[go: up one dir, main page]

WO2024112287A1 - Benzimidazole compounds and pharmaceutical compositions and uses thereof - Google Patents

Benzimidazole compounds and pharmaceutical compositions and uses thereof Download PDF

Info

Publication number
WO2024112287A1
WO2024112287A1 PCT/TR2023/050887 TR2023050887W WO2024112287A1 WO 2024112287 A1 WO2024112287 A1 WO 2024112287A1 TR 2023050887 W TR2023050887 W TR 2023050887W WO 2024112287 A1 WO2024112287 A1 WO 2024112287A1
Authority
WO
WIPO (PCT)
Prior art keywords
trifluoromethyl
phenyl
methyl
benzamide
compound
Prior art date
Application number
PCT/TR2023/050887
Other languages
French (fr)
Inventor
Erden BANOGLU
Burcu CALISKAN
Azize Gizem ERGUL
Gur Maz ZEHRA TUGCE
Oliver Werz
Paul Mike JORDAN
Original Assignee
Banoglu Erden
Caliskan Burcu
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Banoglu Erden, Caliskan Burcu filed Critical Banoglu Erden
Priority to PCT/TR2023/050887 priority Critical patent/WO2024112287A1/en
Publication of WO2024112287A1 publication Critical patent/WO2024112287A1/en
Priority to PCT/TR2024/051005 priority patent/WO2025048759A1/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C07D235/14—Radicals substituted by nitrogen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/06—Antimigraine agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/18—Benzimidazoles; Hydrogenated benzimidazoles with aryl radicals directly attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • C07D235/28—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/08—Bridged systems

Definitions

  • the present invention relates to novel compounds, to pharmaceutical compositions comprising the compounds, to processes for making the compounds and to the use of the compounds as inhibitors of microsomal prostaglandin E2 synthase- 1 (mPGES-1) in therapy.
  • mPGES-1 microsomal prostaglandin E2 synthase- 1
  • Prostaglandin Ei is the main prostaglandin (PG) involved in pain, fever, and inflammatory processes.
  • the biosynthesis of PGE2 occurs with several enzymatic steps that take place after the arachidonic acid (AA) is formed from membrane phospholipids by the action of cytosolic phospholipase A2 [1].
  • cyclooxygenases COX- 1/2 converts AA to the common precursor PGH2, which subsequently is converted to PGE2, PGI2, PGD2, PGF2 and thromboxane A2 by the action of various synthases [2].
  • cytosolic prostaglandin E2 synthase cPGES
  • microsomal prostaglandin E2 synthase- 1 mPGES-1
  • mPGES-2 cytosolic prostaglandin E2 synthase- 1
  • mPGES-2 mPGES-2
  • Stimulants such as IL-ip, TNFo, Lipopolysaccharide (LPS) and epidermal growth factor induce the expression of mPGES-1 in various tissues [4].
  • Non-steroidal anti-inflammatory drugs inhibit the production of PGE2 from the preceding step via non-selective inhibition of COX-1 and COX-2, and therefore affect the generation of all prostanoids that will be synthesized from PGH2 [1].
  • COX enzymes are non-selectively inhibited, gastrointestinal, renal and cardiovascular side effects were observed as a result of suppression of the biosynthesis of physiologically important PGs such as PGh and TXA2 along with inflammatory PGE2 [5] .
  • selective COX-2 inhibitors have been developed as a next-generation NSAIDs to avoid these side effects.
  • the use of COX-2 inhibitors has been disappointing since they are associated with an increased risk of cardiovascular events such as myocardial infarction.
  • PF-4693627 a potent mPGES-1 inhibitor named PF-4693627 from benzoxazole piperidine carboxamide derivatives with a high-throughput screening approach (IC50: 3 nM).
  • IC50 3 nM
  • This compound has high potency in in vitro experiments with selective inhibition against mPGES-1, with in vivo efficacy and good pharmacokinetic profile [8].
  • IC50 ⁇ 250 nM potent derivatives with improved whole blood activity
  • Compound PF-4693627 has advanced to the clinical trial phase in patients with osteoarthritis and rheumatoid arthritis due to its safety profile for preliminary clinical studies, but there are no current results reported [9].
  • Boehringer Ingelheim's 2-amino benzimidazole derivatives are also of high potency (IC50: 3-220 nM) (WO2012/022793A1), they developed a new framework and entered clinical studies. The compound is recently owned by Gesynta Pharma as GS-248 (OX-MPI/ BI- 1029539), and the Phase-II clinical trial (NCT04036227) for systemic sclerosis is in progress [10].
  • Lilly s LY3031207 and LY3023703, 2-acylamino imidazole derivatives, are the first compounds to enter the clinical trials, demonstrating that mPGES-1 can be a therapeutic target for treatment of pain and inflammation.
  • clinical studies were discontinued in Phase- II because these compounds caused drug-dependent hepatotoxicity [12, 13].
  • Dainippon Sumitomo Pharma discovered a new skeleton, working on candidate compounds with a good oral bioavailability from imidazoquininoline-derivatives containing phenyl in positions 2 and 7, which are 1,000-fold more selective to mPGES-1 than COX- 1/2, with a good ADME profile and potent inhibitor efficiency (IC50: 4.1 nM) [14, 15].
  • Eli Lilly company with the support of molecular modeling studies, discovered two new potent derivatives containing 2- amino imidazole, 2-chlorobenzamide and pivaloyl amide or isosteric structures in their skeleton (IC50: 26-27 nM). While these compounds showed potent inhibition of mPGES-1, they also had FLAP inhibition and were found to act as dual inhibitors [16].
  • mPGES-1 expression and PGE2 production are characteristic in diseases such as atherosclerosis, rheumatoid arthritis, osteoarthritis, periodontitis, inflammatory kidney damage, Alzheimer's and cancer.
  • mPGES-1 has been identified as a good target for drug development against inflammatory diseases including above ones but not limited to [4],
  • the present invention relates to compounds having the following Formula I:
  • RI is selected from the group consisting of methyl or trifluoromethyl
  • R2 is selected from the group consisting of hydrogen or methyl
  • R3 is selected from the group consisting of o-, m- and/or p-substituted phenyl and pyridine rings;
  • A is selected from the group consisting of methylene, ethylene, oxy-methylene, thio-methylene, methylene-thio or is omitted;
  • the aim of the present invention is to develop new compounds that inhibit the inducible mPGES-1, an enzyme that catalyzes the last step in the biosynthesis PGE2 from the AA for treatment of inflammatory diseases such as Parkinson's disease, autoimmune diseases, allergic disorders, rhinitis, coronary heart disease, ulcers, osteoarthritis, rheumatoid arthritis, systemic sclerosis, periodontitis, colon cancer, inflammatory bowel disease, cutaneous sclerosis, neuropathic pain, inflammation, pain, fever, migraine, chronic pain, acute pain, headache, asthma, pulmonary fibrosis, fibromyalgia, dysmenorrhea, atherosclerosis, gout, arthritis, osteoarthritis, rheumatoid arthritis, rheumatic fever, multiple sclerosis, Hodgkin's disease, conjunctivitis, ankylosing spondylitis, eczema, psoriasis, systemic lupus erythemat
  • the present invention relates to compounds having the following Formula I: Ri is selected from the substituent group whose structure is drawn below,
  • R2 is selected from the substituent group whose structure is drawn below,
  • R3 is selected from the substituent group whose structure is drawn below,
  • A is selected from the substitution group whose structure is drawn below or is omitted
  • X is selected from the substitution group whose structure is drawn below, relates to a compound obtained with these substitution groups, and/or pharmaceutically acceptable salts and/or solvates thereof.
  • the compounds of the present invention may be any of the following compounds:
  • Step A 4-aminophenylacetic acid, MeOH and H2SO4 were refluxed to give methyl 2-(4-aminophenyl)acetate (compound 1) (Method A).
  • Step B Amide formation on the amino group: For 2a, compound 1 was reacted with 2-chlorobenzoyl chloride in DCM in the presence of Et 3 N, at room temperature and under nitrogen gas. (Method Bl). For 2b-j; compound 1 was reacted with appropriate acid derivatives in the presence of EDC.HC1 and DMAP in DCM at room temperature and under nitrogen gas (Method B2).
  • Step C Ester hydrolysis: The 2a-j intermediate amide derivatives from Step B were hydrolyzed at the ester group in a mixture of THF:water (1:1) and LiOH.thO to give acid derivatives 2a-j (Method C).
  • Step D, E Compounds 3-12 were synthesized by reaction of 2a-j with 4- (trifluoromethyl)benzene-l,2-diamine in DCM in the presence of EDC.HC1 and DMAP, at room temperature under nitrogen gas, and then refluxed in AcOH (Method D, E).
  • Step B Ester hydrolysis: Acid derivatives 13a-d were obtained by ester hydrolysis reaction under the same condition that was used in Method C.
  • Step C Acid derivatives (13a-d) and compound 1 were reacted under the same condition that was used in Method B2 to give ester intermediate products.
  • Step D Carboxylic acid derivatives (14a-d) were obtained by ester hydrolysis reaction by using same condition that was used in Method C.
  • Step E F: Compounds 15-18 were prepared by using Method D, E.
  • Ri is -CF3
  • R2 is -H
  • X is -NH-CO- and R3 is 2- chlorophenyl:
  • Step A To a solution of 4-nitrophenol (for 21a) or 4-nitrothiophenol (for 21b) in AcCN, K2CO3 and methyl bromoacetate were added. The reaction mixture was refluxed to obtain compounds 21a-b.
  • Step B Compounds 22a-b were obtained by catalytic hydrogenation of 21a or 21b with Pd/C under hydrogen gas at room temperature.
  • Step C, D Compounds 23a-b were prepared by reaction of compound 22a or 22b with 2-chlorobenzoyl chloride according to Method B 1 in the first amidation step, and then Method C in the second ester hydrolysis step.
  • Step E, F Compounds 24-25 were prepared from Compounds 23a-b according to Method D, E.
  • Step A Sulfonamide intermediate was prepared by reaction of compound 1 with 2- chlorobenzene sulfonyl chloride under the same conditions that was used in Method Bl. Urea intermediate was synthesized by reaction of Compound 1 with 2-chloro- 2-isocyanatobenzene in DMF.
  • Step B Acid derivatives 31a-b were prepared from the intermediates from Step A by ester hydrolysis under the same condition that was used in Method C.
  • Step C, D Compound 32, 33 were prepared by reaction of 4- (trifluoromethyl)benzene-l,2-diamine with acid derivatives 31a-b under the same conditions that were used in Method D, E.
  • Step D, E Compound 36, 37 and 38 were prepared by reaction of 4- (trifluoromethyl)benzene-l,2-diamine with acid derivatives 35a, b or c under the same conditions that were used in Method D, E.
  • Step A, B Amide formation on the primer amine group was accomplished according to Method F: Briefly, for 44: 3,3,3-trifluoro-2,2-dimethyl propionic acid, for 45: pivalic acid, for 46: l-(trifluoromethyl)cyclopropane-l -carboxylic acid or for 47: 1- (trifluoromethyl)cyclobutane-l -carboxylic acid was dissolved in DCM, and then SOCh and a catalytic amount of DMF were added, and stirred at 50°C under nitrogen gas for 3 hours.
  • Method F Briefly, for 44: 3,3,3-trifluoro-2,2-dimethyl propionic acid, for 45: pivalic acid, for 46: l-(trifluoromethyl)cyclopropane-l -carboxylic acid or for 47: 1- (trifluoromethyl)cyclobutane-l -carboxylic acid was dissolved in DCM, and then SOCh and a catalytic amount of D
  • Step C, D The reaction of compound 34 with compound 44-47 under the same conditions that were applied to Method B2, to synthesize amide intermediates, which were subsequently hydrolyzed at the ester group to acid derivatives 48-51 according to the Method C.
  • Step E, F Compounds 52-55 were prepared from 4-(trifluoromethyl)benzen-l,2- diamine and compounds 48-51 under the same conditions that were used in Method D, E.
  • Step D, E Compounds 58-59 were prepared from 4-(trifluoromethyl)benzen-l,2- diamine and compounds 57a and 57b, respectively, under the same conditions that were used in Method D, E.
  • A549 cells were prepared according to the method specified in the literature [17]. Briefly, A549 cells were incubated for 72 hours at 37°C under 5% CO2 in DMEM (Dulbecco's Modified Eagle Media) medium containing FCS (Fetal calf serum, 2%) and IL-ip (2 ng/mL).
  • DMEM Dulbecco's Modified Eagle Media
  • microsomes were diluted with glutathione (2 mM) in potassium phosphate buffer (0.1 M, pH 7.4) and pre-incubated for 15 minutes with the addition of test compound or control (0.1% DMSO). After pre-incubation, 20 pM PGH2 substrate was added. After 1 min at 4°C, the reaction was terminated by adding 100 pl of solution (40 pM FeCh, 80 pM citric acid and 10 pM I IP-PGE2) stop solution. The formation of the PGE2 product was analyzed by HPLC method. The activity results of the compounds whose mPGES- 1 inhibition activities were tested using this method are shown in Table 2.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Engineering & Computer Science (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Biomedical Technology (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Diabetes (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Immunology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Endocrinology (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Emergency Medicine (AREA)
  • Dermatology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Psychology (AREA)
  • Hospice & Palliative Care (AREA)
  • Psychiatry (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention relates to benzimidazole derivatives of formula (I) and their mPGES-1 inhibitory activity. The present invention also relates to pharmaceutical compositions containing these benzimidazole derivatives and their use in the treatment of mPGES-1- mediated diseases.

Description

BENZIMIDAZOLE COMPOUNDS AND PHARMACEUTICAL COMPOSITIONS
AND USES THEREOF
Field of Invention:
The present invention relates to novel compounds, to pharmaceutical compositions comprising the compounds, to processes for making the compounds and to the use of the compounds as inhibitors of microsomal prostaglandin E2 synthase- 1 (mPGES-1) in therapy.
Background of the Invention:
Prostaglandin Ei (PGE2) is the main prostaglandin (PG) involved in pain, fever, and inflammatory processes. The biosynthesis of PGE2 occurs with several enzymatic steps that take place after the arachidonic acid (AA) is formed from membrane phospholipids by the action of cytosolic phospholipase A2 [1]. Then, cyclooxygenases (COX- 1/2) converts AA to the common precursor PGH2, which subsequently is converted to PGE2, PGI2, PGD2, PGF2 and thromboxane A2 by the action of various synthases [2]. Three enzymes cytosolic prostaglandin E2 synthase (cPGES), microsomal prostaglandin E2 synthase- 1 (mPGES-1) and -2 (mPGES-2) are involved in the terminal step of AA cascade in PGE2 biosynthesis, in which the inducible isoform mPGES-1, which is functionally coupled to upstream COX-2, catalyzes the transformation of PGH2 to pro-inflammatory PGE2, and is induced by inflammatory stimulants [3]. Stimulants such as IL-ip, TNFo, Lipopolysaccharide (LPS) and epidermal growth factor induce the expression of mPGES-1 in various tissues [4].
Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit the production of PGE2 from the preceding step via non-selective inhibition of COX-1 and COX-2, and therefore affect the generation of all prostanoids that will be synthesized from PGH2 [1]. When COX enzymes are non-selectively inhibited, gastrointestinal, renal and cardiovascular side effects were observed as a result of suppression of the biosynthesis of physiologically important PGs such as PGh and TXA2 along with inflammatory PGE2 [5] . Since gastrointestinal side effects have often been observed with the use of these NSAIDs, selective COX-2 inhibitors have been developed as a next-generation NSAIDs to avoid these side effects. However, the use of COX-2 inhibitors has been disappointing since they are associated with an increased risk of cardiovascular events such as myocardial infarction.
In 1999, the membrane-associated GSH-dependent mPGES-1 protein was discovered in A549 cells, and studies in this area have grown rapidly. It was observed that the expression of mPGES-1 is increased as a result of stimulation with IL-ip [6]. During the search for a new biological target with a good safety profile, which does not show the side effects encountered with the use of traditional NSAIDs and COX-2 selective inhibitors, it was aimed to regulate the inflammatory PGE2 biosynthesis by inhibition of mPGES-1, and mPGES-1 has become a potential new target for development of next generation NSAIDs [5].
Many pharmaceutical companies have continued their research in this field for 22 years, but there have been difficulties transferring mPGES-1 inhibitors to the clinic due to various reasons. These reasons include the high lipophilicity of the active compounds, high plasma protein binding, insufficient physicochemical properties, and activity changes due to differences between species in in-vivo and in-vitro studies [4].
Merck Frosst discovered the mPGES-1 inhibitor MF-63, which has a phenanthrene imidazole structure, by a high-throughput screening (HTS) approach. While it showed potent activity in humans and guinea pigs (IC50: 1-3 and 0.9 nM), inhibition of mPGES-1 was greatly reduced in human whole blood experiments (IC50: 1300 nM). MF-63 has been identified as a potent, selective and orally active inhibitor of mPGES-1, and did not show any side effects observed with traditional NSAIDs [1].
Researchers from Merck Frosst obtained new compounds with potent activity by optimizing 2,4-biarylimidazole derivatives (IC50: 1 nM). The phenyl alkyne moiety added to the structure of the compound selected as the best in the series increased the lipophilicity of the molecule, and a loss of activity was observed in whole blood due to its high binding to plasma proteins (IC50: 1600 nM) [7].
Pfizer researchers have discovered a potent mPGES-1 inhibitor named PF-4693627 from benzoxazole piperidine carboxamide derivatives with a high-throughput screening approach (IC50: 3 nM). This compound has high potency in in vitro experiments with selective inhibition against mPGES-1, with in vivo efficacy and good pharmacokinetic profile [8]. However, since the low water solubility of this compound caused dose limitation in clinical studies and the acidic group reduces metabolic stability, researchers have made several structural optimizations and obtained potent derivatives with improved whole blood activity (IC50 < 250 nM). Compound PF-4693627 has advanced to the clinical trial phase in patients with osteoarthritis and rheumatoid arthritis due to its safety profile for preliminary clinical studies, but there are no current results reported [9].
Although Boehringer Ingelheim's 2-amino benzimidazole derivatives are also of high potency (IC50: 3-220 nM) (WO2012/022793A1), they developed a new framework and entered clinical studies. The compound is recently owned by Gesynta Pharma as GS-248 (OX-MPI/ BI- 1029539), and the Phase-II clinical trial (NCT04036227) for systemic sclerosis is in progress [10].
When Glenmark Pharma researchers investigated the mPGES-1 inhibitory properties of quinazolin-4(3H)-one, pyrido[4,3-d]pyrimidin-4(3H)-one, and pyrido[2,3-d]pyrimidin-4(3H)- one derivatives, they showed potent mPGES-1 inhibition (IC50: 4-16 nM) in cell-free experiments, while also showing good inhibitory activity (IC50: 234-328 nM) in whole blood experiments. A pyrido[4,3-d]pyrimidin-4(3H)-one derivative from these series as selective mPGES-1 inhibitor has been observed to decrease PGE2 production in in vivo animal experiments (IC50: 5 nM) [5]. Glenmark Pharma researchers also studied mPGES-1 inhibition of 2-aminobenzimidazole derivatives and potent inhibitory activities were observed [11].
Lilly’s LY3031207 and LY3023703, 2-acylamino imidazole derivatives, are the first compounds to enter the clinical trials, demonstrating that mPGES-1 can be a therapeutic target for treatment of pain and inflammation. However, clinical studies were discontinued in Phase- II because these compounds caused drug-dependent hepatotoxicity [12, 13].
Dainippon Sumitomo Pharma discovered a new skeleton, working on candidate compounds with a good oral bioavailability from imidazoquininoline-derivatives containing phenyl in positions 2 and 7, which are 1,000-fold more selective to mPGES-1 than COX- 1/2, with a good ADME profile and potent inhibitor efficiency (IC50: 4.1 nM) [14, 15].
Eli Lilly company, with the support of molecular modeling studies, discovered two new potent derivatives containing 2- amino imidazole, 2-chlorobenzamide and pivaloyl amide or isosteric structures in their skeleton (IC50: 26-27 nM). While these compounds showed potent inhibition of mPGES-1, they also had FLAP inhibition and were found to act as dual inhibitors [16].
In 2020, the identified compound ISC-27864 (GRC-27864), a novel mPGES-1 inhibitor, completed Phase-II study in treating moderate osteoarthritis pain. Although the results of the phase studies have not been published yet, no negative reports have been made during the studies [10].
It has been observed that mPGES-1 expression and PGE2 production are characteristic in diseases such as atherosclerosis, rheumatoid arthritis, osteoarthritis, periodontitis, inflammatory kidney damage, Alzheimer's and cancer. mPGES-1 has been identified as a good target for drug development against inflammatory diseases including above ones but not limited to [4],
In this invention, new benzimidazole compounds as mPGES-1 inhibitors were designed and synthesized to solve the problems with preceding mPGES-1 inhibitors. Brief Description of the Invention:
The present invention relates to compounds having the following Formula I:
Figure imgf000005_0001
Formula 1.
RI is selected from the group consisting of methyl or trifluoromethyl;
R2 is selected from the group consisting of hydrogen or methyl;
R3 is selected from the group consisting of o-, m- and/or p-substituted phenyl and pyridine rings;
A is selected from the group consisting of methylene, ethylene, oxy-methylene, thio-methylene, methylene-thio or is omitted;
X is selected from the group consisting of amide (-NH-C(=O)-), sulfonamide (-NH-SO2-), and urea (-NH-C(=O)-NH-), relates to a compound, and/or its pharmaceutically acceptable salts and/or solvates.
Purpose of the Invention:
The aim of the present invention is to develop new compounds that inhibit the inducible mPGES-1, an enzyme that catalyzes the last step in the biosynthesis PGE2 from the AA for treatment of inflammatory diseases such as Parkinson's disease, autoimmune diseases, allergic disorders, rhinitis, coronary heart disease, ulcers, osteoarthritis, rheumatoid arthritis, systemic sclerosis, periodontitis, colon cancer, inflammatory bowel disease, cutaneous sclerosis, neuropathic pain, inflammation, pain, fever, migraine, chronic pain, acute pain, headache, asthma, pulmonary fibrosis, fibromyalgia, dysmenorrhea, atherosclerosis, gout, arthritis, osteoarthritis, rheumatoid arthritis, rheumatic fever, multiple sclerosis, Hodgkin's disease, conjunctivitis, ankylosing spondylitis, eczema, psoriasis, systemic lupus erythematosus, pancreatitis, diabetes, cancer, vasculitis, neurodegenerative disorders such as Alzheimer's disease.
Since the result of the epidemiological studies conducted between 1990 and 2017 indicates that almost 50% of the world population has a chronic inflammatory disease (10), the selective inhibition of the mPGES-1 with a low side-effect profile as compared to traditional NSAIDs and COX-2 inhibitors, provides new treatment options for all inflammation-related disorders as outlined above.
Detailed Description of the Invention: The present invention relates to compounds having the following Formula I:
Figure imgf000006_0001
Ri is selected from the substituent group whose structure is drawn below,
Figure imgf000006_0002
R2 is selected from the substituent group whose structure is drawn below,
Figure imgf000006_0003
R3 is selected from the substituent group whose structure is drawn below,
Figure imgf000006_0004
A is selected from the substitution group whose structure is drawn below or is omitted,
Figure imgf000006_0005
X is selected from the substitution group whose structure is drawn below,
Figure imgf000007_0001
relates to a compound obtained with these substitution groups, and/or pharmaceutically acceptable salts and/or solvates thereof.
The compounds of the present invention may be any of the following compounds:
2-Chloro--N--(4-((5-(trifluoromethyl)-1H -benzo[<i]imidazol-2-yl)methyl)phenyl)benzamide
(Compound 3),
2-Chloro-4-nitro-N--(4-((5-(trifluoromethyl)-1H -benzo[d]]imidazol-2-yl)methyl)phenyl) benzamide (Compound 4),
2-Chloro-N--(4-((5-(trifluoromethyl)-1H -benzo[<i]imidazol-2-yl)methyl)phenyl) nicotinamide (Compound 5),
3-Chloro-N--(4-((5-(trifluoromethyl)-1H -benzo[<i]imidazol-2-yl)methyl)phenyl) isonicotinamide (Compound 6),
2-Methyl-N--(4-((5-(trifluoromethyl)-1H -benzo[<i]imidazol-2-yl)methyl)phenyl)benzamide
(Compound 7),
2-(Trifluoromethyl)-N--(4-((5-(trifluoromethyl)- 1H --benzo1H i-midazol-2-yl)methyl)phenyl) benzamide (Compound 8),
2-(Difluoromethyl)-N--(4-((5-(trifluoromethyl)- 1H -benzo[d]imidazol-2-yl)methyl)phenyl) benzamide (Compound 9),
2-Chloro-6-fluoro-N--(4-((5-(trifluoromethyl)-1H -benzo1H i-midazol-2-yl)methyl)phenyl) benzamide (Compound 10),
2-Fluoro-N--(4-((5-(trifluoromethyl)-1H -benzo1H i-midazol-2-yl)methyl)phenyl)benzamide
(Compound 11),
2-(Trifluoromethoxy)-N--(4-((5-(trifluoromethyl)- 1H --benzo1H i-midazol-2-yl)methyl) phenyl) benzamide (Compound 12),
2-Chloro-5-((3,3,3-trifluoro-2,2-dimethylpropanamido)methyl)-N--(4-((5-(trifluoromethyl)-
1H -benzo[d/]imidazol-2-yl)methyl)phenyl)benzamide (Compound 15),
2-Chloro-5-(pivalainidoincthyl)-AM4-((5-(trifhioroincthyl)- l/7-bcnzoh/]imidazol-2- yl)methyl)phenyl)benzamide (Compound 16), 2-Chloro-N--(4-((5-(trifluoromethyl)-1H -benzo[<i]imidazol-2-yl)methyl)phenyl)-5-((l- (trifluoromethyl)cyclopropane-l-carboxamido)methyl)benzamide (Compound 17),
2-Chloro-Nf-(4-((5-(trifluoromethyl)1H --benzo[d]]imidazol-2-yl)methyl)phenyl)-5-((l-
(trifluoromethyl)cyclobutane- 1 -carboxamido)methyl)benzamide (Compound 18),
2-Chloro-N--(4-((5-methyl-1H -benzo[d]]imidazol-2-yl)methyl)phenyl)benzamide
(Compound 19),
2-Chloro-N--(4-((l-methyl-5-(trifluoromethyl)-1H -benzo1H i-midazol-2-yl)methyl) phenyl)benzamide (Compound 20),
2-Chloro-N--(4-((5-(trifluoromethyl)-1H -benzo[d]]imidazol-2-yl)methoxy)phenyl) benzamide (Compound 24),
2-Chloro-Nf-(4-(((5-(trifluoromethyl)-1H -benzo[d]]imidazol-2-yl)methyl)thio)phenyl) benzamide (Compound 25),
2-Chloro-N--(4-(((5-(trifluoromethyl)-1H -benzo[d]]imidazol-2-yl)thio)methyl)phenyl) benzamide (Compound 27),
2-Chloro-N--(4-(2-(5-(trifluoromethyl)-1H -benzo[d]]imidazol-2-yl)ethyl)phenyl)benzamide
(Compound 30),
2-Chloro-N--(4-((5-(trifluoromethyl)-1H -benzo[d]]imidazol-2-yl)methyl)phenyl) benzenesulfonamide (Compound 32),
1 -(2-Chlorophenyl) -3 -(4- ((5-(trifluoromethyl)- 1 H- benzo \d\ imidazol-2-yl)methyl)phenyl) urea (Compound 33),
2-Chloro-N--(4-(5-(trifluoromethyl)-1H -benzo[d]]imidazol-2-yl)phenyl)benzamide
(Compound 36),
2-(Trifluoroincthyl)-A/-(4-(5-(trifluoromcthyl)-l/7-bcnzo[d]]iinidazol-2-yl)phcnyl) benzamide (Compound 37),
2-(Difluoromethyl)-Nf-(4-(5-(trifluoromethyl)-1H -benzo[d]]imidazol-2-yl)phenyl) benzamide (Compound 38),
2-Chloro-5-((3,3,3-trifluoro-2,2-dimethylpropanamido)methyl)7V-(4-(5-(trifluoromethyl)-
1H -benzo[d]]imidazol-2-yl)phenyl)benzamide (Compound 40),
2-Chloro-5-(pivalamidomethyl)-Nf-(4-(5-(trifluoromethyl)-1H -benzo1H i-midazol-2- yl)phenyl)benzamide (Compound 41),
2-Chloro-Nf-(4-(5-(trifluoromethyl)-1H -benzo[d]]imidazol-2-yl)phenyl)-5-((l-
(trifluoromethyl)cyclopropane-l-carboxamido)methyl)benzamide (Compound 42),
2-Chloro-Nf-(4-(5-(trifluoromethyl)-1H -benzo[d]]imidazol-2-yl)phenyl)-5-((l-
(trifluoromethyl)cyclobutane- l-carboxamido)methyl)benzamide (Compound 43), 2-(Difluoromethyl)-5-((3,3,3-trifluoro-2,2-dimethylpropanamido)methyl)-A-(4-(5-
(trifluoromethyl)- 1 /7-bcnzo[d]| i midazol-2-yl )phenyl )benzamide (Compound 52),
2-(Difluoromethyl)-5-(pivalamidomethyl)-A-(4-(5-(trifluoromethyl)-1H -benzo[<i]imidazol-
2-yl)phenyl)benzamide (Compound 53),
2-(Difluoromethyl)-Nf-(4-(5-(trifluoromethyl)-1H -benzo[<i]imidazol-2-yl)phenyl)-5-((l-
(trifluoromethyl)cyclopropane-l-carboxamido)methyl)benzamide (Compound 54),
2-(Difluoromethyl)-Nf-(4-(5-(trifluoromethyl)-1H -benzo[<i]imidazol-2-yl)phenyl)-5-((l-
(trifluoromethyl)cyclobutane- l-carboxamido)methyl)benzamide (Compound 55),
2-Chloro-A-(3-((5-(trifluoromethyl)-1H -benzo[<i]imidazol-2-yl)methyl)phenyl)benzamide
(Compound 58),
2-Chloro-Nf-(3-(5-(trifluoromethyl)1H --benzo[<i]imidazol-2-yl)phenyl)benzamide
(Compound 59).
Synthetic Methodology for Compounds of the Invention:
Figure imgf000009_0001
Derivatives with R3 modifications when A is methylene, Ri is -CF3, R2 is -H, and X is -NH-
CO-:
Synthesis methods including the following steps for Compounds 3-12 are shown in Scheme 1: i) Step A: 4-aminophenylacetic acid, MeOH and H2SO4 were refluxed to give methyl 2-(4-aminophenyl)acetate (compound 1) (Method A). ii) Step B - Amide formation on the amino group: For 2a, compound 1 was reacted with 2-chlorobenzoyl chloride in DCM in the presence of Et3N, at room temperature and under nitrogen gas. (Method Bl). For 2b-j; compound 1 was reacted with appropriate acid derivatives in the presence of EDC.HC1 and DMAP in DCM at room temperature and under nitrogen gas (Method B2). iii) Step C - Ester hydrolysis: The 2a-j intermediate amide derivatives from Step B were hydrolyzed at the ester group in a mixture of THF:water (1:1) and LiOH.thO to give acid derivatives 2a-j (Method C). iv) Step D, E: Compounds 3-12 were synthesized by reaction of 2a-j with 4- (trifluoromethyl)benzene-l,2-diamine in DCM in the presence of EDC.HC1 and DMAP, at room temperature under nitrogen gas, and then refluxed in AcOH (Method D, E).
Figure imgf000010_0001
Scheme 1. Synthesis of compounds 3-12. Reagents and conditions: A) H2SO4, MeOH, A; B) For 2a; 2-Chlorobenzoyl chloride, EtsN, DCM, room temperature, under nitrogen gas; For 2b: 2-chloro-4-nitrobenzoic acid, for 2c: 2-chloronicotinic acid, for 2d: 3- chloroisonicotinic acid, for 2e: 2-methylbenzoic acid, for 2f: 2-(trifluoromethyl)benzoic acid, for 2g: 2-(difluoromethyl)benzoic acid, for 2h: 2-chloro-6-fluorobenzoic acid, for 2i: 2-fluorobenzoic acid or for 2j: 2-(trifluoromethoxy) benzoic acid, EDC.HC1, DMAP, DCM, room temperature, under nitrogen gas; C) EiOH.thO, THF:Water (1:1), A; D) 4- (trifluoromethyl)benzene-l,2-diamine, EDC.HC1, DMAP, DCM, room temperature, under nitrogen gas; E) AcOH, A.
Synthesis methods including the following steps for Compounds 15-18 are shown in Scheme 2: i) Step A - Amide formation on the primer amine group: For 13a: 3,3,3-trifluoro-2,2- dimethyl propionic acid, for 13b: pivalic acid, for 13c: 1-
(trifluoromethyl)cyclopropane-l -carboxylic acid and for 13d: l-(trifluoromethyl) cyclobutane- 1 -carboxylic acid was taken into DCM, and SOCh and a catalytic amount of DMF were added. It was stirred at 50°C under nitrogen gas for 3 hours to obtain acyl chloride derivative. The obtained solution was slowly added to mixture of methyl 5-(aminomethyl)-2-chlorobenzoate hydrochloride and EtiN in DCM at 0°C, brought to room temperature and stirred under nitrogen gas (Method F). ii) Step B - Ester hydrolysis: Acid derivatives 13a-d were obtained by ester hydrolysis reaction under the same condition that was used in Method C. iii) Step C: Acid derivatives (13a-d) and compound 1 were reacted under the same condition that was used in Method B2 to give ester intermediate products. Step D: Carboxylic acid derivatives (14a-d) were obtained by ester hydrolysis reaction by using same condition that was used in Method C. iv) Step E, F: Compounds 15-18 were prepared by using Method D, E.
Figure imgf000011_0001
Scheme 2. Synthesis of compounds 15-18. Reagents and conditions: A) z) For 13a: 3,3,3- trifluoro-2,2-dimethylpropionic acid, for 13b: pivalic acid, for 13c: 1-
(trifluoromethyl)cyclo propane- 1 -carboxylic acid, for 13d: l-(trifluoromethyl)cyclobutane- 1-carboxylic acid, SOCI2, cat. DMF, DCM; z’z) first step reaction mixtures, EtsN, DCM, room temperature, under nitrogen gas; B) LiOH.FhO, THF:Water (1:1), A; C) Compound 1, EDC.HC1, DMAP, DCM, room temperature, under nitrogen gas; D) LiOH.FhO, THF:Water (1:1), A; E) 4-(trifluoromethyl) benzene- 1,2-diamine, EDC.HC1, DMAP, DCM, room temperature, under nitrogen gas; F) AcOH, A.
Compounds with the one of the Ri or R2 is -CH3 when A is methylene, B is phenyl, R3 is 2-chlorophenyl, and X is -CO: Synthesis methods including the following steps for Compounds 19-20 are shown in Scheme 3: i) Step A, B: Prepared from 4-(methyl)benzene-l,2-diamine (for 19) or A/-mcthyl-4- (trifluoromethyl) benzene- 1,2-diamine (for 20) and compound 2a under the same conditions that were used in Method D, E.
Figure imgf000012_0001
Scheme 3. Synthesis of compounds 19 and 20. Reagents and conditions: A) For 19: 4- (methyl)benzene- 1,2-diamine, for 20: A7-methyl-4-(trifluoromethyl)benzene- 1,2-diamine, EDC.HC1, DMAP, DCM, room temperature, under nitrogen gas; B) AcOH, A.
Derivatives with A group modifications, Ri is -CF3, R2 is -H, X is -NH-CO- and R3 is 2- chlorophenyl:
Synthesis methods including the following steps for Compounds 24-25 are shown in Scheme 4: i) Step A: To a solution of 4-nitrophenol (for 21a) or 4-nitrothiophenol (for 21b) in AcCN, K2CO3 and methyl bromoacetate were added. The reaction mixture was refluxed to obtain compounds 21a-b. ii) Step B: Compounds 22a-b were obtained by catalytic hydrogenation of 21a or 21b with Pd/C under hydrogen gas at room temperature. iii) Step C, D: Compounds 23a-b were prepared by reaction of compound 22a or 22b with 2-chlorobenzoyl chloride according to Method B 1 in the first amidation step, and then Method C in the second ester hydrolysis step. v) Step E, F: Compounds 24-25 were prepared from Compounds 23a-b according to Method D, E.
Figure imgf000013_0002
Scheme 4. Synthesis of compounds 24 and 25. Reagents and conditions: A) K2CO3, methylbromoacetate, AcCN, A; B) Pd/C, MeOH, room temperature, under hydrogen gas; C) 2- Chlorobenzoyl chloride, EtsN, DCM, room temperature, under nitrogen gas; D) LiOH.H2O, THF:Water (1:1), A; E) 4-(trifluoromethyl) benzene- 1,2-diamine, EDC.HC1, DMAP, DCM, room temperature, under nitrogen gas; F) AcOH, A.
Synthesis method including the following steps for Compound 27 is shown in Scheme 5: i) Step A: 4-(Trifluoromethyl)benzene-l,2-diamine was dissolved in EtOH, then KOH and CS2 were added and refluxed to give compound 26. ii) p- Aminobenzyl alcohol was dissolved in THF, 2-chlorobenzoyl chloride was added and stirred at 0°C to give 2-chloro-A-(4-(hydroxymethyl)phenyl)benzamide. The obtained product was dissolved in DCM, CBr4 and PPhs were added and stirred at 0°C to give A-(4-(bromomethyl)phenyl)-2-chlorobenzamide. Step B: Compound 26 obtained in step A and A-(4-(bromomethyl)phenyl)-2-chlorobenzamide were dissolved in AcCN, then K2CO3 was added and stirred at 50°C to give compound 27.
Figure imgf000013_0001
Scheme 5. Synthesis of compound 27. Reagents and conditions: A) KOH, CS2, EtOH, A;
B) A-(4-(bromomethyl)phenyl)-2-chlorobenzamide, K2CO3, AcCN, 50°C.
Synthesis method including the following steps for Compound 30 is shown in Scheme 6: i) Step A: Compound 28 was prepared from 3-(4-aminophenyl)propanoic acid under the same conditions that was used in Method A. ii) Step B, C: Amide derivative was prepared from Compound 28 and 2-chlorobenzoyl chloride under the same condition that was used in Method Bl. Acid derivative 29 was synthesized by ester hydrolysis under the same condition that was used in Method C. iii) Step D, E: Compound 30 was prepared by reaction of acid derivative 29 with 4- (trifluoromethyl)benzene-l,2-diamine under the same conditions that were used in Method D, E.
Figure imgf000014_0001
Scheme 6. Synthesis of compound 30. Reagents and conditions: A) H2SO4, MeOH, A; B) 2- Chlorobenzoyl chloride, EtsN, DCM, room temperature, under nitrogen gas; C) LiOH.fUO, THF:D.Water (1:1), A; D) 4-(trifluoromethyl)benzene-l,2-diamine, EDC.HC1, DMAP, DCM, room temperature, under nitrogen gas; E) AcOH, A.
Derivatives with X modifications when A is methylene, Ri is -CF3, R2 is -H, and R3 is 2- chlorophenyl:
Synthesis methods including the following steps for Compounds 32-33 are shown in Scheme 7: i) Step A: Sulfonamide intermediate was prepared by reaction of compound 1 with 2- chlorobenzene sulfonyl chloride under the same conditions that was used in Method Bl. Urea intermediate was synthesized by reaction of Compound 1 with 2-chloro- 2-isocyanatobenzene in DMF. Step B: Acid derivatives 31a-b were prepared from the intermediates from Step A by ester hydrolysis under the same condition that was used in Method C. ii) Step C, D: Compound 32, 33 were prepared by reaction of 4- (trifluoromethyl)benzene-l,2-diamine with acid derivatives 31a-b under the same conditions that were used in Method D, E.
Figure imgf000015_0001
Scheme 7. Synthesis of compounds 32 and 33. Reagents and conditions: A) For 31a; 2- chlorobenzene sulfonyl chloride, EtsN, DCM, room temperature, under nitrogen gas; for 31b: 2-chloro-2-isocyanatobenzene, DMF, room temperature; B) LiOH.FhO, THF:water (1:1), A; C) 4-(trifluoromethyl)benzene-l,2-diamine, EDC.HC1, DMAP, DCM, room temperature, under nitrogen gas; D) AcOH, A.
Derivatives with modifications of R3 when A is omitted, Ri is -CF3, R2 is -H, and X is -NH-
CO-:
Synthesis methods including the following steps for Compounds 36-38 are shown in Scheme 8: i) Step A: Methyl 4-aminobenzoate 34 was prepared from 4-aminobenzoic acid under the same condition that was used in Method A. ii) Step B, C: First Compound 34 and 2-chlorobenzoyl chloride was reacted to form amide intermediate under the same condition that was used in Method Bl, which was subsequently hydrolyzed to give compound 35a in the second step. Compound 35b or c were prepared by reaction of compound 34 with 2-(trifluoromethyl)benzoic acid or 2-(difluoromethyl)benzoic acid under the same conditions that were used in Method B2, and then with ester hydrolysis by using Method C. iii) Step D, E: Compound 36, 37 and 38 were prepared by reaction of 4- (trifluoromethyl)benzene-l,2-diamine with acid derivatives 35a, b or c under the same conditions that were used in Method D, E.
Figure imgf000015_0002
Scheme 8. Synthesis of compounds 36, 37 and 38. Reagents and conditions: A) H2SO4, MeOH, A; B) For 35 a: 2-Chlorobenzoyl chloride, EtsN, DCM, room temperature, under nitrogen gas; for 35b and c: 2-(trifluoromethyl)benzoic acid or 2-(difluoromethyl)benzoic acid, EDC.HC1, DMAP, DCM, room temperature, under nitrogen gas; C) LiOH.tkO, THF:Water (1:1), A; D) 4-(trifluoromethyl)benzene-l,2-diamine, EDC.HC1, DMAP, DCM, room temperature, under nitrogen gas; E) AcOH, A.
Synthesis methods including the following steps for Compounds 40-43 are shown in Scheme 9: i) 3,3,3-trifluoro-2,2-dimethyl propionic acid (For 40), pivalic acid (for 41), 1- (trifluoromethyl)cyclopropane-l -carboxylic acid (for 42) or 1- (trifluoromethyl)cyclo butane- 1 -carboxylic acid (for 43) was used to obtain Compounds 13a-d by using Method F, and then Method C. ii) Step A, B: Acid derivatives 39a-d were prepared from compound 13a-d by using Method B2 and then Method C. iii) Step C, D: Compounds 40-43 were prepared from 4-(trifluoromethyl)benzen-l,2- diamine and compounds 39a-d under the same conditions that were used in Method D, E.
Figure imgf000016_0001
Compound 41 Compound 43
Scheme 9. Synthesis of compounds 40-43. Reagents and conditions: A) Compound 34, EDC.HC1, DMAP, DCM, room temperature, under nitrogen gas; B) LiOH.tEO, THF:Water (1:1), A; C) 4-(trifluoromethyl)benzene-l,2-diamine, EDC.HC1, DMAP, DCM, room temperature, under nitrogen gas; D) AcOH, A.
Synthesis methods including the following steps for Compounds 52-55 are shown in Scheme 10: i) Step A, B : Amide formation on the primer amine group was accomplished according to Method F: Briefly, for 44: 3,3,3-trifluoro-2,2-dimethyl propionic acid, for 45: pivalic acid, for 46: l-(trifluoromethyl)cyclopropane-l -carboxylic acid or for 47: 1- (trifluoromethyl)cyclobutane-l -carboxylic acid was dissolved in DCM, and then SOCh and a catalytic amount of DMF were added, and stirred at 50°C under nitrogen gas for 3 hours. In another flask, EtsN was added to methyl 5- (aminomethyl)-2-chlorobenzoate hydrochloride in DCM and stirred at 30°C for 30 minutes. Afterwards, the first reaction mixture was slowly added to the 2nd mixture at 0°C, then stirred at room temperature under nitrogen gas, and the obtained amide intermediates are hydrolyzed under the same conditions that were applied in Method D, to give 44-47. ii) Step C, D: The reaction of compound 34 with compound 44-47 under the same conditions that were applied to Method B2, to synthesize amide intermediates, which were subsequently hydrolyzed at the ester group to acid derivatives 48-51 according to the Method C. iv) Step E, F: Compounds 52-55 were prepared from 4-(trifluoromethyl)benzen-l,2- diamine and compounds 48-51 under the same conditions that were used in Method D, E.
Figure imgf000017_0001
Scheme 10. Synthesis of compound 52-55. Reagents and conditions: A) For 44: 3,3,3- trifluoro-2,2-dimethyl propionic acid, for 45: pivalic acid, for 46: 1- (trifluoromethyl)cyclopropane-l -carboxylic acid or for 47: 1 -(trifluoromethyl)cyclobutane-l- carboxylic acid, EDC.HC1, DMAP, DCM, room temperature, under nitrogen gas; B) LiOH.H2O, THF: Water (1:1), A; C) Compound 34, EDC.HC1, DMAP, DCM, room temperature, under nitrogen gas; D) LiOH.h2O, THF:D.Water (1:1), A; E) 4- (trifluoromethyl)benzene-l,2-diamine, EDC.HC1, DMAP, DCM, room temperature, under nitrogen gas; F) AcOH, A.
When Ri is -CF3, R2 is -H, R3 is 2-chlorophenyl, X is -NH-CO-, when A is omitted or methylene and derivatives with modifications at their bonding positions: Synthesis methods including the following steps for Compounds 58-59 are shown in Scheme 11: i) Step A: Ester derivatives 56a or 56b were prepared from 3-(amino)phenylacetic acid (for 56a) or 3 -aminobenzoic acid (for 56b) under the same conditions that were applied at Method A. ii) Step B, C: First, amide intermediates are prepared by reaction of compound 56a or 56b with 2-chlorobenzoyl chloride under the same conditions that were applied to Method Bl. Second, the obtained amide intermediates were then hydrolyzed at the ester group under the same conditions that were applied in Method C to give acid derivatives 57a or 57b. v) Step D, E: Compounds 58-59 were prepared from 4-(trifluoromethyl)benzen-l,2- diamine and compounds 57a and 57b, respectively, under the same conditions that were used in Method D, E.
Figure imgf000018_0001
Compound 56a -b Compound 57a-b Compound 58 n: 1
Compound 59 n: 0
Scheme 11. Synthesis of compounds 58 and 59. Reagents and conditions: A) H2SO4, MeOH, A; B) 2-Chlorobenzoyl chloride, EtsN, DCM, room temperature, under nitrogen gas; C) LiOH.thO, THF:Water (1:1), A; D) 4-(trifluoromethyl)benzene-l,2-diamine, EDC.HC1, DMAP, DCM, room temperature, under nitrogen gas; E) AcOH, A.
Table 1. Chemical structures of the compounds of the present invention
Figure imgf000018_0002
Figure imgf000019_0001
Figure imgf000020_0001
Figure imgf000021_0001
Biological Activity
Determination of microsomal Prostaglandin E2 synthase activity For mPGES-1 activity assay, A549 cells were prepared according to the method specified in the literature [17]. Briefly, A549 cells were incubated for 72 hours at 37°C under 5% CO2 in DMEM (Dulbecco's Modified Eagle Media) medium containing FCS (Fetal calf serum, 2%) and IL-ip (2 ng/mL). After incubation, cells were harvested and stored in potassium phosphate buffer (0.1 M, pH 7.4), phenylmethanesulfonyl fluoride (PMSF, 1 pM), soy trypsin inhibitor (STI, 60 pg/mL), leupeptin (1 pg/mL), 2.5 pM glutathione, and After suspended in 1 mL homogenization solution consisting of sucrose (250 pM), it was diluted with 0.1 M potassium phosphate buffer containing 2.5 pM glutathione. Next, the cells were frozen in liquid nitrogen, sonicated three times for 20 seconds each, differential centrifugation was first performed at 4°C for 10 minutes and then centrifuged again for 1 hour at 4°C. The pellets were then resuspended in the same homogenization buffer. Microsomes were diluted with glutathione (2 mM) in potassium phosphate buffer (0.1 M, pH 7.4) and pre-incubated for 15 minutes with the addition of test compound or control (0.1% DMSO). After pre-incubation, 20 pM PGH2 substrate was added. After 1 min at 4°C, the reaction was terminated by adding 100 pl of solution (40 pM FeCh, 80 pM citric acid and 10 pM I IP-PGE2) stop solution. The formation of the PGE2 product was analyzed by HPLC method. The activity results of the compounds whose mPGES- 1 inhibition activities were tested using this method are shown in Table 2.
Table 2. mPGES-1 activity values of the compounds of the present invention
Figure imgf000022_0001
Figure imgf000023_0001
Table 3. XH-NMR, 13C-NMR and LC-MS values of the compounds of the present invention
Figure imgf000023_0002
Figure imgf000024_0001
Figure imgf000025_0001
Figure imgf000026_0001
Figure imgf000027_0001
Figure imgf000028_0001
REFERENCES
1. Cote, B., et al., Substituted phenanthrene imidazoles as potent, selective, and orally active mPGES-1 inhibitors. Bioorganic & Medicinal Chemistry Letters, 2007. 17(24): p. 6816-6820.
2. Giroux, A., et al., Discovery of disubstituted phenanthrene imidazoles as potent, selective and orally active mPGES-1 inhibitors. Bioorganic & Medicinal Chemistry Letters, 2009. 19(20): p. 5837-5841. 3. Wang, J., et al., Selective inducible microsomal prostaglandin E2 synthase-1 (mPGES- 1 ) inhibitors derived from an oxicam template. Bioorganic & Medicinal Chemistry Letters, 2010. 20(5): p. 1604-1609.
4. Koeberle, A. and O. Werz, Perspective of microsomal prostaglandin E2 synthase-1 as drug target in inflammation-related disorders. Biochemical Pharmacology, 2015. 98(1): p. 1-15.
5. Banerjee, A., et al., Development of 2-aryl substituted quinazolin-4(3H)-one, pyrido[4,3-d]pyrimidin-4(3H)-one and pyrido[2,3-d]pyrimidin-4(3H)-one derivatives as microsomal prostaglandin E2 synthase-1 inhibitors. Bioorganic & Medicinal Chemistry Letters, 2014. 24(20): p. 4838-4844.
6. Jakobsson, P.J., et al., Identification of human prostaglandin E synthase: a microsomal, glutathione-dependent, inducible enzyme, constituting a potential novel drug target. Proceedings of the National Academy of Sciences of the United States of America, 1999. 96(13): p. 7220-7225.
7. Wu, T.Y.H., et al., Biarylimidazoles as inhibitors of microsomal prostaglandin E2 synthase-1. Bioorganic & Medicinal Chemistry Letters, 2010. 20(23): p. 6978-6982.
8. Arhancet, G.B., et al., Discovery and SAR ofPF-4693627, a potent, selective and orally bioavailable mPGES-1 inhibitor for the potential treatment of inflammation. Bioorganic & Medicinal Chemistry Letters, 2013. 23(4): p. 1114-1119.
9. Walker, D.P., et al., Synthesis and biological evaluation of substituted benzoxazoles as inhibitors of mPGES-1: Use of a conformation-based hypothesis to facilitate compound design. Bioorganic & Medicinal Chemistry Letters, 2013. 23(4): p. 1120-1126.
10. Zhang, Y.-Y., et al., Microsomal prostaglandin E2 synthase-1 and its inhibitors: Molecular mechanisms and therapeutic significance. Pharmacological Research, 2022. 175: p. 105977.
11. Muthukaman, N., et al., Discovery of2-((2-chloro-6-fluorophenyl)amino)-N-(3-fluoro- 5-(trifluoromethyl)phenyl)-l-methyl-7,8-dihydro-lH-[l,4]dioxino[2',3':3,4]benzo[l,2- d]imidazole-5-carboxamide as potent, selective and efficacious microsomal prostaglandin E2 synthase-1 (mPGES-1 ) inhibitor. Bioorganic & Medicinal Chemistry Letters, 2016. 26(24): p. 5977-5984.
12. Norman, B.H., et al., Identification and Mitigation of Reactive Metabolites of 2- Aminoimidazole-Containing Microsomal Prostaglandin E Synthase-1 Inhibitors Terminated Due to Clinical Drug-Induced Liver Injury. Journal of Medicinal Chemistry, 2018. 61(5): p. 2041-2051.
13. Schiffler, M.A., et al., Discovery and Characterization of 2 -Acylaminoimidazole Microsomal Prostaglandin E Synthase-1 Inhibitors. Journal of Medicinal Chemistry, 2016. 59(1): p. 194-205.
14. Shiro, T., et al., Synthesis and SAR study of imidazoquinolines as a novel structural class of microsomal prostaglandin E2 synthase-1 inhibitors. Bioorganic & Medicinal Chemistry Letters, 2012. 22(1): p. 285-288.
15. Shiro, T., et al., 7-Phenyl-imidazoquinolin-4(5H)-one derivatives as selective and orally available mPGES-1 inhibitors. Bioorganic & Medicinal Chemistry, 2013. 21(11): p. 2868-2878.
16. Ho, J.D., et al., Structure-based, multi-targeted drug discovery approach to eicosanoid inhibition: Dual inhibitors of mPGES-1 and 5 -lipoxygenase activating protein (FLAP). Biochimica et Biophysica Acta (BBA) - General Subjects, 2021. 1865(2): p. 129800.

Claims

1. At least one of the compounds shown in Formula (I) and/or its pharmaceutically acceptable salt and/or solvate thereof:
Figure imgf000030_0001
Formula 1. wherein,
Ri is selected from the group consisting of methyl or trifluoromethyl;
R2 is selected from the group consisting of hydrogen or methyl;
R3 is selected from the substituent group whose structure is drawn below,
Figure imgf000030_0002
A is selected from the group consisting of methylene, ethylene, oxy-methylene, thio-methylene, methylene-thio or is omitted;
X is selected from the group consisting of amide, sulfonamide and urea; relates to a compound, and/or its pharmaceutically acceptable salts and/or solvates.
2. The compound according to claim 1 is a compound and/or its pharmaceutically acceptable salts and/or solvates from the compounds whose chemical structure is drawn below:
Figure imgf000031_0001
Figure imgf000032_0001
Figure imgf000033_0001
3. The compounds or pharmaceutically acceptable salts and/or solvates thereof according to claim 1 and 2 selected from the group consisting of the following compounds: 2-Chloro-N--(4-((5-(trifluoromethyl)-1H-benzo[d]]imidazol-2-yl)methyl)phenyl)benzamide(Compound3) 2-Chloro-4-nitro-Nf-(4-((5-(trifluoromethyl)1H--benzo[<i]imidazol-2-yl)methyl)phenyl)benzamide(Compound4) 2-Chloro-Nf-(4-((5-(trifluoromethyl)1H--benzo[<i]imidazol-2-yl)methyl)phenyl)nicotinamide(Compound5) 3-Chloro-Nf-(4-((5-(trifluoromethyl) 1H--benzo[d]imidazol-2-yl)methyl)phenyl)isonicotinamide(Compound6) 2-Methyl-Nf-(4-((5-(trifluoromethyl)-1H-benzo[<i]imidazol-2-yl)methyl)phenyl)benzamide (Compound7) 2-(Trifluoromethyl)-N--(4-((5-(trifluoromethyl)- 1H-benzo1Hi-midazol-2-yl)methyl)phenyl)benzamide(Compound8) 2-(Difluoromethyl)-Nf-(4-((5-(trifluoromethyl)- 1H--benzo[d]imidazol-2-yl)methyl)phenyl)benzamide(Compound9) 2-Chloro-6-fluoro-Nf-(4-((5-(trifluoromethyl)-1H-benzo[d]]imidazol-2-yl)methyl)phenyl)benzamide(Compound10) 2-Fluoro-N--(4-((5-(trifluoromethyl)-1H-benzo[d]]imidazol-2-yl)methyl)phenyl)benzamide(Compound11) 2-(Trifluoromethoxy)-Nf-(4-((5-(trifluoromethyl)1H--benzo1Hi-midazol-2-yl)methyl)phenyl)benzamide(Compound12) 2-Chloro-5-((3,3,3-trifluoro-2,2-dimethylpropanamido)methyl)-N--(4-((5- (trifluoromethyl)-1H--benzo[d]]imidazol-2-yl)methyl)phenyl)benzamide(Compound15) 2-Chloro-5-(pivalamidomethyl)-Nf-(4-((5-(trifluoromethyl)-1H-benzo1Hi-midazol-2-yl)methyl)phenyl)benzamide(Compound16) 2-Chloro-N--(4-((5-(trifluoromethyl)-1H-benzo[d]]imidazol-2-yl)methyl)phenyl)-5-((l- (trifluoromethyl)cyclopropane-l-carboxamido)methyl)benzamide(Compound17) 2-Chloro-N--(4-((5-(trifluoromethyl)-1H-benzo[d]]imidazol-2-yl)methyl)phenyl)-5-((l- (trifluoromethyl)cyclobutane-1-carboxamido)methyl)benzamide(Compound18) 2-Chloro-N-(4-((5-methyl-1H-benzo[d]imidazol-2-yl)methyl)phenyl)benzamide (Compound19) 2-Chloro-Nf-(4-((l-methyl-5-(trifluoromethyl)- 1H--benzo[d]]imidazol-2-yl)methyl)phenyl)benzamide(Compound20) 2-Chloro-N--(4-((5-(trifluoromethyl)-1H-benzo[d]]imidazol-2-yl)methoxy)phenyl)benzamide(Compound24) 2-Chloro-N--(4-(((5-(trifluoromethyl)-1H -benzo[d]]imidazol-2-yl)methyl)thio)phenyl) benzamide (Compound 25)
2-Chloro-N--(4-(((5-(trifluoromethyl)-1H -benzo[d]]imidazol-2-yl)thio)methyl)phenyl) benzamide (Compound 27)
2-Chloro-Nf-(4-(2-(5-(trifluoromethyl)1H --benzo[d]]imidazol-2-yl)ethyl)phenyl) benzamide (Compound 30)
2-Chloro-N--(4-((5-(trifluoromethyl)-1H -benzo[d]]imidazol-2-yl)methyl)phenyl) benzenesulfonamide (Compound 32)
1-(2-Chlorophenyl)-3-(4-((5-(trifluoromethyl)-1H -benzo[d]]imidazol-2-yl)methyl) phenyl)urea (Compound 33)
2-Chloro-N--(4-(5-(trifluoromethyl)-1H -benzo[d]]imidazol-2-yl)phenyl)benzamide
(Compound 36)
2-(Trifluoromethyl)-Nf-(4-(5-(trifluoromethyl)-1H -benzo1H i-midazol-2-yl)phenyl) benzamide (Compound 37)
2-(Difluoromethyl)-Nf-(4-(5-(trifluoromethyl)-1H -benzo[d]]imidazol-2-yl)phenyl) benzamide (Compound 38)
2-Chloro-5-((3,3,3-trifluoro-2,2-dimethylpropanamido)methyl)-N--(4-(5-
(trifluoromethyl)- 1H --bcnzo[d]] i midazol-2-yl (phenyl (benzamide (Compound 40)
2-Chloro-5-(pivalamidomethyl)-Nf-(4-(5-(trifluoromethyl)-1H -benzo[d]]imidazol-2- yl)phenyl)benzamide (Compound 41)
2-Chloro-Nf-(4-(5-(trifluoromethyl)-1H -benzo[d]]imidazol-2-yl)phenyl)-5-((l-
(trifluoromethyl)cyclopropane- 1 -carboxamido)methyl)benzamide (Compound 42)
2-Chloro-Nf-(4-(5-(trifluoromethyl)-1H -benzo[d]]imidazol-2-yl)phenyl)-5-((l-
(trifluoromethyl)cyclobutane- l-carboxamido)methyl)benzamide (Compound 43)
2-(Difluoromethyl)-5-((3,3,3-trifluoro-2,2-dimethylpropanamido)methyl)-N--(4-(5-
(trifluoromethyl)- 1 /7-bcnzo[d] i midazol-2-yl (phenyl (benzamide (Compound 52)
2-(Difluoromethyl)-5-(pivalamidomethyl)-N- (4-(5-(trifluoromethyl)-1H -benzo [d]]imidazol-2-yl)phenyl)benzamide (Compound 53)
2-(Difluoromcthyl)-N- 4-(5-(trifluoromcthyl)-1H -bcnzo[d]]imidazol-2-yl)phenyl )-5-
((l-(trifluoromethyl)cyclopropane-l-carboxamido)methyl)benzamide (Compound 54)
2-(Difluoromcthyl)-N- 4-(5-(trifluoromcthyl)- 1H -bcnzo[d]]imidazol-2-yl)phenyl )-5-
((l-(trifluoromethyl)cyclobutane-l-carboxamido)methyl)benzamide (Compound 55)
2-Chloro-N--(3-((5-(trifluoromethyl)-1H -benzo[d]]imidazol-2-yl)methyl)phenyl) benzamide (Compound 58) 2-Chloro-N--(3-(5-(trifluoromethyl)-1H -benzo[<i]imidazol-2-yl)phenyl)benzamide (Compound 59).
4. Compound according to claims 1, 2 and 3 are inhibitors of microsomal prostaglandin E2 synthase- 1 (mPGES-1).
5. A method for treating an mPGES-1 -mediated disease, disorder or syndrome, comprising administering an effective amount of a compound according to any one of claims 1, 2 and 3.
6. The method of claim 5, wherein the disease, disorder, syndrome or condition is chronic or acute pain.
7. The method of claim 5, wherein the disease, disorder, syndrome or condition is rheumatoid arthritic pain or osteoarthritic pain.
8. The method of claim 5, wherein the disease, disorder, syndrome or condition is inflammation or inflammatory disease.
9. A use of the compounds according to claims 1, 2 and 3 or pharmaceutically acceptable salt thereof for treating or preventing inflammation, pain, fever, migraine, chronic pain, acute pain, headache, neuropathic pain, inflammatory bowel disease, asthma, pulmonary fibrosis, fibromyalgia, dysmenorrhea, atherosclerosis, gout, arthritis, osteoarthritis, rheumatoid arthritis, rheumatic fever, multiple sclerosis, Hodgkin's disease, conjunctivitis, ankylosing spondylitis, eczema, psoriasis, systemic lupus erythematosus, pancreatitis, diabetes, cancer, vasculitis, neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, autoimmune diseases, allergic disorders, rhinitis, coronary heart disease, periodontitis, cancer, endometriosis, systemic sclerosis and ulcers.
10. A pharmaceutical composition comprising a compound according to any one of claims 1, 2 or 3.
11. Pharmaceutical composition for oral and/or intravenous administration according to claim 1, 2 or 3.
12. Use of a compound of the formula according to claim 1, 2 or 3 or a pharmaceutically acceptable salt and/or solvates of a medicament for the treatment of inflammatory diseases or conditions.
13. Pharmaceutical composition comprising at least one compound according to any one of claims 1, 2 and 3 or a pharmaceutically acceptable salt and/or solvates.
PCT/TR2023/050887 2023-08-29 2023-08-29 Benzimidazole compounds and pharmaceutical compositions and uses thereof WO2024112287A1 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
PCT/TR2023/050887 WO2024112287A1 (en) 2023-08-29 2023-08-29 Benzimidazole compounds and pharmaceutical compositions and uses thereof
PCT/TR2024/051005 WO2025048759A1 (en) 2023-08-29 2024-08-28 Benzimidazole derivatives as mpges-1 inhibitors

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/TR2023/050887 WO2024112287A1 (en) 2023-08-29 2023-08-29 Benzimidazole compounds and pharmaceutical compositions and uses thereof

Publications (1)

Publication Number Publication Date
WO2024112287A1 true WO2024112287A1 (en) 2024-05-30

Family

ID=88188872

Family Applications (2)

Application Number Title Priority Date Filing Date
PCT/TR2023/050887 WO2024112287A1 (en) 2023-08-29 2023-08-29 Benzimidazole compounds and pharmaceutical compositions and uses thereof
PCT/TR2024/051005 WO2025048759A1 (en) 2023-08-29 2024-08-28 Benzimidazole derivatives as mpges-1 inhibitors

Family Applications After (1)

Application Number Title Priority Date Filing Date
PCT/TR2024/051005 WO2025048759A1 (en) 2023-08-29 2024-08-28 Benzimidazole derivatives as mpges-1 inhibitors

Country Status (1)

Country Link
WO (2) WO2024112287A1 (en)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008084218A1 (en) * 2007-01-12 2008-07-17 Boehringer Ingelheim International Gmbh Benzazole derivatives for the treatment of inflammations
WO2011099832A2 (en) * 2010-02-12 2011-08-18 Crystalgenomics, Inc. Novel benzimidazole compound, preparation method thereof and pharmaceutical composition comprising the same
WO2012022793A1 (en) 2010-08-20 2012-02-23 Boehringer Ingelheim International Gmbh New compounds
CN111875545A (en) * 2020-07-17 2020-11-03 安阳师范学院 A kind of directional synthesis method and application of 6-position substituted benzimidazole derivatives

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008084218A1 (en) * 2007-01-12 2008-07-17 Boehringer Ingelheim International Gmbh Benzazole derivatives for the treatment of inflammations
WO2011099832A2 (en) * 2010-02-12 2011-08-18 Crystalgenomics, Inc. Novel benzimidazole compound, preparation method thereof and pharmaceutical composition comprising the same
WO2012022793A1 (en) 2010-08-20 2012-02-23 Boehringer Ingelheim International Gmbh New compounds
CN111875545A (en) * 2020-07-17 2020-11-03 安阳师范学院 A kind of directional synthesis method and application of 6-position substituted benzimidazole derivatives

Non-Patent Citations (27)

* Cited by examiner, † Cited by third party
Title
ARHANCET, G.B. ET AL.: "Discovery and SAR of PF-4693627, a potent, selective and orally bioavailable mPGES-1 inhibitor for the potential treatment of inflammation.", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 23, no. 4, 2013, pages 1114 - 1119
BANERJEE, A. ET AL.: "Development of 2-aryl substituted quinazolin-4(3H)-one, pyrido[4,3-d]pyrimidin-4(3H)-one and pyrido[2,3-d]pyrimidin-4(3H)-one derivatives as microsomal prostaglandin E2 synthase-1 inhibitors.", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 24, no. 20, 2014, pages 4838 - 4844, XP029048246, DOI: 10.1016/j.bmcl.2014.08.056
CHEMISTRY LETTERS, vol. 22, no. 1, 2012, pages 285 - 288
CÔTÉ, B. ET AL.: "Substituted phenanthrene imidazoles as potent, selective, and orally active mPGES-1 inhibitors.", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 17, no. 24, 2007, pages 6816 - 6820, XP022339579, DOI: 10.1016/j.bmcl.2007.10.033
DATABASE Registry [online] Chemical Abstracts Service; 19 April 2018 (2018-04-19), ANONYMOUS: "4-(6-methyl-1H-benzimidazol-2-yl)-N-(2-methylphenyl)-benzamide", XP093131824, retrieved from STN Database accession no. 2215416-77-4 *
DATABASE Registry [online] Chemical Abstracts Service; 19 April 2018 (2018-04-19), ANONYMOUS: "N-(2-fluorophenyl)-4-(6-methyl-1H-benzimidazol-2-yl)-benzamide", XP093131823, retrieved from STN Database accession no. 2215416-81-0 *
DATABASE Registry [online] Chemical Abstracts Service; 20 April 2018 (2018-04-20), ANONYMOUS: "N-(2-chlorophenyl)-4-(6-methyl-1H-benzimidazol-2-yl)-benzamide", XP093131890, retrieved from STN Database accession no. 2216691-73-3 *
DATABASE Registry [online] Chemical Abstracts Service; 26 October 2007 (2007-10-26), ANONYMOUS: "2-methyl-N-[4-[2-(6-methyl-1H-benzimidazol-2- yl)ethyl]phenyl]-benzenesulfonamide", XP093131831, retrieved from STN Database accession no. 951593-30-9 *
DATABASE Registry [online] Chemical Abstracts Service; 3 March 2009 (2009-03-03), ANONYMOUS: "2-fluoro-N-[4-[2-(6-methyl-1H-benzimidazol-2-yl)ethyl]phenyl]-benzamide", XP093131828, retrieved from STN Database accession no. 1114604-50-0 *
DATABASE Registry [online] Chemical Abstracts Service; 3 May 2009 (2009-05-03), ANONYMOUS: "2-chloro-N-[4-[2-(6-methyl-1H-benzimidazol-2-yl)ethyl]phenyl]-benzamide", XP093131826, retrieved from STN Database accession no. 1114618-75-5 *
DATABASE Registry [online] Chemical Abstracts Service; 5 May 2008 (2008-05-05), ANONYMOUS: "2-fluoro-N-[4-[2-(6-methyl-1H-benzimidazol-2- yl)ethyl]phenyl]-benzenesulfonamide", XP093131830, retrieved from STN Database accession no. 1019175-26-8 *
DATABASE Registry [online] Chemical Abstracts Service; 7 August 2006 (2006-08-07), ANONYMOUS: "2-chloro-N-[4-(6-methyl-1H-benzimidazol-2-yl)phenyl]-4-nitro-benzamide", XP093131832, retrieved from STN Database accession no. 899296-33-4 *
DATABASE Registry [online] Chemical Abstracts Service; 7 August 2006 (2006-08-07), ANONYMOUS: "2-chloro-N-[4-(6-methyl-1H-benzimidazol-2-yl)phenyl]-benzamide", XP093131834, retrieved from STN Database accession no. 899295-39-7 *
DATABASE Registry [online] Chemical Abstracts Service; 7 August 2006 (2006-08-07), ANONYMOUS: "2-methyl-N-[4-(6-methyl-1H-benzimidazol-2-yl)phenyl]-benzamide", XP093131833, retrieved from STN Database accession no. 899295-63-7 *
DATABASE Registry [online] Chemical Abstracts Service; 7 July 2006 (2006-07-07), ANONYMOUS: "2-fluoro-N-[4-(6-methyl-1H-benzimidazol-2-yl)phenyl]-benzamide", XP093131835, retrieved from STN Database accession no. 890996-41-5 *
GIROUX, A. ET AL.: "Discovery of disubstituted phenanthrene imidazoles as potent, selective and orally active mPGES-1 inhibitors.", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 19, no. 20, 2009, pages 5837 - 5841, XP026640582, DOI: 10.1016/j.bmcl.2009.08.085
HO, J.D. ET AL.: "Structure-based, multi-targeted drug discovery approach to eicosanoid inhibition: Dual inhibitors of mPGES-1 and 5-lipoxygenase activating protein (FLAP).", BIOCHIMICA ET BIOPHYSICA ACTA (BBA) - GENERAL SUBJECTS, vol. 1865, no. 2, 2021, pages 129800
JAKOBSSON, P.J. ET AL.: "Identification of human prostaglandin E synthase: a microsomal, glutathione-dependent, inducible enzyme, constituting a potential novel drug target.", PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, vol. 96, no. 13, 1999, pages 7220 - 7225
KOEBERLE, A.O. WERZ: "Perspective of microsomal prostaglandin E2 synthase-1 as drug target in inflammation-related disorders.", BIOCHEMICAL PHARMACOLOGY, vol. 98, no. 1, 2015, pages 1 - 15, XP029291325, DOI: 10.1016/j.bcp.2015.06.022
MUTHUKAMAN, N. ET AL.: "Discovery of 2-((2-chloro-6fluorophenyl)amino)-N-(3-fluoro-5-(trifluoromethyl)phenyl)-1-methyl-7,8-dihydro-1H-[1,4]dioxino[2',3':3,4]benzo[1,2-d]imidazole-5-carboxamide as potent, selective and efficacious microsomal prostaglandin E2 synthase-1 (mPGES-1) inhibitor.", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 26, no. 24, 2016, pages 5977 - 5984, XP029824617, DOI: 10.1016/j.bmcl.2016.10.079
NORMAN, B.H. ET AL.: "Identification and Mitigation of Reactive Metabolites of 2-Aminoimidazole-Containing Microsomal Prostaglandin E Synthase-1 Inhibitors Terminated Due to Clinical Drug-Induced Liver Injury.", JOURNAL OF MEDICINAL CHEMISTRY, vol. 61, no. 5, 2018, pages 2041 - 2051
SCHIFFLER, M.A. ET AL.: "Discovery and Characterization of 2-Acylaminoimidazole Microsomal Prostaglandin E Synthase-1 Inhibitors.", JOURNAL OF MEDICINAL CHEMISTRY, vol. 59, no. 1, 2016, pages 194 - 205
SHIRO, T. ET AL.: "7-Phenyl-imidazoquinolin-4(5H)-one derivatives as selective and orally available mPGES-1 inhibitors.", BIOORGANIC & MEDICINAL CHEMISTRY, vol. 21, no. 11, 2013, pages 2868 - 2878, XP028535205, DOI: 10.1016/j.bmc.2013.03.069
WALKER, D.P. ET AL.: "Synthesis and biological evaluation of substituted benzoxazoles as inhibitors of mPGES-1: Use of a conformation-based hypothesis to facilitate compound design.", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 23, no. 4, 2013, pages 1120 - 1126
WANG, J.: "Selective inducible microsomal prostaglandin E2 synthase-1 (mPGES-1) inhibitors derived from an oxicam template.", LETTERS, vol. 20, no. 5, 2010, pages 1604 - 1609, XP026911315, DOI: 10.1016/j.bmcl.2010.01.060
WU, T.Y.H. ET AL.: "Biarylimidazoles as inhibitors of microsomal prostaglandin E2 synthase-1.", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 20, no. 23, 2010, pages 6978 - 6982, XP027459340, DOI: 10.1016/j.bmcl.2010.09.129
ZHANG, Y.-Y.: "Molecular mechanisms and therapeutic significance.", PHARMACOLOGICAL RESEARCH, vol. 175, 2022, pages 105977

Also Published As

Publication number Publication date
WO2025048759A1 (en) 2025-03-06

Similar Documents

Publication Publication Date Title
US11001563B2 (en) SSAO inhibitor
EP0745596B1 (en) Heteroaromatic oxazole compounds and use thereof
JP5725475B2 (en) Hydroxamic acid derivative and HDAC8 inhibitor using the same
HUP0202477A2 (en) Use of phthalazine derivatives
JP2014518886A (en) New imidazole derivatives useful for the treatment of arthritis
US8362056B2 (en) 4-heteroaryl-substituted phenoxyphenylacetic acid derivatives
JP2004509941A (en) Carbamic acid compounds containing amide bonds as HDAC inhibitors
AU2011255281A1 (en) Selective HDAC inhibitors
Banerjee et al. Development of 2-aryl substituted quinazolin-4 (3H)-one, pyrido [4, 3-d] pyrimidin-4 (3H)-one and pyrido [2, 3-d] pyrimidin-4 (3H)-one derivatives as microsomal prostaglandin E2 synthase-1 inhibitors
WO2007043653A9 (en) Benzimidazole-5-carboxamide derivative
JP2005508355A (en) Bis-heteroarylalkanes as therapeutic agents
US20040198768A1 (en) Method for inhibiting 5-lipoxygenase using a benzoxazole derivative or an analogue thereof
CN103221386A (en) Matrix metalloproteinase inhibitors
EP2419410B1 (en) Imidazolidine-2,4-dione derivatives, and use thereof as a cancer drug
JPH10101650A (en) New isoquinoline derivative
EP0249407A2 (en) Antiallergy and antiinflammatory agents
Zavareh et al. Design, synthesis and biological evaluation of 4-benzamidobenzoic acid hydrazide derivatives as novel soluble epoxide hydrolase inhibitors
Ergül et al. Novel potent benzimidazole-based microsomal prostaglandin E2 synthase-1 (mPGES-1) inhibitors derived from BRP-201 that also inhibit leukotriene C4 synthase
WO2024112287A1 (en) Benzimidazole compounds and pharmaceutical compositions and uses thereof
US20070208026A1 (en) N-Containing Heteroaromatic Compounds As Modulators Of Ppars And Methods Of Treating Metabolic Disorders
JP7337260B2 (en) Indolecarboxamide derivative and pharmaceutical composition containing the same
WO2007043652A1 (en) 2-thienylurea derivative
WO2018077898A1 (en) N,n&#39;-diarylurea, n,n&#39;-diarylthiourea and n,n&#39;-diarylguanidino compounds for use in treatment and prevention of inflammatory disease
US7301033B2 (en) PPAR-activating compound
US20230219925A1 (en) Benzo five-membered nitrogen heterocyclic compound and application thereof

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 23776487

Country of ref document: EP

Kind code of ref document: A1