Thyromimetic organic compounds

• US 6,689,896 B2
• Filed: 08/16/2001
• Issued: 02/10/2004
• 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): Rotman, Alan L.
• Assistant Examiner(s): TRUONG, TAMTHOM NGO
• Application Number:
  US09/931,683
• Publication Number:
  US 20020107390A1
• Time in Patent Office: 908 Days
• Field of Search: 514/535, 514/563, 514/617, 560/19, 560/143, 562/433, 564/155
• US Class Current: 560/19
• 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 for the preparation of a compound of the formula

in which R4 is aryl;

R2 is hydrogen, halogen or lower alkyl;

R3 is halogen or lower alkyl; and

n represents zero, 1 or 2;

or a pharmaceutically acceptable salt thereof;

which method comprises;

(a) reacting a compound of the formula

in which R4 has meaning as defined for formula A1 with a compound of the formula

in which R2 and R3 have meaning as defined for formula A1 to obtain a compound of the formula

(b) converting the nitro compound of formula D to a corresponding amine of the formula

in which R2, R3 and R4 have meaning as defined for formula A1;

(c) condensing the amine of formula E with an acylating agent corresponding to a carboxylic acid of the formula

2. The method according to claim 1, wherein the compound of formula B in step (a) is prepared by reacting 1,4-benzoquinone with a sulfinic acid of the formula

3. The method according to claim 2, wherein the sulfinic acid of formula G is prepared by reducing a compound of the formula

4. The method according to claim 1 for the preparation of a compound of the formula

in which R4 is monocyclic aryl;

or a pharmaceutically acceptable salt thereof.

5. The method according to claim 4 for the preparation of a compound of the formula of claim 4, wherein R4 is phenyl optionally substituted by lower alkyl, halogen, lower alkoxy or trifluoromethyl.

6. The method according to claim 1 for the preparation of a compound of formula A1, wherein the compound of formula A1 is selected from the group consisting of:

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

N-[4-(3-Benzenesulfonyl)-4-hydroxyphenoxyl]-3,5-dimethylphenyl]oxamic acid;

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

N-{4-[4-Hydroxy-3-toulene-4-sulfonyl)phenoxy]-3,5-dimethylphenyl}oxamic acid;

N-{4-[4-Hydroxy-3-(4-methoxybenzesulfonyl)phenoxy]-3,5-dimethylphenyl}oxamic acid;

N-{4-[4-Hydroxy-3-(4-trifluoromethoxybenzesulfonyl)phenoxy]-3,5-dimethylphenyl}oxamic acid;

N-{4-[3-(4-Fluorobenzenesulfonyl)-4-hydroxyphenoxyl]-3,5-dimethylphenyl}malonamic acid;

N-{4-[3-(4-Fluorobenzenesulfonyl)-4-hydroxyphenoxyl]-3,5-dimethylphenyl}succinamic acid;

N-{4-[3-(4-Fluorobenzenesulfonyl)-4-hydroxyphenoxyl]-3-methylphenyl}oxamic acid; and

a

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

or a pharmaceutically acceptable salt thereof.

7. The method according to claim 1 for the preparation of a compound of formula A1, wherein the compound of formula A1 is N-{4-[3-(4-Fluorobenzenesulfonyl)-4-hydroxyphenoxy]-3,5-dimethylphenyl}oxamic acid.

8. A method for the preparation of a compound of the formula

in which R4 is aryl;

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

R2 is hydrogen, halogen or lower alkyl;

R3 is halogen or lower alkyl; and

n represents zero, 1 or 2;

which method comprises;

(a) reacting a compound of the formula

in which R4 has meaning as defined for formula A2 with a compound of the formula

in which R2 and R3 have meaning as defined for formula A2 to obtain a compound of the formula

(b) converting the nitro compound of formula D to a corresponding amine of the formula

in which and R4 have meaning as defined for formula A2; and

(c) condensing the amine of formula E with an acylating agent corresponding to a carboxylic acid of the formula

9. The method according to claim 8 for the preparation of a compound of formula A2, wherein R1 is lower alkoxy;

R2 and R3 are methyl;

R4 is aryl; and

n is zero.

10. The method according to claim 8 for the preparation of a compound of formula A2, wherein the compound of formula A2 is N-{4-[3-(4-Fluorobenzenesulfonyl)-4-hydroxyphenoxyl-3,5-dimethylphenyl}oxamic acid ethyl ester.

11. A method for the preparation of a compound of the formula

in which R4 is aryl;

R2 is hydrogen, halogen or lower alkyl; and

R3 is halogen or lower alkyl;

which method comprises reacting a compound of the formula

in which R4 has meaning as defined for formula D with a compound of the formula

in which R2 and R3 have meaning as defined above to obtain the compound of formula D.

12. A method for the preparation of a compound of the formula

in which R4 is aryl;

R2 is hydrogen, halogen or lower alkyl; and

R3 is halogen or lower alkyl;

which method comprises;

reacting a compound of the formula

in which R4 has meaning as defined for formula E, with a compound of the formula

in which R2 and R3 have meaning as defined for formula E to obtain a compound of the formula

(b) converting the nitro compound of formula D to the amine of formula E in which R2, R3 and R4 have meaning as defined above.