Compounds used to treat diseases associated with excessive hyaluronic acid production.

Abstract

The present invention provides compounds of formula (I): [hyaluronic acid production inhibitor]—[unstable connector]—X(I), which can be used to treat diseases associated with excessive hyaluronic acid production.

Description

Technical Field

[0001] The field of this invention relates to compounds, compositions comprising such compounds, and the use of such compounds and compositions in medicine.

[0002] This invention relates to novel compounds, compositions comprising such compounds, and the use of such compounds and compositions in medicine. In particular, this invention relates to the use of such compounds and compositions in methods for treating and preventing diseases associated with excessive hyaluronic acid production, such as rheumatoid arthritis (e.g., arthritis and osteoarthritis), which are believed to occur through inhibition of hyaluronic acid production. Background Technology

[0003] The enumeration or discussion of previously disclosed documents in this specification should not be construed as an admission that such documents are part of current advanced technology or common knowledge.

[0004] Hyaluronic acid is synthesized by alternately transferring the precursor nucleotide sugars UDP-GlcNac and UDP-GlcA to the reducing end of UDP-hyaluronic acid (Prehm, P., Biochem.J., 1983, 211, 181-189; Prehm, P. Biochem.J., 1983, 211, 191-198). Compared with other glycosaminoglycans, hyaluronic acid is synthesized at the plasma membrane and directly exported to the extracellular matrix (Prehm, P., Biochem.J., 1990, 267, 185-189). It is exported from fibroblasts and chondrocytes via the ABC transporter MRP5 (Prehm, P. and Schumacher, U., Biochem. Pharmacol., 2004, 68, 1401-1410; Schulz, T. et al., J Biol. Chem., 2007, 282, 20999-21004) and from epithelial cells via CFTR (Schulz, T. et al., Pathobiology, 2010, 77, 200-209).

[0005] Excessive hyaluronic acid production is associated with a variety of diseases and disorders, including myocardial infarction, stroke, metastatic tumors, and rheumatoid arthritis (for serum hyaluronic acid as a disease marker, see, for example: Laurent TC, Laurent UB, Fraser JR, Ann Med., 1996, 28: 241–53; for liver fibrosis, see, for example: Yang YM et al., Sci Transl Med. 2019, 11(496): eaat9284; for cancer, see, for example: Itano N, Kimata K. Semin Cancer Biol. 2008, 18(4): 268-74; for inflammatory bowel disease, see, for example: Kessler SP, Obery DR, de la Motte C. Int J Cell Biol. 2015; 2015: 745237; for osteoarthritis, see, for example: Stracke D, Schulz T, Prehm P. Mol Nutr Food Res. 2011, 55(3): 485-94; For myocardial infarction, see, for example: Petz A et al., Circ Res. 2019, 124(10): 1433-1447; For renal dysfunction, see, for example: Hansell P, Palm F. Acta Physiol (Oxf). 2015, 213(4): 795-804; For autoimmune diseases, see, for example: Nagy N et al., Matrix Biol. 2019, 78-79: 292-313; For rheumatoid arthritis, see, for example: Yoshioka Y et al., Arthritis Rheum. 2013, 65(5): 1160-70; For rheumatoid diseases, see, for example: Hochberg, MC et al., Rheumatology 2018. Elsevier; Pitsillides AA et al., Arthritis Rheum. 1994. 37(7):1030-8.

[0006] Rheumatoid arthritis affects many tissues, including joints, tendons, ligaments, bones, and muscles.

[0007] Common symptoms include joint pain, loss of mobility in one or more joints, and inflammation, swelling, redness, and heat in the joint or affected area. Most of these conditions result from an improper immune response in the body's tissues. In the case of rheumatoid arthritis, the immune system reacts against the joint tissues.

[0008] Both osteoarthritis and rheumatoid arthritis are forms of arthritis (joint diseases).

[0009] Unlike most other rheumatoid diseases, osteoarthritis does not appear to be primarily related to immune system problems. Instead, osteoarthritis appears to be caused by trauma and damage to the joints and cartilage. The diagnostic criteria for osteoarthritis are changes visible on X-rays of the joints. X-rays may show narrowing of the joint space or the presence of bone spurs. A definitive diagnosis is usually provided by MRI (magnetic resonance imaging) of the joints (Chaudhari AS et al., J Magn Reson Imaging. 2020. 52(5):1321-1339).

[0010] Osteoarthritis is characterized by cartilage erosion, proteolytic activity of proteoglycans and collagen, and disruption of proteoglycan and hyaluronic acid synthesis rates caused by chondrocytes. Excessive hyaluronic acid production is a recognized early change in the pathogenesis of osteoarthritis.

[0011] Key events in osteoarthritis cartilage include increased hyaluronic acid production, decreased proteoglycan synthesis, and proteolytic degradation of type II collagen and proteoglycan core proteins.

[0012] In healthy cartilage, the synthesis of hyaluronic acid and proteoglycans is finely tuned to each other, and most hyaluronic acid is endocytosed after binding with intact CD44. Osteoarthritic cartilage shows a significant increase in hyaluronic acid production (15-fold), accompanied by a decrease in proteoglycan production (60%) and more detachment from cartilage into the environment (D'Souza, AL et al., Arch. Biochem. Biophys. 2000, 374, 59-65). The primary cause of this detachment is the proteolytic cleavage of CD44. Excessive hyaluronic acid production also leads to the enlargement of hypertrophic pits in the growth plate, and reduced binding of proteoglycans to hyaluronic acid induces apoptosis.

[0013] Hyaluronic acid overproduction is a very early response to tissue activation, and its purpose is to swell the tissue due to its large hydration volume; this response “opens” the tissue, allowing immune cells to enter for repair. Therefore, hyaluronic acid overproduction occurs as a prelude to inflammation in most tissues. However, cartilage is a special tissue because it is so dense, with a large amount of extracellular matrix, that lymphocytes cannot enter the damaged site for repair. Nevertheless, traumatized cartilage tissue still reacts with hyaluronic acid overproduction, leading to irreversible damage. Increased hyaluronic acid overproduction has indeed been documented in the literature at a very early stage of osteoarthritis development.

[0014] Although it has long been known that the increase in hyaluronic acid production precedes the loss of proteoglycans and collagen degradation, interfering with this process has remained challenging until recently due to the lack of available inhibitors of hyaluronic acid production.

[0015] The only hyaluronic acid production inhibitor that has been studied in detail is 4-methylumbelliferone. Its mode of action is indirect, as it depletes the intracellular UDP-GlcA pool used for precursors in hyaluronic acid synthesis. Therefore, side effects on the glucuronidation reaction of biotransformation or on the production of glucuronic acid-containing proteoglycans (such as those with chondroitin sulfate glycosaminoglycans) must be anticipated (Urakawa, H. et al., Int. J. Cancer. 2012, 130, 454-466; Piccioni, F. et al., Glycobiology., 2012, 22, 400-410; Nagy, N. et al., Circulation, 2010, 122, 2313-2322; Twarock, S., J. Biol. Chem., 2010, 285, 23276-23284).

[0016] Hyaluronic acid is reportedly exported via ATP binding to MRP5 (Stracke D. et al., Mol. Nutr. Food Res., 2011, 485-494). MRP5 inhibitors have been described (Stracke D. et al., Mol. Nutr. Food Res., 2011, 485-494; Prehm, P., Food. Chem. Toxicol., 2013, 76-81).

[0017] To the best of our knowledge, there is currently no effective treatment for diseases associated with excessive hyaluronic acid production, where the mechanism of action of the therapeutic agents involves the inhibition of hyaluronic acid production.

[0018] Furthermore, in the case of osteoarthritis, despite its prevalence, there is currently no effective treatment that can alter the disease course or repair existing damage. Current treatment strategies for osteoarthritis are purely symptomatic, consisting of anti-inflammatory drugs, analgesics, physical therapy, and massage.

[0019] Therefore, there is still a need for alternative, effective therapies for diseases associated with excessive hyaluronic acid production, and in particular, there is still a need for effective therapies for osteoarthritis.

[0020] Madelmont et al. have explored the possibility of attaching quaternary ammonium groups to various molecules (Madelmont et al., Bioorg. Med. Chem. 2007, 15, 2368-2374; Madelmont et al., Bioorg. Med. Chem. 2003, 11, 5007-5012; Madelmont et al., Bioconjug. Chem. 2003, 14, 500-506; Madelmont et al., Bioconjug. Chem. 2000, 11, 212-218; Madelmont et al., J. Med. Chem. 1999, 42, 5235-5240; Vidal et al., Eur. J. Med. Chem. 2010, 45, 405-410; US2004208822).

[0021] This invention focuses on using compounds disclosed below to both inhibit an early increase in hyaluronic acid synthesis and to effectively target cartilage in order to limit any potentially serious, systemic off-target effects. Detailed Implementation

[0022] It has now been surprisingly discovered that hyaluronic acid production inhibitor compounds that are attached to the cationic moiety (or masked cationic moiety) via unstable junctions can effectively inhibit the production of hyaluronic acid and have properties that make them useful for the treatment and prevention of diseases characterized by excessive hyaluronic acid production, such as rheumatoid arthritis, especially arthritis and osteoarthritis.

[0023] Unbound by theory, the compounds of the present invention are believed to act as prodrugs. The cationic moiety is believed to target hyaluronic acid production sites, such as those near cartilage. Unstable ester junctions are thought to undergo hydrolysis, such as via plasma esterases (e.g., nonspecific esterases in the synovial fluid of osteoarthritis joints, which are particularly concentrated at erosion sites). Therefore, it is anticipated that the hyaluronic acid production inhibitor will preferably be released from the junction at a desired site near the hyaluronic acid production site (such as at eroded cartilage).

[0024] Compounds of the present invention containing a masked charged moiety (e.g., a masked thiazolyl) are believed to be converted in vivo into charged analogs (e.g., into thiazolyl salts). The resulting charged compound is then considered to act as a prodrug, as outlined above. Compounds containing a masked thiazolyl are believed to be particularly suitable for oral administration due to their increased lipophilicity.

[0025] It is believed that the compounds of the present invention containing long-chain fatty acid counterions are particularly suitable for topical application due to their excellent transdermal delivery. Background of the Invention

[0027] This invention relates to compounds of formula (I):

[0028] [Hyaluronic acid production inhibitor]—[Unstable junction]—X(I)

[0029] Or a pharmaceutically acceptable salt thereof, wherein the hyaluronic acid production inhibitor fragment is selected from the group consisting of: formulas A, B, C, D, and E, wherein formula A is:

[0030]

[0031] Where Y is a group selected from the group consisting of the following:

[0032]

[0033] R A1 R A2 R A3 and R A4 Each can be independently selected from the following groups: -OH, -OR A5 Halogenated, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 The alkynyl group is optionally substituted with one or more groups selected from halogenated, -OH, and -OMe; and an R A1 R A2 R A3 Or R A4 Group is

[0034]

[0035] n is between 0 and 5;

[0036] m is between 0 and 5; and

[0037] R A5 C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 The alkynyl group, these three groups are optionally replaced by one or more groups selected from halogen, -OH and -OMe;

[0038] Equation B is:

[0039]

[0040] Where R B1 R B2 and R B3Each can be independently selected from the following groups: -OH, -OR B4 Halogenated, C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 alkynyl group, C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 The alkynyl group is optionally substituted with one or more groups selected from halogenated, -OH, and -OMe; and an R B2 Or R B3 Group is

[0041]

[0042] n is between 0 and 4;

[0043] m is between 0 and 5;

[0044] R B4 C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 The alkynyl group, these three groups are optionally replaced by one or more groups selected from halogen, -OH and -OMe;

[0045] Equation C is:

[0046]

[0047] The wavy lines represent the connection points with the unstable joint segments;

[0048] Equation D is:

[0049]

[0050] The waveform line represents the connection point with the unstable joint segment; or

[0051] Equation E is:

[0052]

[0053] The wavy lines represent the connection points with the unstable joint segments;

[0054] The unstable joint segment is -OC(O)R L1 -;

[0055] Where R L1 Selected from C 1-6 Alkylene, C 2-6 imidene group, C 2-6 The five groups—ethynyl, arylene, or heteroarylene—are optionally and independently selected from halogenated, -OR L2 Or, one or more groups of the =O group are substituted;

[0056] R L2 Indicates H or C 1-6 alkyl;

[0057] X is selected from the group consisting of: quaternary ammonium salts, quaternary phosphorus salts, pyridinium salts, and thiazolylium salts; or X is...

[0058] Where R 4 C 1-6 alkyl.

[0059] Compounds of Formula I as defined below, particularly including compounds of Formula Ia (including pharmaceutically acceptable salts thereof), may be referred to herein as "compounds of the present invention".

[0060] In a first aspect of the invention, a compound of formula Ia is provided.

[0061] [Hyaluronic acid production inhibitor]—[Unstable junction]—X(Ia)

[0062] Or a pharmaceutically acceptable salt thereof, wherein the hyaluronic acid production inhibitor fragment is selected from the group consisting of: formulas A, B, C, D, and E, wherein formula A is:

[0063]

[0064] Where Y is a group selected from the group consisting of the following:

[0065]

[0066] R A1 R A2 and R A4 Each can be independently selected from the following groups: -OH, -OR A5 Halogenated, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 The alkynyl group is optionally substituted with one or more groups selected from halogenated, -OH, and -OMe; and an R A1 R A2 Or R A4 Group is

[0067]

[0068] n is between 0 and 5;

[0069] m is between 0 and 5; and

[0070] RA5 C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 The alkynyl group, these three groups are optionally replaced by one or more groups selected from halogen, -OH and -OMe;

[0071] Equation B is:

[0072]

[0073] Where R B1 R B2 and R B3 Each can be independently selected from the following groups: -OH, -OR B4 Halogenated, C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 alkynyl group, C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 The alkynyl group is optionally substituted with one or more groups selected from halogenated, -OH, and -OMe; and an R B2 Or R B3 Group is

[0074]

[0075] n is between 0 and 4;

[0076] m is between 0 and 5;

[0077] R B4 C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 The alkynyl group, these three groups are optionally replaced by one or more groups selected from halogen, -OH and -OMe;

[0078] Equation C is:

[0079]

[0080] The wavy lines represent the connection points with the unstable joint segments;

[0081] Equation D is:

[0082]

[0083] The waveform line represents the connection point with the unstable joint segment; or

[0084] Equation E is:

[0085]

[0086] The wavy lines represent the connection points with the unstable joint segments;

[0087] The unstable joint segment is -OC(O)R L1 -;

[0088] Where R L1 Selected from C 1-6 Alkylene, C 2-6 imidene group, C 2-6 The five groups—ethynyl, arylene, or heteroarylene—are optionally and independently selected from halogenated, -OR L2 Or, one or more groups of the =O group are substituted;

[0089] R L2 Indicates H or C 1-6 alkyl;

[0090] X is selected from the group consisting of: quaternary ammonium salts, quaternary phosphorus salts, pyridinium salts, and thiazolylium salts; or X is...

[0091] Where R 4 C 1-6 alkyl.

[0092] To avoid any doubt, those skilled in the art will understand that references herein to compounds of a particular aspect of the invention (such as the first aspect of the invention, i.e., compounds of formula Ia as defined in the first aspect of the invention) will include references to all embodiments and specific features thereof, which may be combined to form other embodiments and features of the invention.

[0093] Unless otherwise indicated, all technical and scientific terms used herein shall have the common meaning as understood by one of ordinary skill in the art to which this invention relates.

[0094] Pharmaceutically acceptable salts include acid addition salts and base addition salts. Such salts can be formed by conventional means, for example by reacting the compounds of the invention in free acid or free base form with one or more equivalents of a suitable acid or base, optionally in a solvent or medium (where the salt is insoluble), followed by removal of the solvent or medium using standard techniques (e.g., in a vacuum, by freeze-drying or by filtration). Salts can also be prepared using techniques known to those skilled in the art, such as by exchanging the counter ion of the compounds of the invention in salt form with another counter ion, for example using a suitable ion exchange resin.

[0095] Specific acid addition salts that may be mentioned include those that protonate the compounds of the present invention by reacting with the corresponding acids to form the following salts: carboxylates (e.g., formate, acetate, trifluoroacetate, propionate, isobutyrate, heptanoate, caprate, octanoate, stearate, acrylate, hexanoate, propynate, ascorbate, citrate, glucuronide, glutamate, glycolate, α-hydroxybutyrate, lactate, tartrate, phenylacetate, mandelate, phenylpropionate, phenylbutyrate, benzoate, chlorobenzoate, methylbenzoate, hydroxybenzoate, methoxybenzoate, dinitrobenzoate, o-acetoxybenzoate). Salts, salicylates, nicotinates, isonicotinates, cinnamates, oxalates, malonates, succinates, octanoates, sebacic acid salts, fumarates, malates, maleates, hydroxymaleates, hippurates, phthalates or terephthalates), halide salts (e.g., chloride salts, bromide salts or iodide salts), sulfonates (e.g., benzenesulfonates, methylbenzenesulfonates, bromobenzenesulfonates or chlorobenzenesulfonates, xylenesulfonates, methanesulfonates, ethanesulfonates, propanesulfonates, hydroxyethanesulfonates, 1- or 2-naphthalenesulfonates or 1,5-naphthalenedisulfonates), or sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates or nitrates, etc.

[0096] Specific base addition salts that may be mentioned include those formed by reacting with a corresponding base to remove a proton from the compound of the invention, thereby forming a salt with an alkali metal (such as Na and K salts), an alkaline earth metal (such as Mg and Ca salts), an organic base (such as ethanolamine, diethanolamine, triethanolamine, tromethamine, and lysine), and an inorganic base (such as ammonia and aluminum hydroxide). More particularly, base addition salts that may be mentioned include Mg salts, Ca salts, and most specifically K and Na salts.

[0097] To avoid any doubt, the compounds of the present invention can exist as solids, and therefore the scope of the invention includes all their amorphous, crystalline, and partially crystalline forms, and can also exist as oils. In the case of the compounds of the present invention existing in crystalline and partially crystalline forms, such forms may include solvates, which are included within the scope of the invention.

[0098] To avoid any doubt, the compounds of the present invention can also be present in solution (i.e., in a solution in a suitable solvent). For example, the compounds of the present invention can be present in aqueous solution, in which case the compounds of the present invention can exist in their hydrated form.

[0099] The compounds of this invention may contain double bonds and, unless otherwise indicated, may therefore exist as E (entgegen) and Z (zusammen) geometric isomers surrounding each individual double bond. Unless otherwise specified, all such isomers and mixtures thereof are included within the scope of this invention.

[0100] The compounds of this invention can also exhibit tautomerism. All tautomeric forms and mixtures thereof are included within the scope of this invention (especially those with sufficient stability to allow their separation).

[0101] The compounds of the present invention may also contain one or more asymmetric carbon atoms and may therefore exhibit optical and / or diastereomeric phenomena (i.e., exist in enantiomeric or diastereomeric forms). Diastereomers can be separated using conventional techniques (e.g., chromatography or fractional crystallization). Various stereoisomers (i.e., enantiomers) can be separated by using conventional techniques, such as fractional crystallization or HPLC, to separate racemic mixtures or other mixtures of the compounds. Alternatively, the desired enantiomers or diastereomerics can be obtained from suitable optically active starting materials under conditions that do not cause racemization or epimerization (i.e., the “chiral pool” method), by reacting the suitable starting material with a “chiral auxiliary” (which can subsequently be removed at a suitable stage by derivatization (i.e., resolution, including dynamic resolution; e.g., reaction with an isochiral acid, followed by separation of diastereomeric derivatives by conventional means such as chromatography) or by reacting with a suitable chiral reagent or chiral catalyst. All methods and processes can be performed under conditions known to those skilled in the art. Unless otherwise specified, all stereoisomers and mixtures thereof are included within the scope of this invention.

[0102] To avoid any doubt, those skilled in the art will understand that where a particular group is described herein as being bonded to a ring system via a floating bond (i.e., a bond not shown that is attached to a specific atom within the ring), the relevant group may be bonded to any suitable atom within the relevant ring system (i.e., a ring within which the floating bond is terminated).

[0103] Unless otherwise specified, C as defined herein 1-z The alkyl group (where z is the upper limit of the range) can be straight-chain, or branched and / or cyclic (thus forming C) when there are a sufficient number of carbon atoms (i.e., depending on the case, at least two or three). 3-z Cycloalkyl groups). Such groups can also be partially cyclic when there are a sufficient number (i.e., at least four) of carbon atoms (thus forming C1646). 4-zPartially cycloalkyl groups). For example, cycloalkyl groups that may be mentioned include cyclopropyl, cyclopentyl, and cyclohexyl. Similarly, partially cycloalkyl groups that may be mentioned (which may also be referred to as “partially cycloalkyl” groups) include cyclopropylmethyl. Such groups can also be polycyclic (e.g., bicyclic or tricyclic) and / or spirocyclic when a sufficient number of carbon atoms are present. To avoid ambiguity, specific alkyl groups that may be mentioned include straight-chain (i.e., unbranched and / or cyclic) alkyl groups.

[0104] Unless otherwise specified, C as defined herein 2-z The alkenyl group (where z is the upper limit of the range) can be straight-chain, or branched and / or cyclic when a sufficient number (i.e., at least three) of carbon atoms are present (thus forming C...). 4-z Cyclic alkenyl groups). Such groups can also be partially cyclic when a sufficient number (i.e., at least five) of carbon atoms are present. For example, partially cyclic alkenyl groups (which may also be referred to as “partially cyclic” groups) include cyclopentenylmethyl and cyclohexenylmethyl. Such groups can also be polycyclic (e.g., bicyclic or tricyclic) or spirocyclic when a sufficient number of carbon atoms are present. To avoid ambiguity, specific alkenyl groups that may be mentioned include straight-chain (i.e., unbranched and / or cyclic) alkenyl groups.

[0105] Unless otherwise specified, C as defined herein 2-z The alkynyl group (where z is the upper limit of the range) can be straight-chain or branched when a sufficient number (i.e., at least four) of carbon atoms are present. For the avoidance of doubt, specific alkynyl groups may be mentioned including straight-chain (i.e., unbranched and / or cyclic) alkynyl groups.

[0106] To avoid any doubt, when a sufficient number of carbon atoms are present, C 2-z alkenyl and C 2-z The alkynyl group may have one or more carbon-carbon double bonds and / or triple bonds.

[0107] To avoid ambiguity, unless otherwise specified, groups referred to herein as “alkyl,” “alkenyl,” and / or “alkynyl” will be considered to refer to the highest degree of unsaturation present in the bonds of such groups. For example, a group having a carbon-carbon double bond and a carbon-carbon triple bond in the same group will be referred to as “alkynyl.” Alternatively, it may be specifically specified that such groups will contain only the specified degree of unsaturation (i.e., in one or more of the bonds, as the case may be; for example, in one of the bonds).

[0108] To avoid any doubt, alkyl, alkenyl, and alkynyl groups as described herein may also act as connector groups (i.e., groups that join two or more parts of the compound), in which case such groups may be referred to as “alkylene”, “alkenyl”, and / or “alkynyl” groups, respectively.

[0109] To avoid any doubt, as used herein, references to heteroatoms will be taken in the normal sense as understood by those skilled in the art. Specific heteroatoms that may be mentioned include phosphorus, selenium, tellurium, silicon, boron, oxygen, nitrogen, and sulfur (e.g., oxygen, nitrogen, and sulfur, such as oxygen and nitrogen).

[0110] As used herein, the term heterocyclic group can refer to non-aromatic monocyclic and polycyclic (e.g., bicyclic) heterocyclic groups (which can also be bridged if they contain a sufficient number of atoms), wherein at least one (e.g., one to four) of the atoms in the ring system is not carbon (i.e., a heteroatom), and wherein the total number of atoms in the ring system is between three and twelve (e.g., between five and ten, such as between three and eight; for example, thus forming a 5- or 6-membered heterocyclic group). Furthermore, such heterocyclic groups can be saturated, thus forming a heterocyclic alkyl group; or unsaturated, containing one or more carbon-carbon bonds, or, where possible, carbon-heteroatom or heteroatom-heteroatom double and / or triple bonds, thus forming, for example, C 2-z (e.g., C) 4-z Heterocyclic alkenyl groups (where z is the upper limit of the range) or C 7-z Heterocyclic alkynyl group.

[0111] To avoid any doubt, those skilled in the art will understand that the heterocyclic groups that can form part of the compounds of the present invention are those that are chemically available, as known to those skilled in the art. Various heterocyclic groups are well known to those skilled in the art, such as 7-azabicyclo-[2.2.1]heptyl, 6-azabicyclo[3.1.1]heptyl, 6-azabicyclo[3.2.1]octyl, 8-azabicyclo[3.2.1]octyl, aziridinyl, azabicyclobutyl, 2,3-dihydroisothiazolyl, dihydropyranyl, dihydropyridinyl, dihydropyrroleyl (including 2,5-dihydropyrroleyl), dioxacyclopentyl (including 1,3-dioxacyclopentyl), dioxacyclohexyl (including 1,3-dioxacyclohexyl and 1,4-dioxacyclohexyl), dithiaalkyl (including 1,4-dithiaalkyl), dithiocyclopentyl (including 1,3- Dithiocyclopentyl), imidazoalkyl, imidazolinyl, isothiazolyl, morpholinyl, 7-oxabicyclo[2.2.1]heptyl, 6-oxabicyclo[3.2.1]octyl, oxabicyclobutyl, ethylene oxide, piperazinyl, piperidinyl, pyranyl, pyrazolyl, pyrrolidone, pyrrolyl, pyrrolinyl, quininecyclo, cyclobutanesulfonyl, 3-cyclobutenylsulfonyl, tetrahydropyranyl, tetrahydrofurfuryl, tetrahydropyridinyl (such as 1,2,3,4-tetrahydropyridinyl and 1,2,3,6-tetrahydropyridinyl), dithiocyclobutyl, cyclothioethane, thiocyclopentyl, tetrahydrothiaranyl, thiomorpholinyl, trithiaalkyl (including 1,3,5-trithiaalkyl), scopolane, etc.

[0112] Where appropriate, the substituents on the heterocyclic group can be located on any atom (including heteroatoms) in the ring system. Furthermore, where the substituent is another cyclic compound, the cyclic compound can be linked by a single atom on the heterocyclic group, thereby forming a spirocyclic compound. The linking point of the heterocyclic group can be via any suitable atom in the ring system, including (where appropriate) other heteroatoms (such as nitrogen atoms); or via an atom on any fused carbon ring that can be present as part of the ring system. The heterocyclic group can also be in N- or S-oxidized form, as known to those skilled in the art.

[0113] In each instance when mentioned herein, the specific heterocyclic groups that may be mentioned include 3- to 8-membered heterocyclic groups (e.g., 4- to 6-membered heterocyclic groups, such as 5- or 6-membered heterocyclic groups).

[0114] For the avoidance of ambiguity, references to polycyclic (e.g., bicyclic or tricyclic) groups (e.g., when used in the context of heterocyclic or cycloalkyl groups, e.g., heterocyclic) will refer to a ring system in which at least two chain breaks are required to convert such a ring into an acyclic (i.e., straight-chain or branched) chain, wherein the minimum number of such chain breaks corresponds to the defined number of rings (e.g., the term bicyclic may indicate that at least two chain breaks are required to convert a ring into a straight chain). For the avoidance of ambiguity, the term bicyclic (e.g., when used in the context of alkyl groups) can refer to a group in which the second ring of a bicyclic system is formed between two adjacent atoms of the first ring; a group in which two non-adjacent atoms are connected by an alkyl (which may be called an alkylene group when connecting two parts) group (optionally containing one or more heteroatoms), wherein the latter group may be called bridging; or a group in which the second ring is connected to a single atom, wherein the latter group may be called a spiro compound.

[0115] Specific heterocyclic groups that may be mentioned include piperidinyl (e.g., piperidin-1-yl), octahydro-1H-isoindolyl (e.g., octahydro-1H-isoindolyl-2-yl), aziridine (e.g., aziridine-1-yl), oxacyclobutane (e.g., oxacyclobutane-3-yl), morpholinyl (e.g., morpholinyl-4-yl), piperazine (e.g., piperazine-1-yl or piperazine-4-yl), aziridine-heptane (e.g., aziridine-1-yl), imidazoalkyl (e.g., imidazoalkyl-2-yl), pyrrolidine (e.g., pyrrolidine-1-yl), and diazacycloheptane (e.g., 1,4-diazacycloheptane-1-yl).

[0116] As may be used herein, the term aryl can refer to C 6-14 (e.g., C) 6-10 Aromatic groups. These groups can be monocyclic or bicyclic, and when bicyclic, they can be fully aromatic or partially aromatic. C can be mentioned. 6-10 Aryl groups include phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, indanyl, etc. (e.g., phenyl, naphthyl, etc.). To avoid ambiguity, the substituents on the aryl group can be connected via any suitable carbon atom in the ring system.

[0117] To avoid any doubt, those skilled in the art will understand that the aryl groups that can form part of the compounds of the present invention are those that are chemically available, as known to those skilled in the art. Specific aryl groups that may be mentioned include phenyl and naphthyl groups, such as phenyl.

[0118] As may be used herein, references to heteroaryl (which may also be referred to as heteroaromatic) groups can refer to 5- to 14-membered (e.g., 5- to 10-membered) heteroaromatic groups containing one or more heteroatoms (such as one or more heteroatoms selected from oxygen, nitrogen, and / or sulfur). Such heteroaryl groups may contain one, two, or three rings, at least one of which is aromatic. Where appropriate, substituents on the heteroaryl / heteroaromatic group may be located on any suitable atom (including heteroatoms) in the ring system (e.g., on a suitable N atom).

[0119] The connection point of a heteroaryl / heteroaromatic group can be via any atom in the ring system, including (where appropriate) heteroatoms. A bicyclic heteroaryl / heteroaromatic group may contain a benzene ring fused with one or more other aromatic or non-aromatic heterocycles, in which case the connection point of a polycyclic heteroaryl / heteroaromatic group can be via any ring (including a benzene ring or a heteroaryl / heteroaromatic or heterocyclic ring).

[0120] To avoid any doubt, those skilled in the art will understand that the heteroaryl groups that can form part of the compounds of the present invention are those that are chemically available, as known to those skilled in the art. Various heteroaryl groups are well known to those skilled in the art, such as pyridyl, pyrroloyl, furanyl, thiophene, oxadiazolyl, thiadiazolyl, thiazolyl, oxazolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, imidazolyl, imidazopyrimidinyl, imidazothiazolyl, thiophenezothiazolyl, pyrimidinyl, furanylpyridinyl, indolyl, azaindolyl, pyrazinyl, pyrazolylpyrimidinyl, indolyl, pyrimidinyl, quinolinyl, isoquinolinyl, quinazolinyl, benzofuranyl, benzothiophene, benzimidazolyl, benzooxazolyl, benzothiazolyl, benzotriazolyl, and purine.

[0121] To avoid any doubt, oxides of heteroaryl / heteroaryl groups are also included in the scope of this invention (e.g., N-oxides).

[0122] As mentioned above, heteroaryl groups include polycyclic (e.g., bicyclic) groups, one ring of which is aromatic (while the other ring may or may not be aromatic). Therefore, other heteroaryl groups that may be mentioned include groups such as benzo[1,3]dioxacyclopentenyl, benzo[1,4]dioxinyl, dihydrobenzo[d]isothiazolium, 3,4-dihydrobenzo[1,4]oxazinyl, dihydrobenzothiopheneyl, dihydroindolyl, 5H,6H,7H-pyrrolo[1,2-b]pyrimidinyl, 1,2,3,4-tetrahydroquinolinyl, dihydrobenzothiaranyl, etc.

[0123] Specific heteroaryl groups that can be mentioned include morpholine, piperidine, pyridine, pyrazine, pyridazine, and pyrazole.

[0124] To avoid any doubt, when a ring is described as having a circle, its presence should indicate that the relevant ring is aromatic. Alternatively, an aromatic group can be described as a cyclic group containing an appropriate number of double bonds to allow for aromaticity.

[0125] This invention also covers compounds with the same isotopic labeling as those described herein, but in fact, one or more atoms are replaced by atoms having an atomic mass or mass number different from that found in nature (or the most abundant atomic mass or mass number found in nature). All isotopes of any particular atom or element as specified herein are considered within the scope of the compounds of this invention. Therefore, the compounds of this invention also include deuterated compounds, i.e., compounds of this invention in which one or more hydrogen atoms are replaced by the hydrogen isotope deuterium.

[0126] To avoid any doubt, where the identity of two or more substituents in the compounds of the present invention may be identical, the actual identity of the individual substituents does not depend on each other in any way. For example, where there are two or more R... A1 In the case of groups, these R A1 The groups can be the same or different. Similarly, when two or more R groups are present... A1 Groups and each representing C 1-6 In the case of alkyl groups, the C discussed 1-6 The alkyl groups can be the same or different.

[0127] Similarly, to avoid any ambiguity, when terms such as “0 to 5” are used herein, those skilled in the art will understand that this means 0 and 5 (inclusive). Unless otherwise stated, the same inference will apply to other such terms used herein.

[0128] Furthermore, to avoid any doubt, when the specified substituent is optionally substituted by one or more substituents (e.g., optionally substituted by one or more groups selected from halogen, OH, and -OMe), the C-terminal is specified. 1-6 When alkyl is used, these substituents can be positioned on the same or different atoms, where possible. Such optional substituents can be present in any suitable number (e.g., the relevant group can be replaced by one or more such substituents, such as one such substituent).

[0129] To avoid any doubt, in cases where a group is referred to herein as optionally substituted, especially considering that such optional substituents may not be present (i.e., the reference to such optional substituents may be removed), the optionally substituted group may be referred to as unsubstituted.

[0130] Symbols displayed perpendicular to the keys Indicates the point where the displayed portion connects to the rest of the molecule.

[0131] To avoid any doubt, those skilled in the art will understand that the compounds of this invention, which are the subject of this invention, include those compounds that are available, i.e., those compounds that can be prepared in a stable form. That is, the compounds of this invention include those compounds that are robust enough to withstand, for example, separation from the reaction mixture to a usable purity.

[0132] In a particular embodiment (i.e., a particular embodiment of the first aspect of the invention), the compound of formula Ia causes the hyaluronic acid production inhibitor fragment to have formula A or B.

[0133] In a more specific embodiment, the compound of formula Ia causes the hyaluronic acid production inhibitor fragment to have formula A.

[0134] In such embodiments, the Y group is selected from... Preferably, Y is

[0135] Where R A1 R A2 and R A4 Each can be independently selected from the following groups: -OH, -OR A5 Halogenated, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 The alkynyl group is optionally substituted with one or more groups selected from halogenated, -OH, and -OMe; and an R A1 R A2 Or R A4 Group is

[0136]

[0137] R A5 C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 The alkynyl group, these three groups are optionally replaced by one or more groups selected from halogenated, -OH, and -OMe. Preferably, R A5 C 1-6 Alkyl, more preferably, R A5 It is a methyl group.

[0138] In a particular embodiment, R A1 R A2 and R A4 Each can be independently selected from the following groups: OH, -OR A5 C 1-6Alkyl, C 2-6 alkenyl and C 2-6 Alkyne group.

[0139] In a further specific embodiment, R A1 R A2 and R A4 Each can be independently selected from the following groups: OH, -OR A5 C 1-6 Alkyl and C 2-6 Alkenyl group.

[0140] In a further specific embodiment, R A1 R A2 and R A4 Each can be independently selected from the following groups: OH, -OR A5 and C 2-6 Alkenyl group.

[0141] In a further specific embodiment, R A1 R A2 and R A4 Each can be independently selected from the group consisting of: OH, OMe, and C5-alkenyl (e.g., isoprene).

[0142] In alternative specific embodiments, R A1 R A2 and R A4 Each can be independently selected from the following groups: OH, -OR A5 Halogenated and C 2-6 Alkenyl group.

[0143] In some embodiments, at least two R A2 and R A4 At positions 3 and 4 of the aromatic ring.

[0144] In a particular embodiment, n is 0 to 5, such as 1 to 4, or 2 to 4.

[0145] In a particular embodiment, m is 0 to 5, such as 1 to 4, or 2 to 4.

[0146] In some embodiments, the unstable joint is located at the 3- or 4-position of the aromatic ring. Preferably, the unstable joint is located at the 4-position of the aromatic ring.

[0147] In a particular embodiment, the compound of formula Ia causes the hyaluronic acid production inhibitor fragment to have formula B.

[0148] In a further specific embodiment, R B1 R B2 and R B3 Each can be independently selected from the following groups: -OH, -ORB4 Halogenated, C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 alkynyl group, C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 The alkynyl group may optionally be replaced by one or more groups selected from halogenated, -OH and -OMe.

[0149] In a further specific embodiment, R B1 R B2 and R B3 Each can be independently selected from the following groups: -OH, -OR B4 C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 alkynyl group, C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 The alkynyl group may optionally be replaced by one or more groups selected from halogenated, -OH and -OMe.

[0150] In a further specific embodiment, R B1 R B2 and R B3 Each can be independently selected from the following groups: -OH, -OR B4 C 2-6 Alkyl and C 2-6 alkenyl, C 1-6 Alkyl, C 2-6 The alkenyl group is optionally replaced by one or more groups selected from halogenated, -OH and -OMe.

[0151] In a particular embodiment, R B1 R B2 and R B3 Each can be independently selected from the following groups: -OH, -OR B4 and C 2-6 alkenyl, C 2-6 The alkenyl group is optionally substituted with one or more groups selected from halogen, OH and -OMe.

[0152] In a particular embodiment, R B1 R B2 and R B3 Each can be independently selected from the group consisting of: -OH, OMe, and C5-alkenyl (e.g., isoprene).

[0153] In a particular embodiment, R B1 R B2 and R B3 Each is OH.

[0154] In a particular embodiment, n is 0 to 5, such as 1 to 4, or 2 to 4.

[0155] In a particular embodiment, m is 0 to 5, such as 1 to 4, or 2 to 4.

[0156] In some embodiments, the unstable joint is located at the 3- or 4-position of the aromatic ring. Preferably, the unstable joint is located at the 4-position of the aromatic ring.

[0157] In certain embodiments, the compound of formula Ia causes the hyaluronic acid production inhibitor fragment to have formula C, D, or E. In more specific embodiments, the hyaluronic acid production inhibitor fragment has formula C. Alternatively, the hyaluronic acid production inhibitor fragment has formula D. Alternatively, the hyaluronic acid production inhibitor fragment has formula E.

[0158] Unstable connector is -OC(O)R L1 -

[0159] In a particular embodiment, R L1 Selected from C 1-6 Alkylene, C 2-6 imidene group, C 2-6 The three groups, alkynyl, are optionally and independently selected from halogenated, -OR L2 Or, one or more groups of the =O group are substituted.

[0160] In a further specific embodiment, R L1 Selected from C 1-6 Alkylene and C 2-6 The three groups, alkenyl, are optionally and independently selected from halogenated, -OR L2 Or, one or more groups of the =O group are substituted.

[0161] In a further specific embodiment, R L1 C 1-6 Alkylene, such as butene, propylene, ethylene, or methylene, wherein the group is optionally independently selected from halogenated, -OR L2 Or, one or more groups of the =O group are substituted.

[0162] In a further specific embodiment, R L1 It is a methylene group.

[0163] In a particular embodiment, X is selected from the group consisting of: quaternary ammonium salts, quaternary phosphorus salts, pyridinium salts, and thiazolylium salts.

[0164] In a particular embodiment, X is selected from the group consisting of the following:

[0165]

[0166] The group is optionally surrounded by one or more R 3 Group substitution;

[0167] In a further specific embodiment, X is selected from the group consisting of:

[0168] Each of them is optionally controlled by one or more R 3 Group substitution;

[0169] In a further specific embodiment, X is... Each of them is optionally controlled by one or more R 3 Group substitution;

[0170] In a further specific embodiment, X is...

[0171] In a particular embodiment, R 1 C that is optionally halogenated or =O substituted 1-6 Alkyl groups, C groups optionally halogenated or =O substituted 2-6 Alkenyl groups, C groups optionally substituted with halogenated or =O 2-6 alkynyl group;

[0172] In a further specific embodiment, R 1 C that is optionally halogenated or =O substituted 1-6 alkyl.

[0173] In a further specific embodiment, R 1 Choose the group consisting of the following: n-butyl, n-propyl, ethyl, methyl.

[0174] In a further specific embodiment, R 1 It is a methyl group.

[0175] In a particular embodiment, R 2 C 1-6 alkyl.

[0176] In a further embodiment, R 2 C 1-4 alkyl.

[0177] In a further embodiment, R 2 It is a methyl group.

[0178] In a particular embodiment, R 3 C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkynyl, aryl, heteroaryl.

[0179] In a further specific embodiment, R 3 C1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne group.

[0180] In a further specific embodiment, R 3 C 1-6 alkyl.

[0181] In a particular embodiment, Z - Choose the group consisting of the following items: Cl - F - ,Br - I - p-Toluenesulfonate, methanesulfonate, acetate, benzoate, salicylate, or R 4 CO2 - ;

[0182] In a further specific embodiment, Z - Choose the group consisting of the following items: Cl - F - ,Br - I - p-Toluenesulfonate, methanesulfonate, acetate, salicylate, or R 4 CO2 - .

[0183] In a further specific embodiment, Z - For Cl - ,Br - Or I - .

[0184] In an alternative embodiment, Z - Choose the group consisting of the following items: Cl - F - ,Br - I - and R 4 CO2 - .

[0185] In a further embodiment, Z - For R 4 CO2 - .

[0186] In a particular embodiment, R 4 C 2-28 Alkyl, C 2-28 alkenyl, C 2-28 Alkyne group.

[0187] In a further specific embodiment, R 4 C 2-28 Alkenyl group.

[0188] In a further specific embodiment, Z - It is a conjugate base of long-chain fatty acids.

[0189] As used in this article, long-chain fatty acids refer to straight-chain fatty acids (carboxylic acids with aliphatic chains) containing twelve or more carbon atoms.

[0190] In a particular embodiment, Z - It is the conjugate base of oleic acid, transoleic acid, isoleic acid, linoleic acid, translinoleic acid, α-linolenic acid, arachidonic acid, and erucic acid.

[0191] In an alternative embodiment, X is Where R 5 C 1-6 alkyl.

[0192] In a particular embodiment, R 5 It is a methyl group.

[0193] In certain embodiments, the compound of formula Ia causes:

[0194] (i) The hyaluronic acid production inhibitor fragment has formula A, B, C, D or E, such as formula A or B, wherein if the hyaluronic acid production inhibitor fragment has formula A, then Y is selected from the group consisting of the following:

[0195] (ii) Unstable joints have the form -OC(O)R L1 -,in

[0196] R L1 Choose the group consisting of the following items: C 1-6 Alkylene, C 2-6 imidene group, C 2-6 Alynyl groups; such as

[0197] R L1 Choose the group consisting of the following items: C 1-6 Alkylene and C 2-6 alkenyl; or

[0198] R L1 Choose from the group consisting of: butene, propylene, ethylene, or methylene;

[0199] (iii) The X group is selected from the group consisting of the following:

[0200]

[0201] Such as or

[0202]

[0203] Z - For Cl - F - ,Br - I - p-Toluenesulfonate, methanesulfonate, acetate, benzoate, salicylate, or R 4 CO2 - ;

[0204] Such as Z - For Cl - ,Br - Or I - and R 4 CO2 - ;or

[0205] Z - For R 4 CO2;

[0206] Where R 4 C 2-28 Alkyl, C 2-28 alkenyl, C 2-28 Alkyne groups, such as C 2-28 Alkenyl group.

[0207] In certain embodiments, the compound of formula Ia causes:

[0208] (i) Hyaluronic acid production inhibitor fragments have formula A, B, C, D, or E, such as formula A or B,

[0209] If the hyaluronic acid production inhibitor fragment has formula A, then Y is selected from the group consisting of the following items:

[0210]

[0211] (ii) Unstable joints have the form -OC(O)R L1 -,in

[0212] R L1 Choose the group consisting of the following items: C 1-6 Alkylene, C 2-6 imidene group, C 2-6 Alynyl groups; such as

[0213] R L1 Choose the group consisting of the following items: C 1-6 Alkylene and C 2-6 alkenyl; or

[0214] R L1 Choose from the group consisting of: butene, propylene, ethylene, or methylene;

[0215] (iii) X is Where R 5 C 1-6 Alkyl groups, such as methyl groups.

[0216] Therefore, in the specific embodiments that may be mentioned, the compound of formula (Ia) is the compound of formula (II):

[0217]

[0218] Where R A1 R A2 X, m, n and unstable connectors are as described herein (i.e., for compounds of the first aspect of the invention, including all embodiments thereof).

[0219] In certain embodiments of this invention (i.e., particularly for compounds of formula II), the compounds of formula (IIa) may be mentioned:

[0220]

[0221] In further specific embodiments of this invention (i.e., particularly for compounds of formula II), the compounds of the invention may also be mentioned, including those of formula (IIb):

[0222]

[0223] Where R 1 and Z - As described herein (i.e., for compounds of the first aspect of the invention, including all embodiments thereof).

[0224] In further specific embodiments of this invention (i.e., particularly for compounds of formula II), the compounds of the invention may also include those of formula (IIc):

[0225]

[0226] Where R 5 As described herein (i.e., for compounds of the first aspect of the invention, including all embodiments thereof).

[0227] In further specific embodiments of this invention (i.e., particularly for compounds of formula II), the compounds of formula (III) may also be mentioned:

[0228]

[0229] In specific embodiments that may be mentioned, the compound of formula Ia is a compound of formula (VI):

[0230]

[0231] Where RA1 R A4 X, n, m and unstable connectors are as described herein (i.e., for compounds of the first aspect of the invention, including all embodiments thereof).

[0232] In certain embodiments of this invention (i.e., particularly for compounds of formula VI), the compounds of formula (VIa) may also be mentioned:

[0233]

[0234] In further specific embodiments of this invention (i.e., particularly for compounds of formula VI), the compounds of formula (VIb) may also be mentioned:

[0235]

[0236] Where R 1 and Z - As described herein (i.e., for compounds of the first aspect of the invention, including all embodiments thereof).

[0237] In further specific embodiments of this invention (i.e., particularly for compounds of formula VI), the compounds of formula (VII) may also be mentioned:

[0238]

[0239] In specific embodiments that may be mentioned, the compound of formula Ia is a compound of formula (VIII):

[0240]

[0241] Where R B1 R B2 R B3 X, n, m and unstable connectors are as described herein (i.e., for compounds of the first aspect of the invention, including all embodiments thereof).

[0242] In certain embodiments of this invention (i.e., particularly for compounds of formula VIII), the compounds of formula (VIIIa) may also be mentioned:

[0243]

[0244] In further specific embodiments of this invention (i.e., particularly for compounds of formula VIII), the compounds of formula (VIIIb) may also be mentioned:

[0245]

[0246] Where R1 Z - As described herein (i.e., for compounds of the first aspect of the invention, including all embodiments thereof).

[0247] In further specific embodiments of this invention (i.e., particularly for compounds of formula VIII), the compounds of the invention may also include those of formula (VIIIc):

[0248]

[0249] Where R 5 As described herein (i.e., for compounds of the first aspect of the invention, including all embodiments thereof).

[0250] In further specific embodiments of this invention (i.e., particularly for compounds of formula VIII), the compounds of formula (IX) may also be mentioned:

[0251]

[0252] Wherein X is as described herein (i.e., for compounds of the first aspect of the invention, including all embodiments thereof).

[0253] Specific compounds of the invention that may be mentioned include those compounds described in the examples provided herein, and their pharmaceutically acceptable salts. For the avoidance of doubt, in cases where such compounds of the invention include compounds in a specific salt form, the compounds of the invention include those compounds in a non-salt form and in any pharmaceutically acceptable salt form thereof (which may include the salt forms present in such examples).

[0254] Therefore, specific compounds of the present invention that may be mentioned include:

[0255]

[0256] And its pharmaceutically acceptable salts.

[0257] Medical use

[0258] As indicated herein, the compounds of the present invention, as well as compositions and kits comprising them, can be used as pharmaceuticals.

[0259] Therefore, according to a second aspect of the invention, a compound of the invention as defined above (i.e., a compound as defined in the first aspect of the invention, including all its embodiments and specific features) is provided for use as a medicament (or for medical purposes).

[0260] To avoid any doubt, references to compounds as defined in the first aspect of the invention will include references to compounds of formula Ia (including all embodiments thereof, such as compounds of formulas II to IX) and their pharmaceutically acceptable salts.

[0261] Although the compounds of the present invention may themselves possess pharmacological activity, certain pharmaceutically acceptable (e.g., "protected") derivatives of the compounds of the present invention may be present or prepared, which may not possess such activity but can be administered parenterally or orally and subsequently metabolized in the body to form the compounds of the present invention. Therefore, such compounds (which may possess some pharmacological activity, provided that such activity is significantly lower than that of the active compounds they are metabolized into) can be described as "prodrugs" of the compounds of the present invention.

[0262] To avoid any doubt, the compounds of the present invention are therefore usable because they possess pharmacological activity, and / or they are metabolized in the body after oral or parenteral administration to form pharmacologically active compounds. In particular, the compounds of the present invention are believed to be usable because they deliver pharmacologically active compounds to their site of action (e.g., cartilage).

[0263] As indicated herein, the compounds of the present invention can be used in medicine.

[0264] As indicated herein, the compounds of the present invention can be used specifically for the treatment and prevention of diseases associated with excessive hyaluronic acid production, such as rheumatoid arthritis.

[0265] In a third aspect of the invention, a compound of formula I is provided:

[0266] [Hyaluronic acid production inhibitor]—[Unstable junction]—X(I)

[0267] Or a pharmaceutically acceptable salt thereof, wherein the hyaluronic acid production inhibitor fragment is selected from the group consisting of: formulas A, B, C, D, and E, wherein formula A is:

[0268]

[0269] Where Y is a group selected from the group consisting of the following:

[0270]

[0271] R A1 R A2 R A3 and R A4 Each can be independently selected from the following groups: -OH, -OR A5 Halogenated, C 1-6 Alkyl, C 2-6alkenyl, C 2-6 alkynyl group, C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 The alkynyl group is optionally substituted with one or more groups selected from halogenated, -OH, and -OMe; and an R A1 R A2 R A3 Or R A4 Group is

[0272]

[0273] n is between 0 and 5;

[0274] m is between 0 and 5; and

[0275] R A5 C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 The alkynyl group, these three groups are optionally replaced by one or more groups selected from halogen, -OH and -OMe;

[0276] Equation B is:

[0277]

[0278] Where R B1 R B2 and R B3 Each can be independently selected from the following groups: -OH, -OR B4 Halogenated, C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 alkynyl group, C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 The alkynyl group is optionally substituted with one or more groups selected from halogenated, -OH, and -OMe; and an R B2 Or R B3 Group is

[0279]

[0280] n is between 0 and 4;

[0281] m is between 0 and 5;

[0282] R B4 C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 The alkynyl group, these three groups are optionally replaced by one or more groups selected from halogen, -OH and -OMe;

[0283] Equation C is:

[0284]

[0285] The wavy lines represent the connection points with the unstable joint segments;

[0286] Equation D is:

[0287]

[0288] The waveform line represents the connection point with the unstable joint segment; or

[0289] Equation E is:

[0290]

[0291] The wavy lines represent the connection points with the unstable joint segments;

[0292] The unstable joint segment is -OC(O)R L1 -;

[0293] Where R L1 Selected from C 1-6 Alkylene, C 2-6 imidene group, C 2-6 The five groups—ethynyl, arylene, or heteroarylene—are optionally and independently selected from halogenated, -OR L2 Or, one or more groups of the =O group are substituted;

[0294] R L2 Indicates H or C 1-6 alkyl;

[0295] X is selected from the group consisting of: quaternary ammonium salts, quaternary phosphorus salts, pyridinium salts, and thiazolylium salts; or X is...

[0296] Where R 4 C 1-6 Alkyl groups are used to treat or prevent diseases associated with excessive production of hyaluronic acid, including rheumatoid arthritis.

[0297] The compounds used according to the third aspect of the invention may have any of the features described above with respect to the first aspect of the invention (including all embodiments thereof, such as compounds of formulas II to IX).

[0298] The compound of formula I may be referred to as "the compound of the third aspect of the present invention".

[0299] In specific embodiments that may be mentioned, the compound used according to the third aspect of the invention is a compound of formula (IV):

[0300]

[0301] Where R A1 R A3 X, n, m and unstable connectors are as described herein (i.e., for compounds of the first aspect of the invention, including all embodiments thereof).

[0302] In a particular embodiment, R A1 and R A3 Each can be independently selected from the following groups: OH, -OR A5 C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 Alkyne group.

[0303] In a further specific embodiment, R A1 and R A3 Each can be independently selected from the following groups: OH, -OR A5 C 1-6 Alkyl and C 2-6 Alkenyl group.

[0304] In a further specific embodiment, R A1 and R A3 Each can be independently selected from the following groups: OH, -OR A5 and C 2-6 Alkenyl group.

[0305] In a further specific embodiment, R A1 and R A3 Each can be independently selected from the group consisting of: OH, OMe, and C5-alkenyl (e.g., isoprene).

[0306] In alternative specific embodiments, R A1 and R A3 Each can be independently selected from the following groups: OH, -OR A5 Halogenated and C 2-6 Alkenyl group.

[0307] In some embodiments, m is at least two (e.g., two) and R A2 The groups are located at the 3- and 4-positions of the aromatic ring.

[0308] In certain embodiments of this invention (i.e., particularly for compounds of formula IV), the compounds of formula (IVa) may also be mentioned:

[0309]

[0310] In further specific embodiments of this invention (i.e., particularly for compounds of formula IV), the compounds of formula (V) may also be mentioned:

[0311]

[0312] Specific diseases and conditions associated with excessive hyaluronic acid production that may be mentioned include rheumatoid arthritis, inflammation, cancer, metastasis, myocardial infarction, renal dysfunction, stroke, fibrosis, ischemia-reperfusion injury, autoimmune diseases, chemotherapy resistance, type 1 diabetes (T1D), multiple sclerosis, cirrhosis, asthma, Werner syndrome, and cutaneous hyaluronanosis.

[0313] Preferably, the disease is rheumatoid arthritis, inflammation, cancer, metastasis, myocardial infarction, renal dysfunction, stroke, fibrosis, ischemia-reperfusion injury, or autoimmune disease.

[0314] Specific rheumatoid diseases that can be mentioned include ankylosing spondylitis, bursitis, Crohn's disease, gout, hemophilia, infectious arthritis, inflammatory muscle disease, juvenile idiopathic arthritis, neurogenic arthropathy, osteoarthritis, osteoporosis, osteonecrosis, polymyalgia rheumatica (PMR), polymyositis, psoriatic arthritis, rheumatoid arthritis (RA), scleroderma, hypertrophic bone, Sjögren's syndrome, spondyloarthritis, spondyloarthropathy, systemic lupus erythematosus, systemic sclerosis, tendinitis and vasculitis, and von Willebrand disease.

[0315] In a preferred embodiment of the invention, the compound of the third aspect of the invention (i.e., the compound of formula I) is used to treat or prevent rheumatoid arthritis. Rheumatoid arthritis can be rheumatoid arthritis, osteoarthritis, infectious arthritis, spondyloarthritis, psoriatic arthritis, Sjögren's syndrome, systemic lupus erythematosus, systemic sclerosis, inflammatory muscle disease, vasculitis, gout, hypertrophic bone disease, neurogenic arthropathy, osteonecrosis, hemophilia, or von Willebrand disease.

[0316] In a more preferred embodiment of the present invention, the disease is rheumatoid arthritis, osteoarthritis, or infectious arthritis.

[0317] In a more preferred embodiment of the invention, the disease is osteoarthritis.

[0318] In an alternative third aspect of the invention, a method is provided for treating and preventing diseases associated with excessive hyaluronic acid production (such as rheumatoid arthritis, inflammation, cancer, metastasis, myocardial infarction, renal dysfunction, stroke, fibrosis, ischemia-reperfusion injury, autoimmune diseases, chemotherapy resistance, type 1 diabetes (T1D), multiple sclerosis, cirrhosis, asthma, Werner syndrome, and hyaluronic acid hyperpigmentation), the method comprising administering to a patient in need a therapeutically effective amount of a compound of the third aspect of the invention (i.e., compound of formula I), as defined above.

[0319] In a further alternative third aspect of the invention, the use of compounds of the third aspect of the invention as defined above (i.e., compounds of formula I) for the manufacture of medicaments for the treatment and prevention of diseases or disorders associated with excessive hyaluronic acid production, such as rheumatoid arthritis, inflammation, cancer, metastasis, myocardial infarction, renal dysfunction, stroke, fibrosis, ischemia-reperfusion injury, autoimmune diseases, chemotherapy resistance, type 1 diabetes (T1D), multiple sclerosis, cirrhosis, asthma, Werner syndrome, and hyaluronic acid hyperplasia.

[0320] For the avoidance of doubt, those skilled in the art will understand that, as used herein, the term “hyaluronic acid overproduction” refers to an excess of hyaluronic acid in the synovial fluid or serum of a subject experiencing the same condition. In particular, it can refer to a subject (e.g., a human subject) with a serum hyaluronic acid level higher than 56.0 ± 16.0 μg / L. The serum level in healthy humans is 56.0 ± 16.0 μg / L. Hyaluronic acid concentrations are elevated in osteoarthritis and rheumatoid arthritis, and remission is associated with the reversal of these changes (Sasaki E et al., Int Orthop. 2013. 37(5): 925-30; Pothacharoen P et al., Osteoarthritis Cartilage. 2006. 14(3): 299-301; Pitsillides AA et al., Arthritis Rheum., July 1994; 37(7): 1030-8). The serum hyaluronic acid level was 104.9 ± 16 μg / L in patients with osteoarthritis, while it was 197.1 ± 122.9 μg / L in patients with rheumatoid arthritis. In some patients, excessive production of hyaluronic acid may lead to an increase in the volume of the synovial cavity, and in some cases, physical extraction of excess hyaluronic acid may be necessary.

[0321] The concentration of hyaluronic acid can be determined using appropriate techniques known to those skilled in the art, such as ELISA.

[0322] Technicians will understand that references to the treatment of a specific condition (or similarly, the cure of the condition) will take on their normal meaning in the medical field. Specifically, the term may refer to the reduction of the severity and / or frequency of one or more clinical symptoms associated with the condition, as determined by a physician treating a patient who has or is susceptible to such symptoms. For example, in the case of osteoarthritis, the term may refer to a reduction in pain and a slowing of the further progression of damage to the articular cartilage.

[0323] As used herein, the term prevention (and similarly, avoidance) will include references to the prevention of a disease or ailment (and vice versa). Thus, a reference to avoidance can also be a reference to prevention, and vice versa. In particular, such a term can refer to achieving a reduction (e.g., a reduction of at least 10%, such as a reduction of at least 20%, 30%, or 40%, such as a reduction of at least 50%) in the likelihood that a patient (or healthy subject) will develop a condition (which can be understood to mean that the patient's condition changes to the point that the patient is diagnosed by a physician with a related disease or ailment, such as requiring treatment for the related disease or ailment).

[0324] As used herein, references to a patient (or multiple patients) will refer to a living subject receiving treatment, including mammalian (e.g., human) patients. In particular, references to a patient will refer to human patients.

[0325] To avoid any doubt, those skilled in the art will understand that such treatment or prevention will be administered to patients (or subjects) who require it. Those skilled in the art can use standard techniques to assess a patient's (or subject's) need for such treatment or prevention.

[0326] As used herein, the terms disease and ailment (and similarly, the terms symptom, illness, medical problem, etc.) are used interchangeably.

[0327] As used herein, the term "effective amount" will refer to the amount of compound that imparts a therapeutic effect to the treated patient. This effect can be observed in an objective (i.e., measurable by some test or biomarker) or subjective (i.e., the subject gives indications of the effect and / or feels the effect). In particular, the effect can be observed (e.g., measured) objectively using appropriate tests as known to those skilled in the art. For example, in osteoarthritis, in humans, X-rays can be used to analyze synovial clefts or narrowing of the joint space, as well as osteophyte formation or subchondral sclerosis. MRI can be used to visualize erosion in greater detail.

[0328] In certain embodiments, the compounds of the third aspect of the invention (i.e., compounds of formula I, including all embodiments thereof) are used to treat diseases associated with excessive hyaluronic acid production (or can be used to manufacture medicaments for such treatments, or methods for such treatments, as described herein).

[0329] In a specific embodiment of the third aspect of the invention, the disease is rheumatoid arthritis, such as rheumatoid arthritis selected from the list consisting of: rheumatoid arthritis, osteoarthritis, infectious arthritis, spondyloarthritis, psoriatic arthritis, Sjögren's syndrome, systemic lupus erythematosus, systemic sclerosis, inflammatory muscle disease, vasculitis, gout, hypertrophic bone, neuropathic arthropathy, osteonecrosis, hemophilia, and von Willebrand disease.

[0330] In certain embodiments, the treatment may involve a disease associated with excessive hyaluronic acid production in patients at risk of developing rheumatoid arthritis. Therefore, the compound of the third aspect of the invention (i.e., the compound of formula I) can be used for the prevention of rheumatoid arthritis.

[0331] As indicated herein, the compounds of the third aspect of the invention can be used specifically for the prevention of osteoarthritis following traumatic injuries that often occur during physical activities such as tennis, football, or vigorous jogging, or in cases of overweight or elderly individuals.

[0332] In a particular embodiment, the compound of the third aspect of the present invention (i.e., the compound of formula I) is used to treat or prevent cancer.

[0333] In some embodiments, the cancer is a soft tissue cancer, such as sarcoma (e.g., chondrosarcoma, angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyosarcoma, fibroma, lipoma, and teratoma.

[0334] In a preferred embodiment, the cancer is a sarcoma. More preferably, the cancer is chondrosarcoma.

[0335] In certain embodiments, treatment of diseases associated with excessive hyaluronic acid production (which, as defined herein, particularly include rheumatoid arthritis and osteoarthritis) includes intravenous, topical, intra-articular (i.e., via intra-articular application), transdermal (e.g., via iontophoresis), or oral administration of a compound of formula I or Ia (including pharmaceutically acceptable salts thereof) or a pharmaceutical composition comprising thereof.

[0336] More specifically, treatment of diseases associated with excessive hyaluronic acid production (which, as defined herein, specifically include rheumatoid arthritis and osteoarthritis) includes intravenous, topical, intra-articular (i.e., via intra-articular application), or transdermal (e.g., via iontophoresis) administration of a compound of formula I or Ia (including pharmaceutically acceptable salts thereof) or a pharmaceutical composition containing such a compound.

[0337] In certain embodiments, the compounds of the present invention are administered intravenously.

[0338] In certain embodiments, the compounds of the present invention are applied topically.

[0339] In certain embodiments, the compounds of the present invention are administered intra-articularly.

[0340] In certain embodiments, the compounds of the present invention are administered transdermally.

[0341] In specific embodiments that may be mentioned, compounds of the present invention (i.e., compounds of formula I or Ia, as defined herein, including pharmaceutically acceptable salts thereof) are provided for the treatment of a disease associated with excessive hyaluronic acid production (which, as defined herein, includes rheumatoid arthritis and osteoarthritis in particular), wherein the compounds are administered intra-articularly, for example, to individual affected joints.

[0342] Pharmaceutical Composition

[0343] As described herein, the compounds of the present invention can be used as pharmaceuticals. Such compounds can be administered alone or in combination with known pharmaceutical compositions / formulations.

[0344] In a fourth aspect of the invention, a pharmaceutical composition is provided comprising a compound of the first aspect of the invention as defined herein (i.e., a compound of formula Ia); and optionally one or more pharmaceutically acceptable excipients.

[0345] As used herein, the term pharmaceutically acceptable excipients includes references to mediators, adjuvants, carriers, diluents, pH adjusters and buffers, tension modifiers, stabilizers, humectants, etc. In particular, such excipients may include adjuvants, diluents, or carriers.

[0346] In a particular embodiment of the fourth aspect of the invention, the pharmaceutical composition comprises at least one pharmaceutically acceptable excipient.

[0347] To avoid any doubt, references herein to compounds of the invention for specific purposes (and similarly, to uses and methods of use of compounds relating to the invention) may also be applied to pharmaceutical compositions comprising compounds of the invention, as described herein.

[0348] Therefore, in a fifth aspect of the invention, a pharmaceutical composition as defined in the fourth aspect of the invention is provided for treating or preventing a disease characterized by excessive hyaluronic acid production (as defined herein, refer to the third aspect of the invention and all embodiments thereof).

[0349] Those skilled in the art will understand that the compounds of the present invention can act systematically and / or locally (i.e. at specific sites), and therefore can be applied accordingly using suitable techniques known to those skilled in the art.

[0350] Those skilled in the art will understand that the compounds and compositions described herein are generally to be administered orally, intravenously, subcutaneously, buccally, rectally, transdermally, nasally, tracheally, bronchially, sublingually, intranasally, topically, via any other parenteral route, or by inhalation in pharmaceutically acceptable dosage forms.

[0351] The pharmaceutical compositions described herein will include compositions in the following forms: tablets, capsules or elixirs for oral administration; suppositories for rectal administration; and sterile solutions or suspensions for parenteral or intramuscular administration. Alternatively, particularly where such compounds of the present invention act locally, the pharmaceutical compositions may be formulated for local application (including for iontophoresis).

[0352] Therefore, in certain embodiments, the pharmaceutical formulation is provided in a pharmaceutically acceptable dosage form, including tablets or capsules, liquid forms for oral or injectable administration, suppositories, creams, gels, foams, inhalers (e.g., for intranasal application), or forms suitable for topical application. To avoid any doubt, in such embodiments, the compounds of the present invention may be present as solids (e.g., solid dispersions), liquids (e.g., in solutions), or in other forms (such as micelles).

[0353] For example, in the preparation of pharmaceutical formulations for oral administration, compounds can be mixed with solid powdered ingredients (such as lactose, sucrose, sorbitol, mannitol, starch, amylopectin, cellulose derivatives, gelatin, or other suitable ingredients), as well as with disintegrants and lubricants (such as magnesium stearate, calcium stearate, sodium stearate fumarate, and polyethylene glycol wax). The mixture can then be processed into granules or compressed into tablets.

[0354] Soft gelatin capsules can be prepared using capsules containing one or more active compounds (such as those of the first, and therefore the second and third, aspects of this invention, and optionally additional therapeutic agents), together with, for example, vegetable oils, fats, or other media suitable for soft gelatin capsules. Similarly, hard gelatin capsules can contain such compounds in combination with solid powdered ingredients such as lactose, sucrose, sorbitol, mannitol, potato starch, corn starch, amylopectin, cellulose derivatives, or gelatin.

[0355] Dosage units for rectal administration can be prepared in the following forms: (i) as suppositories containing a compound mixed with a neutral fatty acid base; (ii) as gelatin rectal capsules containing an active substance mixed with a mixture of vegetable oil, paraffin oil, or other mediators suitable for gelatin rectal capsules; (iii) as ready-made microenemas; or (iv) as dried microenema formulations to be reconstituted in a suitable solvent prior to administration.

[0356] Liquid formulations for oral administration can be prepared as syrups or suspensions (e.g., solutions or suspensions containing compounds and the remainder of a formulation consisting of sugars or sugar alcohols, and mixtures of ethanol, water, glycerol, propylene glycol, and polyethylene glycol). If desired, such liquid formulations may contain colorants, flavoring agents, saccharin, and carboxymethyl cellulose or other thickeners. Liquid formulations for oral administration can also be prepared as dry powders for reconstitution with a suitable solvent prior to use.

[0357] Solutions for parenteral administration can be prepared as solutions of the compound in pharmaceutically acceptable solvents. These solutions may also contain stabilizing and / or buffering components and are dispensed as unit doses in ampoules or vials. Solutions for parenteral administration can also be prepared as dry formulations for temporary reconstitution with a suitable solvent prior to use.

[0358] In certain embodiments, the compounds of the present invention are administered intravenously, and therefore the pharmaceutical compositions of the present invention can be formulated for intravenous administration. This route of administration is preferred because it is rapid and ensures complete bioavailability. The compounds of the present invention are particularly suitable for intravenous administration.

[0359] Alternatively, the compounds of the present invention are applied topically, and the pharmaceutical compositions of the present invention can be formulated for topical application.

[0360] More specifically, the compounds of the present invention are administered via intra-articular application, and the compositions of the present invention can be formulated for intra-articular application.

[0361] Intra-articular application (such as direct injection into the synovial fluid) may be particularly suitable for patients whose individual joints are affected by disease, such as patients with arthritis (e.g., osteoarthritis) affecting one or more knees and / or hips.

[0362] In further specific embodiments, the compounds of the present invention are administered transdermally, and the compositions are formulated for transdermal administration, particularly via iontophoresis.

[0363] For topical application, the pharmaceutical compositions of the present invention can be encapsulated in an aqueous dispersion of glyceryl monooleate (Puglia C. et al., J. Pharm Sci, 2013, 102(7), 2349-2361).

[0364] Alternatively, for topical application, the compounds of the present invention can be used in hydrophobic ion-pair delivery systems (Al-Dujaili EA Indian Drugs 2020.57(01), 7-18; Torky AS et al., Int J Pharm, 2018, 76-86), preferably wherein the ion-pair complexing agent is oleic acid (Lu et al., Mol. Pharm, 2018, 216-225).

[0365] The pharmaceutical compositions of the present invention can also be formulated for oral administration.

[0366] Depending on the potency and physical characteristics of compounds (i.e., active ingredients) such as those of the present invention, pharmaceutical formulations that may be mentioned include those in which the active ingredient is present in an amount of at least 1% (or at least 10%, at least 30%, or at least 50%) by weight. That is, the ratio of the active ingredient of the pharmaceutical composition to other components (i.e., adjuvants, diluents, and carriers) is at least 1:99 (or at least 10:90, at least 30:70, or at least 50:50) by weight.

[0367] Those skilled in the art will understand that the compounds of the present invention can be administered in different doses (e.g., as formulations as described above), wherein a suitable dose can be readily determined by those skilled in the art. Oral, pulmonary, and topical doses (and subcutaneous doses, although these doses may be relatively low) can range from about 0.01 μg / kg body weight (μg / kg / day) to about 200 μg / kg / day, preferably from about 0.01 to about 10 μg / kg / day, and more preferably from about 0.1 to about 5.0 μg / kg / day. For example, when administered orally, treatment with such compounds may include administration of a formulation typically containing between about 0.01 μg and about 2000 mg, for example between about 0.1 μg and about 500 mg, or between 1 μg and about 100 mg (e.g., from about 20 μg to about 80 mg). When administered intravenously, the most preferred dose during constant-rate infusion will be in the range of about 0.001 to about 10 μg / kg / hour. Advantageously, treatment may include administration of such compounds and compositions in a single daily dose, or administration of a total daily dose in divided doses twice, three or four times daily (e.g., twice daily, such as doses of 25 mg, 50 mg, 100 mg or 200 mg twice daily, referring to the doses described herein).

[0368] When used in this document in relation to specific values ​​(such as quantities), the term “about” (or similar terms such as “approximately”) will be understood to indicate that such values ​​may vary by up to 10% of the defined value (specifically, up to 5%, such as up to 1%). It is expected that, in each case, such a term may be replaced by a symbol such as “±10%” (or by indicating the variance of a specific quantity calculated based on the relevant value). It is also expected that, in each case, such a term may be omitted.

[0369] To avoid any doubt, a skilled technician (such as a physician) will be able to determine the actual dosage most suitable for an individual patient, which may vary depending on: the route of administration, the type and severity of the condition to be treated, and the species, age, weight, sex, renal function, liver function, and response of the specific patient to be treated. Although the above dosages are examples of average cases, there may, of course, be individual cases in which higher or lower dosage ranges are required, and such dosages are within the scope of this invention.

[0370] Kits-of-parts and combination formulations

[0371] Those skilled in the art will understand that treatments using the compounds of the present invention may further include (i.e., in combination with) further treatment or prevention methods for the same condition. In particular, treatments using the compounds of the present invention may be combined with means for treating diseases associated with excessive hyaluronic acid production (such as rheumatoid arthritis, arthritis, or osteoarthritis as described herein), such as treatments using one or more therapeutic agents that can be used to treat or prevent diseases associated with excessive hyaluronic acid production and / or treatments using one or more physical methods (such as surgical treatments) for treating or preventing diseases associated with excessive hyaluronic acid production, as known to those skilled in the art.

[0372] As described herein, the compounds of the present invention can also be combined with one or more other (i.e., different) therapeutic agents (i.e., agents not of the compounds of the present invention) that can be used to treat or prevent diseases associated with excessive hyaluronic acid production. Such combination products providing the combined administration of the compounds of the present invention with one or more other therapeutic agents can be presented as individual formulations, wherein at least one of those formulations contains the compounds of the present invention, and at least one formulation contains other therapeutic agents, or can be presented as a combined formulation (i.e., formulated) (i.e., as a single formulation containing the compounds of the present invention and the one or more other therapeutic agents).

[0373] Therefore, according to a sixth aspect of the present invention, a combination product is provided, comprising:

[0374] (I) The compounds of the present invention, as defined above (i.e., in the first aspect of the invention, including all embodiments and specific features thereof); and

[0375] (II) One or more other therapeutic agents that can be used to treat or prevent diseases associated with excessive hyaluronic acid production (such as rheumatoid arthritis as described herein), wherein each of components (I) and (II) is optionally formulated by mixing with one or more pharmaceutically acceptable excipients.

[0376] In a seventh aspect of the invention, a kit is provided, comprising:

[0377] (a) a pharmaceutical formulation, as defined above (i.e., in the fifth aspect of the invention); and

[0378] (b) One or more other therapeutic agents that can be used to treat or prevent diseases associated with excessive hyaluronic acid production, such as rheumatoid arthritis as described herein, wherein the therapeutic agent is optionally mixed with one or more pharmaceutically acceptable excipients, wherein components (a) and (b) are each provided in a form suitable for application in combination with each other (i.e., incidentally or sequentially).

[0379] Regarding the formulations described herein, by “combined administration” (and similarly “through combined administration”), we include the respective formulations administered sequentially, individually, or simultaneously as part of a medical intervention aimed at treating the relevant condition.

[0380] Therefore, in relation to this invention, the term "combined administration" (and similarly "administered in combination") includes the administration (optionally repeated) of two active ingredients (i.e., the compound of this invention and other agents for treating diseases associated with excessive hyaluronic acid production, or compositions comprising them) together (optionally repeatedly), or in sufficiently close proximity in time, such that a greater beneficial effect on the patient can be achieved during the same treatment or prevention process compared to the administration (optionally repeated) of either agent alone in the absence of other components during the treatment or prevention of the relevant condition. The determination of whether the combination provides a greater beneficial effect in the treatment or prevention of a particular condition, and during the treatment or prevention of a particular condition, will depend on the condition to be treated or prevented, but can be conventionally performed by those skilled in the art.

[0381] Furthermore, in the context of this invention, the term "combination" includes the possibility that one or more of two formulations may be administered before, after, and / or simultaneously with the administration of another component (optionally repeated). When used in this context, the terms "simultaneous administration" and "simultaneous administration with..." include situations where a single dose of a compound of the present invention and an additional compound or a pharmaceutically acceptable salt thereof for treating a disease associated with excessive hyaluronic acid production are administered to each other at intervals of 48 hours (e.g., 24 hours, 12 hours, 6 hours, 3 hours, 2 hours, 1 hour, 45 minutes, 30 minutes, 20 minutes, or 10 minutes).

[0382] As used herein, a reference to other therapeutic agents that are “available” in a certain way (e.g., in the treatment of a disease or ailment) will refer to agents known to be suitable for use in that manner (e.g., agents commonly used for that purpose). Thus, such references can be replaced by references to agents that are “suitable” for the relevant purpose.

[0383] Other therapeutic agents that can be used to treat or prevent diseases associated with excessive hyaluronic acid production, such as rheumatoid arthritis as described herein, will be well known to those skilled in the art. For example, such other therapeutic agents may include inhibitors of inflammation, such as aspirin, ibuprofen, naproxen, meloxicam, celecoxib, indomethacin, corticosteroids (such as prednisone), and antimalarial drugs (such as hydroxychloroquine). Other therapeutic agents may include disease-modifying antirheumatic drugs (DMARDs), such as methotrexate, sulfasalazine, leflunomide, azathioprine, and cyclophosphamide. Other therapeutic agents may also include biologics, such as infliximab, etanercept, adalimumab, cetrus, golimumab, abatacept, tocilizumab, and rituximab.

[0384] Preparation of compounds / compositions

[0385] The pharmaceutical compositions / formulations, combination products, and kits described herein can be prepared in accordance with standards and / or recognized pharmaceutical practices.

[0386] Therefore, in a further aspect of the invention, a process for preparing a pharmaceutical composition / formulation as defined above is provided, the process comprising associating a compound of the invention as defined above with one or more pharmaceutically acceptable excipients.

[0387] In a further aspect of the invention, a process is provided for preparing a combination product or kit formulation as defined above, the process comprising associating a compound of the invention as defined above with other therapeutic agents that can be used to treat a related disease or ailment and at least one pharmaceutically acceptable excipient.

[0388] As used herein, references to associate something with something will mean that the two components are suitable for combined administration.

[0389] Therefore, regarding the process for preparing a complete formulation as defined above, by "associating" the two components with each other, the two components of the complete formulation can be:

[0390] (i) provided as separate formulations (i.e., independent of each other), and subsequently pooled for use in combination therapy; or

[0391] (ii) Packaged and presented together as separate components of a “combination pack” for use in combination therapy.

[0392] The compounds of the present invention as described herein can be prepared according to techniques well known to those skilled in the art (such as those described in the examples provided below).

[0393] According to an eighth aspect of the invention, a process is provided for preparing compounds of the invention as defined above (i.e., compounds of formula Ia), the process comprising reacting a compound of formula (XI) with an organic nucleophile (Nu).

[0394] [Hyaluronic Acid Production Inhibitor] — [Unstable Connector] — LG 1 (XI),

[0395] The hyaluronic acid production inhibitor fragments and unstable linkers are as defined above, and LG 1 The organic nucleophile is selected from the group consisting of chlorine, bromine, fluorine, iodine, and protected alcohols (such as toluenesulfonates, methanesulfonates, and acetates), and the organic nucleophile is selected from the group consisting of tertiary amines, tertiary phosphines, pyridines, and thiazoles.

[0396] The reaction can be carried out, for example, in a suitable solvent (such as THF) and at a suitable reaction temperature (e.g., between room temperature and reflux temperature).

[0397] In a particular embodiment, Nu is selected from the group consisting of the following: The group is optionally surrounded by one or more R 3 Group substitution;

[0398] R 1 C that is optionally halogenated or =O substituted 1-6 Alkyl groups, C groups optionally halogenated or =O substituted 2-6 Alkenyl groups, C groups optionally substituted with halogenated or =O 2-6 alkynyl group;

[0399] R 2 C1-6 alkyl;

[0400] R 3 C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkynyl, aryl, heteroaryl.

[0401] Compounds of formula XI can be obtained by reacting a hyaluronic acid production inhibitor (wherein the hyaluronic acid production inhibitor is as defined above) with a compound of formula XII containing an acyl chloride (such as chloroacetyl chloride).

[0402] ClC(O)R L1 —LG 1 (XII),

[0403] Where R L1 As defined above.

[0404] LG 1 Choose from the group consisting of: chlorine, bromine, fluorine, iodine, and protected alcohols (such as toluenesulfonates, methanesulfonates, and acetates).

[0405] The reaction can be carried out, for example, in a suitable solvent (such as THF), in the presence of a suitable base (such as pyridine), and at a suitable reaction temperature (e.g., between room temperature and reflux temperature).

[0406] In this step, the reaction of the hyaluronic acid production inhibitor compound with the compound of formula XII forms an ester of an unstable linker fragment by reacting the hydroxyl group on the hyaluronic acid production inhibitor with the acyl chloride of the compound of formula XII.

[0407] Alternatively, in this aspect of the invention, a process is provided for preparing the compounds of the invention as defined above (i.e., compounds of formula Ia), the process comprising reacting a hyaluronic acid production inhibitor compound as defined above with a compound of formula XIII.

[0408] ClC(O)R L1 —X(XIII),

[0409] Where R L1 And X as defined above.

[0410] The reaction can be carried out, for example, in a suitable solvent (such as pyridine) and at a suitable reaction temperature (e.g., between room temperature and reflux temperature).

[0411] In this step, the reaction of the hyaluronic acid production inhibitor compound with the compound of formula XIII forms an ester of an unstable linker fragment by reacting the hydroxyl group on the hyaluronic acid production inhibitor with the acyl chloride of the compound of formula XIII.

[0412] Compound XIII can be obtained by reacting compound XIV with a chlorinating agent (such as thionyl chloride).

[0413] HO—C(O)R L1 —X(XIV),

[0414] Where R L1 And X as defined above.

[0415] The reaction can be carried out, for example, in a suitable solvent or in the absence of a solvent (e.g., in a pure reagent), at a suitable reaction temperature (e.g., between room temperature and reflux temperature).

[0416] The starting materials in the following examples are commercially available and known in the literature; or they can be obtained by analogy with the processes described herein, or by conventional synthetic procedures using appropriate reagents and reaction conditions from available starting materials according to standard techniques. In this regard, those skilled in the art may in particular refer to “Comprehensive Organic Synthesis” by B.M. Trost and I. Fleming, Pergamon Press, 1991. Other references that may be used include “Heterocyclic Chemistry”, 3rd edition by J.A. Joule, K. Mills, and G.F. Smith, published by Chapman & Hall; “Comprehensive Heterocyclic Chemistry II” by A.R. Katritzky, C.W. Rees, and E.F. V. Criven, Pergamon Press, 1996; and “Science of Synthesis”, Volumes 9–17 (Hetarenes and Related Ring Systems), Georg Thieme Verlag, 2006.

[0417] Those skilled in the art will understand that substituents, as defined herein, and any substituents thereon, may be modified once or more after or during the processes described above for preparing the compounds of the present invention by methods well known to those skilled in the art. Examples of such methods include substitution, reduction, oxidation, dehydrogenation, alkylation, dealkylation, acylation, hydrolysis, esterification, etherification, halogenation, and nitration. The precursor group may be changed to a different such group or to a group defined in Formula Ia at any point during the reaction sequence. Those skilled in the art may also refer to “Comprehensive Organic Functional Group Transformations” by AR. Katritzky, O. Meth-Cohn, and C. W. Rees, Pergamon Press, 1995 and / or “Comprehensive Organic Transformations” by R. C. Larock, Wiley-VCH, 1999.

[0418] The compounds of the present invention can be separated from their reaction mixtures and, if necessary, purified using conventional techniques known to those skilled in the art. Therefore, methods for preparing the compounds of the present invention as described herein may include the separation and, optionally, purification of the compounds of the present invention as a final step.

[0419] Those skilled in the art will understand that, in the processes described above and below, the functional groups of the intermediate compounds may need to be protected by protecting groups. The protection and deprotection of functional groups can be carried out before or after the reactions in the above schemes.

[0420] Protecting groups can be applied and removed according to techniques well known to those skilled in the art and as described below. For example, standard deprotection techniques can be used to chemically convert the protected compound / intermediate described herein into an unprotected compound. The type of chemistry involved will specify the need for and type of protecting group, as well as the sequence to complete the synthesis. The use of protecting groups is fully described in “Protective Groups in Organic Synthesis,” 3rd edition, TW Greene & P. ​​GMWutz, Wiley-Interscience (1999), the contents of which are incorporated herein by reference.

[0421] The compounds of the present invention may have the following advantages: they may be more effective, less toxic, have a longer duration of action, be more potent, produce fewer side effects, be more easily absorbed, and / or have better pharmacokinetic characteristics (e.g., higher oral bioavailability and / or lower clearance), and / or have other available pharmacological, physical, or chemical properties, whether for the aforementioned indications or other uses. In particular, the compounds of the present invention may have the following advantages: they are more effective in vivo and / or exhibit advantageous properties. Attached Figure Description

[0422] Figure 1 The results of the Almar Blue toxicity assay are shown, which indicate that fulvicol (X), fulvicol-betaine (XB), fulvicol-prophiazole (X-Pro), quercetin (Q), and quercetin-prophiazole (Q-Pro) are non-toxic at concentrations below 100 μM.

[0423] Figure 2A and 2B This study demonstrates the concentration- and time-dependent uptake of flavonoids into chondrosarcoma cells via intracellular fluorescence. Figure 2A The results showed that the derived flavonoids (X-Pro, Q-Pro, and XB) were absorbed in a concentration-dependent manner, while the original xanthohumol and quercetin did not accumulate in cells. Figure 2B The study showed that the intake of the derived flavonoids was initially very rapid, and reached a stable level after 10 hours.

[0424] Figure 3 The effect of the compound on the growth of chondrosarcoma cells was shown. The compound inhibited cell growth in a dose-dependent manner.

[0425] Figure 4 The effect of the compound on inhibiting hyaluronic acid output is shown.

[0426] Figure 5A and 5B Xanthohumol (shown) Figure 5A ) and xanthohumol-betaine ( Figure 5B It inhibits the shedding of proteoglycans from bovine cartilage slices.

[0427] Figures 6A to 6E It shows xanthohumol-betaine ( Figure 6A ), xanthohumol-prophiazole ( Figure 6B ), quercetin-prophiazole ( Figure 6C ), quercetin ( Figure 6D ), xanthohumol ( Figure 6E Inhibition of proteoglycan loss.

[0428] Figures 7A to 7E Xanthohumol (shown) Figure 7A ), xanthohumol-prophiazole ( Figure 7B ), xanthohumol-betaine ( Figure 7C ), quercetin ( Figure 7D ), quercetin-prophiazole ( Figure 7E Concentration dependence of collagen loss in bovine cartilage sections.

[0429] Figure 8A and 8B Treatment with hylin-betaine (compound of Example 1) and xantho-betaine (compound of Example 2) does not alter the trabecular bone of the metaphysis. Trabecular bone phenotypes in Str / ort mice treated with the mediator, hylin-betaine, and xantho-betaine. (A) Representative 3D micro-CT thickness color-coded images of tibial trabeculae. Ex vivo high-resolution analysis of the distal proximal metaphysical tibia was performed to determine (B) bone length, trabecular volume / total volume, trabecular TV, trabecular BV, trabecular eccentricity, trabecular thickness, separation, and number. Images represent mean ± SEM. For micro-CT (mediator and hylin-betaine), the group size was n = 6, and for xantho-betaine-treated mice, n = 5. One-way ANOVA was performed between groups using Bonferroni post-hoc analysis. None of the parameters violated the normality and homogeneity assumptions of variance.

[0430] Figure 9 shows that treatments with hylin-betaine (the compound of Example 1) and xantho-betaine (the compound of Example 2) significantly altered cortical bone. The mean cortical bone thickness (A) and cross-sectional area (CSA) of Str / ort mice treated with the mediator, hylin-betaine, and xantho-betaine ranged from 10% to 90% of the total tibial length (excluding the proximal and distal metaphyseal bones containing trabeculae). Line plots represent mean ± SEM. The group size was n = 6 for the mediator and hylin-betaine groups and 5 for the xantho-betaine group. Graphical heatmaps summarize the statistical differences at specific matching locations along the tibial length and also show representations of the overall effects of the treatments and Bonferroni post-hoc analysis.

[0431] Figure 10 shows the significant alterations in cortical bone caused by treatment with hylin-betaine (the compound of Example 1) and xantho-betaine (the compound of Example 2). The (A) minimum area second moment and (B) maximum area second moment (I0, I ... 最小 and I 最大(C)J (torsional resistance) and (D) ellipticity. Whole-bone analysis was performed on cortical bone ranging from 10% to 90% of the total tibial length (excluding proximal and distal metaphyseal bones). Line plots represent mean ± SEM. Group size was n = 6 for the mediator and hylin-betaine groups and 5 for the xantho-betaine group. Graphical heatmaps summarize statistical differences at specific matching locations along the tibial length and also show representations of the overall treatment effect and Bonferroni post-hoc analysis.

[0432] Figure 11 This study demonstrates that treatment with hylin-betaine (H) instead of xantho-betaine (X) prevents / improves articular cartilage damage in Str / ort mice. Sections were stained with toluidine blue and scored according to the OARSI scoring system. Both the vector and treatment groups exhibited localized lesions. Mean and maximum ± SEM lesion severity scores are shown for each compartment of the vector and treated joints. * indicates statistical significance p < 0.05

[0433] To avoid any doubt, the compounds hylin, hylin-betaine, xanthohumol-betaine (XB), xanthohumol-prophiazole (X-Pro), and quercetin-prophiazole (Q-Pro) used in the figures refer to the compounds in the examples provided herein.

[0434] aspect

[0435] Certain aspects and embodiments of the present invention are set forth in the following numbered paragraphs:

[0436] 1. A compound of formula Ia:

[0437] [Hyaluronic acid production inhibitor]—[unstable junction]—X(Ia),

[0438] Or its pharmaceutically acceptable salt.

[0439] The hyaluronic acid production inhibitor fragment has the following characteristics:

[0440] Formula A

[0441]

[0442] Where Y is a group selected from the group consisting of the following:

[0443]

[0444] R A1 R A2 and R A4 Each can be independently selected from the following groups: -OH, -OR A5 Halogenated, C 1-6Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 The alkynyl group is optionally substituted with one or more groups selected from halogenated, -OH, and -OMe; and an R A1 R A2 Or R A4 Group is

[0445]

[0446] n is between 0 and 5;

[0447] m is between 0 and 5; and

[0448] R A5 C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 The alkynyl group, these three groups are optionally replaced by one or more groups selected from halogen, -OH and -OMe;

[0449] Formula B

[0450]

[0451] Where R B1 R B2 and R B3 Each can be independently selected from the following groups: -OH, -OR B4 Halogenated, C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 alkynyl group, C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 The alkynyl group is optionally substituted with one or more groups selected from halogenated, -OH, and -OMe; and an R B2 Or R B3 Group is

[0452]

[0453] n is between 0 and 4;

[0454] m is between 0 and 5;

[0455] R B4 C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 The alkynyl group, these three groups are optionally replaced by one or more groups selected from halogen, -OH and -OMe;

[0456] Formula C

[0457]

[0458] The wavy lines represent the connection points with the unstable joint segments;

[0459] Formula D

[0460]

[0461] The waveform line represents the connection point with the unstable joint segment; or

[0462] Formula E

[0463]

[0464] The wavy lines represent the connection points with the unstable joint segments;

[0465] The unstable joint segment is -OC(O)R L1 -;

[0466] Where R L1 Selected from C 1-6 Alkylene, C 2-6 imidene group, C 2-6 The five groups—ethynyl, arylene, or heteroarylene—are optionally and independently selected from halogenated, -OR L2 Or, one or more groups of the =O group are substituted;

[0467] R L2 Indicates H or C 1-6 alkyl;

[0468] X is selected from the group consisting of: quaternary ammonium salts, quaternary phosphorus salts, pyridinium salts, and thiazolylium salts; or X is...

[0469] Where R 5 C 1-6 alkyl.

[0470] 2. The compound according to paragraph 1, wherein the hyaluronic acid production inhibitor fragment has formula A or B.

[0471] 3. The compound according to any one of the preceding paragraphs, wherein the compound has formula II:

[0472]

[0473] 4. The compound according to any one of the preceding paragraphs, wherein the compound has Formula III:

[0474]

[0475] 5. The compound according to any one of the preceding paragraphs, wherein the compound is:

[0476]

[0477] 6. The compound according to any one of paragraphs 1 to 2, wherein the compound has formula (VI):

[0478]

[0479] 7. The compound according to paragraph 6, wherein the compound has formula (VII):

[0480]

[0481] 8. The compound according to paragraph 7, wherein the compound is

[0482]

[0483] 9. The compound described in paragraph 7, wherein the compound is:

[0484]

[0485] 10. The compound according to paragraph 1 or 2, wherein the compound has formula VIII:

[0486]

[0487] 11. The compound according to paragraph 10, wherein the compound has formula IX:

[0488]

[0489] 12. The compound described in paragraph 11, wherein the compound is:

[0490]

[0491] 13. The compound according to paragraph 1, wherein the hyaluronic acid production inhibitor fragment has the formula C, D or E.

[0492] 14. The compound according to any one of paragraphs 1 to 4, 6, 7, 10, 11 or 13, wherein X is selected from the group consisting of:

[0493]

[0494] The group is optionally surrounded by one or more R 3 Group substitution;

[0495] R 1 C that is optionally halogenated or =O substituted1-6 Alkyl groups, C groups optionally halogenated or =O substituted 2-6 Alkenyl groups, C groups optionally substituted with halogenated or =O 2-6 alkynyl group;

[0496] R 2 C 1-6 alkyl;

[0497] R 3 C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, heteroaryl;

[0498] Z - Choose the group consisting of the following items: Cl - F - ,Br - I - p-Toluenesulfonate, methanesulfonate, acetate, benzoate, salicylate, or R 4 CO2 - ;

[0499] R 4 C 2-28 Alkyl, C 2-28 alkenyl, C 2-28 Alkyne group.

[0500] 15. The compound according to paragraph 14, wherein the X group is

[0501]

[0502] 16. The compound according to any one of paragraphs 14 or 15, wherein Z - The group is R 4 CO2 - , where R 4 C 4-28 Alkyl or C 4-28 Alkenyl group.

[0503] 17. The compound according to paragraph 1, wherein R A1 To R A4 and R B1 To R B3 Choose from the following groups: OH, OMe, C 2-6 Alkenyl group.

[0504] 18. A pharmaceutical composition comprising a compound as defined in any one of paragraphs 1 to 17, the compound comprising a pharmaceutically acceptable salt thereof; and optionally one or more pharmaceutically acceptable excipients.

[0505] 19. The compound according to any one of paragraphs 1 to 17 or the pharmaceutical composition according to paragraph 18, used as a medicine.

[0506] 20. The compound according to any one of paragraphs 1 to 17 or the pharmaceutical composition according to paragraph 18, for the treatment or prevention of a disease characterized by excessive production of hyaluronic acid.

[0507] 21. The compound according to any one of paragraphs 1 to 17 or the pharmaceutical composition according to paragraph 18, for the treatment or prevention of rheumatoid arthritis.

[0508] 22. The compound or pharmaceutical composition used according to paragraph 20 or 21, wherein the disease is arthritis.

[0509] 23. The compound or pharmaceutical composition used according to any one of paragraphs 20 to 22, wherein the disease is osteoarthritis.

[0510] 24. A method of treating or preventing a disease characterized by excessive hyaluronic acid production, the method comprising administering to a patient in need a therapeutically effective amount of a compound as defined in any one of paragraphs 1 to 17 or a pharmaceutical composition as described in paragraph 18.

[0511] 25. A method of treating or preventing rheumatoid arthritis, the method comprising administering to a patient in need a therapeutically effective amount of a compound as defined in any one of paragraphs 1 to 17 or a pharmaceutical composition as described in paragraph 21.

[0512] 26. The treatment method described in paragraph 24 or 25, wherein the disease is arthritis.

[0513] 27. The treatment method according to any one of paragraphs 24 to 26, wherein the disease is osteoarthritis.

[0514] 28. Use of a compound as defined in any one of paragraphs 1 to 17 or a pharmaceutical composition according to paragraph 18 for the manufacture of a medicament for treating a disease characterized by excessive hyaluronic acid production.

[0515] 29. Use of a compound as defined in any one of paragraphs 1 to 17 or a pharmaceutical composition as described in paragraph 18 for the manufacture of a medicament for the treatment of rheumatoid arthritis.

[0516] 30. Use of the compound or pharmaceutical composition described in paragraph 28 or 29, wherein the disease is arthritis.

[0517] 31. Use of the compound or pharmaceutical composition according to any one of paragraphs 28 to 30, wherein the disease is osteoarthritis.

[0518] 32. A compound of formula (I):

[0519] [Hyaluronic acid production inhibitor]—[Unstable junction]—X(I)

[0520] Or a pharmaceutically acceptable salt thereof, wherein the hyaluronic acid production inhibitor fragment is selected from the group consisting of: formulas A, B, C, D, and E, wherein formula A is:

[0521]

[0522] Where Y is a group selected from the group consisting of the following:

[0523]

[0524] R A1 R A2 R A3 and R A4 Each can be independently selected from the following groups: -OH, -OR A5 Halogenated, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 The alkynyl group is optionally substituted with one or more groups selected from halogenated, -OH, and -OMe; and an R A1 R A2 R A3 Or R A4 Group is

[0525]

[0526] n is between 0 and 5;

[0527] m is between 0 and 5; and

[0528] R A5 C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 The alkynyl group, these three groups are optionally replaced by one or more groups selected from halogen, -OH and -OMe;

[0529] Equation B is:

[0530]

[0531] Where R B1 R B2 and R B3 Each can be independently selected from the following groups: -OH, -OR B4 Halogenated, C1-6 Alkyl, C 2-6 alkenyl and C 2-6 alkynyl group, C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 The alkynyl group is optionally substituted with one or more groups selected from halogenated, -OH, and -OMe; and an R B2 Or R B3 Group is

[0532]

[0533] n is between 0 and 4;

[0534] m is between 0 and 5;

[0535] R B4 C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 The alkynyl group, these three groups are optionally replaced by one or more groups selected from halogen, -OH and -OMe;

[0536] Equation C is:

[0537]

[0538] The waveform line represents the connection point with the unstable joint segment; Equation D is:

[0539]

[0540] The waveform line represents the connection point with the unstable joint segment; or

[0541] Equation E is:

[0542]

[0543] The wavy lines represent the connection points with the unstable joint segments;

[0544] The unstable joint segment is -OC(O)R L1 -;

[0545] Where R L1 Selected from C 1-6 Alkylene, C 2-6 imidene group, C 2-6 The five groups—ethynyl, arylene, or heteroarylene—are optionally and independently selected from halogenated, -OR L2 Or, one or more groups of the =O group are substituted;

[0546] R L2 Indicates H or C 1-6 alkyl;

[0547] X is selected from the group consisting of: quaternary ammonium salts, quaternary phosphorus salts, pyridinium salts, and thiazolylium salts; or X is... Where R 4 C 1-6 alkyl,

[0548] It is used to treat or prevent diseases associated with excessive production of hyaluronic acid, including rheumatoid arthritis.

[0549] 33. The compound or a pharmaceutically acceptable salt thereof used according to paragraph 32, wherein the compound has formula IV:

[0550]

[0551] 34. The compound or a pharmaceutically acceptable salt thereof used according to paragraph 32, wherein the compound has the formula (V):

[0552]

[0553] 35. The compound or a pharmaceutically acceptable salt thereof used as described in paragraphs 32 to 34, wherein the use is for the treatment or prevention of rheumatoid arthritis.

[0554] 36. The compound used according to paragraph 35, wherein the disease is arthritis.

[0555] 37. The compound used according to paragraph 32 or 36, wherein the disease is osteoarthritis.

[0556] 38. The compound used according to paragraph 32, wherein the disease associated with excessive production of hyaluronic acid is cancer.

[0557] 39. The compound used according to paragraph 38, wherein the cancer is a sarcoma, preferably chondrosarcoma.

[0558] 40. A method for treating or preventing a disease characterized by excessive hyaluronic acid production, the method comprising administering to a patient in need a therapeutically effective amount of a compound as defined in any one of paragraphs 32 to 34.

[0559] 41. A method for treating or preventing rheumatoid arthritis, the method comprising administering to a patient in need a therapeutically effective amount of a compound as defined in any one of paragraphs 32 to 34.

[0560] 42. The treatment method according to paragraph 40 or 41, wherein the disease is arthritis, preferably osteoarthritis.

[0561] 43. The treatment method according to paragraph 40, wherein the disease is cancer, preferably sarcoma, more preferably chondrosarcoma.

[0562] 44. The use of a compound as defined in any of paragraphs 32 to 34 for the manufacture of a medicament for the treatment of a disease characterized by excessive production of hyaluronic acid.

[0563] 45. Use of a compound as defined in any of paragraphs 32 to 34 for the manufacture of a medicament for the treatment of rheumatoid arthritis.

[0564] 46. ​​The use of the compound according to paragraph 44 or 45, wherein the disease is arthritis, preferably osteoarthritis.

[0565] 47. The use of the compound according to paragraph 44, wherein the disease is cancer, preferably sarcoma, more preferably chondrosarcoma.

[0566] Example

[0567] The invention will be further described by reference to the following examples, but these examples are not intended to limit the scope of the invention.

[0568] abbreviation

[0569] The following abbreviations may be used in this article.

[0570] DCM dichloromethane

[0571] DMSO (dimethyl sulfoxide)

[0572] EtOAc (ethyl acetate)

[0573] LC-MS (Liquid Chromatography / Mass Spectrometry)

[0574] NMR (Nuclear Magnetic Resonance)

[0575] THF Tetrahydrofuran

[0576] Experimental Procedure

[0577] If there is a difference between the nomenclature and the graphical representation of any compound, the latter shall prevail (unless it contradicts any experimental details that may be given, or unless it is clear from the context).

[0578] The starting materials and intermediates used to synthesize the compounds described herein are commercially available or can be prepared by the methods described herein or by methods known in the art.

[0579] Experiments are typically performed in an inert atmosphere (nitrogen or argon), especially when oxygen-sensitive reagents or humidity-sensitive reagents or intermediates are used.

[0580] Mass spectrometry data are reported using liquid chromatography-mass spectrometry (LC-MS) with electrospray ionization. Chemical shifts in NMR data are expressed in parts per million (ppm, δ), with reference to residual peaks from the deuterated solvent used.

[0581] For synthesis following a general procedure, reaction conditions (such as reaction length or temperature) may vary. Generally, thin-layer chromatography or LC-MS is performed after the reaction, and post-processing is carried out as appropriate. Purification may vary between experiments: generally, the solvent and solvent ratio used for the eluent / gradient are selected to provide adequate Reluent. f And / or retention time.

[0582] Where applicable, the compound names indicated in the following examples have been generated using the structural naming function of ChemBioDraw Ultra version 12.0.

[0583] Example compounds

[0584] Example 1: 2-(4-((1E,4E)-5-(4-hydroxy-3-methoxyphenyl)-3-oxopent-1,4-dien-1-yl)-2-methoxyphenoxy)-N,N,N-trimethyl-2-oxoethylammonium chloride (Hylin-betaine)

[0585]

[0586] 1,5-Bis(4-hydroxy-3-methoxyphenyl)-1,4-pentadien-3-one (Hylin)

[0587] Hylin was synthesized according to the published procedure (Quincoces Suarez JA et al., Bioorg MedChem. 2010, 18, 6275-81).

[0588] Vanillin (0.2 mol; 30.4 g) and acetone (0.1 mol; 7.3 ml) were mixed and subjected to sonication at 40 °C for 2 hours in the presence of concentrated hydrochloric acid (2 ml). The mixture was poured into an ice-water mixture. The crude product was dissolved in sodium hydroxide solution, and the filtrate was neutralized with hydrochloric acid. The precipitate was filtered, washed with water, and dried to obtain hylin, which was a yellow powder (yield: 80%). 1 H NMR (DMSO-d6): δ = 3.65 (6H, s), 6.55 (2H, d, J = 15.7Hz), 6.78 (2H, dd, J = 8.4, 0.4Hz) ,7.23(2H,dd,J=1.9,0.4Hz), 7.38(2H,d,J=15.7Hz), 7.58(2H,dd,J=8.4,1.9Hz).

[0589] 4-[(1E,4E)-5-(4-hydroxy-3-methoxyphenyl)-3-oxopent-1,4-dien-1-yl]-2-methoxyphenyl chloroacetic acid ester

[0590] Hylin (30 g; 93 mmol) and pyridine (9.7 mL; 120 mmol) were dissolved in 120 mL of THF and heated to boiling. Chloroacetyl chloride (9.6 mL; 120 mmol) was added dropwise to the boiling solution. The solution was refluxed for an additional hour and, after cooling, added to a mixture of water and DCM. The organic layer was washed with 0.5 N HCl, evaporated, and dried over MgSO4. The product was purified on a silica gel column using DCM / MeOH (100:2) as the eluent (yield: 54%). 1 H NMR (DMSO-d6): δ=3.76(3H,s),3.78(3H,s),4.21(2H,s),6.57(1H,d,J=15.6Hz),6.67(1 H,d,J=15.7Hz),6.78(1H,dd,J=8.4,0.4Hz),7.21-7.27(2H,7.24(dd,J=8.3,0.5Hz),7. 23(dd,J=1.9,0.4Hz)),7.34-7.43(2H,7.41(dd,J=1.9,0.5Hz),7.39(d,J=15.6Hz)),7. 49-7.61(2H,7.58(dd,J=8.4,1.9Hz),7.54(d,J=15.7Hz)),7.73(1H,dd,J=8.3,1.9Hz).

[0591] 2-(4-((1E,4E)-5-(4-hydroxy-3-methoxyphenyl)-3-oxopent-1,4-dien-1-yl)-2-methoxy Hylin-betaine)-N,N,N-trimethyl-2-oxoethylammonium chloride

[0592] 4-[(1E,4E)-5-(4-hydroxy-3-methoxyphenyl)-3-oxopent-1,4-dien-1-yl]-2-methoxyphenylchloroacetate (18.8 g; 50 mmol) was dissolved in 100 mL of THF and a solution of 2 M trimethylamine in THF (120 mL; 240 mmol) was added. The solution was stirred overnight at room temperature. The precipitate was filtered, thoroughly washed with DCM, and dried under vacuum (yield: 60%). 1H NMR (DMSO-d6): δ=2.88(9H,s),3.75(3H,s),3.78(3H,s),4.06(2H,s),6.57(1H,d,J=15.6Hz ),6.67(1H,d,J=15.7Hz),6.78(1H,dd,J=8.4,0.4Hz),7.22-7.28(2H,7.23(dd,J=1.9,0.4H z),7.25(dd,J=8.3,0.5Hz)),7.34-7.43(2H,7.39(d,J=15.6Hz),7.41(dd,J=1.9,0.5Hz)), 7.49-7.61(2H),7.54(d,J=15.7Hz),7.58(dd,J=8.4,1.9Hz)),7.73(1H,dd,J=8.3,1.9Hz).

[0593] Example 2: (E)-2-(4-(3-(2,4-dihydroxy-6-methoxy-3-(3-methylbut-2-en-1-yl)phenyl)-3-oxoprop-1-en-1-yl)phenoxy)-N,N,N-trimethyl-2-oxoethylammonium chloride (Xantho-betaine)

[0594]

[0595] Betaine (0.32 g, 2.7 mmol) was converted to acyl chloride by heating with 3 ml of thionyl chloride at 80 °C for 30 min. Excess thionyl chloride was evaporated, and the remaining trace amount was co-evaporated with toluene. Betaine chloride was dissolved in 5 ml of anhydrous pyridine and added to a concentration of 0.34 g of xanthohumol. After stirring for 1 hour, the solvent was evaporated, and the remaining trace amount was again co-evaporated with toluene. The residue was dissolved in 3 ml of methanol, and xanthohumol-betaine ester was precipitated by adding 4 ml of tetrahydrofuran. 1 H NMR (DMSO-d6): δ=1.66-1.67(6H,1.66(s),1.66(s)),2.89(9H,s),3.22(2H,d,J=6.7Hz),3.95(3H,s),4.06(2H,s),5.31(1H,t,J=6.7Hz), 6.15(1H,s),6.70(1H,d,J=15.6Hz),7.35(2H,ddd,J=8.2,1.4,0.5Hz),7.40-7.50(3H,7.47(ddd,J=8.2,1.5,0.5Hz),7.44(d,J=15.6Hz)).

[0596] Example 3: 4-((E)-3-(2,4-dihydroxy-6-methoxy-3-(3-methylbut-2-en-1-yl)phenyl)-3-oxoprop-1-en-1-yl)phenyl 2-(N-((Z)-2-(acetylthio)vinyl)formamido)acetate (Xantho-prophiazole)

[0597]

[0598] 5-N-(4-acetic acid)-thiazolonium iodide

[0599] Thiazole (20 g, 580 mmol) was refluxed with iodoacetic acid (120 g, 580 mmol) in 300 ml of dichloromethane for 2 days. After cooling to room temperature, the precipitate (101 g; 64%) was separated by filtration.

[0600] {[2-(acetylthio)vinyl](formyl)amino}acetic acid

[0601] As described below, the thiazolium ring is opened and the thiophene is acetylated: Koltunova and Berezovskii (Koltunova, VI and Berezovskii, NM (1969) Coenzymes and phosphates. XXI. S-acyland N,Sdiacylcocarboxylase and other N,S-derivatives of thiaminephosphates. The Journal of General Chemistry of the USSR 39, 102-109).

[0602] In summary, 5-N-(4-acetic acid)-thiazolyl iodide (20 g; 73.8 mmol) was mixed with 10 ml of water and dissolved by slowly adding 10 M NaOH. The reaction vessel was cooled in an ice bath and 10 M NaOH was added while maintaining the pH between 10 and 11. The thiazole ring was opened, and NaOH was added further at 10-minute intervals over a 3-hour period. Acetyl chloride (10.8 ml; 150 mmol) was added dropwise while maintaining the pH between 10 and 11 with 10 M NaOH and keeping the temperature below 15°C. The solution was adjusted to pH 3.6 with concentrated HCl and the precipitated product (6.3 g; 42%) was separated by filtration.

[0603] Xanthohumol-{[2-(acetylthio)vinyl](formyl)amino}acetate

[0604] The compound {[2-(acetylthio)vinyl](formyl)amino}acetic acid was dissolved in 5 mL of tetrahydrofuran and esterified with xanthohumol via a Steglich reaction. 4-Dimethylaminopyridine (0.06 g; 0.5 mmol) and alkali-treated xanthohumol (0.89 g, 2.5 mmol) were added. The solution was cooled to 0 °C and dicyclohexylcarbodiimide (0.52 g, 2.5 mmol) was added. After stirring overnight at room temperature, the precipitate was removed by filtration, and the solution was concentrated by evaporation. Xanthohumol-propizolate was purified by preparative thick-layer chromatography using chloroform / methanol (50:3). Yield: 20%.

[0605] 1 H NMR (DMSO-d6): δ=1.56-1.57(6H,1.56(s),1.56(s)),2.11(3H,s),3.22(2H,d,J=6. 7Hz),3.95(3H,s),4.07(2H,s),5.31(1H,t,J=6.7Hz),5.52(1H,d,J=9.9Hz),6.15(1 H,s),6.70(1H,d,J=15.6Hz),6.91(1H,d,J=9.9Hz),7.36(2H,ddd,J=8.3,1.4,0.5H z),7.40-7.50(3H,7.47(ddd,J=8.3,1.5,0.5Hz),7.44(d,J=15.6Hz)),8.61(1H,s).

[0606] Example 4: (Z)-2-hydroxy-4-(3,5,7-trihydroxy-4-oxo-4H-chromen-2-yl)phenyl-2-(N-(2-(acetylthio)vinyl)formamido)acetate (quercetin-propitheazole)

[0607]

[0608] Quercetin-propizoline was obtained using 0.76 g of quercetin in a similar reaction as shown in Example 3.

[0609] 1 H NMR (DMSO-d6): δ=2.11(3H,s),5.95(1H,d,J=9.8Hz),6.27(1H,d,J=1.9Hz),6.44(1H,d,J=1.9Hz),7.12(1H,d ,J=9.8Hz),7.41(1H,dd,J=8.4,0.5Hz),7.45(1H,dd,J=1.8,0.5Hz),7.79(1H,dd,J=8.4,1.8Hz),8.74(1H,s).

[0610] Bioassay

[0611] The following bioassays were used to evaluate the bioactivity of the exemplary compounds described above.

[0612] General methods

[0613] Hyaluronic acid synthase activity (Prehm, P. and Schumacher, U., Biochem. Pharmacol. 2004, 68, 1401-1410), drug cytotoxicity (O'Brien, J. et al., Eur. J. Biochem. 2000, 267, 5421-5426), proteoglycan synthesis rate, hyaluronic acid (Prehm, PJ Rheumatol., 2005, 32, 690-696) and proteoglycan (Bjornsson, S. Anal. Biochem. 1993, 210, 282-291) were determined as follows. The effect of isoprenyl flavonoids on the MRP5 output rate was measured using the fluorescein diacetate described above (Schulz, T., Schumacher, U. and Prehm, P., J Biol. Chem., 2007, 282, 20999-21004). The IC50 value of phosphodiesterase 5 was determined according to the instructions of BPSBioscience. The culture of bovine chondrocytes in alginate beads and the culture of bovine cartilage explants have been previously described (Deiters, B. and Prehm, P. Arthritis Res. Ther., 2008, 10, R8; Prehm, PJRheumatol. 2005, 32, 690-696). Osteoarthritis responses were induced in chondrocytes grown in alginate beads by incubation for 6 days with a medium containing 10 ng / ml Il-17, and in cartilage explants containing 10 ng / ml Il-17 and 5 ng / ml Il-1α. The supernatant was collected and stored at -20°C for subsequent analysis. Explants were weighed and extracted with 1 ml 4M guanidine-HCl at 4°C for 72 h. The proteoglycan concentration in the extract was determined.

[0614] Material

[0615] The bovine articular cartilage comes from a local slaughterhouse. HABP is from Calbiochem, and the hyaluronic acid is also present. The gift was from Genzyme, Cambridge, MA. The xanthohumol was a gift from Dr. Martin Biendl, Hallertauer Hopfenveredelungsgesellschaft, Mainburg, Germany. Additional chemicals were from Sigma-Aldrich Chemical Corporation.

[0616] Cell culture

[0617] Chondrosarcoma cells (SW1353 from the American Center for Type Culture Collection) were grown in Dulbecco medium supplemented with streptomycin / penicillin (100 units / ml each) and 10% fetal bovine serum, or in serum-free Quantum medium supplemented with streptomycin / penicillin (100 units / ml each) and kanamycin (100 units / ml).

[0618] Histochemical staining of collagen in cartilage

[0619] Cartilage explants were incubated together for 14 days with and without a mixture of 10 ng / ml Il-1α, 10 ng / ml Il-1β, and 25 ng / ml Il-17. Cytokines were added daily. Tissues were fixed in 3.7% paraformaldehyde for 24 hours, embedded in paraffin, and stained using the van Giesson method.

[0620] Enzyme profile analysis of matrix proteases

[0621] Bovine chondrocytes from alginate beads were cultured in serum-free DMEM for 3 days in the absence or presence of Il-17 (25 ng / ml) and 12.5 μM or 50 μM inhibitors of xanthohumulin, isoxanthohumulin, 8-isoprenylnaringenin, and icariin. Protein concentrations in the culture medium were determined, and equal volumes of protein were directly applied to a 7.5% SDS-polyacrylamide gel containing 0.1% gelatin. After electrophoresis, the gel was washed twice with 2.5% Triton X-100 for 30 min, three times with water for 10 min, and incubated at 37°C for 5 days in a solution of 50 mM Tris-HCl, 5 mM CaCl2, 1 μM ZnSO4, pH 8.0. The gel was stained with Coomassie blue.

[0622] Determination of proteoglycans

[0623] Cartilage explants were weighed (average wet weight: 20 mg) and incubated for 5 days in the absence of IL-1 (2 ng / ml) and in the presence of different concentrations of inhibitors. The tissue was extracted with a solution of 1.5 ml 4 M guanidine hydrochloride, 0.1 M ε-aminohexanoidacid, 5 mM benzalkonium chloride, 10 mM N-ethylmaleimide, and 0.5 mM benzyl sulfonyl fluoride at 4 °C for 3 days. The solution was centrifuged at 10,000 g for 5 min, and proteoglycans were identified in the supernatant using the Alcian Blue method described above (Bjornsson, S., Anal. Biochem., 1993, 210, 282-291).

[0624] Histochemical staining of collagen in cartilage

[0625] Cartilage explants were incubated together for 14 days with or without a mixture of 10 ng / ml Il-17 and 5 ng / ml Il-1α. Cytokines were added daily. Tissues were fixed with 3.7% paraformaldehyde for 24 hours, embedded in paraffin, and stained using the van Gieson method (van Gieson, I. (1889) Laboratory notes of technical methods for the nervous system. New York Medical Journal 50, 57-60).

[0626] Flavonoid uptake into chondrosarcoma cells

[0627] Monolayers of chondrosarcoma cells in 96-well microtiter plates were incubated in serum-free Quantum medium with 100 μM flavonoid solution. Specifically, for xanthohumol, fluorescence changes were monitored from the bottom of the wells at excitation and emission wavelengths of 340 nm and 450 nm, respectively, and for quercetin, at excitation and emission wavelengths of 440 nm and 530 nm, respectively.

[0628] result

[0629] Example 5: Toxicity

[0630] Toxicity was determined using the Almar Blue assay. Figure 1 It was shown that all the tested compounds were non-toxic at concentrations below 100 μM.

[0631] Example 6: Introducing flavonoids into chondrosarcoma cells

[0632] Flavonoids exhibit weak fluorescence in aqueous buffer, but their fluorescence is significantly enhanced in the presence of proteins (Sengupta, B. and Sengupta, PK, Biochem. Biophys. Res. Commun., 2002, 299, 400-403). This property has been used to track the uptake of quercetin and xanthohumol by chondrosarcoma cells. Figure 2A The results showed that the derived flavonoids were absorbed in a concentration-dependent manner, while the original xanthohumol and quercetin did not accumulate in cells. Figure 2B The study showed that intake was initially very rapid and reached a stable level after 10 hours.

[0633] Example 7: Inhibition of Cell Growth

[0634] Chondrosarcoma cells were seeded on 24-well microtiter plates in the presence of increased concentrations of flavonoids. After 2 days, the cells were trypsinized and cell counts were determined using a Coulter counter.

[0635] Hyaluronic acid synthesis is known to be essential for cell mitosis and the growth of fibroblasts and melanoma cells. Therefore, we tested the effects of flavonoids on the growth of chondrosarcoma cells. Figure 3 The study showed that flavonoids inhibited cell growth in a concentration-dependent manner. Propylthiazole derivatives of xanthohumol and quercetin (i.e., the compounds in Examples 3 and 4) were even more effective at sub-micromolar concentrations.

[0636] Example 8: Inhibition of Hyaluronic Acid Output

[0637] Chondrosarcoma cells were seeded onto 96-well microtiter plates, and the procedure was performed in the presence of increased concentrations of flavonoids. Two days later, the concentration of hyaluronic acid was determined in the culture supernatant.

[0638] The effects of flavonoids and their derivatives on the output of hyaluronic acid from chondrosarcoma cells were analyzed. Figure 4 The results show that all compounds inhibited hyaluronic acid output in a concentration-dependent manner. Xanthumol-betaine (the compound of Example 2) was less effective than xanthumol, while xanthumol-prophiazole (the compound of Example 3) and quercetin-prophiazole (the compound of Example 4) were more effective than their parent compounds, especially at concentrations below 3 μM.

[0639] Example 9: Inhibition of proteoglycan shedding from bovine cartilage sections

[0640] Excessive hyaluronic acid production leads to significant proteoglycan shedding from cartilage. Bovine cartilage sections were cultured in organ culture, and an osteoarthritis response was induced by the addition of interleukin and increased xanthohumol-betaine concentrations. The amount of proteoglycan in the cartilage sections and culture medium was determined after one week of incubation.

[0641] With unmodified xanthohumol ( Figure 5A Compared to ) xanthohumol-betaine ( Figure 5B It appears to be more effective in reducing proteoglycan shedding into the culture medium.

[0642] Example 10: Inhibition of proteoglycan loss.

[0643] Bovine cartilage explants were administered in the absence and presence of interleukin (for stimulating a response to osteoarthritis) and at indicated concentrations of xanthohumol-betaine (…). Figure 6A ), xanthohumol-prophiazole ( Figure 6B ), quercetin-prophiazole ( Figure 6C ), quercetin ( Figure 6D ) and xanthohumol ( Figure 6E Incubate for 5 days. Weigh the cartilage explants and determine the proteoglycan concentration in the cartilage explants (solid strips) and culture supernatant (hollow strips).

[0644] As previously reported, isoprenoid flavonoids also inhibited the loss of proteoglycans in interleukin-activated bovine cartilage explants (Stracke, D. et al., Mol. Nutr. Food Res., 2011, 55, 485-494). The protective effects of flavonoid derivatives were analyzed here. Figure 6 shows that xanthohumol-betaine (the compound of Example 2), xanthohumol-prophiazole (the compound of Example 3), and quercetin-prophiazole (the compound of Example 4) exhibited similar efficacy.

[0645] Example 11: Isoprene flavonoids reduce collagen degradation

[0646] It is known that excessive hyaluronic acid production leads to collagen degradation in cartilage (Deiters, B. and Prehm, P., Arthritis Res. Ther., 2008, 10, R8; Prehm, P., J. Rheumatol., 2005, 32, 690-696). Preliminary experimental results using Il-17 alone indicated that this treatment was insufficient to induce detectable collagen degradation. Therefore, cartilage explants were incubated for 14 days with a mixture of osteoarthritis-inducing chemokines Il-1α, Il-1β, and Il-17, along with 12.5 μM and 50 μM isoprenoid flavonoids, and collagen was stained using the van Giesson method. Figures 7A to 7E This demonstrates that xanthohumol is particularly effective in protecting cartilage from collagen loss.

[0647] Example 12: IC50

[0648] Table 1 - IC50 values ​​(in μmol) of the test compounds obtained from three assays.

[0649]

[0650]

[0651] In vivo studies

[0652] The experiments described below explored whether xantho-betaine and hylin-betaine treatments altered gait, bone structure, and slowed / reversed articular cartilage damage in a spontaneous osteoarthritis (OA) model in Str / ort mice.

[0653] animal

[0654] Str / ort mice were housed in a pathogen-free facility at the Royal Veterinary College (RVC) at 21±2°C, with a 12-hour light / dark cycle, in polycarbonate or polypropylene cages with wood shavings and paper pads. A maximum of four mice were housed per cage. Weaned mice were fed a standard rodent reproductive diet up to 8 weeks of age, followed by a standard rodent maintenance diet (Special Diet Services, South Witham, UK). All procedures performed at this facility were in accordance with the Animals Act 1986 (Scientific Procedures) and the local RVC Ethics Guidelines.

[0655] Treatment with "Hylin-betaine" and "xantho-betaine"

[0656] At 10 to 13 weeks of age, 21 male Str / ort mice (n = 7 / group) were randomly assigned to the mediator group, the hylin-betaine group, and the xantho-betaine group, and were treated intraperitoneally for 18 weeks with the mediator (a solution of 5% DMSO in 95% peanut oil), 50 mg / kg of the compound of Example 1 (“hylin-betaine”) in a solution of 5% DMSO and 95% peanut oil, or 50 mg / kg of the compound of Example 2 (“xantho-betaine”) in a solution of 5% DMSO and 95% peanut oil.

[0657] Health assessment

[0658] To assess the health status of mice after treatment with hylin-betaine and xantho-betaine, the health status was monitored. Monitoring criteria included body surface temperature, body weight, gait, coat condition, skin bulging during dehydration, kyphosis, activity level, respiratory rate, and general physical condition. Except for body weight and temperature, each of these criteria was blinded to a score of 1–5.

[0659] Gait analysis

[0660] Gait was monitored at three time points (week 1, week 9, and week 18) in three mouse treatment groups using a treadmill-based video system (Digigait™ system). The number of mice in groups 1, 2, and 3 were 7, 7, and 5, respectively.

[0661] Two hundred and seventy-nine gait descriptors were used in this analysis. Thirty-four descriptors were obtained directly from the system software for the four limbs (LF: left anterior; RF: right anterior; LR: left posterior; RR: right posterior). All other (143) were calculated indices from gait measurements, including: swing time, stand time, braking time, advance time and stride time, stride length, frequency and coefficient of variation, claw area and claw angle and the variability of these two traits, coefficient of variation of the midline distance of the swing duration, and minimum and maximum dAdT. Time ratios in the four limbs were calculated: braking time, advance time and swing time relative to stand time and stride time, stand / swing, and stand / stride. In addition, the following additional indices were considered:

[0662] Symmetry index (SI; 100*(|RL|) / [0.5*(R+L)])

[0663] Symmetrical ratio:

[0664] The minimum ratio of 3 / 4 hind limb to forelimb on the same (right and left) side

[0665] 3 / 4 of the minimum ratio between the two forelimbs and between the two hindlimbs

[0666] Compensation or balance between the contralateral forelimb and hindlimb:

[0667] Between 3 / 4 of the right hind limb and the left forelimb: dgr = |RR - LF|

[0668] Between 3 / 4 of the left hind limb and the right forelimb: dgl = |LR - RF|

[0669] Where RR, LR, RF, and LF refer to the right hind limb, left hind limb, right forelimb, and left forelimb, respectively. Calculate the minimum and maximum values ​​of these values, as well as the minimum value of the ratio between them.

[0670] These measurements of asymmetry allow OA to unpredictably target specific hind limb knee joints in this Str / ort mouse strain. Greater symmetry indicates a more “normal” gait pattern (provided that, alternatively, both limbs may be affected in the same way).

[0671] To investigate whether there were inter-group differences for each descriptor at the three experimental dates, ANOVA was performed using data corresponding to each descriptor and date. Bonferroni correction was applied to address the problem of multiple comparisons.

[0672] A t-test analysis comparing only the two groups was also performed. To assess whether the difference between the two groups might be due to differences in gait changes relative to the initial conditions (at 2014 / 12 / 23), logistic regression analysis was performed on two separate datasets for data at 2015 / 02 / 18 and 2015 / 04 / 14. The model included two independent variables: the initial value for each descriptor, and the difference between the corresponding value at 2015 / 02 / 18 (or 2015 / 04 / 14) and the initial value. Bonferroni correction was also applied.

[0673] High-resolution micro-computed tomography (micro-CT)

[0674] I. Scan

[0675] Miniature CT scans and analyses were performed as previously described. In short, tibias from groups treated with mediators, hylin-betaine, and xantho-betaine were scanned using a Skyscan 1172 (Skyscan, Kontich, Belgium), with the X-ray tube operated at 50 kV and 200 Micro-A, an exposure time of 1600 ms (using a 0.5 mm aluminum filter), and a voxel size of micro-m 5. The scan time for each sample was approximately 2 hours. The sections were then reconstructed using NRecon 1.6.9.4 (Skyscan, Kontich, Belgium). 2D / 3D analysis was performed using CTAn 1.15.4.0+ software (Skyscan, Kontich, Belgium). Furthermore, 3D visualization and generation of color-coded images of the trabeculae, cortical bone, and skull were performed using Avizo 9.0.0 software (FEI, Oregon USA).

[0676] II. Morphometric Analysis

[0677] a. Trabecular Analysis: Prior to analysis, mini-CT images were reoriented in DataViewer 1.5.0 (Skyscan, Kontich, Belgium) so that cross-sections in the transverse plane were perpendicular to the long axis of the bone. Tibial length was measured using the linear measurement tool in CTAn 1.15.4.0+ software, and the appearance of the trabecular "bridge" connecting the two major cancellous bone "islands" was set as a reference point for analyzing the trabecular bone adjacent to the epiphyseal growth plate. 5% of the total bone length (towards the diaphysis) from this point was used for trabecular analysis of the proximal tibia. The target trabecular region was hand-drawn freehand using CTAn's selection tool, several voxels away from the inner cortical surface to avoid including remnants of the major corpus cavernosum associated with cortical bone. The selected target trabecular region was analyzed using CTAnBatMan software (Skyscan, Kontich, Belgium), and morphometric parameters were recorded.

[0678] b. Whole Bone Cortical Analysis: Whole bone analysis was performed on a dataset derived from CT scans using BoneJ (version 1.4.0) (an ImageJ plugin). After segmentation, alignment, and removal of the fibula from the dataset, a minimum bone threshold was selected using a histogram-based method in ImageJ, which utilizes all pixels in the stack to construct a histogram, and further validation was performed using ImageJ's "threshold function". The threshold was in the range of 22000–22100 and applied to all datasets to separate higher-density bone from soft tissue and air. This threshold was used in BoneJ's "slice geometry" function to calculate the bone cross-sectional area (CSA), the second moment of area about the minor axis (Imin), the second moment of area about the major axis (Imax), the average thickness (Ct.Th) determined by the two-dimensional local thickness, the ellipticity, and the torsional resistance (J). The proximal (15%) and distal (25%) portions of the tibia were excluded from the analysis because these regions include trabeculae.

[0679] Histology and grading of articular cartilage (AC) injuries

[0680] The dissected right knee was fixed in neutral buffered formalin, decalcified (Immunocal, Quarett, Berlin), embedded in paraffin, and cut in a 6 μm coronal section. Multiple sections (five per slide) from 120 μm intervals throughout the joint were stained with toluidine blue (0.1% in 0.1 M acetate buffer, pH 5.6) and graded for AC injury severity.

[0681] Sections from Str / ort joints treated with right mediators, hylin-betaine, and xantho-betaine were stained with safranin O. The sections were dewaxed and the severity of AC injury in Str / ort mice was scored using the method of Chambers et al. (Chambers et al., Expression of collagen and aggrecan genes in normal and osteoarthritic murine knee joints. Osteoarthritis and cartilage / OARS, Osteoarthritis Research Society. 2002; 10(1):51-61), consistent with internationally recognized systems. In short, grade 0: normal; grade 1: rough surface or superficial injury; grade 2: injury extending to the intermediate zone; grade 3: injury extending to the tideline or loss of AC; grades 4 and 5: loss of AC between 20% and 50% of the condylar surface or between 50% and 80% of the surface; grade 6: loss due to exposure of subchondral bone. Multiple slides (~10) were graded, each containing five 6 μm sections sampled across each entire joint at 120 μm intervals. Grading within each joint compartment (lateral / medial, tibia / femur) allowed for the assignment of a maximum (most severe) grade within each section and was used to generate an overall "mean" maximum grade for the entire joint and for each compartment in each group of mice. Furthermore, mean scores were generated for each joint and for each compartment, and these scores were similarly used to generate an overall "mean" mean grade for each group of mice. The mean grade provides a measurement of the "degree" (representing relative volume) of AC damage in each joint / compartment.

[0682] Statistical analysis

[0683] Statistical analyses were performed using GraphPad Prism 6 (GraphPad Software, Inc., San Diego, CA) or “R” version 3.1.1 (R Foundation for Statistical Computing, Vienna, Austria; http: / / www.r-project.org). Continuous measurements were summarized as mean ± SEM. One-way ANOVA was used to determine treatment effects. The Shapiro–Wilk test was used to assess normality in the distribution of the data. Bonferroni post-hoc correction was performed for whole-bone measurements from 10% to 90% of tibial length. This was to preserve the original inferred statistics over 10% to 90% of tibial length and to interpret results cautiously over tibial length. Data are expressed as mean ± SEM, and a value was considered statistically significant when p ≤ 0.05.

[0684] result

[0685] Example 13: Treatment with hylin-betaine and xantho-betaine did not have an adverse effect on the health status of mice.

[0686] After 18 weeks of treatment with hylin-betaine and xantho-betaine, we formally assessed the welfare status of the mice by measuring several well-known health indicators (Guide for the Care and Use of Laboratory Animals, National Research Council, 2010). Our data showed that 18 weeks of treatment with hylin-betaine and xantho-betaine did not alter weight, kyphosis, gait, activity, vocalization and respiratory scores, or coat condition between the mediator and either treatment group.

[0687] Example 14: Hylin-betaine treatment, rather than xantho-betaine treatment, significantly reduced gait drop-out, but neither treatment significantly altered any gait descriptors.

[0688] In the mediator group, 3 mice failed to complete the treadmill task in 4 runs (“dropped out”). In the hylin-betaine group, no mice refused to run. In the xantho-betaine group, 2 mice refused to run during the gait study. Therefore, the percentages of dropouts relative to the total number of runs in groups 1, 2, and 3 were 19.0%, 0%, and 13.3%, respectively. A total of 51 runs from 19 mice were collected. The distribution of data by group and animal is shown in Table 2.

[0689] Table 2. Data distribution by processing group

[0690] 2014 / 12 / 23 2015 / 02 / 18 2015 / 04 / 14 vehicle 7 6 4 Hylin-betaine 7 7 7 Xantho-betaine 4 4 5

[0691] Our data show that, when all descriptors of the gait study were analyzed, neither hylin-betaine nor xantho-betaine treatments showed significant effects compared to the mediator group at any time point during the study period.

[0692] Example 15: Hylin-betaine and xantho-betaine treatments did not significantly alter the trabecular microstructure, but significantly enhanced cortical bone mass and structure.

[0693] To investigate whether hylin-betaine and xantho-betaine treatments affect trabecular and cortical tissue and quality, we performed detailed microcomputed tomography analysis on the metaphyseal trabeculae and the entire cortical bone (excluding 10% from the proximal and distal tibias).

[0694] Our data show that neither hylin-betaine treatment nor xantho-betaine treatment significantly altered tibial length, trabecular volume / total volume (BV / TV), total trabecular volume (TV), trabecular volume (BV), trabecular eccentricity, thickness, separation, and number. Figure 8A and 8B These data collectively reveal that in the Str / ort model of naturally occurring osteoarthritis, hylin-betaine and xantho-betaine do not alter the structure and mass of the metaphyseal trabeculae.

[0695] In addition, we performed a whole-cortical bone analysis. We excluded the anterior and posterior 10% of the total length, where significant trabecular volume was present, and removed the fibula by manual segmentation.

[0696] Our examination revealed that hylin-betaine treatment significantly increased the mean cortical cross-sectional thickness in multiple regions spanning approximately 15% to 60% of tibial length. Compared to the mediator-treated group, xantho-betaine showed a higher effect on thickness in some regions and a lower effect in others. Figure 9A Hylin-betaine and xantho-betaine did not significantly affect the cross-sectional area (CSA) (except for the distal region in one of the two groups and the region near the tibiofibular junction). Figure 9B ).

[0697] To estimate the resistance of the tibia to bending forces, we also calculated the resistance around the short axis (I). 最小 ) and major axis (I 最大 The area second moment of ) . These data show that hylin-betaine does not affect I 最小However, xantho-betaine significantly reduced I in a proximal region. 最小 ( Figure 10A Furthermore, hylin-betaine does not affect I. 最大 However, xantho-betaine significantly increases I at approximately 35% to 55% of tibial length. 最大 ( Figure 10B Xantho-betaine treatment also altered tibial ellipticity, but hylin-betaine treatment did not. Figure 10C Among them, compared with the stromal-treated Str / ort mice, xantho-betaine showed a greater ellipticity in a region along the tibia between approximately 40% and 50%. In the xantho-betaine group, predicted tibial torsional resistance was higher in multiple regions along the tibial length. Figure 10C Our data indicate that hylin-betaine treatment alters cortical bone mass (greater cortical thickness), while xantho-betaine treatment leads to changes in the tissue and shape of cortical bone, which provide significantly enhanced torsional resistance compared to the mediator group.

[0698] Example 16: Treatment with hylin-betaine instead of xantho-betaine prevents / improves articular cartilage damage in Str / ort mice.

[0699] Detailed analysis of compartment-specific development of OA in Str / ort mice revealed a protective effect from treatment with hylin-betaine, but no such protection was observed in response to xantho-betaine. Figure 11 Two independent blind raters found that, in response to treatment with hylin-betaine instead of xantho-betaine, the mean OA scores in both the tibial and lateral femoral patellar septa (known as the site where OA initially develops in this mouse strain) were statistically significantly reduced. Although a trend toward lower maximum scores was observed in H rather than Xantho mice compared to the vector-treated Str / ort mice, no statistically significant maximum OA score was found per mouse.

[0700] It is believed that xantho-betaine may be less stable than hylin-betaine (which is converted to isoxanthol-betaine), and this is thought to be the reason why any differences may be found between the two.

Claims

1. A compound of formula Ia: [Hyaluronic acid production inhibitor]—[unstable junction]—X (Ia), Or its pharmaceutically acceptable salt. The hyaluronic acid production inhibitor fragment has the following characteristics: Formula A (A)， Where Y is: ； R A1 and R A2 Each is either OH or -OR A5 ; and an R A1 or R A2 Group is Formula Ia Fragment; n is between 2 and 4; m is 2 to 4; and R A5 C 1-6 alkyl; The unstable joint segment is -OC(O)R L1 -; Where R L1 C 1-6 Alkylene, which is optionally independently selected from halogenated, -OR L2 Or, one or more groups of =O are substituted; R L2 Indicates H or C 1-6 alkyl; X is selected from , , and , in , and The group is optionally surrounded by one or more R 3 Group substitution; R 1 C that is optionally halogenated or =O substituted 1-6 Alkyl groups, C groups optionally halogenated or =O substituted 2-6 Alkenyl groups, C groups optionally substituted with halogenated or =O 2-6 alkynyl group; R 2 C 1-6 alkyl; R 3 C 1-6 Alkyl, C 2-6 alkenyl or C 2-6 alkynyl group; Z - Choose the group consisting of the following items: Cl - F - ,Br - I - p-Toluenesulfonate, methanesulfonate, acetate, benzoate, salicylate and R 4 CO2 - ; R 4 C 2-28 Alkyl, C 2-28 alkenyl or C 2-28 Alkyne group.

2. The compound according to claim 1, wherein the compound has formula II: (II)。 3. The compound according to claim 1, wherein the compound has formula III: (III)。 4. The compound according to claim 1, wherein the compound is: 。 5. The compound according to claim 1, wherein the X group is... or .

6. The compound according to any one of claims 1 to 5, wherein Z - The group is R 4 CO2 - , where R 4 C 4-28 Alkyl or C 4-28 Alkenyl group.

7. The compound according to claim 1, wherein R A1 and R A2 Selected from OH and OMe.

8. A pharmaceutical composition comprising a compound as defined in any one of claims 1 to 7, said compound comprising a pharmaceutically acceptable salt thereof; and optionally one or more pharmaceutically acceptable excipients.

9. Use of the compound according to any one of claims 1 to 7 or the pharmaceutical composition according to claim 8 in the preparation of a medicament for treating or preventing a disease characterized by excessive hyaluronic acid production.

10. Use of the compound according to any one of claims 1 to 7 or the pharmaceutical composition according to claim 8 in the preparation of a medicament for the treatment or prevention of rheumatoid diseases.

11. The use according to claim 9 or 10, wherein the disease is arthritis.

12. The use according to claim 9 or 10, wherein the disease is osteoarthritis.

13. The use according to claim 9, wherein the disease characterized by excessive hyaluronic acid production is cancer.

14. The use according to claim 13, wherein the cancer is a sarcoma.

15. The use according to claim 14, wherein the sarcoma is chondrosarcoma.

Images