Guanidine compound
Inventors
Yoshihara, Kousei • Suzuki, Daisuke • Yamaki, Susumu • Yamada, Hiroyoshi • Mihara, Hisashi • Seki, Norio
Assignees
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Publication Number
US-9556160-B2
Publication Date
2017-01-31
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 compounds represented by formula (I) or salts thereof, including substituted urea and carbamimidoylcarbamate motifs and fluorinated aromatic or heteroaromatic scaffold variations. The structure is defined by variables including A, E, G, J, L, U, V, W, and X, together with substituent sets such as RQ1, RQ2, RQ4, RQ5, RQ12, RQ22, RQ42, RQ52 and R1 to R4. The permitted options include single bonds or lower alkylene linkages, heteroatom-containing linkages, and substituents such as H, lower alkyl, O-(lower alkyl), NH or N(lower alkyl), halogen, SO2, and oxo variants.
The formula (I) framework further constrains X and GXA1 through enumerated functional-group classes including halogen, OH, substituted lower alkyl, O-(lower alkyl) and substituted O-(lower alkyl), NH2 and substituted NH variants, N(lower alkyl)2, cycloalkyl, cycloalkenyl, aryl, hetero ring group, O-(hetero ring group), SO2-containing options, NHSO2-(lower alkyl), and oxo. The disclosed embodiments include multiple example chemical structures and named compound embodiments within the same formula (I) family, illustrating variations in ring systems, linkers, and functional groups while maintaining the common variable scaffold.
The disclosed compounds are repeatedly described as VAP-1 (SSAO) inhibitors and as compounds of therapeutic relevance for diabetic nephropathy and diabetic macular edema. The examples include hydrochloride salt forms and represent substituted heteroaryl, benzyl-linked, and nitrogen-containing ring systems within the formula (I) space.
Claims Coverage
The consolidated claim coverage centers on one broad independent claim to a compound represented by formula (I) or a salt thereof, with multiple inventive structural features constrained by variable positions and permitted substituent sets. Dependent coverage narrows these variables, includes enumerated specific compound embodiments, and extends to pharmaceutical composition and therapeutic method claims.
Formula (I) compound and salts
A compound represented by formula (I) or a salt thereof, with structural variables A, E, G, J, L, U, V, W, X and substituent groups RQ1, RQ2, RQ4, RQ5, RQ12, RQ22, RQ42, RQ52 and R1 to R4 defined by permitted selections including H, lower alkyl, O-(lower alkyl), NH and N(lower alkyl) variants, halogen, SO2, and oxo options.
Linkage and heteroatom options for the scaffold
E, G, J, L, U, V, and W are limited to single bond or lower alkylene options and related heteroatom-containing linkages, including O, NH, N(lower alkyl), and SO2, with oxo-substituted lower alkylene permitted in selected positions.
Functional group set for X and GXA1
X and GXA1 are defined by an explicitly listed set including halogen, OH, lower alkyl and substituted lower alkyl, O-(lower alkyl) and substituted O-(lower alkyl), NH2 and substituted NH variants, N(lower alkyl)2, cycloalkyl, cycloalkenyl, aryl, hetero ring group, O-(hetero ring group), SO2-containing groups, NHSO2-(lower alkyl), and oxo.
Enumerated substituted compound embodiments
Specific compound embodiments are explicitly listed within the formula (I) family, including substituted urea, carbamimidoylcarbamate, and related fluorinated heteroaryl or nitrogen-containing ring structures, with hydrochloride and other salt forms.
Pharmaceutical composition with pharmaceutically acceptable excipient
A pharmaceutical composition including the compound or a salt thereof together with a pharmaceutically acceptable excipient.
Treatment of diabetic nephropathy or diabetic macular edema
A method for treating diabetic nephropathy or diabetic macular edema by administering an effective amount of the compound or a salt thereof to a patient.
The claims cover a broadly defined formula (I) compound family and salts, with explicit control over scaffold linkages, heteroatom choices, and substituent classes, including GXA1 functional-group options. The scope is further narrowed by enumerated compound examples and extended to pharmaceutical composition and therapeutic use for diabetic nephropathy and diabetic macular edema.
Stated Advantages
The compounds of formula (I) inhibit VAP-1 (SSAO).
The compounds may be used to prevent and/or treat VAP-1-related diseases.
The compounds produce rat plasma inhibition after oral dosing.
In diabetic rat models, the compounds are assessed for effects including reduced albuminuria and retinal vascular permeability.
Documented Applications
Treatment of diabetic nephropathy by administering an effective amount of a compound or a salt thereof to a patient.
Treatment of diabetic macular edema by administering an effective amount of a compound or a salt thereof to a patient.
A pharmaceutical composition including the compound or a salt thereof together with a pharmaceutically acceptable excipient.
Prevention and/or treatment of VAP-1-related diseases.
Use as VAP-1 (SSAO) inhibitors evaluated in human and rat enzyme assays.
In vivo rat plasma inhibition after oral dosing of formula (I) compounds.
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