Guanidine compound
Inventors
Yoshihara, Kousei • Suzuki, Daisuke • Yamaki, Susumu • Yamada, Hiroyoshi • Mihara, Hisashi • Seki, Norio
Assignees
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Publication Number
US-8716470-B2
Publication Date
2014-05-06
Expiration Date
Abstract
[Problem]The present invention provides a compound which is useful as an active ingredient of a pharmaceutical composition, in particular, a pharmaceutical composition for preventing and/or treating VAP-1-related diseases.[Means for Solution]The present inventors have conducted intensive studies on a compound having a VAP-1 inhibitory activity, and as a result, they have found that the compound or a salt thereof of the present invention exhibits an excellent VAP-1 inhibitory activity and is useful for preventing and/or treating VAP-1-related diseases, in particular, diabetic nephropathy or diabetic macular edema, thereby completing the present invention. In addition, the present invention relates to a pharmaceutical composition, in particular, a pharmaceutical composition for preventing and/or treating VAP-1-related diseases, which comprises the compound or a salt thereof of the present invention, and an excipient.
Core Innovation
The invention relates to a compound selected from a defined group of carbamimidoylcarbamate structures, and to salts of said compounds. The selected compounds include fluorinated aromatic cores linked to heteroaromatic systems and benzyl carbamimidoylcarbamate frameworks, with named members such as 2-fluoro-3-[2-(morpholin-4-yl)pyrimidin-5-yl]benzyl carbamimidoylcarbamate and 2-fluoro-3-[2-(3-methoxyazetidin-1-yl)pyrimidin-5-yl]benzyl carbamimidoylcarbamate, together with piperazinyl and piperidinyl variants.
The disclosed structures include specific substituted pyrimidinyl benzyl carbamimidoylcarbamate members, additional 3-substituted examples, and further named members such as 3-(4-{4-[5-(3-{[(carbamimidoylcarbamoyl)oxy]methyl}-2-fluorophenyl)pyrimidin-2-yl]piperazin-1-yl}phenyl)propanoic acid, 3-{2-[(1-acetylpiperidin-4-yl)methoxy]pyrimidin-5-yl}-2-fluorobenzyl carbamimidoylcarbamate, and 3-(2-{[1-(cyclopropylcarbonyl)piperidin-4-yl]methoxy}pyrimidin-5-yl)-2-fluorobenzyl carbamimidoylcarbamate. The document also presents stereochemical variants, salt forms including hydrochloride, L-tartrate, and phosphate, and structural depictions within tables of related compounds.
The claim set extends the compound selection to pharmaceutical composition coverage using a pharmaceutically acceptable carrier or excipient, and to therapeutic use by administration of an effective amount to a patient in need. The stated therapeutic indications are diabetic macular edema and diabetic nephropathy, and the documented applications correspond to treatment of these diabetic complications and to pharmaceutical compositions containing the claimed compound or salt.
Claims Coverage
The independent claim covers a compound selected from a defined group of named carbamimidoylcarbamate structures, or a salt of that compound. Across the consolidated claim coverage, the inventive features center on the selected compound group, specific named member selections, pharmaceutical composition with a pharmaceutically acceptable carrier or excipient, and treatment methods for diabetic macular edema and diabetic nephropathy, for a total of four main inventive feature areas.
Selected carbamimidoylcarbamate compound group
A compound selected from the group consisting of 2-fluoro-3-[2-(morpholin-4-yl)pyrimidin-5-yl]benzyl carbamimidoylcarbamate, 2-fluoro-3-[2-(3-methoxyazetidin-1-yl)pyrimidin-5-yl]benzyl carbamimidoylcarbamate, 3-(4-{4-[5-(3-{[(carbamimidoylcarbamoyl)oxy]methyl}-2-fluorophenyl)pyrimidin-2-yl]piperazin-1-yl}phenyl)propanoic acid, 3-{2-[(1-acetylpiperidin-4-yl)methoxy]pyrimidin-5-yl}-2-fluorobenzyl carbamimidoylcarbamate, and 3-(2-{[1-(cyclopropylcarbonyl)piperidin-4-yl]methoxy}pyrimidin-5-yl)-2-fluorobenzyl carbamimidoylcarbamate; or a salt of said compound.
Specific named member selection
2-fluoro-3-[2-(morpholin-4-yl)pyrimidin-5-yl]benzyl carbamimidoylcarbamate, or a salt of said compound; and 2-fluoro-3-[2-(3-methoxyazetidin-1-yl)pyrimidin-5-yl]benzyl carbamimidoylcarbamate, or a salt of said compound.
Pharmaceutical composition with pharmaceutically acceptable carrier or excipient
A pharmaceutical composition containing the compound according to claim 1 (or its salt) together with a pharmaceutically acceptable carrier or excipient.
Method of treating diabetic macular edema by administration
A method for treating diabetic macular edema by administering an effective amount of a compound according to claim 1 (or a salt of that compound) to a patient in need.
Method of treating diabetic nephropathy or diabetic macular edema by administration
A method for treating diabetic nephropathy or diabetic macular edema by administering an effective amount of the compound of claim 1 (or a salt of that compound) to a patient in need thereof.
The claim coverage centers on a defined group of named fluorinated carbamimidoylcarbamate compounds and salts, with dependent claims narrowing to particular named members and adding pharmaceutical composition and administration-based methods for treating diabetic macular edema and diabetic nephropathy.
Stated Advantages
Treating diabetic macular edema.
Treating diabetic nephropathy.
Preventing and/or treating VAP-1-related diseases.
Compounds of formula (I) or salts inhibit VAP-1.
The document reports inhibition of human/rat VAP-1 (SSAO) by formula (I) compounds in vitro.
The document reports in vivo VAP-1 inhibition in rat plasma after oral dosing.
The document reports effects on albuminuria in streptozotocin-diabetic rats.
The document reports retinal permeability effects in diabetic rats.
The document concludes that the compounds may treat VAP-1-related diseases, including diabetic/ocular complications.
Providing a pharmaceutical composition comprising the compound with a pharmaceutically acceptable carrier or excipient.
Documented Applications
Treatment of diabetic macular edema by administering an effective amount of the compound or a salt to a patient in need.
Treatment of diabetic nephropathy by administering an effective amount of the compound or a salt to a patient in need.
Pharmaceutical composition containing the compound with a pharmaceutically acceptable carrier or excipient.
Preventing and/or treating VAP-1-related diseases.
In vitro inhibition of human/rat VAP-1 (SSAO) for formula (I) compounds.
In vivo VAP-1 inhibition in rat plasma after oral dosing of formula (I) compounds.
Effects on albuminuria in streptozotocin-diabetic rats.
Retinal vascular permeability in diabetic rats measured using Evans Blue Dye.
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