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US 6,664,291 B2Granted
Malonamic acids and derivatives thereof as thyroid receptor ligands
AssigneePfizer Inc.
InventorsYuan-Ching P. Chiang, Gary E. Aspnes, Kimberly G. Estep
Life of this patent
Estimating the term…
Abstract
The present invention relates to novel thyroid receptor ligands and, more particularly, relates to malonamic acids and derivatives thereof of Formula I, which are useful in the treatment of obesity, overweight condition, hyperlipidemia, glaucoma, cardiac arrhythmias, skin disorders, thyroid disease, hypothyroidism, thyroid cancer and related disorders and diseases such as diabetes mellitus, atherosclerosis, hypertension, coronary heart disease, congestive heart failure, hypercholesteremia, depression, osteoporosis and hair loss. The present invention also provides methods, pharmaceutical compositions and kits for treating such diseases and disorders.
Claims30
A compound of Formula I
- an isomer thereof, a prodrug of said compound or isomer, or a pharmaceutically acceptable salt of said compound, isomer or prodrug;
- wherein
- W is —O—:
- R0 is hydrogen;
- R1 and R2 are each independently hydrogen, —(C1-C6)alkyl, halogen or CN;
- R1 is located at the 5-position and R2 is located at the 3-position;
- R3 is hydrogen, —(C1-C4)alkyl or halogen;
- R4 is (a) —(C1-C10)alkyl substituted with zero to three substituents dependently selected from F, hydroxy, oxo, aryl, heteroaryl, —(C3-C8)cycloalkyl, or heterocycloalkyl, (b) —(C3-C8) cycloalkyl, (c) heterocycloalkyl, (d) —C(O)Rc, (e) —ORb, (f) —NRaC(O)Rd, (g) —NRaC(O)NRcRd or (h) —NRaS(O)2Rd;
- or R3 and R4 are taken together along with the carbon atoms to which they are attached to form a carbocyclic ring of formula —(CH2)i— or a heterocyclic ring of formula —(CH2)k—Q—(CH2)1— wherein Q is —O—, —S— or —NRa—;
- i is 3, 4, 5 or 6;
- k is 0, 1, 2, 3, 4 or 5;
- and l is 0, 1, 2, 3, 4 or 5;
- and wherein the carbocyclic ring and the heterocyclic ring are each substituted with zero to four substituents independently selected from (a) —(C1-C4)alkyl, (b) —ORb,(c) oxo, (d) —CN, (e) phenyl or (f) —NRRR8;
- provided that when the substituent R4 is —(C1-C10)alkyl substituted with zero to three substituents, the oxo group is substituted on a carbon atom other than the C1 carbon atom in —(C1-C10)alkyl;
- R5 is (a) —OH, (b) —O(C1-C6)alkyl, (c) —OC(O)Rf, (d) F, or (e) —C(O)ORc;
- or R4 and R5 are taken together along with the carbon atoms to which they are attached to form a heterocyclic ring selected from the group consisting of —CRc═CRa—NH—, —N═CRa—NH, —CRo═CRa—O—, —CRc═CRa—NH— and —CRa═CRa—CRa═N—;
- R6 is (a) hydrogen, (b) halogen, (c) —(C1-C8)alkyl, (d) —CF3, (e) —OCF3, (f) —O(C1-C8)alkyl, or (g) —CN;
- R7 is (a) hydrogen or (b) —(C1-C6)alkyl;
- R8 and R9 are each independently (a) hydrogen, (b) —(C1-C6)alkyl, (c) aryl, or (d) halogen;
- R10 is (a) —(C0-C1)alkyl-C(O)OH, (b) —(C0-C1)alkyl-C(O)ORf, (c) —(C0-C1)alkyl —C(O)NRcRd, or (d) —(C0-C1)alkyl-OH;
- Ra for each occurrence is independently (a) hydrogen or (b) —(C1-C6)alkyl substituted with zero or one —(C3-C6)cycloalkyl or methoxy;
- Rb for each occurrence is independently (a) hydrogen, (b) —(C1-C12)alkyl substituted with zero to three substituents independently selected from Group V, (c) aryl, (d) heteroaryl, (e) —(C3-C10) cycloalkyl, (f) heterocycloalkyl, (g) —C(O)NRcRd, or (h) —C(O)Rf;
- Rc and Rd for each occurrence are each independently (a) hydrogen, (b) —(C1-C12)alkyl substituted with zero to three substituents independently selected from Group VI, (c) —(C2-C12)alkenyl, (d) —(C2-C12)alkynyl, (e) aryl, (f) heteroaryl, (g) —(C3-C10)cycloalkyl or (h) heterocycloalkyl;
- or Rc and Rd are taken together along with the atom(s) to which they are attached to form a 3-10 membered heterocyclic ring which may optionally contain a second heterogroup selected from —O—, —NRe— or —S—;
- and wherein the heterocyclic ring is substituted with zero to four substituents independently selected from (a) —(C1-C4)alkyl, (b) —ORb, (c) oxo, (d) —CN, (e) phenyl or (f) —NRaRb;
- Re for each occurrence is (a) hydrogen, (b) —CN, (c) —(C1-C10)alkyl substituted with zero to three substitutents independently selected from Group V, (d) —(C2-C10)alkenyl, (e) —(C2-C10) alkoxy, (f) —(C3-C10)cycloalkyl, (g) aryl, (h) heteroaryl, (i) —C(O)Rf, (j) —C(O)ORf, (k) —C(O)NRaRf or (l) —S(O)2Rf;
- Rf for each occurrence is independently (a) —(C1-C10)alkyl substituted with zero to three substituents independently selected from the Group VI, (b) —(C2-C10)alkenyl, (c) —(C2-C10)alkynyl, (d) —(C3-C10)cycloalkyl, (e) aryl, (f) heteroaryl or (g) heterocycloalkyl;
- R8 for each occurrence is independently (a) hydrogen, (b) —(C1-C6)alkyl, (c) —(C2-C6)alkenyl, (d) aryl, (e) —C(O)Rf, (f) —C(O)ORf, (g) —C(O)NRaRf, (h) —S(O)2Rf or (i) —(C3-C8)cycloalkyl;
- Rb is (a) —(C1-C6)alkyl substituted with zero or one substituent selected from the group consisting of (1) —(C3-C6)cycloalkyl, (2) heterocycloalkyl and (3) phenyl substituted with zero or one substituent selected from the group consisting of (i) —(C1-C4)alkyl, (ii) halogen, (iii) —CF3 and (iv) —OCF3;
- (b) phenyl substituted with zero to two substituents independently selected from the group consisting or (1) —(C1-C4)alkyl, (2) halogen, (3) —CF3, and (4) —OCF3;
- (c) —(C3-C6)cycloalkyl or (d) heterocycloalkcyl;
- Group V is (a) halogen, (b) —CF3, (c) —OCF3, (d) —OH, (e) -oxo, (f) —(C1-C6)alkoxy, (g) —CN, (h) aryl, (i) heteroaryl, (j) —(C3-C10)cycloalkyl, (k) heterocycloalkyl, (l) —SRf, (m) —S(O)Rf, (n) —S(O)2Rf, (o) —S(O)2NRaRf (p) —NRaRg or (q) —C(O)NRaRf;
- Group VI is (a) halogen, (b) hydroxy, (c) oxo, (d) —(C1-C6)alkoxy, (e) aryl, (f) heteroaryl, (g) —(C3-C8)cycloalkyl, (h) heterocycloalkyl, (i) —CN, or (j) —OCF3;
- aryl for each occurrence is independently phenyl or naphthyl substituted with zero to four substituents independently selected from (a) halogen, (b) —(C1-C6)alkyl, (c) —CN, (d) —SRf, (e) —S(O)Rf, (f) —S(O)2Rf, (g) —(C3-C6)cycloalkyl, (h) —S(O)2NRaRf, (i) —NRaRg, (j) —C(O)NRaRf, (k) —ORb, (l)-perfluoro-(C1-C4)alkyl, or (m) —COORf;
- provided that when the substituent(s) on aryl are —SRf, —S(O)Rf, —S(O)2Rf, —S(O)2NRaRf, —NRaRg, —C(O)NRaRf, —ORb, or —COORf, the substituents Rb, Rf and Rg are other than aryl or heteroaryl;
- heteroaryl for each occurrence is independently a 5-, 6-, 7-, 8-, 9- or 10-membered monocyclic or bicyclic ring having from 1 to 3 heteroatoms selected from O, N or S;
- wherein in the bicyclic ring, a monocyclic heteroaryl ring is fused to a benzene ring or to another heteroaryl ring;
- and having zero to three substituents independently selected from (a) halogen, (b) —(C1-C4)alkyl, (c) —CF3, (d) —ORb, (e) —NRaRg, or (f) —CO2Rf;
- provided that when the substituent(s) on heteroaryl are —ORb, —NRaRg or —CO2Rf, the substituents Rb, Rf and Rg are other than aryl or heteroaryl;
- heterocycloalkyl for each occurrence is independently a 4-, 5-, 6-, 7-, 8-, 9- or 10-membered monocyclic or bicyclic cycloalkyl ring having from 1 to 3 heteroatoms selected from O, NRc or S;
- and having zero to four substituents independently selected from (a) —(C1-C4)alkyl, (b) —ORb, (c) oxo, (d) —CN, (e) phenyl or (f) —NRaRg.
38 more elements
A compound of claim 13 selected from the group consisting of:
- a compound wherein R1 is CH3, R2 is CH3, R3 and R4 are taken together along with the carbon atoms to which they are attached to form an indanyl, and R10 is —C(O)OH;
- a compound wherein R1 is Cl, R2 is CH3, R3 and R4 are taken together along with the carbon atoms to which they are attached to form an indanyl, and R10 is —C(O)OH;
- a compound wherein R1 is Cl, R2 is CH3, R3 and R4 are taken together along with the carbon atoms to which they are attached to form a 2-methyl-1-oxo-2,3-dihydro-1H-isoindolyl, and R10 is —C(O)OH;
- a compound wherein R1 is CH3, R2 is CH3, R3 and R4 are taken together along with the carbon atoms to which they are attached to form a 2-methyl-1-oxo-2,3-dihydro-1H-isoindolyl, and R10 is —C(O)OH;
- a compound wherein R1 is CH3, R2 is CH3, R3 and R4 are taken together along with the carbon atoms to which they are attached to form a 2-methyl-1-oxo-indanyl, and R10 is —C(O)OH;
- and
- a compound wherein R1 is CH3, R2 is CH3, R3 and R4 are taken together along with the carbon atoms to which they are attached to form a 2,2-dimethyl-1-oxo-indanyl, and R10 is —C(O)OH.
4 more elements
A compound of formula A
- an isomer thereof, a prodrug of said compound or isomer, or a pharmaceutically acceptable salt of said compound, isomer or prodrug;
- wherein R1 and R2 are each independently —CH3 or —Cl;
- R4 is —SO2—CH2-cyclopropyl, —SO2—CH2-cyclobutyl, —SO2—CH2-cyclopentyl, —SO2—CH2-cyclohexyl, —SO2-cyclpentyl or —SO2-cyclohexyl;
- ;
- R8 and R9 are each independently hydrogen or methyl;
- and R10 is —C(O)OH, —C(O)OCH3 or —C(O)OCH2CH3.
3 more elements
N-[3-chloro-4-(3-cyclobutylmethanesulfonyl-4-hydroxy-phenoxy)-5-methyl-phenyl]-malonamic acid, or a pharmaceutically acceptable salt thereof.
Dependencies are inferred from the claim text.