Dihydropyridazine-3,5-dione derivative and pharmaceuticals containing the same

Patent metadata

Field	Value
Publication number	US-9499553-B2
Application number	US-201514852738-A
Country	US
Kind code	B2
Filing date	Sep 14, 2015
Priority date	Mar 13, 2013
Publication date	Nov 22, 2016
Grant date	Nov 22, 2016

Abstract

The present invention provides a dihydropyridazine-3,5-dione derivative or a salt thereof, or a solvate of the compound or the salt, a pharmaceutical drug, a pharmaceutical composition, a sodium-dependent phosphate transporter inhibitor, and a preventive and/or therapeutic agent for hyperphosphatemia, secondary hyperparathyroidism, chronic renal failure, chronic kidney disease, and arteriosclerosis associated with vascular calcification comprising the compound as an active ingredient, and a method for prevention and/or treatment.

First claim

The invention claimed is:

1. A compound represented by the formula (I) or a salt thereof, or a solvate of the compound or the salt:

wherein R 1 , R 4 , and R 5 are as defined in any one of the following (1) to (3):
(1) R 1 is a hydrogen atom or C 1-10 alkyl;
R 4 is a hydrogen atom, C 1-4 alkyl optionally substituted with one or more substituents Rf, C 6-10 aryl optionally substituted with one or more substituents Rg, (C 1-6 alkyl)carbonyl, (C 6-10 aryl)carbonyl, a group —C(O)NR 37 R 38 , C 3-7 cycloalkyl, or 5- to 8-membered heterocycloalkyl; and
R 5 is a hydrogen atom or C 1-4 alkyl;
(2) R 1 and R 5 together with the carbon atom to which they are attached form a C 3-6 saturated carbocyclic ring; and
R 4 is as defined above; and
(3) R 1 is a hydrogen atom or linear C 1-10 alkyl;
R 4 and R 5 together with the carbon atom and the nitrogen atom to which they are attached form a 5- to 8-membered saturated heterocyclic ring, wherein the saturated heterocyclic ring is optionally substituted with one or more substituents R 2 ;
R 3 is C 1-10 alkyl optionally substituted with one or more substituents Rh, or R 3 is C 1-4 alkyl substituted with Re;
R 37 and R 38 are each independently selected from a hydrogen atom and C 1-3 alkyl;
each R 2 is independently selected from C 1-5 alkyl and a halogen atom; and/or
two or more substituents R 2 on the 5- to 8-membered saturated heterocyclic ring may together form C 1-5 alkylene that links the ring atoms to which they are attached;
each Rh is independently selected from a halogen atom, (C 1-4 alkoxy)carbonyl, and a group —(O(CH 2 ) a ) b —C 1-4 alkoxy, wherein a is an integer selected from 2 to 4, and b is an integer selected from 1 to 4;
Re is C 6-10 aryl optionally substituted with one or more substituents Ra, or 5- to 10-membered heteroaryl optionally substituted with one or more substituents Ra;
each Rf is independently selected from a halogen atom, hydroxy, cyano, carboxy, (C 1-6 alkoxy)carbonyl, C 1-6 alkoxy, and C 6-10 aryl optionally substituted with one or more substituents Rg;
each Rg is independently selected from a halogen atom, C 1-6 alkyl, C 2-6 alkynyl, and C 1-6 alkoxy, wherein the alkyl, alkynyl, and alkoxy groups are each optionally substituted with one or more substituents selected from hydroxy and cyano;
each Ra is independently selected from a halogen atom, hydroxy, nitro, cyano, (C 1-4 alkoxy)carbonyl, 3- to 10-membered heterocycloalkyloxy (the heterocycloalkyloxy group is optionally substituted with optionally C 1-4 alkoxy-substituted C 1-4 alkyl), C 1-10 alkyl optionally substituted with one or more substituents R 10 , C 2-10 alkenyl optionally substituted with one or more substituents R 15 , C 2-10 alkynyl optionally substituted with one or more substituents R 11 , C 1-8 alkoxy optionally substituted with one or more substituents R 12 , C 1-4 alkylthio optionally substituted with one or more substituents R 13 , a group —(O(CH 2 ) q1 ) q2 —NR 41 R 42 (wherein q1 is an integer selected from 1 to 4, and q2 is an integer selected from 2 to 6), a group —(O(CH 2 ) r1 ) r2 —C(O)NR 43 R 44 (wherein r1 is an integer selected from 1 to 4, and r2 is an integer selected from 1 to 4), a group —(O(CH 2 ) s1 ) s2 —NR 45 —C(O)R 46 (wherein s1 and s2 are each independently an integer selected from 2 to 4), a group —C(O)NR 47 R 48 , pyridinyl, pyrrolyl, a group —NR 49 R 50 , and a group —(O(CH 2 ) y1 ) y2 —O—CH 2 —C(O)NR 51 R 52 (wherein yl is an integer selected from 1 to 4, and y2 is an integer selected from 1 to 4);
R 10 , R 11 , R 12 , R 13 , and R 15 are each independently selected from a halogen atom, hydroxy, carboxy, C 1-6 alkoxy optionally substituted with one or more hydroxy groups, (C 1-4 alkoxy)C 1-6 alkoxy, (C 1-4 alkoxy)carbonyl, a group —(O(CH 2 ) o ) p —OH (wherein o and p are each independently an integer selected from 2 to 4), C 3-6 cycloalkyl optionally substituted with one or more hydroxy groups, 3- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, and a group —NR 39 R 40 , wherein the 3- to 10-membered heterocycloalkyl group is optionally substituted with one or more substituents selected from oxo, a halogen atom, C 1-4 alkyl (wherein the alkyl group is optionally substituted with one or more hydroxy groups), C 1-4 alkoxy)C 1-4 alkyl (wherein the alkoxy moiety is optionally substituted with one or more hydroxy groups), C 1-4 alkoxy, (C 1-4 alkoxy)carbonyl, C 1-4 alkylthio, morpholino, (C 1-3 alkyl)sulfonyl, and —C(O)NR 53 R 54 ;
Ar 1 is C 6-10 aryl or 5- to 10-membered heteroaryl, wherein the aryl and heteroaryl groups are each optionally substituted with one to three substituents selected from Rb, Rc, and Rd;
Rb, Rc, and Rd are each independently selected from optionally C 1-4 alkoxy-substituted C 1-5 alkoxy, a halogen atom, C 1-10 alkyl optionally substituted with one or more halogen atoms, a group —SF 5 , cyano, hydroxy, 5- to 10-membered heterocycloalkyl optionally substituted with one or more substituents R 14 , C 6-10 aryl optionally substituted with one or more substituents R 14 , and 5- to 10-membered heteroaryl optionally substituted with one or more substituents R 14 ;
each R 14 is independently selected from a halogen atom, oxo, cyano, nitro, C 1-4 alkyl optionally substituted with one or more halogen atoms, C 1-4 alkoxy optionally substituted with one or more halogen atoms, (C 1-6 alkoxy)carbonyl, a group —NR 27 R 28 , a group —SO 2 NR 35 R 36 , C 1-4 alkylthio, and 5- to 10-membered heterocycloalkyl;
R 27 and R 28 are each independently selected from a hydrogen atom and C 1-4 alkyl optionally substituted with (C 1-4 alkoxy)carbonyl;
R 35 and R 36 are each independently selected from a hydrogen atom and C 1-4 alkyl;
R 39 is a hydrogen atom, or optionally C 1-6 alkoxy-substituted C 1-6 alkyl;
R 40 is a hydrogen atom, optionally C 1-6 alkoxy-substituted C 1-6 alkyl, ((C 1-4 alkoxy)carbonyl)C 1-6 alkyl, hydroxy-substituted C 1-6 alkyl, a group —(CH 2 ) u —NR 55 R 56 (wherein u is an integer selected from 1 to 4), a group —CH((CH 2 ) v1 COOR 57 )—(CH 2 ) v2 —COOR 57 (wherein v1 is an integer selected from 0 to 2, and v2 is an integer selected from 1 to 3), a group —(CH 2 ) w —SO 3 H (wherein w is an integer selected from 1 to 4), a group —(CH 2 ) x1 —CH(COOH)—(CH 2 ) x2 —SO 3 H (wherein x1 is an integer selected from 0 to 2, and x2 is an integer selected from 1 to 3), 3- to 6-membered oxacycloalkyl, or a group —(CH 2 ) t1 —O—(CH 2 ) t2 —C(O)NR 58 R 59 (wherein t1 and t2 are each independently an integer selected from 1 to 3);
R 41 is a hydrogen atom or C 1-3 alkyl;
R 42 is C 1-8 alkyl substituted with one or more hydroxy groups, or (C 1-3 alkoxy)C 1-4 alkyl;
R 43 is a hydrogen atom or C 1-3 alkyl;
R 44 is C 1-8 alkyl substituted with one or more hydroxy groups, or
R 43 and R 44 together with the nitrogen atom to which they are attached may form morpholino;
R 45 is a hydrogen atom or C 1-3 alkyl;
R 46 is C 1-6 alkyl substituted with one or more hydroxy groups;
R 47 is C 1-3 alkyl;
R 48 is (C 1-3 alkoxy)C 1-4 alkyl;
R 49 is a hydrogen atom and C 1-4 alkyl;
R 50 is —(CH 2 ) z —NR 60 R 61 (z is an integer selected from 1 to 4, R 60 is a hydrogen atom or C 1-4 alkyl, and R 61 is (C 1-3 alkoxy)C 1-4 alkyl, or R 60 and R 61 together with the nitrogen atom to which they are attached may form morpholino);
R 51 is a hydrogen atom or C 1-4 alkyl;
R 52 is C 1-8 alkyl substituted with one or more hydroxy groups;
R 53 and R 54 are each independently selected from a hydrogen atom and C 1-4 alkyl;
R 55 is a hydrogen atom or C 1-4 alkyl;
R 56 is (C 1-4 alkyl)carbonyl;
R 57 is a hydrogen atom or C 1-4 alkyl;
R 58 is a hydrogen atom or C 1-3 alk

Assignees

• Chugai Pharmaceutical Co Ltd

Inventors

• Ohtake Yoshihito
• Okamoto Naoki
• Ono Yoshiyuki
• Kashiwagi Hirotaka
• Kimbara Atsushi
• Harada Takeo
• Hori Nobuyuki
• Murata Yoshihisa
• Tachibana Kazutaka
• Tanaka Shota
• Nomura Kenichi
• Ide Mitsuaki
• Mizuguchi Eisaku
• Ichida Yasuhiro
• Ohtomo Shuichi
• Horiba Naoshi

Classifications

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• C07D401/12

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D471/04

  Ortho-condensed systems · CPC title

• A61K31/5377

  not condensed and containing further heterocyclic rings, e.g. timolol · CPC title

• C07D491/08

  Bridged systems · CPC title