Thyromimetic organic compounds

• US 6,599,942 B1
• Filed: 10/25/2000
• Issued: 07/29/2003
• Est. Priority Date: 03/29/1999
• Status: Expired due to Fees

• Current Assignee: Novartis Ag
• Original Assignee: Novartis Ag
• Inventors: Kukkola, Paivi Janna
• Primary Examiner(s): Shah, Mukund J.
• Assistant Examiner(s): TRUONG, TAMTHOM NGO
• Application Number:
  US09/696,502
• Time in Patent Office: 1,007 Days
• Field of Search: 514/535, 514/563, 514/617, 560/19, 560/143, 562/433, 564/155
• US Class Current: 514/563
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07C 235/62 having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring
• CPC Class Codes: C07C 2601/14 The ring being saturated
• CPC Class Codes: C07C 311/29 having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
• CPC Class Codes: C07C 317/22 with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
• CPC Class Codes: C07C 323/67 containing sulfur atoms of sulfonamide groups, bound to the carbon skeleton
• CPC Class Codes: C07D 213/64 attached in position 2 or 6
• CPC Class Codes: C07D 213/75 Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
• CPC Class Codes: C07D 295/192 from aromatic carboxylic acids
• CPC Class Codes: C07D 295/26 Sulfur atoms

Abstract

Compounds of the formula

in which W is O, S, S(O) or S(O)₂; X is —SR4, —S(O)R4, or —S(O)₂R4, —S(O)₂NR5R6; or X is —C(O)NR5R6 provided that —C(O)NR5R6 is located at the 3′, 4′ or 5′ position; Y is O or H₂; Z is hydrogen, halogen, hydroxy, optionally substituted alkoxy, aralkoxy, acyloxy or alkoxycarbonyloxy; R is hydrogen, halogen, trifluoromethyl, lower alkyl or cycloalkyl; R1 is hydroxy, optionally substituted alkoxy, aryloxy, heteroaryloxy, aralkyloxy, cycloalkoxy, heteroaralkoxy or —NR5R6; R2 is hydrogen, halogen or alkyl; R3 is halogen or alkyl; R4 is optionally substituted alkyl, aryl, aralkyl, heteroaralkyl or heteroaryl; R5, R6 and R7 are independently hydrogen, optionally substituted alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl; or R5 and R6 combined are alkylene optionally interrupted by O, S, S(O), S(O)₂ or NR7 which together with the nitrogen atom to which they are attached form a 5- to 7-membered ring; n represents zero or an integer from 1 to 4; pharmaceutically acceptable salts thereof; pharmaceutical compositions comprising said compounds; a method to prevent and treat diseases associated with an imbalance of thyroid hormones, such as hypo- and hyperthyroidism, obesity, osteoporosis and depression; and, a method of lowering LDL cholesterol and Lp(a) levels in mammals using such compounds.

Claims

1. A method of lowering Lp(a) levels in mammals which comprises administering to a mammal in need thereof an effective Lp(a) lowering amount of a compound of the formula

in which

W is O, S, S(O) or S(O)₂;

X is —

SR4, —

S(O)R4, —

S(O)₂R4, or —

S(O)₂NR5R6;

or X is —

C(O)NR5R6 located at the 3′

-, 4′

- or 5′

position;

Y is O or H₂;

Z is hydrogen, halogen, hydroxy, optionally substituted alkoxy, aralkoxy, acyloxy or alkoxycarbonyloxy;

R is hydrogen, halogen, trifluoromethyl, lower alkyl or cycloalkyl;

R1 is hydroxy, optionally substituted alkoxy, aryloxy, heteroaryloxy, aralkoxy, cycloalkoxy, heteroaralkoxy or —

NR5R6;

R2 is hydrogen, halogen or alkyl;

R3 is halogen or alkyl;

R4 is optionally substituted alkyl, aryl, aralkyl, heteroaralkyl or heteroaryl;

R5, R6 and R7 are independently hydrogen, optionally substituted alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl;

or R5 and R6 combined are alkylene optionally interrupted by O, S, S(O), S(O)₂ or NR7 which together with the nitrogen atom to which they are attached form a 5- to 7-membered ring;

n represents zero or an integer from 1 to 4;

with the proviso that when X is —

C(O)NR5R6, Z is different from hydrogen;

or a pharmaceutically acceptable salt thereof.

2. A method according to claim 1 in which W is O and Y is O.

3. A method according to claim 1 of lowering Lp(a) levels in mammals which comprises administering to a mammal in need thereof an effective Lp(a) lowering amount of a compound of formula I in which

W is O or S;

X is —

S(O)₂R4;

R4 being lower alkyl, phenyl or phenyl substituted by one or more substituents selected from the group consisting of lower alkyl, lower alkoxy, halogen and trifluoromethyl;

or is —

S(O)₂NR5R6;

or is —

C(O)NR5R6 located at the 3′

, 4′

or 5′

-position;

R5, in each case, being hydrogen or lower alkyl and R6, in each case, being hydrogen, lower alkyl, lower alkyl substituted by NR5R6, 3- to 7-membered cycloalkyl, phenyl, phenyl substituted by one or more substituents selected from the group consisting of lower alkyl, lower alkoxy, halogen and trifluoromethyl, pyridyl or N-lower alkyl-2-pyridone;

or

R5 and R6 combined, in each case, being alkylene or alkylene interrupted by O or S(O)₂ which together with the nitrogen atom to which they are attached form a 5- to 7-membered ring;

Y is O or H₂;

Z is hydrogen or hydroxy;

R is hydrogen;

R1 is hydroxy, lower alkoxy or NR5R6;

R5 being hydrogen or lower alkyl and R6 being hydrogen, or lower alkyl, or R5 and R6 combined being alkylene or alkylene interrupted by O which together with the nitrogen atom to which they are attached form a 5- to 7-membered ring;

R2 is hydrogen, halogen or lower alkyl;

R3 is halogen or lower alkyl; and

n represents zero, 1 or 2;

with the proviso that when X is —

C(O)NR5R6, Z is different from hydrogen;

or a pharmaceutically acceptable salt thereof.

4. A method according to claim 3 in which W is O and Y is O.

5. A method according to claim 1 which comprises administering to a mammal in need thereof of effective Lp(a) lowering amount of a compound of the formula

in which

W is O or S;

X is —

SR4, —

S(O)R4, —

S(O)₂R4, —

S(O)₂NR5R6 or —

C(O)NR5R6;

Y is O or H₂;

Z is hydrogen, halogen, hydroxy, alkoxy, aralkoxy, acyloxy or alkoxycarbonyloxy;

R1 is hydroxy, lower alkoxy or aryloxy;

R2 is hydrogen, halogen or lower alkyl;

R3 is halogen or lower alkyl;

R4 is optionally substituted alkyl, aryl, aralkyl, heteroaryl or heteroaralkyl;

R5, R6 and R7 are independently hydrogen, optionally substituted alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl;

or R5 and R6 combined are alkylene optionally interrupted by O, S, S(O), S(O)₂ or NR7 which together with the nitrogen atom to which they are attached form a 5- to 7-membered ring;

n represents zero, 1 or 2;

with the proviso that when X is —

C(O)NR5R6, Z is different from hydrogen;

or a pharmaceutically acceptable salt thereof.

6. A method according to claim 5 in which W is O and Y is O.

7. A method according to claim 1 which comprises administering to a mammal in need thereof an effective Lp(a) lowering amount of a compound of the formula

wherein

X is —

S(O)₂R4, —

S(O)₂NR5R6 or —

C(O)NR5R6;

Z is hydroxy, lower alkanoyloxy or alkoxy;

R1 is hydroxy or lower alkoxy;

R2 and R3 are lower alkyl;

R4 is aryl;

R5, R6 and R7 are independently hydrogen, optionally substituted alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl;

or R5 and R6 combined are alkylene optionally interrupted by O, S, S(O), S(O)2 or NR7 which together with the nitrogen atom to which they are attached form a 5- to 7-membered ring;

or a pharmaceutically acceptable salt thereof.

8. A method according to claim 7 wherein X is —

S(O)₂R4 or —

S(O)₂NR5R6.

9. A method of lowering Lp(a) levels in mammals which comprises administering to a mammal in need thereof an effective Lp(a) lowering amount of a compound of the formula

wherein

X is —

S(O)₂R4 or —

S(O)₂NR5R6;

R4 is monocyclic aryl;

R5, R6 and R7 are independently hydrogen, optionally substituted alkyl or aryl;

or R5 and R6 combined are CH₂CH₂—

Q—

CH₂CH₂ wherein Q is CH₂, O, NR7, S, S(O) or S(O)₂ which together with the nitrogen atom to which they are attached from a 6-membered ring;

or a pharmaceutically acceptable prodrug ester thereof;

or a pharmaceutically acceptable salt thereof.

10. A method according to claim 9 wherein X is S(O)₂R4 and R4 is phenyl optionally substituted by lower alkyl, halo, lower alkoxy or trifluoromethyl;

or a pharmaceutically acceptable salt thereof;

or a pharmaceutically acceptable prodrug ester thereof.

11. A method according to claim 10 of lowering Lp(a) levels in mammals which comprises administering to a mammal in need thereof an effective Lp(a) lowering amount of

N-{4[3-(4-fluorobenzenesulfonyl)-4-hydroxyphenoxy]-3,5-dimethylphenyl}oxamic acid;

or a pharmaceutically acceptable salt thereof;

or a pharmaceutically acceptable prodrug ester thereof.

12. A method of treating cardiovascular conditions in which Lp(a) is implicated which comprises administering to a mammal in need thereof an effective Lp(a) lowering amount of a compound of the formula

in which

W is O, S, S(O) or S(O)₂;

X is —

SR4, —

S(O)R4, —

S(O)₂R4, or —

S(O)₂NR5R6;

or X is —

C(O)NR5R6 located at the 3′

-, 4′

- or 5′

position;

Y is O or H₂;

Z is hydrogen, halogen, hydroxy, optionally substituted alkoxy, aralkoxy, acyloxy or alkoxycarbonyloxy;

R is hydrogen, halogen, trifluoromethyl, lower alkyl or cycloalkyl;

R1 is hydroxy, optionally substituted alkoxy, aryloxy, heteroaryloxy, aralkoxy, cycloalkoxy, heteroaralkoxy or —

NR5R6;

R2 is hydrogen, halogen or alkyl;

R3 is halogen or alkyl;

R4 is optionally substituted alkyl, aryl, aralkyl, heteroaralkyl or heteroaryl;

R5, R6 and R7 are independently hydrogen, optionally substituted alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl;

or R5 and R6 combined are alkylene optionally interrupted by O, S, S(O), S(O)₂ or NR7 which together with the nitrogen atom to which they are attached form a 5- to 7-membered ring;

n represents zero or an integer from 1 to 4;

with the proviso that when X is —

C(O)NR5R6, Z is different from hydrogen;

or a pharmaceutically acceptable salt thereof.

13. A method according to claim 12 in which W is O and Y is O.

14. A method according to claim 12 in which the compound is a compound of formula I in which

W is O or S;

X is —

S(O)₂R4;

R4 being lower alkyl, phenyl or phenyl substituted by one or more substituents selected from the group consisting of lower alkyl, lower alkoxy, halogen and trifluoromethyl;

or is —

S(O)₂NR5R6;

or is —

C(O)NR5R6 located at the 3′

, 4′

or 5′

-position;

R5, in each case, being hydrogen or lower alkyl and R6, in each case, being hydrogen, lower alkyl, lower alkyl substituted by NR5R6, 3- to 7-membered cycloalkyl, phenyl, phenyl substituted by one or more substituents selected from the group consisting of lower alkyl, lower alkoxy, halogen and trifluoromethyl, pyridyl or N-lower alkyl-2-pyridone;

or

R5 and R6 combined, in each case, being alkylene or alkylene interrupted by O or S(O)₂ which together with the nitrogen atom to which they are attached form a 5- to 7-membered ring;

Y is O or H₂;

Z is hydrogen or hydroxy;

R is hydrogen;

R1 is hydroxy, lower alkoxy or NR5R6;

R5 being hydrogen or lower alkyl and R6 being hydrogen or lower alkyl, or R5 and R6 combined being alkylene or alkylene interrupted by O which together with the nitrogen atom to which they are attached form a 5- to 7-membered ring;

R2 is hydrogen, halogen or lower alkyl;

R3 is halogen or lower alkyl; and

n represents zero, 1 or 2;

with the proviso that when X is —

C(O)NR5R6, Z is different from hydrogen;

or a pharmaceutically acceptable salt thereof.

15. A method according to claim 14 in which W is O and Y is O.

16. A method according to claim 12 in which the compound is a compound of the formula

in which

W is O or S;

X is —

SR4, —

S(O)R4, —

S(O)₂R4, —

S(O)₂NR5R6 or —

C(O)NR5R6;

Y is O or H₂;

Z is hydrogen, halogen, hydroxy, alkoxy, aralkoxy, acyloxy or alkoxycarbonyloxy;

R1 is hydroxy, lower alkoxy or aryloxy;

R2 is hydrogen, halogen or lower alkyl;

R3 is halogen or lower alkyl;

R4 is optionally substituted alkyl, aryl, aralkyl, heteroaryl or heteroaralkyl;

R5, R6 and R7 are independently hydrogen, optionally substituted alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl;

or R5 and R6 combined are alkylene optionally interrupted by O, S, S(O), S(O)₂ or NR7 which together with the nitrogen atom to which they are attached form a 5- to 7-membered ring;

n represents zero, 1 or 2;

with the proviso that when X is —

C(O)NR5R6, Z is different from hydrogen;

or a pharmaceutically acceptable salt thereof.

17. A method according to claim 16 in which W is O and Y is O.

18. A method according to claim 12 in which the compound is a compound of the formula

wherein

X is —

S(O)₂R4, —

S(O)₂NR5R6 or —

C(O)NR5R6;

Z is hydroxy, lower alkanoyloxy or alkoxy;

R1 is hydroxy or lower alkoxy;

R2 and R3 are lower alkyl;

R4 is aryl;

R5, R6 and R7 are independently hydrogen, optionally substituted alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl;

or R5 and R6 combined are alkylene optionally interrupted by O, S, S(O), S(O)₂ or NR7 which together with the nitrogen atom to which they are attached form a 5- to 7-membered ring;

or a pharmaceutically acceptable salt thereof.

19. A method according to claim 18 wherein X is —

S(O)₂R4 or —

S(O)₂NR5R6.

21. A method according to claim 12 wherein X is S(O)₂R4 and R4 is phenyl optionally substituted by lower alkyl, halo, lower alkoxy or trifluoromethyl;

or a pharmaceutically acceptable salt thereof;

or a pharmaceutically acceptable prodrug ester thereof.

20. A method of treating cardiovascular conditions in which Lp(a) is implicated which comprises administering to a mammal in need thereof an effective Lp(a) lowering amount of a compound of the formula

wherein

X is —

S(O)₂R4 or —

S(O)₂NR5R6;

R4 is monocyclic aryl;

R5, R6 and R7 are independently hydrogen, optionally substituted alkyl or aryl;

or R5 and R6 combined are CH₂CH₂—

Q—

CH₂CH₂ wherein Q is CH₂, O, NR7, S, S(O) or S(O)₂ which together with the nitrogen atom to which they are attached from a 6-membered ring;

or a pharmaceutically acceptable prodrug ester thereof;

or a pharmaceutically acceptable salt thereof.

22. A method according to claim 20 in which the compound is

N-{4[3-(4-fluorobenzenesulfonyl)-4-hydroxyphenoxy]-3,5-dimethylphenyl}oxamic acid;

or a pharmaceutically acceptable salt thereof;

or a pharmaceutically acceptable prodrug ester thereof.