US 6,441,015 B2Granted

Tetrazole compounds as thyroid receptor ligands

AssigneePfizer Inc.

InventorsGary E. Aspnes, Yuan-Ching P. Chiang

Life of this patent

Estimating the term…

Abstract

The present invention relates to tetrazole compounds of Formula I, stereoisomers, pharmaceutically acceptable salts and prodrugs thereof, and pharmaceutically acceptable salts of the prodrugs. The invention also relates to compositions comprising the tetrazole compounds and to methods of treating obesity, diabetes, atherosclerosis, hypertension, coronary heart disease, hypercholesterolemia, hyperlipidemia, thyroid disease, thyroid cancer, hypothyroidism, depression, glaucoma, cardiac arrhythmias, congestive heart failure, and osteoporosis using the tetrazole compounds.

Claims31

Dependent claims

A compound of Formula I

or a stereoisomer, or a pharmaceutically acceptable salt thereof wherein:
W is O, S, SO, SO2, CH2, CF2, CHF, C(═O), CH(OH), NRa, or
X is O, CH2, CH2CH2, S, SO, SO2, CH2NRa, NRa or a bond;
each Ra is independently hydrogen, C1-C6alkyl, or C1-C6alkyl substituted with one substituent selected from C3-C6cycloalkyl or methoxy;
R1, R2, R3 and R6 are independently hydrogen, halogen, C1-C8alkyl, —CF3, —OCF3, —OC1-C8alkyl, or —CN;
R4 is hydrogen, C1-C12alkyl, C1-C12alkyl that is substituted with from one to three substituents independently selected from Group V, C2-C12 alkenyl, C2-C12 alkynyl, halogen, —CN, —ORb, —SRc, —S(═O)Rc, —S(═O)2Rc, aryl, heteroaryl, C3-C10 cycloalkyl, heterocycloalkyl, —S(═O)2NRcRd, —C(═O)NRcRd, —C(═O)ORc, —NRaC(═O)Rd, —NRaC(═O)NRcRd, —NRaS(═O)2Rd, —NRaRd, —C(═O)Rc,
or R3 and R4 are taken together with the carbon atoms to which they are attached to form an unsubstituted or substituted carbocyclic ring of formula —(CH2)i— or an unsubstituted or substituted heterocyclic ring selected from the group consisting of —Q—(CH2)j— and —(CH2)k—Q—(CH2)l— wherein Q is O, S or NRa;
i is 3, 4, 5, 6 or 7;
j is 2, 3, 4, 5, or 6;
k and l are each independently 1, 2, 3, 4, or 5, and any substituents up to four are selected from C1-C4alkyl, —ORb, oxo, —CN, phenyl, or —NRaRg;
Rb is hydrogen, C1-C12alkyl, C1-C12alkyl substituted with one to three substituents independently selected from Group V, aryl, heteroaryl, C3-C10 cycloalkyl, heterocycloalkyl, —C(═O)NRcRd, or —C(═O)Rf;
Rc and Rd are each independently selected from hydrogen, C1-C12alkyl, C1-C12alkyl substituted with one to three substituents independently selected from Group VI, C2-C12alkenyl, C2-C12alkynyl, aryl, heteroaryl, C3-C10 cycloalkyl, heterocycloalkyl,
or Rc and Rd may together along with the atom(s) to which they are attached form a 3-10 membered unsubstituted or substituted heterocyclic ring, which may contain a second heterogroup selected from O, NRe, or S, wherein any substitutents up to four are selected from C1-C4alkyl, —ORb, oxo, —CN, phenyl, or —NR Rg;
R5 is —OH, —OC1-C6alkyl, —OC(═O)Rf, —F, —C(═O)ORc,
or R4 and R5 may together with the atom(s) to which they are attached form a heterocyclic ring selected from the group consisting of —CRc═CRa—NH—, —N═CRa—NH—, —CRc═CRa—O—, —CRc═CRa—S—, —CRc═N—NH—, or —CRa═CRa—CRa═N—;
Group V is halogen;
—CF3;
—OCF3;
hydroxy;
oxo;
C1-C6alkoxy;
—CN;
aryl;
heteroaryl;
C3-C10cycloalkyl;
heterocycloalkyl;
—SR5;
—S(═O)Rf;
—S(═O)2Rf;
—S(═O)2NRaRf, wherein Ra and Rf may together along with the atom(s) to which they are attached form a 3-8 membered heterocyclic ring, which may contain a second heterogroup selected from O, NRe or S;
—NRaRg;
or —C(═O)NRaRf, wherein Ra and Rf may together along with the atom(s) to which they are attached form a 3-8 membered heterocyclic ring, which may contain a second heterogroup selected from O, NRe or S;
Group VI is halogen, hydroxy, oxo, C1-C6alkoxy, aryl, heteroaryl, C3-C8cycloalkyl, heterocycloalkyl, —CN, or —OCF3;
Re is hydrogen, —CN, C1-C10alkyl, C1-C10alkyl substituted with one to three substitutents independently selected from Group V, C2-C10alkenyl, C2-C10alkoxy, C3-C10cycloalkyl, aryl, heteroaryl, —C(═O)Rf, —C(═O)ORf, —C(═O)NRaRf —S(═O)2NRaRf, or —S(═O)2Rf;
Rf is hydrogen, C1-C10alkyl, C1-C10alkyl substituted with from one to three substituents selected from Group VI, C2-C10alkenyl, C2-C10alkoxy, C3-C10cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
and
Rg is hydrogen, C1-C6alkyl, C3-C8cycloalkyl, C2-C6 alkenyl, aryl, —C(═O)Rf, —C(═O)ORf, —C(═O)NRaRf, or —S(═O)2Rf, provided that R1 and R2 are not both hydrogen, further provided that when X is CH2, W is NRa, R3 is hydrogen and R5 is —OH, then R6 and R4 are not both —C(H3)3, further provided that when X is CH2 or CH2CH2, W is O, and R3 and R6 are hydrogen, then R4 is not halogen, —CF3, C1-C6alkyl or C3-C7cycloalkyl, and further provided that when R3 and R4 are hydrogen and W is O then R6 is not halogen, —CF3, C1-C6alkyl or C3-C7cycloalkyl.

34 more elements

The compound:

2-cyclobutylmethanesulfonyl-4-[2,6-dimethyl-4-(2H-tetrazol-5-ylamino)-phenoxy]-phenol;
2-cyclobutylmethanesulfonyl-4-[2,6-dichlorol-4-(2H-tetrazol-5-ylamino)-phenoxy]-phenol;
4-[2-chloro-6-methyl-4-(2H-tetrazol-5-ylamino)-phenoxy]-2-cyclobutylmethanesulfonyl-phenol;
2-cyclopentylmethanesulfonyl-4-[2,6-dimethyl-4-(2H-tetrazol-5-ylamino)-phenoxy]-phenol;
2-cyclopentylmethanesulfonyl-4-[2,6-dichlorol-4-(2H-tetrazol-5-ylamino)-phenoxy]-phenol;
4-[2-chloro-6-methyl-4-(2H-tetrazol-5-ylamino)-phenoxy]-2-cyclopentylmethanesulfonyl-phenol;
2-cyclohexylmethanesulfonyl-4-[2,6-dimethyl-4-(2H-tetrazol-5-ylamino)-phenoxy]-phenol;
2-cyclohexylmethanesulfonyl-4-[2,6-dichlorol-4-(2H-tetrazol-5-ylamino)-phenoxy]-phenol;
4-[2-chloro-6-methyl-4-(2H-tetrazol-5-ylamino)-phenoxy]-2-cyclohexylmethanesulfonyl-phenol;
4-[2,6-dimethyl-4-(2H-tetrazol-5-ylamino)-phenoxy]-2-(4-fluoro-benzenesulfonyl)-phenol;
4-[2,6-dichloro-4-(2H-tetrazol-5-ylamino)-phenoxy]-2-(4-fluoro-benzenesulfonyl)-phenol;
4-[2-chloro-6-methyl-4-(2H-tetrazol-5-ylamino)-phenoxy]-2-(4-fluoro-benzenesulfonyl)-phenol,
5-[2,6-dichloro-4-(2H-tetrazol-5-ylamino)-phenoxyl]-2-hydroxy-N-methyl-benzamide;
N-butyl-5-[2,6-dichloro-4-(2H-tetrazol-5-ylamino)-phenoxy]-2-hydroxy-benzamide;
5-[2,6-dichloro-4-(2H-tetrazol-5-ylamino)-phenoxy]-2-hydroxy-N-isopropyl-benzamide;
5-[2,6-dichloro-4-(2H-tetrazol-5-ylamino)-phenoxy]-N-heptyl-2-hydroxy-benzamide;
5-[2,6-dichloro-4-(2H-tetrazol-5-ylamino)-phenoxy]-2-hydroxy-N-nonylbenzamide;
5-[2,6-dichloro-4-(2H-tetrazol-5-ylamino)-phenoxy]-N-(4-fluoro-phenyl)-2-hydroxy-benzamide;
N-cyclopentyl-5-[2,6-dichloro-4-(2H-tetrazol-5-ylamino)-phenoxy]-2-hydroxy-benzamide;
N-cyclohexyl-5-[2,6-dichloro-4-(2H-tetraol-5-ylamino)-phenoxy]-2-hydroxy-benzamide;
N-cycloheptyl-5-[2,6-dichloro-4-(2H-tetrazol-5-ylamino)-phenoxy]-2-hydroxy-benzamide;
N-cyclooctyl-5-[2,6-dichloro-4-(2H-tetrazol-5-ylamino)-phenoxy]-2-hydroxy-benzamide;
5-[2,6-dichloro-4-(2H-tetrazol-5-ylamino)-phenoxy]-2-hydroxy-N-(1-isopropyl-2-methyl-propyl)-benzamide;
N-cyclohexylmethyl-5-[2,6-dichloro-4-(2H-tetrazol-5-ylamino)-phenoxy]-2-hydroxy-benzamide;
N-(R-1-cyclohexyl-ethyl)-5-[2,6-dichloro-4-(2H-tetrazol-5-ylamino)-phenoxy]-2-hydroxy-benzamide;
N-(S-1-cyclohexyl-ethyl)-5-[2,6-dichloro-4-(1H-tetrazol-5-ylamino)-phenoxy]-2-hydroxy-benzamide;
N-cyclopentyl-5-[2,6-dichloro-4-(2H-tetrazol-5-ylamino)-phenoxy]-2-hydroxy-N-methyl-benzamide;
N-cyclohexyl-5-[2,6-dichloro-4-(2H-tetrazol-5-ylamino)-phenoxy-2-hydroxy-N-methyl-benzamide;
N-cycloheptyl-5-[2,6-dichloro-4-(2H-tetrazol-5-ylamino)-phenoxy]-2-hydroxy-N-methyl-benzamide;
N-cyclooctyl-5-[2,6-dichloro-4-(2H-tetrazol-5-ylamino)-phenoxy]-2-hydroxy-N-methyl-benzamide;
5-[2,6-dichloro-4-(2H-tetrazol-5-ylamino)-phenoxy]-2-hydroxy-N-(1-isopropyl-2-methyl-propyl)-N-methyl-benzamide;
N-cyclohexylmethyl-5-[2,6-dichloro-4-(2H-tetrazol-5-ylamino)-phenoxy]-2-hydroxy-N-methyl-benzamide;
N-(R-1-cyclohexyl-ethyl)-5-[2,6-dichloro-4-(2H-tetrazol-5-ylamino)-phenoxy]-2-hydroxy-N-methyl-benzamide;
and
N-(S-1-cyclohexyl-ethyl)-5-[2,6-dichloro-4-(1H-tetrazol-5-ylamino)-phenoxy]-2-hydroxy-N-methyl-benzamide, or a stereoisomer, or a pharmaceutically acceptable salt thereof.

32 more elements

Dependencies are inferred from the claim text.

Facts

Application: 09/767,771Filed 23 Jan 2001 · us provisional application
Priority: 25 Jan 2000
Published: US 2002/0006946 A117 Jan 2002
Granted: 27 Aug 2002
Term ends: Not estimatedThe source records don’t support an estimate.

Classification17 codes

C07D 257/04
Not condensed with other rings: five-membered rings
A61P 3/04
Drugs for disorders of the metabolism: anorexiants; Antiobesity agents
A61P 3/06
Drugs for disorders of the metabolism: antihyperlipidemics
A61P 3/10
For glucose homeostasis: for hyperglycaemia, e.g. antidiabetics

Family

Application60/177,987Us provisional application · filed 25 Jan 2000
US 2002/0006946 A1Published application
US 6,441,015 B2This patent

From the US filing history. Foreign family members aren’t listed.

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Citations

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Abstract

A compound of Formula I

or a stereoisomer, or a pharmaceutically acceptable salt thereof wherein:
W is O, S, SO, SO2, CH2, CF2, CHF, C(═O), CH(OH), NRa, or
X is O, CH2, CH2CH2, S, SO, SO2, CH2NRa, NRa or a bond;
each Ra is independently hydrogen, C1-C6alkyl, or C1-C6alkyl substituted with one substituent selected from C3-C6cycloalkyl or methoxy;
R1, R2, R3 and R6 are independently hydrogen, halogen, C1-C8alkyl, —CF3, —OCF3, —OC1-C8alkyl, or —CN;
R4 is hydrogen, C1-C12alkyl, C1-C12alkyl that is substituted with from one to three substituents independently selected from Group V, C2-C12 alkenyl, C2-C12 alkynyl, halogen, —CN, —ORb, —SRc, —S(═O)Rc, —S(═O)2Rc, aryl, heteroaryl, C3-C10 cycloalkyl, heterocycloalkyl, —S(═O)2NRcRd, —C(═O)NRcRd, —C(═O)ORc, —NRaC(═O)Rd, —NRaC(═O)NRcRd, —NRaS(═O)2Rd, —NRaRd, —C(═O)Rc,
or R3 and R4 are taken together with the carbon atoms to which they are attached to form an unsubstituted or substituted carbocyclic ring of formula —(CH2)i— or an unsubstituted or substituted heterocyclic ring selected from the group consisting of —Q—(CH2)j— and —(CH2)k—Q—(CH2)l— wherein Q is O, S or NRa;
i is 3, 4, 5, 6 or 7;
j is 2, 3, 4, 5, or 6;
k and l are each independently 1, 2, 3, 4, or 5, and any substituents up to four are selected from C1-C4alkyl, —ORb, oxo, —CN, phenyl, or —NRaRg;
Rb is hydrogen, C1-C12alkyl, C1-C12alkyl substituted with one to three substituents independently selected from Group V, aryl, heteroaryl, C3-C10 cycloalkyl, heterocycloalkyl, —C(═O)NRcRd, or —C(═O)Rf;
Rc and Rd are each independently selected from hydrogen, C1-C12alkyl, C1-C12alkyl substituted with one to three substituents independently selected from Group VI, C2-C12alkenyl, C2-C12alkynyl, aryl, heteroaryl, C3-C10 cycloalkyl, heterocycloalkyl,
or Rc and Rd may together along with the atom(s) to which they are attached form a 3-10 membered unsubstituted or substituted heterocyclic ring, which may contain a second heterogroup selected from O, NRe, or S, wherein any substitutents up to four are selected from C1-C4alkyl, —ORb, oxo, —CN, phenyl, or —NR Rg;
R5 is —OH, —OC1-C6alkyl, —OC(═O)Rf, —F, —C(═O)ORc,
or R4 and R5 may together with the atom(s) to which they are attached form a heterocyclic ring selected from the group consisting of —CRc═CRa—NH—, —N═CRa—NH—, —CRc═CRa—O—, —CRc═CRa—S—, —CRc═N—NH—, or —CRa═CRa—CRa═N—;
Group V is halogen;
—CF3;
—OCF3;
hydroxy;
oxo;
C1-C6alkoxy;
—CN;
aryl;
heteroaryl;
C3-C10cycloalkyl;
heterocycloalkyl;
—SR5;
—S(═O)Rf;
—S(═O)2Rf;
—S(═O)2NRaRf, wherein Ra and Rf may together along with the atom(s) to which they are attached form a 3-8 membered heterocyclic ring, which may contain a second heterogroup selected from O, NRe or S;
—NRaRg;
or —C(═O)NRaRf, wherein Ra and Rf may together along with the atom(s) to which they are attached form a 3-8 membered heterocyclic ring, which may contain a second heterogroup selected from O, NRe or S;
Group VI is halogen, hydroxy, oxo, C1-C6alkoxy, aryl, heteroaryl, C3-C8cycloalkyl, heterocycloalkyl, —CN, or —OCF3;
Re is hydrogen, —CN, C1-C10alkyl, C1-C10alkyl substituted with one to three substitutents independently selected from Group V, C2-C10alkenyl, C2-C10alkoxy, C3-C10cycloalkyl, aryl, heteroaryl, —C(═O)Rf, —C(═O)ORf, —C(═O)NRaRf —S(═O)2NRaRf, or —S(═O)2Rf;
Rf is hydrogen, C1-C10alkyl, C1-C10alkyl substituted with from one to three substituents selected from Group VI, C2-C10alkenyl, C2-C10alkoxy, C3-C10cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
and
Rg is hydrogen, C1-C6alkyl, C3-C8cycloalkyl, C2-C6 alkenyl, aryl, —C(═O)Rf, —C(═O)ORf, —C(═O)NRaRf, or —S(═O)2Rf, provided that R1 and R2 are not both hydrogen, further provided that when X is CH2, W is NRa, R3 is hydrogen and R5 is —OH, then R6 and R4 are not both —C(H3)3, further provided that when X is CH2 or CH2CH2, W is O, and R3 and R6 are hydrogen, then R4 is not halogen, —CF3, C1-C6alkyl or C3-C7cycloalkyl, and further provided that when R3 and R4 are hydrogen and W is O then R6 is not halogen, —CF3, C1-C6alkyl or C3-C7cycloalkyl.

34 more elements

Facts

Application

09/767,771Filed 23 Jan 2001 · us provisional application

Priority

25 Jan 2000

Published

US 2002/0006946 A117 Jan 2002

Granted

27 Aug 2002

Term ends

Not estimatedThe source records don’t support an estimate.

Classification17 codes

C07D 257/04
Not condensed with other rings: five-membered rings
A61P 3/04
Drugs for disorders of the metabolism: anorexiants; Antiobesity agents
A61P 3/06
Drugs for disorders of the metabolism: antihyperlipidemics
A61P 3/10
For glucose homeostasis: for hyperglycaemia, e.g. antidiabetics