis modes in living animals. For example, for the arthritis model, see also U.S. Patent No. 6,3 2 9 5 4 2 9. Clinicians can use standard assessment questionnaires such as WOMAC or Patient Global Impression of Change (" PGIC ")

Need or respond to treatment of osteoarthritis, rheumatoid arthritis, impaired joint function, pain including osteoarthritis pain, rheumatoid arthritis pain, acute pain, joint pain, chronic pain, inflammatory pain, IL- 6. IL-6sR, or IL-6 receptor-regulated pain, or mechanical pain. In addition to assessing patients' needs or responding to the above-mentioned pain states and bone cancer pain, pain regulated by endothelin · 1, static touch pain, and dynamic touch pain, physicians can use a pain assessment scale called, for example, Visua 1 Analog Scale (" VAS "), which will require the patient to represent the pain-free left anchor (anchor bone needle) and the right anchor that may be the most painful -80- (77) (77) 200410677 at 100 mm, based on the degree of pain No, or Likert score on the line, in which patients will be required to indicate their pain from several hundred (no pain) to 10 (most painful). The method, composition, or compound used in the composition of the present invention can be individually prepared or combined with a Or a variety of other therapeutic agents that can be formulated into the desired combination, including the different half-life of the different drugs to form the sustained-release drugs with different release times to achieve a more uniform drug use; or, for non-human patients The combination type in the medicinal feed dosage form uses the medicine to coexist with the tincture in the feed ingredients. The present invention also provides a method for combining medicine, wherein the medicine The combination is achieved by the simultaneous, or non-synchronous, sequential or simultaneous administration of the specified drugs in the combination; including the combination of different dosage forms and administration routes; or the combination of regular and continuous administration according to different administration schedules In order to maintain the drug at the required level in the plasma of the patient to be treated, it can be achieved even when the individual drugs made into the combination are not administered to the patient at the same time. In determining the active compound of the method of the present invention, or A pharmaceutically acceptable salt, or the same combination as a selective COX-2 inhibitor, to relieve pain, prevent or treat osteoarthritis, prevent or treat rheumatoid arthritis, improve joint function, or prevent or inhibit cartilage When treating the effective amount of damage, many factors that a general practitioner or veterinarian can consider are the experience of the practitioner or veterinarian, published clinical research reports, the age of the patient (ie, mammal), gender, weight, and general symptoms, and The type and extent of the disease, disorder or symptom to be treated, and other drugs (if any) used by the patient. This amount will generally be between About 0.1 mg / kg to about 300 mg / kg of patient weight. A typical normal weight adult dose will be between about 10 to about 5000 milli-81-(78) (78) 200410677 g / day Clinically, a competent authority such as the United States, such as the United States Food and Drug Administration, may specify a specific effective therapeutic amount. The administered dose may be in the above range or content, or may be lower or higher than the range of ±, these ranges depending on each The specific needs of the patient, the severity of the symptoms of the treatment, and the particular treatment formulation used. It is well-known medical or veterinary techniques to determine the appropriate dosage for a particular situation. Generally speaking, treatment can be applied to the invention first The method begins with a lower dose of the active compound, or a pharmaceutically acceptable salt thereof, or a combination of the same substance and another therapeutic agent, which is below the optimal amount for this particular patient. The dose can then be increased in small amounts until the optimum effect is reached. For convenience, the total daily dose may be administered in divided portions throughout the day, if necessary. The method of the present invention can be individually formulated or prepared into a pharmaceutically acceptable form by administering an active compound suitable for the method of the present invention, or a pharmaceutically acceptable salt thereof, or a combination of the same substance and another therapeutic agent. Composition is carried out. The pharmaceutical composition active compound, or a pharmaceutically acceptable salt thereof, which is briefly described herein and will be described in detail below, is made by formulating a dosage unit form of the active compound and a medical carrier. Some examples of dosage unit types are tablets, capsules, medicines, powders, water-soluble and non-water-soluble alpha solutions and suspensions, and packages containing one or more dosage units in a container that can be subdivided into single doses. Injection. Examples of some suitable pharmaceutical carriers (including pharmaceutical diluents) are gelatin capsules; sugars such as lactose and sucrose; starches such as corn starch and potato starch; cellulose derivatives such as carboxymethyl cellulose pins, ethyl fiber; Ethyl cellulose, methyl cellulose, and cellulose acetate phthalate-82- (79) (79) 200410677 • 'Gelatin; Talc, Stearic acid; Magnesium stearate; Vegetable oils such as peanut oil, cottonseed oil , Sesame oil, olive oil, corn oil, and coffee oil; propylene glycol, glycerin; sorbitol; polyethylene glycol; water; agar; alginic acid; isotonic physiological saline, and phosphate buffer solution; and other pharmaceuticals Compatible substances commonly used in formulations. The composition used in the present invention may also contain other ingredients such as a coloring agent, a flavoring agent, and / or a preservative. Such materials, if any, are usually used in smaller amounts. The composition may also include other treatments commonly used in the treatment of osteoarthritis II, as required. In addition, the composition may optionally include other therapeutic agents for treating secondary symptoms, for example, cartilage damage may or may not be accompanied by inflammation or pain. For example, the composition may contain aspirin, methacrylic acid, or similar anti-inflammatory painkillers. The percentage of the active ingredient of the aforementioned composition varies widely, but in practice the concentration of the solid composition can be at least 10%, and the first-class liquid composition can be at least 2%, both of which are as high as about 95%. A typical active compound to which the method of the present invention is applied, or a pharmaceutically acceptable salt thereof, or a combination of the same substance and another therapeutic agent, is administered orally or parenterally or parenterally. For example, a suitable intravenous dose is between 5 and 50 mg, while a suitable oral dose is between 20 and 800 mg. The dosage is within the scope of administration for the treatment of diseases that cause cartilage damage, joint loss of energy, or pain, such as rheumatoid arthritis and osteoarthritis, or it will be determined by the physician according to the needs of the patients mentioned above. Substituted dialkyl ethers, substituted aryl-alkyl ethers, substituted dialkyl sulfides, substituted dialkyl ketones, -83- (80) (80) 200410677 or a substituted-alkyl compound, or a pharmaceutically acceptable salt thereof, or the above combination of the same substance with another therapeutic agent, can be administered in any form, including unit dosage forms. The active compound of the present invention or a pharmaceutically acceptable salt thereof in a unit dosage form of the present invention may also include other compounds for treating diseases that cause cartilage damage and joint loss. The advantages of the present invention include the application of the present invention Substituted dialkyl ethers, substituted aryl-alkyl ethers, substituted dialkyl sulfides, substituted one-based ketones, or substituted one-based compounds are less non-toxic; easier Preparation; in fact, the resistance of substituted dialkyl ethers, substituted aryl-alkyl ethers, substituted dialkyl sulfides, substituted dialkyl ketones, or substituted Good acceptability, and easy for IV and oral administration. Another important advantage is a substituted dialkyl ether, a substituted aryl-alkyl ether, a substituted dialkyl sulfide, a substituted dialkyl ketone, or a substituted -Alkyl compounds represent a new mechanical treatment for arthritis pain and cartilage damage. This is important to patients based on the efficacy and / or safety limitations of current OA, OA pain, RA pain, cartilage damage, and similar treatments described above. For example, 'Research found that 6 · (5-carboxy · 5-methylhexyloxy> > 2,2-dimethyl-hexanoic acid salt consumption does not inhibit the performance of rat leukocytes stimulated by bromide ion channel agents. Prostaglandin-F2a (,, PGF2a ") or leukotriene B4 (,, LTB4") expressed by basophil leukocytes stimulated by calcium channel agents in mice, and therefore does not have a gastrointestinal tendency (eg, stomach Ulcers and wounds, dyspepsia, indigestion, etc.) cyclooxygenase inhibitors, such as methacrylic acid or indomethacin or 5 _ -84- (81) 200410677 fat oxygenase inhibitors. G — important The advantage is that the substituted dialkyl alcohol, substituted aryl-alkyl ether, substituted dialkyl sulfide, substituted dialkyl ketone, or substituted-alkyl compound are suitable for the method of the present invention. No increase in blood pressure observed in some patients using Arthritis Pain Relief Agent VI OXX®. For example, 6- (5-carboxy-5methyl-hexyloxy) -2,2-dimethyl -

Hexanoic acid # 5 salt has no effect on blood pressure in normal healthy humans or even makes it slightly lower (1-5 mm Hg).

Another important advantage is a substituted dialkyl alcohol, a substituted aryl-alkyl ether, a substituted dialkyl sulfide, a substituted dialkyl ketone, or a substituted -Alkyl compounds provide disease ameliorating activity to osteoarthritis and other diseases and disorders with pathological cartilage damage. At present, no drug has been approved for efficacy in the market. In addition, it has been found that there is a drug that has this cartilage damage inhibitory effect and the treatment effect of OA and RA symptoms (pain). And this substituted dialkyl ether, substituted aryl-alkyl ether, substituted dialkyl Alkyl sulfide, substituted dialkyl ketones, or substituted -alkyl compounds can be administered once daily. The patient's compliance is improved if the patient has to take only one drug instead of two and only one drug nine instead of two or more 'each day. In addition, the present invention may reduce or even eliminate the amount of anti-inflammatory and / or pain alleviating agents currently used to treat patients with cartilage damage and inflammation and / or pain, as needed. It is currently known that anti-inflammatory and analgesic agents can cause adverse side effects such as gastrointestinal bleeding and ulcers. The use of the present invention to inhibit cartilage damage can avoid, reduce or eliminate such side effects. -85- (82) (82) 200410677 The active compound suitable for the method of the present invention, or a pharmaceutically acceptable salt thereof suitable for the method of the present invention, and intermediates thereof which are pharmaceutically acceptable salts can be familiar to a professional Organic chemistry techniques are prepared with a variety of synthetic techniques and different organic chemical synthesis procedures. These synthetic steps can be found in, for example: Reagents for Organic Synthesis, by Fieser and Fieser, John Wiley & Sons, Inc, New York, 2000; Comprehensive Organic Transformations, by Richard C. Larock, VCH Publishers, Inc, New York, 1 98 9; the series Compendium of Organic Synthetic Methods, 1989, by Wiley-Interscience; the text Advanced Organic Chemistry, 4th edition, by Jerry March, W i 1 ey -1 nterscience 5 New

York, 1992; or the Handbook of Heterocyclic Chemistry by Alan R. Katritzky? Pergamon Press Ltd, London, 1985. In addition, skilled artisans can find methods for preparing intermediates from many chemical literatures, such as the Chemical Abstracts Service, Columbus, Ohio, or MDL Information Systems

GmnbH (formerly Beilstein Information Systems GmnbH) 5 Frankfurt, Germany. The starting materials, reagents, solvents, and catalysts used in the method, composition, or composition of the compound formulations of the present invention can be purchased from the business community or they can be easily prepared using procedures in the above references or resources. Starting materials for the preparation of substituted dialkyl ethers, substituted aryl-alkyl ethers, substituted dialkyl sulfides, substituted dialkyl ketones, or substituted -k-based compounds -86- (83) (83) 200410677 for reagents, solvents, and catalysts, such as: T he A1 drich C hemica 1 Company, and Sigma_Aldrich Corporation, St. Louis, Missouri, BACHEM, BACHEM AG ,, Switzerland, or Lancaster Synthesis Ltd, other subsidiaries of the United Kingdom. When synthesizing some compounds suitable for the method, composition, or composition of the present invention, a starting material, an intermediate, or a reaction product containing a reactive functional group can be used. In chemical reactions, the reactive functional group may be protected with a protecting group so that the reactive group is inert under the reaction conditions used. The protecting group is introduced onto the starting material before carrying out the reaction step requiring the protecting group. Once the protecting group is not needed, the protecting group can be removed. Those skilled in the art know how to introduce protective groups into synthetic active compounds or their medically acceptable salts before removing them. Known procedures and references for the introduction and removal of protecting groups are, for example, Protective Groups in Organic Synthesis, 2nd ed., Greene TW and Wuts PG, John Wiley & Sons, New York, New York, 1991, incorporated herein by reference data. Thus, for example, the following protecting groups can be used to protect amine, hydroxyl, and other groups: carboxyfluorenyl groups such as methylamino, ethylfluorenyl, and trifluoroethylfluorenyl; alkoxycarbonyl groups such as ethoxycarbonyl , Third butoxycarbonyl (BOC), β, β5β-trichloroethoxycarbonyl (TCEC), and β-iodoethoxycarbonyl; aralkyloxycarbonyl groups such as benzyloxycarbonyl (CBZ), p-methoxy Benzyloxycarbonyl, and 9-fluorenylmethoxycarbonyl (FMOC); trialkylsilyl groups such as trimethylsilyl (TMS) and third butyldimethylsilyl (TBDMS); and other groups such as , Trityl (trityl), tetrahydropiperanyl, vinyloxycarbonyl, n-nitrophenylphosphinofluorenyl, -87- (84) (84) 200410677 diphenylphosphinofluorene Group, p-toluenesulfonyl (Ts), methanesulfonyl, trifluoromethanesulfonate sulfonyl, and benzyl. Examples of protecting group removal steps include: using, for example, hydrogen to hydrolyze CBZ groups in the presence of hydrogenation catalysts such as 10% palladium / carbon at 50 psi; using, for example, hydrogen chloride in dichloromethane, trifluoroacetic acid (TFA) Acidic hydrolysis of BOC groups in dichloromethane and the like; reaction of silane groups with fluoride ions, and reductive cleavage of TCEC groups with zinc metal; active compounds suitable for the method of the present invention, or preparations thereof which are pharmaceutically acceptable salts The above patents and patent application announcements are incorporated herein by reference. In the following studies, the dose mg / kg means the milligrams of the weight of the test compound per kg of the weight of the test animal. In the following biological methods 1, 2, 4, and 5, there are control joints on the limbs and paws (animals to which the test compound vehicle is administered only) and reverse joints on the limbs and paws (only to the test compound vehicle) Control group or induction group of the agent and animals treated with the test compound dissolved in the test compound vehicle) The difference in paw load was measured by a small animal pain evaluation device, model 2KG (Linton Instrumentation, Norfolk, United Kingdom) . The upper part of the small animal pain evaluation device supports the forelegs of the rat with an oblique front wall, and a weight-sensing pad on each of the two hind paws to assist the measurement. The difference in hind paw load is expressed in grams and is calculated as follows: (average weight in grams of the control group limbs of each induced or treated animal minus average weight in grams of the contralateral test limbs) minus (animals of each control group) In the control group, the average weight in grams of the limbs was subtracted from the average weight in grams of the opposite lateral test limbs -88-(85) (85) 200410677). All results are analyzed by covariance analysis (`` ANCOVA '') and Ho eh berg's step statistical analysis is performed to compare the average results of each induction or treatment group with the average results of the control group at the same time point, unless otherwise stated, which Statistical significance was p < 0.05. The data of the present invention need not be statistically analyzed with ANCOVA and then with Hochber §'s steps. Other known methods of statistical analysis can be used, such as using ANCOVA without Hochberg's program, analysis of variance (`` ANOVA ") and Hochberg's program, ANOVA without Hochberg's program, t-test and Hochberg's program, and t-test No Hochberg's program is used. All IL-6 and IL-6sR mentioned in the following examples are commercially available recombinant human IL-6 and human IL-6sR, purchased from R & D Systems, Minneapolis, Minnesota. Biological Methods 1, 2 Before injection of IL-6 and IL-6sR in MIA or Biological Method 5 in 4, rats were anesthetized with < v / v " isoflurane and gas until coma and 2 with % v / v isoflurane is maintained. When the administration of isoflurane was stopped for about 5 minutes, the rats completely recovered their consciousness. At the same time, in Biological Method 5, the cytokinin vehicle contained 0.5% HPMC and 0.2% polyoxyethylene adiponic acid unit oleate in water (" HP MC / Polyoxyethylene adiponic acid unit oleate "). The 6- (5-carboxy-5-methyl-hexyloxy) -2,2-dimethyl-hexanoic acid calcium salt was shown to be administered in the following biological method 5 Will inhibit pain induced by (丨 L_6 and IL-6sR)-. -89- (86) (86) 200410677 substituted dialkyl acids, substituted aryl-alkyl ethers, substituted Of dialkyl sulfate, substituted diethyl ketone, or substituted 3-endyl compounds, or their pharmaceutically acceptable salts are novel capabilities for inhibiting cartilage damage, alleviating pain, and treating osteoarthritis The following animal models have been established: Biological method 1 Rat model of cartilage damage osteoarthritis induced by monosodium acetoacetate-acetate ("MIA rats"): an end point for inducing osteoarthritis in this model The result (determined by tissue analysis) is the occurrence within the affected joint. Symptoms of inflammation, characterized by loss of toluidine blue staining and formation of osteophytes. The relevant tissue change is concentration-dependent degradation of articular cartilage, which can affect the weight distribution of hind paw and hind paw of affected joints, and biochemical analysis reveals proteins in the joints Histopathological analysis of increased polysaccharide or hydroxyproline acid or osteoarthritis damage was confirmed. Substituted dialkyl ethers, substituted aryl-alkyl ethers, substituted dioxane suitable for the method of the present invention Thiosulfide, substituted dialkyl ketone, or substituted -alkyl compound, or a pharmaceutically acceptable salt thereof, on the hind paw weight distribution effect (or expected effect observed) 'applicable to the method of the present invention Substituted dialkyl ether, substituted aryl-hono acid, substituted dialkyl sulfide, substituted dialkyl ketone, or substituted alkyl compound, or a pharmacologically The ability of acceptable salts to directly inhibit articular cartilage damage will be reported below. Generally, on day 0 of the MIA mouse model, male Wistar -90- (87) (87) 200410677 arthritis on the right side of the mouse The weight difference of the hind paw between the joint and the left healthy joint (150 grams) was measured using a small animal pain evaluation device, model 2KG (Linton Instrumentation, Norfolk, United Kingdom). The small animal pain evaluation device is directed upward The oblique front wall supports the forelegs of rats, and a weight-sensing pad on each of the hind paws, to assist in the measurement. The rats are then anesthetized with isofluoride, and a 1.0 mg single injection is made from the right hind knee via the hip ligament. -Iodoacetate (" MIA "). Injecting MIA into the joints results in inhibition of glycolysis and eventually death of surrounding chondrocytes. Rats can further administer the active compound suitable for the method of the present invention, or a pharmaceutically acceptable salt thereof, or a vehicle (water in this case) for a period of 14 days or 28 days per day. A substituted dialkyl ether, a substituted aryl-alkyl ether, a substituted dialkyl sulfide, a substituted dialkyl ketone, or a substituted -alkyl compound suitable for use in the method of the present invention, or The pharmaceutically acceptable salts thereof are typically administered at a dose of 30 mg per kg of rat per day for substituted dialkyl ethers, substituted aryl-alkyl ethers, and substituted dialkyl ethers suitable for the method of the present invention. Alkyl sulfide, substituted dialkyl ketone, or substituted -alkyl compound, or a pharmaceutically acceptable salt thereof (30 mg / kg / day), but the compound can be studied Other dosages required are, for example: 10 mg / kg / day, 60 mg / kg / day, 90 mg / kg / day, or 100 mg / kg / day. A person skilled in the art of pharmacology will usually be able to determine the appropriate dosage of the active compound, or a pharmaceutically acceptable salt thereof, to which the method of the present invention is applicable. In this mode, a substituted dialkyl ether, substituted -91-(88) (88) suitable for the method of the present invention can be administered orally or intravenously through an osmotic pump if necessary.

200410677 Aryl-alkyl ether, substituted dialkyl sulfide, substituted dialkyl ketone, or substituted -alkyl compound, or a pharmaceutically acceptable salt thereof. After 7 and 14 days of two-week research, or 7, 14, and 28 days of four-week research, the weight distribution of the rear paws was measured again. Typically, the weight of the left hind paw, which is not affected when the vehicle is administered alone, is greater than that of the right hind paw, and the application of an active compound suitable for the method of the present invention, or a pharmaceutically acceptable salt thereof, shows that The weight distribution between the claws is more normal (ie more like a healthy animal). This change in weight distribution is proportional to the degree of articular cartilage damage. The percentage inhibition of changes in hind paw joint function was calculated as the percentage change in the hind paw weight distribution of the treated animals relative to the control animals. Take the two-week study as an example, the inhibition percentage of the change in the hind paw weight distribution is 1 ^ (AWG) I — (△ Wc) X100 where: △ Wc is a vehicle administered alone, measured on the 14th day, healthy left hind limbs and Hind paw weight difference between hind limbs of arthritic animals in control group; and ΔW. The weight difference between the healthy left limb of the animal and the hind paw between the healthy left limb of the animal and this arthritic limb was measured on the 14th day after the active compound to which the method of the present invention was applied or a pharmaceutically acceptable salt thereof was administered. In order to 'test' the biochemical or histopathological end point of the MIA mouse model, certain intensive animal sacrifices will be described, and biochemical analysis will be used to determine the free protein polysaccharides in the right knee joint and contralateral left knee joint of osteoarthritis. Its content is -92- (89) (89) 200410677. The free proteoglycan content of the contralateral left knee joint provides a baseline of healthy joint free proteoglycan content. The proteoglycan content of the right knee joint of animal osteoarthritis administered with the active compound to which the method of the present invention is applied, and the proteoglycan content of the right knee joint of animal osteoarthritis administered with a vehicle alone, compared to the reverse left knee The proteoglycan content of the joints is not related. The amount of proteoglycans lost in the right knee joint of osteoarthritis is expressed as a percentage of the amount of proteoglycans lost in the left knee joint on the opposite side of the control group. The percentage inhibition of proteoglycan loss can be calculated as {1-[(Proteoglycan loss of joint loss in the vehicle group (%))-(Substituted dialkyl ethers, substituted aryl groups for the method of the invention) Ether, substituted difluorenyl sulfide, substituted diethyl ketone, or proteoglycan lost in joints of the substituted-alkyl compound group) = (proteoglycan lost in joints of the vehicle group (%)) X 1 00. It is expected that MIA mouse data from proteoglycan loss analysis will establish substituted dialkyl ethers, substituted aryl groups, substituted ethers, substituted dialkyl sulfides, substituted Alkyl ketones, or substituted -alkyl compounds, including their pharmaceutically acceptable salts, including the compound name 6- (5-carboxy-5-methylhexyloxy) -2,2-dimethyl Hexanoic acid salt can effectively inhibit cartilage damage, improve joint function, and treat osteoarthritis in mammalian patients (including humans). The compound name of the MI A test is 6- (5-residue- 5-methyl-hexyloxy) -2,2-dimethylhexanoic acid calcium salt, and the results are described below Method 2. Biological Method 2 6- (5-Carboxy-5-methyl-hexyloxy) -2,2-dimethyl-hexanoic acid-93- (90) (90) 200410677 in IA In a specific experiment, monosodium iodoacetate ("MIA") (1 mg / joint) was injected into anesthetized male Wistar mice via the hip ligament of the right knee. The control knee was injected with 50 microliters of physiological saline Changes in hind paw weight distribution using a small animal's palatal pain evaluation device. 'Using the difference between right (arthritis) and left (contralateral control) knees as an index of arthritis knee function limitation in this technique. Joint function The limitation is determined at 7, 14, and 28 days after the induction of arthritis. The severity of corrosion of the tibial plateau is determined from the joints of arthritis after sacrificing. This sample is also subjected to histological analysis. The basis of the present invention is derived from daily oral administration Twice 30-mg / kg and 10-mg / kg 6- (5-carboxy-5-methyl-hexyloxy) _2,2-dimethyl-hexanoic acid calcium salt (ie PO; two daily Times), can significantly reduce the severity of cartilage corrosion and can reduce joint function limitations, which is defined as reducing the hind leg bearing Weight difference 〇 Oral administration of 6- (5-carboxy-5-methyl-hexyloxy) -2,2-dimethyl-hexanoic acid calcium salt is dissolved in double distilled water (all calculations are based on the parent drug Percentage). Dose at 3-, 10-, and 30-mg / kg [oral (,, PO ,,); twice daily ("twice a day")] doses-response study instructions 6- (5-carboxy-5-methyl-hexyloxy) -2,2-dimethyl-hexanoic acid calcium salt, at a dose of 30 mg / kg 4 weeks after MIA, significantly reduced the degree of cartilage structural damage and Significant reduction in joint pain. The results of such oral administration studies are shown in the table; "[jFL (% +/- SEM)", where IJFL means inhibition of joint function limitation and SEM means mean standard error; " SDCES ", where SDCES means a significant -94- (91) 200410677 reduction in the severity of cartilage corrosion, and" reducing the size of rotten uranium ", where reducing the size of corrosion means reducing the size of the joint corrosion area significantly or not. Han 1 · Oral administration of CI- 1 02 7, twice / day / dose, four weeks research:, amount (mg / kg) IJFL (% + /-SEM) SDCESb reduce the size of corrosion __ 30 63 + / -8 a Yes d No 10 36 + / -9 Yes 6 Yes C __ 3 3 +/- 156 Yes f No — 30 60 +/- 8 a No g No (a) Relative to carrier p < 0.05 (unidirectional Variation analysis (π one-way ANOVA ,,

D u η ne 11 's multiple comparison method); (b) p < 0.05 relative to the carrier (Ridit analysis); (o relative to the carrier ρ < 〇 · 〇5 ("one-way ANOVA ");; d) actual ρ = 0.001; (e) actual ρ = 0.001;

(f) actual ρ = 〇 · 〇43; (g) actual ρ = 0 · 100. R i d i t analysis was used to determine differences in the severity of uranium decay. This parameter can simultaneously indicate the corrosion level (0 = non-corrosive uranium, corrosion extended to the surface or intermediate layer, or 11 = depth of layer corrosion), and area (small, medium and large, the area of maximum corrosion of each fraction) Divided into three classes to be quantified). This analysis confirms the differences in the severity units, but does not guarantee the mathematical relationship between the units. -95- (92) (92) 200410677 The MIA mouse data reported in Table 1 above establishes a substituted dialkyl ether, a substituted aryl-alkyl ether, and a substituted one-base sulfur Ether, substituted dialkyl ketone, or substituted -alkyl compound 'or a pharmaceutically acceptable salt thereof, including the compound name 6- (5-residue-5_methyl-hexyloxy ) Calcium 2,2-dimethyl-hexanoate can effectively prevent or inhibit cartilage damage, improve joint function, relieve joint pain, and prevent or treat osteoarthritis. The compound 6- (5-carboxy-5-methyl-hexyloxy) -2,2-dimethyl-hexanoic acid can also be administered subcutaneously through an osmotic pump. Administration can be, for example, 100-mg / kg / day, 90-mg / kg / day, 30-mg / kg / day, and 10-mg / kg / day. Biological Method 3 Induction of Experimental Osteoarthritis in Rabbits (" EOA Rabbits "): Anesthetize normal rabbits and cut through the anterior medial side of the right knee. Visually as well as the anterior cruciate ligament. Seal wounds and place animals individually in cages, move freely, and eat at will. Carrier (water) or 6_ (5-carboxy-5 · methyl-hexyloxy) -2,2-dimethyl-hexanoic acid calcium salt for rabbits, or a pharmaceutically acceptable salt thereof (10 rabbits per group). Each group was administered 6- (5-carboxy-5-methyl-hexyloxy) -2,2-monomethyl-hexanoic acid, or its pharmaceutically acceptable salt three times a day, receiving 30-mg / Kg / dose or 10-mg / kg / dose. Rabbits were euthanized 8 weeks after surgery, and the proximal tibia and distal femur were removed from each animal. -96- (93) (93) 200410677 Macroscopic grading Changes in cartilage on the femoral condyle and tibial plateau can be graded using a dissecting microscope (Stereozoom, Bausch & Lo mb, Rochester, NY). The depth of the carrion can be divided into the following grades 0 to 4 ... Grade 0 = normal surface; grade 1 = minimal muscle fiber tremor or pale yellow discoloration on the surface; grade 2 = corrosion extends only to the surface or middle layer; grade 3 == Uranium decay extends to deep levels; level 4 = corrosion extends to subchondral bone. Surface area change is measured and expressed in mm square. Representative specimens can also be used for tissue grading (see below). Tissue classification Tissue evaluation was performed from the sagittal section of the cartilage at the area of injury to the femoral condyle and tibial plateau. Prepare serial sections (5 μm) and stain with Saffron-O. The severity of OA damage was graded by independent observers using the tissue-histochemical scale of Mankin et al. On a scale of 0-14. This scale assesses OA based on loss of saffron-〇 staining (grades 0-4), changes in cells (grades 0-3), vascular invasion tide points (grades 0-1), and structural changes (grades 0-6). The severity of the damage. On the last scale, 0 means normal cartilage structure and 6 means cartilage corrodes to the subchondral bone. The scoring system is based on the most severe tissue changes in multiple sections. A typical specimen of the synovial membrane of the knee compartment in the middle and side was obtained from the dissection of the underlying tissue. Specimens were fixed, embedded, and sectioned (5 microns) and stained with hematoxylin-eosin. In each compartment, two joint synovial fluid membrane examination scores were taken and the examination with the highest score was retained from each compartment. Calculate the average score and consider this as the unit of the overall knee. Two -97- (94) (94) 200410677 independent observers classified the severity of synovitis according to 3 tissue criteria from 0 to 10: hyperplasia of the lining cells of the synovial fluid (grade 0-2) Villous hyperplasia (grade 0-3); and the degree of mononuclear and polymononuclear cell infiltration (grade 0-5); 0 means normal structure. Statistical analysis Use Vlann-Whitney U-test calculations and statistical analysis to average 値 and SEM. If such an EOA is to use a substituted dialkyl ether, a substituted aryl-alkyl ether, a substituted dialkyl sulfide, a substituted dialkyl ketone, or a substituted -alkyl Compounds are performed and the results will show the active compound, or a pharmaceutically acceptable salt thereof, including the compound 6- (5-carboxy.methyl-methyl-hexyloxy) -2,2-dimethyl-hexanoate Salt can reduce the size of damage to the tibial plateau and may also reduce damage to the tibial or femoral condyles. In summary, the EO A results will show substituted dialkyl ethers, substituted aryl-alkyl ethers, substituted compounds, or pharmaceutically acceptable salts thereof, including compounds 6-( 5 -carboxy-5 -methyl-hexyloxy) -2 5 2 -dimethyl-hexanoic acid calcium salt, has a significant effect of inhibiting cartilage damage. Biological method 4 Monosodium iodoacetate (" ΜΙΑ ")-induced osteoarthritis: Male Wistar rats (175-200 g) were housed in solid bottom isolation cages' with 2-4 mice per cage, covered with corn Cob as cushion, 12 hours: 12 hours light: dark cycle. Animals can freely eat standard rat feed and -98- (95) (95) 200410677。 water. Use rats at 5% volume / volume (" v / v ") isoflurane gas anesthesia and maintenance at 2% v / v isoflurane gas. Anesthetized mice were given a single intra-articular injection of MIA via the hip ligament of the right knee. MIA was dissolved in physiological saline, and the administration volume was 50 microliters. The knee of the control group was injected with 50 microliters of physiological saline. The dosing of isoflurane gas was stopped, and the rats were fully awake after about 5 minutes. The weight distribution of the hind paw from the right to the left hind paw supports the leg (knee joint) behind the right (arthritis) and left (anti-lateral control group) as a joint pain index and as a measuring compound. The hind paw weight distribution was measured using a small animal palatal pain evaluation device (model 2KG, Linton Instrumentation, UK). Each data point is the average of three readings over a 5-second duration. CI-1027 (that is, 6- (5 -Uncle-5-methyl-hexyloxy) -252-dimethyl_hexanoic acid calcium salt) is soluble in hydroxypropyl methylcellulose (" HPMC ") Agent (0 · 0 5% Η PMC + 0 · 2% polyoxyethylene adiponic acid unit oleic acid vinegar; compound amount is based on free acid, ie 6- (5-carboxy-5-methyl-hexyloxy) _2,2 -Percent adjustment of dimethylhexanoic acid). Two dosing paradigms were used to test the effects of CI-1 027 in this model: (1) A single (acute) dose was used to measure CI-1 0 2 7 to relieve joint pain after acute, single administration Effects; and (2) chronic (multi-day; twice daily) dosing is used to determine the inhibitory effect of CI-107 on joint pain and / or cartilage damage. Examples of acute administration of osteoarthritis symptoms include mobility and joint function and osteoarthritis symptoms such as joint pain. The chronic administration paradigm confirms the disease-modifying osteoarthritis drug -99- (96) (96) 200410677 (" DMOADs ,,). In the acute (single) dosing paradigm, changes in hind paw weight distribution were measured on the morning of 13 or 14 days after MIA injection and described as before 'to establish baseline pain readings. Mice were then given a single dose of 10, 30, or 100 mg / kg C1- 1 027 via oral gavage (P0). Changes in hind paw weight distribution were measured at 2, 4, and 6 hours after compound administration. In the chronic (multiple) dosing example, MIA and saline were injected on day 0. CI-1 027 was administered 0.5 hours before MIA injection. Ci-10 27 (3, 10, or 30 mg / kg) is then administered approximately every 12 hours for a period of 28 days. Changes in hind paw weight distributions were measured on days 7, 14, and 28. After administering C 1-107 2 twice daily for 4 weeks, mice were euthanized with c 0 2. Remove the soft tissue from the right (arthritis) leg (the joint is dislocated) and carefully remove the meniscus to expose the surface of the tibial plateau. The tibia was removed and placed in saline until corrosion analysis was performed. Analysis of tibial plateau corrosion on the day of sacrifice. Each platform was immersed in I n d i a stain for approximately 30 seconds to help mediate corrosion, rinsed with physiological saline, and blotted onto paper towels. Use a solid microscope equipped with a digital camera to photograph each platform. Two ordinary professionals who are familiar with this technique use the following systems to take pictures and grade the tibial plateau: Grade 0 = no corrosion; grade bu corrosion extends to the surface or middle layer; grade 11 = deep corrosion; no cartilage, subchondral exposure. The photo was transferred to an image analysis computer, and the total corrosion area of each grade was determined using an image analysis system of z e s s K S 300-100- (97) (97) 200410677, which is expressed in millimeter square (', millimeter 2' '). Ridit analysis (see above) was used to determine differences in total corrosion severity. This analysis can simultaneously explain the corrosion level and area (small, medium, and large, and divide the maximum corrosion area of each fraction into three grades for quantification). This analysis confirms the differences in severity units, but does not guarantee mathematical relationships between the units. Results after acute administration to alleviate joint pain: CI-1 027 was tested in a mouse MIA model as described in the previous acute administration example. · All mice were injected with MIA on the right knee and saline solution on day 0 To the left knee. On the 14th day, mice were evaluated using a small animal pain evaluation device, and then C 1-107 (10, 30, or 100 mg / kg 'PO) was administered. Re-evaluate the mice after two, four and six hours. The results are shown graphically in Figure 1, which is a dose-response line graph showing changes in the weight distribution of the hind paws of a mouse, expressed in grams. In Figure 1, compared with the pre-dosimetry, CI-1 02 7 (100 mg / kg) was administered at 2, 4, and 6 hours to statistically significantly alter the possible weight-bearing displacement (joint pain) of arthritic mice. At a dose of 30 mg / kg, there was a statistically significant change only 4-hours after the point of administration. Administration of 10 mg / kg in rats did not significantly change their possible weight-bearing displacement. System. The difference between the ten Tibetans was determined using a one-way A Ν Ο V Α and a Du η n e 11,11 s multiple comparison method. The data are expressed as the average SEM. N = 8 mice per group. -101-(98) (98) 200410677 Chronic administration of a single dose to alleviate joint pain: MIA and saline were injected on day 0. CI-1 02 7 (30 mg / kg) was administered 0.5 hours before MIA injection. C1-1027 was then given every two weeks for 28 days. Changes in hind paw weight distribution were measured at 7.14, 14, and 28 days. The results are shown in Figure 2, which is a time course graph showing changes in the weight distribution of the hind paws of a mouse, expressed in grams. As shown in Figure 2, CI-1 027 reduced statistically significant changes in hind paw weight distribution at all three test time points (inhibitions at 7, 14 and 28 days were 4 7 ± 8%, 71 ± 9 ° / 〇, 60 ± 8%; ρ < 0.05). Statistically significant differences were determined using one-way ANOVA and subsequent Dunnett's multiple comparisons (* ρ < 0.05). Data are expressed as the average sema. Ν = 12 mice per group. Dose response of chronic single-dose administration to alleviate joint pain: A dose response of C 1-107 was also performed. Joint pain was measured after multiple dose changes in the hind paw. MIA and physiological saline were injected on the 0th day. Cl-1 027 (3, 10, or 30 mg / kg) was administered via PO 0.5 hours before MIA injection. CI-1027 was then administered twice daily for 28 days. Changes in hind paw weight distribution were measured on days 7 · 14, 14, and 28. The results are shown in Figure 3, which is a time course and dose-response line graph showing changes in the weight distribution of hind paws in mice, expressed in grams. As shown in Figure 3, consistent with previous experiments, CI-1027 at 30 mg / kg significantly reduced the hind paw weight distribution on days 14 and 28 (50 ± 10% and 62 ± 8% inhibition, respectively). ; P < 0.05). However, on day 7, the significant effects observed in the first experiment were not repeated (inhibition of 38 ± 14 ° / 〇). There was no statistically significant change in hind paw weight distribution at all three -102- (99) (99) 200410677 timepoint tests at 10 and 3 mg / kg doses. Statistically significant differences were determined using one-way ANOVA and subsequent Dunnett's multiple comparisons (* ρ < 0.05). Data are expressed as mean SEM SEM. Ν = 12 mice per group. Results of chronic inhibition of articular cartilage degradation after administration: The ability of CI-1 027 to preserve cartilage structure was tested in the mouse MIA mode. The mice were dosed at 30 mg / kg twice daily for 28 days and sacrificed on the 28th day. Remove the tibial plateau and analyze in the manner previously described. MIA and physiological saline were injected on day 0. C0 1 027 (30 mg / kg) was administered p0 0.5 hours before MIA injection, and then twice daily for 28 days. Corrosion analysis was performed on day 28. When analyzed using the RID IT test, CI-1 02 7 had no statistically significant effect on the severity of tibial plateau corrosion (ρ = 0 · 10). N = 12 mice per group. Two of the 12 vehicle-treated mice were non-corrosive, which may indicate a lack of statistical significance locally. Five of the two CI-1027 treated rats were non-corrosive. The effect of CI-1 027 on the total corrosion area (regardless of grade) was also determined. MIA and saline were injected on day 0. CI-1 027 (30 mg / kg) was administered PO at 0.5 hours before MIA injection, and then twice daily for 28 days. Corrosion analysis was performed on the 28th day. There is no statistically significant difference, and C I-1 0 2 7 reduces the total corrosion area by 43%. However, this reduction was not statistically significant (determined by t-test; p = 0.179; equivalent = 12 mice / group), which can be explained locally again with two vehicle mice without the aforementioned corrosion. -103- (100) (100) 200410677 Results of chronic post-administration dose response inhibition of articular cartilage degradation: Rats were administered 3, 10, or 30 mg / kg (p0) twice daily for 28 days. The tibial plateau was removed and analyzed using the Rid IT test described above. MIA and saline were injected on day 0. CI-1027 (3, 10, or 30 mg / kg) was administered P0 0.5 hours before MIA injection, and then twice daily for 28 days. Corrosion analysis was performed on day 28. All three doses were statistically significant by RID IT analysis (ρ <0.05); N = 12 mice / group. The results are shown in Figure 4, which is a dose-response bar graph showing the following effects (0 cartilage decay uranium severity, grade 0 (non-corrosive), grade I (corrosion extends to the surface or middle cartilage layer and further its Characterized by small, medium, and large size), or grade 11 (deep corrosion; no cartilage remains in spots, subchondral bone is exposed by spots, and further characterized by small, medium, and large sizes) are indicated and ( ii) The size of cartilage (expressed as a percentage of hunger distribution) is equivalent to that of a vehicle-injected control group animal. As shown in Figure 4, all three doses of CI-1 0 2 7 have statistically significant inhibitory effects on the severity of corrosion Effect. Contrary to the experiments described previously, all vehicle-treated mice were corroded. 疋 c I-1 0 2 7 (3, 10, and 30 mg / kg) was also measured against total rotten contact area (regardless of grade) The effect was injected on the 0th day with MIA and physiological water intake. C I -1 0 2 7 (3, 10, or 30 mg / kg) was administered P 0 0.5 hours before the MIA injection, and then twice a day as 28 days. Corrosion on day 28 Analysis. One-way ANOVA, Dunnetfs multiple comparison step was used to determine the statistical significance (P <0.05; N = 12 mice / group). The results are shown in Figure 5, which is a dose-response bar graph showing whether cartilage corrosion is affected Severity, grade, Fengme-104- (101) (101) 200410677 Total cartilage corrosion area effect (in mm squared) on vehicle-injected control animals. As shown in Figure 5, only at 10 mg A statistically significant reduction in total corrosion area (62.4%) at CI-1 027 / kg dose. A single dose of CI_i〇27 at 30 or 100 mg / kg can effectively alleviate the nodal pain of MIA-induced arthritis mice It shows that CI-1 027 and other active compounds of the method of the present invention have a direct antihyperalgesic effect on joint pain. Chronic administration of CI-1 〇27 in mouse MIA mode can also improve joint pain. 30 mg / kg PO administration of CI-1027, twice a day, after 1-2 weeks of administration can improve joint pain and prolong the effect to 4 weeks. In addition, 3, 10 or 30 mg / kg (PO) is administered twice daily for a period of time 28 days of CI-1 027 can effectively reduce middle tibial plateau corrosion Small, it shows that CI_ 1 027 and other active compounds of the method of the present invention have a direct inhibitory effect on cartilage damage in cartilage damage. Biological method 5 interleukin-6 ("1] _6") and interleukin- 6 Soluble receptors ("11 ^ 6311")-induced joint pain: The IL-6 / IL-6sR model is about osteoarthritis pain. Male Wistar rats (175-200 g) were raised in a solid, isolated base Cages, 2 to 4 mice per cage, lined with corn cobs as cushions, 12 hours: 12 hours light: dark cycle. Animals have free access to standard rat feed and decoction. Human recombinant IL-6 (100 μg / rat; R & D Systems, Minneapolis, Minnesota) and human weight-105- (102) (102) 200410677 group Dissolved receptors (300 μg / rat; R & D Systems, Minneapolis, Minnesota) phosphate-buffered saline (f, PBS ”) were reacted for 15 minutes. Mice were treated with 5% vol / vol Γν / v ") Isoflurane gas anesthesia and isoflurane gas maintained at 2% Wv. Anesthetized mice were given a single intra-articular injection of 50 mL of IL-6 / IL-6sR via the hip ligament of the right knee. The knees of the contralateral control group were injected with 50 μl of PBS. The administration of isoflurane gas was discontinued, and the rats were fully awake after about 5 minutes. The paw weight distribution from the right (arthritis) to the left (reverse lateral control group) paw was used as the joint pain index and the effect of the measurement compound. The hind paw weight distribution was measured using a small animal palpitation evaluation device (model 2KG5 Linton Instrumentation, UK). Each data point is an average of three readings of 5 seconds duration. Cl-1 02 7 was dissolved in HPMC vehicle as described above. Hind paw weight distribution read 値 The change in baseline was determined one day before the injection of IL-6 / IL-6SR. On the day of the experiment, (day 0), a single dose of CI-1027 (10, 30 or 100 mg / kg) via oral gavage 3 hours before the injection of IL-6 / IL-6sR (n = 10 mice / group) . Changes in hind paw weight distribution were measured one, three, and six hours after L-6 / IL-6sR injection. The effect of CI-1 02 7 (10, 30, and 100 mg / kg) on joint pain was tested in the mouse 1L-6 / IL-6SR mode. Small animals were read on day 1 at baseline using a pain evaluation device. On day 0, IL-6 / 1 / 1L-6sR and PBS were injected. PO administration 3 hours before IL-6 / JL-6sR injection (: 1-1 02 7 (3, 10, or 30 mg / kg). Changes in hind paw weight distribution were measured at 1, 3, and 6 hours after injection ( CI-1 0 2 7 4, 6, and 9 -106- (103) (103) 200410677 hours after injection). The results are shown in Fig. 6, which is a time course and dose response plot. The change is expressed in grams. As shown in Figure 6, all three CI-1 02 7 doses can reduce the change in weight distribution of the hind paw 1 hour after injection, and there are 4 hours after CI-1 0 2 7 injection Statistical significance (53, 9%, 74, 8%, and 57 ± 15% inhibition at 10, 30, and 100 mg / kg, respectively). Statistically significant differences were achieved using one-way ANOVA and subsequent Hochberg's assay (* ρ < 〇〇〇〇ι). The data are expressed by the average soil soil S EM. N = 10 mice per group. 3 and 6 hours after injection no significant effect was administered (CI-1 6 and 9 hours after 027). Repeat the above experiment with the following changes: CI-10 2 7 test only at 10 and 30 mg / kg, and all small animals 鎭The readings of the evaluation device were blind. The baseline readings of the small animal pain evaluation device were read on day 1. IL-6 / IL-6sR and PBS were injected on day 0. Before IL-6 / IL-6sR injection. CI-1027 (10 or 30 mg / kg) was administered at 3 hours PO. Changes in hind paw weight distribution were measured at 1, 3, and 6 hours after injection (CI-1 027 at 4, 6, and 9 hours after injection). Statistically significant The difference was measured by one-way ANOVA and subsequent Hochberg's determination (* ρ < 0.001). The data are expressed by mean soil SEM. N = 10 mice per group. The results are shown in Figure 7, which is the time course, dose response Line graph showing the change in weight distribution of the hind paw of a mouse, expressed in grams. As shown in Figure 7 and as shown in the first experiment before, when compared to the vehicle group 10 and 30 mg / kg dose C 1- 1 027 can statistically significantly reduce the change in hind paw weight distribution (10 ± 30 mg / kg 63 ± 6% and 71 ± 10% inhibition respectively). In mouse IL-6 / lL-6sR knee injection mode After injection of IL-6 / IL- -107- (104) (104) 200410677 6 s R hours, CI-1 0 2 7 significantly relieved joint pain c I-1 0 2 7 and other active compounds of the method of the present invention have a direct antihyperalgesic effect on joint pain. Biological method 6 Red algae-induced thermal hyperalgesia: Objective: To screen the analgesic effect of possible hyperalgesia ( Compounds that relieve inflammatory pain such as rheumatoid arthritis. Male Sprague Dawley mice (200-3 00 g, purchased from Sprague D awey), 2 per cage, 12-hour light / dark cycle, free to eat food and simmer water. Animals are allowed to acclimate in the test room for one hour before testing. The mouse plantar test (from Uni v · Ca 1 i f ο r n aa, San Di e g 0) was used to evaluate the thermal hyperalgesia in a modified Hargreaves et al. 5 1 9 8 8 method. The rats were placed in a testing device, which consisted of three groups of plexiglass boxes, each of which placed two rats separately on a raised glass table. Place a flowing radiant heat source (halogen lamp) under the glass table and focus on the rear paws. Record the paw retraction delay (PWL) in seconds (" s). The automatic cut-off point is set to 22.5s to prevent tissue damage. The average of two to three PWLs of each hind paw at each time point is recorded値. Calibrate the instrument so that the PWL before the administration of red algae is about 10 s. After measuring the basic PWL, the animal injects 100 microliters of 10 mg / ml of compound from the sole of the foot to the right hind paw. Red algae (Sigma Chemical Co.) is dissolved in isotonic physiological saline. Red algae treatment (this time point represents the onset of spike hyperalgesia) is evaluated at -108- (105) (105) 200410677 2 hours after evaluation Hyperalgesia has developed. 6- (5-carboxy-5-methyl-hexyloxy) -2,2-dimethyl-hexyl is then orally administered via an oral administration needle 2.5 hours after the injection of red algae Acid calcium salt, PWL was recorded at 30- or 60 intervals 6 hours after administration of the drug. Data are composed of 2-3 readings / average cymbals of individual animals. Group data are individual averages. Percent inhibition at each time point The calculation is as follows: (mean 値 in the drug treatment group-average 値 in the control group) / (baseline average 値-control group)値) x 100. The inhibition results are then analyzed statistically. The results of using CI-1 027 to alleviate joint pain are expressed as a percentage of inhibition of changes in hind paw weight distribution (MIA and IL-6) or delay in paw withdrawal (CITH). As shown in Table 2. Table 2. A single oral dose of 30 mg / kg of 6- (5-carboxy-5-methyl-) was administered on Day 7 (MIA) or Day 1 (IL-6 and CITH) Hexyloxy) -2,2-dimethyl-hexanoic acid calcium salt, 4 hours after administration to reduce joint pain distribution (M IA and IL-6) or paw retraction delay (CITH) measurement to relieve joint pain : Table 2 · Inhibition of model pain (% vs. control group) MIA (acute) 67 ± 8% * _ IL-6 7 1 ± 10% * CITH 6 5 ± 2 0% * _ * p < 0.0 5 -109- 200410677 (10) The following substituted dialkyl ether compounds (reference numbers) and substituted fluorene-based compounds (reference numbers are widely used to determine at least one of the above methods, which is selected from MIA, IL -6 / IL-6SR and CITH, alleviate the effects of pain 757, oxybis (2,2 • dimethylheptanoic acid) (A1); Keto ) (Eight 2); 4,4'-oxybis (2,2-dimethylbutanoic acid) (A3); and 252512512-tetramethyltridecanedicarboxylic acid (A4). Data are shown in the table below 3 to 5. In Table 3 below, the data of the biological method 4 method are expressed as the percentage inhibition of the mean paw weight distribution change and the mean standard error. The percentage of inhibition is calculated according to the above formula of biological method 1. -110- 200410677 ρ, = (N3ST%) # a, f / 9 ~ Η < Buρ, = (S3SS) Ning, H < A ^} XN3SS) ^ S, Η < Α Yi, ^ Yi ^ Desong ^ Daddy® 07), ^ s§? 5 4 ^ 1 4ΠΘ > Wang target phase ^ Κ1 ^ < πθ > inch νι ^ ιν 鼷 · ^ 样 * N \ t «s / job Wοε _lssiin ^^ g 丨酹 _Η < ΗΙ ^ ΙΚΑ move, _ban 枳? ^ Ban 佗 songhu τ rinse: = (NasT%) basket 7 9 hH < Hp ^ K1: (sHS = F%) 7-inch plate, Η < Η move :,: (H3ST%) # H Seven < N · Η < Inch one on the 14th day, 6 hours (0 / 〇 ± SEM) N / d N / d 27 + 9 55 + 7 on the 14th day, 4 hours ( % ± SEM) -9 ± 17 9 ± 20 36 ± 3 29 ± 8 1 Day 14, 2 hours (% ± SEM) -3 ± 15 9 Soil 13 33 ± 7 35 ± 6 Day 7, 6 hours (% SEM) N / d, N / d 81 66 43 ± 6 Day 7, 4 hours (% SEM) 15 1414 16 士 15 34 55 3 8 77 Day 7, 2 hours (% SEM ) 50 11 11 -11 15 15 20 4 4 25 5 5 Compound Reference Number ▼ Η (N < ΓΛ < inch <

—I I -111-(108) 200410677 The data of the method of 'Biological Method 5' in Table 4 below are expressed as the percentage inhibition of the change in the hind paw weight distribution ± the mean standard error. The percentage inhibition is calculated as follows. Percent inhibition of change in hind paw weight distribution [(AWG) 1 = J 1--[X100 (AWC) where: AWc is a healthy limb and a control group of animals administered with a vehicle alone injected with hr IL-6 + hr IL-6 s R limb, paw weight difference after 1, 3, or 6 hours of injection; and

△ ... ^ are the limbs of healthy limbs and animals in the treatment group injected with hrIL-6 + hrIL-6sR, and the paw weight difference was measured after 1, 3, or 6 hours of injection. Table 4 · After the method of biological method 5, the compound of reference number A4 was orally administered at a single dose of 30 mg / kg on the first day and 1, 3, or 6 after the administration of 1 ethyl-6 / IL-6sR Hours to inhibit IL-6 / IL-6sR-induced changes in hind paw weight distribution. To relieve joint pain, expressed as inhibition percentage ± mean standard error, shown in the following column headings, respectively, compound reference number 1 hour (0 / 0: tSEM) " ,,, 3 hours (% ± SEM) ,,,,, 6 hours (% ± SEM) ": Compound 1 hour, 3 hours, and 6 hours reference number (% ± SEM) (% ± SEM) (% ± SEM) ( % SE SE Μ A 4 70 9 9 79 5 5 2 6 6 6 -112-(109) 200410677 Table 5 · After the method of biological method 6, a single oral dose of 30 mg / kg is administered on the first day The reference numbers A1 to A4 compounds are used to measure CITE's paw retraction delay measurement to relieve joint pain, expressed as a percentage of inhibition, and are shown in the following columns titled "Compound Reference Number", "Dose (mg / kg)" " And MCITH (%)-: _ Compound Reference Number Dose (mg / kg) CIT H (° / 〇) A1 3 0 22 A2 30 -3 A3 30 2 0 A4 3 0 118 A4 100 115 Biological method 7 The method according to biological method 5, wherein IL-6, IL-6sR, or IL-6 and IL -6sR is replaced by a protein or a protein and its receptor, respectively, which are selected from the group consisting of Oncostatin-M, Oncostatin-M and Oncostatin-M Receptor, Leukemia Inhibitory Factor (LIF), LIF, and Leukemia inhibitory factor receptor (" LIFR "), type 11 interleukin (" IL-l 1"), and IL-11 and type 11 interleukin receptor (" IL-1 1 R "). Determination of substituted dialkyl ethers, substituted aryl-alkyl ethers, substituted dialkyl sulfides, substituted dialkyl ketones, or substituted -alkyl compounds. The method for the activity in rheumatoid arthritis is as described in the biological method 8 below. -113- (110) (110) 200410677 Biological method 8 Single-cell-induced mouse arthritis ("M AIA,") Modes: The use of towels sold by the autologous inflammation-inducing monoclonal antibody mixture can quickly induce mouse arthritis mode. This mixture contains four different monoclonal antibodies (& quo t; mAbs "), which is derived from active collagen-induced arthritis (,, CIA"; immunization of natural type II bovine collagen containing complete Freund's adjuvant in mouse skin can induce CIA, but generally takes 6 years At -8 weeks, the incidence and severity of the disease varies considerably, requiring a relatively large number of mice to achieve statistical significance) DBA / 1 (H-29 haplotype) mice. Three of these mAbs recognize epitopes of autoantigens within 84 amino acid residue fragments, LyC2 of CB 1 1 (the smallest fragment of type II collagen producing arthritis), and the fourth mAb can react with LyC2 ( Terato, K., Harper, D., Griffiths, M ·, Hasty, D · 5 Ye, J ·, Cremer, M · an d J 5 S eyer · C ο 11 age η-induced arthritis in mice: synergistic effect of Escherichia coli (丨 'E. coli ”) lipopolysaccharide bypasses epitopespecificity in the induction of arthritis with monoclonal antibodies to type II collagen. Autoimmunity. 22 (3): 137-147). More importantly, all four mAbs are Recognizes the epitopes of type II collagen that are conserved in many species, and therefore reacts with homologous and heterologous type II collagen. One of the main advantages of monoclonal antibody-induced arthritis over the CIA model is Can induce CIA arthritis in strains other than DBA / 1 mice. Most genetically deleted mice are 129 / SvJ, BALB / c, or C57BL / 6 strains rather than DBA / 1, so it is difficult to remove genes to confirm rheumatoid arthritis Joint -114- (111) (111) 200410677 inflammation target. Researchers have spent years performing backcrossing between genetically-deleted mice and DBA / 1 background mice to test whether genetic defects can affect arthritis. Caused by or severe effects. When tested with 129 / SvJ, BALB / c, C3H / FeJ, and C57BL / 6 strains, it was found that DBA / 1 was most susceptible, but BALB / c, C57BL / 6, and 1 29 / The SvJ strain is only slightly worse than DB A / 1. The C3H / HeJ mice are quite unresponsive. The 129 / SvJ mice also have a low response to the combination of mAb and LPS, but they are still statistically significant only higher than those injected with LPS. 29 / SvJ mice. One of the hallmarks of a good preclinical disease model is that agents that alleviate human disease can also be used in animal models. Methotrexate, cyclosporine, and anti-TNF-α antibodies are successfully used For the treatment of human rheumatoid arthritis. When tested with BALB / C mice using a monoclonal antibody-induced arthritis model, methotrexate (4 mg / kg) and anti-TNF-a antibody (8 3.3 3 μg) ) Can significantly suppress swelling of the foot pads and ankles during the course of the disease. On the first and fifth days after injection of Arthrogen-CIA antibody, anti-TNF-a antibody (8 3.3 3 μg / animal) was administered i.p. Cyclosporin (25 mg / kg.) Inhibited the swelling response early, but was no different from the vehicle control group on day 9. ΜΑΙΛ experimental guidelines: In a typical MAIA experiment, four groups of mice were injected intraperitoneally ("i · p.) With 0.4 ml (BALB / c and DBA / 1 strains) or 0.8 ml (C5 7BL / 6 , 129Xl / SvJ, C3H / HeJ, and C 3 H / F e J strains) 10 mg / ml Arthrogen-CIA monoclonal antibody mixed (Chemicon International, Inc.) solution. Two days later, mice were injected with ip 0.2 ml -115- (112) (112) 200410677 0.25 mg / ml LPS (Lipopolysaccharide from E. coli strain 0111B4) in PBS solution. Use Dyer Digital Caliper (# 655-030-4916) on the day of m A b injection and LPS injection The footpad and ankle size were evaluated every two days thereafter. The experiment included the oral administration of 0, 100, or 200 mg / kg 6- (5-carboxy- 5-methyl-hexyloxy) -2,2-dimethyl-hexanoic acid calcium salt. Oral administration vehicle or 30, 100, or 200 mg / kg 6- (5-carboxy-5- The results of the methyl-hexyloxy) -2,2-dimethyl-hexanoic acid calcium salt are shown in Fig. 8. In Fig. 8, the time course and the dose-response diagram show the compound 6_ (5-carboxy-5-formaldehyde) -Hexyloxy) -2,2-dimethyl-hexanoic acid calcium salt at a dose of 200 mg / kg on days 4, 7, and 9 and at a dose of 100 mg / kg at day Statistically significant changes in swelling of ankle and paw swelling in mice (expressed in millimeters) at 7 days. Biological method 9 Effect of a combination of substituted dialkyl ethers and COX-2 inhibitors in MIA to alleviate pain: Acute Results of alleviating joint pain after administration: 6- (5-carboxy-5-methyl-hexyloxy) -2,2-dimethyl-hexanoic acid calcium salt ("(: 1_1〇 27 ") and Luofenxixi (1 > (^^ 〇? ^ 13) δ formula described above as an acute administration model. All mice injected μια to the right knee and physiological saline to the left knee on day 0 On the 4th day, mice were evaluated with a small animal pain evaluation device, and then 6- (5-carboxy-5- -116- (113) (113) 200410677 methyl-hexyloxy) -2,2-dimethylamine was administered. -Caproic acid calcium salt (10 mg / kg, and rofecoxib (3 mg / kg, p0). Mice were reassessed after two hours. The results of pain suppression are based on the percentage standard The miscarriage indicates that the development is not shown in Table 5. The percentage of pain inhibition is determined by the above-mentioned biological method 1. In Table 5, 6- (5-carboxy-5 · methyl-hexyloxybuth 2,2 · dimethyl is administered. · Calcium hexanoate and rofecoxib are administered with 6- (5-Uncylmethyl-hexyloxy) -2,2-dimethyl-hexanoate and rofecoxib ) 2 hours later compared with 6- (5-carboxy · 5-methyl-hexyloxy) -2,2-dimethyl-hexanoic acid calcium salt or rofencox (r 〇f ecoxib) Statistically significant changes in weight bearing displacement of arthritic mice. Statistically significant differences. Gastric one-way ANOVA and subsequent Dunnett's multiple comparisons were measured, as shown in Table 5, * ,. Data are expressed as mean 値% ± SEM. N = 8 rats pe; r group. Table 5. CI-1 0 2 7 (10 mg / kg) rofecoxib (3 mg / kg) CI-1027 (10 mg / kg) + Luo cent Cofe (rofeco X ib) (3 mg / kg) 2 hours after administration 20 soil 9 23 people 7 3 6 soil 1 1 Mean pain relief (% SEM) P < 0.05 -117- (114) (114) 200410677 The foregoing research has established (or will establish) a substituted dialkyl ether, a substituted aryl-alkyl ether, a substituted dialkyl sulfide, a substituted dialkyl ketone, Or substituted-alkyl compounds, or pharmaceutically acceptable salts thereof, including the compound carboxy-5-methyl-hexyloxy) -2,2-dimethyl-hexanoic acid calcium salt, or containing The combination of the compound and a coxj inhibitor is effective in preventing and inhibiting cartilage damage, enhancing joint function, and alleviating pain, including joint pain induced by IL-6, mechanical pain, OA pain, inflammatory pain, RA pain, acute Pain, chronic pain, relief of acute pain, relief of chronic pain, etc., as well as prevention and treatment of human and other mammalian patients Osteoarthritis and rheumatoid arthritis. This treatment offers significant advantages over existing treatments that only modify pain and other secondary symptoms. A substituted dialkyl ether, a substituted aryl-alkyl ether, a substituted dialkyl sulfide, a substituted dialkyl ketone, or a substituted-indigo compound, suitable for use in the method of the present invention, or The effectiveness of its pharmaceutically acceptable salts, including the compound 6- (5-carboxymethyl-hexyloxy) _2,2-dimethyl-hexanoic acid calcium salt in the MIA mode, indicates that the present invention is applicable Processed substituted dialkyl ethers, substituted aryl-co-based ethers, substituted dialkyl thioethers, substituted dialkyl ketones, or substituted -alkyl compounds, or their pharmacy Acceptable salts, including the compound 6- (5-carboxy-5-methyl-hexyloxy) -2,2-monomethyl-hexanoic acid trans salt, in the prevention and / or treatment of cartilage damage and joint improvement There are clinically applicable effects on function and pain relief. Administration of the active compound of the method of the present invention, or a pharmaceutically acceptable salt thereof, to mammals for the treatment of the above-mentioned diseases is not required. -118- (115) (115) 200410677 The compound or The pharmaceutical form of its salts. A substituted dialkyl ether, a substituted aryl-honoether, a substituted dialkyl sulfide, a substituted dihonoketone, or a substituted -alkyl compound suitable for use in the method of the present invention, or Its pharmaceutically acceptable salts can be prepared according to the method of the invention into various oral and parenteral pharmaceutical dosage forms for administration. Therefore, a substituted dialkyl ether, a substituted aryl-alkyl ether, a substituted dialkyl sulfide, a substituted dialkyl ketone, or a substituted -alkyl compound is suitable for the method of the present invention. , Or its pharmaceutically acceptable salts can be administered by injection, that is, intravenously, intramuscularly, intradermally, subcutaneously, duodenal, or intraperitoneally. And, a substituted dialkyl ether, a substituted aryl-alkyl ether, a substituted dialkyl sulfide, a substituted dialkyl ketone, or a substituted -alkyl compound to which the method of the present invention is applied. Or its pharmaceutically acceptable salts can be administered by inhalation such as intranasally. In addition, substituted dialkyl ethers, substituted aryl-alkyl ethers, substituted dialkyl sulfides, substituted dialkyl ketones, or substituted -alkyl compounds are suitable for use in the method of the present invention. Or its pharmaceutically acceptable salts can be administered transdermally. For those skilled in the art, the following dosage forms may contain the active compounds suitable for the method of the present invention, or the active ingredients of their pharmaceutically acceptable salts. Generally the active compound is present at a concentration of from about 5% to about 95% by weight of the formulation. In order to prepare a substituted dimeryl acid, a substituted aryl-alkyl ether, a substituted dialkyl sulfide, a substituted dialkyl ketone, or a substituted -alkyl compound suitable for use in the method of the present invention , Or its pharmaceutically acceptable salt (ie, active ingredient) pharmaceutical composition, pharmaceutically acceptable carrier -119- (116) (116) 200410677 can be solid or liquid. Solid form preparations include: powders, tablets, medicines, capsules, starch capsules, suppositories, and dispersible granules. The solid carrier can be one or more substances, and can also be used as a diluent, flavoring agent, dissolving agent, lubricant, suspending agent, binding agent, preservative, tablet disintegrant, or encapsulated material in powder. The carrier is finely divided Solid, mixed with finely divided active ingredients. The powder suitable for intravenous injection or injection is freeze-dried. In tablets, the active ingredient is mixed with a carrier having the necessary properties in proper proportions and compacted into the shape and size required. Generally powders and tablets contain about 5% to about 70% of the total active ingredient. Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacon gum, methyl cellulose, sodium carboxymethyl cellulose, low Melting wax, cocoa butter, etc. The "formulation" herein includes a carrier made of a formulation of the active ingredient and the encapsulating material as a capsule, wherein the active ingredient (with or without other carriers) is surrounded by the carrier and is also attached in this manner. Similarly, starch capsules and lozenges are included. Tablets, powders, capsules (capsules), medicine nine, starch capsules, and lozenges can be used as solid dosage forms suitable for oral administration. Suppositories can be prepared by melting a low melting wax (such as a mixture of fatty acid glycerides or cocoa butter) and dispersing the homogeneous active ingredient with stirring. The molten homogeneous mixture is then poured into a suitable screening mold and allowed to cool and solidify. Liquid form preparations include solutions, suspensions, and emulsions, for example, water or aqueous propylene glycol solutions. For parenteral injection, the liquid preparation can be adjusted to -120- (117) (117) 200410677 polyethylene glycol aqueous solution. When preparing an aqueous solution suitable for oral use, the active ingredient can be dissolved in water and appropriate colorants, flavors, stabilizers, and thickeners can be added. When preparing an aqueous suspension solution suitable for oral administration, the finely divided active ingredients and viscous materials can be dispersed in water, such as natural or synthetic resins, resins, methyl cellulose, sodium carboxymethyl cellulose, and other conventional Suspensions 0 also include solid form preparations, which can be quickly converted to liquid form preparations for oral administration before use. The liquid forms include solutions, suspensions, and emulsions. In addition to the active compounds, such preparations may contain colorants, flavoring agents, stabilizers, buffer solutions, artificial and natural sweeteners, dispersants, thickeners, solubilizers, and the like. The preferred pharmaceutical formulation is in unit dosage form. The formulation in this form is a subdivided unit dose containing an appropriate amount of the active ingredient. The unit dosage form can be a packaged preparation, and each package can contain divided preparations, such as packet sachets, capsules, and powders in vials or ampoules. The unit dosage form may also be a capsule, tablet, starch capsule, or lozenge, or may be in any suitable number of such packaging forms. Depending on the specific use and efficacy of the active ingredient, the content of the active ingredient in the unit dosage formulation may vary from 0.0 1 to 1000 mg, including 1 to 500 mg or 10 to 250 mg. The ingredients may contain other compatible therapeutic agents as needed. When using the above-mentioned agent to treat diseases, the substituted dialkyl ether, substituted aryl-alkyl ether, substituted dialkyl sulfur-121-(118) (118) 200410677 ether, A substituted dialkyl ketone, or a substituted -alkyl compound, or a pharmaceutically acceptable salt thereof, or a combination of the same substance and another therapeutic agent is administered in a dose effective to improve at least one clinical Dosage, pathological characteristics, or symptoms of the disease or condition to be treated. Effective starting doses are from about 1 mg / kg to about 1000 mg / kg of active ingredient per day. Typical daily doses range from about 25 mg / kg to about 75 mg / kg of active ingredient. The dosage may, however, depend on the needs of the patient, the severity of the symptoms to be treated, and the particular substituted dialkyl ether, substituted aryl-alkyl ether, substituted dialkyl sulfide, The substituted dialkyl ketone, or the substituted -alkyl compound, or a pharmaceutically acceptable salt thereof, or a combination thereof varies. Determining the appropriate dosage for a particular situation as described above is a well-known technique. A typical dose is about 0.1 mg / kg to about 500 mg / kg, and an ideal dose is about 25 mg / kg to about 250 mg / kg. This dose can effectively treat a specific disease or to be treated Of illness. Typical ingredients for dogs include oral pharmaceutical ingestion liquids, which are selected from the group consisting of: solutions, suspensions, emulsions, transformation emulsions, elixirs, extracts, elixirs, and concentrates, which can be added to the dog's water to be treated as needed in. Any such liquid dosage form, when prepared according to methods known in the art, can be administered directly to the dog to be treated, or it can be added to the drinking water of the dog to be treated. On the other hand, when preparing a concentrated liquid form, first add a certain amount of water, and take out the dispensed volume and directly put it into the dog or add dog drinking water. The active compound ingredients to which the method of the present invention is applied, or pharmaceutically acceptable salts thereof, can be formulated into extended-, long-acting- and / or sustained-release dosage forms. This group -122- (119) 200410677 adult contains all of this dosage form, which can inhibit cartilage degradation or pain, and cause plasma concentrations of active ingredients, such as at least 2 hours; at least 4 hours; at least 8 hours; at least 1 2 hours; 16 hours; at least 20 hours; or at least 3 times the active ingredient in 24 hours. For example, included in the above dosage form, it can produce 240% inhibition of cartilage reduction pain, and cause the plasma concentration of the active ingredient to be at least 2 hours; at least 2 hours; at least 8 hours; 12 hours; at least 20 hours; Or at least 5 times the active ingredient in 24 hours. Also included in the above dosage form, it can produce a 25% inhibition of cartilage reduction pain, and cause the plasma concentration of the active ingredient to be at least 2 hours; at least 4 hours; at least 8 hours; 12 hours; at least 20 hours ; Or 5 times the active ingredient for at least 24 hours. The examples of the above formulations illustrate that the pharmaceutical composition of the present invention has an effective amount of an active chemical composition, or composition, which is an active ingredient composition and a pharmaceutically acceptable carrier, diluent or excipient, and A pharmaceutically acceptable carrier, diluent, or discrete formulation. The examples are merely representative and are to be construed as limiting the invention from any angle. It may be satisfactory to co-produce another therapeutic agent and 6- (5-5-methyl-hexyloxy) -2,2-dimethyl-hexanoic acid calcium salt, or a pharmaceutically acceptable salt thereof in A capsule, tablet, ampoule, solution, etc. are used together without necessarily implementing the method of the present invention. For example, valdecoxib and 6- (5-residue-5-methyl-hexyloxy) -2,2-> 40% at least ED 4 〇 or, for example, at least ED 4 〇 or At least ED 4 O, the hair agent, and the unrefinable form of the agent _ succinic acid-123- (120) (120) 200410677 calcium hexanoate, or a pharmaceutically acceptable salt thereof Similarly, the composition of the present invention can be individually prepared or in any form, such as any one of the formulations of Examples 1 to 16, and can be administered simultaneously or simultaneously. The method of the present invention comprises administering a composition of the present invention to a mammal to treat a disease or concurrently treat different conditions listed above. For example, administration of valdecoxib, a composition according to the present invention, can treat inflammation, arthritis pain, menstrual cramp-related pain, and periodic migraine, while active compounds suitable for use in the method of the present invention, or Pharmaceutically acceptable salts can be administered to treat osteoarthritis, rheumatoid arthritis, improve joint function, ease pain, or inhibit cartilage damage. As shown above, the method of the present invention provides significant advantages in treating diseases such as osteoarthritis, including cartilage damage. Existing treatments can only modify pain or secondary symptoms without altering the effects of the disease. A substituted dialkyl ether, a substituted aryl alkyl ether, a substituted dialkyl sulfide, a substituted dialkyl ketone, or a substituted alkyl compound, or a substituted alkyl compound suitable for the method of the present invention. Pharmaceutically acceptable salts, including the compound 6- (5-carboxy-5-methyl-hexyloxy) -2,2-dimethyl-hexanoic acid calcium salt, have been shown to be useful in inhibiting cartilage damage , Prevent or treat rheumatoid arthritis, improve joint function, treat osteoarthritis or relieve pain. The above invention has been described and illustrated through a special system and specific embodiments. Professionals who are familiar with this technology will be able to make various adaptations, changes, modifications, substitutions, deletions, or additions to the method (experimental guidelines) without breaking away. The scope of the present invention. The present invention is defined by the following patent application scope, and the patent application scope should be reasonably interpreted in a broad sense -124- (121) (121) 200410677. All patents and patent applications cited herein And publications, including patent application publications, which are incorporated herein by reference in their entirety. After describing the methods, compositions, and combinations of the invention, various systems, and specific embodiments of the invention, the invention makes the following applications [ Brief Description of the Drawings] Figure 1 Γ Figure 1 is a dose-response line chart showing changes in the weight distribution (in grams) of the hind paws of mice with knee arthritis on the 14th day. Knee joint arthritis induced by injection of 1 mg of monosodium iodoacetate (" ΜΙΑ ") in the sub-hip ligament of the knee, Oral administration of 10, 30, or 100 mg / kg of 6- (5-carboxy-5-methyl-hexyloxy) -2,2-dimethyl-hexanoic acid calcium salt (" Cb 1027 ' ). The measurement time of the hind paw weight distribution data of the mice is 0, 2, 4, and 6 hours after the compound treatment. Fig. 2 ("Fig. 2") is a time course line chart showing that the knee arthritis mice are on the 7th, Changes in the weight distribution of the hind paws of mice (in grams) on days 1, 4, and 28. On day 0, the rats were injected with 1 mg of monosodium iodoacetate (ΓΜΙΑ) through the sub knee hip ligament of the right knee to induce knee arthritis. Then, the long-term oral administration of 30 mg / kg of 6- (5-carboxy-5-methyl-hexyloxy) -2,2-dimethyl-hexanoic acid and a vehicle was administered twice a day, of which The compound was started 0.5 hours before injection of IA and then taken approximately every 12 hours to day 28. 125- (122) (122) 200410677 Figure 3 ("Figure 3") is a time course and dose-response line chart showing the knee paw weight distribution of mice with knee arthritis on days 7, 14, and 28. Changes (expressed in grams), mice were induced with knee arthritis by injecting 1 mg of monosodium iodoacetate (" ΜΙΑ ") in normal saline through the sub hip hip ligament of the right knee on day 0, followed by long-term oral administration twice daily 3 , 10, or 30 mg / kg of 6- (5-carboxy-5-methyl-hexyloxy) -2,2-dimethyl-hexanoic acid calcium salt and a carrier, wherein the administered compound is from Start 0.5 hours before MIA injection and then take it approximately every 12 hours to day 28. Figure 4? Figure 4 ") is a dose-response bar graph showing the effect of (i) the severity of cartilage corrosion, expressed as grade 0 ( No corrosion), level 1 (corrosion extends to the surface or middle cartilage layer, and its size can be further characterized by small, medium, and large), or level 11 (deep corrosion; no cartilage remains at the corrosion point, The subchondral bone is exposed from the point of corrosion, and its size can be further characterized by small, medium, and large Cartilage) and (ii) cartilage size of knee arthritis mice on day 28, expressed as a percentage of corrosion distribution relative to vehicle-injected control animals. On day 0, mice were injected with 1 mg of iodine through the right hip inferior ligament. Knee joint arthritis induced by monosodium acetate ("MIA") saline, followed by long-term oral administration of 3, 10, or 30 mg / kg of 6- (5-carboxy-5-methyl) -Hexyloxy) -2,2-dimethyl-hexanoic acid calcium salt and a vehicle, wherein the compound to be administered was started 0.5 hours before MI A injection and then taken approximately every 12 hours to the 28th day. Figure 5 ("Figure 5") is a dose-response bar graph showing the effect of total articular cartilage erosion area of mice with knee arthritis relative to vehicle injection control group on day 28 (expressed in square centimeters, regardless of cartilage corrosion (Severity rating) -126- (123) (123) 200410677. Rats were injected with 1 mg of monosodium iodoacetate (" MIA π) physiological saline via right sub knee hip ligament on day 0, followed by chronic arthritis. Oral administration of 3, 10, or 30 mg / kg of 2- (5 -Carboxy-5-methyl-hexyloxy))-2,2-dimethyl-hexanoic acid calcium salt with a carrier, wherein the compound to be administered starts from 0.5 hours before the injection of MIA and then approximately every 12 hours Take it once to day 28. Figure 6 (" Figure 6 '') is a time course and dose-response line chart showing the change in weight distribution of the hind paw of a mouse (expressed in grams) 'administered at time-1 hour 10, 30 Or 100 mg / kg 6- (5-carboxy-5-methylhexyloxy2,2-dimethyl-hexanoic acid calcium salt, followed by intra-articular injection A combination of 100 nanograms of IL-6 and 300 nanograms of IL-6 Sr in 50 microliters of PBS (control group treated with vehicle) into joint space. Mouse hind paw weight distribution data were measured at 0, 1, 3, and 6 hours after injection or 1, 2, 4, and 7 hours after compound treatment, respectively. Figure 7 ('' Figure 7 is a time course and dose-response line chart showing the change in weight distribution of the hind paw of a rat (expressed in grams). 30 mg / kg 6- (5-carboxy-5- Methylhexyloxy) -2,2-dimethyl-hexanoate calcium salt, followed by intra-articular injection of iliac ligament at time 0 hours, 100 nanograms of IL-6 dissolved in 50 microliters of PBS and 300 milligrams The combination of micrograms of IL-6 Sr (control group treated with vehicle) into the joint space. Data on the weight distribution of hind paws in mice were measured at 0, 1, 3, and 6 hours after injection or 1, 2, 4, and 6 after compound treatment, respectively. And 7 hours. Figure 8 ("Figure 8") is a time course, dose-response line chart showing the changes in swelling of the mouse ankle and paw (expressed in millimeters, "mm from -127- (124) 200410677 1 day to 1 1-day dosing vehicle or 30, 100, or 200 mg / kg 6- (5-carboxy5-methyl-hexyloxy) -2,2-dimethyl- A mixture of calcium caproate and a single anti-collagen antibody injected intraperitoneally on day 0. -128-

Claims (1)

(1) (1) 200410677, patent application scope 1. A treatment of mammalian diseases regulated by 1L-6 or selected from: arthritis, cartilage damage, joint pain, arthritis, systemic lupus erythema, mixed connective tissue Disease and septic pharmaceutical composition 'which comprises a therapeutically effective amount of a substituted dialkyl ether (formula I) Or a pharmaceutically acceptable salt thereof, wherein: η and m are each independently an integer from 2 to 9; R1, R2, R3, and R4 are each independently a CrC6 alkyl group, a C2_C6 alkenyl group, or a C ^ C6 alkyne Or R] and R2 and the carbon atom to which they are attached, or R3 and R4 to the carbon atom to which they are attached, or R1 and R2 to the carbon atom to which they are attached and R3 and R4 to the carbon atom to which they are attached, which together may form A carbocyclic ring of 3 to 6 carbons; Y1 and Y2 are independently COOH, CHO, tetrazole, or COOR5, where 115 is an alkyl group, a c2-C6 alkenyl group, or a C2-C6 alkynyl group; The alkynyl group and the alkynyl group may be substituted by one or two groups. The substituent is selected from the group consisting of halogen, hydroxy, Cl_C6 alkoxy, and phenyl. 2. The pharmaceutical composition according to the scope of application for patent, wherein the arthritis is selected from osteoarthritis and rheumatoid arthritis. 3. The pharmaceutical composition according to the scope of the patent application, wherein the joint pain is selected from joint pain of osteoarthritis, joint pain of rheumatoid arthritis, and inflammatory joint pain. -129- (2) (2) 200410677 4 The pharmaceutical composition according to item 1 of the patent application range, wherein the joint pain is selected from the group consisting of acute joint pain and chronic joint pain. 5. The pharmaceutical composition according to the scope of the patent application, wherein the arthritis is arthritis of rheumatoid arthritis. 6. The pharmaceutical composition according to any one of claims 1-5, wherein the substituted dialkyl ether compound is 6- (5-carboxyl5-methyl-hexyloxy2.2-dimethyl -Caproic acid, or a pharmaceutically acceptable salt thereof. 7 · The pharmaceutical composition according to item 6 of the patent application, wherein the substituted @ = alkyl ether is selected from: 6- (5 -residue-5 -Methyl-hexyloxy 2,2-dimethyl-hexanoic acid, calcium hydrated salt: 6-(5 -residue-5 -methyl-hexyloxy2,2-dimethyl-hexanoic acid j Crystal form 1 of beggar salt; and crystal form 2 of 6- (5- Junction-5-methyl-hexyloxy) _2,2-dimethyl-hexanoic acid calcium salt 8. Scope of patent as claimed in § 靑The pharmaceutical composition according to item 6, wherein the substituted ~~ nolyl ether compound is 6- (5-carboxy-5-methyl-hexyloxy) -2,2-dimethyl-, hexanoic acid, and calcium salt. 9. A pharmaceutical composition for treating mammalian diseases regulated by IL-6 or selected from the group consisting of: arthritis-< cartilage damage, joint pain, arthritis, systemic lupus erythematosus and connective tissue disease, and sepsis, It contains a Coy inhibitor, which is selected from the group consisting of Valdecoxib, several of its pharmaceutically acceptable salts, and substituted dialkyl ether compounds] & 'It is selected from the compound 6- (5-carboxy-5_, methyl-hexyloxy ) -2,2-Di-130- (3) 200410677 Methyl-hexanoic acid, or a pharmaceutically acceptable salt thereof. 10. The pharmaceutical composition according to item 9 of the scope of patent application, wherein the substituted The dialkyl ether is selected from: 6- (5-carboxy-5-methyl-hexyloxy) -2,2-dimethyl-hexanoic acid, calcium hydrate salt: 6- (5-carboxy-5-methyl -Hexyloxy) -2,2-dimethyl-hexanoic acid, calcium hydrated salt: 6- (5-carboxy-5-methyl-hexyloxy) -2,2-dimethyl-hexanoic acid calcium salt in crystalline form I; and 6- (5-carboxy-5-methyl-hexyloxy) ) The crystalline form of the 2,2-dimethyl-hexanoic acid calcium salt 2. 1 1 · A pharmaceutical composition for treating mammalian diseases regulated by IL-6 or selected from the group consisting of: arthritis, cartilage damage, joint pain, arthritis, systemic lupus erythema, mixed connective tissue disease, and sepsis, Its department contains: a ·) substituted dialkyl ether compounds (formula; [) Or a pharmaceutically acceptable salt thereof, wherein: η and m are independently integers of 2 to 9; R1, R2, R3, and R4 are independently Cl-C6 alkyl, C2_C6 alkenyl, or C2-C6 Alkynyl; or -131-(4) 200410677 R1 and R2 are attached to each other, or R3 and R4 are attached to each other, or R1 and R2 are attached to each other, and R3 and R4 are attached to each other. Carbon atoms, which together form a carbon atom with 3 to 6 carbons. Y1 and Y2 are independently COOH, CHO, tetrazole, or COOR5, where F5 is an alkyl group, a C2-C6 alkenyl group, or a C2-C6 alkynyl group; and the alkyl group, the alkenyl group, and the alkynyl group may be substituted by one or two groups. The substituent is selected from the group consisting of halogen, hydroxy , C! -C6 alkoxy, and phenyl; b ·) a selective COX-2 inhibitor or a pharmaceutically acceptable salt thereof; and c ·) a pharmaceutically acceptable carrier or diluent. 1 2. The pharmaceutical composition according to item 11 of the scope of patent application, wherein COX-2 inhibits Qi U to LAS-3 447 5; LTR- 8 8 8 0; ABT- 9 6 3; valdecoxib BMS-347070; xylidine; tilacoxib; compound of formula (B) -132- 200410677 CS- 5 02; (6aR, 10aR) _3- (l, budimethylheptyl) _6a, 7,10510a -tetrahydro-buhydroxy-dimethyl-6H-dibenzo [b, d] piran -9-carboxylic acid; CV-247; ^ 2 (5H) -furanone, 5,5-dimethyl-3- (1-methylethoxy) -4- [4- (methylsulfonyl) Phenyl]-(" DFP "); Carprofen; Deracoxib; Etoricoxib; GW-4063 8 1; Tiracoxib; Meloxicam; Nimesul Lee; 2- (Ethyloxy) benzoic acid, 3-[(nitrooxy) methyl] phenyl ester; lumiracoxib; parecoxib; P54; Luofenxixi (Rofecoxib); -133- (6) (6) 200410677 rev 1 M i D; 2,6-bis (1,1-dimethylethyl) -4- [0)-(2-ethyl-1 1,2-diketonyl-5 -isothiazolylidyl) methyl] phenol; 5 (R) -thiyl-6-sulfamin-3 (2H) -benzofuranone; N- [3- (formamidine Group) -4 -keto-6-phenoxy-4H-1-benzopiperan-7-yl: l · methanesulfonamide; or a pharmaceutically acceptable salt thereof. The pharmaceutical composition according to item 11, wherein the dialkyl ether is 6- (5-carboxy-5-methyl -Hexyloxy) -2,2-dimethyl-hexanoic acid, or a pharmaceutically acceptable salt thereof. 1 4. The pharmaceutical composition according to item 11 of the patent application scope, wherein the dialkyl ether It is 6- (5-carboxy-5-methyl-hexyloxy) -2,2-dimethyl-hexanoic acid, a calcium hydrate salt; 6- (5-carboxy-5-methyl-hexyloxy)- 2,2-dimethyl-hexanoic acid, calcium salt: 6- (5-carboxy-5-methyl-hexyloxy) -2,2-dimethyl-hexanoic acid calcium salt crystal form 1; or 6 -(5-carboxy-5-methyl-hexyloxy) -2,2-dimethyl-hexanoic acid calcium salt crystal form 2. 1 5. The pharmaceutical composition according to item 11 of the patent application scope, wherein The dialkyl ether is 6- (5-carboxy-5-methyl-hexyloxy) -2,2-dimethyl-hexanoic acid, the calcium salt and the COX-2 inhibitor is parecoxib, rofencorsi (Rofecoxib), valdecoxib, or xyloxane. -134-