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WO2008066145A1 - Dérivé de thiazole et son utilisation en tant qu'inhibiteur de la vap-1 - Google Patents

Dérivé de thiazole et son utilisation en tant qu'inhibiteur de la vap-1 Download PDF

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Publication number
WO2008066145A1
WO2008066145A1 PCT/JP2007/073137 JP2007073137W WO2008066145A1 WO 2008066145 A1 WO2008066145 A1 WO 2008066145A1 JP 2007073137 W JP2007073137 W JP 2007073137W WO 2008066145 A1 WO2008066145 A1 WO 2008066145A1
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ethyl
disease
mmol
thiazole
acetamide
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Japanese (ja)
Inventor
Tatsuya Matsukawa
Kazuhiro Masuzaki
Noriyuki Yamamoto
Makoto Takewaki
Hiroyuki Tanaka
Yosuke Kawai
Sumiyo Yamamoto
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R Tech Ueno Ltd
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R Tech Ueno Ltd
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members 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 to ring carbon atoms
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Definitions

  • the present invention relates to a novel thiazole derivative (a compound represented by the following formula (I) (hereinafter also referred to as compound (I)) and a pharmaceutically acceptable salt thereof. Also referred to as a compound).
  • the present invention relates to a blood vessel adhesion protein-1 inhibitor, a medicament for the prevention or treatment of vascular adhesion protein-1 related diseases, etc. comprising the compound of the present invention as an active ingredient.
  • Vascular adhesion protein-1 (hereinafter abbreviated as VAP-1) is an aminoxidase (semicarbazide-sensitive amine oxidase, SSAO) that is abundant in human plasma. Its expression is markedly increased in vascular endothelium and vascular smooth muscle at the site of inflammation. Although the physiological role of VAP-1 has not been elucidated until recently, the VAP-1 gene was cloned in 1998, and VAP-1 is an adhesion molecule under the control of inflammatory site force-in expression. As reported to be a membrane protein that regulates the rolling and migration of lymphocytes and NK cells! The substrate amine is thought to be an unknown force S, methylamine produced at any site in the body. It is also known that hydrogen peroxide and aldehydes resulting from the aminoxidase activity in the molecule are important factors for attachment activity.
  • VAP-1 has been reported to be associated with the following diseases (1) to (6): (1) cirrhosis, essential stabilized hypertension, diabetes, arteries Hardening (see JP 61-239891 (Patent Document 1) and US Pat. No.
  • Patent Document 2 Endothelial damage (in diabetes, arteriosclerosis and hypertension) , Cardiovascular disease associated with diabetes and uremia, pain associated with gout and arthritis, retinopathy (in diabetic patients) (see WO 1993/23023); (3) (connective tissue) Inflammatory diseases or symptoms (rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis and osteoarthritis or degenerative joint disease, Reiter syndrome, Siedalen syndrome, Behcet syndrome, relapsing polychondritis, systemic lupus erythematosus, discoid Lupus erythematosus, systemic sclerosis, eosinophilic fasciitis, polymyositis, dermatomyositis, polymyalgia rheumatica, vasculitis, transient arthritis, polyarteritis nodosa, Wegener's granuloma Disease, mixed connect
  • Patent Document 6 (4) Diabetes (see International Publication No. 2002/38152 (Patent Document 7)); and (5 ) SSAO-mediated complications [diabetes (insulin-dependent diabetes mellitus (IDDM) and non-insulin-dependent diabetes mellitus (NIDDM)) and vascular complications (heart attack, angina pectoris, stroke, amputation, blindness and renal failure)] (international Open 2002/38153 Pan Fret (see Patent Document 8); (6) Diseases with increased vascular permeability [Age-related macular degeneration, age-related discoid macular degeneration, cystoid macular edema, eyelid edema, retinal edema, diabetic retinopathy, chorioretinopathy, neovascular macular disease, neovascular glaucoma, uveitis, iris Inflammation, retinal vasculitis, endophthalmitis, panophthalmitis, metastatic permeability
  • Patent Document 10 International Publication No. 2004/067521
  • Patent Document 9 International Publication No. 2004/0 87138
  • Patent Document 11 International Publication No. 2006/011631
  • Patent Document 12 describes a thiazole derivative having a specific structure and is used for the prevention or treatment of VAP-1-related diseases such as macular edema and hypervascular disease. Is described.
  • the thiazole derivative having a specific structure conceptually includes a compound having a hydrazino group or a hydrazino carbonyl group at the end of the molecule.
  • the thiazole derivative having a specific structure conceptually includes a compound having a hydrazino group or a hydrazino carbonyl group at the end of the molecule.
  • there are no specific disclosures (examples) or suggestions for compounds having a hydrazino group or a hydrazino carbonyl group at the end of the molecule nor are there any specific disclosures or suggestions regarding pharmacological activities such as SSAO inhibitory activity or safety. .
  • Patent Document 1 JP-A 61-239891
  • Patent Document 2 U.S. Pat.No. 4,888,283
  • Patent Document 3 International Publication No. 1993/23023 Pamphlet
  • Patent Document 4 Pamphlet of International Publication No. 2002/02090
  • Patent Document 5 International Publication No. 2002/02541 Pamphlet
  • Patent Document 6 US Patent Application Publication No. 2002/0173521
  • Patent Document 7 International Publication No. 2002/38152 Pamphlet
  • Patent Document 8 International Publication No. 2002/38153 Pamphlet
  • Patent Document 9 International Publication No. 2004/087138 Pamphlet
  • Patent Document 10 International Publication No. 2004/067521 Pamphlet
  • Patent Document 11 International Publication No. 2006/011631 Pamphlet
  • Patent Document 12 International Publication No. 2006/028269 Pamphlet
  • Non-patent document 1 Diabetologia, 42 (1999) 233—237
  • Non-Patent Document 2 Diabetes Medicine, 16 (1999) 514— 521
  • An object of the present invention is to provide a novel thiazole derivative useful as a VAP-1 inhibitor, a medicament for the prevention and treatment of VAP-1 related diseases, and the like.
  • the present inventors have a thiazole derivative having a specific functional group (hydrazino group or hydrazinocarbonyl group) at the molecular end, an excellent VAP-1 inhibitory activity, and The inventors have found that side effects which are excellent in enzyme selectivity and can be eliminated can be eliminated, and further research has been made to complete the present invention.
  • R 1 is asil
  • n is an integer from 0 to 6.
  • L is a bond, O— — NH— — CO, or — SO —;
  • M is a bond, lower alkylene, lower alkenylene, or lower alkynylene.
  • J is (CH 2) 2 O
  • L is not O NH and SO—
  • L is not —CO, but if J is — (CH 2) —SO—, L is —O
  • A is a divalent residue induced by benzene force, or a divalent residue induced by thiophene force
  • B is one NR 2 — CO, one (CH) —, or one (CH) —CO— (wherein R 2 is hydrogen,
  • n represents an integer of 0 to 6;
  • D is —NR 3 — (wherein R 3 represents hydrogen, lower alkyl, alkoxycarbonyl or acyl);
  • E represents an optionally substituted amino. ⁇ ; Or a pharmaceutically acceptable salt thereof.
  • the compound represented by the formula (I) is N— ⁇ 4 [2- (4hydrazinocarbophenyl) ethyl] -1,3 thiazole-2-yl ⁇ acetamide,
  • a pharmaceutical composition comprising, as an active ingredient, the compound of any one of (1) to (3) above, or any of the compounds described above or a pharmaceutically acceptable salt thereof.
  • a VAP-1 inhibitor comprising, as an active ingredient, the compound of any one of (1) to (3) above, or any one of the compounds described above or a pharmaceutically acceptable salt thereof.
  • a pharmaceutical composition for preventing or treating a VAP-1-related disease which comprises, as an active ingredient, the compound according to any one of (1) to (3) above, or any one of the compounds or a pharmaceutically acceptable salt thereof.
  • VAP-1 related diseases are macular edema (diabetic and non-diabetic macular edema), age-related macular degeneration, age-related discoid macular degeneration, cystoid macular edema, eyelid edema, retinal edema, glycouria Pathological retinopathy, chorioretinopathy, neovascular macular disease, neovascular glaucoma, uveitis, ulceris, retinal vasculitis, endophthalmitis, panophthalmitis, metastatic ophthalmitis, choroiditis, retinitis pigmentosa, Result Meningitis, ciliary inflammation, scleritis, episclerosis, optic neuritis, retrobulbar neuritis, keratitis, blepharitis, exudative retinal detachment, corneal ulcer, conjunctival ulcer, chronic monkey keratitis, tygeson
  • VAP-1 related diseases are macular edema (diabetic and non-diabetic macular edema), age-related macular degeneration, age-related discoid macular degeneration, cystoid macular edema, eyelid edema, retinal edema, diabetic Retinopathy, choroidal retinopathy, neovascular macular disease, neovascular glaucoma, uveitis, ulceris, retinal vasculitis, endophthalmitis, panophthalmitis, metastatic ophthalitis, choroiditis, retinitis pigmentosa, conjunctivitis , Ciliitis, scleritis, episclerosis, optic neuritis, retrobulbar neuritis, keratitis, blepharitis, exudative retinal detachment, corneal ulcer, conjunctival ulcer, chronic monkey keratitis, Tigerson keratitis, Ocular
  • Symptoms caused by ocular inflammatory diseases including edema and ulcers, erythema, polymorphic exudative erythema, erythema nodosum, erythema nodosum, edematous sclerosis, dermatitis (psoriasis, allergic lesions, lichen planus, Rose sucrose eczema, contact dermatitis, atopic dermatitis, erythema erythematosus, vascular neuropathic edema, pharyngeal edema, glottic edema, hypoglottic pharyngitis, bronchitis, rhinitis, pharyngitis, accessory Associated with rhinitis and pharyngitis or otitis media, cirrhosis, essential fixed hypertension, diabetes, arteriosclerosis, endothelial damage (in diabetes, arteriosclerosis and hypertension), cardiovascular disease associated with diabetes and ur
  • a method for inhibiting VAP-1 in a subject which comprises administering to the subject an effective amount of the compound of any one of the above (1) to (3) or any one of the above or a pharmaceutically acceptable salt thereof .
  • VAP-1-related disease in the subject comprising administering to the subject an effective amount of the compound of any one of (1) to (3) above, or any of the above, or a pharmaceutically acceptable salt thereof. Prevention or treatment method.
  • VAP-1 related diseases are macular edema (diabetic and non-diabetic macular edema), age-related macular degeneration, age-related discoid macular degeneration, cystoid macular edema, eyelid edema, retinal edema, diabetic Retinopathy, chorioretinopathy, neovascular macular disease, neovascular glaucoma, uveitis, ulceris, retinal vasculitis, endophthalmitis, panophthalmitis, metastatic ophthalmitis, choroiditis, retinitis pigmentosa, conjunctivitis , Ciliary inflammation, scleritis, episclerosis, optic neuritis, retrobulbar neuritis, keratitis, blepharitis, exudative retinal detachment, corneal ulcer, conjunctival ulcer, chronic monkey keratitis, Tigerson keratitis, Ocular e
  • the compound of the present invention is excellent in VAP-1 inhibitory activity and excellent in enzyme selectivity and can eliminate undesirable side effects and the like as a pharmaceutical product, it is useful for VAP-1 inhibitors and VAP-1 related diseases. It is useful as a preventive or therapeutic drug.
  • “Lower alkyl” includes linear or branched alkyl having 1 to 6 carbon atoms (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec butyl, tert-butyl, pentyl, tert pentyl) And hexyl), among them, more preferred is C 1 -C alkyl.
  • “Lower alkylene” includes linear or branched alkylene having 1 to 6 carbon atoms (eg, methylene, ethylene, trimethylene, propylene, ethylidene and propylidene), among others. More preferred is CC alkylene.
  • “Lower alkenylene” includes linear or branched alkenylene having 2 to 6 carbon atoms (eg, vinylene, 1-propenylene, 1-methylenol, 1-propenylene, 2-methylinole).
  • the lower alkenylene may be E-form or Z-form, respectively.
  • the compound of the present invention includes all stereoisomers in which the lower alkenylene moiety has an E structure and a Z structure.
  • “Lower alkynylene” includes a straight or branched chain anolequinylene having 2 to 6 carbon atoms and having 3 to 3 bonds (eg, ethynylene, 1-propynylene, 1-methynylene, 1-propynylene, and 2 methylolene).
  • Aryl includes C C aryl (eg, phenyl and naphthyl) and the like,
  • the “aryl” may be substituted with 1 to 3 substituents, and the substitution position is not particularly limited.
  • “Aralkyl” has 6 to 6 aryl moieties; that is, the aryl moiety is a C 1 -C aryl of the above “aryl” and 1 to 6 alkyl moieties.
  • Aralkyl eg, benzyl, phenethyl, 1-naphthylmethyl, 2-naphthylmethyl, 3-phenylpropyl, 4-phenylbutyl and 5-phenylpentinole.
  • Cyclo lower alkyl includes cycloalkyl having 3 to 6 carbon atoms (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl) and the like.
  • Cyclolower alkoxycarbonyl includes cycloalkoxycarbonyl having a cycloalkyl portion of 3 to 6 carbon atoms (eg, cyclopropyloxycarbonyl, cyclobutynole, xicanoreponinore, cyclopentinore, xicanorepo). Ninore, cyclohexenole and xyloxycarbonyl).
  • Heterocycle includes “aromatic heterocycle” and “non-aromatic heterocycle”.
  • “Aromatic heterocycle” is selected from nitrogen, oxygen and sulfur atoms in addition to carbon atoms;! To 5 to 10 containing 3 heteroatoms, including 10-membered aromatic heterocycles, etc.
  • thiophene furan, pyronore, imidazolone, pyrazonole, thiazonole, isothiazonole, oxazole, isoxazole, pyridine, pyridazine, pyrimidine, pyrazine and the like.
  • Non-aromatic heterocycles include 5- to 10-membered non-aromatic heterocycles containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur atoms in addition to carbon atoms. Examples thereof include pyrrolidine, imidazoline, virazolidine, pyrazoline, piperidine, piperazine, morpholine, thioline monoreforin, dioxolane, diaxazolidine, thiazolidine, triazolidine and the like.
  • Alkylcarbonyl includes alkylcarbonyl, allylcarbonyl, and the like.
  • Alkylcarbonyl includes an alkyl moiety having 1 to 6 carbon atoms [ie, the alkyl moiety is a C C alkyl of the above “lower alkyl”]
  • Arylcarbonyl has an aryl moiety of 6 to 10 carbon atoms [that is, the aryl moiety is a C C aryl of the above “aryl”]
  • Alkoxycarbonyl includes alkyloxycarbonyl, aralkyloxycarbonyl and the like.
  • Alkyloxycarbonyl includes an aralkyloxycarbonyl in which the alkyl moiety has 1 to 10 carbon atoms (eg, methoxycarbonyl, ethoxycarbonyl, propoxy force noreboninole, isopropoxynoreponinole, butoxycanoleponinole, Isobutoxycanoleponinore, sec butoxycanoleponinore, tert butoxycanoleponinore, pentinorexanoreponinore, tert pentinorexanoreponinore, hexinorexanoreponinore and decinorexoxyl Etc.).
  • Alkyloxycarbonyl has an aryl moiety of 6 to 10 carbon atoms [ie, the aryl moiety is a C C aryl of the above “aryl”] and an alkyl
  • the moiety has 1 to 6 carbon atoms [ie, the alkyl moiety is a C alkyl as defined above for “lower alkyl”] aralkyloxycarbonyl (eg, benzyloxycarboxyl)
  • acyl represented by R 1 includes those defined above, and alkylcarbonyl (wherein the alkylcarbonyl is as defined above) is preferred. Acetyl and the like are particularly preferred.
  • “Thiazole” may have a substituent, and the substitution position is not particularly limited.
  • Examples of the “substituent” of the “optionally substituted thiazole” include the groups described in the following (1) to (; 12).
  • Halogen eg, fluorine, chlorine, bromine
  • alkoxycarbonyl as defined above (eg, ethoxycarbonyl);
  • aryl is as defined above, the aryl is SO (lower alkyl) (wherein the lower alkyl is as defined above)
  • substitution position that may be substituted is not particularly limited) (eg, phenyl and 4 (methylsulfonyl) phenyl);
  • R a is hydrogen, lower alkyl, aryl or aralkyl
  • R b is hydrogen, lower alkyl, aryl or aralkyl, where the lower class Alkyl, aryl and aralkyl are as defined above (eg, N-methylaminocarbonyl, N-phenylaminocarbonyl, N, N dimethylamino force norbonyl and N benzylaminocarbonyl);
  • Secondary alkyl is as defined above), -CF and O aryl (wherein
  • the aryl may have 1 to 5 substituents selected from the group consisting of: and / or the substitution position is not particularly limited! ;
  • R w is hydrogen, lower alkyl, aryl or aralkyl, and the lower alkyl, aryl and aralkyl are as defined above), one CO (lower alkyl) (wherein Lower alkyl is as defined above.
  • Kill is as defined above); -co- (heterocycle) wherein the heterocycle is as defined above (eg, pyrrolidine, piperazine and morpholine), and lower alkyl ( The lower alkyl is as defined above) and halogen (eg, fluorine, chlorine
  • R j is hydrogen, acyl, lower alkyl, aryl or aralkyl, wherein the acyl, lower alkyl, aryl or aranolyl is as defined above, wherein the lower alkyl is , Formula: CONRkR 1 (wherein R k is hydrogen, lower alkyl, aryl or aralkyl, R 1 is hydrogen, lower alkyl, aryl or aralkyl, and the lower alkyl, aryl and aralkyl are Having 1 to 5 substituents selected from the group consisting of groups as defined above! /, And the substitution positions are not particularly limited! /,] Groups;
  • substitution position is not particularly limited; T is hydrogen; Formula: CONR n R ° (where R n is water) R, R, alkyl, aryl or aralkyl; Is a group of hydrogen, lower alkyl, aryl or aralkyl, wherein the lower alkyl, aryl and aralkyl are as defined above; NH—CO—R P (wherein R P is as defined above) A group of lower alkyl as defined above or aralkyl as defined above; —NH—SO (lower alkyl)
  • a primary alkyl, aryl or aralkyl is hydrogen, lower alkyl, aryl or aralkyl, where the lower alkyl, aryl and aralkyl are as defined above.
  • substitution position on the aryl or heterocyclic ring is not particularly limited, and may be any position.
  • Preferred examples of the above-mentioned “substituted, may! /, Thiazole” / and “substituent” include methylsulfonylbenzyl, sulfamoylbenzyl (eg, 4-sulfamoylbenzyl), and the like.
  • the substitution position of the methylsulfonyl group, sulfamoyl group and the like is not particularly limited.
  • Examples of lower alkylene, lower alkenylene and lower alkynylene represented by J and M in JLM include those defined above.
  • n 2 n 2 n 2 n 2 2 2 n is — (CH 2) — NH—SO— (CH 2) — (where n is an integer from 0 to 6), etc.
  • Examples of the lower alkyl and acyl represented by R 2 in NR 2 —CO— represented by B include those defined above.
  • B is specifically a bond, NH—CO— (CH 2) 2 —CO— (wherein n is an integer from 0 to 2)) (CH 2) (where n is 0
  • 2 n is an integer from 2 n to 3.
  • Examples of lower alkyl, alkoxycarbonyl and acyl represented by R 3 in NR 3 — represented by D include those defined above. Specific examples of D include NHN (CH 3) —. [0037] "Substituted! /, May! /, Amino" represented by E includes an unsubstituted amino group and an amino substituted with 1 or 2 substituents. “Optionally substituted amino” is represented by the formula —NR 4 R 5 .
  • R 4 and R 5 are each optionally substituted with hydrogen, unsubstituted or hydroxy, etc., lower alkyl, acyl (especially lower alkylcarbonyl, hydroxy lower alkyl force norbornyl), alkoxycarbonyl, hydroxyalkoxycarbonyl, aryleno, Examples include alcoholol, cyclo lower alkyl, cyclo lower alkoxycarbonyl, sulfuryl, sulfinyl, phosphoryl, and heterocyclic groups.
  • the lower alkyl, asil (especially lower alkylcarbonyl), alkoxycarbonyl, aryl, aranolalkyl, cyclo lower alkyl, cyclo lower alkoxycarbonyl, and heterocycle are as defined above.
  • R 4 and R 5 include hydrogen, lower alkyl (eg, methyl, ethyl, etc.), acetyl, butanol, decanol, 3-hydroxypropanoyl, and 6-hydroxy. Examples include ethoxycarbonyl, ethoxycarbonyl, butoxycarbonyl, decyloxycarbonyl, 2-hydroxyethoxycarbonyl, and the like.
  • the B—D—E moiety includes CO—NH—NH—CH—CO—NH—NH CH—CO—NH—NH
  • I can get lost.
  • Compound (I) includes N ⁇ 4 [2- (4 hydrazinocarbophenyl) ethyl] 1,3 thiazole-2-yl ⁇ acetoamide,
  • N- ⁇ 4- [2- (4 hydrazinocarbonylmethylphenyl) ethyl] -1,3-thiazole-2yl ⁇ acetamide and the like are preferable.
  • the present invention includes all enantiomers and diastereomers.
  • Compound (I) may be a pharmaceutically acceptable salt.
  • the pharmaceutically acceptable salt in the present invention is a normal pharmaceutically acceptable salt, and is not particularly limited as long as it is non-toxic, and examples thereof include salts with inorganic or organic bases, acid addition salts and the like.
  • Salts with inorganic or organic bases include alkali metal salts (eg, sodium salts, potassium salts, etc.), alkaline earth metal salts (eg, calcium salts, magnesium salts, etc.), ammonium salts, and amine salts (eg, bird And acid addition salts include mineral acids (eg, hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, metaphosphoric acid, nitric acid and sulfuric acid).
  • organic acids e.g., tartaric acid, acetic acid, citrate, malic acid, lactic acid, fumaric acid, maleic acid, benzoic acid, glycolic acid, darconic acid, succinic acid, and arenosulfonic acid (e.g., p- And salts derived from toluenesulfonic acid)).
  • the compound of the present invention can be used as a prodrug for the following medicaments.
  • prodrug is intended to encompass all compounds that, after administration, convert to VAP-1 inhibitors in the body.
  • the prodrug may be any pharmaceutically acceptable prodrug of the compound of the present invention.
  • the compound of the present invention can be used as an active ingredient of a medicament such as a VAP-1 inhibitor, a medicament for preventing or treating a VAP-1 related disease.
  • VAP-1 vascular adhesion protein 1
  • Macular edema eg, diabetic and non-diabetic macular edema
  • age-related macular degeneration e.g, diabetic and non-diabetic macular edema
  • cystoid macular edema eyelid edema
  • retinal edema diabetic retinopathy
  • chorioretinopathy Angiogenic macular disease
  • neovascular glaucoma uveitis, ulceris, retinal vasculitis
  • endophthalmitis panophthalmitis, metastatic ophthalmitis, choroiditis, retinitis pigmentosa, conjunctivitis, ciliitis, sclera
  • superior scleritis optic neuritis, retrobulbar neuritis, keratitis, blepharitis, ex
  • rheumatoid arthritis ankylosing spondylitis, psoriatic arthritis and osteoarthritis or osteoarthritis, Reiter's syndrome, Siedalen syndrome, Behcet's syndrome, relapsing polychondritis, systemic lupus erythematosus, discoid lupus erythematosus, Systemic sclerosis, eosinophilic fasciitis, polymyositis, dermatomyositis, rheumatic polymyalgia, vasculitis, transient arthritis, nodular polyarteritis, Wegener's granulomatosis, Mixed connective tissue disease and juvenile rheumatoid arthritis), inflammatory diseases or symptoms of the gastrointestinal tract [eg, Crohn's disease, ulcerative colitis, irritable bowel syndrome (eg, convulsive colon), fibrosis of the liver, oral mucosa Inflammation (eg, stomatitis
  • VAP-1 vascular adhesion protein 1 (VAP-1) -related diseases” refers to the treatment of VAP-1-related diseases with the compounds of the present invention having VAP-1 inhibitory activity (ie, VAP-1 inhibitors) ( It is intended to be administered to subjects for the purposes of prevention, symptom relief, symptom reduction, progression arrest and cure).
  • VAP-1 inhibitory activity ie, VAP-1 inhibitors
  • the medicament there are various administration targets for the medicament, pharmaceutical composition, VAP-1 inhibitor, medicament for preventing or treating VAP-1 related diseases in the present invention (hereinafter collectively referred to as the medicament of the present invention).
  • Mammals eg, mammals such as humans, mice, rats, pigs, dogs, cats, horses, tusks, etc. Human).
  • the medicament of the present invention can be administered by any route.
  • Administration routes in the present invention include systemic administration (eg, oral administration or injection administration), local administration, periocular administration (eg, subtenon administration), conjunctival administration, intraocular administration, subretinal administration, and choroidal administration. Administration (suprachoroidal) and post-ocular administration.
  • the mode of administration of the medicament of the present invention may be appropriately determined depending on whether the application to a VAP-1 related disease is prophylactic or therapeutic.
  • the medicament of the present invention is preferably administered immediately after it has been determined that there is a risk of a target VAP-1 related disease such as mammals, particularly humans (prophylactic treatment), Or it is administered immediately after the subject begins to develop VAP-1 related disease (therapeutic treatment).
  • the treatment plan may be appropriately determined according to the type of active ingredient to be used, the dose, the route of administration, the cause, and, if necessary, the degree of awareness of the VAP-1-related disease.
  • an effective route may be appropriately selected, and one or more routes can be used. Therefore, the above administration routes are merely examples, and are not limited thereto.
  • the dose (dosage) of the medicament of the present invention in an animal including humans, particularly in a subject to be administered such as a human, may be an amount sufficient to exert a desired reaction on the subject to be administered over a reasonable period of time.
  • the dose is appropriately determined according to the strength of the active ingredient used, the age, species, symptom or disease state and weight of the subject to be administered, various factors including the degree of the disease, route of administration, timing and frequency. That's fine.
  • the dose may be appropriately adjusted according to the route of administration, timing and frequency. Depending on the symptom or disease state, long-term treatment requiring multiple doses may be required.
  • the dose and dosing schedule can be determined by techniques found in the usual range known to those skilled in the art. In general, treatment or prophylaxis begins with a dose that is less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under circumstances is reached.
  • the medicament of the present invention (such as a VAP-1 inhibitor) is usually about 0.03 ng / kg body weight. 1 dose per day to about 300 mg / kg body weight / day, preferably about 0.003 ⁇ g / kg body weight / day to about 10 mg / kg body weight / day, or 2 to 4 doses per day Administration can be continuous or continuous.
  • the pharmaceutical composition of the present invention preferably comprises a “pharmaceutically acceptable carrier” and, as an active ingredient, an amount of a compound of the present invention sufficient to prevent or therapeutically treat a VAP-1-related disease.
  • the carrier may be any of those commonly used as pharmaceuticals, except where limited by physicochemical considerations (eg, solubility and lack of reactivity to the compound) and route of administration. There is no particular limitation.
  • the amount of the compound of the present invention in the medicament of the present invention may vary depending on the formulation of the composition.
  • . 1S usually 0. 00001-10 0 weight 0/0, preferably ⁇ (or 0. 00;! ⁇ 5 weight 0/0, which is still more preferably ⁇ or 0. 001 ;!% by weight.
  • the dosage form of the medicament of the present invention is not particularly limited, and can be administered in various forms in order to achieve the desired VAP-1 inhibitory action.
  • the medicament of the present invention can be formulated orally or parenterally by formulating the compound of the present invention alone or in combination with an additive such as a pharmaceutically acceptable carrier or diluent.
  • the characteristics and properties of the formulation are determined by the solubility and chemical properties of the active ingredient used, the chosen route of administration and standard pharmaceutical practice.
  • Preparations for oral administration include solid dosage forms (eg, capsules, tablets, powders) or liquid forms (eg, solutions or suspensions). Examples of the preparation used for parenteral administration include injection and infusion in the form of a sterile solution or suspension.
  • the solid oral preparation may contain usual excipients and the like.
  • Liquid oral preparations may contain various fragrances, colorants, preservatives, stabilizers, solubilizers or suspending agents and the like.
  • Parenteral preparations are, for example, sterile aqueous or non-aqueous solutions or suspensions and may contain various various preservatives, stabilizers, buffers, solubilizers or suspending agents and the like.
  • Various isotonic agents may be added as necessary.
  • the medicament of the present invention may contain other pharmaceutically active compounds as long as the effects of the present invention are not inhibited.
  • the medicament of the present invention may also have other pharmaceutically active compounds as long as the effects of the present invention are not inhibited. Can be co-administered.
  • “Simultaneous administration” means that other pharmaceutically active compounds are administered prior to, at the same time (eg, in the same formulation or in another formulation) or after administration of the medicament of the present invention.
  • a corticosteroid, prednisone, methylprednisone, dexamethasone, or triamcinolone acetinide or a non-corticosteroid anti-inflammatory compound eg, ibuprofen or flubiprofen
  • vitamins and minerals eg, zinc, antioxidants (eg, carotenoids (eg, xanthophyll carotenoid-like zeaxanthin or rutin))
  • micronutrients can be co-administered.
  • the compounds of the present invention are useful for the manufacture of a medicament such as a VAP-1 inhibitor, a pharmaceutical agent for preventing or treating VAP-1 related diseases.
  • Compound (I) can be produced by the following procedure, but is not limited to this procedure. One skilled in the art can modify the procedure according to a conventional method known per se. Compound (I) has the formula:
  • Compound (I) can be produced by chemically bonding three compounds (1), (2) and (3) as partial structures represented in Scheme 1 below.
  • Compounds (1), (2) and (3) may use salts thereof.
  • L 2 is a reactive functional group that forms a chemical bond with L 3 of compound (2) to form Y.
  • L 3 is a reactive functional group that forms a chemical bond with L 2 of compound (1) to form Y.
  • L 4 is a functional group that reacts with compound (3) to construct B in order to construct a hydrazine structure or an acyl hydrazine structure at the molecular end of compound (I).
  • L 5 is hydrogen, lower alkyl, alkoxycarbonyl, acyl or protecting group.
  • L 2 of compound (1) forms a chemical bond with L 3 of compound (2) and is a reactive functional group necessary to form Y.
  • (CH 2) CHO (CH 2) OH (CH )
  • Halogen One (CH) — C ⁇ H
  • One (CH) — C ⁇ One Halogen One (CH) — NH u 2 u 2 u 2 u 2-(CH)-SO H-(CH)-SO —Halogen, or one (CH) — invited from ⁇ H
  • Wittig reagent derived from 2 u 2 3 2 u and the like (wherein u is an integer of 06.
  • halogen include chlorine, bromine and iodine). It is not limited to.
  • Compound (1) or a salt thereof may be commercially available, or can also be produced according to a method known per se described in International Publication No. 2004/047521.
  • L 3 of compound (2) forms a chemical bond with L 2 of compound (1) and is a reactive functional group necessary for forming Y.
  • (CH 3) CHO (CH 2) OH (CH)
  • Norephonic acid ester eg, one (CH) -OSO CH, etc.
  • L 4 is a functional group necessary for reacting with the compound (3) to construct a hydrazine structure or a acyl hydrazine structure at the molecular end of the compound (I) and constructing B.
  • Examples of the gene include chlorine, bromine and iodine.
  • R 2 is the same as defined above. ) Is not particularly limited.
  • Compound (2) or a salt thereof may be commercially available, or produced according to a method known per se described in International Publication No. 2004/047521, International Publication No. 2006/011631, and the like. You can also
  • Compound (3) is a hydrazine equivalent for constructing a hydrazine structure or an acyl hydrazine structure at the molecular end of compound (I), and may be a commercially available product or a method known per se Can also be manufactured.
  • the protecting group in L 5 is a functional group that is introduced for the purpose of avoiding unnecessary reactions and removed by the final step. For example, protection such as (CH 3) 2 C OCO shown in the production example Groups. Low at L 5
  • Examples of the primary alkyl, alkoxycarbonyl, and acyl are the same as the lower alkyl, alkoxycarbonyl, and acyl represented by the aforementioned R 3 .
  • compound (1) is obtained using Wittig reaction, Horner-Emmons reaction, aldol condensation reaction, Claisen condensation, or similar carbon-carbon bond-forming reaction.
  • a salt thereof with a compound (2) or a salt thereof some! /, Is a compound obtained by condensing compounds (2) and (3) in advance
  • lower alkenylene is included! /
  • Suitable salts of compounds (1) and (2) may be the same as those exemplified for compound (I).
  • Various carbon-carbon bond forming reactions can be used.
  • L 2 is — (CH 2 ) —CHO, and L 3 is — (CH 2). Derived from halogen, etc. From phosphonium salts (Wittig reagent), or L 2 is one (CH) — from halogen, etc.
  • u V is the same as defined above.
  • the halogen include chlorine, bromine, and iodine.
  • the reaction is usually carried out in potassium tert butoxide, hydrogen in conventional solvents such as N, N dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, dichloromethane, and other organic solvents that do not adversely affect the reaction, or mixtures thereof. It is carried out in the presence of a common base such as sodium hydroxide or sodium hydroxide.
  • the reaction is not particularly important, and the reaction is carried out under cooling or heating.
  • the product can be isolated or purified by known separation or purification means such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transition, chromatography, etc., and the compound (I ) Can be converted to the same salts as those exemplified above.
  • lower alkenylene or lower alkynylene can be hydrogenated to be converted to lower alkylene.
  • a hydrogenation reaction is carried out according to a conventional method in the presence of various homogeneous or heterogeneous catalysts.
  • catalytic hydrogenation using a heterogeneous catalyst is preferably performed in the presence of a catalyst such as palladium carbon.
  • compound (1) or a salt thereof is converted to compound (2) or a salt thereof (or compound (2) and ( 3) is condensed with a pre-condensed compound) to form an ester or amide bond.
  • L 2 is-(CH) —OH (CH) -NH (CH) halogen, etc.
  • L 3 is (CH) COOH (CH) CO halogen, CH) SO H
  • L 3 is — (CH 2) — ⁇ H— (CH 2) —NH— (CH 2) —halogen, etc.
  • Y can be constructed based on a typical organic synthesis method (in each formula, uV is the same as defined above.
  • halogen include chlorine, bromine, and iodine).
  • the reaction is usually normal solvents such as dichloromethane, acetone, tetrahydrofuran, jetyl ether, N, N dimethylformamide, and does not adversely affect the reaction! /, Any other organic solvents It is carried out in a medium or a mixture thereof.
  • a condensing agent such as 1-ethyl-3- (3-dimethylaminopropyl) carpositimide hydrochloride, N, N'-dicyclohexyl carpositimide, N, N'-carbonyldiimidazole is used. It can also be used in the presence of additives such as N, N-dimethylenoyl 4-aminoviridine, 1-hydroxybenzotriazole, 1-hydroxysuccinimide, 3,4 dihydro-3 hydroxy-4oxo1,2,3 benzotriazine. Done.
  • the reaction temperature is not particularly important. The reaction is carried out under cooling or heating.
  • L 3 is-(CH) 1 CH 0, 1 (CH 2) 1 halogen, etc.
  • L 2 is one (CH) — CH ⁇ , one (CH) — halogen, etc.
  • L 3 is one (CH) — N
  • H or its salt, etc., and Y can be constructed based on general organic synthesis methods.
  • U and V are as defined above.
  • the halogen include chlorine, bromine and iodine.
  • the reaction is usually performed using a conventional solvent such as tetrahydrofuran, jetyl ether, alcohols, and any other organic solvent that does not adversely affect the reaction, or a mixture thereof as a reaction solvent by condensing an amine with an aldehyde to form a Schiff base. This is reduced with sodium borohydride or sodium borohydride to construct a secondary amine structure. Alternatively, the same structure is constructed by a condensation reaction between an amine and a halogen compound.
  • N, N diisopropylamine, triethylamine, potassium carbonate and other bases are used as reactants, which adversely affect normal solvents such as tetrahydrofuran, acetonitrile, N, N dimethylformamide, and reactions. Or other organic solvents or mixtures thereof are used as reaction solvents.
  • the reaction is not particularly important, and the reaction is carried out under cooling to heating.
  • the product can also be converted to a salt similar to the salt exemplified for compound (I).
  • L 3 is one (CH) ⁇ H,-(CH) -halogen, one (CH) -sulfone
  • L 2 is one (CH 3) ⁇ H,-(CH) halogen
  • L 3 is-(CH 2) — ⁇ H, etc.
  • Y can be constructed based on organic synthesis techniques (where u and V are as defined above) It is. Examples of halogen include chlorine, bromine and iodine. ).
  • the ether bond can be formed by the Williamson method, an ether synthesis method from an aromatic halide using a copper catalyst or the like, a Mitsunobu reaction, or other known production methods. These reactions are usually carried out in conventional solvents such as acetonitrile, dichloromethane, acetone, tetrahydrofuran, N, N dimethylformamide, and any other organic solvent that does not adversely affect the reaction, or mixtures thereof. Done.
  • the reaction temperature is not particularly important. The reaction is carried out under cooling or heating.
  • the product can be converted to a salt similar to the salt exemplified for compound (I).
  • the molecular end of the compound (I) is a hydrazinocarbonyl group or a hydrazino group.
  • Esters such as-(CH) -COOCH, or one (CH) — C 0 halogen
  • w is the same as defined above.
  • the halogen include chlorine, bromine and iodine.
  • Structure is required.
  • the compound (2) may be incorporated in advance as a carboxyl group from the raw material stage, or may be constructed as a part of the synthesis process by hydrolysis of the corresponding carboxylic acid ester, oxidation of alcohol or the like. By condensing carboxylic acid, carboxylic acid ester, or acid halide and hydrazine or protected hydrazine), hydrazinocarbonyl group (in formula (I), B is one (CH ) — CO—, D is one NR 3 —, E is an optionally substituted amino group)
  • the reaction is usually a conventional solvent such as dichloromethane, acetonitrile, tetrahydrofuran, N, N dimethylformamide, and any reaction that does not adversely affect the reaction. It is carried out in other organic solvents or mixtures thereof.
  • a condensing agent such as 1, 1'-carbonyldiimidazole or N, ''-dicyclohexyl carpositimide is used.
  • the condensation reaction may be carried out after induction into an acid halide with thionyl chloride, oxalyl chloride or the like.
  • the condensation reaction with hydrazine can be carried out according to various known methods.
  • NHR 2 When producing compound (I) where ⁇ is NR 2 — CO 2 , the structure of NHR 2 is required as L 4 .
  • the compound (2) may be preliminarily incorporated as an amino group or protected amino group from the raw material stage, and may be constructed as a part of the synthesis process by reduction of the nitro group.
  • B By treating the amino group with, for example, tert butyl 2 (1H-imidazole-1-ylcarbonyl) hydrazinecarboxylate prepared from 1,1′-carbonyldiimidazole and tert-butoxy-powered rubazate, B is NR 2 — CO—, D is NR 3 —, E is substituted! /, May!
  • the reaction can be constructed as a terminal structure of an amino group.
  • the reaction is usually carried out in a conventional solvent such as dichloromethane, acetonitrile, tetrahydrofuran, N, N dimethylformamide, and any other organic solvent or mixture thereof that does not adversely affect the reaction! .
  • the reaction temperature is not particularly important.
  • the reaction is carried out under cooling or heating.
  • Mitsunobu reaction can be used as a method for constructing a hydrazino group from a hydroxyl group (alcohol).
  • a hydroxyl group alcohol
  • tert-butyl (1,3-dioxone 1,3-dihydro-2H-isoindole-2-yl) rubamate as the hydrazine equivalent
  • condensing triphenylphosphine and jetylazodicarboxylate as reactants
  • the phthalimide moiety is removed by hydrazine decomposition, and then the tert-butoxycarbonyl group is removed with an acid to form a hydrazino group at the molecular end of compound (I) (in formula (I), B is CH , D is NR 3 —
  • E can be substituted amino groups).
  • hydrazino groups can be constructed according to various known organic chemical methods.
  • the compound (I) thus produced can be isolated or purified by a known separation or purification means such as crystallization, recrystallization, phase transition, chromatography and the like. It can also be converted to a pharmaceutically acceptable salt.
  • the raw material compounds used in the following production examples can be produced by a known method (International Publication No. 2004/067521, International Publication No. 2006/011631, International Publication No. 2006/028269), etc. .
  • Ethyl 2-acetylamino-5_ (4-chlorosulfonylbenzyl) -1,3-thiazole-4-carboxylate (8.00 g, 19.9 mmol) in tetrahydrofuran (160 ml) at 0 ° C with 28% aqueous ammonia ( 90.7 ml, 1.34 mol) was added dropwise and stirred at room temperature for 2 hours. Saturated ammonium chloride water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate.
  • Lithium borohydride was suspended in a suspension of ethyl 2-acetylamino-5_ (4-sulfamoylbenzyl) -1,3-thiazole-4-carboxylate (6.50 g, 17.0 mmol) in tetrahydrofuran (195 ml). (4.36 g, 170 mmol) was added, and the mixture was heated to reflux for 17 hours. The reaction mixture was cooled to 0 ° C., and 6N hydrochloric acid (28.3 ml, 170 mmol) was added dropwise. The mixture was concentrated to about 1/5 volume under reduced pressure, water (210 ml) was added, and the mixture was extracted with ethyl acetate.
  • Triphenylphosphine (9.059 g, 34.54 mmol) was added to a solution of 3- [4- (bromomethyl) phenyl] -2-propenoic acid (8.327 g, 34.54 mmol) in anhydrous toluene (135 ml) and heated for 4 hours. Refluxed. After cooling to room temperature, the precipitated solid was collected by filtration and washed three times with diisopropyl ether.
  • N'-tert-butoxycarbonyl _4- (4- ⁇ 2- [2- (acetylylamino) -1,3-thiazol-4-yl] ethyl ⁇ phenyl) semicarbazide (629.3mg, 1.500mmol)
  • a 4M hydrogen chloride dioxane solution (7.5 ml, 30 mmol) was added to a dichloromethane (7.5 ml) solution, and the mixture was stirred at room temperature for 2.5 hours.
  • N- [4- ⁇ 2- [4_ (N '- ⁇ 3-[(triethylsilyl) oxy] propanoyl ⁇ hydrazinocanole (Bonylmethinole) phenenoyl] ethyl ⁇ -1,3-thiazol-2-yl) acetamide 515.8 mg, 1.0 22 mmol, yield 68.1%) was obtained.
  • Step-1 Hydrazine 'monohydrate (1.27 ml, 26. lmmol) was suspended in anhydrous tetrahydrofuran (20ml), and decylchloroformate (1.50ml, 6.52mmol) was added dropwise at 0 ° C. The mixture was warmed to room temperature and stirred for 6.5 hours. After concentration under reduced pressure, water (20 ml) was added, and the mixture was extracted twice with ethyl acetate. The combined organic layers were washed with saturated brine and dried over anhydrous magnesium sulfate.
  • Imidazole (245. lmg, 3.601mmol) was added to a solution of 2-hydroxyethylhydrazinecarboxylate (360.9mg, 3.005mmol) in anhydrous N, N_dimethylformamide (lml).
  • Triethylsilyl chloride (0.60 ml, 3.60 mmol) was added dropwise at 0 ° C and stirred for 30 minutes. The mixture was warmed to room temperature and stirred for 2.5 hours. Water and ethyl acetate were added and stirred, and the mixture was allowed to stand and separated.
  • the reaction solution was filtered through a silica gel pad (Fuji Silysia BW-300SP, 100 g) and washed with a mixed solvent of ethyl acetate / hexane (2: 1). The filtrate was concentrated to dryness and ethyl acetate (50 ml) was added. The resulting solid was collected by filtration, and washed once with ethyl acetate and five times with disopropyl ether. The residue was dried under reduced pressure to obtain tert-butyl 2-[(4-hydroxypheneno) acetyl] hydrazinecarboxylate (2.301 g, 8.639 mmol, yield 66.8%) as a white solid. Secondary crystals (529.7 mg, 1.989 mmol, yield 15.4%) were recovered from the mother liquor concentrate. (Total yield of primary and secondary crystals 82.2%)
  • Disopropyl ether 100 ml was added dropwise at room temperature and stirred for 1 hour. The precipitate was collected by filtration and washed 3 times with diisopropyl ether. After drying under reduced pressure, 4- ⁇ 2- [2- (tert-butoxycarbonyl) hydrazino] carbonylmethyl ⁇ phenyl 2- (acetylamino) -1,3-thiazole-4-carboxylate (1.539 g, 3.542 as a white solid) mmol, yield 87.9%).
  • Jetyl ether (100 ml) was added and suspended therein, and hexane (50 ml) was added. The resulting solid was collected by filtration and washed with a 20% jetyl ether / hexane mixed solvent. Drying under reduced pressure gave ⁇ 4-[(2-acetylamino-1,3-thiazol-4-yl) methoxy] phenyl ⁇ methyl acetate (1.385 g, 4.32 7 mmol, yield 20.6%) as a white solid .
  • N, N-dimethylformamide (40 ml) was added to fine yellowish solid (640.0 mg, 1.998 mmol) and dissolved by heating at about 60 ° C. After cooling to room temperature, ethyl acetate (160 ml) was added dropwise. After stirring for 1 hour at room temperature, the precipitated crystals were collected by filtration and washed with ethyl acetate three times. Drying under reduced pressure gave the title compound (549.7 mg, 1.716 mmol, recovery rate 85.9%) as a white solid.
  • N- (4-Formyl-1,3-thiazol-2-inole) acetamide (510.6 mg, 3.000 mmol) and tert-butyl 2-[(4-aminophenino) acetyl] hydrazine carboxylate (795.9 mg, 3.000 mmol) was dissolved in anhydrous tetrahydrofuran (50 ml) and heated to reflux for 2 hours. The solvent was distilled off, ethyl acetate (5 ml) and tert-butyl methyl ether (50 ml) were added to the residue, and the precipitated solid was collected by filtration.
  • Step-4 [0203] tert-Butyl 2- ⁇ [4-( ⁇ [2- (acetylylamino) -1,3-thiazol-4-yl] methylidene ⁇ amino) phenenole] acetyl ⁇ hydrazine carboxylate (918.5 mg, 2.200 mmol) was dissolved in anhydrous methanol (25 ml) and cooled to 0 ° C. Sodium borohydride (83.2 mg, 2.20 mmol) was added and stirred at 0 ° C. for 40 minutes. Acetic acid (0.5 ml) was added and stirred for 30 minutes.
  • N-bromosuccinimide (30.00 g, 168.6 mmol) was added to a solution of m-tolylacetic acid (25.00 g, 166.5 mmol) in anhydrous carbon tetrachloride (200 ml), and the temperature was gradually raised to the boiling point. The mixture was heated to reflux for 5.5 hours and then cooled to room temperature. The reaction solution was filtered to remove insoluble matters, and the insoluble matters were washed twice with carbon tetrachloride (100 ml). The filtrate was concentrated, carbon tetrachloride (60 ml) was added to the residue, and it was dissolved by heating at about 70 ° C.
  • Triphenylphosphine (7.703 g, 29.37 mmol) was added to a solution of N- (4-chloromethyl-1,3-thiazol-2-yl) acetamide (4.000 g, 20.98 mmol) in anhydrous acetonitrile (100 ml). The mixture was heated to reflux for 15 hours. After cooling to room temperature, the solvent was distilled off to about half amount. The precipitated crystals were collected by filtration and washed with isopropyl ether.
  • Step— 5 [0227] N- (4- ⁇ 2- [5_ (Imidazol-1-carbonyl) thiophen-2-yl] ethyl ⁇ -1, 1M hydrazine / tetrahydrofuran solution (4.76ml, 4.76mmol) at 0 ° C, A suspension of 3-thiazol-2-yl) acetamide (330.0 mg, 0.953 mmol) in anhydrous tetrahydrofuran (15 ml) was added dropwise. After stirring at 0 ° C for 1 hour, the mixture was stirred at room temperature for 30 minutes. Water (2 ml) was added at 0 ° C, and the mixture was concentrated under reduced pressure.
  • Ethylene glycol (69.18 g 1115 mmol) and p-toluenesulfonic acid (424.0 mg 2.229 mmol) were added to a solution of thiophene-3-carbaldehyde (25.00 g 222.9 mmol) in toluene (250 ml). While separating the water produced by the water sample tube (Dean-Stark trap), the mixture was cooled to 0 ° C., heated under reflux for 4 hours, added with saturated aqueous sodium hydrogen carbonate (50 ml), stirred, allowed to stand and separated. The aqueous layer was extracted twice with ethyl acetate.
  • N- ⁇ 4- [2- (4-Aminopheninole) ethyl] -1,3-thiazole-2-inole ⁇ acetamide (525.3 mg, 2 • OlOmmol) in a suspension of water (15 ml) with 6N
  • a solution of hydrochloric acid (1.0 ml, 6.0 mmol), ice (lg) and sodium nitrite (14 Omg, 2.00 mmol) in water (lml) was added, and the mixture was stirred at 0 ° C for 45 minutes.
  • a solution of sodium sulfite (1.26 7 g, 10.05 mmol) in water (7 ml) was added at 0 ° C, and the temperature was raised to 65 ° C.
  • Step-4 tert-butyl 2- (4- ⁇ 2- [2- (acetylamino) -1,3-thiazole-4-inole] ethyl ⁇ phenylmethyl) hydrazinecarboxylate (1.624 g, 4.159 mmol) in anhydrous dichloromethane (20.8 ml)
  • a 4M hydrogen chloride dioxane solution (41.6 ml, 1.66 mmol) was added to the suspension, and the mixture was stirred at room temperature for 3 hours.
  • the mixture was concentrated under reduced pressure, ethyl acetate was added to the residue, and the resulting solid was collected by filtration.
  • Jetyl ether (50 ml) was added to the residue and filtered. The resulting solid is jetil Washed 3 times with ether and 2 times with ethyl acetate. It was dried under reduced pressure to give the title compound (1.260 g, 3.340 mmol, yield 99.1%) as an off-white solid.
  • N-dimethylformamide 4.5 ml
  • 1,1′-carbonyldiimidazole 799.1 mg, 4.928 mmol
  • methanol 4.0 ml, 99 mmol
  • water 200 ml
  • the combined organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
  • Jetyl ether (20 ml) was added to the residue and filtered, and the resulting solid was washed three times with jetyl ether and five times with dichloromethane. Dry under reduced pressure to give the title compound (369.4 mg, 1.0 84 mmol, yield 94.4%).
  • N-methylformanilide 28.67 g, 212. 10101 0 1
  • 2-thiophen-2-ylethyl acetate 36.1 lg, 212.1 mmol
  • N-methylformanilide 1.34 g, 10.61 mmol
  • phosphorus oxychloride 1.627 g, 10.61 mmol
  • Triethylamine (21.01 g, 207.6 mmol) was added to a solution of 2- (5_hydroxymethylthiophen-2-yl) ethyl acetate (39.60 g, 197.8 mmol) in anhydrous dichloromethane (200 ml) at 0 ° C.
  • Thionyl chloride (24.70 g, 207.6 mmol) was added dropwise. After stirring at 0 ° C for 5 hours, the reaction mixture was poured into ice water (200 g) and extracted with jetyl ether. The organic layer was washed with saturated brine, saturated aqueous sodium hydrogen carbonate, saturated aqueous ammonium chloride and saturated brine.
  • Triphenylphosphine (50.37 g, 192.0 mmol) was added to a solution of 2- (5_chloromethylthiophen-2-inole) ethyl acetate (42.00 g, 192.0 mmol) in anhydrous acetonitrile (210 ml). After stirring at 80 ° C for 6 hours, the mixture was cooled to room temperature. Diisopropyl ether (420 ml) was added dropwise and stirred for 1 hour. The precipitated crystals were collected by filtration and washed with diisopropyl ether. After drying under reduced pressure, [5_ (2-acetoxyl) thiophen-2-ylmethyl] triphenylphosphine chloride (72.09 g, 149.9 mmol, yield 78.1%) was obtained as a white solid.
  • the organic layer was washed successively with saturated brine, saturated aqueous sodium bicarbonate, saturated aqueous ammonium chloride and saturated brine.
  • Anhydrous magnesium sulfate and activated carbon were added, stirred and filtered.
  • the filtrate was concentrated to about 75 m, and diisopropyl ether (200 ml) was added dropwise. The mixture was stirred for 30 minutes, and the precipitated crystals were collected by filtration. The crystals were washed with diisopropyl ether and dried under reduced pressure.
  • the concentrated residue was dissolved in anhydrous methanol (15 ml), and diethyl ether (200 ml) was added.
  • the precipitated crystals were collected by filtration, washed with anhydrous jetyl ether and ethyl acetate, and dried under reduced pressure.
  • the crystals were dissolved again in anhydrous methanol (10 ml), and ethyl acetate (200 ml) was added.
  • the precipitated crystals were collected by filtration and washed with anhydrous jetyl ether and ethyl acetate. After drying under reduced pressure, the title compound (460.8 mg, 1.080 mmol, yield) was obtained as a pale yellow solid. 44.5%).
  • reaction solution was concentrated under reduced pressure, jetyl ether (100 ml) was added, and insoluble material was collected by filtration. The insoluble material was washed with Jetier® Tel and the filtrate was concentrated. Ethyl acetate (30 ml) was added to the concentrated residue, and the insoluble material was collected by filtration. The insoluble material was washed with ethyl acetate and the filtrate was concentrated.
  • tert-butyl N- (3- ⁇ 5- [2- (2-acetylamino-1,3-thiazol-4-yl) ethyl] thiophene-2-inole ⁇ propyl) hydrazinecarboxylate (purity 95.3%, 580.0 mg, pure content 1.30 mmo 1) was dissolved in a mixed solvent of dichloromethane (4 ml) and methanol (8 ml). A 1M hydrogen chloride ethyl ether solution (19.2 ml, 19.2 mmol) was added, and the mixture was stirred at room temperature for 10.5 hours and concentrated under reduced pressure.
  • Jetyl ether (20 ml) was added to the concentrated residue, and the mixture was concentrated again under reduced pressure to remove hydrogen chloride.
  • the residue was filtered by adding jetyl ether (20 ml), and the resulting solid was washed five times with jetyl ether. Drying under reduced pressure gave the title compound (430.5 mg, 1.193 mmol, yield 91.6%) as a white solid.
  • VAP-1 enzyme (SSAO) activity in both humans and rats was measured by radiochemical enzyme assay using 14 C-benzylamine as an artificial substrate.
  • cDNA libraries Karahi preparative and rat VAP-1 was cloned, was expressed cell extract, together with the test compound solution (final concentration 1 X 10- 7 ⁇ 1 X 10- 11 mol / L), 20 at room temperature Pre-incubated for minutes. Then is added the 14 C_ Penjinoreamin (final concentration 1 X 10- 5 mol / L) , in a final volume of 200 mu L, they were incubated for 2 hours at 37 ° C. The enzymatic reaction was terminated by adding 2 mol / L (200 L) citrate. The oxidized product was extracted into 1 mL toluene / ethyl acetate (1: 1), and its radioactivity was measured with a liquid scintillation counter. The results are shown in Tables 1 and 2.
  • the compounds of the present invention significantly inhibited the enzyme activity of human and rat SSAO.
  • Diabetes in rats was induced by intravenous injection of 50 mg / mL / kg streptozotocin (STZ) in 2 mmol / L citrate buffer (pH 4.5) after fasting for about 20 hours. Plasma glucose levels were checked by the hexokinase method. Three days after STZ treatment, the rats were diagnosed with diabetes showing plasma glucose levels of 350 mg / dl or higher.
  • STZ streptozotocin
  • a test compound solution (lmg / ml) was injected subconjunctivally (0.05 mg / eye) into the rear eye of rats.
  • the retinas were harvested 3 hours after administration, the SSAO activity in the retina, using a 14 C_ Benjiruamin (final concentration 1 X 10- 5 mol / L) as substrates, it has been conducted under the measured radiochemical enzyme Atsusi.
  • the results are shown in Table 3.
  • Enzyme activity inhibitory effect on human monoamine oxidase enzymes (MAO-A and MAO-B)
  • human monoamine oxidase enzymes (MAO-A and MAO-B) The enzyme activity inhibitory effect on) was investigated.
  • Recombinant human MAO-A and MAO-B enzymes were obtained from Sigma. Human MAO-A and MAO-B activities were measured using MAO Detection Kit (Fluoro MAO, Cell Technorogy Inc.). Atsey was performed in a 96-well plate. f Reaction buffer was added to each well 40 ⁇ L, and 50 L of MAO-A or MAO-B was added. Then test compound solution (final concentration 1 X 10- 5 ⁇ 1 X 10- 1Q m 0 l / L) was added 10 mu L, and 20 minutes Incubate Pies at 37 ° C. The reaction cocktail was charged with 100 ⁇ L and incubated at 37 ° C for 2 hours with a final volume of 200 ⁇ L. Then, using a Manoletis petatro microplate reader (Varioskan, Thermo Fisher Scientific), the excitation light was 570 nm and fluorescence at 590 nm was detected. The results are shown in Table 4.
  • the compounds of the present invention had no significant inhibitory effect on human MAO-A and MAO-B. Since it does not substantially inhibit other monoamine oxidases, it can be seen that the compound of the present invention selectively inhibits SSAO.
  • the present invention provides a compound of formula (I) useful as a VAP-1 inhibitor.
  • VAP-1 related diseases such as macular edema and hypervascular disease To do.

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Abstract

La présente invention concerne un composé représenté par la formule (I) ou un sel pharmaceutiquement acceptable de celui-ci utilisable en tant qu'inhibiteur de la VAP-1 ; une composition pharmaceutique ; un agent pharmaceutique de prévention ou de traitement d'une maladie associée à la VAP-1 telle que l'œdème maculaire ou d'une maladie associée à l'augmentation de la perméabilité vasculaire ; et d'autres. (I) dans laquelle chaque symbole est tel que défini dans la description.
PCT/JP2007/073137 2006-11-30 2007-11-30 Dérivé de thiazole et son utilisation en tant qu'inhibiteur de la vap-1 Ceased WO2008066145A1 (fr)

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WO2009145360A1 (fr) * 2008-05-30 2009-12-03 R-Tech Ueno, Ltd. Dérivé de benzène ou de thiophène et son utilisation en tant qu'inhibiteur de la vap-1
JP2011510911A (ja) * 2008-01-31 2011-04-07 株式会社アールテック・ウエノ チアゾール誘導体およびｖａｐ−１阻害剤としてのその使用
CN103408454A (zh) * 2013-08-16 2013-11-27 兰州大学 一种酰肼类化合物的制备方法
WO2016194390A1 (fr) 2015-06-05 2016-12-08 R-Tech Ueno, Ltd. Composition pharmaceutique pour utilisation dans le traitement du cancer
US9776960B2 (en) 2013-03-15 2017-10-03 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
US9981939B2 (en) 2013-03-15 2018-05-29 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
US10017491B2 (en) 2013-03-15 2018-07-10 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
US10034879B2 (en) 2011-12-28 2018-07-31 Global Blood Therapeutics, Inc. Substituted benzaldehyde compounds and methods for their use in increasing tissue oxygenation
US10077249B2 (en) 2016-05-12 2018-09-18 Global Blood Therapeutics, Inc. Process for synthesizing 2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)-pyridin-3-yl)methoxy)benzaldehyde
US10100043B2 (en) 2013-03-15 2018-10-16 Global Blood Therapeutics, Inc. Substituted aldehyde compounds and methods for their use in increasing tissue oxygenation
US10100040B2 (en) 2013-03-15 2018-10-16 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
US10137118B2 (en) 2014-02-07 2018-11-27 Global Blood Therapeutics, Inc. Crystalline polymorphs of the free base of 2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde
US10266551B2 (en) 2013-03-15 2019-04-23 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
US10377741B2 (en) 2011-12-28 2019-08-13 Global Blood Therapeutics, Inc. Substituted heteroaryl aldehyde compounds and methods for their use in increasing tissue oxygenation
US10450269B1 (en) 2013-11-18 2019-10-22 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
US10493035B2 (en) 2016-10-12 2019-12-03 Global Blood Therapeutics, Inc. Tablets comprising 2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde
US10683285B2 (en) 2018-11-19 2020-06-16 Global Blood Therapeutics, Inc. Modulators of hemoglobin
US11014884B2 (en) 2018-10-01 2021-05-25 Global Blood Therapeutics, Inc. Modulators of hemoglobin
US11020382B2 (en) 2015-12-04 2021-06-01 Global Blood Therapeutics, Inc. Dosing regimens for 2-hydroxy-6-((2-(1-isopropyl-1h-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde
US11053195B2 (en) 2013-03-15 2021-07-06 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
US11236109B2 (en) 2013-03-15 2022-02-01 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
WO2024145662A1 (fr) * 2022-12-30 2024-07-04 Altay Therapeutics, Inc. Compositions de thiazole et de benzothiazole 2-substituées en tant qi'inhibiteurs de dux4 et procédés

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EP2599498A1 (fr) * 2007-06-25 2013-06-05 R-Tech Ueno, Ltd. Composition pour une maladie ophtalmique associée à une hypoxie ou une ischémie
WO2009001857A1 (fr) * 2007-06-25 2008-12-31 R-Tech Ueno, Ltd. Composition pour une maladie ophtalmique associée à une hypoxie ou une ischémie
EP2639229A3 (fr) * 2008-01-31 2013-12-25 R-Tech Ueno, Ltd. Dérivé de thiazole et son utilisation en tant qu'inhibiteur VAP-1
JP2011510911A (ja) * 2008-01-31 2011-04-07 株式会社アールテック・ウエノ チアゾール誘導体およびｖａｐ−１阻害剤としてのその使用
US8507690B2 (en) 2008-01-31 2013-08-13 R-Tech Ueno, Ltd. Thiazole derivative and use thereof as VAP-1 inhibitor
EP2650287A1 (fr) * 2008-01-31 2013-10-16 R-Tech Ueno, Ltd. Dérivé de thiazole et son utilisation en tant qu'inhibiteur VAP-1
EP2676955A1 (fr) 2008-01-31 2013-12-25 R-Tech Ueno, Ltd. Dérivé de thiazole et son utilisation en tant qu'inhibiteur VAP-1
JP2011523649A (ja) * 2008-05-30 2011-08-18 株式会社アールテック・ウエノ ベンゼンまたはチオフェン誘導体およびｖａｐ−１阻害剤としてのその使用
WO2009145360A1 (fr) * 2008-05-30 2009-12-03 R-Tech Ueno, Ltd. Dérivé de benzène ou de thiophène et son utilisation en tant qu'inhibiteur de la vap-1
US9603833B2 (en) 2008-05-30 2017-03-28 R-Tech Ueno, Ltd. Benzene or thiophene derivative and use thereof as VAP-1 inhibitor
JP2014205687A (ja) * 2008-05-30 2014-10-30 株式会社アールテック・ウエノ ベンゼンまたはチオフェン誘導体およびｖａｐ−１阻害剤としてのその使用
US8999989B2 (en) 2008-05-30 2015-04-07 R-Tech Ueno, Ltd. Benzene or thiophene derivative and use thereof as VAP-1 inhibitor
EP2886534A1 (fr) * 2008-05-30 2015-06-24 R-Tech Ueno, Ltd. Dérivé de benzène ou thiophène et son utilisation en tant qu'inhibiteur VAP-1
US10806733B2 (en) 2011-12-28 2020-10-20 Global Blood Therapeutics, Inc. Substituted benzaldehyde compounds and methods for their use in increasing tissue oxygenation
US10034879B2 (en) 2011-12-28 2018-07-31 Global Blood Therapeutics, Inc. Substituted benzaldehyde compounds and methods for their use in increasing tissue oxygenation
US10822326B2 (en) 2011-12-28 2020-11-03 Global Blood Therapeutics, Inc. Substituted heteroaryl aldehyde compounds and methods for their use in increasing tissue oxygenation
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US10266551B2 (en) 2013-03-15 2019-04-23 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
US9776960B2 (en) 2013-03-15 2017-10-03 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
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US11236109B2 (en) 2013-03-15 2022-02-01 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
CN103408454A (zh) * 2013-08-16 2013-11-27 兰州大学 一种酰肼类化合物的制备方法
CN103408454B (zh) * 2013-08-16 2015-09-23 兰州大学 一种酰肼类化合物的制备方法
US10450269B1 (en) 2013-11-18 2019-10-22 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
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US10722502B2 (en) 2014-02-07 2020-07-28 Global Blood Therapeutics, Inc. Crystalline polymorphs of the free base of 2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde
US10137118B2 (en) 2014-02-07 2018-11-27 Global Blood Therapeutics, Inc. Crystalline polymorphs of the free base of 2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde
WO2016194390A1 (fr) 2015-06-05 2016-12-08 R-Tech Ueno, Ltd. Composition pharmaceutique pour utilisation dans le traitement du cancer
US11020382B2 (en) 2015-12-04 2021-06-01 Global Blood Therapeutics, Inc. Dosing regimens for 2-hydroxy-6-((2-(1-isopropyl-1h-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde
US11944612B2 (en) 2015-12-04 2024-04-02 Global Blood Therapeutics, Inc. Dosing regimens for 2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde
US10577345B2 (en) 2016-05-12 2020-03-03 Global Blood Therapeutics, Inc. Process for synthesizing 2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)-pyridin-3-yl)methoxy)benzaldehyde
US10077249B2 (en) 2016-05-12 2018-09-18 Global Blood Therapeutics, Inc. Process for synthesizing 2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)-pyridin-3-yl)methoxy)benzaldehyde
US10493035B2 (en) 2016-10-12 2019-12-03 Global Blood Therapeutics, Inc. Tablets comprising 2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde
US11014884B2 (en) 2018-10-01 2021-05-25 Global Blood Therapeutics, Inc. Modulators of hemoglobin
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