Taxus mairei analogs and methods of use thereof

Abstract

The present disclosure provides a taxus mairei and analogues thereof useful in the treatment of inflammatory diseases or conditions (e.g., inflammatory bowel disease), as well as a pharmaceutical composition comprising the taxus mairei and analogues thereof, and methods of use and preparation thereof.

Description

[0001] Citation to Related Applications

[0002] This application claims priority to U.S. Provisional Patent Application No. 63 / 364,727, filed on May 16, 2022, which is incorporated herein by reference in its entirety. Technical Field

[0003] Provided herein are taxamairin and its analogs for treating inflammatory diseases or conditions (eg, inflammatory bowel disease), as well as a pharmaceutical composition comprising the taxamairin and its analogs, and a method for using and preparing the same. Background Art

[0004] Abnormal inflammatory responses are a major component of a variety of diseases and health conditions. Subjects suffering from inflammatory diseases or conditions often exhibit excess pro-inflammatory cytokines in their body systems, which leads to a host of medical problems.

[0005] One such medical problem is inflammatory bowel disease (IBD), a chronic and progressive immune-mediated inflammatory disease that affects the intestine. In Hong Kong, China, the prevalence of IBD has increased significantly over the past three decades and is on an upward trend. The age-adjusted incidence of IBD has increased significantly, increasing 31-fold from 1985 to 2014. As IBD is an early-onset disease and requires lifelong treatment, the disease has a huge impact on the patient's quality of life and is a burden on the public health system.

[0006] To date, there is no cure for IBD. Therefore, the goal of IBD treatment is to induce and maintain remission without any complications. In Hong Kong, China, the anti-inflammatory drug 5-aminosalicylic acid (5-ASA) remains the most commonly prescribed drug for IBD patients. Since the drug requires multiple doses, long-term patient compliance is low. In addition, more than 25% of IBD patients eventually require surgical intervention within 5 years. Therefore, the discovery and development of new anti-inflammatory drug candidates with high efficacy is imperative.

[0007] Infiltration and activation of intestinal macrophages play an important role in the pathogenesis of IBD. Activated macrophages produce proinflammatory cytokines, such as tumor necrosis factor alpha (TNF-α), IL-1β, IL-6, and nitric oxide (NO), which are able to trigger the activation of NF-κB, MAP kinase, JAK / STAT3, and NLRP3 signaling. Activation of these pathways is known to play an important role in inducing the expression of proinflammatory cytokines, and upregulation of their activity has been demonstrated in patients with IBD. Therefore, strategies targeting the inhibition of proinflammatory signaling pathways and downregulation of cytokines and cytokine-induced inflammatory responses are very important for the development of therapeutic strategies for IBD.

[0008] In view of the above shortcomings, a lot of efforts have been made to discover new drugs and novel mechanisms of action. At the same time, many scientists are interested in the development of natural products, which play a key role in drug discovery due to their huge structural diversity and diverse biological activities with unique mechanisms.

[0009] Icetexane is a series of natural diterpenes isolated from various natural plants. This class of compounds exhibits a series of interesting biological activities and has unique structural characteristics, which have become a hot research topic for biologists and chemists. Icetexane can be divided into different categories according to the presence or absence of oxidation at the C3, C11, C14 and C19 positions ( Figure 1 ).

[0010] Among them, salprzeside represents a highly unsaturated subclass of icetexane. Salprzeside A and B were first isolated and discovered in 1987 from the bark of Taxus mairei, a tree rich in active chemical components, among which taxane diterpenes and corresponding alkaloids are the most well-known, such as the anticancer drug Taxol. The isolation and characterization of salprzeside DH from the young branches of Taxus mairei was first reported in 1998. Brevitaxin was the first terpenoid compound isolated from the bark of Taxus brevifolia in 1995. In 2005, two new salprzesides, namely, unnamed 1 and unnamed 2, were isolated and identified from the dark brown callus culture of Taxus cuspidate. In 2021, two new icetexane diterpenes, Salprzeside A and B, were isolated from Salvia glabra. Extensive studies of derivatives based on the parent core structure have not been conducted. In addition, few biological studies have been conducted on these compounds.

[0011] There is a need to develop drugs based on natural sources and new cellular targets with better safety profiles for the treatment of inflammation. Summary of the invention

[0012] The present disclosure provides sedumin and sedumin analogs with anti-inflammatory activity, pharmaceutical compositions containing sedumin and sedumin analogs, and methods of use and preparation thereof. Such compounds and compositions containing these compounds can be used to treat acute or chronic infectious and inflammatory diseases, and other diseases related to the biological response process of body tissues to harmful stimuli, such as colitis, inflammatory bowel disease, and related health conditions.

[0013] In a first aspect, provided herein is a compound represented by Formula 1:

[0014]

[0015] or a pharmaceutically acceptable salt thereof, wherein:

[0016] R 1 and R 2 are independently selected from hydrogen, halide, nitrile, nitro, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, -N(R 12 )2, -(C=O)N(R 12 )2、-N(R 12 )(C=O)R 12 、-OR 12 、-(C=O)R 12 、-(C=O)OR 12 、-OC(C=O)R 12 、-O(C=O)OR 12 ,-O(P=O)(OR 12 )2, -O(C=O)N(R 12 )2、-N(R 12 )(C=O)OR 12 、-N(R 12 )(C=O)N(R 12 2. -SO2R 12 , -OSO2OH, trifluoromethanesulfonate, mesylate, tosylate and -(CR2) m The group composed of Y;

[0017] R 3 is an alkyl group;

[0018] R 4 It is hydrogen, halide, -OR 12 、-SR 12 、-N(R 12 )2. -OC(C=O)R 12 、-O(C=O)OR 12 ,-O(P=O)(OR 12 )2, -O(C=O)N(R 12 )2、-N(R 12 )(C=O)OR 12 、-N(R 12 )(C=O)N(R 12 )2、-N(R 12 )(C=O)R 12 、-(C=O)N(R 12 )2、-N(R 12 )(OR 12 ),-SO2R12 or -(CR2) m Y; or R 4 and R 5 Together with the carbon to which they are covalently bonded, they form =O, =S, =N (R 12 ), = N(OR 12 ), or R 4 and R 5 Together with the carbon to which they are covalently bonded, they form an optionally substituted 5-6 membered heterocycloalkyl group comprising 2 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur;

[0019] R 5 is hydrogen, nitrile, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, -OR 12 、-N(R 12 )2 or -(CR2) m Y;

[0020] R 6 and R 7 are independently alkyl;

[0021] R 8 It is hydrogen, halide, -OR 12 、-SR 12 、-N(R 12 )2. -OC(C=O)R 12 、-O(C=O)OR 12 ,-O(P=O)(OR 12 )2, -O(C=O)N(R 12 )2、-N(R 12 )(C=O)OR 12 、-N(R 12 )(C=O)N(R 12 )2、-N(R 12 )(C=O)R 12 、-(C=O)N(R 12 )2、-N(R 12 )(OR 12 ),-SO2R 12 or -(CR2) m Y; or R 8 and R 9 Together with the carbon to which they are covalently bonded, they form =O, =S, =N (R 12 ), = N(OR 12 ) or an optionally substituted 5-6 membered heterocycloalkyl containing 2 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur;

[0022] R 9is hydrogen, nitrile, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, -OR 12 or -N(R 12 )2;

[0023] R 10 is hydrogen, halide, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or aralkyl;

[0024] R 11 is hydrogen, halide, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, -SR 12 , -SeR 12 or -N(R 12 )2;

[0025] R 12 is independently selected from the group consisting of hydrogen, alkyl, perhaloalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl and -(CR2) m A group consisting of Y; or two R 12 Together with the atoms to which they are covalently bonded, they form a 3-7 membered cycloalkyl group or a 3-7 membered heterocycloalkyl group;

[0026] R is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and aralkyl at each occurrence; or two Rs and the atoms to which they are covalently bonded form a 3-7 membered cycloalkyl or 3-7 membered heterocycloalkyl;

[0027] m is independently at each occurrence 1-10; and

[0028] Y is independently at each occurrence -N(R)2, -(C=O)N(R)2, -N(R)(C=O)R, -OR, -(C=O)R, -(C=O)OR, -OC(C=O)R, -O(C=O)OR, -O(P=O)(OR)2, -O(C=O)N(R)2, -N(R)(C=O)OR, -N(R)(C=O)N(R)2, -SO2R or -OCH2CO2H,

[0029] Provided that the compound of Formula 1 is not selected from the group consisting of:

[0030]

[0031] In certain embodiments, R 1 and R 2 Independently choose from -OR 12 、-(C=O)R 12 、-OC(C=O)R 12 、-O(C=O)OR 12,-O(P=O)(OR 12 )2, -O(C=O)N(R 12 )2, -OSO2OH, trifluoromethanesulfonate, methanesulfonate and toluenesulfonate.

[0032] In certain embodiments, R 4 Yes-OR 12 、-N(R 12 )2. -OC(C=O)R 12 、-O(C=O)OR 12 、-O(C=O)N(R 12 )2、-N(R 12 )(C=O)OR 12 、-N(R 12 )(C=O)N(R 12 )2、-N(R 12 )(C=O)R 12 or -N(R 12 )(OR 12 ); and R 5 is hydrogen, nitrile, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl or -(CR2) m Y; or R 4 and R 5 Together with the carbon to which they are covalently bonded, they form =O, =N(R 12 ) or = N(OR 12 ); or R 4 and R 5 Together with the carbon to which they are covalently bonded, they form an optionally substituted 1,3-dioxane or an optionally substituted 1,3-dioxolane.

[0033] In certain embodiments, R 8 Yes-OR 12 、-N(R 12 )2. -OC(C=O)R 12 、-O(C=O)OR 12 、-O(C=O)N(R 12 )2、-N(R 12 )(C=O)OR 12 、-N(R 12 )(C=O)N(R 12 )2、-N(R 12 )(C=O)R 12 or -N(R 12 )(OR 12 ); and R 9 is hydrogen, nitrile, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl or -(CR2)m Y; or R 8 and R 9 Together with the carbon to which they are covalently bonded, they form =O, =N(R 12 ) or = N(OR 12 ); or R 4 and R 5 Together with the carbon to which they are covalently bonded, they form an optionally substituted 1,3-dioxane or an optionally substituted 1,3-dioxolane.

[0034] In certain embodiments, R 10 is hydrogen; and R 11 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, or -SR 12 .

[0035] In certain embodiments, R 3 is isopropyl; and R 6 and R 7 Each is a methyl group.

[0036] In certain embodiments, R 1 and R 2 Independently choose from -OR 12 、-(C=O)R 12 、-OC(C=O)R 12 、-O(C=O)OR 12 ,-O(P=O)(OR 12 )2, -O(C=O)N(R 12 )2, -OSO2OH, triflate, mesylate and tosylate;

[0037] R 3 is isopropyl;

[0038] R 4 Yes-OR 12 、-N(R 12 )2. -OC(C=O)R 12 、-O(C=O)OR 12 、-O(C=O)N(R 12 )2、-N(R 12 )(C=O)OR 12 、-N(R 12 )(C=O)N(R 12 )2、-N(R 12 )(C=O)R 12 or -N(R 12 )(OR 12); or R 4 and R 5 Together with the carbon to which they are covalently bonded, they form =O, =N(R 12 ) or = N(OR 12 ); or R 4 and R 5 Together with the carbon to which they are covalently bonded, they form an optionally substituted 1,3-dioxane or an optionally substituted 1,3-dioxolane;

[0039] R 5 is hydrogen, nitrile, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl or -(CR2) m Y;

[0040] R 6 and R 7 each is a methyl group;

[0041] R 8 Yes-OR 12 、-N(R 12 )2. -OC(C=O)R 12 、-O(C=O)OR 12 、-O(C=O)N(R 12 )2、-N(R 12 )(C=O)OR 12 、-N(R 12 )(C=O)N(R 12 )2、-N(R 12 )(C=O)R 12 or -N(R 12 )(OR 12 ); or R 8 and R 9 Together with the carbon to which they are covalently bonded, they form =O, =N(R 12 ) or = N(OR 12 ); or R 8 and R 9 Together with the carbon to which they are covalently bonded, they form an optionally substituted 1,3-dioxane or an optionally substituted 1,3-dioxolane;

[0042] R 9 is hydrogen, nitrile, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl or -(CR2) m Y;

[0043] R 10 It is hydrogen;

[0044] R 11 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, or -SR12 ;

[0045] R 12 is independently selected from the group consisting of hydrogen, alkyl, perhaloalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl and -(CR2) m A group consisting of Y; or two R 12 Together with the atoms to which they are covalently bonded, they form a 3-7 membered cycloalkyl group or a 3-7 membered heterocycloalkyl group;

[0046] R is independently selected from the group consisting of hydrogen and alkyl at each occurrence; or two Rs and the atoms to which they are covalently bonded form a 3-7 membered cycloalkyl or 3-7 membered heterocycloalkyl;

[0047] m is independently in each occurrence 2-6; and

[0048] Y is independently at each occurrence -N(R)2, -(C=O)N(R)2, -N(R)(C=O)R, -OR, -(C=O)R, -(C=O)OR, -OC(C=O)R, -O(C=O)OR, -O(P=O)(OR)2, -O(C=O)N(R)2, -N(R)(C=O)OR, -N(R)(C=O)N(R)2, -SO2R or -OCH2CO2H.

[0049] In certain embodiments, R 1 and R 2 Independently choose from -OR 12 、-(C=O)R 12 、-OC(C=O)R 12 and -O(C=O)N(R 12 )2;

[0050] R 3 is isopropyl;

[0051] R 4 and R 5 Together with the carbon to which they are covalently bonded, they form =O, =N(R 12 ) or = N(OR 12 );

[0052] R 6 and R 7 each is a methyl group;

[0053] R 8 Yes-OR 12 、-OC(C=O)R 12 or -O(C=O)N(R 12 )2; or R 8 and R 9Together with the carbon to which they are covalently bonded, they form =O, =N(R 12 ) or = N(OR 12 );

[0054] R 9 It is hydrogen;

[0055] R 10 and R 11 Each is hydrogen;

[0056] R 12 is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl and -(CR2) m Y; or two R 12 Together with the atoms to which they are covalently bonded, they form a 3-7 membered cycloalkyl group or a 3-7 membered heterocycloalkyl group;

[0057] R is in each case hydrogen;

[0058] m is independently in each occurrence 2-6; and

[0059] Y is independently at each occurrence -N(R)2, -(C=O)N(R)2, -N(R)(C=O)R, -OR, -(C=O)R, -(C=O)OR, -OC(C=O)R, -O(C=O)OR, -O(P=O)(OR)2, -O(C=O)N(R)2, -N(R)(C=O)OR, -N(R)(C=O)N(R)2, -SO2R or -OCH2CO2H.

[0060] In certain embodiments, the compound has Formula 2:

[0061]

[0062] or a pharmaceutically acceptable salt thereof, wherein:

[0063] R 1 Yes-OR 12 or -OC(C=O)R 12 ;

[0064] R 2 Yes-OR 12 ;

[0065] R 4 and R 5 Together with the carbon to which they are covalently bonded, they form =O or =N (OR 12 );

[0066] R 8 Yes-OR 12 、-OC(C=O)R 12or -O(C=O)N(R 12 )2; or R 8 and R 9 Together with the carbon to which they are covalently bonded, they form =O, =N(R 12 ) or = N(OR 12 );

[0067] R 9 It is hydrogen;

[0068] R 12 is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl and -(CR2) m Y; or two R 12 Together with the atoms to which they are covalently bonded, they form a 3-7 membered cycloalkyl group or a 3-7 membered heterocycloalkyl group;

[0069] R is in each case hydrogen;

[0070] m is independently in each occurrence 2-6; and

[0071] Y is independently at each occurrence -N(R)2, -(C=O)N(R)2, -N(R)(C=O)R, -OR, -(C=O)R, -(C=O)OR, -OC(C=O)R, -O(C=O)OR, -O(P=O)(OR)2, -O(C=O)N(R)2, -N(R)(C=O)OR, -N(R)(C=O)N(R)2, -SO2R or -OCH2CO2H.

[0072] In certain embodiments, R 8 Yes-OC(C=O)R 12 , and R 9 is hydrogen; or R 8 and R 9 Together with the carbon to which they are covalently bonded, they form =O or =N (OR 12 ).

[0073] In certain embodiments, R 1 is -OCH3 or -OC(C=O)R 12 ; and R 2 It is -OCH3.

[0074] In certain embodiments, R 1 and R 2 Each is -OCH3;

[0075] R 4 and R 5 Together with the carbon to which they are covalently bonded, they form =O;

[0076] R8 Yes-OC(C=O)R 12 ;

[0077] R 9 is hydrogen; and

[0078] R 12 In each case - (CR2) m Y;

[0079] R is in each case hydrogen;

[0080] m is independently in each occurrence 2-6; and

[0081] Y is independently at each occurrence -N(R)2, -(C=O)N(R)2, -N(R)(C=O)R, -OR, -(C=O)R, -(C=O)OR, -OC(C=O)R, -O(C=O)OR, -O(P=O)(OR)2, -O(C=O)N(R)2, -N(R)(C=O)OR, -N(R)(C=O)N(R)2, -SO2R or -OCH2CO2H.

[0082] In certain embodiments, the compound is selected from the group consisting of:

[0083]

[0084]

[0085] or a pharmaceutically acceptable salt thereof.

[0086] In a second aspect, provided herein is a pharmaceutical composition comprising a compound of the first aspect and at least one pharmaceutically acceptable excipient.

[0087] In a third aspect, provided herein is a method for treating an inflammatory disease or condition in a subject in need thereof, the method comprising administering a therapeutically effective amount of malutraceutin or a compound described herein.

[0088] In certain embodiments, the inflammatory disease or condition is selected from the group consisting of asthma, autoimmune diseases, chronic rheumatoid arthritis, refractory colitis, ulcerative colitis, Crohn's disease, glomerulonephritis, systemic lupus erythematosus, scleroderma, multiple sclerosis, psoriasis, Sjögren's syndrome, chronic inflammation, chronic prostatitis, glomerulonephritis, allergic reactions, inflammatory bowel disease, pelvic inflammatory disease, reperfusion injury, arthritis, rheumatoid arthritis, transplant rejection, vasculitis, sepsis, fatty liver disease, gout, nosocomial pneumonia, acute respiratory distress syndrome, ankylosing spondylitis, psoriatic arthritis, lupus erythematosus, chronic obstructive pulmonary disease, pulmonary fibrosis, liver fibrosis and septic shock.

[0089] In a fourth aspect, provided herein is a method for treating inflammatory bowel disease in a subject in need thereof, the method comprising administering a therapeutically effective amount of malathin or a compound described herein.

[0090] In certain embodiments, the inflammatory bowel disease is selected from the group consisting of ulcerative colitis (UC), indeterminate colitis, Crohn's disease (CD), lymphocytic colitis, microscopic colitis, collagenous colitis, autoimmune bowel disease, allergic gastrointestinal disease, and eosinophilic gastrointestinal disease.

[0091] In certain embodiments, the inflammatory bowel disease is selected from the group consisting of UC, CD, and indeterminate colitis.

[0092] In certain embodiments, administration of salvia chinensis or a compound described herein results in a decrease in nitric oxide (NO) production or a decrease in iNOS expression levels in a subject.

[0093] In certain embodiments, administration of a compound of salviae chinensis or a compound described herein results in a decrease in the levels of pro-inflammatory cytokines in a subject.

[0094] In certain embodiments, the taxol is selected from the group consisting of:

[0095]

[0096] or a pharmaceutically acceptable salt thereof.

[0097] In certain embodiments, the proinflammatory cytokine is selected from the group consisting of IL-1β, IL-6, TNF-α, and combinations thereof.

[0098] In certain embodiments, administration of salvia avium or a compound described herein results in an increase in anti-inflammatory cytokines in a subject.

[0099] In certain embodiments, the anti-inflammatory cytokine is IL-10.

[0100] In certain embodiments, administration of salvia chinensis or a compound described herein results in a reduction in inflammation-induced structural damage to intestinal tissue.

[0101] In certain embodiments, administration of salutaricin or a salutaricin analog results in restoration of inflammation-induced reduction in intestinal goblet cell expression and mucin secretion.

[0102] BRIEF DESCRIPTION OF THE DRAWINGS

[0103] The above objects and features as well as other objects and features of the present disclosure will become apparent by reading the following description of the present disclosure in conjunction with the accompanying drawings.

[0104] Figure 1 The skeleton structure of Icetexane is shown;

[0105] Figure 2 An exemplary naturally occurring Icetexane is shown;

[0106] Figure 3 Data showing that non-toxic doses of tausin B inhibit NO production and iNOS expression in LPS-induced RAW264.7 macrophages are shown. RAW264.7 macrophages were treated with the indicated concentrations of tausin for 24 hours. Cell viability was determined by MTT assay. (A) Cell viability of tausin B. RAW264.7 macrophages were pretreated with the indicated concentrations of tausin B for 1 hour and further incubated for 24 hours with or without LPS (1 μg / ml), and then (B) NO production and (C) iNOS protein expression were evaluated by Griess assay and Western blotting, respectively. β-actin was used as an internal loading control. *P<0.05, **P<0.01, ***P<0.001 compared with LPS-induced control;

[0107] Figure 4 Data showing that tausin B reduces the transcription and secretion of proinflammatory cytokines in LPS-induced macrophages are shown. RAW264.7 macrophages were pretreated with the indicated concentrations of tausin B for 1 hour and further incubated for 24 hours with or without LPS (1 μg / ml), and then the protein levels and mRNA expression of inflammatory cytokines were evaluated. (A) The protein expression of IL-1β, IL-6 and TNF-α in LPS-induced macrophages was evaluated using ELISA kits. (B) The mRNA expression of iNOS, IL-6, IL-1β and TNF-α was evaluated by qPCR. Compared with LPS-induced control, *P<0.05, **P<0.01, ***P<0.001;

[0108] Figure 5 Data showing that silymarin B reduces the susceptibility of mice to DSS-induced experimental colitis are shown. C57BL / 6 mice were induced with 2.5% DSS in their drinking water for 7 days. Mice were orally administered vehicle (0.5% CMC), silymarin B-LD (50 mg / kg in 0.5% CMC), silymarin B-HD (100 mg / kg in 0.5% CMC) or 5-ASA (200 mg / kg in 0.5% CMC) and DSS induction daily. Uninduced control mice received filtered water and 0.5% CMC. (A) Longitudinal changes in relative body weight, (B) food consumption, (C) water consumption, and (D) disease activity index (DAI). At the end of the experiment, the colon was removed, (E) the length was measured, and (F) representative colon images were taken. Evaluation of (G) inflammatory cytokine protein levels, (H) CD45 staining, (I) H&E staining, and (J) Alcian blue staining in colon tissues was performed. The values ​​shown are the mean ± SEM of three independent experiments. Compared with the 2% DSS + vehicle group, *P < 0.05, **P < 0.01, ***P < 0.001;

[0109] Figure 6 The chemical structures of the taxol analogs 3-8 according to certain embodiments described herein are shown, wherein the taxol analogs 3-8 comprise a chemical modification at C11;

[0110] Figure 7 Shown are the chemical structures of malutoxadiin analogs 9-11 and malutoxadiin analogs 12-15 according to certain embodiments described herein, where malutoxadiin 9-11 analogs comprise chemical modifications at C3, C7, C11, and C12, and malutoxadiin 12-15 analogs comprise a chemical modification at C3. DETAILED DESCRIPTION

[0111] The present disclosure provides a salviaxin and salviaxin analogs useful as anti-inflammatory agents for treating acute or chronic inflammatory diseases and other diseases associated with the biological response process of body tissues to noxious stimuli, such as colitis, inflammatory bowel disease, and related disorders.

[0112] definition

[0113] The definitions of the terms used herein are intended to include the most recent definitions currently recognized in the chemical and pharmaceutical fields for each term. Examples are provided where appropriate. These definitions apply to the terms used in this specification, unless the definitions of these terms are otherwise limited in specific cases, either individually or as part of a larger group.

[0114] The term "heteroatom" is generally understood in the art to refer to an atom of any element other than carbon or hydrogen. Exemplary heteroatoms include boron, nitrogen, oxygen, phosphorus, sulfur and selenium.

[0115] The term "alkyl" is a common understanding in the art and includes saturated aliphatic groups, including straight chain alkyl, branched chain alkyl, cycloalkyl (alicyclic) groups, alkyl substituted cycloalkyl and cycloalkyl substituted alkyl. In certain embodiments, straight chain or branched chain alkyl has about 30 or less carbon atoms in its main chain (e.g., straight chain has C1-C30, branched chain has C3-C30), or about 20 or less carbon atoms. Similarly, cycloalkyl has about 3 to about 10 carbon atoms in its ring structure, or has about 5, 6 or 7 carbon atoms in the ring structure.

[0116] Except where the number of carbon atoms is otherwise specified, "lower alkyl" refers to an alkyl group as defined above, but having 1 to about 10 carbon atoms, or 1 to about 6 carbon atoms in its backbone structure. Similarly, "lower alkenyl" and "lower alkynyl" have similar chain lengths.

[0117] The term "aralkyl" is recognized in the art and refers to an alkyl group substituted with an aryl group (eg, an aromatic or heteroaromatic group).

[0118] The terms "alkenyl" and "alkynyl" are art-recognized and refer to unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond, respectively.

[0119] The term "aryl" is a common understanding in the art and refers to 5-, 6- and 7-membered monocyclic aromatic groups that may contain 0-4 heteroatoms, such as benzene, naphthalene, anthracene, pyrene, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine and pyrimidine, etc. Aromatic groups having heteroatoms in the ring structure may also be referred to as "aryl heterocycles" or "heteroaromatic compounds". The aromatic ring may be substituted at one or more ring positions by the above-mentioned substituents, such as halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxy, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester, heterocyclic group, aromatic or heteroaromatic moiety, -CF3 or -CN, etc. The term "aryl" also includes polycyclic ring systems having two or more rings in which two or more carbon atoms are common to two adjacent rings (these rings are "fused rings"), wherein at least one ring is aromatic and the other rings may be, for example, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl and / or heterocyclyl.

[0120] The terms ortho, meta, and para are commonly used in the art to refer to 1,2-disubstituted benzene, 1,3-disubstituted benzene, and 1,4-disubstituted benzene, respectively. For example, the names 1,2-xylene and ortho-xylene are synonyms.

[0121] The term "heterocyclyl", "heterocycloalkyl", "heteroaryl" or "heterocyclic group" is generally understood in the art and refers to a 3 to about 10-membered ring structure, or a 3 to about 7-membered ring structure, which contains 1 to 4 heteroatoms. The heterocycle can also be polycyclic. Examples of heterocyclic groups include thiophene, thianthrene, furan, pyran, isobenzofuran, benzopyran, xanthene, phenylxanthene, pyrrole, imidazole, pyrazole, isothiazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, pyrimidine, phenanthroline, phenazine, phenarsazine, phenothiazine, furazan, phenoxazine, pyrrolidine, oxolane, thiolane, oxazole, piperidine, piperazine, morpholine, lactones, lactams (e.g., azetidinone and pyrrolidone), sultams and sultones, and the like. The heterocycle can be substituted at one or more positions with substituents as described above, such as halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxy, amino, nitro, thiol, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, heterocyclic group, aromatic or heteroaromatic moiety, -CF3 or -CN, etc.

[0122] The term "optionally substituted" refers to chemical groups such as alkyl, cycloalkyl and aryl, in which one or more hydrogen atoms may be replaced by substituents as described herein, such as halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxy, alkoxy, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester, heterocyclic group, aromatic or heteroaromatic moiety, -CF3 or -CN, etc.

[0123] The term "nitro" is a term commonly used in the art and refers to NO2; the term "halogen" is a term commonly used in the art and refers to -F, -Cl, -Br or -I; the term "thiol" is a term commonly used in the art and refers to -SH; the term "hydroxyl" refers to -OH; the term "sulfonyl" is a term commonly used in the art and refers to -SO2-. "Halide" means the corresponding anion of a halogen, and "halide-like" has the definition given by Cotton and Wilkinson in "Advanced Inorganic Chemistry" on page 560.

[0124] The terms "amine" and "amino" are commonly used in the art to refer to unsubstituted and substituted amines, such as moieties represented by the following general formula:

[0125]

[0126] Where R 50 , R 51 and R 52 Each independently represents hydrogen, alkyl, alkenyl, -(CH2) m R 61 , or R 50 and R 51 Together with the N atom to which they are attached, they form a heterocyclic ring having 4 to 8 atoms in the ring structure; R 61 represents aryl, cycloalkyl, cycloalkenyl, heterocyclic or polycyclic; m is zero or an integer in the range of 1-8. In other embodiments, R 50 and R 51 (Optionally R 52 ) each independently represents hydrogen, alkyl, alkenyl or -(CH2) m R 61 Thus, the term "alkylamine" comprises an amine group as defined above to which is attached a substituted or unsubstituted alkyl group, i.e., R 50 and R 51 At least one of them is an alkyl group.

[0127] The term "alkoxy" is a term commonly used in the art and refers to an alkyl group as defined above to which an oxygen radical is attached. Representative alkoxy groups include methoxy, ethoxy, propoxy, and tert-butoxy, among others. An "ether" is two hydrocarbons covalently linked by an oxygen atom. Thus, the alkyl substituent that makes an alkyl group an ether is or is similar to an alkoxy group, such as -O-alkyl, -O-alkenyl, -O-alkynyl, -O-(CH2) m R 61 One of them means that m and R 61 As mentioned above.

[0128] Certain compounds included in the compositions of the present invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis and trans isomers, R- and S-enantiomers, diastereomers, (D)-isomers, (L)-isomers, racemic mixtures thereof, and other mixtures, which are within the scope of the present invention. Additional asymmetric carbon atoms may be present in the substituents (e.g., alkyl). All such isomers and mixtures thereof are included in the present invention.

[0129] For example, if a specific enantiomer of a compound of the invention is desired, it can be prepared by asymmetric synthesis or by derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide the pure desired enantiomer. Alternatively, in the case where the molecule contains a basic functional group (e.g., amino) or an acidic functional group (e.g., carboxyl), diastereomeric salts are formed with an appropriate optically active acid or base, followed by resolution of the diastereomers thus formed by fractional crystallization or chromatographic methods well known in the art, followed by recovery of the pure enantiomer.

[0130] In the absence of specific stereochemistry, all stereoisomers of the compounds of the present invention are included within the scope of the present invention as pure compounds and mixtures thereof. Except as otherwise indicated, individual enantiomers, diastereomers, geometric isomers and combinations and mixtures thereof are included within the present invention. Polymorphic crystal forms and solvates are also included within the scope of the present invention.

[0131] Where a chemical structure contains dashed carbon-carbon bonds as shown below:

[0132]

[0133] The chemical structures are intended to encompass structures containing carbon-carbon double bonds, carbon-carbon single bonds, and both carbon-carbon double bonds and carbon-carbon single bonds.

[0134] It is understood that "substitution" or "substituted with" includes the implicit restriction that such substitution is consistent with the allowed valences of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., a compound that does not spontaneously undergo transformations such as rearrangement, cyclization, elimination or other reactions.

[0135] The term "substituted" is also considered to include all permitted substituents of organic compounds. In a broad sense, permitted substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. Exemplary substituents include, for example, those substituents described above. For appropriate organic compounds, permitted substituents may be one or more and may be the same or different. For purposes of the present invention, heteroatoms (e.g., nitrogen) may have hydrogen substituents and / or any permitted substituents of organic compounds described herein that satisfy the valence of the heteroatoms. The present invention should not be limited in any way by permitted substituents of organic compounds.

[0136] For purposes of this disclosure, the chemical elements are identified according to the CAS version of the Periodic Table of the Elements on the inside cover of the Handbook of Chemistry and Physics, 67th Edition, 1986-87.

[0137] The term "pharmaceutically acceptable salt" or "salt" refers to a salt of one or more compounds. Suitable pharmaceutically acceptable salts of a compound include acid addition salts, which can be formed, for example, by mixing a solution of the compound with a solution of a pharmaceutically acceptable acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, fumaric acid, maleic acid, succinic acid, benzoic acid, acetic acid, citric acid, tartaric acid, phosphoric acid or carbonic acid, etc. In the case of a compound with one or more acidic moieties, a pharmaceutically acceptable salt can be formed by treating a solution of the compound with a pharmaceutically acceptable base solution, such as lithium hydroxide, sodium hydroxide, potassium hydroxide, tetraalkylammonium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, ammonia or alkylamine, etc.

[0138] The term "subject" as used herein refers to an animal, typically a mammal or a human, that will be or has been the target of treatment, observation, and / or experiment. When the term is used in conjunction with the administration of a compound or drug, the subject is the target of treatment, observation, and / or administration of the compound or drug.

[0139] As used herein, the term "therapeutically effective amount" refers to that amount of an active compound or agent that elicits the biological or medical response that is being sought by the researcher, veterinarian, clinician or physician in a cell culture, tissue system, animal or human, including alleviation of the symptoms of the disease, condition or disorder being treated.

[0140] The term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.

[0141] The term "pharmaceutically acceptable carrier" refers to a medium for preparing a compound in a desired dosage form. Pharmaceutically acceptable carriers may include one or more solvents, diluents or other liquid carriers; dispersion or suspension aids; surfactants; isotonic agents; thickeners or emulsifiers; preservatives; solid binders and lubricants, etc. The 15th edition of Remington's Pharmaceutical Sciences edited by EW Martin (Mack Publishing Co., Easton, Pennsylvania, 1975) and the third edition of Handbook of Pharmaceutical Excipients edited by AH Kibbe (American Pharmaceutical Association, 2000) disclose various carriers used to prepare pharmaceutical compositions and their known preparation techniques.

[0142] As used herein, the phrase "parenteral administration" refers to modes of administration other than enteral and topical administration (usually by injection), including, but not limited to, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcutaneous, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion.

[0143] As used herein, the phrases "systemic administration" and "peripheral administration" refer to administration whereby a compound, drug or other substance enters a patient's system by means other than direct entry into the central nervous system and thereby undergoes metabolism and other similar processes, such as subcutaneous administration.

[0144] The present disclosure provides a compound represented by Formula I:

[0145]

[0146] or a pharmaceutically acceptable salt thereof, wherein:

[0147] R 1 and R 2 are independently selected from hydrogen, halide, nitrile, nitro, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, -N(R 12 )2, -(C=O)N(R 12 )2、-N(R 12 )(C=O)R 12 、-OR 12 、-(C=O)R 12 、-(C=O)OR 12 、-OC(C=O)R 12 、-O(C=O)OR 12 ,-O(P=O)(OR 12 )2, -O(C=O)N(R 12 )2、-N(R 12 )(C=O)OR 12 、-N(R 12 )(C=O)N(R 12 2. -SO2R 12 , -OSO2OH, triflate / ester, mesylate / ester, tosylate / ester and -(CR2) m The group composed of Y;

[0148] R 3 is an alkyl group;

[0149] R 4 It is hydrogen, halide, -OR 12 、-SR 12 、-N(R 12 )2. -OC(C=O)R 12 、-O(C=O)OR 12 ,-O(P=O)(OR 12 )2, -O(C=O)N(R 12 )2、-N(R 12 )(C=O)OR 12、-N(R 12 )(C=O)N(R 12 )2、-N(R 12 )(C=O)R 12 、-(C=O)N(R 12 )2、-N(R 12 )(OR 12 ),-SO2R 12 or -(CR2) m Y; or R 4 and R 5 Together with the carbon to which they are covalently bonded, they form =O, =S, =N (R 12 ), = N(OR 12 ), or R 4 and R 5 together with the carbon to which they are covalently bonded form an optionally substituted 5-6 membered heterocycloalkyl comprising 2 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur;

[0150] R 5 is hydrogen, nitrile, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, -OR 12 、-N(R 12 )2 or -(CR2) m Y;

[0151] R 6 and R 7 are independently alkyl;

[0152] R 8 It is hydrogen, halide, -OR 12 、-SR 12 、-N(R 12 )2. -OC(C=O)R 12 、-O(C=O)OR 12 ,-O(P=O)(OR 12 )2, -O(C=O)N(R 12 )2、-N(R 12 )(C=O)OR 12 、-N(R 12 )(C=O)N(R 12 )2、-N(R 12 )(C=O)R 12 、-(C=O)N(R 12 )2、-N(R 12 )(OR 12 ),-SO2R 12 or -(CR2) m Y; or R 8 and R 9Together with the carbon to which they are covalently bonded, they form =O, =S, =N (R 12 ), = N(OR 12 ) or an optionally substituted 5-6 membered heterocycloalkyl comprising 2 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur;

[0153] R 9 is hydrogen, nitrile, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, -OR 12 or -N(R 12 )2;

[0154] R 10 is hydrogen, halide, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or aralkyl;

[0155] R 11 is hydrogen, halide, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, -SR 12 , -SeR 12 or -N(R 12 )2;

[0156] R 12 is independently selected from the group consisting of hydrogen, alkyl, perhaloalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl and -(CR2) m A group consisting of Y; or two R 12 Together with the atoms to which they are covalently bonded, they form a 3-7 membered cycloalkyl group or a 3-7 membered heterocycloalkyl group;

[0157] R is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and aralkyl at each occurrence; or two Rs and the atoms to which they are covalently bonded form a 3-7 membered cycloalkyl or 3-7 membered heterocycloalkyl;

[0158] m is independently at each occurrence 1-10; and

[0159] Y is independently at each occurrence -N(R)2, -(C=O)N(R)2, -N(R)(C=O)R, -OR, -(C=O)R, -(C=O)OR, -OC(C=O)R, -O(C=O)OR, -O(P=O)(OR)2, -O(C=O)N(R)2, -N(R)(C=O)OR, -N(R)(C=O)N(R)2, -SO2R or -OCH2CO2H.

[0160] In certain embodiments, the compound of Formula 1 does not include naturally occurring malutraceutins, such as malutraceutins selected from the group consisting of:

[0161]

[0162] The present disclosure also provides a pharmaceutical composition comprising any one of the compounds described herein and at least one pharmaceutically acceptable excipient.

[0163] The compounds described herein and their pharmaceutically acceptable salts can be administered to mammalian subjects in pharmaceutical compositions alone or in combination with a pharmaceutically acceptable carrier or diluent according to standard pharmaceutical practice. The compounds can be administered orally or parenterally. Parenteral administration includes intravenous, intramuscular, intraperitoneal, subcutaneous and topical administration, with intravenous administration being a preferred method.

[0164] Therefore, the present disclosure provides a pharmaceutically acceptable composition comprising a therapeutically effective amount of one or more compounds described herein, which are formulated with one or more pharmaceutically acceptable carriers (additives) and / or diluents. The pharmaceutical compositions of the present disclosure can be specifically formulated for administration in solid or liquid form, including forms suitable for the following situations: (1) parenteral administration, such as by subcutaneous, intramuscular, intravenous or epidural injection, such as as a sterile solution or suspension, or a sustained release formulation; and (2) oral administration, such as a drench (aqueous or non-aqueous solution or suspension), tablets (e.g., tablets for oral, sublingual and systemic absorption), pills, powders, granules, and pastes applied to the tongue.

[0165] As described herein, some embodiments of the compounds described herein may contain a basic functional group (e.g., amino or alkylamino) so that a pharmaceutically acceptable salt can be formed with a pharmaceutically acceptable acid. In this regard, the term "pharmaceutically acceptable salt" refers to relatively nontoxic inorganic and organic acid addition salts of the compounds of the present invention. These salts can be prepared on site during the production of a dosing carrier or dosage form, or by reacting the purified compounds of the present invention in the form of free alkali with appropriate organic or inorganic acids alone and separating the salts so formed in the subsequent purification process. Representative salts include hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, toluenesulfonate, citrate, maleate, fumarate, succinate, tartrate, naphthalenesulfonate (napthylate), mesylate, glucoheptonate, lactobionate and laurylsulfonate, etc.

[0166] Pharmaceutically acceptable salts of the compounds of the present disclosure include conventional non-toxic salts or quaternary ammonium salts of the compounds, such as salts produced from non-toxic organic or inorganic acids. For example, such conventional non-toxic salts include salts derived from inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, aminosulfonic acid, phosphoric acid and nitric acid, and salts prepared from organic acids, such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, palmitic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid and isothiocyanic acid, etc.

[0167] In other cases, the compounds described herein may contain one or more acidic functional groups, and thus can form pharmaceutically acceptable salts with pharmaceutically acceptable bases. In these cases, the term "pharmaceutically acceptable salts" refers to relatively nontoxic inorganic and organic base addition salts of the compounds of the present invention. These salts can also be prepared in situ during the production of the administration carrier or dosage form, or by reacting the purified compound in the form of a free acid with an appropriate base (e.g., a pharmaceutically acceptable hydroxide, carbonate or bicarbonate of a metal cation) and ammonia or a pharmaceutically acceptable organic primary amine, secondary amine or tertiary amine independently. Representative alkali metal or alkaline earth metal salts include lithium salts, sodium salts, potassium salts, calcium salts, magnesium salts and aluminum salts, etc. Representative organic amines for forming base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine and piperazine, etc.

[0168] Wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives, solubilizers, buffers and antioxidants can also be present in the compositions.

[0169] The method for preparing these preparations or compositions comprises the step of combining the compound described herein with a carrier and optionally one or more auxiliary components. Generally, the preparation is prepared by uniformly and closely combining the compound of the present disclosure with a liquid carrier (liquid preparation) (followed by freeze drying (powder preparation for reconstitution using sterile water, etc.) or a finely divided solid carrier or both, and then molding or packaging the product as needed.

[0170] The pharmaceutical composition of the present disclosure suitable for parenteral administration comprises one or more compounds as described herein and one or more pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or can be re-formulated into sterile injection solutions or sterile powders of dispersions before use, and these components can include sugar, alcohol, antioxidants, buffers, antibacterial agents, chelating agents, solutes or suspending agents or thickening agents that make the preparation isotonic with the blood of the intended recipient. In an embodiment, active ingredient and pharmaceutically acceptable carrier are mixed in solution, and then lyophilized to obtain dry powder. The dry powder is packaged as a unit dose form, and can be reconstructed by adding a sterile solution (such as water or saline) to the powder later, so that parenteral administration.

[0171] Examples of suitable aqueous and non-aqueous carriers that can be used in the pharmaceutical compositions of the present invention include water, ethanol, polyols (e.g., glycerol, propylene glycol, and polyethylene glycol, etc.), and suitable mixtures thereof, vegetable oils (e.g., olive oil), and injectable organic esters (e.g., ethyl oleate). Suitable fluidity can be maintained, for example, by using coating materials (e.g., lecithin), by maintaining the desired particle size (in the case of dispersions), and by using surfactants.

[0172] These compositions can also contain adjuvants, such as preservatives, wetting agents, emulsifiers and dispersants. By including various antibacterial and antifungal agents, such as parabens, chlorobutanol and phenol sorbic acid, it is possible to ensure that the effect of microorganisms on the compounds of the present invention is prevented. It is also possible to wish to include isotonic agents, such as sugar and sodium chloride, etc. in the compositions. In addition, the extended absorption of injectable pharmaceutical forms can be achieved by including agents that delay absorption (such as aluminum monostearate and gelatin).

[0173] In some cases, in order to prolong the effect of a drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This can be accomplished by using a liquid suspension of a poorly water-soluble crystalline or non-crystalline material. The absorption rate of the drug depends on its dissolution rate, which in turn depends on crystal size and crystalline morphology. Alternatively, delayed absorption of a parenteral administration form can be accomplished by dissolving or suspending the drug in an oil vehicle.

[0174] The present disclosure also provides a method for preparing the compounds described herein. The compounds can be easily prepared by many well-known methods known to those of ordinary skill in the art.

[0175] In certain embodiments, the method of preparing the compounds described herein comprises contacting a compound of Formula 3 with a compound of Formula 4, wherein the compound of Formula 3 is:

[0176]

[0177] or a pharmaceutically acceptable salt thereof, wherein:

[0178] R 2 is selected from the group consisting of hydrogen, halide, nitrile, nitro, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, -N(R 12 )2, -(C=O)N(R 12 )2、-N(R 12 )(C=O)R 12 、-OR 12 、-(C=O)R 12 、-(C=O)OR 12 、-OC(C=O)R 12 、-O(C=O)OR 12 ,-O(P=O)(OR 12 )2, -O(C=O)N(R 12 )2、-N(R 12 )(C=O)OR 12 、-N(R 12 )(C=O)N(R 12 2. -SO2R 12 , -OSO2OH, triflate / ester, mesylate / ester, tosylate / ester and -(CR2) m The group composed of Y;

[0179] R 3 is an alkyl group;

[0180] R 4 It is hydrogen, halide, -OR 12 、-SR 12 、-N(R 12 )2. -OC(C=O)R 12 、-O(C=O)OR 12 ,-O(P=O)(OR 12 )2, -O(C=O)N(R 12 )2、-N(R 12 )(C=O)OR 12 、-N(R 12 )(C=O)N(R 12 )2、-N(R 12 )(C=O)R 12 、-(C=O)N(R 12 )2、-N(R 12 )(OR 12 ),-SO2R 12 or -(CR2) m Y; or R 4 and R 5Together with the carbon to which they are covalently bonded, they form =O, =S, =N (R 12 ), = N(OR 12 ), or R 4 and R 5 together with the carbon to which they are covalently bonded form an optionally substituted 5-6 membered heterocycloalkyl comprising 2 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur;

[0181] R 5 is hydrogen, nitrile, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, -OR 12 、-N(R 12 )2 or -(CR2) m Y;

[0182] R 6 and R 7 are independently alkyl;

[0183] R 8 It is hydrogen, halide, -OR 12 、-SR 12 、-N(R 12 )2. -OC(C=O)R 12 、-O(C=O)OR 12 ,-O(P=O)(OR 12 )2, -O(C=O)N(R 12 )2、-N(R 12 )(C=O)OR 12 、-N(R 12 )(C=O)N(R 12 )2、-N(R 12 )(C=O)R 12 、-(C=O)N(R 12 )2、-N(R 12 )(OR 12 ),-SO2R 12 or -(CR2) m Y; or R 8 and R 9 Together with the carbon to which they are covalently bonded, they form =O, =S, =N (R 12 ), = N(OR 12 ) or an optionally substituted 5-6 membered heterocycloalkyl comprising 2 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur;

[0184] R 9 is hydrogen, nitrile, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, -OR 12 or -N(R 12)2;

[0185] R 10 is hydrogen, halide, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or aralkyl;

[0186] R 11 is hydrogen, halide, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, -SR 12 , -SeR 12 or -N(R 12 )2;

[0187] R 12 is independently selected from the group consisting of hydrogen, alkyl, perhaloalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl and -(CR2) m A group consisting of Y; or two R 12 Together with the atoms to which they are covalently bonded, they form a 3-7 membered cycloalkyl group or a 3-7 membered heterocycloalkyl group;

[0188] R is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and aralkyl at each occurrence; or two Rs and the atoms to which they are covalently bonded form a 3-7 membered cycloalkyl or 3-7 membered heterocycloalkyl;

[0189] m is independently at each occurrence 1-10; and

[0190] Y is independently at each occurrence -N(R)2, -(C=O)N(R)2, -N(R)(C=O)R, -OR, -(C=O)R, -(C=O)OR, -OC(C=O)R, -O(C=O)OR, -O(P=O)(OR)2, -O(C=O)N(R)2, -N(R)(C=O)OR, -N(R)(C=O)N(R)2, -SO2R or -OCH2CO2H

[0191] The compound of formula 4 is:

[0192]

[0193] wherein LG is a leaving group, thereby forming a compound described herein.

[0194] In certain embodiments, a method of preparing a compound described herein comprises contacting a compound of Formula 5:

[0195]

[0196] or a pharmaceutically acceptable salt thereof, wherein:

[0197] R1 and R 2 are independently selected from hydrogen, halide, nitrile, nitro, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, -N(R 12 )2, -(C=O)N(R 12 )2、-N(R 12 )(C=O)R 12 、-OR 12 、-(C=O)R 12 、-(C=O)OR 12 、-OC(C=O)R 12 、-O(C=O)OR 12 ,-O(P=O)(OR 12 )2, -O(C=O)N(R 12 )2、-N(R 12 )(C=O)OR 12 、-N(R 12 )(C=O)N(R 12 2. -SO2R 12 , -OSO2OH, triflate / ester, mesylate / ester, tosylate / ester and -(CR2) m The group composed of Y;

[0198] R 3 is an alkyl group;

[0199] R 4 It is hydrogen, halide, -OR 12 、-SR 12 、-N(R 12 )2. -OC(C=O)R 12 、-O(C=O)OR 12 ,-O(P=O)(OR 12 )2, -O(C=O)N(R 12 )2、-N(R 12 )(C=O)OR 12 、-N(R 12 )(C=O)N(R 12 )2、-N(R 12 )(C=O)R 12 、-(C=O)N(R 12 )2、-N(R 12 )(OR 12 ),-SO2R 12 or -(CR2) m Y; or R 4 and R 5 Together with the carbon to which they are covalently bonded, they form =O, =S, =N (R 12), = N(OR 12 ), or R 4 and R 5 Together with the carbon to which they are covalently bonded, they form an optionally substituted 5-6 membered heterocycloalkyl group comprising 2 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur;

[0200] R 5 is hydrogen, nitrile, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, -OR 12 、-N(R 12 )2 or -(CR2) m Y;

[0201] R 6 and R 7 are independently alkyl;

[0202] R 10 is hydrogen, halide, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or aralkyl;

[0203] R 11 is hydrogen, halide, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, -SR 12 , -SeR 12 or -N(R 12 )2;

[0204] R 12 is independently selected from the group consisting of hydrogen, alkyl, perhaloalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl and -(CR2) m A group consisting of Y; or two R 12 Together with the atoms to which they are covalently bonded, they form a 3-7 membered cycloalkyl group or a 3-7 membered heterocycloalkyl group;

[0205] R is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and aralkyl at each occurrence; or two Rs and the atoms to which they are covalently bonded form a 3-7 membered cycloalkyl or 3-7 membered heterocycloalkyl;

[0206] m is independently at each occurrence 1-10; and

[0207] Y is independently at each occurrence -N(R)2, -(C=O)N(R)2, -N(R)(C=O)R, -OR, -(C=O)R, -(C=O)OR, -OC(C=O)R, -O(C=O)OR, -O(P=O)(OR)2, -O(C=O)N(R)2, -N(R)(C=O)OR, -N(R)(C=O)N(R)2, -SO2R or -OCH2CO2H

[0208] The compound of formula 4 is:

[0209]

[0210] wherein LG is a leaving group, thereby forming a compound described herein.

[0211] LG can independently be any leaving group known in the art. Exemplary leaving groups include, but are not limited to, Cl, Br, I,

[0212]

[0213]

[0214] The compound of formula 4 can be formed in situ, for example, by reaction of the corresponding carboxylic acid and a carbonyl activating agent and optionally a coupling additive.

[0215] Exemplary carbonyl activators include, but are not limited to, carbodiimides (e.g., DCC, DIC, EDC, CIC, BMC, CPC, BDDC, PIC, PEC, and BEM), uronium / ammonium salts (e.g., HATU, HBTU, TATU, TBTU, HAPyU, TAPipU, HAPipU, HBPipU, HAMBU, HBMDU, HAMTU, 5,6-B (HATU), 4,5-B (HATU), HCTU, TCTU, and ACTU), phosphonium salts (e.g., AOP, BOP, PyAOP, PyBOP, PyOxm, PyNOP, PyFOP, NOP, and PyClock), iminium salts (e.g., BOMI, BDMP, BMMP, BPMP, and AOMP).

[0216] Exemplary coupling additives include, but are not limited to, HOBt, 6-NO2-HOBt, 6-Cl-HOBt, 6-CF3-HOBt, HOAt, HODhbt, HODhat, HOSu, and Oxyma.

[0217] The step of contacting the compound of Formula 3 or Formula 5 with the compound of Formula 4 can be carried out in any solvent. The selection of an appropriate solvent may depend on the chemical structure of the starting material and the nature of the chemical reaction required to prepare the compounds described herein. The selection of an appropriate solvent is entirely within the skill of those of ordinary skill in the art. The solvent may be an aprotic or protic organic solvent. In certain embodiments, the solvent is a polar aprotic solvent. Exemplary solvents include, but are not limited to, alkyl halides, ethers, esters, ketones, formamides, alkyl nitriles, alkyl sulfoxides, and aromatic solvents. Exemplary solvents include, but are not limited to, tetrahydrofuran, tetrahydropyran, dioxane, dichloromethane, dichloroethane, chloroform, dimethylformamide, dimethyl sulfoxide, and mixtures thereof.

[0218] The step of contacting the compound of Formula 3 or Formula 5 with the compound of Formula 4 can be carried out in the presence of a base. The base can be an organic or inorganic Bronsted base. In certain embodiments, the base is an organic amine, a metal hydroxide, a metal carbonate, a metal alkoxide, and a mixture thereof. Exemplary bases include, but are not limited to, Hünig bases, pyridine, pyrazine, trimethylamine, morpholine, N-methylmorpholine, piperidine, piperazine, pyrrolidine, DABCO, quinuclidine, TBD, DBU, DBN, DMAP, NaOH, CsOH, KOH, Na2CO3, K2CO3, and Cs2CO3, etc.

[0219] The present disclosure provides a method for treating an inflammatory disease or condition in a subject in need thereof, the method comprising administering a therapeutically effective amount of sedumin or a compound described herein.

[0220] In certain embodiments, the inflammatory disease or condition is selected from the group consisting of asthma, autoimmune diseases, chronic rheumatoid arthritis, refractory colitis, ulcerative colitis, Crohn's disease, glomerulonephritis, systemic lupus erythematosus, scleroderma, multiple sclerosis, psoriasis, Sjögren's syndrome, chronic inflammation, chronic prostatitis, glomerulonephritis, allergic reactions, inflammatory bowel disease, pelvic inflammatory disease, reperfusion injury, arthritis, rheumatoid arthritis, transplant rejection, vasculitis, sepsis, fatty liver disease, gout, nosocomial pneumonia, acute respiratory distress syndrome, ankylosing spondylitis, psoriatic arthritis, lupus erythematosus, chronic obstructive pulmonary disease, pulmonary fibrosis, liver fibrosis and septic shock.

[0221] The present disclosure also provides a method of treating inflammatory bowel disease in a subject in need thereof, the method comprising administering a therapeutically effective amount of malathin or a compound described herein.

[0222] In certain embodiments, the inflammatory bowel disease is selected from the group consisting of ulcerative colitis (UC), indeterminate colitis, Crohn's disease (CD), lymphocytic colitis, microscopic colitis, collagenous colitis, autoimmune bowel disease, allergic gastrointestinal disease, and eosinophilic gastrointestinal disease.

[0223] In certain embodiments, the method of treating inflammatory bowel disease further comprises the step of co-administering to the subject a therapeutically effective amount of an anti-inflammatory agent.

[0224] The anti-inflammatory agent can be any anti-inflammatory agent known in the art. In certain embodiments, the anti-inflammatory agent is any anti-inflammatory agent that can be used to treat IBD or IBS. Exemplary anti-inflammatory agents include nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, antibiotics, immunomodulators, and biological drugs, but are not limited to 5-aminosalicylic acid, hydrocortisone, infliximab, and adalimumab.

[0225] The scutellarin described in this article exhibited potent anti-inflammatory activity in lipopolysaccharide (LPS)-induced macrophage and dextran sulfate sodium (DSS)-induced acute colitis mouse models. Scutellarin was able to effectively inhibit LPS-induced nitric oxide production, iNOS expression, and the transcription and secretion of proinflammatory cytokines (including IL-1β, TNF-α, and IL-6). Scutellarin also significantly inhibited inflammatory responses and reduced the susceptibility of mice to DSS-induced colitis. These results provide strong evidence for the anti-inflammatory effects of scutellarin and highlight its potential as a therapeutic agent for the treatment of IBD.

[0226] In addition, the anti-inflammatory activity of scutellarin was evaluated by the inhibitory behavior on the transcription and secretion of pro-inflammatory cytokines (including IL-1β, IL-6 and TNF-α). The results showed that scutellarin could inhibit the secretion of IL-1β, IL-6 and TNF-α in a dose-dependent manner ( Figure 4 A) and the production of pro-inflammatory cytokines at the mRNA level ( Figure 4 B). In addition, taxol was able to significantly reduce the level of iNOS mRNA in LPS-induced macrophages.

[0227] The in vitro inhibitory effect of salvia miltiorrhiza was studied in a mouse model of acute colitis induced by dextran sodium sulfate (DSS), a well-established model that has been widely used for anti-inflammatory and IBD drug development. As shown, 2.5% DSS given to mice via drinking water for 7 days significantly reduced the average body weight of mice, shortened colon length, and increased the levels of proinflammatory cytokines (IL-1β, IL-6, and TNF-α) in colon tissue compared with the control group. Combination treatment with low-dose (50 mg / kg) salvia miltiorrhiza or high-dose (100 mg / kg) salvia miltiorrhiza in DSS-induced mice increased their body weight and food and water consumption ( Figure 5 AC). Compared with the vehicle control, malathionin also reduced the disease activity index (DAI) ( Figure 5 D). Treatment with high and low doses of scutellarin increased colon length by 14.27% and 12.64%, respectively ( Figure 5 EF). Taxol treatment also reduced the levels of pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α) while increasing the production of the anti-inflammatory cytokine IL-10 ( Figure 5G). Since chemokines released during inflammation attract leukocytes and lead to a positive feedback loop of cytokine production, inducing further inflammatory responses, we also examined the infiltration of leukocytes into colonic tissues by immunohistochemical (IHC) staining of CD45, a common leukocyte antigen. IHC results showed that the infiltration of CD45-positive cells into colonic tissues was significantly increased, and treatment with taurotaxel or 5-ASA was able to reduce this infiltration ( Figure 5 H). Of note, administration of 200 mg / kg 5-ASA, which is commonly prescribed for IBD patients, did not induce the same degree of improvement as taurotaxel. Histological evaluation of colon sections obtained from DSS-induced mice identified inflammatory cell infiltration, epithelial cell architecture disruption, and crypt loss typical of acute colitis. Figure 5 As shown in Figure 1, treatment with taurotaxel had a beneficial effect on colon histology. Both low-dose and high-dose taurotaxel B treatments were able to reduce DSS-induced damage compared to the vehicle group. Notably, colon sections from mice treated with taurotaxel showed only negligible epithelial damage or crypt loss compared to the vehicle control group or the 5-ASA treatment group, and these results were comparable to those of the uninduced control group. In addition, Alcian blue staining of colon tissues showed that taurotaxel B treatment also reduced damage to goblet cells and maintained mucin secretion ( Figure 5 J).

[0228] In summary, the above results provide solid evidence to support the effective anti-inflammatory activity of taxol and demonstrate its potential for development as a therapeutic agent for inflammatory bowel disease.

[0229] Example

[0230] Example 1 - Representative Procedure for C11 Acylation of Taxolin A (1)

[0231] Taxolin A (1) and B (2) were isolated from natural sources. Compounds 3-8 were prepared by acylation of taxolin A (1).

[0232] To a stirred solution of 0.2 M of the beautiful taxol A (1) in dichloromethane was added the corresponding acid chloride or anhydride (2 equivalents) at 0°C under argon. The resulting solution was warmed to room temperature and stirred until TLC analysis indicated a consumption of 1. The reaction was then terminated by the addition of saturated aqueous sodium bicarbonate and the aqueous phase was extracted with dichloromethane (×3). The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated. The crude product was purified by silica gel column chromatography using hexane / ethyl acetate.

[0233] Example 2 - Representative Procedure for Derivatization of Taxol B (2)

[0234] Compounds 9-15 were prepared from taxol B (2). Compounds 9-11 were prepared by demethylation, oxidation or enamine formation. Compounds 12-15 were prepared by 1,2-reduction followed by acylation.

[0235] Example 2A - Demethylation of Taxolin B (2)

[0236] To a stirred solution of 0.2 M dichloromethane of sedumin B (2) was added BBr3 in acetic acid (2 eq.) at 0°C under argon. The resulting solution was warmed to room temperature and stirred until TLC analysis indicated a consumption of 2. The reaction was worked up according to the above procedure.

[0237] Example 2B - Oxidation of Compound 9

[0238] To a stirred solution of compound 9 in methanol / water (1:1, 0.2 M) was added NaIO4 (3 eq.) at room temperature. The resulting solution was stirred at room temperature until TLC analysis indicated consumption of 9. The reaction was worked up according to the above procedure.

[0239] Example 2C - Enamine formation of malvaceae B (2)

[0240] To a stirred solution of leucine B (2) in ethanol / water (2:1, 0.2 M) at room temperature, NH2OH·HCl (5 eq.) and NaOAc·3H2O (10 eq.) were added. The resulting solution was stirred at room temperature until TLC analysis indicated a consumption of leucine B of 2. The reaction was worked up according to the above procedure.

[0241] Example 2D - 1,2-Reduction of Taxolin B (2)

[0242] To a stirred solution of 0.2 M of styracin B (2) in dry THF at -40°C under argon, LiAlH(OBu)3 (3 eq.) was slowly added. The resulting solution was stirred at -40°C until TLC analysis indicated consumption of styracin B (2). The reaction was worked up according to the above procedure.

[0243] Example 3 - Cytotoxicity of Taxusin

[0244] RAW264.7 macrophages were treated with 6.25 μM, 12.5 μM, 25 μM, or 50 μM tauropin for 24 h. The cytotoxicity of tauropin on cells was evaluated using the MTT assay. The results showed that the viability of cells treated with tauropin was not significantly different from that of the control, indicating that tauropin did not exhibit cytotoxicity in macrophages ( Figure 3 A).

[0245] Example 4 - Anti-inflammatory activity of Taxusin

[0246] The anti-inflammatory activity of tausin on nitric oxide production was investigated in LPS-activated RAW264.7 macrophages. The results showed that treatment with tausin significantly reduced LPS-induced nitric oxide production ( Figure 3 B). A dose as low as 12.5 μM of tausin also significantly inhibited the protein expression of iNOS, an upstream regulator of nitric oxide production ( Figure 3 C) Compared with the control, truncatulin at a dose higher than 25 μM significantly inhibited LPS-induced iNOS expression by approximately 90%.

[0247] Example 5 - Inhibition of Nitric Oxide Production

[0248] Inhibition of nitric oxide production by compounds 3-8 at a dose of 12.5 μM (%). In general, acylation of tausin A (1) with the exception of moieties with polar functional groups (e.g., amines or carboxylic acids) resulted in enhanced inhibition of nitric oxide production. In this series, compound 4 showed the best activity in inhibiting nitric oxide production.

[0249]

[0250] Inhibition of nitric oxide production at 12.5 μM (%) = -75. Inhibition of nitric oxide production at 12.5 μM (%) = -28.84.

[0251] Inhibition of nitric oxide production by compounds 9-15 at 12.5 μM (%). Demethylation or oxidation of scutellarin B (2). Enamine formation resulted in a slight decrease in activity. In general, acylation after 1,2-reduction resulted in a significant decrease in activity, with the exception of compound 13, which showed enhanced activity but was highly toxic at higher concentrations.

[0252]

Claims

1. A compound of formula 1: or a pharmaceutically acceptable salt thereof, wherein: R 1 and R 2 are independently selected from hydrogen, halide, nitrile, nitro, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, -N(R 12 )2, -(C=O)N(R 12 )2、-N(R 12 )(C=O)R 12 、-OR 12 、-(C=O)R 12 、-(C=O)OR 12 、-OC(C=O)R 12 、-O(C=O)OR 12 ,-O(P=O)(OR 12 )2, -O(C=O)N(R 12 )2、-N(R 12 )(C=O)OR 12 、-N(R 12 )(C=O)N(R 12 2. -SO2R 12 , -OSO2OH, triflate / ester, mesylate / ester, tosylate / ester and -(CR2) m The group composed of Y; R 3 is an alkyl group; R 4 It is hydrogen, halide, -OR 12 、-SR 12 、-N(R 12 )2. -OC(C=O)R 12 、-O(C=O)OR 12 ,-O(P=O)(OR 12 )2, -O(C=O)N(R 12 )2、-N(R 12 )(C=O)OR 12 、-N(R 12 )(C=O)N(R 12 )2、-N(R 12 )(C=O)R 12 、-(C=O)N(R 12 )2、-N(R 12 )(OR 12 ),-SO2R 12 or -(CR2) m Y; or R 4 and R 5 Together with the carbon to which they are covalently bonded, they form =O, =S, =N (R 12 ), = N(OR 12 ), or R 4 and R 5 together with the carbon to which they are covalently bonded form an optionally substituted 5-6 membered heterocycloalkyl comprising 2 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur; R 5 is hydrogen, nitrile, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, -OR 12 、-N(R 12 )2 or -(CR2) m Y; R 6 and R 7 are independently alkyl; R 8 It is hydrogen, halide, -OR 12 、-SR 12 、-N(R 12 )2. -OC(C=O)R 12 、-O(C=O)OR 12 ,-O(P=O)(OR 12 )2, -O(C=O)N(R 12 )2、-N(R 12 )(C=O)OR 12 、-N(R 12 )(C=O)N(R 12 )2、-N(R 12 )(C=O)R 12 、-(C=O)N(R 12 )2、-N(R 12 )(OR 12 ),-SO2R 12 or -(CR2) m Y; or R 8 and R 9 Together with the carbon to which they are covalently bonded, they form =O, =S, =N (R 12 ), = N(OR 12 ) or an optionally substituted 5-6 membered heterocycloalkyl comprising 2 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur; R 9 is hydrogen, nitrile, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, -OR 12 or -N(R 12 )2; R 10 is hydrogen, halide, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or aralkyl; R 11 is hydrogen, halide, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, -SR 12 , -SeR 12 or -N(R 12 )2; R 12 is independently selected from the group consisting of hydrogen, alkyl, perhaloalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl and -(CR2) m A group consisting of Y; or two R 12 Together with the atoms to which they are covalently bonded, they form a 3-7 membered cycloalkyl group or a 3-7 membered heterocycloalkyl group; R is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and aralkyl at each occurrence; or two Rs and the atoms to which they are covalently bonded form a 3-7 membered cycloalkyl or 3-7 membered heterocycloalkyl; m is independently in each instance 1-10; and Y is independently at each occurrence -N(R)2, -(C=O)N(R)2, -N(R)(C=O)R, -OR, -(C=O)R, -(C=O)OR, -OC(C=O)R, -O(C=O)OR, -O(P=O)(OR)2, -O(C=O)N(R)2, -N(R)(C=O)OR, -N(R)(C=O)N(R)2, -SO2R or -OCH2CO2H, Provided that the compound of Formula 1 is not selected from the group consisting of:

2. The compound according to claim 1, wherein R 1 and R 2 Independently choose from -OR 12 、-(C=O)R 12 、-OC(C=O)R 12 、-O(C=O)OR 12 ,-O(P=O)(OR 12 )2, -O(C=O)N(R 12 )2, -OSO2OH, trifluoromethanesulfonate / ester, methanesulfonate / ester and toluenesulfonate / ester.

3. The compound according to claim 1, wherein R 4 Yes-OR 12 、-N(R 12 )2. -OC(C=O)R 12 、-O(C=O)OR 12 、-O(C=O)N(R 12 )2、-N(R 12 )(C=O)OR 12 、-N(R 12 )(C=O)N(R 12 )2、-N(R 12 )(C=O)R 12 or -N(R 12 )(OR 12 ); and R 5 is hydrogen, nitrile, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl or -(CR2) m Y; or R 4 and R 5 Together with the carbon to which they are covalently bonded, they form =O, =N(R 12 ) or = N(OR 12 ); or R 4 and R 5 Together with the carbon to which they are covalently bonded, they form an optionally substituted 1,3-dioxane or an optionally substituted 1,3-dioxolane.

4. The compound according to claim 1, wherein R 8 Yes-OR 12 、-N(R 12 )2. -OC(C=O)R 12 、-O(C=O)OR 12 、-O(C=O)N(R 12 )2、-N(R 12 )(C=O)OR 12 、-N(R 12 )(C=O)N(R 12 )2、-N(R 12 )(C=O)R 12 or -N(R 12 )(OR 12 ); and R 9 is hydrogen, nitrile, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl or -(CR2) m Y; or R 8 and R 9 Together with the carbon to which they are covalently bonded, they form =O, =N(R 12 ) or = N(OR 12 ); or R 4 and R 5 Together with the carbon to which they are covalently bonded, they form an optionally substituted 1,3-dioxane or an optionally substituted 1,3-dioxolane.

5. The compound according to claim 1, wherein R 10 is hydrogen; and R 11 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, or -SR 12 .

6. The compound according to claim 1, wherein R 3 is isopropyl; and R 6 and R 7 Each is a methyl group.

7. The compound according to claim 1, wherein R 1 and R 2 Independently choose from -OR 12 、-(C=O)R 12 、-OC(C=O)R 12 、-O(C=O)OR 12 ,-O(P=O)(OR 12 )2, -O(C=O)N(R 12 )2, -OSO2OH, trifluoromethanesulfonate / ester, mesylate / ester and tosylate / ester; R 3 is isopropyl; R 4 is - OR 12 、 - N(R 12 )2、 - OC(C=O)R 12 、 - O(C=O)OR 12 、 - O(C=O)N(R 12 )2、 -N(R 12 )(C=O)OR 12 、-N(R 12 )(C=O)N(R 12 )2、-N(R 12 )(C=O)R 12 or -N(R 12 )(OR 12 ); or R 4 and R 5 Together with the carbon to which they are covalently bonded, they form =O, =N(R 12 ) or = N(OR 12 ); or R 4 and R 5 Together with the carbon to which they are covalently bonded, they form an optionally substituted 1,3-dioxane or an optionally substituted 1,3-dioxolane; R 5 is hydrogen, nitrile, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl or -(CR2) m Y; R 6 and R 7 each is a methyl group; R 8 is - OR 12 、 - N(R 12 )2、 - OC(C=O)R 12 、 - O(C=O)OR 12 、 - O(C=O)N(R 12 )2、 -N(R 12 )(C=O)OR 12 、-N(R 12 )(C=O)N(R 12 )2、-N(R 12 )(C=O)R 12 or -N(R 12 )(OR 12 ); or R 8 and R 9 Together with the carbon to which they are covalently bonded, they form =O, =N(R 12 ) or = N(OR 12 ); or R 8 and R 9 Together with the carbon to which they are covalently bonded, they form an optionally substituted 1,3-dioxane or an optionally substituted 1,3-dioxolane; R 9 is hydrogen, nitrile, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl or -(CR2) m Y; R 10 It is hydrogen; R 11 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, or -SR 12 ; R 12 is independently selected from the group consisting of hydrogen, alkyl, perhaloalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl and -(CR2) m A group consisting of Y; or two R 12 Together with the atoms to which they are covalently bonded, they form a 3-7 membered cycloalkyl group or a 3-7 membered heterocycloalkyl group; R is independently selected from the group consisting of hydrogen and alkyl at each occurrence; or two Rs and the atoms to which they are covalently bonded form a 3-7 membered cycloalkyl or 3-7 membered heterocycloalkyl; m is independently in each occurrence 2-6; and Y is independently at each occurrence -N(R)2, -(C=O)N(R)2, -N(R)(C=O)R, -OR, -(C=O)R, -(C=O)OR, -OC(C=O)R, -O(C=O)OR, -O(P=O)(OR)2, -O(C=O)N(R)2, -N(R)(C=O)OR, -N(R)(C=O)N(R)2, -SO2R or -OCH2CO2H.

8. The compound according to claim 1, wherein R 1 and R 2 Independently choose from -OR 12 、-(C=O)R 12 、-OC(C=O)R 12 and -O(C=O)N(R 12 )2; R 3 is isopropyl; R 4 and R 5 Together with the carbon to which they are covalently bonded, they form =O, =N(R 12 ) or = N(OR 12 ); R 6 and R 7 each is a methyl group; R 8 Yes-OR 12 、-OC(C=O)R 12 or -O(C=O)N(R 12 )2; or R 8 and R 9 Together with the carbon to which they are covalently bonded, they form =O, =N(R 12 ) or = N(OR 12 ); R 9 It is hydrogen; R 10 and R 11 Each is hydrogen; R 12 is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl and -(CR2) m Y; or two R 12 Together with the atoms to which they are covalently bonded, they form a 3-7 membered cycloalkyl group or a 3-7 membered heterocycloalkyl group; R is in each case hydrogen; m is independently in each occurrence 2-6; and Y is independently at each occurrence -N(R)2, -(C=O)N(R)2, -N(R)(C=O)R, -OR, -(C=O)R, -(C=O)OR, -OC(C=O)R, -O(C=O)OR, -O(P=O)(OR)2, -O(C=O)N(R)2, -N(R)(C=O)OR, -N(R)(C=O)N(R)2, -SO2R or -OCH2CO2H.

9. The compound according to claim 1, wherein the compound has Formula 2: or a pharmaceutically acceptable salt thereof, wherein: R 1 Yes-OR 12 or -OC(C=O)R 12 ; R 2 is - OR 12 ; R 4 and R 5 Together with the carbon to which they are covalently bonded, they form =O or =N (OR 12 ); R 8 Yes-OR 12 、-OC(C=O)R 12 or -O(C=O)N(R 12 )2; or R 8 and R 9 Together with the carbon to which they are covalently bonded, they form =O, =N(R 12 ) or = N(OR 12 ); R 9 It is hydrogen; R 12 is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl and -(CR2) m Y; or two R 12 Together with the atoms to which they are covalently bonded, they form a 3-7 membered cycloalkyl group or a 3-7 membered heterocycloalkyl group; R is in each case hydrogen; m is independently in each occurrence 2-6; and Y is independently at each occurrence -N(R)2, -(C=O)N(R)2, -N(R)(C=O)R, -OR, -(C=O)R, -(C=O)OR, -OC(C=O)R, -O(C=O)OR, -O(P=O)(OR)2, -O(C=O)N(R)2, -N(R)(C=O)OR, -N(R)(C=O)N(R)2, -SO2R or -OCH2CO2H.

10. The compound according to claim 9, wherein R 8 Yes-OC(C=O)R 12 , and R 9 is hydrogen; or R 8 and R 9 Together with the carbon to which they are covalently bonded, they form =O or =N (OR 12 ).

11. The compound according to claim 10, wherein R 1 is -OCH3 or -OC(C=O)R 12 ; and R 2 It is -OCH3.

12. The compound according to claim 9, wherein R 1 and R 2 Each is -OCH3; R 4 and R 5 Together with the carbon to which they are covalently bonded, they form =O; R 8 is - OC(C=O)R 12 ; R 9 is hydrogen; and R 12 In each case - (CR2) m Y; R is in each case hydrogen; m is independently in each occurrence 2-6; and Y is independently at each occurrence -N(R)2, -(C=O)N(R)2, -N(R)(C=O)R, -OR, -(C=O)R, -(C=O)OR, -OC(C=O)R, -O(C=O)OR, -O(P=O)(OR)2, -O(C=O)N(R)2, -N(R)(C=O)OR, -N(R)(C=O)N(R)2, -SO2R or -OCH2CO2H.

13. The compound according to claim 1, wherein the compound is selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

14. A pharmaceutical composition comprising the compound according to claim 1 and at least one pharmaceutically acceptable excipient.

15. A method for treating an inflammatory disease or condition in a subject in need thereof, the method comprising administering a therapeutically effective amount of salvia chinensis or a compound according to claim 1.

16. The method of claim 15, wherein the inflammatory disease or condition is selected from the group consisting of asthma, autoimmune disease, chronic rheumatoid arthritis, refractory colitis, ulcerative colitis, Crohn's disease, glomerulonephritis, systemic lupus erythematosus, scleroderma, multiple sclerosis, psoriasis, Sjögren's syndrome, chronic inflammation, chronic prostatitis, glomerulonephritis, allergic reaction, inflammatory bowel disease, pelvic inflammatory disease, reperfusion injury, arthritis, rheumatoid arthritis, transplant rejection, vasculitis, sepsis, fatty liver, gout, nosocomial pneumonia, acute respiratory distress syndrome, ankylosing spondylitis, psoriatic arthritis, lupus erythematosus, chronic obstructive pulmonary disease, pulmonary fibrosis, liver fibrosis, and septic shock.

17. A method for treating inflammatory bowel disease in a subject in need thereof, the method comprising administering a therapeutically effective amount of malathionin or a compound according to claim 1.

18. The method of claim 17, wherein the inflammatory bowel disease is selected from the group consisting of ulcerative colitis (UC), indeterminate colitis, Crohn's disease (CD), lymphocytic colitis, microscopic colitis, collagenous colitis, autoimmune bowel disease, allergic gastrointestinal disease, and eosinophilic gastrointestinal disease.

19. The method of claim 18, wherein the inflammatory bowel disease is selected from the group consisting of UC, CD and indeterminate colitis.

20. The method of claim 17, wherein administration of the taxin or the compound results in a decrease in nitric oxide (NO) production or a decrease in iNOS expression levels in the subject.

21. The method of claim 17, wherein administration of the compound of tauricin or the compound results in a reduction in pro-inflammatory cytokine levels in the subject.

22. The method according to claim 15 or 17, wherein the taxol is selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

23. The method of claim 21, wherein the pro-inflammatory cytokine is selected from the group consisting of IL-1β, IL-6, TNF-α, and combinations thereof.

24. The method of claim 15 or 17, wherein administration of the taxin or the compound results in an increase in anti-inflammatory cytokines in the subject.

25. The method of claim 24, wherein the anti-inflammatory cytokine is IL-10.

26. The method of claim 15 or 17, wherein administration of the taxol or the compound results in a reduction in inflammation-induced structural damage to intestinal tissue.

27. The method of claim 15 or 17, wherein administration of the tauricin or the compound results in restoration of inflammation-induced reduction in intestinal goblet cell expression and mucin secretion.

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