US 2016/0002251 A1 · DIHYDROPYRIDAZINE-3,5-DIONE DERIVATIVE AND PHARMACEUTICALS CONTAINING THE SAME

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.

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

wherein R1, R4, and R5 are as defined in any one of the following (1) to (3):
(1) R1 is a hydrogen atom or C1-10 alkyl;
R4 is a hydrogen atom, C1-4 alkyl optionally substituted with one or more substituents Rf, C6-10 aryl optionally substituted with one or more substituents Rg, (C1-6 alkyl)carbonyl, (C6-10 aryl)carbonyl, a group —C(O)NR37R38, C3-7 cycloalkyl, or 5- to 8-membered heterocycloalkyl;
and
R5 is a hydrogen atom or C1-4 alkyl;
(2) R1 and R5 together with the carbon atom to which they are attached form a C3-6 saturated carbocyclic ring;
and
R4 is as defined above;
and
(3) R1 is a hydrogen atom or linear C1-10 alkyl;
R4 and R5 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 R2;
R3 is C1-10 alkyl optionally substituted with one or more substituents Rh, or R3 is C1-4 alkyl substituted with Re;
R37 and R38 are each independently selected from a hydrogen atom and C1-3 alkyl;
each R2 is independently selected from C1-5 alkyl and a halogen atom;
and/or
two or more substituents R2 on the 5- to 8-membered saturated heterocyclic ring may together form C1-5 alkylene that links the ring atoms to which they are attached;
each Rh is independently selected from a halogen atom, (C1-4 alkoxy)carbonyl, and a group —(O(CH2)a)b—C1-4 alkoxy, wherein a is an integer selected from 2 to 4, and b is an integer selected from 1 to 4;
Re is C6-10 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, (C1-6 alkoxy)carbonyl, C1-6 alkoxy, and C6-10 aryl optionally substituted with one or more substituents Rg;
each Rg is independently selected from a halogen atom, C1-6 alkyl, C2-6 alkynyl, and C1-6 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, (C1-4 alkoxy)carbonyl, 3- to 10-membered heterocycloalkyloxy (the heterocycloalkyloxy group is optionally substituted with optionally C1-4 alkoxy-substituted C1-4 alkyl), C1-10 alkyl optionally substituted with one or more substituents R10, C2-10 alkenyl optionally substituted with one or more substituents R15, C2-10 alkynyl optionally substituted with one or more substituents R11, C1-8 alkoxy optionally substituted with one or more substituents R12, C1-4 alkylthio optionally substituted with one or more substituents R13, a group —(O(CH2)q1)q2—NR41R42 (wherein q1 is an integer selected from 1 to 4, and q2 is an integer selected from 2 to 6), a group —(O(CH2)r1)r2—C(O)NR43R44 (wherein r1 is an integer selected from 1 to 4, and r2 is an integer selected from 1 to 4), a group —(O(CH2)s1)s2—NR45—C(O)R46 (wherein s1 and s2 are each independently an integer selected from 2 to 4), a group —C(O)NR47R48, pyridinyl, pyrrolyl, a group —NR49R50, and a group —(O(CH2)y1)y2—O—CH2—C(O)NR51R52 (wherein yl is an integer selected from 1 to 4, and y2 is an integer selected from 1 to 4);
R10, R11, R12, R13, and R15 are each independently selected from a halogen atom, hydroxy, carboxy, C1-6 alkoxy optionally substituted with one or more hydroxy groups, (C1-4 alkoxy)C1-6 alkoxy, (C1-4 alkoxy)carbonyl, a group —(O(CH2)o)p—OH (wherein o and p are each independently an integer selected from 2 to 4), C3-6 cycloalkyl optionally substituted with one or more hydroxy groups, 3- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, and a group —NR39R40, wherein the 3- to 10-membered heterocycloalkyl group is optionally substituted with one or more substituents selected from oxo, a halogen atom, C1-4 alkyl (wherein the alkyl group is optionally substituted with one or more hydroxy groups), (C1-4 alkoxy)C1-4 alkyl (wherein the alkoxy moiety is optionally substituted with one or more hydroxy groups), C1-4 alkoxy, (C1-4 alkoxy)carbonyl, C1-4 alkylthio, morpholino, (C1-3 alkyl)sulfonyl, and —C(O)NR53R54;
Ar1 is C6-10 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 C1-4 alkoxy-substituted C1-5 alkoxy, a halogen atom, C1-10 alkyl optionally substituted with one or more halogen atoms, a group —SF5, cyano, hydroxy, 5- to 10-membered heterocycloalkyl optionally substituted with one or more substituents R14, C6-10 aryl optionally substituted with one or more substituents R14, and 5- to 10-membered heteroaryl optionally substituted with one or more substituents R14;
each R14 is independently selected from a halogen atom, oxo, cyano, nitro, C1-4 alkyl optionally substituted with one or more halogen atoms, C1-4 alkoxy optionally substituted with one or more halogen atoms, (C1-6 alkoxy)carbonyl, a group —NR27R28, a group —SO2NR35R36, C1-4 alkylthio, and 5- to 10-membered heterocycloalkyl;
R27 and R28 are each independently selected from a hydrogen atom and C1-4 alkyl optionally substituted with (C1-4 alkoxy)carbonyl;
R35 and R36 are each independently selected from a hydrogen atom and C1-4 alkyl;
R39 is a hydrogen atom, or optionally C1-6 alkoxy-substituted C1-6 alkyl;
R40 is a hydrogen atom, optionally C1-6 alkoxy-substituted C1-6 alkyl, ((C1-4 alkoxy)carbonyl)C1-6 alkyl, hydroxy-substituted C1-6 alkyl, a group —(CH2)u—NR55R56 (wherein u is an integer selected from 1 to 4), a group —CH((CH2)v1COOR57)—(CH2)v2—COOR57 (wherein v1 is an integer selected from 0 to 2, and v2 is an integer selected from 1 to 3), a group —(CH2)w—SO3H (wherein w is an integer selected from 1 to 4), a group —(CH2)x1—CH(COOH)—(CH2)x2—SO3H (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 —(CH2)t1—O—(CH2)t2—C(O)NR58R59 (wherein t1 and t2 are each independently an integer selected from 1 to 3);
R41 is a hydrogen atom or C1-3 alkyl;
R42 is C1-8 alkyl substituted with one or more hydroxy groups, or (C1-3 alkoxy)C1-4 alkyl;
R43 is a hydrogen atom or C1-3 alkyl;
R44 is C1-8 alkyl substituted with one or more hydroxy groups, or
R43 and R44 together with the nitrogen atom to which they are attached may form morpholino;
R45 is a hydrogen atom or C1-3 alkyl;
R46 is C1-6 alkyl substituted with one or more hydroxy groups;
R47 is C1-3 alkyl;
R48 is (C1-3 alkoxy)C1-4 alkyl;
R49 is a hydrogen atom and C1-4 alkyl;
R50 is —(CH2)z—NR60R61 (z is an integer selected from 1 to 4, R60 is a hydrogen atom or C1-4 alkyl, and R61 is (C1-3 alkoxy)C1-4 alkyl, or R60 and R61 together with the nitrogen atom to which they are attached may form morpholino);
R51 is a hydrogen atom or C1-4 alkyl;
R52 is C1-8 alkyl substituted with one or more hydroxy groups;
R53 and R54 are each independently selected from a hydrogen atom and C1-4 alkyl;
R55 is a hydrogen atom or C1-4 alkyl;
R56 is (C1-4 alkyl)carbonyl;
R57 is a hydrogen atom or C1-4 alkyl;
R58 is a hydrogen atom or C1-3 alkyl;
and
R59 is C1-8 alkyl substituted with one or more hydroxy groups.

46 more elements

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

Life of this patent

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

Life of this patent

Abstract

Claims48