Substituted amines for treating cardiac diseases
Inventors
Matsunaga, Nobuyuki • Nakahata, Takashi • Tanaka, Yuta • TAKAHAGI, Hiroki • Miyamoto, Yasufumi • Okamoto, Rei • Yoshikawa, Takeshi • Terao, Yoshito • Yukawa, Takafumi • KAKEGAWA, Keiko • Nishikawa, Yoichi • Takagi, Terufumi • Takahashi, Masashi • Komandla, Mallareddy • Kwok, Lily • Miura, Joanne • Sabat, Mark • Scorah, Nicholas • TANIS, Paul • Tyhonas, John • Vu, Phong H. • Wang, Haixia • Wang, Xiaolun • Shirai, Junya • Okawa, Tomohiro • Shiokawa, Zenyu • Shibuya, Akito
Assignees
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Publication Number
US-11197858-B2
Publication Date
2021-12-14
Expiration Date
Abstract
The present invention provides a compound having a CaMKII inhibitory action, which is expected to be useful as an agent for the prophylaxis or treatment of cardiac diseases (particularly catecholaminergic polymorphic ventricular tachycardia, postoperative atrial fibrillation, heart failure, fatal arrhythmia) and the like.The present invention relates to a compound represented by the formula (I): wherein each symbol is as defined in the specification, or a salt thereof.
Core Innovation
The invention relates to a method for the prophylaxis or treatment of a cardiac disease in a mammal by administering a therapeutically effective amount of a compound represented by formula (I), or a pharmaceutically acceptable salt thereof. The compounds include a defined core structure with Ring A, Ring B, and Ring C, together with Z selected from CH2, O, N(RZ), S, S(O), or S(O2), and substituent definitions for Rz, R1, R2, and R3. The method targets catecholaminergic polymorphic ventricular tachycardia, postoperative atrial fibrillation, heart failure, and fatal arrhythmia.
Ring A is selected from substituted benzene rings and multiple heteroaryl or non-aromatic ring systems, including pyridine, pyrimidine, pyridazine, pyrazine, pyrazole, isoxazole, thiazole, isothiazole, imidazole, thiadiazole, and thiophene rings, with additional fused, bridged, or spiro-configured ring options in some embodiments. The substituent classes include halogen, cyano, carboxy, alkoxy, alkyl, alkyl-carbonyl, carbamoyl, sulfamoyl, alkylsulfanyl, alkylsulfonyl, heterocyclylcarbonyl, heterocyclylsulfonyl, hydroxy, and heterocyclic substituents. Rz is a hydrogen atom, and R1, R2, and R3 are defined by enumerated substituent selections.
The disclosure presents substituted pyrimidin-2-amine and related pyrimidinyl compounds, including embodiments bearing benzonitrile, benzamide, tetrazolyl, pyrazole, and chlorophenyl motifs, together with stereocontrolled oxyalkyl side chains. The examples vary terminal substituent motifs and cyclic amine fragments such as piperidine, piperazine, morpholine, diazepane, oxetane, tetrahydro-2H-pyran, and spiro bicyclic amines. Several embodiments are described as pharmaceutically acceptable salts, including hydrochloride, dihydrochloride, and fumarate forms.
Claims Coverage
One independent claim is identified. The claim covers a method for the prophylaxis or treatment of a cardiac disease in a mammal using a therapeutically effective amount of a formula (I) compound, with three main inventive feature groups: the therapeutic method, the defined formula (I) scaffold, and the listed cardiac disease targets.
Method of prophylaxis or treatment of cardiac disease using formula (I) compounds
A method for the prophylaxis or treatment of a cardiac disease in a mammal comprising administering to the mammal in need thereof a therapeutically effective amount of a compound represented by formula (I), including pharmaceutically acceptable salts, wherein the cardiac disease is selected from catecholaminergic polymorphic ventricular tachycardia, postoperative atrial fibrillation, heart failure, and fatal arrhythmia.
Formula (I) scaffold with Ring A, Ring B, Ring C, Z, and substituent definitions
The compound of formula (I) is defined by Ring A selected from substituted benzene, pyridine, pyrimidine, pyridazine, pyrazine, pyrazole, isoxazole, thiazole, isothiazole, imidazole, thiadiazole, thiophene, and related ring options, together with Ring B and Ring C, Z selected from CH2, O, N(RZ), S, S(O), or S(O2), Rz as hydrogen atom, and R1, R2, and R3 defined by enumerated substituent options.
Selected substituted pyrimidin-2-amine structures and salts
The method is characterized by selecting the compound from specified substituted pyrimidin-2-amine derivative structures bearing benzonitrile, benzamide, tetrazolyl, pyrazole, chlorophenyl/pyrimidinyl, and related heteroaryl or cyclic amine substituent patterns, including pharmaceutically acceptable salts.
The claim coverage centers on administering a therapeutically effective amount of a formula (I) compound for prophylaxis or treatment of specified cardiac diseases. The inventive scope is defined by the chemical framework of formula (I), the listed ring and substituent variables, and the inclusion of pharmaceutically acceptable salts.
Stated Advantages
In-vivo kinetics/toxicity advantages are described for a CaMKII inhibitor compound.
Documented Applications
Prophylaxis or treatment of cardiac diseases in a mammal, including catecholaminergic polymorphic ventricular tachycardia, postoperative atrial fibrillation, heart failure, and fatal arrhythmia.
Concomitant use with defined concomitant drug classes.
Use with a biological product that is an antibody.
Use with gene therapy as an adjunct modality.
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