US 8,871,934 B2 · Fluorene compound and pharmaceutical use thereof

Abstract

The present invention provides an agent for the prophylactic or treatment of diabetes, diabetic complications, insulin resistance syndrome, metabolic syndrome, hyperglycemia, dyslipidemia, atherosclerosis, cardiac failure, cardiomyopathy, myocardial ischemia, brain ischemia, cerebral apoplexy, pulmonary hypertension, hyperlactacidemia, mitochondrial disease, mitochondrial encephalomyopathy or cancer, namely, a PDHK inhibitor and the like. A compound represented by the following formula [I] or a pharmaceutically acceptable salt thereof, or a solvate thereof: wherein each symbol is as defined in the specification.

A compound of formula [Vd]

wherein,
Ra is
(1) a hydrogen atom, or
(2) a halogen atom;
Rb0 is a substituent that can be converted to Rb by a functional group conversion reaction;
Rb is
(1) a hydrogen atom,
(2) a halogen atom,
(3) a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group A,
(4) a C2-6 alkenyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group C,
(5) a C2-6 alkynyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group C,
(6) a cyano group,
(7) —C(═O)—Rb1 wherein Rb1 is a hydrogen atom or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group B,
(8) —C(═O) —ORb2 wherein Rb2 is a hydrogen atom or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group B,
(9) —C(═O)—NRb3Rb4 wherein Rb3 and Rb4 are the same or different and each is a hydrogen atom or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group B,
(10) —C(═O)—NRb5—ORb6 wherein Rb5 and Rb6 are the same or different and each is a hydrogen atom or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group B,
(11) —ORb7 wherein Rb7 is a hydrogen atom or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group B,
(12) —NRb8Rb9 wherein Rb8 and R9 the same or different and each is a hydrogen atom or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group B,
(13) —NRb10—C(═O)—Rb11 wherein Rb10 and Rb11 are the same or different and each is a hydrogen atom or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group B,
(14) —NRb12—C(═O)—ORb13 wherein Rb12 is a hydrogen atom or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group B, and Rb13 is a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group B,
(15) —O—C(═O)—NRb14Rb15 wherein Rb14 and Rb15 are the same or different and each is a hydrogen atom or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group B, or
(16) a group represented by the following formula:
wherein
Yb is
(i) a single bond,
(ii) a C1-6 alkylene,
(iii) a C2-6 alkenylene,
(iv) —O—(CH2)n1-wherein n1 is an integer of 0 , or 1 to 4,
(v) —O—(CH2)n2—C(═O)-wherein n2 is an integer of 0 , or 1 to 4,
(vi) —C(═O)—, or
(vii) —NRb16-wherein Rb16 is a hydrogen atom or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group B;
ring T is
(i) a C6-10 aryl group,
(ii) a C3-10 cycloalkyl group,
(iii) a C5-10 bridged cycloalkyl group,
(iv) a monocyclic aromatic heterocyclic group which contains, besides carbon atom, 1 to 4 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, and has 3 to 7 ring-constituting atoms, or
(v) a monocyclic non-aromatic heterocyclic group which contains, besides carbon atom, 1 to 4 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, and has 3 to 7 ring-constituting atoms,
Rj are the same or different and each is a substituent selected from the following group D, and p is an integer of 0 , or 1 to 4;
Rc is
(1) a hydrogen atom,
(2) a halogen atom,
(3) a C1-6 alkyl group,
(4) —C(═O)—ORc1 wherein Rc1 is a hydrogen atom or a C1-6 alkyl group,
(5) —ORc2 wherein Rc2 is a hydrogen atom or a C1-6 alkyl group,
(6) —NRc3Rc4 wherein Rc3 and Rc4 are the same or different and each is a hydrogen atom or a C1-6 alkyl group, or
(7) —NRc5—C(═O)—Rc6 wherein Rc5 and Rc6 are the same or different and each is a hydrogen atom or a C1-6 alkyl group;
Re are the same or different and each is,
(1) a halogen atom, or
(2) a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group C;
and
n is an integer of 0 , or 1 to 3,
Group A is selected from the group consisting of
(a) a halogen atom,
(b) a cyano group,
(c) —C(═O)—RA1 wherein RA1 is a hydrogen atom or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group B,
(d) —C(═O)—ORA2 wherein RA2 is a hydrogen atom or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group B,
(e) —C(═O)—NRA3RA4 wherein RA3 and RA4 are the same or different and each is a hydrogen atom or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group B,
(f) —C(═O)—NRA5ORA6 wherein RA5 and RA6 are the same or different and each is a hydrogen atom or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group B,
(g) —ORA7 wherein RA7 is a hydrogen atom or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group B,
(h) —NRA8RA9 wherein RA8 and RA9 are the same or different and each is a hydrogen atom or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group B,
(i) —NRA10—C(═O) —RA11 wherein RA10 and RA11 are the same or different and each is a hydrogen atom or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group B,
(j) —NRA12—C(═O)—ORA13 wherein RAl2 is a hydrogen atom or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group B, and RA13 is a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group B,
(k) —S(═O)2—ORA14 wherein RA14 is a hydrogen atom or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group B,
(l) —S(═O)2—ORA15 wherein RA15 is a hydrogen atom or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group B, and
(m) —Si—(CH2- CH3)3,
Group B is selected from the group consisting of
(a) a halogen atom,
(b) a cyano group,
(c) —C(═O)—RB1 wherein RB1 is a hydrogen atom or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group C,
(d) —C(═O)—ORB2 wherein RB2 is a hydrogen atom or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group C,
(e) —C(═O)—NRB3RB4 wherein RB3 and RB4 are the same or different and each is a hydrogen atom or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group C,
(f) —C(═O)—NRB5—ORB6 wherein RB5 and RB6 are the same or different and each is a hydrogen atom or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group C,
(g) —ORB7 wherein RB7 is a hydrogen atom or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group C,
(h) —NRB8RB9 wherein RB8 and RB9 are the same or different and each is a hydrogen atom or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group C,
(i) —NRB10—C(═O) —RB11 wherein RB10 and RB11 are the same or different and each is a hydrogen atom or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group C,
(j) —NRB12—S(═O)2 —RB13 wherein RB12 and RB13 are the same or different and each is a hydrogen atom or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group C,
(k) —NRB14—C(═O)—ORB15 wherein RB14 is a hydrogen atom or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group C, and RB15 is a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group C,
(l) —S(═O)2RB16 wherein RB16 is a hydrogen atom or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group C, and
(m) —S(═O)2—ORB17 wherein RB17 is a hydrogen atom or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group C,
Group C is selected from the group consisting of
(a) a halogen atom,
(b) —C(═O)—RC1 wherein RC1 is a hydrogen atom or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 halogen atoms,
(c) —C(═O)—ORC2 wherein RC2 is a hydrogen atom or a C1-6 alkyl group, and
(d) —ORC3 wherein RC3 is a hydrogen atom or a C1-6 alkyl group,
Group D is selected from the group consisting of
(a) a halogen atom,
(b) a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group E,
(c) a C1-6 alkyl group substituted by a C6-10 aryl group optionally substituted by the same or different 1 to 5 substituents selected from the following group F,
(d) a C1-6 alkyl group substituted by a C3-10 cycloalkyl optionally substituted by the same or different 1 to 5 substituents selected from the following group F,
(e) a C1-6 alkyl group substituted by a C5-10 bridged cycloalkyl optionally substituted by the same or different 1 to 5 substituents selected from the following group F,
(f) a C1-6 alkyl group substituted by a monocyclic aromatic heterocyclic group optionally substituted by the same or different 1 to 5 C1-6 alkyl groups (the monocyclic aromatic heterocyclic group contains, besides carbon atom, 1 to 4 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, and has 3 to 7 ring-constituting atoms),
(g) a C3-10 cycloalkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group F,
(h) a C5-10 bridged cycloalkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group F,
(i) a cyano group,
(j) —C(═O)—RD1 wherein RD1 is a hydrogen atom, a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group E, or a monocyclic non-aromatic heterocyclic group optionally substituted by the same or different 1 to 5 substituents selected from the following group F (the monocyclic non-aromatic heterocyclic group contains, besides carbon atom, 1 to 4 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, and has 3 to 7 ring-constituting atoms),
(k) —C(═O)—ORD2 wherein RD2 is a hydrogen atom, or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group E,
(l) C(═O)—NRD3RD4 wherein RD3 and RD4 are the same or different and each is a hydrogen atom, or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group E,
(m) —C(═O)—NRD5—ORD6 wherein RD5 and RD6 are the same or different and each is a hydrogen atom, or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group E,
(n) —ORD7 wherein RD7 is a hydrogen atom, or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group E,
(o) —NRD8RD9 wherein RD8 and RD9 are the same or different and each is a hydrogen atom, or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group E,
(p) —NRD10—C(═O)—RD11 wherein RD10 and RD11 are the same or different and each is a hydrogen atom, or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group E,
(q) —NRD12 —C(═O)—ORD13 wherein RD12 is a hydrogen atom, or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group E, and RD13 is a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group E,
(r) —S(═O)2—RD14 wherein RD14 is a hydrogen atom, or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group E, and
(s) —S(═O)2—ORD15 wherein RD15 is a hydrogen atom, or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group E,
Group E is selected from the group consisting of
(a) a halogen atom,
(b) a cyano group,
(c) —C(═O)—RE1 wherein RE1 is a hydrogen atom or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group F,
(d) —C(═O)—ORE2 wherein RE2 is a hydrogen atom or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group F,
(e) —C(═O)—NRE3RE4 wherein RE3 and RE4 are the same or different and each is a hydrogen atom or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group F,
(f) —C(═O)—NRE5—ORE6 wherein RE5 and RE6 are the same or different and each is a hydrogen atom or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group F,
(g) —ORE7 wherein RE7 is a hydrogen atom or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group F,
(h) —NRE8RE9 wherein RE8 and RE9 are the same or different and each is a hydrogen atom or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group F,
(i) —NRE10—C(═O)—RE11 wherein RE10 and RE11 are the same or different and each is a hydrogen atom or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group F,
(j) —NRE12—C(═O)—ORE13 wherein RE12 is a hydrogen atom or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group F, and RE13 is a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group F,
(k) —S(═O)2—RE14 wherein RE14 is a hydrogen atom or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group F,
(l) —S(═O)2—ORE15 wherein RE15 is a hydrogen atom or a C1-6 alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group F, and
(m) —NRE16—S(═O)2—RE17 wherein RE16 and RE17 are the same or different and each is a hydrogen atom or a C1-6 alkyl group,
Group F is selected from the group consisting of
(a) —(CH2)nF1—C(═O)—ORF1 wherein RF1 is a hydrogen atom or a C1-6 alkyl group, and nF1 is an integer of 0 , or 1 to 4 , and
(b) —(CH2)nF2—ORF2 wherein RF2 is a hydrogen atom or a C1-6 alkyl group, and nF2 is an integer of 0 , or 1 to 4.

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Fluorene compound and pharmaceutical use thereof

Life of this patent

Fluorene compound and pharmaceutical use thereof

Life of this patent

Abstract

Claims1