4-aminomethylbenzoic acid derivative
Inventors
Uemoto, Kazuhiro • Sato, Yoshimichi • Okada, Naoki • Iimori, Emiko • Kageyama, Masayuki
Assignees
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Publication Number
US-9714213-B2
Publication Date
2017-07-25
Expiration Date
Abstract
A compound represented by general formula (1) a pharmaceutically acceptable salt thereof or a solvate thereof; wherein Ar represents an aryl group, or a 5- or 6-membered heteroaryl group containing a nitrogen atom, an oxygen atom or a sulfur atom; Y represents, for example, a hydrogen atom or a C1-C6 alkyl group; A represents a C1-C3 alkylene chain which may be substituted with two C1-C2 alkyl groups; X represents a hydrogen atom or a halogen atom; V represents an oxygen atom or a methylene chain; and R represents a group selected from the formulae below:
Core Innovation
The invention provides a compound represented by formula (1), including a pharmaceutically acceptable salt thereof or a solvate thereof. The compound is defined by structural variables including Ar, Y, A, X, V, and R, where Ar is an aryl group or a 5- or 6-membered heteroaryl group containing a nitrogen atom, an oxygen atom or a sulfur atom, and Y and X are selected from hydrogen, specified alkyl, haloalkyl, cyano, or halogen options. The scaffold includes A as a C1-C3 alkylene chain with specified substitution and possible ring formation, and V as oxygen or a methylene chain.
The variable R is selected from groups having substituent sets R2 and R3, with constraints on allowable substituent types and carbon ranges for alkyl, alkoxy, cycloalkyl, cycloalkoxy, haloalkyl, aryl, aryloxy, benzyl, phenethyl, and benzyloxy. The integer n is 1 to 3, and when n is 2 or more, the n instances of R1 may be different from each other. The description further provides preferred embodiments, example compound structures and names, and reference examples supported by 1H NMR spectral datasets.
The compounds are asserted to activate soluble guanylate cyclase (sGC) in a heme-independent manner. The mechanism is tied to cGMP generation associated with sGC activation and vascular relaxation activity that is dependent on ODQ. The patent further describes pharmaceutical composition and pharmaceutical use of the compound family for diseases involving sGC, including heart failure, hypertension, pulmonary hypertension, and ischemic heart disease.
Claims Coverage
The consolidated claims coverage centers on the formula (1) compound family with defined substituent variables, together with therapeutic use and pharmaceutical composition aspects. In total, the inventive features are centered on the formula (1) compounds, heme-independent sGC activation, treatment of heart failure or pulmonary hypertension, and a pharmaceutical composition with a pharmaceutically acceptable carrier.
Formula (1) compound with defined substituent classes
A compound represented by formula (1), including a pharmaceutically acceptable salt or a solvate, wherein Ar is an aryl group or a 5- or 6-membered heteroaryl group containing a nitrogen atom, an oxygen atom or a sulfur atom; Y is hydrogen, a C1-C6 alkyl group, a halo C1-C4 alkyl group, a cyano group, or a halogen atom; A is a C1-C3 alkylene chain with specified substitution and possible formation of a C3-C5 saturated hydrocarbon ring; X is hydrogen or a halogen atom; V is an oxygen atom or a methylene chain; and R is selected from the formulae below with constraints on R2, R3, W, and n as specified.
Heme-independent soluble guanylate cyclase activation
The compound family is described as activating soluble guanylate cyclase (sGC) in a heme-independent manner.
Therapeutic use for heart failure or pulmonary hypertension
A method of treating heart failure or pulmonary hypertension by administering an effective amount of the compound, its pharmaceutically acceptable salt, or its solvate to a subject in need.
Pharmaceutical composition with pharmaceutically acceptable carrier
A pharmaceutical composition comprising the compound or its pharmaceutically acceptable salt or solvate together with a pharmaceutically acceptable carrier.
The claims cover a formula (1) compound class with tightly enumerated structural definitions, heme-independent sGC activation, treatment of heart failure or pulmonary hypertension, and a pharmaceutical composition with a pharmaceutically acceptable carrier.
Stated Advantages
Heme-independent activation of soluble guanylate cyclase (sGC).
cGMP generation associated with sGC activation.
Vascular relaxation activity that is dependent on ODQ.
Pharmaceutical treatment for diseases involving sGC, including heart failure, hypertension, pulmonary hypertension, and ischemic heart disease.
Documented Applications
Use of the compound, its pharmaceutically acceptable salt, or its solvate for treating heart failure or pulmonary hypertension by administering an effective amount to a subject in need.
Treating ischemic heart disease.
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