US20150266834A1 - Triazine compounds and pharmaceutical use thereof - Google Patents

Triazine compounds and pharmaceutical use thereof Download PDF

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US20150266834A1
US20150266834A1 US14/626,243 US201514626243A US2015266834A1 US 20150266834 A1 US20150266834 A1 US 20150266834A1 US 201514626243 A US201514626243 A US 201514626243A US 2015266834 A1 US2015266834 A1 US 2015266834A1
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compound
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Hironobu Nagamori
Ikuo Mitani
Masaki Yamashita
Takahiro Hotta
Yuichi Nakagawa
Masatoshi Ueda
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Japan Tobacco Inc
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Japan Tobacco Inc
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Assigned to JAPAN TOBACCO INC. reassignment JAPAN TOBACCO INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: HOTTA, TAKAHIRO, MITANI, IKUO, NAGAMORI, HIRONOBU, NAKAGAWA, YUICHI, YAMASHITA, MASAKI, UEDA, MASATOSHI
Publication of US20150266834A1 publication Critical patent/US20150266834A1/en
Priority to US16/396,503 priority Critical patent/US20200087266A1/en
Priority to US17/575,931 priority patent/US20230011968A1/en
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Definitions

  • the present invention relates to a triazine compound having a microsomal prostaglandin E2 synthase-1 (mPGES-1) inhibitory activity or a pharmaceutically acceptable salt thereof, a pharmaceutical composition containing same, pharmaceutical use thereof and the like.
  • mPGES-1 microsomal prostaglandin E2 synthase-1
  • Non-steroidal anti-inflammatory drugs are often used for the treatment of diseases accompanying inflammation, fever and pain, for example, rheumatism, osteoarthritis, headache and the like.
  • NSAIDs show an anti-inflammatory action, an antipyretic action and an analgesic action by preventing production of prostanoids by inhibiting cyclooxygenase (COX).
  • COX cyclooxygenase
  • COX includes two isoforms of COX-1 which is ubiquitously distributed and constitutively expressed, and COX-2 which expression is induced by various pro-inflammatory stimulations, for example, cytokines such as interleukin-1 ⁇ (IL-1 ⁇ ) and the like.
  • COX-1 and COX-2 are enzymes that convert arachidonic acid derived from cell membrane phospholipids to prostaglandin H2 (PGH2) which is a prostanoid precursor.
  • COX-1 or COX-2 suppresses all prostanoids production in the downstream thereof. This is considered to cause side effects of NSAIDs. Since NSAIDs that non-selectively inhibit COX also suppress production of PGE2 by COX-1 and PGE2 protectively acts on stomach mucosal injury, NSAIDs are considered to suppress secretion of gastric mucus and gastric mucosal blood flow, thereby increasing the risk of stomach perforations, bleeding and the like.
  • COX-2 selective inhibitors suppress production of PGI2 having a vasodilation action and a platelet aggregation inhibitory action in vascular endothelial cells, they do not suppress production of TXA2 which is a blood coagulation factor produced by platelet COX-1. Therefore, they are considered to disrupt the balance of the blood coagulation system to increase the risk of cardiovascular disorder.
  • Microsomal prostaglandin E2 synthase-1 (mPGES-1) is an enzyme that catalyzes the final step of PGE2 biosynthesis, and belongs to the membrane-associated proteins in eicosanoid and glutathione metabolism family (MAPEG family).
  • the human mPGES-1 gene was cloned in 1999, and indicated to be constitutively expressed in placenta, prostate, testis and mammary gland (non-patent document 1). In other organs, human mPGES-1 gene expression is induced by various pro-inflammatory stimulations, conjugated with COX-2.
  • inflammatory cytokine IL-1 ⁇ and Tumor Necrosis Factor- ⁇ induce mPGES-1 expression in synovial cell, osteoblast, endothelial cell, orbital fibroblast, gingival cell, chondrocyte, endothelial cell, myocardial cell and the like.
  • LPS Lipopolysaccharide
  • mPGES-1 inhibitor is considered to selectively suppress PGE2 production only in the topical site of inflammation or tissues where mPGES-1 is expressed, and does not suppress production of prostanoids (PGI2, PGD2, PGF2 ⁇ , TXA2 etc.) other than PGE2 (non-patent documents 2, 3). Therefore, mPGES-1 inhibitor is considered to be a medicament having an efficacy equivalent to that of NSAIDs but free of side effects of NSAIDs derived from a decreased production of prostanoids other than PGE2.
  • mPGES-1 knockout mice intraperitoneal PGE2 production amount and nociceptive response per unit time significantly decrease as compared to WT mice, in the evaluation of nociceptive response by LPS stimulation which is an acute inflammatory pain model. Therefore, mPGES-1 inhibitor is considered to be an analgesic for acute inflammatory pain (non-patent documents 3, 6).
  • mPGES-1 gene of Swedish females contains some single nucleotide polymorphisms that increase the onset risk and severity of rheumatism.
  • An increase in the mPGES-1 expression is immunohistologically confirmed in the synovium of rheumatism patients showing single nucleotide polymorphism (Reference SNP ID number: rs23202821) that increases severity, as compared to patients free of mutation (non-patent document 5).
  • mPGES-1 knockout mice intraarticular infiltration of inflammatory cells, articular destruction and tumentia of the four limbs are markedly suppressed in a collagen-induced arthritis model, which is an animal model of rheumatism, as compared to WT mice (non-patent document 6). Therefore, mPGES-1 inhibitor is considered to be a therapeutic drug for rheumatism.
  • mRNA expression of mPGES-1 increases in meniscus cells of osteoarthritis patients (non-patent document 7).
  • mPGES-1 inhibitor reduces nociceptive responses in osteoarthritis model using monoiodoacetic acid, as compared to WT mice (patent document 1). Therefore, mPGES-1 inhibitor is considered to be a therapeutic drug for osteoarthritis.
  • mPGES-1 knockout mice body temperature elevation due to LPS stimulation is suppressed as compared to WT mice (non-patent document 8). Therefore, mPGES-1 inhibitor is considered to be an antipyretic drug.
  • Glaucoma is a disease showing a characteristic change in the optic nerve and the field of vision. Optic nerve disorder can be generally improved or suppressed by sufficiently decreasing the intraocular pressure. Glaucoma can be categorized into open angle glaucoma and closed angle glaucoma.
  • PGE2 When PGE2 is instilled into the eyes of healthy individuals, the intraocular pressure increases, along with the expansion of blood vessels, for 2 hours after instillation (non-patent document 12).
  • PGE2 When PGE2 is administered to rabbits subconjunctivally, the intraocular pressure increases due to dilatation of ciliary body and increase in the aqueous humor production (non-patent document 13).
  • PGF2 ⁇ and PGD2 which are prostaglandins that may increase when mPGES-1 is inhibited, decrease the intraocular pressure of rabbit (non-patent document 14).
  • PGF2 ⁇ formulations increase outflow of aqueous humor and are used as therapeutic drugs for glaucoma that decrease the intraocular pressure.
  • PGI2 does not show a clear action on the intraocular pressure of rabbits. That is, the intraocular pressure is considered to decrease since decrease of PGE2 suppresses aqueous humor production by mPGES-1 inhibition, and/or since increased PGD2 and PGF2 ⁇ promote outflow of aqueous humor due to shunt. Also, PGE2 promotes expression of vascular endothelial growth factor (VEGF) from retina (non-patent document 15).
  • VEGF vascular endothelial growth factor
  • mPGES-1 inhibitor Since VEGF produced in retina transfers to the anterior ocular segment to cause angiogenesis glaucoma, which is increase of the intraocular pressure that is caused by obstruction of corner angle due to angiogenesis in iris, mPGES-1 inhibitor is considered to show an improvement or prophylactic effect on angiogenesis glaucoma as well. Furthermore, considering an anti-inflammatory action by the inhibition of PGE2 production, mPGES-1 inhibitor is applicable to patients having intraocular inflammation, who require careful administration of the existing prostaglandin formulations (latanoprost etc.). Therefore, mPGES-1 inhibitor is considered to be a therapeutic drug also effective for glaucoma having various background diseases.
  • VEGF vascular endothelial growth factor
  • PGE2 promotes expression of VEGF (non-patent document 15)
  • mPGES-1 inhibitor is considered to improve these diseases.
  • mPGES-1 knockout mice the polyp number and size were markedly suppressed in azoxymethane-induced colorectal cancer model mice, which are animal model of colorectal cancer, as compared to WT mice.
  • PGE2 production in large intestinal tumor tissue decreased and production amount of PGI2 that inhibits adhesion of cancer cells and PGD2 that induces cell death via peroxisome proliferator-activated receptor ⁇ (PPAR ⁇ ) increased, as compared to WT mice.
  • PPAR ⁇ peroxisome proliferator-activated receptor ⁇
  • mPGES-1 inhibitor is considered to be an anticancer drug that suppresses the growth and metastasis of cancer including colorectal cancer.
  • the mPGES-1 inhibitor is considered to be beneficial for the prophylaxis or treatment of pain, rheumatism, osteoarthritis, fever, Alzheimer's disease, multiple sclerosis, arteriosclerosis, glaucoma, ocular hypertension, ischemic retinal disease, systemic scleroderma, cancer including colorectal cancer and diseases for which suppression of PGE2 production is effective.
  • the present inventors have found a triazine compound having an mPGES-1 inhibitory activity, which is represented by the following formula [I], and completed the present invention.
  • R b15 is
  • R b14 and R b15 optionally form a 4-, 5- or 6-membered lactam together with the nitrogen atom the nitrogen atom that R b14 is bonded to and the carbon atom that R b15 is bonded to (said lactam is optionally substituted by 1, 2 or 3 C 1-6 alkyls, and/or optionally form a fused ring with a benzene ring),
  • m2 and m3 are each independently 1, 2 or 3, m4 is 0, 1, 2, 3 or 4, R b16 is C 1-6 alkyl or C 1-6 alkoxy, and when m4 is 2, 3 or 4, each R b16 is selected independently, or
  • R 1 , R 3 and R 4 are as defined in [01] [04]
  • R 2 is —(C n H 2n )—R b (n is 1 or 2, —(C n H 2n )— may be straight or branched chain, and R b is
  • An mPGES-1 inhibitor comprising the compound of any of [01] to [12] or a pharmaceutically acceptable salt thereof.
  • a therapeutic or prophylactic agent for glaucoma or ocular hypertension comprising the compound of any of [01] to [12] or a pharmaceutically acceptable salt thereof, and one or more kinds of other therapeutic agents for glaucoma in combination.
  • a method of treating or preventing pain, rheumatism, fever, osteoarthritis, arteriosclerosis, Alzheimer's disease, multiple sclerosis, glaucoma, ocular hypertension, ischemic retinal disease, systemic scleroderma, cancer or a disease for which suppression of PGE2 production is effective comprising administering a pharmaceutically effective amount of the compound of any of [01] to [12] or a pharmaceutically acceptable salt thereof to a human.
  • the method of [18] for treating or preventing glaucoma or ocular hypertension further comprising administering a pharmaceutically effective amount of one or more kinds of other therapeutic agents for glaucoma to the human.
  • the compound of the present invention is effective as a therapeutic or prophylactic agent for pain, rheumatism, fever, osteoarthritis, arteriosclerosis, Alzheimer's disease, multiple sclerosis, glaucoma, ocular hypertension, ischemic retinal disease, systemic scleroderma, cancer including colorectal cancer, a disease for which suppression of PGE2 production is effective and the like.
  • FIG. 1 shows effect of a test article (compounds of Example 2-98), a reference article (Xalatan (registered trademark)) or a vehicle (methylcellulose, MC) on the intraocular pressure immediately before and after administration in Macaca fascicularis.
  • halogen is fluoro, chloro, bromo or iodo.
  • C 1-6 alkyl means straight chain or branched chain alkyl having 1 to 6 carbon atoms. Examples thereof include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl and the like.
  • the “C 1-8 alkyl” means straight chain or branched chain alkyl having 1 to 8 carbon atoms. Examples thereof include methyl, ethyl, propyl, isopropyl, 1,1-dimethylpropyl, 1-ethyl-propyl, l-methyl-1-ethyl-propyl, butyl, isobutyl, sec-butyl, tert-butyl, 1-methyl-1-propyl-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl and the like.
  • C 1-6 alkoxy means alkoxy wherein the alkyl moiety is the above-defined “C 1-6 alkyl”. Examples thereof include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, neopentyloxy, 1,2-dimethylpropyloxy, 1-ethylpropyloxy, hexyloxy, isohexyloxy, 1,2,2-trimethylpropyloxy, 1,1-dimethylbutyloxy, 2,2-dimethylbutyloxy, 3,3-dimethylbutyloxy, 2-ethylbutyloxy and the like.
  • haloC 1-4 alkyl means straight chain or branched chain alkyl having 1-4 carbon atoms, which is substituted by 1 to 9 the above-defined “halogens”. When it is substituted by plural halogens, respective halogens may be the same or different.
  • Examples thereof include 2-fluoroethyl, 2-chloroethyl, 2-bromoethyl, 3-fluoropropyl, 3-chloropropyl, 4-fluorobutyl, 4-chlorobutyl, 1,1-difluoroethyl, 1,1-difluoropropyl, 1,1-difluoro-2-methylpropyl, trifluoromethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl, pentafluoroethyl, 2,2,2-trifluoro-1-trifluoromethyl-ethyl and the like.
  • haloC 1-4 alkoxy means alkoxy wherein the alkyl moiety is the above-defined “haloC 1-4 alkyl”. Examples thereof include fluoromethoxy, chloromethoxy, bromomethoxy, 2-fluoroethoxy, 2-chloroethoxy, 2-bromoethoxy, 3-fluoropropoxy, 3-chloropropoxy, 4-fluorobutoxy, 4-chlorobutoxy, 1,1-difluoroethoxy, 2,2-difluoroethoxy, 1,1-difluoropropoxy, 2,2-difluoropropoxy, 3,3-difluoropropoxy, 1,1-difluoro-2-methylpropoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, 3,3,3-trifluoropropoxy, 4,4,4-trifluorobutoxy, pentafluoroethoxy, 2,2,2-trifluoro-1-trifluoromethyl-ethoxy and the like.
  • hydroxyC 1-6 alkyl means the above-defined “C 1-6 alkyl” substituted by 1 or 2 hydroxy. Examples thereof include hydroxymethyl, 2-hydroxyethyl, 1-hydroxy-1-methylethyl, 1,2-dihydroxyethyl, 3-hydroxypropyl, 1-hydroxy-2,2-dimethylpropyl, 4-hydroxybutyl, 1-hydroxy-2,2-dimethylbutyl, 5-hydroxypentyl, 6-hydroxyhexyl and the like.
  • C 1-6 alkyl-carbonyl means carbonyl bonded to the above-defined “C 1-6 alkyl”. Examples thereof include acetyl, propionyl, 2,2-dimethylpropionyl, butyryl, 3-methylbutyryl, 2,2-dimethylbutyryl, pentanoyl, 4-methylpentanoyl, hexanoyl and the like.
  • C 1-6 alkyl-carbonyloxy means carbonyloxy bonded to the above-defined “C 1-6 alkyl”. Examples thereof include methylcarbonyloxy, ethylcarbonyloxy, propylcarbonyloxy, isopropylcarbonyloxy, butylcarbonyloxy, isobutylcarbonyloxy, sec-butylcarbonyloxy, tert-butylcarbonyloxy, pentylcarbonyloxy, isopentylcarbonyloxy, 2-methylbutylcarbonyloxy, 1,1-dimethylpropylcarbonyloxy, neopentylcarbonyloxy, 3,3-dimethylbutylcarbonyloxy, 1-ethylpropylcarbonyloxy, hexylcarbonyloxy and the like.
  • C 3-7 cycloalkyl means 3- to 7-membered monocyclic cycloalkyl. Examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
  • C 6-10 aryl means 6- to 10-membered aryl. Examples thereof include phenyl, 1-naphthyl, 2-naphthyl and the like. Of these, preferred is phenyl.
  • the “5- or 6-membered heteroaryl containing 1, 2 or 3 nitrogen atoms, oxygen atoms or sulfur atoms” means 5- or 6-membered monocyclic heteroaryl containing, besides carbon atoms, 1, 2 or 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom.
  • Examples thereof include furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl(1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl), thiadiazolyl(1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,4-thiadiazolyl), triazolyl(1,2,3-triazolyl, 1,2,4-triazolyl), pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, 1,3,5-triazinyl and the like. Of these, preferred is pyridyl.
  • the “4-, 5- or 6-membered saturated heterocyclyl containing 1, 2 or 3 nitrogen atoms, oxygen atoms or sulfur atoms” means 4-, 5- or 6-membered monocyclic saturated heterocyclyl containing, besides carbon atoms, 1, 2 or 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom.
  • the carbon atom of the heterocycle is optionally substituted by oxo.
  • the sulfur atom is optionally monooxidized or dioxidized.
  • Examples thereof include oxetanyl, azetidinyl, tetrahydrofuryl, tetrahydropyranyl, tetrahydrothienyl, tetrahydrothiopyranyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolidinyl, piperidyl (including piperidino), morpholinyl (including morpholino), thiomorpholinyl (including thiomorpholino), piperazinyl, 1,1-dioxidoisothiazolidinyl, 1,1-dioxidotetrahydrothienyl, 1,1-dioxidotetrahydrothiopyranyl, 1,1-dioxidothiomorpholinyl (including 1,1-dioxidothiomorpholino) and the like.
  • saturated heterocyclyl may be partially saturated.
  • examples thereof include imidazolinyl, oxazolinyl, pyrazolinyl, thiazolinyl and the like. Of these, preferred is oxetanyl.
  • C 1-6 alkylsulfanyl means sulfanyl bonded to the above-defined “C 1-6 alkyl”. Examples thereof include methylsulfanyl, ethylsulfanyl, propylsulfanyl, isopropylsulfanyl, n-butylsulfanyl, isobutylsulfanyl, sec-butylsulfanyl, tert-butylsulfanyl, pentylsulfanyl, 1,1-dimethylpropylsulfanyl, 2,2-dimethylpropylsulfanyl, hexylsulfanyl and the like.
  • the “—(C n H 2n )—” means straight chain or branched chain alkylene having n carbon atoms and 2n hydrogen atoms. Examples thereof include —CH 2 —, —CH 2 CH 2 —, —CH(CH 3 )—, —CH 2 CH 2 CH 2 —, —C(CH 3 ) 2 —, —CH(CH 3 )CH 2 — and the like.
  • R 2 is (10) —(C n H 2n )—R b and R b is (k) —NR b14 C(O)R b15
  • “(ii) C 1-8 alkyl (said C 1-8 alkyl is optionally substituted by 1, 2 or 3 substituents selected from the group consisting of hydroxy, haloC 1-4 alkyl, C 1-6 alkoxy and C 6-10 aryl)” for R b15 means the above-defined “C 1-8 alkyl” substituted or not substituted by the same or different, 1, 2 or 3 substituents selected from the group consisting of hydroxy, the above-defined “haloC 1-4 alkyl”, the above-defined “C 1-6 alkoxy” and the above-defined “C 6-10 aryl”, at the substitutable position(s) thereof.
  • R b include 2-ethoxy-3-methoxypropylcarbonylamino, 1-methyl-1-methoxy-2,2,2-trifluoroethylcarbonyla
  • R b examples include 3,4-dimethyl-2-oxo-pyrrolidin-1-yl, 1-oxo-1,3-dihydro-isoindol-2-yl, 3,3-dimethyl-2-oxo-2,3-dihydro-indol-1-yl and the like.
  • R 1 is preferably chloro, methyl, cyano or trifluoromethyl, more preferably chloro or trifluoromethyl, and further preferably chloro.
  • R 2 is preferably
  • R b is preferably
  • n is preferably 1 or 2, more preferably 1.
  • R b14 is preferably hydrogen or methyl, more preferably hydrogen.
  • R b15 is preferably
  • R 3 is preferably
  • R c is preferably methyl optionally substituted by 1 or 2 substituents selected from the following (e) and (f);
  • R 4 is preferably hydrogen, fluoro, chloro, or methyl, more preferably hydrogen.
  • R d is preferably C 1-8 alkyl (said C 1-8 alkyl is optionally substituted by 1, 2 or 3 substituents selected from the group consisting of the following (i) to (v);
  • R e is preferably
  • m1 is preferably 0, 1 or 2, more preferably 1 or 2.
  • one of preferable embodiments is a compound represented by the following formula [I-A]:
  • one of the preferable other embodiments is a compound represented by the following formula [I-B]:
  • R 1 is chloro or trifluoromethyl
  • one of the preferable other embodiments is a compound represented by the following formula [I-C]:
  • X is CH or N
  • R b15 is
  • a pharmaceutically acceptable salt of a compound represented by the formula [I](hereinafter to be also referred to as the compound of the present invention) may be any salt as long as it forms a nontoxic salt with the compound of the present invention, and examples thereof include salts with inorganic acid, salts with organic acid, salts with inorganic base, salts with organic base, salts with amino acid and the like.
  • examples of the salts with organic base include salts with arecoline, betaine, clemizole, N-methylglucamine, N-benzylphenethylamine or tris(hydroxymethyl)methylamine.
  • salts with hydrochloric acid, sulfuric acid or p-toluenesulfonic acid.
  • the solvates can be obtained by a known method.
  • the compound of the present invention may exist as a tautomer.
  • the compound of the present invention can be a single tautomer or a mixture of individual tautomers.
  • a compound represented by the formula [I] may contain a tautomer shown below
  • the compound of the present invention may have a carbon double bond.
  • the compound of the present invention can be present as E form, Z form, or a mixture of E form and Z form.
  • the compound of the present invention may contain a stereoisomer that should be recognized as a cis/trans isomer.
  • the compound of the present invention can be present as a cis form, a trans form, or mixture of a cis form and a trans form.
  • the compound of the present invention may contain one or more asymmetric carbons.
  • the compound of the present invention may be present as a single enantiomer, a single diastereomer, a mixture of enantiomers or a mixture of diastereomers.
  • a diastereomeric mixture can be separated into each diastereomer by conventional methods such as chromatography, crystallization and the like.
  • each diastereomer can also be formed by using a stereochemically single starting material, or by a synthesis method using a stereoselective reaction.
  • a substantially purified compound represented by the formula [I] or a pharmaceutically acceptable salt thereof is preferable. More preferred is a compound represented by the formula [I] or a pharmaceutically acceptable salt thereof or a solvate thereof, which is purified to have a purity of more than 80%.
  • compositions examples include oral preparations such as tablet, capsule, granule, powder, troche, syrup, emulsion, suspension and the like, and parenteral agents such as external preparation, suppository, injection, eye drop, nasal preparations, pulmonary preparation and the like.
  • “pharmaceutically acceptable carrier” examples include various organic or inorganic carrier substances conventionally used as preparation materials, for example, excipient, disintegrant, binder, glidant, lubricant and the like for solid preparations, and solvent, solubilizing agent, suspending agent, isotonicity agent, buffering agent, soothing agent, surfactant, pH adjuster, thickening agent and the like for liquid preparations. Where necessary, moreover, additives such as preservative, antioxidant, colorant, sweetening agent and the like are used.
  • disintegrant examples include carmellose, carmellose calcium, carmellose sodium, sodium carboxymethyl starch, croscarmellose sodium, crospovidone, low-substituted hydroxypropylcellulose, hydroxypropylmethylcellulose, crystalline cellulose and the like.
  • binder examples include hydroxypropylcellulose, hydroxypropylmethylcellulose, povidone, crystalline cellulose, sucrose, dextrin, starch, gelatin, carmellose sodium, gum arabic and the like.
  • Examples of the “glidant” include light anhydrous silicic acid, magnesium stearate and the like.
  • lubricant examples include magnesium stearate, calcium stearate, talc and the like.
  • solvent examples include purified water, ethanol, propylene glycol, macrogol, sesame oil, corn oil, olive oil and the like.
  • Examples of the “solubilizing agent” include propylene glycol, D-mannitol, benzyl benzoate, ethanol, triethanolamine, sodium carbonate, sodium citrate and the like.
  • suspending agent examples include benzalkonium chloride, carmellose, hydroxypropylcellulose, propylene glycol, povidone, methylcellulose, glycerol monostearate and the like.
  • isotonicity agent examples include glucose, D-sorbitol, sodium chloride, D-mannitol and the like.
  • buffering agent examples include sodium hydrogenphosphate, sodium acetate, sodium carbonate, sodium citrate and the like.
  • Examples of the “soothing agent” include benzyl alcohol and the like.
  • surfactant examples include polyoxyethylene hydrogenated castor oil, polyethylene glycol monostearate, polyoxyethylene sorbitan fatty acid ester, alkyldiaminoethylglycine, alkylbenzenesulfonate, benzethonium chloride and the like.
  • pH adjuster examples include hydrochloric acid, sulfuric acid, phosphoric acid, citric acid, acetic acid, sodium hydrogen carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, monoethanolamine, triethanolamine and the like.
  • thickening agent examples include polyvinyl alcohol, carboxyvinyl polymer, methylcellulose, hydroxyethylcellulose, polyethylene glycol, dextran and the like.
  • preservative examples include ethyl parahydroxybenzoate, chlorobutanol, benzyl alcohol, sodium dehydroacetate, sorbic acid and the like.
  • antioxidant examples include sodium sulfite, ascorbic acid and the like.
  • colorant examples include food colors (e.g., Food Color Red No. 2 or 3, Food Color Yellow No. 4 or 5 etc.), 3-carotene and the like.
  • sweetening agent examples include saccharin sodium, dipotassium glycyrrhizinate, aspartame and the like.
  • the pharmaceutical composition of the present invention can be administered orally or parenterally (e.g., topical, rectal, intravenous administration etc.) to human as well as mammals other than human (e.g., hamster, guinea pig, cat, dog, swine, bovine, horse, sheep, monkey etc.).
  • the dose varies depending on the subject of administration, disease, symptom, dosage form, administration route and the like.
  • the daily dose for oral administration to an adult patient is generally within the range of about 0.1 g to 10 g, based on the compound of the present invention as the active ingredient. This amount can be administered in one to several portions.
  • carbonic anhydrase inhibitor examples include dorzolamide hydrochloride, brinzolamide and the like.
  • anticholinesterase agent examples include distigmine bromide and the like.
  • Rho kinase inhibitor examples include ripasudil hydrochloride hydrate and the like.
  • An example of the specific combination of medicaments is a combination of one medicament selected from latanoprost, travoprost, tafluprost, timolol maleate, dorzolamide hydrochloride and brinzolamide, and the above-mentioned compound represented by the formula [I] or a pharmaceutically acceptable salt thereof, or a solvate thereof.
  • the steps may be modified for efficient production of the compound, such as introduction of a protecting group into a functional group with deprotection in a subsequent step, changing the order of Production Methods and steps, appropriate use of reagents other than the exemplified reagents to promote progress of the reactions, and the like.
  • Hal 1 is chloro or bromo
  • R 6 is C 1-6 alkyl such as methyl, ethyl and the like or benzyl
  • Z is a boron substituent used for the Suzuki coupling reaction such as —B(OH) 2 , —B(OR 7 ) 2 (wherein R 7 is C 1-4 alkyl or one R 7 may be bonded to the other R 7 to form a ring), —BF 3 , the formula
  • Compound [3] can be obtained by the Suzuki coupling reaction of compound [1] and compound [2].
  • compound [3] can be obtained by reacting compound [1] with compound [2] under heating in a solvent in the presence of a base and a palladium catalyst.
  • a ligand may be added.
  • Not less than 1.5 equivalents of compound [1] are preferably used relative to compound [2] to prevent the Suzuki coupling reaction from progressing twice.
  • Examples of the palladium catalyst to be used for the reaction include palladium acetate, tetrakistriphenylphosphinepalladium, bis(triphenylphosphine)palladium dichloride, (bis(diphenylphosphino)ferrocene)palladium dichloride-methylene chloride complex and the like.
  • Examples of the base to be used for the reaction include inorganic bases such as alkali metal salts (e.g., potassium phosphate, sodium carbonate, sodium hydrogen carbonate, potassium carbonate, potassium acetate, sodium acetate, cesium fluoride etc.) and the like, and organic bases such as triethylamine and the like.
  • inorganic bases such as alkali metal salts (e.g., potassium phosphate, sodium carbonate, sodium hydrogen carbonate, potassium carbonate, potassium acetate, sodium acetate, cesium fluoride etc.) and the like
  • organic bases such as triethylamine and the like.
  • Examples of the ligand to be used for the reaction include organic phosphine ligands (e.g., triphenylphosphine, tricyclohexylphosphine, 2,2′-bis(diphenylphosphino)-1,1′-binaphthalene, 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl etc.) and the like.
  • organic phosphine ligands e.g., triphenylphosphine, tricyclohexylphosphine, 2,2′-bis(diphenylphosphino)-1,1′-binaphthalene, 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl etc.
  • solvent to be used for the reaction examples include ether solvents such as 1,4-dioxane, tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, cyclopentyl methyl ether and the like; alcohol solvents such as methanol, ethanol, 1-propanol, 2-propanol and the like; hydrocarbon solvents such as toluene, xylene, hexane and the like; polar solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, acetonitrile and the like; a mixed solvent thereof, and a mixed solvent thereof with water.
  • ether solvents such as 1,4-dioxane, tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, cyclopentyl methyl ether and the like
  • alcohol solvents such as methanol, ethanol, 1-propanol
  • Compound [1] may be a commercially available product such as 2,4-dichloro-6-methoxy-1,3,5-triazine, or may be obtained by converting a commercially available product as appropriate by a method well known to those of ordinary skill in the art.
  • Compound [5] can be obtained by the Suzuki coupling reaction of compound [3] and compound [4].
  • compound [5] can be obtained by reacting compound [3] with compound [4] under heating in a solvent in the presence of a base and a palladium catalyst. Where necessary, a ligand may be added.
  • Examples of the palladium catalyst to be used for the reaction include palladium acetate, tetrakistriphenylphosphinepalladium, bis(triphenylphosphine)palladium dichloride, (bis(diphenylphosphino)ferrocene)palladium dichloride-methylene chloride complex and the like.
  • Examples of the base to be used for the reaction include inorganic bases such as alkali metal salts (e.g., potassium phosphate, sodium carbonate, sodium hydrogen carbonate, potassium carbonate, potassium acetate, sodium acetate, cesium fluoride etc.) and the like, and organic bases such as triethylamine and the like.
  • inorganic bases such as alkali metal salts (e.g., potassium phosphate, sodium carbonate, sodium hydrogen carbonate, potassium carbonate, potassium acetate, sodium acetate, cesium fluoride etc.) and the like
  • organic bases such as triethylamine and the like.
  • Examples of the ligand to be used for the reaction include organic phosphine ligands such as triphenylphosphine, tricyclohexylphosphine, 2,2′-bis(diphenylphosphino)-1,1′-binaphthalene, 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl and the like, and the like.
  • organic phosphine ligands such as triphenylphosphine, tricyclohexylphosphine, 2,2′-bis(diphenylphosphino)-1,1′-binaphthalene, 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl and the like, and the like, and the like.
  • solvent to be used for the reaction examples include ether solvents such as 1,4-dioxane, tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, cyclopentyl methyl ether and the like; alcohol solvents such as methanol, ethanol, 1-propanol, 2-propanol and the like; hydrocarbon solvents such as toluene, xylene, hexane and the like; polar solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, acetonitrile and the like; a mixed solvent thereof, and a mixed solvent thereof with water.
  • ether solvents such as 1,4-dioxane, tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, cyclopentyl methyl ether and the like
  • alcohol solvents such as methanol, ethanol, 1-propanol
  • Compound [I] can be obtained by converting the alkoxy of compound [5] to hydroxy by hydrolysis.
  • R 6 is C 1-6 alkyl
  • compound [I] can be obtained by reacting compound [5] in a solvent in the presence of a base at room temperature to under heating, and neutralizing the obtained solution.
  • Examples of the base to be used for the reaction include lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium methoxide and the like.
  • the solvent to be used for the reaction examples include a mixed solvent of water and alcohol solvents such as methanol, ethanol, 1-propanol, 2-propanol and the like; and a mixed solvent thereof with ether solvents such as 1,4-dioxane, tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, cyclopentyl methyl ether and the like.
  • alcohol solvents such as methanol, ethanol, 1-propanol, 2-propanol and the like
  • ether solvents such as 1,4-dioxane, tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, cyclopentyl methyl ether and the like.
  • Compound [2] can be obtained by, for example, Production Method 1-2.
  • L 1 is a leaving group such as bromo, iodo, trifluoromethanesulfonyloxy and the like
  • X, R 5 and m1 are as defined in the aforementioned formula [I]
  • Z is as defined in the aforementioned Production Method 1-1.
  • Compound [2] can be obtained by borating compound [6].
  • compound [2] can be obtained by reacting compound [6] with a boron reagent under heating in the presence of a base and a palladium catalyst. Where necessary, a ligand may be added
  • Examples of the boron reagent to be used for the reaction include 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi-1,3,2-dioxaborolane, 5,5,5′,5′-tetramethyl-2,2′-bi-1,3,2-dioxaborinane, tetrahydroxydiboron, 4,4,5,5-tetramethyl-1,3,2-dioxaborolane and the like.
  • Examples of the base to be used for the reaction include inorganic bases such as alkali metal salts (e.g., potassium phosphate, sodium carbonate, sodium hydrogen carbonate, potassium carbonate, potassium acetate, sodium acetate, cesium fluoride etc.) and the like, and organic bases such as triethylamine and the like.
  • inorganic bases such as alkali metal salts (e.g., potassium phosphate, sodium carbonate, sodium hydrogen carbonate, potassium carbonate, potassium acetate, sodium acetate, cesium fluoride etc.) and the like
  • organic bases such as triethylamine and the like.
  • solvent to be used for the reaction examples include ether solvents such as 1,4-dioxane, tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, cyclopentyl methyl ether and the like; alcohol solvents such as methanol, ethanol, 1-propanol, 2-propanol and the like; hydrocarbon solvents such as toluene, xylene, hexane and the like; polar solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, acetonitrile and the like; a mixed solvent thereof, and a mixed solvent thereof with water.
  • ether solvents such as 1,4-dioxane, tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, cyclopentyl methyl ether and the like
  • alcohol solvents such as methanol, ethanol, 1-propanol
  • Compound [2] can also be obtained by adding an organic metal reagent to compound [6] in a solvent at ⁇ 78° C. to room temperature, and reacting the product with a boron compound at ⁇ 78° C. to room temperature.
  • organic metal reagent to be used for the reaction examples include n-butyllithium, tert-butyllithium, isopropylmagnesium chloride and the like.
  • Examples of the boron reagent to be used for the reaction include trimethyl borate, triisopropyl borate, 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane and the like.
  • compound [6] may be a commercially available product such as those shown below, or may be obtained by converting a commercially available product as appropriate by a method well known to those of ordinary skill in the art.
  • compound [2] may be a commercially available product such as those shown below, or may be obtained by converting a commercially available product as appropriate by a method well known to those of ordinary skill in the art.
  • Compound [4] can be obtained by, for example, Production Method 1-3.
  • R 1 , R 2 , R 3 and R 4 are as defined in the aforementioned formula [I]
  • L 1 is as defined in the aforementioned Production Method 1-2
  • Z is as defined in the aforementioned Production Method 1-1.
  • Compound [4] is compound [8a] or [8b].
  • Compound [8a] or [8b] i.e., compound [4] can be obtained by borating compound [7a] or [7b] in the same manner as in Production Method 1-2, Step 1-2.
  • compound [4] may be a commercially available product such as those shown below, or may be obtained by converting a commercially available product as appropriate by a method well known to those of ordinary skill in the art.
  • R 1 , R 4 , R b15 and n are as defined in the aforementioned formula [I], can be obtained by appropriately converting the substituent of ring Cy.
  • R 5 , R 6 and m1 are as defined in the aforementioned formula [I];
  • C 1-6 Alkyl is C 1-6 alkyl;
  • t is 0, 1, 2 or 3, —(C t H 2t )— may be a straight or branched chain;
  • Hal 2 is bromo or iodo;
  • P v is a hydroxy-protecting group such as methoxymethyl and the like;
  • P w is an amino-protecting group such as tert-butoxycarbonyl and the like;
  • L 2 is a leaving group such as halogen (e.g., chloro, bromo and the like), methanesulfonyloxy, p-toluenesulfonyloxy and the like;
  • R 1 , R 4 , R 6 , R b15 and n are as defined in the aforementioned formula [I]
  • Z is as defined in the aforementioned Production Method 1-1.
  • Compound [10] can be obtained by converting the ester of compound [9] to carboxy by hydrolysis.
  • compound [10] can be obtained by reacting compound [9] in a solvent in the presence of a base at room temperature to under heating, and neutralizing the obtained solution.
  • Examples of the base to be used for the reaction include lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium methoxide and the like.
  • the solvent to be used for the reaction examples include a mixed solvent of water and alcohol solvents such as methanol, ethanol, 1-propanol, 2-propanol and the like; and a mixed solvent thereof with ether solvents such as 1,4-dioxane, tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, cyclopentyl methyl ether and the like.
  • alcohol solvents such as methanol, ethanol, 1-propanol, 2-propanol and the like
  • ether solvents such as 1,4-dioxane, tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, cyclopentyl methyl ether and the like.
  • Compound [9] may be a commercially available product such as those shown below, or may be obtained by converting a commercially available product as appropriate by a method well known to those of ordinary skill in the art.
  • Compound [11] can be obtained by converting the carboxy of compound [10] to hydroxy by reduction.
  • compound [11] can be obtained by reacting compound [10] with a reducing agent in a solvent under ice-cooling to room temperature.
  • Examples of the reducing agent to be used for the reaction include lithium aluminum hydride, diisobutylaluminum hydride, sodium bis(2-methoxyethoxy)aluminum hydride, borane-tetrahydrofuran complex and the like.
  • solvent to be used for the reaction examples include tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, cyclopentyl methyl ether, toluene, xylene, hexane and the like and a mixed solvent thereof.
  • Compound [12] can be obtained by protecting the hydroxy group of compound [11].
  • the protection reaction can be performed by a known method according to the protecting group to be employed.
  • compound [12] when P v is methoxymethyl, compound [12] can be obtained by reacting compound [11] with chloromethyl methyl ether in a solvent such as tetrahydrofuran, 1,2-dimethoxyethane, cyclopentyl methyl ether, N,N-dimethylformamide and the like in the presence of a base such as sodium hydride and the like from ice-cooling to room temperature.
  • a solvent such as tetrahydrofuran, 1,2-dimethoxyethane, cyclopentyl methyl ether, N,N-dimethylformamide and the like
  • a base such as sodium hydride and the like from ice-cooling to room temperature.
  • Compound [13] can be obtained by borating compound [12] in the same manner as in Production Method 1-2, Step 1-2.
  • Compound [14] can be obtained by the Suzuki coupling reaction of compound [3] and compound [13] in the same manner as in Production Method 1-1, Step 1-1-2.
  • Compound [15] can be obtained by removing P v of compound [14] by hydroxy-deprotection by a conventional method.
  • the deprotection reaction can be performed by a known method according to the protecting group to be employed.
  • a treatment with an acid such as hydrochloric acid, trifluoroacetic acid, methanesulfonic acid and the like only needs to be performed in a single or mixed solvent of chloroform, 1,4-dioxane, tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, cyclopentyl methyl ether, ethyl acetate, ethanol, methanol, water and the like.
  • R 1 and R 4 are as defined in the aforementioned formula [I]
  • Z is as defined in the aforementioned Production Method 1-1
  • t is as defined in the aforementioned Production Method 2-1, in the same manner as in Production Method 1-1, Step 1-1-2.
  • Compound [16] can be obtained by converting the hydroxy of compound [15] to the leaving group L 2 .
  • L 2 is methanesulfonyloxy
  • compound [16] can be obtained by reacting compound [15] with methanesulfonyl chloride in a solvent in the presence of a base at room temperature.
  • L 2 is bromo
  • compound [16] can be obtained by reacting compound [15] with carbon tetrabromide in a solvent in the presence of triphenylphosphine from ice-cooling to room temperature.
  • Examples of the base to be used for the reaction include triethylamine, pyridine and the like.
  • solvent to be used for the reaction examples include ether solvents such as 1,4-dioxane, tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, cyclopentyl methyl ether and the like; hydrocarbon solvents such as toluene, hexane, xylene and the like; halogenated solvents such as dichloromethane, chloroform and the like; and polar solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, acetonitrile and the like.
  • ether solvents such as 1,4-dioxane, tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, cyclopentyl methyl ether and the like
  • hydrocarbon solvents such as toluene, hexane, xylene and the like
  • halogenated solvents such as dichlor
  • p-Toluenesulfonyl chloride and benzenesulfonyl chloride can be used instead of the above-mentioned methanesulfonyl chloride.
  • Compound [18] can be obtained by reacting compound [16] in a solvent in the presence of a base at room temperature to under heating compound [17].
  • Examples of the protecting group P w include tert-butoxycarbonyl.
  • Examples of the base to be used for the reaction include inorganic bases such as alkali metal salts (e.g., cesium carbonate, potassium phosphate, sodium carbonate, potassium carbonate etc.) and the like.
  • alkali metal salts e.g., cesium carbonate, potassium phosphate, sodium carbonate, potassium carbonate etc.
  • solvent to be used for the reaction examples include polar solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, acetonitrile and the like.
  • Compound [19] can be obtained by removing P w of compound [18] by amine-deprotection by a conventional method.
  • the deprotection reaction can be performed by a known method according to the protecting group to be employed.
  • P w is tert-butoxycarbonyl
  • a treatment with an acid such as hydrochloric acid, trifluoroacetic acid, methanesulfonic acid and the like only needs to be performed in a solvent.
  • solvent to be used for the reaction examples include ether solvents such as 1,4-dioxane, tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, cyclopentyl methyl ether and the like; hydrocarbon solvents such as toluene, hexane, xylene and the like; halogenated solvents such as dichloromethane, chloroform and the like; ester solvents such as ethyl acetate and the like; and alcohol solvents such as methanol, ethanol, 1-propanol, 2-propanol and the like.
  • ether solvents such as 1,4-dioxane, tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, cyclopentyl methyl ether and the like
  • hydrocarbon solvents such as toluene, hexane, xylene and the like
  • halogenated solvents such as dichlor
  • Compound [21] can be obtained by a conventional amide bond forming reaction, for example, by reacting compound [19] with compound [20] in a solvent in the presence of a condensing agent and an additive. A base may be added as necessary.
  • Examples of the condensing agent to be used for the reaction include dicyclohexylcarbodiimide (DCC), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSC.HCl), diisopropylcarbodiimide, 1,1′-carbonyldiimidazole (CDI), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU), (benzotriazol-1-yloxy)tris(pyrrolidino)phosphonium hexafluorophosphate (PyBOP), diphenylphosphoryl azide and the like.
  • DCC dicyclohexylcarbodiimide
  • WSC.HCl 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride
  • CDI 1,1′-
  • additive to be used for the reaction examples include 1-hydroxybenzotriazole (HOBt), 1-hydroxy-7-azabenzotriazole (HOAt), N-hydroxysuccinimide (HOSu), 4-dimethylaminopyridine and the like.
  • Examples of the base to be used for the reaction include organic bases such as pyridine, triethylamine and the like.
  • solvent to be used for the reaction examples include ether solvents such as 1,4-dioxane, tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, cyclopentyl methyl ether and the like; hydrocarbon solvents such as toluene, hexane, xylene and the like; halogenated solvents such as dichloromethane, chloroform and the like; and polar solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, acetonitrile, pyridine and the like. These may be used singly or as a mixture of two or more kinds thereof.
  • ether solvents such as 1,4-dioxane, tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, cyclopentyl methyl ether and the like
  • hydrocarbon solvents such as toluene, hex
  • Compound [20] may be a commercially available product such as cyclopentanecarboxylic acid and 1-(trifluoromethyl)cyclopropane-1-carboxylic acid, or may be obtained by converting a commercially available product as appropriate by a method well known to those of ordinary skill in the art.
  • Compound [21] can be indicated as compound [22].
  • Compound [I-a1] can be obtained by converting the alkoxy of compound [22] to hydroxy by hydrolysis in the same manner as in Production Method 1-1, Step 1-1-3.
  • Compound [10a] can be obtained by halogenating compound [24].
  • compound [10a] can be obtained by reacting compound [24] with N-iodosuccinimide in an acid at room temperature.
  • Examples of the acid to be used for the reaction include concentrated sulfuric acid and the like.
  • Compound [24] may be a commercially available product such as 4-chlorophenylacetic acid, 3-(4-chlorophenyl)propionic acid, 4-(4-chlorophenyl)butanoic acid, 4-methylphenylacetic acid and 2-(4-methylphenyl)propionic acid, or may be obtained by converting a commercially available product as appropriate by a method well known to those of ordinary skill in the art.
  • Compound [25] may be a commercially available product such as 1-(3-bromo-4-chlorophenyl)propan-1-one and 1-(3-bromo-4-chlorophenyl)butan-1-one, or may be obtained by converting a commercially available product as appropriate by a method well known to those of ordinary skill in the art.
  • Compound [28] can be obtained by converting the carboxy of compound [27] to hydroxy by reduction.
  • compound [28] can be obtained by reacting compound [27] with a reducing agent in a solvent under ice-cooling to room temperature.
  • Examples of the reducing agent to be used for the reaction include sodium borohydride and the like.
  • solvent to be used for the reaction examples include methanol, ethanol, 2-propanol, 1,4-dioxane, tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, cyclopentyl methyl ether and the like.
  • Compound [29] can be obtained by converting the hydroxy of compound [28] to the leaving group L 2 in the same manner as in Production Method 2-1, Step 2-1-7.
  • Compound [30] can be obtained by reacting compound [29] with compound [17] in the same manner as in Production Method 2-1, Step 2-1-8.
  • Compound [31] can be obtained by removing P w of compound [30] in the same manner as in Production Method 2-1, Step 2-1-9.
  • Compound [32] can be obtained by reacting compound [31] with compound [20] in the same manner as in Production Method 2-1, Step 2-1-10.
  • Compound [I-a1] can be obtained by converting alkoxy of compound [22] to hydroxy by hydrolysis in the same manner as in Production Method 1-1, Step 1-1-3.
  • R 1 , R 4 and n are as defined in the aforementioned formula [I], can be obtained by subjecting compound [9] to the reactions of Step 2-1-4, Step 2-1-5 and Step 2-1-11.
  • Step 2-1 the amide bond forming reaction is performed by using compound [10] and HNR b1 R b2 such as dimethylamine, tert-butylamine and the like and in the same manner as in Step 2-1-10. Thereafter, the resultant product is subjected to the reactions of Step 2-1-4, Step 2-1-5 and Step 2-1-11, whereby compound [I-a3] which is a compound represented by the formula [I] wherein ring Cy is the formula
  • Step 2-1-11 the reaction of Step 2-1-11 is performed by using compound [15]. Thereafter, the resultant product is reacted with a C 1-6 alkyl-carboxylic anhydride such as acetic anhydride, propionic anhydride and the like, whereby compound [I-a5] which is a compound represented by the formula [I] wherein ring Cy is the formula
  • R 1 , R 4 , R b8 , R b9 and n are as defined in the aforementioned formula [I], can be obtained.
  • R 1 , R 4 , R b14 , R b15 and n are as defined in the aforementioned formula [I], can be obtained.
  • R 1 , R 4 , R b6 , R b7 and n are as defined in the aforementioned formula [I], can be obtained.
  • R 1 , R 4 , R b16 , m2, m3 and m4 are as defined in the aforementioned formula [I] and C 1-6 Alkyl, L 2 , P v , t and Y are as defined in the above-mentioned Production Method 2-1.
  • Compound [36] can be obtained by reacting compound [34] with compound [35] in a solvent in the presence of a base.
  • Examples of the base to be used for the reaction include, lithium diisopropylamide, lithium bis(trimethylsilyl)amide and the like base.
  • solvent to be used for the reaction examples include ether solvents such as tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, cyclopentyl methyl ether and the like; hydrocarbon solvents such as toluene, hexane, xylene and the like, and a mixed solvent thereof.
  • ether solvents such as tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, cyclopentyl methyl ether and the like
  • hydrocarbon solvents such as toluene, hexane, xylene and the like, and a mixed solvent thereof.
  • Compound [35] may be a commercially available product such as benzyl chloromethyl ether, or may be obtained by converting a commercially available product as appropriate by a method well known to those of ordinary skill in the art.
  • Compound [37] can be obtained by removing P v of compound [36] in the same manner as in Production Method 2-1, Step 2-1-6.
  • Compound [38] can be obtained by converting the ester of compound [37] to carboxy by hydrolysis in the same manner as in Production Method 2-1, Step 2-1-1.
  • Compound [39] can be obtained by reacting compound [38] with compound [19] in a solvent in the presence of a condensing agent and an additive in the same manner as in Production Method 2-1, Step 2-1-10.
  • Compound [40] can be obtained by cyclization of compound [39] by intramolecular Mitsunobu reaction.
  • compound [40] can be obtained by reacting compound [39] with an azodicarboxylic acid diester (e.g., diethyl azodicarboxylate, diisopropyl azodicarboxylate, bis(2-methoxyethyl) azodicarboxylate etc.) in a solvent in the presence of a phosphine such as triphenylphosphine, tributylphosphine and the like.
  • an azodicarboxylic acid diester e.g., diethyl azodicarboxylate, diisopropyl azodicarboxylate, bis(2-methoxyethyl) azodicarboxylate etc.
  • a phosphine such as triphenylphosphine, tributylphosphine and the like.
  • Examples of the solvent to be used for the reaction include dichloromethane, chloroform, 1,4-dioxane, tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, cyclopentyl methyl ether, toluene, N,N-dimethylformamide and the like. These may be used singly or as a mixture of two or more kinds thereof.
  • R 1 , R 4 and R c are as defined in the aforementioned formula [I].
  • R 1 , R 4 , R 5 , R c , m1 and X are as defined in the aforementioned formula [I]
  • Z is as defined in the above-mentioned Production Method 1-1
  • Hal 2 and P v are as defined in the above-mentioned Production Method 2-1.
  • Compound [42] can be obtained by protecting the hydroxy group of compound [41] in the same manner as in Production Method 2-1, Step 2-1-3.
  • Compound [44] can be obtained by the Suzuki coupling reaction of compound [3] and compound [43] in the same manner as in Production Method 1-1, Step 1-1-2.
  • Examples of the solvent to be used for the reaction include dichloromethane, chloroform, 1,4-dioxane, tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, cyclopentyl methyl ether, toluene, N,N-dimethylformamide and the like. These may be used singly or as a mixture of two or more kinds thereof.
  • Compound [46] may be a commercially available product such as benzyl alcohol, 2-pyridinemethanol and the like, or may be obtained by converting a commercially available product as appropriate by a method well known to those of ordinary skill in the art.
  • Compound [I-b1] can be obtained by converting the alkoxy of compound [47] to hydroxy by hydrolysis in the same manner as in Production Method 1-1, Step 1-1-3.
  • R y is chloro or trifluoromethyl
  • R 4 is as defined in the aforementioned formula [I]
  • Z is as defined in the aforementioned Production Method 1-1
  • P v is as defined in the aforementioned Production Method 2-1.
  • Compound [49] can be obtained by protecting the hydroxy group of compound [48] in the same manner as in Production Method 2-1, Step 2-1-3.
  • compound [48] may be a commercially available product such as those shown below, or may be obtained by converting a commercially available product as appropriate by a method well known to those of ordinary skill in the art.
  • Compound [43a] can be obtained by reacting compound [49] with a boron compound in a solvent in the presence of a base.
  • compound [43a] can be obtained by adding a base to compound [49] in a solvent at ⁇ 78° C. to room temperature, and reacting the resultant product with a boron reagent at ⁇ 78° C. to room temperature.
  • Examples of the base to be used for the reaction include n-butyllithium, sec-butyllithium and the like.
  • Examples of the boron reagent to be used for the reaction include 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, trimethyl borate and the like.
  • solvent to be used for the reaction examples include tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, cyclopentyl methyl ether and the like.
  • R 5 , R e , X and Cy are as defined in the aforementioned formula [I], m7 is 0, 1 or 2, and when m7 is 2, each R 5 is selected independently, can be obtained by appropriately converting the substituent of compound [2].
  • L 3 is a leaving group such as trifluoromethanesulfonyloxy and the like
  • P x is a hydroxy-protecting group such as benzyl and the like
  • R 5 , R 6 , R e , X and Cy are as defined in the aforementioned formula [I]
  • Hal 1 and Z are as defined in the aforementioned Production Method 1-1
  • m7 is as defined in the aforementioned formula [I-A].
  • Compound [51] can be obtained by the Suzuki coupling reaction of compound [1] and compound [50] in the same manner as in Production Method 1-1, Step 1-1-1.
  • Compound [50] may be a commercially available product such as 4-(benzyloxy)phenylboronic acid, or may be obtained by converting a commercially available product as appropriate by a method well known to those of ordinary skill in the art.
  • Compound [53] can be obtained by removing the phenol protecting group P x of compound [52].
  • the deprotection can be performed by a known method according to the protecting group to be employed.
  • compound [52] when P x is benzyl, compound [52] only needs to be subjected to a hydrogenation reaction in a single or mixed solvent of tetrahydrofuran, ethyl acetate, ethanol, methanol, water and the like in the presence of a catalyst such as palladium carbon, platinum carbon and the like.
  • Compound [54] can be obtained by converting the hydroxy to a leaving group L 3 .
  • the leaving group is trifluoromethanesulfonyloxy
  • compound [54] can be obtained by reacting compound [53] with trifluoromethanesulfonic anhydride, N-phenyl bis(trifluoromethanesulfonimide) and the like in a solvent in the presence of a base from ice-cooling to room temperature.
  • solvent to be used for the reaction examples include ether solvents such as 1,4-dioxane, tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, cyclopentyl methyl ether and the like; hydrocarbon solvents such as toluene, hexane, xylene and the like; halogenated solvents such as dichloromethane, chloroform and the like; polar solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, acetonitrile, pyridine and the like, and the like. These may be used singly or as a mixture of two or more kinds thereof.
  • ether solvents such as 1,4-dioxane, tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, cyclopentyl methyl ether and the like
  • hydrocarbon solvents such as toluene,
  • Compound [56] can be obtained by the Sonogashira reaction of compound [54] and compound [55].
  • compound [56] can be obtained by reacting compound [54] with compound [55] in a solvent preferably under heating in the presence of a base, a palladium catalyst and a copper catalyst.
  • Examples of the copper catalyst to be used for the reaction include copper iodide, copper bromide and the like.
  • solvent to be used for the reaction examples include ether solvents such as 1,4-dioxane, tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, cyclopentyl methyl ether and the like; hydrocarbon solvents such as toluene, hexane, xylene and the like; and polar solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, acetonitrile, pyridine and the like. These may be used singly or as a mixture of two or more kinds thereof.
  • ether solvents such as 1,4-dioxane, tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, cyclopentyl methyl ether and the like
  • hydrocarbon solvents such as toluene, hexane, xylene and the like
  • polar solvents such as N,N
  • Compound [I-c1] can be obtained by converting the alkoxy of compound [56] to hydroxy by hydrolysis in the same manner as in Production Method 1-1, Step 1-1-3.
  • a hydrogenation reaction only needs to be performed in a single or mixed solvent of tetrahydrofuran, ethyl acetate, ethanol, methanol, water and the like in the presence of a catalyst such as palladium carbon or platinum carbon and the like.
  • the reaction mixture was stirred for 20 min and at room temperature for 20 hr. Thereafter, to the reaction mixture were added 6-methyl-2-pyridinemethanol (0.099 g, 0.80 mmol) and triphenylphosphine (0.21 g, 0.80 mmol), and bis(2-methoxyethyl) azodicarboxylate (0.19 g, 0.80 mmol) in 2 portions under ice-cooling. After stirring for 20 min, the reaction mixture was stirred for 10 min at room temperature. To the reaction mixture were added water and ethyl acetate, and the mixture was partitioned.
  • a solution of the residue in N,N-dimethylformamide (2.0 ml) was added to a solution of di-tert-butyl iminodicarboxylate (0.140 g, 0.64 mmol) and sodium hydride (0.026 g, 60 wt % oil dispersion) in N,N-dimethylformamide (1.0 ml) under ice-cooling, and the mixture was stirred at room temperature for 15 min.
  • the reaction mixture were added water and ethyl acetate, and the mixture was partitioned.
  • the reaction mixture was added to a solution of di-tert-butyl iminodicarboxylate (0.32 g, 1.5 mmol) and cesium carbonate (1.2 g, 3.6 mmol) in N,N-dimethylformamide (3.0 ml) at room temperature, and the mixture was stirred for 1 hr.

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WO2016101885A1 (en) * 2014-12-24 2016-06-30 National Institute Of Biological Sciences, Beijing Necrosis inhibitors
US11078412B2 (en) * 2015-03-04 2021-08-03 Shimadzu Corporation Polyamine and tyramine analysis method using pyrene containing fluorescence derivatization reagent and excimer fluorescence
KR20180067678A (ko) * 2015-10-29 2018-06-20 아스카 세이야쿠 가부시키가이샤 피리미딘 유도체
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US11512051B2 (en) * 2016-08-01 2022-11-29 Aptinyx Inc. Spiro-lactam NMDA receptor modulators and uses thereof
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US11786538B2 (en) * 2019-12-11 2023-10-17 Somerset Therapeutics, Llc Low benzalkonium chloride bimatoprost ophthalmic compositions with effective penetration and preservation properties

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IL247319A0 (en) 2016-09-29
WO2015125842A1 (ja) 2015-08-27
CA2936408C (en) 2022-09-13
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BR112016018341B1 (pt) 2023-02-07
TW201620881A (zh) 2016-06-16
EP3456713A1 (de) 2019-03-20
CN106232585A (zh) 2016-12-14
BR112016018341A2 (de) 2017-08-08
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JP6461637B2 (ja) 2019-01-30
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AR099498A1 (es) 2016-07-27

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