Compounds as mPGES-1 inhibitors

Abstract

The present invention relates to amide derivatives of 2-hydroxy-2-methyl-4-(3,5,6-trimethyl-1,4-benzoquinon-2-yl)-butanoic acid for use in therapy to prevent or suppress symptoms mediated by enhanced mPGES-1 expression or activity. In particular, the present invention relates to the use of these compounds to treat diseases and conditions in which inhibition of the activity and / or expression of the enzyme mPGES-1 is beneficial, such as inflammatory diseases, nociceptive pain, autoimmune diseases, respiratory disorders, fever, cancer, inflammation-associated anorexia, Alzheimer's disease, and cardiovascular diseases. [Selection diagram] None

Description

[Technical Field]

[0001] The present invention relates to the fields of human and veterinary medicine and cosmetics, and in particular to amide derivatives of 2-hydroxy-2-methyl-4-(3,5,6-trimethyl-1,4-benzoquinon-2-yl)-butanoic acid for the treatment of conditions in which inhibition of the activity and / or expression of the enzyme mPGES-1 is beneficial, such as inflammatory diseases, nociceptive pain, autoimmune diseases, respiratory disorders, fever, cancer, inflammation-associated anorexia, Alzheimer's disease and cardiovascular diseases. [Background technology]

[0002] Prostaglandins (PGs) are important lipid mediators that maintain physiological and homeostatic functions but also induce pathological responses, such as inflammatory and nociceptive responses (Miller, 2006). Prostaglandins are synthesized from arachidonic acid (AA), which is released from the cell membrane by the action of phospholipase A2 (PLA2). Cyclooxygenase isoforms 1 and 2 (COX-1 and COX-2) enzymes metabolize AA via bis-oxygenation and peroxidation to prostaglandin G2 (PGG2) and subsequently to prostaglandin H2 (PGH2), respectively. PGH2 is the precursor to the four major bioactive prostaglandins PGD2, PGI2, PGE2, and PGF2, which are synthesized by cell- and tissue-specific synthases and isomerases. 2αProstaglandins are a common precursor to prostaglandins, as well as the prostanoid thromboxane A2 (TXA2) (Figure 1). Prostaglandins play an important role in the generation of inflammatory responses (Ricciotti and FitzGerald, 2011). Prostaglandin biosynthesis is significantly increased in inflamed tissues, contributing to the development of the cardinal signs of acute inflammation. Among prostaglandins, PGE2 has the greatest impact on the course of inflammatory pain symptoms (Nakanishi and Rosenberg, 2013). PGE2 is synthesized by three different PGE2 synthases, which are either membrane enzymes (mPGES-1, mPGES-2) or cytosolic (cPGES) types (Hara et al., 2010). Of the three PGE synthases, cPGES and mPGES-2 are constitutively expressed in various organs and tissues, whereas mPGES-1, like COX-2, is upregulated in response to various inflammatory stimuli (Ikeda-Matsuo et al., 2005; Riendeau et al., 2005; Smith et al., 2011). Following inflammatory or nociceptive triggers, mPGES-1 and COX-2 are induced in the periphery (PNS) and central nervous system (CNS), contributing to the production of PGE and the development of chronic pain (Zeilhofer, 2007). Current nonsteroidal anti-inflammatory drugs (NSAIDs) target the upstream COX enzyme in the synthesis of prostaglandins. COX-1 / 2 nonselective inhibitors or COX-2 selective inhibitors (coxibs) are the most commonly prescribed medications for inflammatory pain indications. Both classes of NSAIDs have been associated with serious cardiovascular and gastrointestinal adverse events (Norberg et al., 2013a). The COX-1 enzyme is constitutively expressed in most tissues and has gastroprotective properties; therefore, COX-1 inhibitors may induce gastric damage. Despite being primarily expressed in inflamed tissues, COX-2 selective inhibitors have been associated with adverse cardiovascular effects and hypertension. Studies have shown that adverse cardiovascular effects are due to the suppression of COX-2-mediated prostacyclin (PGI2) synthesis (Catella-Lawson et al.; McAdam et al., 1999; Hui et al., 2010).In fact, PGI2 plays an important role in vasodilation, inhibition of platelet aggregation, and is cardioprotective. mPGES-1 is strongly upregulated by inflammatory stimuli and contributes to the production of proinflammatory, pronociceptive, and proangiogenic PGE2. Targeting the downstream enzyme mPGES-1 has recently emerged as a safer alternative to the current class of NSAIDs or coxibs (Samuelsson et al., 2007; Koeberle and Werz, 2009, 2015a; Chen et al., 2015). In fact, contrary to the upstream enzymes COX-1 and COX-2, inhibition of mPGES-1 selectively blocks inflammation-induced PGE2 without reducing the synthesis and function of other prostaglandins. Therefore, targeting mPGES-1 reduces the adverse effects caused by nonselective inhibition of prostaglandin synthesis by NSAIDs or inhibition of COX-1 itself (Norberg et al., 2013b; Koeberle and Werz, 2015b). mPGES-1 is weakly expressed in normal tissues and upregulated in inflamed tissues, making it less prone to on-target adverse effects. Mice lacking mPGES-1 are feasible and do not exhibit any abnormal phenotypes. These mice exhibited reduced inflammation-related symptoms, such as swelling, anorexia, and fever, and also showed reduced sensitivity to pain (Kamei et al., 2004; Hara et al., 2010). These data support the validity of mPGES-1 as a drug target for inflammation-related diseases.In addition, mPGES-1 expression has been reported to be overexpressed in inflamed tissues of patients with neuroinflammation, including, but not limited to, arthritis, gout, enteropathy, and periodontitis, as well as patients with neuroinflammation, including Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease, cerebral ischemia, epilepsy, brain cancer, and multiple sclerosis (Fahmi, 2004; Westman et al., 2004; Kojima et al., 2005; Chaudhry et al., 2008; Miyagishi et al., 2012; Akitake et al., 2013; Kats et al., 2013; Takeuchi et al., 2013; Ikeda-Matsuo, 2017). mPGES-1 is also overexpressed in many cancers, and inhibition of mPGES-1 has been reported to be an effective treatment in various preclinical models (Larsson et al.; Seo et al.; Yoshimatsu et al.; Hanaka et al., 2009; Beales and Ogunwobi, 2010; Nakanishi et al., 2010; Larsson and Jakobsson, 2015; Sasaki et al., 2015; Kim et al., 2016; Ramanan and Doble, 2017). Overall, mPGES-1 and mPGES-1-induced PGE2 have been implicated in the pathogenesis of a large number of diseases and conditions, including inflammatory diseases, nociceptive pain, autoimmune diseases, respiratory disorders, fever, cancer, inflammation-associated anorexia, Alzheimer's disease, and cardiovascular disease. Therefore, inhibition of mPGES-1 represents an effective option for the treatment of all of the above-mentioned diseases and conditions.

[0003] International Publication No. 2006 / 063466, International Publication No. 2007 / 059610, International Publication No. 2008 / 058514, International Publication No. 2008 / 071173, International Publication No. 2009 / 130242, International Publication No. 2009 / 146696, International Publication No. 2010 / 034796, International Publication No. 2010 / 100249, International Publication No. 2010 / 127152, International Publication No. 2011 / 023812, WO 2012 / 055995, WO 2012 / 076672, WO 2012 / 110860, WO 2013 / 038308, WO 2013 / 072825, WO 2013 / 118071, WO 2013 / 153535 and WO 2015 / 158204 disclose a number of compounds that are stated to be inhibitors of mPGES-1.

[0004] WO 2014 / 011047 and WO 2017 / 060432 disclose amide derivatives of 2-hydroxy-2-methyl-4-(3,5,6-trimethyl-1,4-benzoquinon-2-yl)-butanoic acid for treating or preventing conditions associated with mitochondrial disorders and / or mitochondrial dysfunction. Summary of the Invention [Problem to be solved by the invention]

[0005] However, there remains a need in the art for additional mPGES-1 inhibitor compounds that have improved safety, efficacy, and / or (oral) bioavailability profiles. The present application is directed to additional compounds that act as inhibitors of mPGES-1 and are therefore useful in treating conditions in which inhibition of the enzyme mPGES-1 activity and / or expression is beneficial, including, for example, the prevention or suppression of inflammation and pain in various diseases or conditions. [Means for solving the problem]

[0006] In a first aspect, the present invention provides compounds having the general structure (I): [ka] [In the formula, T is a water-soluble vitamin E derivative having a core chromanyl or chromanylquinone framework and having a carboxylic acid moiety substituted at the 2-position, where T is attached to the nitrogen through the carboxylic acid moiety to form an amide moiety; L is a linker between the amide nitrogen atom and the distal nitrogen atom, comprising 1 to 10 optionally substituted main chain atoms selected from carbon, nitrogen, and oxygen; N * is represented by structure (IIa) or (IIb): [ka] R 1 and R 2 are each independently selected from hydrogen (H), C1-C6 alkyl, or C1-C6 alkenyl, or R 1 and R 2 are bonded together, thereby forming a second linker between the amide nitrogen atom and the distal nitrogen atom, or R 1 is attached to a main chain atom of the linker L in a cyclic structure, and / or R 2 is attached to a main chain atom of the linker L in a cyclic structure, R 3 is selected from hydrogen (H), C1-C6 alkyl, or C1-C6 alkenyl, where the alkyl or alkenyl moieties are optionally substituted with one or more halogen atoms, hydroxyl moieties, or (halo)alkoxy moieties, or R 3 is absent when the distal nitrogen atom is part of an imine moiety, R 4 is selected from hydrogen (H) or C1-C6 alkyl, where the alkyl portion is optionally substituted with one or more halogen atoms or (halo)alkoxy moieties; X is an anion, preferably a pharmaceutically acceptable anion; The present invention relates to compounds for use in therapy to prevent or suppress conditions mediated by enhanced mPGES-1 expression or activity.

[0007] In certain embodiments of this aspect, the invention provides a compound for use in accordance with the invention, wherein the compound has the structure (VI): [ka] [In the formula, N * is -NR 3 or -N + R 3 R 4 X - where T, X, R 3 and R 4 is as defined above].

[0008] In a preferred embodiment of this aspect, the invention provides a compound for use according to the invention, wherein T has the structure (IIIa) or (IIIb): [ka] [Wherein, each R 7 are individually C1-C6 alkyl moieties, preferably each R 7 is methyl].

[0009] In a preferred embodiment of this aspect, the invention provides a compound for use in accordance with the invention, wherein the compound has the structure (VIIb): [ka] [In the formula, Each R 7 is methyl, N * is -NR 3 or -N + R 3 R 4 X - and X is as defined above, preferably Cl - and R 3 is as defined above, preferably hydrogen, R 4 is as defined above and is preferably hydrogen.

[0010] In a preferred embodiment of this aspect, the invention provides a compound for use in accordance with the invention, wherein the symptoms mediated by enhanced mPGES-1 expression or activity include at least one or more of inflammation, pain, swelling, fever, angiogenesis, and loss of appetite. Preferably, the compound is a) acute and chronic inflammation; skin diseases such as dermatitis, eczema, psoriasis, bums, acne vulgaris, hidradenitis suppurativa and tissue trauma; internal diseases such as inflammatory bowel disease, Crohn's disease, ulcerative colitis, diverticulitis, irritable bowel disease (IBS), peptic ulcer, cystitis, (chronic) prostatitis, pancreatitis or nephritis; diseases of the ear, nose, mouth and throat such as influenza, rhinitis, pharyngitis, tonsillitis, conjunctivitis, iritis, scleritis, otitis and uveitis; viral and bacterial infections; inflammation-related anorexia; allergies; pelvic inflammatory disease; reperfusion injury; graft rejection; tendonitis, vasculitis and phlebitis; b) acute pain, chronic pain, neuropathic pain, nociceptive pain, hyperalgesia, pain associated with central sensitization, allodynic inflammatory pain, visceral pain, cancer pain, traumatic pain, dental or surgical pain, postoperative pain, delivery pain, childbirth ache, persistent pain, peripheral mediated pain, central mediated pain, chronic headache, migraine, sinus headache, tension headache, phantom limb pain, peripheral nerve injury chemotherapy pain and cancer pain; c) autoimmune diseases such as arthritis, osteoarthritis, juvenile arthritis, rheumatoid arthritis, ankylosing spondylitis, gout, rheumatic fever, bursitis, systemic lupus erythematosus (SLE) and multiple sclerosis; d) respiratory disorders or lung diseases such as asthma, chronic obstructive pulmonary disease (COPD), sarcoidosis and pulmonary fibrosis; e) Cancers such as brain cancer, prostate cancer, kidney cancer, liver cancer, pancreatic cancer, stomach cancer, breast cancer, lung cancer, head and neck cancer, thyroid cancer, glioblastoma, melanoma, lymphoma, leukemia, cutaneous T-cell lymphoma, and cutaneous B-cell lymphoma; f) diabetic complications, including diabetic vascular injury, diabetic neuropathy, and diabetic retinopathy; g) Neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, Huntington's disease and amyotrophic lateral sclerosis, and h) Cardiovascular diseases such as atherosclerosis, thrombosis, stroke and coronary heart disease The present invention is used to prevent or suppress symptoms mediated by enhanced mPGES-1 expression or activity in the treatment of a disease or condition selected from the group consisting of:

[0011] In a preferred embodiment of this aspect, the present invention provides a compound for use according to the present invention, wherein the total daily dose administered is in the range of about 5 to 2000 mg, preferably about 20 to 800 mg, more preferably about 30 to 400 mg, and most preferably about 150 to 250 mg. Preferably, the compound is administered orally. Preferably, the compound is administered in solid or liquid form, and preferably, the compound is mixed with an aqueous solution prior to administration, more preferably, the aqueous solution is an isotonic aqueous solution, and even more preferably, the isotonic aqueous solution is saline. Preferably, the compound is administered at least twice daily, and more preferably, the compound is administered twice daily in two similar or equal doses. Preferably, the interval between two administrations is at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 hours. Preferably, the subject being treated is a primate, and more preferably, the subject is a human.

[0012] In a second aspect, the present invention provides a method for treating a disease or condition mediated by or associated with enhanced PGES-1 expression or activity, the method comprising administering to a subject suffering from the disease or condition an effective amount of a compound as defined above.

[0013] In a preferred embodiment of this aspect, the invention provides a method as described above, wherein the disease or condition mediated by or associated with enhanced PGES-1 expression or activity is preferably selected from the group consisting of: a) acute and chronic inflammation; skin diseases such as dermatitis, eczema, hidradenitis suppurativa, acne vulgaris, hidradenitis suppurativa and tissue trauma; visceral diseases such as ulcerative colitis, diverticulitis, irritable bowel disease (IBS), peptic ulcer, cystitis, (chronic) prostatitis or nephritis; ear, nose, mouth and throat diseases such as influenza, rhinitis, pharyngitis, tonsillitis, conjunctivitis, iritis, scleritis, otitis and uveitis; viral and bacterial infections; inflammation-associated loss of appetite; allergies pelvic inflammatory disease; graft rejection; tendonitis, vasculitis and phlebitis; b) acute pain, chronic pain, neuropathic pain, nociceptive pain, hyperalgesia, pain associated with central sensitization, allodynic inflammatory pain, visceral pain, cancer pain, traumatic pain, dental or surgical pain, postoperative pain, labor pain, postpartum pain, persistent pain, peripherally mediated pain, centrally mediated pain, chronic headache, migraine, sinus headache, tension headache, phantom limb pain, peripheral nerve injury chemotherapy pain and cancer pain; c) ankylosing spondylitis, gout, rheumatic fever, bursitis, and d) diabetic complications including diabetic vascular injury, diabetic neuropathy and diabetic retinopathy. [Brief explanation of the drawings]

[0014] [Figure 1] Prostaglandin synthesis pathways and targeting strategies. [Figure 2A] (Figures 2A-2C) Levels of prostaglandins (PGs) PGE2 (Figure 2A), PGD2 (Figure 2B), and 6-keto PGF1a (Figure 2C) in supernatants of RAW264.7 murine macrophage cells exposed to vehicle or 1 μg / mL lipopolysaccharide (LPS) for 24 hours normalized to vehicle. [Figure 2B](Figures 2A-2C) Levels of prostaglandins (PGs) PGE2 (Figure 2A), PGD2 (Figure 2B), and 6-keto PGF1a (Figure 2C) in supernatants of RAW264.7 murine macrophage cells exposed to vehicle or 1 μg / mL lipopolysaccharide (LPS) for 24 hours normalized to vehicle. [Figure 2C] (Figures 2A-2C) Levels of prostaglandins (PGs) PGE2 (Figure 2A), PGD2 (Figure 2B), and 6-keto PGF1a (Figure 2C) in supernatants of RAW264.7 murine macrophage cells exposed to vehicle or 1 μg / mL lipopolysaccharide (LPS) for 24 hours normalized to vehicle. [Figure 2D] (Figures 2D-2F) Levels of PGE2, PGD2, and 6-keto PGF1a in supernatants from RAW264.7 murine macrophage cells exposed for 24 h to vehicle or 1 μg / mL LPS alone (set at 100%) or in combination with increasing concentrations of compounds I-IVb-X (compounds of general structure (I), where T is of general structure (IVb) in the S,R configuration, and for compound X the following applies: L = L19; R1 = H; R2-R2' = L3; R3 = H, denoted KH) (Figure 2D), the nonselective COX inhibitor indomethacin (Figure 2E), or the COX-2 inhibitor celecoxib (Figure 2F). [Figure 2E] (Figures 2D-2F) Levels of PGE2, PGD2, and 6-keto PGF1a in supernatants from RAW264.7 murine macrophage cells exposed for 24 h to vehicle or 1 μg / mL LPS alone (set at 100%) or in combination with increasing concentrations of compounds I-IVb-X (compounds of general structure (I), where T is of general structure (IVb) in the S,R configuration, and for compound X the following applies: L = L19; R1 = H; R2-R2' = L3; R3 = H, denoted KH) (Figure 2D), the nonselective COX inhibitor indomethacin (Figure 2E), or the COX-2 inhibitor celecoxib (Figure 2F). [Figure 2F](Figures 2D-2F) Levels of PGE2, PGD2, and 6-keto PGF1a in supernatants from RAW264.7 murine macrophage cells exposed for 24 h to vehicle or 1 μg / mL LPS alone (set at 100%) or in combination with increasing concentrations of compounds I-IVb-X (compounds of general structure (I), where T is of general structure (IVb) in the S,R configuration, and for compound X the following applies: L = L19; R1 = H; R2-R2' = L3; R3 = H, denoted KH) (Figure 2D), the nonselective COX inhibitor indomethacin (Figure 2E), or the COX-2 inhibitor celecoxib (Figure 2F). [Figure 3A] (Figures 3A-3B) PGE2 (Figure 3A) and PGD2 (Figure 3B) levels in the supernatant of human primary dermal fibroblasts exposed to vehicle, 1 μg / mL LPS, or 1 μg / mL interleukin-1β (IL-1β) for 24 hours normalized to vehicle. [Figure 3B] (Figures 3A-3B) PGE2 (Figure 3A) and PGD2 (Figure 3B) levels in the supernatant of human primary dermal fibroblasts exposed to vehicle, 1 μg / mL LPS, or 1 μg / mL interleukin-1β (IL-1β) for 24 hours normalized to vehicle. [Figure 3C] (Figures 3C-3D) PGE2 and PGD2 levels in supernatants of human primary dermal fibroblasts exposed for 24 hours to 1 μg / mL LPS (Figure 3C) or 1 μg / mL IL-1β (Figure 3D) alone (set as 100%) or in combination with increasing concentrations of compounds I-IVb-X (denoted KH). [Figure 3D] (Figures 3C-3D) PGE2 and PGD2 levels in supernatants of human primary dermal fibroblasts exposed for 24 hours to 1 μg / mL LPS (Figure 3C) or 1 μg / mL IL-1β (Figure 3D) alone (set as 100%) or in combination with increasing concentrations of compounds I-IVb-X (denoted KH). [Figure 4A](FIG. 4A) Western blot analysis of mPGES-1, COX-2, cPGES, mPGES-2, and COX-1 enzymes in RAW264.7 murine macrophage cells exposed to vehicle or 1 μg / mL LPS alone or in combination with increasing concentrations of compounds I-IVb-X (denoted KH) for 24 hours. [Figure 4B] (Figures 4B-4F) Quantification of mPGES-1 (Figure 4B), COX-2 (Figure 4C), mPGES-2 (Figure 4D), cPGES (Figure 4E), and COX-1 (Figure 4F) enzyme levels similar to those in vehicle-treated cells (Figure 4A), using actin as a loading reference and normalized to vehicle-treated cells. [Figure 4C] (Figures 4B-4F) Quantification of mPGES-1 (Figure 4B), COX-2 (Figure 4C), mPGES-2 (Figure 4D), cPGES (Figure 4E), and COX-1 (Figure 4F) enzyme levels similar to those in vehicle-treated cells (Figure 4A), using actin as a loading reference and normalized to vehicle-treated cells. [Figure 4D] (Figures 4B-4F) Quantification of mPGES-1 (Figure 4B), COX-2 (Figure 4C), mPGES-2 (Figure 4D), cPGES (Figure 4E), and COX-1 (Figure 4F) enzyme levels similar to those in vehicle-treated cells (Figure 4A), using actin as a loading reference and normalized to vehicle-treated cells. [Figure 4E] (Figures 4B-4F) Quantification of mPGES-1 (Figure 4B), COX-2 (Figure 4C), mPGES-2 (Figure 4D), cPGES (Figure 4E), and COX-1 (Figure 4F) enzyme levels similar to those in vehicle-treated cells (Figure 4A), using actin as a loading reference and normalized to vehicle-treated cells. [Figure 4F] (Figures 4B-4F) Quantification of mPGES-1 (Figure 4B), COX-2 (Figure 4C), mPGES-2 (Figure 4D), cPGES (Figure 4E), and COX-1 (Figure 4F) enzyme levels similar to those in vehicle-treated cells (Figure 4A), using actin as a loading reference and normalized to vehicle-treated cells. [Figure 5A]qPCR quantification of RNA levels of mPGES-1 (Figure 5A), COX-2 (Figure 5B), cPGES (Figure 5C), mPGES-2 (Figure 5D), and COX-1 (Figure 5E) enzymes in RAW 264.7 murine macrophage cells exposed for 24 hours to vehicle, 1 μg / mL LPS alone, or in combination with increasing concentrations of compounds I-IVb-X (denoted KH). [Figure 5B] qPCR quantification of RNA levels of mPGES-1 (Figure 5A), COX-2 (Figure 5B), cPGES (Figure 5C), mPGES-2 (Figure 5D), and COX-1 (Figure 5E) enzymes in RAW 264.7 murine macrophage cells exposed for 24 hours to vehicle, 1 μg / mL LPS alone, or in combination with increasing concentrations of compounds I-IVb-X (denoted KH). [Figure 5C] qPCR quantification of RNA levels of mPGES-1 (Figure 5A), COX-2 (Figure 5B), cPGES (Figure 5C), mPGES-2 (Figure 5D), and COX-1 (Figure 5E) enzymes in RAW 264.7 murine macrophage cells exposed for 24 hours to vehicle, 1 μg / mL LPS alone, or in combination with increasing concentrations of compounds I-IVb-X (denoted KH). [Figure 5D] qPCR quantification of RNA levels of mPGES-1 (Figure 5A), COX-2 (Figure 5B), cPGES (Figure 5C), mPGES-2 (Figure 5D), and COX-1 (Figure 5E) enzymes in RAW 264.7 murine macrophage cells exposed for 24 hours to vehicle, 1 μg / mL LPS alone, or in combination with increasing concentrations of compounds I-IVb-X (denoted KH). [Figure 5E] qPCR quantification of RNA levels of mPGES-1 (Figure 5A), COX-2 (Figure 5B), cPGES (Figure 5C), mPGES-2 (Figure 5D), and COX-1 (Figure 5E) enzymes in RAW 264.7 murine macrophage cells exposed for 24 hours to vehicle, 1 μg / mL LPS alone, or in combination with increasing concentrations of compounds I-IVb-X (denoted KH). [Figure 6A]mPGES-1 activity was assayed as the conversion of PGH2 to PGE2 by microsomal fractions from RAW264.7 cells treated with 1 μg / mL LPS for 24 hours to increase mPGES-1 expression. Microsomal fractions were exposed to increasing concentrations of the tested compound or 3 μM of known mPGES-1 inhibitors MK866 or PF9184 as positive controls. PGE2 levels were normalized to vehicle-treated microsomal samples (100%). (Figure 6A) Compound I-IVb-X; (Figure 6B) Compound I-IVb-AE; (Figure 6C) Compound I-IVb-A-HCl; (Figure 6D) Compound I-IVb-I. [Figure 6B] mPGES-1 activity was assayed as the conversion of PGH2 to PGE2 by microsomal fractions from RAW264.7 cells treated with 1 μg / mL LPS for 24 hours to increase mPGES-1 expression. Microsomal fractions were exposed to increasing concentrations of the tested compound or 3 μM of known mPGES-1 inhibitors MK866 or PF9184 as positive controls. PGE2 levels were normalized to vehicle-treated microsomal samples (100%). (Figure 6A) Compound I-IVb-X; (Figure 6B) Compound I-IVb-AE; (Figure 6C) Compound I-IVb-A-HCl; (Figure 6D) Compound I-IVb-I. [Figure 6C] mPGES-1 activity was assayed as the conversion of PGH2 to PGE2 by microsomal fractions from RAW264.7 cells treated with 1 μg / mL LPS for 24 hours to increase mPGES-1 expression. Microsomal fractions were exposed to increasing concentrations of the tested compound or 3 μM of known mPGES-1 inhibitors MK866 or PF9184 as positive controls. PGE2 levels were normalized to vehicle-treated microsomal samples (100%). (Figure 6A) Compound I-IVb-X; (Figure 6B) Compound I-IVb-AE; (Figure 6C) Compound I-IVb-A-HCl; (Figure 6D) Compound I-IVb-I. [Figure 6D]mPGES-1 activity was assayed as the conversion of PGH2 to PGE2 by microsomal fractions from RAW264.7 cells treated with 1 μg / mL LPS for 24 hours to increase mPGES-1 expression. Microsomal fractions were exposed to increasing concentrations of the tested compound or 3 μM of known mPGES-1 inhibitors MK866 or PF9184 as positive controls. PGE2 levels were normalized to vehicle-treated microsomal samples (100%). (Figure 6A) Compound I-IVb-X; (Figure 6B) Compound I-IVb-AE; (Figure 6C) Compound I-IVb-A-HCl; (Figure 6D) Compound I-IVb-I. DETAILED DESCRIPTION OF THE INVENTION

[0015] The present invention relates to the discovery that compounds of the present invention, such as amide derivatives of 2-hydroxy-2-methyl-4-(3,5,6-trimethyl-1,4-benzoquinon-2-yl)-butanoic acid, can effectively and selectively reduce mPGES-1-induced PGE2 levels by blocking the expression and enzymatic activity of mPGES-1 without affecting the levels of other prostaglandins. Accordingly, the compounds are useful in the treatment of preventing or suppressing conditions mediated by enhanced mPGES-1 expression or activity and / or (as a result) by increased levels of PGE2.

[0016] In a first aspect, the present invention therefore relates to a method for treating, preventing or suppressing a condition mediated by enhanced mPGES-1 expression or activity, comprising administering to a subject in need thereof an effective amount of one or more compounds of the invention as defined hereinbelow, wherein the effective amount is preferably as defined hereinbelow.

[0017] Alternatively, the present invention relates to a compound of the invention, as defined hereinbelow, for use in treating, preventing or suppressing a condition mediated by enhanced mPGES-1 expression or activity, preferably by administering an effective dose of a compound of the invention, as defined hereinbelow.

[0018] The medical uses described herein are formulated as compounds defined herein for use as medicaments for treating the described condition(s) (e.g., by administering an effective amount of the compound), but may equally be formulated as: i) a method of treating the described condition(s) using compounds defined herein, comprising administering an effective amount of the compound to a subject; ii) a compound defined herein for use in the manufacture of a medicament for treating the described condition(s) (wherein, preferably, the compound is administered in an effective amount); and iii) use of a compound defined herein to treat the described condition(s), preferably by administering an effective amount. All such medical uses are contemplated in the present invention.

[0019] The compounds of the present invention can be characterized by the general structure (I). [ka] where: T is a water-soluble vitamin E derivative having a core chromanyl or chromanylquinone framework and having a carboxylic acid moiety substituted at the 2-position, where T is attached to the nitrogen through the carboxylic acid moiety to form an amide moiety; L is a linker between the amide nitrogen atom and the distal nitrogen atom, comprising 1 to 10 optionally substituted main chain atoms selected from carbon, nitrogen, and oxygen; N * is represented by structure (IIa) or (IIb): [ka] R 1 and R 2 are each independently selected from hydrogen (H), C1-C6 alkyl, or C1-C6 alkenyl, or R 1 and R 2are bonded together, thereby forming a second linker between the amide nitrogen atom and the distal nitrogen atom, or R 1 is attached to a main chain atom of the linker L in a cyclic structure, and / or R 2 is attached to a main chain atom of the linker L in a cyclic structure, R 3 is selected from hydrogen (H), C1-C6 alkyl, or C1-C6 alkenyl, where the alkyl or alkenyl moieties are optionally substituted with one or more halogen atoms, hydroxyl moieties, or (halo)alkoxy moieties, or R 3 is absent when the distal nitrogen atom is part of an imine moiety, or optionally, R 3 is attached to a main chain atom of the linker L in a cyclic structure, R 4 is selected from hydrogen (H) or C1-C6 alkyl, where the alkyl portion is optionally substituted with one or more halogen atoms or (halo)alkoxy moieties; X is an anion, preferably a pharmaceutically acceptable anion.

[0020] The compound according to structure (I) contains at least two nitrogen atoms, the nitrogen atom to which T is attached is also called the "amide nitrogen atom" and N * The nitrogen atom of the moiety is also called the "distal nitrogen atom." * may be an amino moiety if the covalent bond between the distal nitrogen atom and the adjacent main chain atom is a single bond, or may be part of an imine moiety if the covalent bond between the distal nitrogen atom and the adjacent main chain atom is a double bond. The distal nitrogen atom may be neutral or cationic. N * When N is neutral, compounds according to the present invention may also be referred to by the general structure (Ia): * When is cationic, compounds according to the present invention may also be referred to by the general structure (Ib): [ka]

[0021] T is a water-soluble vitamin E derivative in which the chromanyl or chromanylquinone framework is substituted at the 2-position with a carboxylic acid. The 2-carboxy variant of vitamin E is also known as Trolox™ (6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid). Water-soluble vitamin E derivatives are known in the art and include 6-hydroxy-2,5,7,8-tetraalkyl-2-carboxy-chromanyl (general structure (IIIa), also referred to as the "closed form") and its oxidized form 2-(3-hydroxy-3-alkyl-4-oxobutyl)-3,5,6-trialkylcyclohexa-2,5-diene-1,4-dione (general structure (IIIb), also referred to as the "open form"). The inventors have found that the open form according to general structure (IIIb) is found as a metabolite of the closed form according to general structure (IIIa) when the latter is administered. Compounds I-IVa-X (compounds of general structure (I) where T is of general structure (IVa) in the S,R configuration, and for compound X the following applies: L=L 19 ;R 1 =H;R 2 -R 2’ =L 3 ;R 3 After 24 hours of treatment of the P4 cell line with α-hydroxybenzoates (=H), approximately 48% (±10%) of the closed compounds were converted to the open form. Approximately 15% (±3%) was converted when incubated in medium alone for the same period. Such conversions have also been disclosed in Beyrath et al., DOI:10.1038 / s41598-018-24900-3 and Koene et al., DOI:10.1186 / s13023-017-0715-0. A preferred chromanyl framework is the 6-hydroxychroman framework. A preferred chromanylquinone framework is the 2-(3-hydroxyalkyl)-cyclohexa-2,5-diene-1,4-dione, where preferably the 3-hydroxyalkyl is 3-hydroxybutyl, more preferably 4-oxo-3-hydroxybutyl, contained in the general structure (IIIb).

[0022] The closed 2-position is the position on the oxane ring that bears the carboxylic acid (or amide in the case of the molecules of the present invention) and R 7 The R7 moiety is the 2-position according to naming conventions known in the art, such as the IUPAC nomenclature. In the open form, the same carbon atom is intended to be the 2-position, thereby referring to the carbon atom bearing the hydroxy moiety and the R7 moiety shown in the general structure (IIIb) below. This position can also be viewed as the 3-position of the alkyl moiety substituted on the quinone. Thus, T is a water-soluble vitamin E derivative in which the chromanyl framework is substituted with a carboxylic acid at the 2-position, or the chromanylquinone framework is substituted with a carboxylic acid at the 3-position of the 3-hydroxyalkyl moiety, which is then substituted on the 2'-position of the cyclohexa-2,5-diene-1,4-dione. [ka] where R 7 Each occurrence of R is independently selected from halogen, alkyl, amino, nitro, or -NHCO-alkyl. 7 Preferred choices for R are halogen and alkyl, most preferably alkyl. 7 In the context of R, halogen is preferably fluorine or chlorine, most preferably chlorine. In the context of alkyl, it is preferably a C1-C6 alkyl moiety, preferably a C1-C6 alkyl moiety, most preferably methyl. 7 In the context of R, amino is preferably —NH. 7 In the context of -NHCO-alkyl is preferably -NHCOMe. Preferably, each R 7 are the same substituent. Most preferably, R 7 is methyl. In a preferred embodiment, T is represented by structure (IVa) or (IVb). In other words, structure (IVa) is a preferred embodiment of structure (IIIa), and structure (IVb) is a preferred embodiment of structure (IIIb). [ka]

[0023] In a preferred embodiment, T is represented by structure IIIa or IIIb, preferably structure IVa or IVb. In a more preferred embodiment, T is represented by structure (IIIa), preferably structure (IVa). In an even more preferred embodiment, T is represented by structure (IIIb), preferably structure (IVb).

[0024] The compounds specified by general structure (I) contain at least one chiral carbon atom (stereocenter), i.e., the atom at position 2 of T (e.g., the oxane ring of structure (IIIa) or the butanoic acid moiety of structure (IIIa)). Both compounds having the S-configuration and the R-configuration of the carbon atom at position 2 are encompassed by the present invention, as are mixtures of different stereoisomers. Such mixtures may have an enantiomeric excess of one configuration or may be racemic. Whenever one or more additional stereocenters are present in a compound of the present invention, e.g., in the linker L, they may each exist individually as the S-configuration, the R-configuration, or a mixture of both configurations. Such mixtures may have an enantiomeric excess of one configuration or may be racemic. When additional stereocenters are present, all diastereomers of the compounds of general structure (I), in each possible ratio, are encompassed by the present invention.

[0025] In a preferred embodiment, the solubility of the compounds of the present invention in water is expressed as log(P ow ) and is 2.0 to 5.0, preferably 2.5 to 4.5, and more preferably 3.0 to 4.0. ow ) is the logarithm of the partition coefficient between 1-octanol and water and is a well-known measure of water solubility. ow A compound having L, R values ​​ideally balances sufficient water solubility in aqueous solution or suspension preparations with sufficient lipophilicity to ensure efficient transport of the compound across cell membranes. Those skilled in the art will appreciate the L, R values ​​as defined herein. 1 , R 2 , R 3 , R 4What combination of X is 3 to 4 log(P ow ) values ​​of the compound. ow Suitable tests for determining the log(P) value of a compound are well known to those skilled in the art and include, but are not limited to, the shake flask method, ITIES, the droplet method, or the use of HPLC. ow ) can also be predicted using QSPR algorithms.

[0026] R 1 and R 2 are each independently selected from hydrogen (H), C1-C6 alkyl, or C1-C6 alkenyl, or R 1 and R 2 One or both of R are embedded in a cyclic structure as described herein below. 1 is H or C1-C2 alkyl, or R 1 and R 2 are bonded together, thereby forming a second linker between the amide nitrogen atom and the distal nitrogen atom, or R 1 is attached to a main chain atom of the linker L in a cyclic structure, and more preferably, R 1 is H or C1-C2 alkyl, and even more preferably, R 1 is H or methyl (Me), and most preferably R 1 is H. Preferably, R 2 is H or C1-C2 alkyl, or R 1 and R 2 are bonded together, thereby forming a second linker between the amide nitrogen atom and the distal nitrogen atom, or R 2 is attached to a main chain atom of the linker L in a cyclic structure, and more preferably, R 2 is H, C1-C2 alkyl, or is attached to the main chain atom of the linker L in a cyclic structure, and even more preferably, R 2 is H, methyl (Me), or is attached to a main chain atom of the linker L in a ring structure. 2 is H, methyl (Me), and preferably R2 is H. In a particularly preferred embodiment, R 2 is attached to a main chain atom of the linker L in a cyclic structure, preferably a saturated cyclic structure, most preferably a piperidine ring, as further defined below.

[0027] In one embodiment, the amide nitrogen atom is connected to the distal nitrogen atom via a second linker. This second linker is connected to the R 1 and R on the distal nitrogen atom 2 and 2 are bonded together. Thus, the amide nitrogen atom, the distal nitrogen atom, the first linker, and the second linker together form a cyclic structure, preferably a 4- to 10-membered cyclic structure, more preferably a 5- to 8-membered cyclic structure, and most preferably a 6-membered cyclic structure. In a preferred embodiment, the second linker is a -CH2-CH2- or a -CH2-CH2-CH2- bridge, most preferably a -CH2-CH2- bridge, and two or three, preferably two, carbon atoms are present between the amide nitrogen atom and the distal nitrogen atom.

[0028] In another embodiment, the amide nitrogen atom is connected to a main chain atom of the linker via a second linker, thereby forming a cyclic structure, preferably a 4- to 10-membered cyclic structure, more preferably a 5- to 8-membered cyclic structure, and most preferably a 6-membered cyclic structure. The main chain atom of the linker to which the nitrogen atom is connected is, in this respect, a substituent R 1’ which has R 1 Thus, the amide nitrogen atom and R 1’ a portion of the first linker disposed between the atom having 1’The main chain atom having the formula (I) and the second linker together form a cyclic structure. In this embodiment, the distal nitrogen atom is not included in the cyclic structure, but instead is included only in a portion of the main chain of the linker. In a preferred embodiment, the connection between the amide nitrogen atom and the main chain atom of the linker is a -CH2-CH2- or -CH2-CH2-CH2- bridge, most preferably a -CH2-CH2- bridge, and two or three, preferably two, carbon atoms are present between the amide nitrogen atom and the main chain atom of the linker. Most preferably, the cyclic structure containing the amide nitrogen atom is a fully saturated ring, preferably selected from a piperidine ring, a pyrrolidine ring, a piperazine ring, an imidazolidine ring, a pyrazolidine ring, and an azepane ring, more preferably a piperazine ring, a piperidine ring, or a pyrrolidine ring, most preferably a piperidine ring.

[0029] In another embodiment, the distal nitrogen atom is connected to a main chain atom of the linker via a second linker, thereby forming a cyclic structure, preferably a 4- to 10-membered cyclic structure, more preferably a 5- to 8-membered cyclic structure, and most preferably a 6-membered cyclic structure. The main chain atom of the linker to which the nitrogen atom is connected is, in this respect, a substituent R 2’ which has R at the distal nitrogen atom 2 Thus, the distal nitrogen atom and the R 2’ a portion of the first linker disposed between the atom having 2’The main chain atom having the formula (I) and the second linker together form a cyclic structure. In this embodiment, the amide nitrogen atom is not included in this cyclic structure, but instead is included only as part of the main chain of the linker. In a preferred embodiment, the connection between this distal nitrogen atom and the main chain atom of the linker is a -CH2-CH2- or -CH2-CH2-CH2- bridge, most preferably a -CH2-CH2- bridge, and two or three, preferably two, carbon atoms are present between the distal nitrogen atom and the main chain atom of the linker. Most preferably, the cyclic structure containing the distal nitrogen atom is a fully saturated ring, preferably selected from a piperidine ring, a pyrrolidine ring, a piperazine ring, an imidazolidine ring, a pyrazolidine ring, and an azepane ring, more preferably a piperidine ring or a pyrrolidine ring, most preferably a piperidine ring. The R of the amide nitrogen atom 1 and linker R 1’ Between the substituents and the distal nitrogen atom R 2 and linker R 2’ It is also possible for there to be a connection between the substituents.

[0030] In another embodiment, the distal nitrogen atom is connected to a linker backbone atom via a second and third linker, thereby forming a bicyclic structure, preferably a 6- to 12-membered ring structure, more preferably a 6- to 9-membered ring structure such as a bicyclooctane-like structure, most preferably a [2.2.2]bicyclooctane-like structure. The linker backbone atom to which the nitrogen atom is connected is, in this respect, a substituent R 2’ and R 3’ and these have R 2 and R 3 Thus, the distal nitrogen atom, the distal nitrogen atom and R 2’ a portion of the first linker disposed between the atom having 2’and the second linker together form one ring of the bicyclic structure, and the portion of the first linker located between the distal nitrogen atom and the atom bearing R3' and the third linker form the second ring of the bicyclic structure. In this embodiment, the amide nitrogen atom is not included in the bicyclic structure, but instead only a portion of the linker's main chain is included. In a preferred embodiment, the connection between the distal nitrogen atom and the linker's main chain atom is a -CH2-, -CH2-CH2-, or -CH2-CH2-CH2- bridge, most preferably a -CH2-CH2- bridge, and two or three, preferably two, carbon atoms are present between the distal nitrogen atom and the linker's main chain atom. Most preferably, the cyclic structure containing the distal nitrogen atom is a fully saturated structure.

[0031] R 2 Of the possibilities described above for R, it is most preferred that the distal nitrogen atom is connected to the backbone atom of the linker via a second linker, where R 2 is R as further defined herein above. 2’ is bonded to.

[0032] If the distal nitrogen atom is part of an imine moiety, the linker L contains at least one double bond located between the distal nitrogen atom and an adjacent main chain atom of the linker, or R 2 is the distance between the distal nitrogen atom and R 2 (i.e., R 2 = C1-C6 alkenyl). 3 is absent. When the distal nitrogen atom is part of an imine moiety and a double bond is positioned between the distal nitrogen atom and the adjacent main chain atom of the linker, the compound of the invention can be represented by structure (Ic). [ka]

[0033] When the distal nitrogen atom is part of an imine moiety and is in structure (Ic), the distal nitrogen atom can be either cationic or neutral.3 N defined by structures (IIa) and (IIb) in which * The same options apply to (Id). When the distal nitrogen atom is neutral and part of an imine moiety, and a double bond is positioned between the distal nitrogen atom and the adjacent main chain atom of the linker, compounds according to the invention can also be referred to by general structure (Id). When the distal nitrogen atom is cationic and part of an imine moiety, and a double bond is positioned between the distal nitrogen atom and the adjacent main chain atom of the linker, compounds according to the invention can also be referred to by general structure (Ie). [ka]

[0034] In the context of this invention, the distal nitrogen being part of an imine moiety includes when the distal nitrogen atom is part of a heteroaromatic ring, in particular a pyrrole ring, a pyridine ring or an imidazole ring, in which case the double bond is not connected to a linker or R 2 In any of the above, a group R is formally present between the distal nitrogen atom and the adjacent carbon atom. Preferred moieties containing an imine moiety include guanidine, amidine, and pyridine. In guanidine and amidine, one of the nitrogen atoms is substituted and forms a connection with the amide nitrogen atom via a linker L. In pyridine, one of the carbon atoms is substituted. When the distal nitrogen atom is part of an amine moiety, it is connected to the linker R via two single bonds. 2 is connected to R 3 The distal nitrogen atom is part of an amine moiety, i.e., R 1 , R 2 , R 3 and optionally R 4 It is preferred that each of the groups has 3 or 4 single bonds.

[0035] R 3 If there is R 3is selected from hydrogen (H), C1-C6 alkyl or C1-C6 alkenyl, where the alkyl or alkenyl moiety is optionally substituted with one or more halogen atoms, hydroxyl groups or (halo)alkoxy moieties, preferably R 3 is H, C1-C6 alkyl, and more preferably, R 3 is H or C1-C4 alkyl, and even more preferably, R 3 is H or C1-C2 alkyl, where the alkyl moiety may be substituted with one or more halogen atoms, hydroxyl groups, or (halo)alkoxy moieties. Halogen atoms include fluorine (F), chlorine (Cl), bromine (Br), iodine (I), and astatine (At), preferably, the halogen atom is fluorine (F). Preferred alkoxy moieties include methoxy and ethoxy. In a haloalkoxy moiety, at least one hydrogen atom of the alkoxy moiety is replaced with a halogen atom, preferably F. Preferred substituents on the alkyl moiety are halogen atoms and alkoxy moieties. R 3 Suitable moieties for include, preferably are limited to, H, methyl (Me), trifluoromethyl (-CF), ethyl (Et), isopropyl (iPr), cyclopropyl (-cPr), methylenecyclopropyl (-CHcPr), n-propyl (n-Pr), 2,2,2-trifluoroethyl (-CHCF), 2-hydroxy-ethyl (-CHCHOH), and methoxymethyl (-CHOCH), more preferably 3 is H or methyl (Me), and most preferably R 3 is H. Or, R 3 is preferably C1-C4 alkyl, where the alkyl moiety is optionally substituted with one or more halogen atoms or (halo)alkoxy moieties, more preferably R 3 is C1-C2 alkyl, where the alkyl portion is optionally substituted with one or more halogen atoms or (halo)alkoxy moieties.

[0036] When the distal nitrogen atom is in cationic form, the distal nitrogen atom is formally generated by protonation or alkylation, preferably protonation or methylation, of the trivalent nitrogen atom. The trivalent nitrogen atom is preferably a primary, secondary, or tertiary amine moiety or a primary or secondary imine moiety. The counterion (X) of the cationic distal nitrogen atom is a negatively charged ion, preferably a monovalent negatively charged ion, more preferably an anion as shown hereinbelow. The synthesis of the compounds of the present invention does not necessarily involve protonation or alkylation of the amine or imine nitrogen atom. The cationic distal nitrogen atom can also be formed via different pathways. Thus, the cationic distal nitrogen atom is merely "formally" generated by protonation or alkylation of the amine or imine nitrogen atom.

[0037] R 4 is a substituent at the cationic distal nitrogen atom resulting from the formal protonation or alkylation of the amine or imine moiety. Therefore, the compound of this embodiment, given the presence of the cationic nitrogen atom and X, is a salt, preferably a pharmaceutically acceptable salt. A pharmaceutically acceptable salt is a salt suitable for administration to humans and / or animals as a drug or pharmaceutical. Pharmaceutically acceptable salts of the amine or imine moiety of the compounds of the present invention are known to those skilled in the art and are generated by formal treatment of the compound with an acid (protonating agent) or an alkylating agent. Suitable acids include organic or inorganic acids. Examples of inorganic acids include, but are not limited to, hydrochloric acid (HCl), hydrobromic acid (HBr), hydroiodic acid (HI), sulfuric acid (HSO), nitric acid (HNO), trifluoroacetic acid (TFAH or CFCOH), and phosphoric acid (HPO). Examples of organic acids include, but are not limited to, formic acid, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, sulfonic acid, and salicylic acid. When the acids exemplified herein are used to formulate salts, R 4is hydrogen, and the type of acid determines the counterion X. Alternatively, salts can be formed by formal treatment with an alkylating agent. Suitable alkylating agents include, but are not limited to, C1-C6 alkyl halides (methyl iodide, ethyl iodide, propyl iodide, butyl chloride, butyl fluoride, butyl bromide, etc.), dimethyl sulfide, dimethyl carbonate, methyl triflate, methyl fluorosulfonate, methyl chlorosulfate, methyl methanesulfonate, and methyl benzenesulfonate. Salts can be prepared by actual treatment of the non-salt compound with an acid or alkylating agent as indicated above, or via other methods known in the art and / or further exemplified below.

[0038] R 4 is selected from hydrogen (H) or C1-C6 alkyl, where the alkyl portion may be optionally substituted with one or more halogen atoms or (halo)alkoxy moieties, preferably R 4 is H or C1-C4 alkyl, where the alkyl moiety may be optionally substituted with one or more halogen atoms or (halo)alkoxy moieties, more preferably R 4 is H or C1-C2 alkyl, where the alkyl moiety may be substituted with one or more halogen atoms or (halo)alkoxy moieties. Halogen atoms include fluorine (F), chlorine (Cl), bromine (Br), iodine (I), and astatine (At), preferably, the halogen atom is fluorine (F). Preferred alkoxy moieties include methoxy and ethoxy. In a haloalkoxy moiety, at least one hydrogen atom of the alkoxy moiety is replaced with a halogen atom, preferably F. R 4 Suitable moieties for include, and preferably are limited to, H, methyl (Me), trifluoromethyl (-CF), ethyl (Et), isopropyl (iPr), cyclopropyl (-cPr), methylenecyclopropyl (-CHcPr), n-propyl (n-Pr), 2,2,2-trifluoroethyl (-CHCF), methoxymethyl (-CHOCH). Even more preferably, R 4is H or methyl (Me), and most preferably R 4 is H.

[0039] X can be any anion, preferably a physiologically or pharmaceutically acceptable anion, more preferably a monovalent anion. X is preferably selected from F, Cl, Br, I, HSO, NO, TFA (CFCO), formate, acetate, propionate, glycolate, pyruvate, oxalate, maleate, malonate, succinate, fumarate, tartrate, citrate, benzoate, cinnamate, mandelate, sulfonate, and salicylate. X is preferably Cl, I, TFA, or formate, more preferably Cl, I, TFA, or formate, even more preferably X is Cl or formate, and most preferably X is Cl. When the cationic nitrogen atom results from formal protonation, this protonation is preferably achieved using hydrogen chloride (HCl), trifluoroacetic acid (TFAH or CFCOH), or formic acid (HCOOH), more preferably using HCl or formic acid. Formal methylation is preferably accomplished using methyl iodide (MeI). Thus, in a preferred embodiment, X=I - In the case of R 4 = Me and X = Cl - , T.F.A. - or for formate, R 4 =H.

[0040] Suitable linkers L connecting the amide nitrogen atom to the distal nitrogen atom are preferably linkers containing 1 to 10 optionally substituted main chain atoms, more preferably 1 to 8 optionally substituted main chain atoms. Thus, L can contain 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 optionally substituted main chain atoms. Preferably, linker L contains 1 to 10 optionally substituted main chain atoms selected from carbon, nitrogen, and oxygen, where the main chain atoms are the atoms that make up the shortest chain between the amide nitrogen atom and the distal nitrogen atom. The main chain can be a linear structure, but (part of) the main chain may be part of a cyclic structure. When the main chain is part of a cyclic structure, the main chain is defined as the shortest chain between the amide nitrogen atom and the distal nitrogen atom. In one embodiment, one of the main chain atoms is a substituent R 5 and one of the main chain atoms is a substituent R 5’ and preferably two different main chain atoms are selected from the group consisting of substituents R 5 and R 5’ where R 5 and R 5’ are linked to form a cyclic structure, preferably a 4- to 10-membered cyclic structure, more preferably a 5- to 8-membered cyclic structure, and most preferably a 6-membered cyclic structure. In this embodiment, the amide nitrogen atom and the distal nitrogen atom are not included in the cyclic structure, but instead are included only as part of the backbone of the linker. In a preferred embodiment, R 5 and R 5’ The connection between the main chain atom(s) of the linker bearing the substituent is -(CH2) n -bridge, where n=1 to 6, preferably a -CH2-CH2- or -CH2-CH2-CH2- bridge, where 1 to 6, preferably 2 or 3 carbon atoms are present between the substituted backbone atom(s) of the linker.

[0041] In a preferred embodiment, the main chain atoms are selected from carbon, nitrogen and oxygen, preferably from carbon and nitrogen. Such a main chain according to this preferred embodiment is C n~m N mwhere n represents the total number of atoms in the main chain and m represents the number of nitrogen atoms in the main chain. n and m are each a non-negative integer. Suitable linkers have n=1-10 and m=0-4, preferably n=2-7 and m=0-3, more preferably n=4-7 and m=0-2. Particularly preferred linkers are C n~m N m where n=2 and m=0 (C2), n=5 and m=1 (CN), n=3 and m=0 (C3), n=4 and m=1 (CN), n=7 and m=2 (CN2), n=4 and m=0 (C4), n=6 and m=1 (CN), or n=5 and m=0 (C5). Most preferably, all main chain atoms are carbon atoms (m=0).

[0042] To satisfy these valence requirements, the carbon and nitrogen backbone atoms of the linker may have hydrogen atoms, may be substituted, or double or triple bonds may exist between adjacent backbone atoms, as would be understood by one skilled in the art. In the context of the present invention, hydrogen is not considered a substituent. Whenever an oxygen atom is present as a backbone atom in a linker, one skilled in the art understands that the oxygen backbone atom does not have a hydrogen atom, a substituent, or a double or triple bond. A triple bond may also exist between two carbon atoms in the backbone. The backbone atoms, together with the hydrogen atoms and / or substituents, constitute the linker. In the context of the present invention, "optionally substituted" is used to indicate that a (backbone) atom may have one or more substituents, or may have no substituents, and sufficient hydrogen atoms may be present instead to satisfy the valence requirements of this (backbone) atom.

[0043] Suitable substituents include halogen, NH2, NHR 6 , N(R 6 )2, NHNH2, N3, NHC(=O)R 6 , NHC(=O)NHR 6 , NHC(=O)NH2, NHC(=O)OR 6 , OH, OR 6 , OC(=O)R6 , R 6 (e.g., alkyl, cycloalkyl), aralkyl, alkenyl, alkynyl, aryl, heteroaryl, OC(=O)OR 6 , OC(=O)NHR 6 , O(SO2)R 6 , O(SO2)OH, O(PO2)OH, SH, SR 6 , C(=O)R 6 , alkyl-NH2, alkyl-OH, alkyl-SH, C(=O)CF3, C(=O)OR 6 , C(=O)OH, C(=O)H, C(=O)OR 6 , C(=O)NH2, C(=O)NMe2, C(=O)N(R 6 )2, C(=S)NH2C(=S)SH, CN, NC, CNO, ONC, OCN, SCN, SNC, CNS, S(=O)R 6 , S(=O)2R 6 , S(=O)2(OH), P(=O)(OH)2 or P(=O)(OH)(OR 6 Atoms with two or more remaining valences, such as carbon backbone atoms, include, but are not limited to, oxo (=O), imino (=NH or =NR 6 ), thioxo (=S), alkylidene (=CH2 or =CHR 6 or =C(R 6 ) 2) and the like. 6 are independently alkyl moieties, preferably C1 to C6 alkyl moieties, more preferably C1 to C2 alkyl moieties. 6Within this range, one or more CH moieties may each independently be replaced by one of O, S, or NH, and / or one or more CH moieties may be replaced by N. Additionally, two substituents on the same or different atoms may be joined to form a cyclic structure. When two substituents on a single main chain atom join to form a cyclic structure, this cyclic structure may be considered to be connected to the main chain via a spiro junction. When two substituents on different main chain atoms join to form a cyclic structure, part of this cyclic structure is (a part of) the main chain, and the main chain is considered to be the shortest chain of atoms between the amide nitrogen atom and the distal nitrogen atom. The cyclic structure thus formed may be all carbon or may contain 0-3 heteroatoms (e.g., N, O, S, and / or P) and may contain 0-3 double bonds. All atoms in these cyclic structures may be optionally substituted. Examples of suitable cyclic structures are optionally substituted cycloalkyl, optionally substituted cycloheteroalkyl, optionally substituted aryl, or optionally substituted heteroaryl. As further shown below, the cyclic structure can be formed by combining a substituent on one of the main chain atoms with the R of the amide nitrogen atom. 1 and or R of the distal nitrogen atom 2 It can also be formed by combining with

[0044] In the context of the present invention, the term "alkyl" refers to saturated aliphatic groups, including straight-chain, branched-chain, cyclic groups, and combinations thereof, having a specified number of carbon atoms, preferably up to 12 carbon atoms if no number is specified. A "straight-chain alkyl" or "linear alkyl" group refers to an alkyl group that is neither cyclic nor branched, and is commonly designated an "n-alkyl" group. One subset of alkyl groups is C1-C6 alkyl, which includes groups such as methyl, ethyl, n-propyl, isopropyl, butyl, n-butyl, isobutyl, sec-butyl, t-butyl, pentyl, n-pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and any other alkyl containing 1 to 6 carbon atoms, where the C1-C6 alkyl group may be attached through any valence of the C1-C6 alkyl group.

[0045] In one embodiment, the main chain atoms are R 6 , carboxy, oxo, and primary amino, or the main chain atoms are optionally substituted by one or more substituents selected from the group consisting of R 1 may be bonded to form a 4- to 10-membered ring structure, and / or the main chain atoms may be bonded to R 2 may be bonded to form a 4- to 10-membered ring structure, or two main chain atoms may be bonded to form a ring structure, where R 6 is as defined above, preferably R 6 is a C1-C6 alkyl, more preferably a C1-C2 alkyl. Preferred substituents on main chain atoms are alkyl, such as methyl (Me or -CH3), carboxyl (-C(=O)OH), oxo (=O), and primary amino (-NH2).

[0046] Preferred linkers L are defined herein below as L 1 ~L 28 It has been identified as: L 1 ~L 26 is more preferred. [Table 1] TIFF0007754623000014.tif226149 TIFF0007754623000015.tif124149 where L 1 ~L 28 The dashed bond on the left side of each structure in indicates the bond between the linker and the amide nitrogen atom, and L 1 ~L 28 The dashed bond on the right side of each structure in preferably indicates the bond between the linker and the distal nitrogen atom.

[0047] R 1’ Each occurrence of represents a connection through a second linker between the linker and the amide nitrogen atom, where R 1’ connects to R via a second linker 1 and R, thereby forming a 4- to 10-membered ring structure, preferably a 5- to 8-membered ring structure, and most preferably a 6-membered ring structure, which is formed by combining the amide nitrogen atom, 1 to 4 main chain atoms of the linker, and R 1 and R 1’ It is constructed from 1 to 4 atoms that make up the bridges connected by R. 2’ Each occurrence of represents a connection by a second linker between the linker and the cationic nitrogen atom, where R 2’ connects to R via a second linker 2 and R, thereby forming a 4- to 10-membered ring structure, preferably a 5- to 8-membered ring structure, and most preferably a 6-membered ring structure, which is formed by combining the cationic nitrogen atom, 1 to 4 main chain atoms of the linker, and R 2 and R 2’ It is constructed from 1 to 4 atoms that make up the bridges connected by R. 5 and R 5’ Each occurrence of R 5 and one main chain atom of the linker having R 5’ represents a connection by a second linker between another main chain atom of a linker having 5’ connects to R via a second linker 5and thereby form a 4- to 10-membered ring structure, preferably a 5- to 8-membered ring structure, and most preferably a 6-membered ring structure, which is formed by bonding 2 to 5 main chain atoms of the linker and R 5 and R 5’ The linker L is constructed from 1 to 5 atoms that form a bridge. 10 , L 22 , L 23 , L 24 and L 25 In R 1’ is connected to R via a second linker, preferably a -CH2-CH2- or a -CH2-CH2-CH2- bridge, more preferably a -CH2-CH2- bridge. 1 Thus, R 1’ and R 1 is attached via a -CH2-CH2- bridge, 10 In compounds comprising: the amide nitrogen atom is embedded in a six-membered ring structure, which is bounded by the amide nitrogen atom, two carbon atoms and one nitrogen atom of the backbone of the linker, and R 1 and R 1’ The amide nitrogen atom and the linker L 10 The -CH2-CH2- bridge between the central nitrogen atom of the main chain of L 1 Similarly, the linker L 18 , L 19 and L 21 In R 2’ is connected to R via a second linker, preferably a -CH2-CH2- or a -CH2-CH2-CH2- bridge, more preferably a -CH2-CH2-CH2- bridge. 2 Similarly, the linker L 20 and L 26 In R 5’ is connected to R via a second linker, preferably a -CH2-CH2- or a -CH2-CH2-CH2- bridge, more preferably a -CH2-CH2- bridge. 5 is bonded to.

[0048] Linker L 26contains a disubstituted cycloalkyl moiety, preferably a disubstituted cyclohexyl moiety, and therefore can occur in either the cis or trans form, preferably the trans form.

[0049] Linker L 27 contains a bicyclic cycloalkyl moiety, preferably a bicyclic cyclooctyl moiety. 27 If L, R 2 and R 3 together contain 7, 8, 9, 10, 11 or 12 carbon atoms. Most preferably, L27 is comprised in an azabicyclooctane, such as azabicyclo[2.2.2]octane.

[0050] Linker L 11 , L 12 , L 13 , L 14 , L 15 , L 18 (R 2 -R 2’ is not -CH(O)-), L 19 (R 2 -R 2’ (unless -CH2-) L 20 (R 5 -R 5’ (unless -CH2-) L 21 (R 2 -R 2’ (unless -CH2-CH2-) L 22 (R 1 -R 1’ (unless -CH2-CH2-) L 23 (R 1 -R 1’ (unless -CH2-CH2-) L 24 (R 1 -R 1’ is not -CH2-) and L 25 (R 1 -R 1’is not -CH2-) includes additional stereocenters. The above stereocenters, when shown in the structures of these linkers, are meant to be exemplary and not limiting. As further indicated above, each stereocenter present in the compounds of the present invention may exist independently as either the S or R stereoisomeric form, or as a mixture of both isomers in any ratio. In view of the stereocenter already present at the 2-position of T, compounds bearing these linkers may be (R,R), (S,R), (R,S), or (S,S). Throughout this description, the first designator of configuration (R or S) refers to the 2-position of T, and the second designator of configuration defines the configuration of the additional stereocenter that may be present in the compounds according to the present invention. L 23 In the above table, the methyl group designated as "Me" is preferably (S).

[0051] In a preferred embodiment, the linker is, among others, L 5 , L 8 , L 11 , L 12 , L 16 , L 17 , L 19 , L 21 , L 26 , L 27 and L 28 Particularly preferred linkers are 5 , L 8 , L 11 , L 12 , L 16 , L 17 , L 19 , L 21 and L 26 An even more preferred linker is L 11 , L 16 , L 19 and L 26 and the most preferred linker is L 19 L 19 is R 2 -R 2’ =L 1 or L 3 and most preferably in combination with R 2 -R 2’=L 3 Combined with L 21 is R 2 -R 2’ =L 1 or L 3 and most preferably in combination with R 2 -R 2’ =L 1 Combined with L 26 is R 5 -R 5’ =L 1 or L 3 and more preferably, R 5 -R 5’ =L 1 and most preferably, the cyclohexyl is trans-1,4-disubstituted. 19 and R 2 -R 2’ =L 3 and R 3 =H, Me, Et, iPr, CH2OCH3 or CH2CF3, more preferably R 3 = Me, Et, iPr or CH2CF3, most preferably R 3 The combination with =H is particularly preferred.

[0052] N * is according to structure (IIa), it is preferred that the linker L contains 1 to 5 optionally substituted main chain atoms and / or that the linker L contains at least one main chain atom other than carbon. * is according to structure (IIa), it is especially preferred that the distal nitrogen atom is connected to a backbone atom of the linker via a second linker, where R 2 is R 2’ and more preferably the ring structure thus formed is a piperidine ring, a pyrrolidine ring, an imidazolidine ring, a pyrazolidine ring or an azepane ring, most preferably a piperidine ring, and / or at least one of the main chain atoms is substituted with a carboxylic acid moiety. * is according to structure (IIa), L is L2 , L 4 ~L 21 , L 23 , L 25 , L 26 , L 27 and L 28 and L is preferably any one of L 2 , L 4 ~L 21 , L 23 , L 25 and L 26 It is particularly preferred that the aryl group is one of the following: 5 , L 8 , L 11 , L 12 , L 16 , L 17 , L 19 , L 21 and L 26 It is one of the N * is according to structure (IIb), then R 4 is H or Me, more preferably R 4 is H and X is Cl, I, TFA or formic acid, even more preferably X is Cl or formic acid, most preferably X is Cl. * is according to structure (IIb), it is preferred that the linker L contains 3 to 10 main chain atoms or 2 main chain atoms, one of which is connected to the distal nitrogen atom via a second linker. * is according to structure (IIb), L is L 2 ~L 28 One of the following: L 2 ~L 26 More preferably, any one of L 5 , L 8 , L 11 , L 12 , L 16 , L 17 , L 19 , L 21 and L 26 It is particularly preferred that the

[0053] In one embodiment, the linker L is L 1 and R 1 and R 2 is a ring structure containing a second linker L 1 and the linker L is linked together via L, thereby forming a 6-membered piperazine ring comprising a total of 4 carbon atoms from the two linkers, the amide nitrogen atom and the distal nitrogen atom. 19 and R 2 and R 2 ' is a linker in the cyclic structure to the second linker L 3 are joined together via the linker and the distal nitrogen atom, thereby forming a six-membered piperidine ring containing a total of five carbon atoms from the linker and the distal nitrogen atom.

[0054] In a preferred embodiment, the compound is represented by the general structure (I), wherein: L is a linker between the amide nitrogen atom and the distal nitrogen atom; N * is according to structure (IIa), T is according to structure (IIa) or (IIb), where R 7 is a C1-C6 alkyl moiety, R 1 is selected from hydrogen (H), C1-C6 alkyl or C1-C6 alkenyl, or R 1 is attached to a main chain atom of the linker L in a cyclic structure, R 2 is bonded to a main chain atom of the linker L to form a cyclic structure selected from a piperidine ring, a pyrrolidine ring, an imidazolidine ring, a pyrazolidine ring, or an azepane ring; R 3 is selected from hydrogen (H), C1-C6 alkyl, or C1-C6 alkenyl, where the alkyl or alkenyl moieties are optionally substituted with one or more halogen atoms, hydroxyl moieties, or (halo)alkoxy moieties, or R 3 is absent when the distal nitrogen atom is part of an imine moiety.

[0055] In an alternatively preferred embodiment, the compounds of the present invention are represented by the general structure (I), wherein: L is a linker between the amide nitrogen atom and the distal nitrogen atom, and contains 3 to 10 main chain atoms or two main chain atoms, one of which is connected to the distal nitrogen atom through a second linker; N * is according to structure (IIb), T is according to structure (IIIa) or (IIIb), where R 7 is a C1-C6 alkyl moiety, R 1 and R 2 are each independently selected from hydrogen (H), C1-C6 alkyl, or C1-C6 alkenyl, or R 1 and R 2 are bonded together, thereby forming a second linker between the amide nitrogen atom and the distal nitrogen atom, or R 1 is attached to a main chain atom of the linker L in a cyclic structure, and / or R 2 is attached to a main chain atom of the linker L in a cyclic structure, R 3 is selected from hydrogen (H), C1-C6 alkyl, or C1-C6 alkenyl, where the alkyl or alkenyl moieties are optionally substituted with one or more halogen atoms, hydroxyl moieties, or (halo)alkoxy moieties, or R 3 is absent when the distal nitrogen atom is part of an imine moiety, R 4 is selected from hydrogen (H) or C1-C6 alkyl, where the alkyl portion is optionally substituted with one or more halogen atoms or (halo)alkoxy moieties; X is an anion, preferably a pharmaceutically acceptable anion.

[0056] Particularly preferred compounds in the context of the present invention are identified herein below by structures (VI) to (IX). Thus, in a preferred embodiment, the compound of general structure (I) is represented by structure (VI). [ka] where R 2 is attached to the main chain atom via a second linker to form a ring structure, thus forming N * is -NR 3 or -N + R 3 R 4 X - where R 3 , R 4 and X are as defined above. Preferably, T is according to structure (IIIa) or (IIIb), more preferably according to structure (IVa) or (IVb), and most preferably according to structure (IIIb) or (IVb). In compounds according to structure (VI), the carbon atom at position 2 of T may be of either the R or S configuration, preferably the S configuration. Similarly, the carbon atom at position 2 of the piperidine ring may be of either the R or S configuration, preferably the R configuration. Thus, the configuration of compounds according to structure (VI) may be (R,R), (S,R), (R,S), or (S,S), preferably the (S,R).

[0057] In preferred embodiments, compounds of general structure (I) are represented by structure (VIIa) or (VIIb). [ka] where R 2 is attached to the main chain atom via a second linker to form a ring structure, thus forming N * is -NR 3 or -N + R 3 R 4 X - where R 3 , R 4 , X and R 7 is as defined above. In the compounds according to structure (VIIa) or (VIIb), R 7is preferably methyl. In the compounds according to structure (VIIa) or (VIIb), the carbon atom at position 2 of T may be of the R or S configuration, preferably of the S configuration. Similarly, the carbon atom at position 2 of the piperidine ring may be of the R or S configuration, preferably of the R configuration. Thus, the configuration of the compounds according to structure (VIIa) or (VIIb) may be (R,R), (S,R), (R,S) or (S,S), preferably (S,R). In one embodiment, the compound of general structure (I) is represented by structure (VIIa). In an alternative embodiment, the compound of general structure (I) is represented by structure (VIIb). In a highly preferred embodiment, the present invention provides a compound for the above-described use, wherein the compound is represented by structure (VIIb), wherein each R 7 is methyl, and N * Ha-NR 3 or -N + R 3 R 4 X - and X is as defined above, preferably Cl - and R 3 is as defined above, preferably hydrogen, and R 4 is as defined above and is preferably hydrogen. Even more preferably, the compound is in the S,R configuration.

[0058] In preferred embodiments, compounds of general structure (I) are represented by structure (VIIIa) or (VIIIb). [ka] where R 2 is linked to a main chain atom via a second linker to form a ring structure, and N * Ha-N + R 3 R 4 X - where R 3 , R 4and X is as defined above. In the compounds according to structure (VIIIa) or (VIIIb), R 3 is preferably H or C1-C2 alkyl, and most preferably R 3 is H. In the compounds according to structure (VIIIa) or (VIIIb), R 4 is preferably H or C1-C2 alkyl, and most preferably R 4 is H. In the compounds according to structure (VIIIa) or (VIIIb), X is preferably Cl, I, TFA, or formate, and most preferably, X is Cl. In the compounds according to structure (VIIIa) or (VIIIb), the carbon atom at position 2 of T may be of either the R or S configuration, preferably the S configuration. Similarly, the carbon atom at position 2 of the piperidine ring may be of either the R or S configuration, preferably the R configuration. Thus, the configuration of the compounds according to structure (VIIIa) or (VIIIb) may be (R,R), (S,R), (R,S), or (S,S), and is preferably (S,R). In one embodiment, the compound of general structure (I) is represented by structure (VIIIa). In an alternative embodiment, the compound of general structure (I) is represented by structure (VIIIb).

[0059] In preferred embodiments, compounds of general structure (I) are represented by structure (IXa) or (IXb). [ka] where R 2 is linked to a main chain atom via a second linker to form a ring structure, and N * Ha-NR 3 where R 3 is as defined above. In the compounds according to structure (VIIIa) or (VIIIb), R 3 is preferably H or C1-C2 alkyl, and most preferably R 3is H. In compounds according to structure (IXa) or (IXb), the carbon atom at position 2 of T may be of the R or S configuration, preferably of the S configuration. Similarly, the carbon atom at position 2 of the piperidine ring may be of the R or S configuration, preferably of the R configuration. Thus, the configuration of compounds according to structure (IXa) or (IXb) may be (R,R), (S,R), (R,S), or (S,S), preferably (S,R). In one embodiment, compounds of general structure (I) are represented by structure (IXa). In an alternative embodiment, compounds of general structure (I) are represented by structure (IXb).

[0060] In a preferred embodiment, the compound is according to general structure (I), where T is represented by structure (IVa) or (IVb), and N * is represented by structure (IIa) or structure (IIb), and R 4 =H and X=Cl; (A)L=L 1 and R 1 -R 2 =L 1 and R 3 =H. (B)L=L 1 and R 1 =H, and R 2 =H, and R 3 =H. (C)L=L 2 and R 1 =H, and R 2 =H, and R 3 =H. (D)L=L 3 and R 1 =H, and R 2 =H, and R 3 =H. (E)L=L 4 and R 1 =H, and R 2 =H, and R 3 =Absent. (F)L=L 5 and R1 =H, and R 2 =H, and R 3 =Absent. (G)L=L 6 and R 1 =H, and R 2 =H, and R 3 =Absent. (H)L=L 3 and R 1 =H, and R 2 =Me and R 3 =Me. (I)L=L 1 and R 1 =H, and R 2 =Me and R 3 =Me. (J)L=L 7 and R 1 =H, and R 2 =H, and R 3 =Absent. (K)L=L 8 and R 1 =H, and R 2 =H, and R 3 =Absent. (L)L=L 9 and R 1 =H, and R 2 =H, and R 3 =Absent. (M)L=L 10 and R 1 -R 1’ =L 1 and R 2 =H, and R 3 =Absent. (N)L=L 11 and R 1 =H, and R 2 =H, and R 3 =H. (O)L=L 12 and R 1 =H, and R 2 =H, and R 3 =Absent. (P)L=L 13 and R1 =H, and R 2 =H, and R 3 =H. (Q)L=L 14 and R 1 =H, and R 2 =H, and R 3 =H. (R)L=L 15 and R 1 =H, and R 2 =H, and R 3 =H. (S)L=L 11 and R 1 =H, and R 2 =Me and R 3 =Me. (T)L=L 16 and R 1 =H, and R 2 =H, and R 3 =H. (U)L=L 17 and R 1 =H, and R 2 =H, and R 3 =H. (V)L=L 16 and R 1 =H, and R 2 =Me and R 3 =Me. (W)L=L 18 and R 1 =H, and R 2 -R 2’ =L 3 and R 3 =H. (X)L=L 19 and R 1 =H, and R 2 -R 2’ =L 3 and R 3 =H. (Y)L=L 20 and R 1 =H, and R 2 =H, and R 5 -R 5’ =L3 and R 3 =Absent. (Z)L=L 21 and R 1 =H, and R 2 -R 2’ =L 1 and R 3 =H. (AA)L=L 22 and R 1 -R 1’ =L 1 and R 2 =H, and R 3 =H. (AB)L=L 23 and R 1 -R 1’ =L 1 and R 2 =H, and R 3 =H. (AC)L=L 24 and R 1 -R 1’ =L 3 and R 2 =H, and R 3 =H. (AD)L=L 25 and R 1 -R 1’ =L 3 and R 2 =H, and R 3 =Absent. (AE)L=L 26 and R 1 =H, and R 2 =H, and R 5 -R 5’ =L 1 and R 3 =H. (AF)L=L 19 and R 1 =H, and R 2 -R 2’ =L 3 and R 3 =Me. (AG)L=L 19 and R 1 =H, and R 2-R 2’ =L 1 and R 3 =H. (AH)L=L 21 and R 1 =H, and R 2 -R 2’ =L 1 and R 3 =Me. (AI)L=L 27 and R 1 =H, and R 2 -R 2’ = -CH2-, and R 3 -R 3’ =L 1 where R4=H and X=Cl. (AJ)L=L 28 and R 1 =H, and R 2 =H, and R 3 =H, and R 4 =H and X=Cl.

[0061] Thus, it is preferred that the compound according to structure (I) is selected from compounds A to AJ as defined above, more preferably from compounds A to AH as defined above, even more preferably from compounds A to AJ based on general structure (IVb), and most preferably from compounds A to AH based on general structure (IVb). Particularly preferred compounds are selected from F, K, N, O, U, V, T, X, Z, AE, AF, AG, AH, AI, and AJ, and more preferred compounds are selected from F, K, N, O, U, V, T, X, Z, AE, AF, AG, and AH, even more preferably from N, T, X, and AE, and most preferably from X. Wherein N * is preferably R 4 =H and X=Cl, and the compounds are preferably of general structure (IVb).

[0062] Compound F may have the R configuration, the S configuration, or a mixture thereof; preferably, compound F is a mixture of the R and S enantiomers, more preferably a racemic mixture. Compound K may have the R configuration, the S configuration, or a mixture thereof; preferably, compound K is a mixture of the R and S enantiomers, more preferably a racemic mixture. Compound N may have the R,R configuration, the R,S configuration, the S,R configuration, the S,S configuration, or any mixture thereof; preferably, compound N has the R,R or S,R configuration, most preferably the R,R configuration. Compound O may have the R,R configuration, the R,S configuration, the S,R configuration, the S,S configuration, or any mixture thereof; preferably, compound O is a mixture of the R,S and S,S diastereomers, more preferably an approximately 1 / 1 (mol / mol) mixture. Compound U may have the R configuration, the S configuration, or a mixture thereof; preferably, compound U has the R or S configuration. Compound V may have the R configuration, the S configuration, or a mixture thereof, preferably compound V has the R configuration. Compound T may have the R configuration, the S configuration, or a mixture thereof, preferably compound T has the R or S configuration, most preferably the R configuration. Compound X may have the R,R configuration, the R,S configuration, the S,R configuration, the S,S configuration, or any mixture thereof, preferably compound X has the R,S or S,R configuration, most preferably the S,R configuration. Compound Z may have the R configuration, the S configuration, or a mixture thereof, preferably compound Z is a mixture of R and S enantiomers, more preferably a racemic mixture. Compound AE may have the R trans configuration, the R cis configuration, the S trans configuration, the S cis configuration, or any mixture thereof, preferably compound AE has the R trans configuration or the S trans configuration, most preferably the R trans configuration. Compound AF may have the R,R configuration, R,S configuration, S,R configuration, S,S configuration, or any mixture thereof, preferably compound AF has the S,R configuration. Compound AG may have the R,R configuration, R,S configuration, S,R configuration, S,S configuration, or any mixture thereof, preferably compound AG has the S,S configuration or S,R configuration.Compound AH may have the R configuration, the S configuration, or a mixture thereof, and preferably compound AH has the S configuration, where the first designator of configuration (R or S) is for the 2-position of T, and if an additional stereocenter is present in the compound of the invention, the second designator defines the configuration. Compound AJ may have the R,R configuration, the R,S configuration, the S,R configuration, the S,S configuration, or a mixture thereof, and preferably compound AJ has the S,R or R,R configuration, or a mixture thereof, and most preferably compound AJ has the R,R configuration.

[0063] Highly preferred compounds include Compound N (R,RN) in the R,R configuration, Compound T (RT) in the R configuration, Compound AE in the R trans configuration (R trans-AE), Compound AJ in the R configuration (R-AJ), and Compound X in any configuration. Most preferred compounds include Compound N (R,RN) in the R,R configuration, Compound T (RT), Compound AE in the R trans configuration (R trans-AE), and Compound X in any configuration, and most preferably, the compound of the present invention is Compound X (S,RX) in the S,R configuration. In one embodiment, these most preferred compounds of the present invention are Compound N (R,RN) in the R configuration, Compound T (RT), Compound AE in the R trans configuration (R trans-AE), and Compound X in any configuration, and optional Compound AJ, which is preferably R,R-AJ, where N * is R 4 More preferably, the compounds of the present invention are compounds X(S,RX) in the S,R configuration, where N * is R 4 In one embodiment, these most preferred compounds of the present invention are compound N in the R,R configuration (R,RN), compound T in the R configuration (RT), compound AE in the R trans configuration (R trans-AE), and compound X in any configuration, and optional compound AJ, which is preferably R,R-AJ, where N * is represented by structure (IIa), and most preferably the compounds of the present invention are compounds X(S,RX) in the S,R configuration, where N* is represented by structure (IIa).

[0064] In one embodiment, these most preferred compounds of the invention are compound N in the R,R configuration (R,RN), compound T in the R configuration (RT), compound AE in the R trans configuration (R trans-AE) and compound X in any configuration, and optional compound AJ, which is preferably R,R-AJ, wherein the compound is of structure (IIIa), and most preferably, the compound of the invention is compound X in the S,R configuration (S,RX), wherein the compound is of structure (IIIa).

[0065] In one embodiment, these most preferred compounds of the present invention are compound N in the R,R configuration (R,RN), compound T in the R configuration (RT), compound AE in the R trans configuration (R trans-AE) and compound X in any configuration, and optional compound AJ, which is preferably R,R-AJ, wherein the compound is of structure (IIIa) and N * is R 4 =H and X=Cl, most preferably the compounds of the present invention are compounds X(S,RX) in the S,R configuration, wherein the compound is of structure (IIIa) and N * is R 4 =H and X=Cl.

[0066] In one embodiment, these most preferred compounds of the present invention are compound N in the R,R configuration (R,RN), compound T in the R configuration (RT), compound AE in the R trans configuration (R trans-AE) and compound X in any configuration, and optional compound AJ, which is preferably R,R-AJ, wherein the compound is of structure (IIIa) and N * is represented by structure (IIa), and most preferably the compound of the present invention is compound X(S,RX) in the S,R configuration, wherein the compound is of structure (IIIa), and N * is represented by structure (IIa).

[0067] In one preferred embodiment, these most preferred compounds of the invention are compound N in the R,R configuration (R,RN), compound T in the R configuration (RT), compound AE in the R trans configuration (R trans-AE) and compound X in any configuration, and optional compound AJ, preferably R,R-AJ, wherein the compound is of structure (IIIb), and most preferably the compound of the invention is compound X in the S,R configuration (S,RX), wherein the compound is of structure (IIIb).

[0068] In one highly preferred embodiment, these most preferred compounds of the present invention are compound N in the R,R configuration (R,RN), compound T in the R configuration (RT), compound AE in the R trans configuration (R trans-AE) and compound X in any configuration, and optional compound AJ, which is preferably R,R-AJ, where the compound is of structure (IIIb) and N * is R 4 =H and X=Cl, most preferably the compounds of the present invention are compounds X(S,RX) in the S,R configuration, wherein the compound is of structure (IIb) and N * is R 4 =H and X=Cl.

[0069] In another highly preferred embodiment, these most preferred compounds of the present invention are compound N in the R,R configuration (R,RN), compound T in the R configuration (RT), compound AE in the R trans configuration (R trans-AE) and compound X in any configuration, and optional compound AJ, which is preferably R,R-AJ, wherein the compound is of structure (IIIb) and N * is represented by structure (IIa), and most preferably the compounds of the present invention are compounds X(S,RX) in the S,R configuration, wherein the compound is of structure (IIIb), and N * is represented by structure (IIa).

[0070] Compounds with an open configuration (containing a chromanylquinone framework, preferably general structure (IIIb)) were found to be more potent mPGES-1 inhibitors than compounds with a closed configuration (containing a chromanyl framework, preferably general structure (IIIa)). However, the compounds with the closed configuration exhibited higher oral bioavailability than the compounds with the open configuration.

[0071] The present invention includes all stereoisomers and geometric isomers of the compounds, including diastereomers, enantiomers, and cis / trans (E / Z) isomers. The present invention also includes mixtures of stereoisomers and / or geometric isomers in any ratio, including, but not limited to, racemic mixtures.

[0072] The compounds of the present invention are selective mPGES-1 inhibitors and can be used as they are. As used herein, the term "selective mPGES-1 inhibitor" refers to a substance that can inhibit or suppress (enhanced) expression and / or functional activity of mPGES-1 in a cell or subject, but does not have any or significant inhibitory effect on the expression of cyclooxygenase, particularly COX-2. Thus, the compounds of the present invention can be used to inhibit or suppress (enhanced) expression and / or functional activity of mPGES-1 in a cell or subject, but does not have any or significant inhibitory effect on the expression of cyclooxygenase, particularly COX-2. 1a and PGI2. The inventors believe that because the selective mPGES-1 inhibitors of the present invention have no significant or no effect on the expression / activity of cyclooxygenase, prostaglandin homeostasis in cells or subjects is maintained relatively stable, thereby alleviating diseases or symptoms associated with overexpression of mPGES-1 and simultaneously reducing the risk of suffering from adverse effects induced by COX-1 / 2 inhibition, such as cardiac events and gastric damage.

[0073] Therefore, the compounds of the present invention can be used in methods for treating or preventing enhanced mPGES-1 expression or activity, and / or treating, preventing, and / or suppressing symptoms associated with enhanced mPGES-1 expression or activity. Such enhanced or increased activity of mPGES-1 is usually brought about by the expression of the mPGES-1 enzyme, i.e., by inducing overexpression of mPGES-1, producing increased levels of PGE2. Therefore, it is understood herein that enhanced mPGES-1 activity, overexpression of mPGES-1, and increased levels of PGE2 are higher than those in corresponding normal, e.g., non-inflammatory, conditions, subjects, organs, tissues, or cells.

[0074] In the context of the present invention, the activity of an enzyme preferably relates to the amount of catalytic reaction per unit time. In the context of the present invention, the amount of enzyme expression preferably relates to the amount of enzyme molecules present or produced per unit time in a cell at a given time.

[0075] Thus, the compounds of the present invention are expected to be useful in the treatment of inflammation. Those skilled in the art will understand that the term "inflammation" includes any condition characterized as a local or systemic protective response that may be elicited by physical trauma, infection, chronic diseases such as those described herein below, and / or a chemical and / or physiological reaction to an external stimulus (e.g., as part of an allergic response). Any such response, which may function to destroy, dilute, or sequester both the injurious agent and the injured tissue, may manifest as symptoms mediated by enhanced mPGES-1 expression or activity, such as fever, swelling, pain, redness, vasodilation, and / or increased blood flow.

[0076] The term "inflammation" is also understood to include any inflammatory disease, disorder, or condition per se, any condition having an associated inflammatory component, and / or any condition characterized by inflammation, including, inter alia, acute, chronic, ulcerative, specific, allergic, pathogen infection, hypersensitivity, invasion by a foreign body, immune response due to physical injury, and necrotizing inflammation, as well as other forms of inflammation known to those skilled in the art. Thus, for purposes of the present invention, the term also includes inflammatory pain, general pain, and / or fever.

[0077] In a preferred embodiment, the compounds of the present invention are used in a method for treating, preventing, or suppressing conditions associated with increased mPGES-1 expression or activity, including at least one or more of inflammation, pain, swelling, fever, angiogenesis, and loss of appetite.

[0078] Preferably, the compounds of the present invention are used in methods for treating, preventing, or suppressing the symptoms of diseases or conditions associated with PGES-1 (enhanced expression and / or activity) associated with mPGES-1, as well as the symptoms of diseases or conditions in which the compounds are expected to be effective due to their analgesic, anti-inflammatory, anti-angiogenic, cytostatic, and / or antipyretic effects by inhibiting mPGES-1.

[0079] The compounds of the present invention are therefore useful in treating a) acute and chronic inflammation; skin diseases such as dermatitis, eczema, psoriasis, ulcers, acne vulgaris, hidradenitis suppurativa and tissue trauma; internal diseases such as inflammatory bowel disease, Crohn's disease, ulcerative colitis, diverticulitis, irritable bowel disease (IBS), peptic ulcer, cystitis, (chronic) prostatitis, pancreatitis or nephritis; ear, nose, mouth and throat diseases such as influenza, rhinitis, pharyngitis, tonsillitis, conjunctivitis, iritis, scleritis, otitis and uveitis; viral and bacterial infections; inflammation-related appetite disorders. depression; allergies; pelvic inflammatory disease; reperfusion injury; graft rejection; tendonitis, vasculitis and phlebitis; b) acute pain, chronic pain, neuropathic pain, nociceptive pain, hyperalgesia, pain associated with central sensitization, allodynic inflammatory pain, visceral pain, cancer pain, traumatic pain, dental or surgical pain, postoperative pain, labor pain, labour pain, persistent pain, peripherally mediated pain, centrally mediated pain, chronic headache, migraine, sinus headache, tension headache, phantom limb pain, peripheral nerve injury chemotherapy pain and cancer pain; c) arthritis, Autoimmune diseases such as osteoarthritis, juvenile arthritis, rheumatoid arthritis, ankylosing spondylitis, gout, rheumatic fever, bursitis, systemic lupus erythematosus (SLE) and multiple sclerosis; d) respiratory or lung diseases such as asthma, chronic obstructive pulmonary disease (COPD), sarcoidosis and pulmonary fibrosis; e) brain cancer, prostate cancer, kidney cancer, liver cancer, pancreatic cancer, stomach cancer, breast cancer, lung cancer, head and neck cancer, thyroid cancer, glioblastoma, melanoma, lymphoma, leukemia, cutaneous T-cell lymphoma and cutaneous B-cell lymphoma. f) diabetic complications including diabetic vascular injury, diabetic neuropathy and diabetic retinopathy; g) neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, Huntington's disease and amyotrophic lateral sclerosis; and h) cardiovascular diseases such as atherosclerosis, thrombosis, stroke and coronary heart disease, for the prevention or suppression of symptoms mediated by enhanced mPGES-1 expression or activity in the treatment of a disease or condition selected from the group consisting of:

[0080] In another embodiment, the present invention relates to a method for treating a disease or condition mediated by or associated with enhanced PGES-1 expression or activity, comprising administering an effective amount of a compound of the present invention to a subject suffering from the disease or condition. The disease or condition mediated by or associated with enhanced PGES-1 expression or activity is preferably selected from the group consisting of: a) acute and chronic inflammation; skin diseases such as dermatitis, eczema, hidradenitis suppurativa, acne vulgaris, hidradenitis suppurativa, and tissue trauma; internal diseases such as ulcerative colitis, diverticulitis, irritable bowel disease (IBS), peptic ulcer, cystitis, (chronic) prostatitis, and nephritis; ear, nose, mouth, and throat diseases such as influenza, rhinitis, pharyngitis, tonsillitis, conjunctivitis, iritis, scleritis, otitis, and uveitis; viral and bacterial infections; inflammation-associated anorexia; allergies; pelvic inflammatory disease; transplant rejection; tendonitis, hematocrit, and the like. vasculitis and phlebitis; b) acute pain, chronic pain, neuropathic pain, nociceptive pain, hyperalgesia, pain associated with central sensitization, allodynic inflammatory pain, visceral pain, cancer pain, traumatic pain, dental or surgical pain, postoperative pain, labor pain, delivery pain, persistent pain, peripherally mediated pain, centrally mediated pain, chronic headache, migraine, sinus headache, tension headache, phantom limb pain, peripheral nerve injury chemotherapy pain and cancer pain; c) ankylosing spondylitis, gout, rheumatic fever, bursitis, and d) diabetic complications including diabetic vascular injury, diabetic neuropathy and diabetic retinopathy.

[0081] An "effective amount" of a compound is the quantity of compound that, when administered to a subject, is sufficient to reduce or eliminate one or more symptoms of a disease, or slow the progression of one or more symptoms of a disease, or reduce the severity of one or more symptoms of a disease, or inhibit the appearance of a disease, or inhibit the appearance of adverse symptoms of a disease. An effective amount can be given in one or more administrations.

[0082] The "effective amount" that can be combined with a carrier material to produce a single dosage form will vary depending on the host to which the active ingredient is administered and the particular mode of administration. The unit dosage selected is typically made and administered to provide the desired final blood concentration of the compound.

[0083] Preferably, the effective amount for an adult (i.e., effective total daily dose) is defined herein as a total daily dose of about 5 to 2000 mg, or about 10 to 1000 mg, or about 20 to 800 mg, or about 30 to 800 mg, or about 30 to 700 mg, or about 20 to 700 mg, or about 20 to 600 mg, or about 30 to 600 mg, or about 30 to 500 mg, or about 30 to 450 mg, or about 30 to 400 mg, or about 30 to 350 mg, or about 30 to 300 mg, or about 50 to 600 mg, or about 50 to 500 mg, or about 50 to 450 mg, or about 50 to 400 mg, about 50 to 300 mg, or about 50 to 250 mg, or about 100 to 250 mg, or about 150 to 250 mg. In a most preferred embodiment, the effective amount is about 200 mg.

[0084] Alternatively, the effective amount of the compound for an adult is preferably administered according to body weight (kg). Thus, the total daily dose for an adult is preferably about 0.05 to about 40 mg / kg, about 0.1 to about 20 mg / kg, about 0.2 mg / kg to about 15 mg / kg, or about 0.3 mg / kg to about 15 mg / kg, or about 0.4 mg / kg to about 15 mg / kg, or about 0.5 mg / kg to about 14 mg / kg, or about 0.3 mg / kg to about 14 mg / kg, or about 0.3 mg / kg to about 13 mg / kg, or about 0.5 mg / kg to about 11 mg / kg.

[0085] The total daily dose for children is preferably up to 200 mg. More preferably, the total daily dose is about 5 to 200 mg, about 10 to 200 mg, about 20 to 200 mg, about 30 to 200 mg, about 40 to 200 mg, or about 50 to 200 mg. Preferably, the total daily dose for children is about 5 to 150 mg, about 10 to 150 mg, about 20 to 150 mg, about 30 to 150 mg, about 40 to 150 mg, or about 50 to 150 mg. More preferably, the total daily dose is about 5 to 100 mg, about 10 to 100 mg, about 20 to 100 mg, about 30 to 100 mg, about 40 to 100 mg, or about 50 to 100 mg. Even more preferably, the total daily dose is about 5 to 75 mg, about 10 to 75 mg, about 20 to 75 mg, about 30 to 75 mg, about 40 to 75 mg, or about 50 to 75 mg.

[0086] Alternative examples of dosages that can be used are within the dosage range of about 0.1 μg / kg to about 300 mg / kg, or within the range of about 1.0 μg / kg to about 40 mg / kg body weight, or within the range of about 1.0 μg / kg to about 20 mg / kg body weight, or within the range of about 1.0 μg / kg to about 10 mg / kg body weight, or within the range of about 10.0 μg / kg to about 10 mg / kg body weight, or within the range of about 100 μg / kg to about 10 mg / kg body weight, or within the range of about 1.0 mg / kg to about An effective amount of the compound of the present invention is within the range of 10 mg / kg body weight, or within the range of about 10 mg / kg to about 100 mg / kg body weight, or within the range of about 50 mg / kg to about 150 mg / kg body weight, or within the range of about 100 mg / kg to about 200 mg / kg body weight, or within the range of about 150 mg / kg to about 250 mg / kg body weight, or within the range of about 200 mg / kg to about 300 mg / kg body weight, or within the range of about 250 mg / kg to about 300 mg / kg body weight. Other dosages that can be used are about 0.01 mg / kg body weight, about 0.1 mg / kg body weight, about 1 mg / kg body weight, about 10 mg / kg body weight, about 20 mg / kg body weight, about 30 mg / kg body weight, about 40 mg / kg body weight, about 50 mg / kg body weight, about 75 mg / kg body weight, about 100 mg / kg body weight, about 125 mg / kg body weight, about 150 mg / kg body weight, about 175 mg / kg body weight, about 200 mg / kg body weight, about 225 mg / kg body weight, about 250 mg / kg body weight, about 275 mg / kg body weight, or about 300 mg / kg body weight.

[0087] Compounds of the present invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three, or four times daily.

[0088] In preferred embodiments of the present invention, a "subject," "individual," or "patient" is understood to be an individual organism, preferably a vertebrate, more preferably a mammal, even more preferably a primate, and most preferably a human.

[0089] The dosages defined herein are preferably suitable for administration to humans. Thus, in a preferred embodiment, the present invention relates to a compound as defined herein above for use in the treatment, prevention or suppression of conditions associated with enhanced mPGES-1 expression or activity by administering an effective amount as defined herein, wherein the subject to be treated is a primate, preferably the subject is a human.

[0090] In a further preferred embodiment of the present invention, the human is an adult, e.g., a human aged 18 years or older. In addition, the average body weight of an adult is 62 kg, although it is known that the average body weight varies from country to country. In another embodiment of the present invention, the average body weight of an adult is therefore between about 50 and 90 kg. It is understood herein that the effective dose defined herein is not limited to subjects with an average body weight. Preferably, the subject has a body weight of 18.0 to 40.0 kg / m. 2 BMI (body mass index) between 18.0 and 30.0 kg / m 2 have a BMI between .

[0091] Alternatively, the subject being treated is a child, e.g., a human under the age of 17. Additionally, the subject being treated can be a human between birth and adolescence, or between adolescence and adulthood. Adolescence is understood herein to begin at age 10-11 for females and age 11-12 for males. Furthermore, the subject being treated can be a newborn (first 28 days postpartum), infant (0-1 year old), toddler (1-3 years old), preschooler (3-5 years old), school-age child (5-12 years old), or adolescent (13-18 years old).

[0092] Compounds used as defined herein (i.e., for treating, preventing, or suppressing a condition mediated by or associated with enhanced mPGES-1 expression or activity by administration of an effective total daily dose) may be administered as a composition.

[0093] Compositions containing the compounds described above can be formulated as pharmaceutical or cosmetic preparations or in various other media, such as human or animal foods, including medical foods and dietary supplements. A "medical food" is a product intended for special dietary management due to a disease or condition for which unique nutritional requirements exist. By way of example, a medical food may include, but is not limited to, vitamin and mineral preparations delivered via a feeding tube (known as enteral administration). A "dietary supplement" refers to a product intended to supplement the human diet and typically provided in formulations such as pills, capsules, and tablets. By way of example, a "dietary supplement" may include, but is not limited to, one or more of the following ingredients: vitamins, minerals, herbs, botanicals, amino acids, dietary substances intended to supplement the diet by increasing total dietary intake, concentrates, metabolites, constituents, extracts, or any combination of the foregoing. The dietary supplements can also be incorporated into foods, including, but not limited to, food bars, beverages, powders, cereals, ready meals, food additives and candies, or other functional foods designed to promote brain health or to prevent or halt the progression of neurodegenerative diseases associated with increased mPGES-1 expression or activity.

[0094] Thus, the compositions may be mixed with other physiologically acceptable materials that may be ingested, including, but not limited to, food. Additionally or alternatively, the compositions used as described herein may be orally administered in combination with (or separately from) the administration of food.

[0095] The composition can be administered alone or in combination with other pharmaceutical or cosmetic agents, and can be combined with a physiologically acceptable carrier.In particular, the compounds described herein can be formulated as pharmaceutical or cosmetic compositions by formulating them with additives such as pharmaceutically or physiologically acceptable excipients, carriers and vehicles.Suitable pharmaceutically or physiologically acceptable excipients, carriers and vehicles include, for example, calcium phosphate, magnesium stearate, talc, monosaccharides, disaccharides, starch, gelatin, cellulose, methylcellulose, sodium carboxymethylcellulose, dextrose, hydroxypropyl-P-cyclodextrin, polyvinylpyrrolidinone, low-melting-point waxes, ion exchange resins, etc., and any combination of two or three of these, processing agents, and drug delivery modifiers and enhancers. Other suitable pharmaceutically acceptable excipients are described in "Remington's Pharmaceutical Sciences," Mack Pub. Co., New Jersey (1991) and "Remington: The Science and Practice of Pharmacy," Lippincott Williams & Wilkins, Philadelphia, 20th edition (2003), 21 st edition(2005)and22 nd edition (2012), which is incorporated herein by reference.

[0096] Pharmaceutical or cosmetic compositions containing compounds used in accordance with the present invention may be in any form suitable for the intended method of administration, including, for example, a solution, a suspension, or an emulsion. In preferred embodiments, the compounds are administered in solid or liquid form.

[0097] Oral solid dosage forms may include capsules, tablets, pills, powders and granules.In such solid dosage forms, the active compound may be mixed with at least one inert diluent such as sucrose, lactose or starch.Such dosage forms may also contain additional substances other than inert diluents, such as lubricants such as magnesium stearate.In the case of capsules, tablets and pills, dosage forms may also contain buffering agents.In addition, tablets and pills may be prepared with enteric coatings.

[0098] Liquid dosage forms for oral administration may include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art, such as water or saline. Such compositions may also contain adjuvants such as wetting agents, emulsifying and suspending agents, cyclodextrins, and sweetening, flavoring, and perfuming agents.

[0099] Liquid carriers are typically used to prepare solutions, suspensions and emulsions. In a preferred embodiment, the liquid carriers / liquid dosage forms that are considered to be used for implementing the present invention include, for example, water, saline, pharmaceutically acceptable organic solvent(s), pharmaceutically acceptable oils and fats, etc., and mixtures of two or more thereof. In a preferred embodiment, the compound used as defined herein is mixed with an aqueous solution before administration. The aqueous solution should be suitable for administration, and such aqueous solutions are well known in the art. It is further known in the art that the suitability of an aqueous solution for administration may depend on the administration route.

[0100] In a preferred embodiment, the aqueous solution is an isotonic aqueous solution. The isotonic aqueous solution is preferably nearly (or completely) isotonic with respect to plasma. In an even more preferred embodiment, the isotonic aqueous solution is saline.

[0101] The liquid carrier may contain other suitable pharmaceutically acceptable additives such as solubilizers, emulsifiers, nutrients, buffers, preservatives, suspending agents, thickeners, viscosity regulators, stabilizers, flavorings, etc. Preferred flavorings are sweeteners such as monosaccharides and / or disaccharides. Suitable organic solvents include, for example, monohydric alcohols such as ethanol and polyhydric alcohols such as glycols. Suitable oils include, for example, soybean oil, coconut oil, olive oil, safflower oil, cottonseed oil, etc.

[0102] For parenteral administration, the carrier can also be an oily ester such as ethyl oleate, isopropyl myristate, and the like. Compositions used in the invention can also be in the form of microparticles, microcapsules, liposome encapsulates, or the like, or combinations of any two or more of these.

[0103] Slow-release, sustained-release, or controlled-release delivery systems, such as diffusion-controlled matrix systems or erodible systems, may be used, as described, for example, by Lee, "Diffusion-Controlled Matrix Systems," pp. 155-198, and Ron and Langer, "Erodible Systems," pp. 199-224, in "Treatise on Controlled Drug Delivery," A. Kydonieus Ed., Marcel Dekker, Inc., New York, 1992. For example, the matrix may be a biodegradable material that can be degraded naturally in situ and in vivo, e.g., by hydrolysis or by enzymatic cleavage, e.g., by proteases. The delivery system may be, for example, a naturally occurring or synthetic polymer or copolymer, e.g., in the form of a hydrogel. Exemplary polymers with cleavable linkages include polyesters, polyorthoesters, polyanhydrides, polysaccharides, poly(phosphate esters), polyamides, polyurethanes, poly(imide carbonates), and poly(phosphazenes).

[0104] The compounds of the present invention can also be administered in the form of liposomes. As known in the art, liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed from mono- or multi-lamellar hydrated liquid crystals dispersed in an aqueous medium. Any non-toxic, physiologically acceptable, and metabolizable lipid capable of forming liposomes can be used. The present composition in liposome form can contain, in addition to the compounds defined herein, stabilizers, preservatives, excipients, and the like. Preferred lipids are both natural and synthetic phospholipids and phosphatidylcholines (lecithins). Methods for forming liposomes are known in the art. See, for example, Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, NY, p. 33 et seq (1976).

[0105] The pharmaceutical or cosmetic composition may be comprised of a unit dose formulation, where the unit dose is a dose sufficient to treat or inhibit a disorder or condition as defined herein. The unit dose may be sufficient as a single dose to treat or inhibit a disorder or condition as defined herein. Alternatively, the unit dose may be a dose administered periodically during the course of treating or inhibiting a disorder or condition as defined herein. During the course of treatment, the concentration of the composition may be monitored to ensure that the desired level of the compound of the present invention is maintained.

[0106] In a preferred embodiment, the invention relates to a compound as defined herein for use in treating, preventing, or suppressing a condition mediated by or associated with enhanced mPGES-1 expression or activity, wherein the compound is administered at an effective total daily dose, and preferably reaches steady-state blood levels within 5 days, more preferably within 4 days, even more preferably within 3 days, and most preferably within 2 days after the first administration.

[0107] Steady state is understood herein to mean that the total intake of the compound as defined above is in (approximately) dynamic equilibrium with the excretion. During steady state, the plasma level of the compound is preferably maintained within the effective therapeutic range. In other words, the blood level of the compound is maintained between the minimum therapeutically effective concentration and the maximum therapeutically effective concentration. Below the minimum concentration, the compound does not have sufficient therapeutic effect to be considered effective. Above the maximum concentration, side effects increase, eventually resulting in toxicity.

[0108] To maintain an effective therapeutic range during treatment, the mean plasma concentration (C av ) is maintained between about 10 ng / ml and about 20,000 ng / ml, or between about 20 ng / ml and about 10,000 ng / ml, or between about 30 ng / ml and about 5,000 ng / ml, or between about 30 ng / ml and about 4,000 ng / ml, or between about 30 ng / ml and about 3,000 ng / ml, or between about 30 ng / ml and about 2,000 ng / ml, or between about 30 ng / ml and about 1,000 ng / ml, or between about 50 ng / ml and about 5,000 ng / ml, or between about 100 ng / ml and about 5,000 ng / ml, or between about 50 ng / ml and about 4,000 ng / ml, or between about 50 ng / ml and about 3,000 ng / ml, or between about 50 ng / ml and about 2,000 ng / ml, or between about 50 ng / ml and about 1,000 ng / ml. In more preferred embodiments, the average plasma concentration of the compound is maintained between about 50 ng / ml and 500 ng / ml or 100 ng / ml and 500 ng / ml.

[0109] The mean plasma concentration can be determined using any conventional method known in the art. However, in a preferred embodiment, the plasma concentration is determined by extracting the compounds defined herein from human plasma by protein precipitation followed by liquid chromatography-tandem mass spectrometry (LC-MS / MS). The concentration of the compound may be subsequently determined using calibration standards.

[0110] The compounds defined herein can be metabolized, and the effective therapeutic range of the metabolized compound can be maintained during treatment instead of or in addition to the non-metabolized compound. In a preferred embodiment of the invention, the mean plasma concentration (C av ) is maintained between about 5 ng / ml and about 5000 ng / ml, or between about 10 ng / ml and about 2000 ng / ml, or between about 20 ng / ml and about 1000 ng / ml, or between about 20 ng / ml and about 800 ng / ml, or between about 20 ng / ml and about 600 ng / ml, or between about 20 ng / ml and about 400 ng / ml, or between about 20 ng / ml and about 200 ng / ml, or between about 30 ng / ml and about 1000 ng / ml, or between about 50 ng / ml and about 1000 ng / ml, or between about 30 ng / ml and about 800 ng / ml, or between about 30 ng / ml and about 600 ng / ml, or between 30 ng / ml and about 400 ng / ml, or between about 30 ng / ml and about 200 ng / ml. In more preferred embodiments, the average plasma concentration of the compound is maintained between about 40 ng / ml and 500 ng / ml or 50 ng / ml and 200 ng / ml.

[0111] During or after administration of the compounds defined herein, the maximum plasma concentration (C max ) remains below about 20,000 ng / ml, or below 10,000 ng / ml, or below 5,000 ng / ml, or below about 4,000 ng / ml, or below about 3,000 ng / ml, or below about 2,000 ng / ml, or below about 1,000 ng / ml. In most preferred embodiments, the maximum plasma concentration remains below about 500 ng / ml.

[0112] Similarly, the maximum plasma concentration of the metabolite compounds remains less than about 5000 ng / ml, or 2000 ng / ml, or 1000 ng / ml, or less than about 800 ng / ml, or less than about 600 ng / ml, or less than about 400 ng / ml. In most preferred embodiments, the plasma concentration of the metabolite compounds remains less than about 250 ng / ml.

[0113] To maintain effective coverage during treatment, the compound may be administered once a day, or once every two, three, four, or five days. Preferably, however, the compound may be administered at least once a day. Thus, in a preferred embodiment, the present invention relates to a compound as defined hereinabove, used to treat, prevent, or suppress symptoms mediated by or associated with enhanced mPGES-1 expression or activity, by administering an effective total daily dose, wherein the effective dose is as defined hereinabove. The total daily dose may be administered in a single daily dose. Alternatively, the compound is administered at least twice a day. Thus, the compound as defined herein may be administered once, twice, three times, four times, or five times a day. In this way, the total daily dose may be divided into several doses (units), resulting in the administration of the total daily dose as defined herein. In a preferred embodiment, the compound is administered twice a day. It is further understood that the terms "twice daily," "bid," and "bis in die" may be used interchangeably herein.

[0114] In a preferred embodiment, the total daily dose is divided into several doses each day.These separate doses can have different amounts.For example, in each total daily dose, the first dose can have a larger amount of compound than the second dose, and vice versa.But preferably, the compound is administered in similar or equal doses.Therefore, in the most preferred embodiment, the compound is administered twice a day in two similar or equal doses.

[0115] In a further preferred embodiment of the present invention, the total daily dose of the compound defined herein above is administered in at least two separate doses, wherein the interval between the administration of the at least two separate doses is at least about 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 hours, preferably the interval between the at least two separate doses is at least about 4, 5, 6, 7, 8, 9, 10, 11 or 12 hours, more preferably the interval between the at least two separate doses is at least about 8, 9, 10, 11 or 12 hours.

[0116] The compositions may be administered to a patient prophylactically or therapeutically, at an effective total daily dose as defined herein, by any of a number of methods, particularly those that may vary based on the individual subject, the state or stage of the disease, and other factors apparent to one skilled in the art.

[0117] The compounds used as defined herein may be administered enterally, orally, parenterally, sublingually, by inhalation (mist or spray), rectally, or topically, using unit dosage formulations containing conventional non-toxic pharmaceutically or physiologically acceptable carriers, adjuvants, and vehicles, as desired. For example, suitable modes of administration include oral, subcutaneous, transdermal, transmucosal, iontophoretic, intravenous, intraarterial, intramuscular, intraperitoneal, intranasal (e.g., via the nasal mucosa), subdural, rectal, gastrointestinal, and the like, and directly into specific or affected organs or tissues. Delivery to the central nervous system can involve spinal and epidural administration, or administration into the ventricles. Local administration may also involve the use of transdermal administration, such as transdermal patches or iontophoretic devices. The term parenteral, as used herein, includes subcutaneous injection, intravenous, intramuscular, and intrasternal injection or infusion techniques.

[0118] The compound is mixed with a pharmaceutically acceptable carrier, adjuvant, and vehicle suitable for the desired administration route. Oral administration is the preferred administration route, and formulations suitable for oral administration are the preferred formulations. Alternatively, the compound can be administered by feeding through a gastric tube or a transdermal tube.

[0119] Thus, in a preferred embodiment, the present invention relates to a compound as defined herein above for use in treating, preventing or suppressing a condition mediated by or associated with enhanced mPGES-1 expression or activity, at an effective total daily dose, wherein the compound is administered orally.

[0120] Oral route is the preferred means of administration, and the dosage form used (at least for adults) is preferably a solid oral dosage form. The category of solid oral dosage forms is mainly composed of tablets and capsules, although other forms are known in the art and may be equally suitable. When used as a solid oral dosage form, the compounds defined herein can be administered in the form of, for example, immediate release tablets (or capsules, etc.) or sustained release tablets (or capsules, etc.). Any suitable immediate release or sustained release solid dosage form can be used in the context of the present invention, and this will be clear to those skilled in the art.

[0121] The compounds described for use as described herein can be administered in solid, liquid, or aerosol form, or in the form of tablets, pills, powder mixtures, capsules, granules, injections, creams, solutions, suppositories, enemas, colon cleansers, emulsions, dispersions, premixed foods, and other suitable forms. The compounds can also be administered in liposomal formulations. The compounds can also be administered as prodrugs, which undergo transformation in the treated subject into a therapeutically effective form. Additional administration methods are known in the art.

[0122] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions, can be formulated according to known techniques using appropriate dispersing or wetting agents and suspending agents. Sterile injectable preparations may also be sterile injectable solutions or suspensions in non-toxic parenterally acceptable diluents or solvents, such as solutions in propylene glycol. Among the acceptable vehicles and solvents that can be used are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile fixed oils are commonly used as solvents or suspending media. For this purpose, any bland fixed oil can be used, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.

[0123] Suppositories for rectal administration of drugs can be prepared by mixing the drug with a suitable non-irritating excipient, such as cocoa butter and propylene glycol, which is solid at room temperature but liquid at the rectal temperature and therefore melts in the rectum to release the drug.

[0124] Although the compounds for use described herein can be administered as the sole active pharmaceutical (or cosmetic) agent, they can also be used in combination with one or more other agents used to treat or inhibit disorders.

[0125] When an additional active agent is used in combination with a compound of the present invention, the additional active agent can generally be used in a therapeutic amount as indicated in the Physicians' Desk Reference (PDR) 53rd Edition (1999), which is incorporated herein by reference, or in a therapeutically effective amount known to those skilled in the art. The compounds of the present invention and other therapeutically active agents can be administered at the maximum recommended clinical dose or at a lower dose. The dosage level of the active compound in the compositions of the present invention can vary to obtain a desired therapeutic response depending on the route of administration, the severity of the disease, and the patient's response. When administered in combination with other therapeutic agents, the therapeutic agents can be formulated as separate compositions given at the same time or at different times, or the therapeutic agents can be given as a single composition.

[0126] In this document and in the claims, the verb "comprise" and its conjugations are used in an open-ended sense to mean that the items following this word are included, but also that items not specifically stated are not excluded. In addition, referring to an element with the indefinite article "a" or "an" does not exclude the possibility that more than one element is present, unless the context clearly requires that only one element be present. Thus, the indefinite article "a" or "an" typically means "at least one."

[0127] The word "about" or "approximately," when used in connection with a numerical value (e.g., about 10), preferably means that the value can be 0.1% more or less than the given value (10).

[0128] All patents and literature references cited herein are incorporated by reference in their entirety.

[0129] The present invention is further described by the following examples, which should not be construed as limiting the scope of the invention. [Example]

[0130] Example 1 Methods and Materials Chemicals and Antibodies Antibodies directed against cPGES, mPGES-1, and mPGES-2 were purchased from Cayman Chemicals. Antibodies directed against COX-1, COX-2, and actin were purchased from R&D Systems, Thermo Fisher Scientific, and Sigma-Aldrich, respectively. COX inhibitors celecoxib and indomethacin, and lipopolysaccharide were purchased from Sigma-Aldrich. mPGES-1 inhibitors MK866 and PF9184, and PGH2 were purchased from Cayman Chemicals. IL-1β was purchased from Cell Signaling Technologies.

[0131] The compounds used according to the present invention were prepared as described in WO 2014 / 011047 or WO 2017 / 060432.

[0132] Raw264.7 cell culture RAW264.7 cells (Sigma-Aldrich, St. Louis) were maintained in DMEM (Thermo Fisher Scientific) containing 10% FBS (Greiner Bio-one) and antibodies (100 U / ml penicillin, 100 μg / ml streptomycin) in a humidified atmosphere of 5% CO at 37°C. Cells were grown to 80% confluence, scraped, and then plated in 96-well plates (2 × 10 4 cells / well) or 6-well plate (4 x 10 5 The cells were cultured for 6 to 24 hours in either a 1000 x ... cells / well culture medium.

[0133] Culture of human primary dermal fibroblasts Cells were maintained in M199, HEPES (Thermo Fischer Scientific) containing 10% FBS (#758093, Greiner Bio-one), 100 IU / ml penicillin, and 100 μg / ml streptomycin (#30-002-CI, Corning) in a humidified atmosphere of 5% CO at 37°C. Cells were trypsinized and passaged every 4–5 days until they reached passage number 20, at which point they were discarded. Cells were grown to 80% confluence, trypsinized, and then plated in 96-well plates (4 × 10 3 The cells were cultured at 1000 x g for 24 hours.

[0134] Prostaglandin quantification PGE2, PGD2 and 6-keto-PGF in the culture medium 1α The concentrations of PGE2 were measured using a PGE2 high-sensitivity EIA kit (Enzo Life Science), a prostaglandin D2-MOX ELISA kit (Cayman Chemicals), and 6-keto prostaglandin F 1α Prostanoid concentrations were determined by enzyme-linked immunosorbent assay (ELISA) using an ELISA kit (Cayman Chemicals) according to the manufacturer's instructions. A 100 μl sample of culture medium from each well was diluted with assay buffer. The values ​​for each prostanoid were calculated using a standard curve and normalized as indicated in the figure legends.

[0135] Western blot analysis After treatment, cells were harvested by scraping and dissolved in radioimmunoprecipitation assay buffer (50 mM Tris-HCl, pH 8.0, 150 mM NaCl, 0.2% Triton, 1× protease inhibitors, and 0.1 mg / ml DNase). Protein concentrations of samples were determined by Bradford assay. Equal amounts of protein from each sample were separated by SDS-polyacrylamide gel electrophoresis (SDS-PAGE) and electrotransferred to a PVDF membrane. The membranes were blocked with Odyssey blocking buffer (Li-Cor) for 1 hour at room temperature and then incubated overnight at 4°C with primary antibodies against mPGES-1 (1:200 dilution), mPGES-2 (1:200 dilution), cPGES (1:200 dilution), COX-1 (1:250 dilution), COX-2 (1:500 dilution), or β-actin (1:10,000 dilution) in TBST. After washing the membranes three times with TBST, secondary antibodies (goat anti-rabbit IgG (H+L) secondary antibody Alexa Fluor 488 or goat anti-mouse IgG (H+L) secondary antibody Alexa Fluor 647, Thermo Fisher Scientific) were added at a dilution of 1:10,000 for 1 hour at room temperature. Fluorescent scanning of the blots was performed using an Odyssey Infrared Imaging System (Li-Cor).

[0136] Microsomal PGES activity PGES activity was measured by assessing the conversion of PGH2 to PGE2. Briefly, after 24 h of incubation with 1 μg / mL LPS, cells were harvested and lysed by sonication (three times for 10 s, separated by 1 min intervals) in 300 μl of 1 M Tris-HCl (pH 8.0). The lysate was centrifuged at 12,000 g for 10 min at 4°C, and the supernatant was collected and further centrifuged at 100,000 g for 1 h at 4°C. The pellet (microsomal membranes) was resuspended in 100 μl of 0.1 M Tris-HCl, pH 8.0 (containing protease inhibitors) and subjected to measurement of microsomal PGES activity. For PGES activity measurements, an aliquot of each sample equivalent to 50 μg of protein was incubated with 2 μg of PGH2 in 0.1 ml of 1 M Tris-HCl containing 2 mM glutathione (Sigma-Aldrich) and 14 μM indomethacin in the absence or presence of test compound for 60 s at 24°C. The reaction was stopped by the addition of 100 mM FeCl2 and further incubated for 15 min at 20–25°C. After centrifugation of the reaction mixture, the PGE2 concentration in the supernatant was measured using a PGE2 high-sensitivity EIA kit (Enzo Life Science) according to the manufacturer's instructions.

[0137] RNA quantification by qRT-PCR After 6 hours of treatment with 1 μg / mL LPS in the absence or presence of test compounds, total RNA was isolated from cells using Trizol reagent (Thermo Fisher Scientific). RNA was transcribed into cDNA using a first-strand cDNA synthesis kit (Thermo Fisher Scientific). cDNA was denatured at 95°C for 10 minutes. Specific DNA fragments of COX-1, COX-2, mPGES-1, mPGES-2, cPGES, and PPIA were amplified by PCR using a SYBR Green (Roche Life Science) cycler for 40 cycles of 95°C for 15 seconds and 60°C for 60 seconds. The oligonucleotide primers used for COX1 were 5′-GATTGTACTCGCACGGGCTAC-3′ (forward) and 5′-GGATAAGGTTGGACCGCACT-3′ (reverse), for COX2 were 5′-AGGACTCTGCTCACGAAGGA-3′ (forward) and 5′-TGACATGGATTGGAACAGCA-3′ (reverse), and for mPGES-1 were 5′-AGCACACTGCTGGTCATCAA-3′ (forward) and 5′-CTCCACATCTGGGTCACTCC-3′ (reverse). The primers were 5'-GCTGGGGCTGTACCACAC-3' (forward) and 5'-GATTCACCTCCACCACCTGA-3' (reverse) for mPGES-2, 5'-GCTGGGGCTGTACCACAC-3' (forward) and 5'-GATTCACCTCCACCACCTGA-3' (reverse) for cPGES, 5'-GGTAGAGACCGCCGGAGT-3' (forward) and 5'-TCGTACCACTTTGCAGAAGCA-3' (reverse) for PPIA, and 5'-AGGGTGGTGACTTTACACGC-3' (forward) and 5'-GATGCCAGGACCTGTATGCT-3' (reverse) for PPIA. PCR amplification was also performed on samples without cDNA as a negative control. The relative gene expression of COX-1, COX-2, mPGES-1, mPGES-2, and cPGES was determined by the ΔΔ (delta-delta) CT method, comparing expression in the vehicle and treatment groups. PPIA was used as a reference gene.

[0138] result Compounds I-IVb-X selectively reduce levels of PGE2. RAW264.7 macrophage cells were treated with the inflammatory stimulus LPS alone or with compounds I-IVb-X (compounds of general structure (I), where T is of general structure (IVb) in the S,R configuration, and the following applies to compound X: L = L 19 ;R 1 =H;R 2 -R 2’ =L 3 ;R 3 The mice were treated with either the NSAID indomethacin or the coxib celecoxib in combination with increasing concentrations of PGD2, PGD2, and 6-keto-PGF. After 24 hours of incubation, the PGE2, PGD2, and 6-keto-PGF 1a The levels of PGE2 were quantified in cell supernatants by ELISA. As expected, LPS efficiently induced the production of the three prostaglandins (Figures 2A-2C) (Ikeda-Matsuo et al., 2005), and the two COX inhibitors, indomethacin and celecoxib, were all able to dose-dependently reduce them (Figures 2E-2F). Unexpectedly, compounds I-IVb-X were able to dose-dependently reduce the levels of PGE2, but not the other two prostaglandins, PGD2 and 6-keto PGF2. 1a Compound I-IVb-X had no effect on inflammatory cytokines, and stable metabolites of PGI2 were measured as a substitute for normal PGI2 (Figure 2D). Similar results were obtained with compound I-IVb-X in human primary skin fibroblasts. After 24 hours of incubation of fibroblasts with either the inflammatory stimuli LPS or IL-1β, PGE2 and PGD2 levels in the supernatant were strongly increased (Figures 3A and 3B). Compound I-IVb-X was able to efficiently reduce the levels of PGE2, but not PGD2, in the supernatant of cells treated with either LPS (Figure 3C) or IL-1β (Figure 3D).

[0139] Compounds I-IVb-X selectively reduce the expression of the mPGES-1 enzyme. RAW264.7 macrophage cells were treated with the inflammatory stimulus LPS alone or in combination with increasing concentrations of compounds I-IVb-X. After 24 h of incubation, mPGES-1, mPGES-2, cPGES, COX-1, and COX-2 protein and RNA levels were quantified in the cells by Western blot or qPCR, respectively. As expected, LPS efficiently induced the expression of the two inducible enzymes mPGES-1 and COX-2 at protein levels (Figures 4A-4C) and RNA levels (Figures 5A and 5B), but had no effect on the protein levels of the constitutively expressed enzymes mPGES-2, cPGES, and COX-1 (Figures 4A, 4D-4F), or RNA levels (Figures 5C-5E). Compounds I-IVb-X were able to dose-dependently reduce the LPS-induced expression of mPGES-1 protein (Figure 4B) and RNA (Figure 5A), but had no effect on COX-2 expression (Figures 4C and 5B). Compounds I-IVb-X had no effect on the other three constitutive enzymes, mPGES-2, cPGES, and COX-1 (Figures 4D-4F and 5C-5E). These results demonstrate that compounds I-IVb-X can selectively inhibit the expression of mPGES-1 enzyme induced by the inflammatory stimulus LPS, explaining its selectivity in reducing only PGE2 but not other prostaglandins.

[0140] Compounds I-IVb-X inhibit mPGES-1 enzyme activity. RAW264.7 macrophage cells were treated with the inflammatory stimulus LPS to increase mPGES-1 expression. After 24 hours of incubation, microsomes were isolated and exposed to increasing concentrations of Compound I-IVb-X or single concentrations of the mPGES-1 inhibitors MK866 and PF9184 for 30 minutes. mPGES-1 activity was then assayed in the microsomal fraction as the conversion of PGH2 to PGE2. The results show that mPGES-1 activity was reduced in purified microsomes treated with Compound I-IVb-X or the two positive controls MK866 and PF9184 (Figure 6A).

[0141] Example 2 - Inhibition of mPGES-1 Enzyme Activity Additional compounds were tested using the methods described in Example 1. Table 1 provides a summary of the compounds tested along with their corresponding IC 50 Figures 6B, 6C and 6D show the corresponding inhibition curves for I-IVb-AE, I-IVb-A-HCl and I-IVb-I, respectively. [Table 2] TIFF0007754623000021.tif155149

[0142] References Akitake, Y., Nakatani, Y., Kamei, D.,Hosokawa, M., Akatsu, H., Uematsu, S., et al. (2013).Microsomal prostaglandin E synthase-1 is induced in alzheimer's disease and its deletion mitigates alzheimer's disease-like pathology in a mouse model. J. Neurosci. Res. 91: 909-919. Beales, ILP, and Ogunwobi, OO (2010).Microsomal prostaglandin E synthase-1 inhibition blocks proliferation and enhances apoptosis in oesophageal adenocarcinoma cells without affectingendothelial prostacyclin production. Int. J. Cancer 126: 2247-55. Catella-Lawson, F., Mcadam, B., Morrison,B.W., Kapoor, S., Kujubu, D., Antes, L., et al. Effects of Specific Inhibitionof Cyclooxygenase-2 on Sodium Balance, Hemodynamics, and Vasoactive Eicosanoids1. Chaudhry, U.A., Zhuang, H., Crain, B.J.,and Dore, S. (2008). Elevated microsomal prostaglandin-E synthase-1 inAlzheimer’s disease. Alzheimer’s Dement. 4: 6-13. Chen, Y., Liu, H., Xu, S., Wang, T., andLi, W. (2015). Targeting microsomal prostaglandin E 2 synthase-1 (mPGES-1): thedevelopment of inhibitors as an alternative to non-steroidal anti-inflammatorydrugs (NSAIDs). Med. Chem. Commun. 6: 2081-2123. Fahmi, H. (2004). mPGES-1 as a novel targetfor arthritis. Curr. Opin. Rheumatol. 16: 623-627. Hanaka, H., Pawelzik, S.-C., Johnsen, J.I.,Rakonjac, M., Terawaki, K., Rasmuson, A., et al. (2009). Microsomalprostaglandin E synthase 1 determines tumor growth in vivo of prostate and lungcancer cells. Proc. Natl. Acad. Sci. U. S. A. 106: 18757-62. Hara, S., Kamei, D., Sasaki, Y., Tanemoto,A., and Nakatani, Y. (2010). Prostaglandin E synthases: Understanding theirpathophysiological roles through mouse genetic models. Biochimie92: 651-659. Hui, Y., Ricciotti, E., Crichton, I., Yu, Z.,Wang, D., Stubbe, J., et al. (2010). Targeted Deletionsof Cyclooxygenase-2 and Atherogenesis in Mice. Circulation 121:. Ikeda-Matsuo, Y. (2017). The Role ofmPGES-1 in Inflammatory Brain Diseases. Biol. Pharm. Bull 40: 557-563. Ikeda-Matsuo, Y., Ikegaya, Y., Matsuki, N.,Uematsu, S., Akira, S., and Sasaki, Y. (2005). Microglia-specific expression ofmicrosomal prostaglandin E2 synthase-1 contributes tolipopolysaccharide-induced prostaglandin E2 production. J. Neurochem. 94: 1546-1558. Kamei, D., Yamakawa, K., Takegoshi, Y.,Mikami-Nakanishi, M., Nakatani, Y., Oh-Ishi, S., et al. (2004). Reduced painhypersensitivity and inflammation in mice lacking microsomal prostaglandin esynthase-1. J. Biol. Chem. 279: 33684-95. Kats, A., Bage, T., Georgsson, P., Jonsson,J., Quezada, H.C., Gustafsson, A., et al. (2013). Inhibition of microsomalprostaglandin E synthase-1 by aminothiazoles decreases prostaglandin E2synthesis in vitro and ameliorates experimental periodontitis in vivo. FASEB J.27: 2328-41. Kim, S.-H., Hashimoto, Y., Cho, S.-N., Roszik,J., Milton, D.R., Dal, F., et al. (2016). Microsomal PGE2 synthase-1 regulatesmelanoma cell survival and associates with melanoma disease progression.Pigment Cell Melanoma Res. 29: 297-308. Koeberle, A., and Werz, O. (2009).Inhibitors of the microsomal prostaglandin E(2) synthase-1 as alternative tonon steroidal anti-inflammatory drugs (NSAIDs)--a critical review. Curr. Med.Chem. 16: 4274-96. Koeberle, A., and Werz, O. (2015a).Perspective of microsomal prostaglandin E2 synthase-1 as drug target ininflammation-related disorders. Biochem. Pharmacol. 98: 1-15. Koeberle, A., and Werz, O. (2015b).Perspective of microsomal prostaglandin E 2 synthase-1 as drug target ininflammation-related disorders. Kojima, F., Kato, S., and Kawai, S. (2005).Prostaglandin E synthase in the pathophysiology of arthritis. Fundam. Clin.Pharmacol. 19: 255-261. Larsson, K., and Jakobsson, J. (2015).Inhibition of microsomal prostaglandin E synthase-1 as targeted therapy incancer treatment. Prostaglandins Other Lipid Mediat. 120: 161-165. Larsson, K., Kock, A., Idborg, H., ArsenianHenriksson, M., Martinsson, T., Johnsen, J.I., et al. COX / mPGES-1 / PGE 2 pathwaydepicts an inflammatory- dependent high-risk neuroblastoma subset. Mcadam, B.F., Catella-Lawson, F., Mardini,I.A., Kapoor, S., Lawson, J.A., and Fitzgerald, G.A. (1999). Systemicbiosynthesis of prostacyclin by cyclooxygenase (COX)-2: The human pharmacologyof a selective inhibitor of COX-2 (prostaglandins platelet monocyte ibuprofencelecoxib). Pharmacology 96: 272-277. Miller, S.B. (2006). Prostaglandins inHealth and Disease: An Overview. Semin. Arthritis Rheum. 36: 37-49. Miyagishi, H., Kosuge, Y., Ishige, K., andIto, Y. (2012). Expression of microsomal prostaglandin E synthase-1 in thespinal cord in a transgenic mouse model of amyotrophic lateral sclerosis. J.Pharmacol. Sci. 118: 225-36. Nakanishi, M., Gokhale, V., Meuillet, E.J.,and Rosenberg, D.W. (2010). mPGES-1 as a target for cancer suppression: Acomprehensive invited review "Phospholipase A2 and lipidmediators". Biochimie 92: 660-4. Nakanishi, M., and Rosenberg, D.W. (2013).Multifaceted roles of PGE2 in inflammation and cancer. Semin. Immunopathol. 35:123-137. Norberg, J.K., Sells, E., Chang, H.-H.,Alla, S.R., Zhang, S., and Meuillet, E.J. (2013a). Targeting inflammation:multiple innovative ways to reduce prostaglandin E2. Pharm. Pat. Anal. 2: 265-88. Norberg, J.K., Sells, E., Chang, H., Alla,S.R., Zhang, S., and Meuillet, E.J. (2013b). Targeting inflammation: multipleinnovative ways to reduce prostaglandin E2. Pharm. Pat. Anal. 2: 265-88. Ramanan, M., and Doble, M. (2017).Transcriptional Regulation of mPGES1 in Cancer: An Alternative Approach to DrugDiscovery? Curr. Drug Targets 18: 119-131. Ricciotti, E., and FitzGerald, G.A. (2011).Prostaglandins and inflammation. Arterioscler. Thromb. Vasc. Biol. 31: 986-1000. Riendeau, D., Aspiotis, R., Ethier, D.,Gareau, Y., Grimm, E.L., Guay, J., et al. (2005). Inhibitors of the induciblemicrosomal prostaglandin E2 synthase (mPGES-1) derived from MK-886. Bioorg.Med. Chem. Lett. 15: 3352-3355. Samuelsson, B., Morgenstern, R., andJakobsson, P.-J. (2007). Membrane Prostaglandin E Synthase-1: A NovelTherapeutic Target. Pharmacol. Rev. Pharmacol Rev 59: 207-224. Sasaki, Y., Nakatani, Y., and Hara, S.(2015). Role of microsomal prostaglandin E synthase-1 (mPGES-1)-derivedprostaglandin E 2 in colon carcinogenesis. Prostaglandins Other Lipid Mediat.121: 42-45. Seo, T., Tatsuguchi, A., Shinji, S.,Yonezawa, M., Mitsui, K., Tanaka, S., et al. Microsomal prostaglandin Esynthase protein levels correlate with prognosis in colorectal cancer patients. Smith, W.L., Urade, Y., and Jakobsson,P.-J. (2011). Enzymes of the Cyclooxygenase Pathways of ProstanoidBiosynthesis. 111: 5821-5865. Takeuchi, C., Matsumoto, Y., Kohyama, K.,Uematsu, S., Akira, S., Yamagata, K., et al. (2013).Microsomal prostaglandin E synthase-1 aggravates inflammation and demyelinationin a mouse model of multiple sclerosis. Neurochem. Int.62: 271-80. Westman, M., Korotkova, M., Klint, E. af,Stark, A., Audoly, L.P., Klareskog, L., et al. (2004).Expression of microsomal prostaglandin E synthase 1 in rheumatoid arthritissynovium. Arthritis Rheum. 50: 1774-1780. Yoshimatsu, K., Altorki, N.K., Golijanin,D., Zhang, F., Jakobsson, J., Dannenberg, A.J., et al. Inducible ProstaglandinE Synthase Is Overexpressed in Non-Small Cell Lung Cancer. Zeilhofer, H.U. (2007). Prostanoids innociception and pain. Biochem. Pharmacol. 73: 165-174.

Claims

1. Structure (VIIb): 【Chemical 1】 [In the formula, Each R ７ is methyl, N ＊ is -NR ３ -or-N ＋ R ３ R ４ X － - and X − is a pharmaceutically acceptable anion; R ３ is hydrogen (H), R ４ is hydrogen (H)] An mPGES-1 inhibitor comprising a compound represented by:

2. 2. The mPGES-1 inhibitor of claim 1, wherein the total daily dose administered is from 5 to 2000 mg.

3. The mPGES-1 inhibitor of claim 1 or 2, wherein the mPGES-1 inhibitor is administered orally.

4. The mPGES-1 inhibitor of any one of claims 1 to 3, wherein the mPGES-1 inhibitor is administered in solid or liquid form.

5. The mPGES-1 inhibitor of any one of claims 1 to 4, wherein the mPGES-1 inhibitor is administered at least twice daily.

6. The mPGES-1 inhibitor according to claim 5, wherein the interval between two administrations is at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 hours.

7. The mPGES-1 inhibitor of any one of claims 1 to 6, wherein the subject to be treated is a primate.

8. The mPGES-1 inhibitor according to any one of claims 1 to 7, wherein the subject to be treated is a human.

Images