Use of indole compounds for fat reduction and skin and soft tissue tightening

1. A method for non-surgical reduction or removal of one or more localized fat deposits in a subject having localized fat accumulation comprising administering to a target site in the fat deposit a compound of Formula (I-1), Formula (I-2), or Formula (I-3), wherein Formula (I-1) is represented by:

wherein

R 1 is hydrogen or C 1-6 alkyl;

R 4 , R 5 , R 6 , and R 7 are independently selected from hydrogen, C 1-6 alkyl, C 1-6 alkoxy, halogen, and —OCH 2 C 6 H 5 ;

R 2 and R 3 , together with the atoms they attach to, form

wherein R 8 , R 10 , and R 11 are independently selected from hydrogen, halogen, —(CH 2 ) x —C(O)—OC 1-6 alkyl, —(CH 2 ) x OH, —(CH 2 ) x —CN, —OCH 2 C 6 H 5 , —OCOCH 3 , —(CH 2 ) x —CONH 2 , —CHO, —(CH 2 ) x —COOH, —(CH 2 ) y —CO—COOH, —(CH 2 ) y —C(H)(OH)—COOH, phenyl, and substituted phenyl; wherein the substituted phenyl is substituted with 1-4 substituents selected from hydroxyl, C 1-6 alkoxy, and C 1-6 alkyl;

R 9 is hydrogen or C 1-6 alkyl;

x is a number from zero to six; and

y is zero;

or a pharmaceutically acceptable salt thereof;

Formula (I-2) is represented by:

wherein

R 1 is hydrogen or C 1-6 alkyl;

R 2 and R 3 are independently hydrogen or C 1-6 alkyl;

R 4 , R 5 , R 6 , and R 7 are independently selected from hydrogen, C 1-6 alkyl, C 1-6 alkoxy, —OCH 2 C 6 H 5 , halogen, —CHO, and —(CH 2 ) x —COOH; and

x is a number from zero to six;

or a pharmaceutically acceptable salt thereof;

provided that at least one of R 4 , R 5 , R 6 , and R 7 is —CHO or —(CH 2 ) x —COOH; and

Formula (I-3) is represented by:

wherein

R 1 is hydrogen or C 1-6 alkyl;

R 2 is hydrogen or C 1-6 alkyl;

R 3 is —(CH 2 ) x —COOH;

R 4 , R 5 , R 6 , and R 7 are independently selected from hydrogen, C 1-6 alkyl, C 1-6 alkoxy, halogen, —(CH 2 ) x —OH, and —OCH 2 C 6 H 5 ; and

x is a number from zero to six;

or a pharmaceutically acceptable salt thereof.

2. A method for reducing a subcutaneous fat deposit in a subject having subcutaneous fat deposit comprising administering to a target site in the subcutaneous fat deposit a compound of formula (I-1), formula (I-2), of formula (I-3), wherein formula (I-1) is represented by:

wherein

R 1 is hydrogen or C 1-6 alkyl;

R 4 , R 5 , R 6 , and R 7 are independently selected from hydrogen, C 1-6 alkyl, C 1-6 alkoxy, halogen, and —OCH 2 C 6 H 5 ;

R 2 and R 3 , together with the atoms they attach to, form

wherein R 8 , R 10 , and R 11 are independently selected from hydrogen, halogen, —(CH 2 ) x —C(O)—OC 1-6 alkyl, —(CH 2 ) x —OH, —(CH 2 ) x —CN, —OCH 2 C 6 H 5 , —OCOCH 3 , —(CH 2 ) x —CONH 2 , —CHO, —(CH 2 ) x —COOH, —(CH 2 ) y —CO—COOH, —(CH 2 ) y —C(H)(OH)—COOH, phenyl, and substituted phenyl; wherein the substituted phenyl is substituted with 1-4 substituents selected from hydroxyl, C 1-6 alkoxy, and C 1-6 alkyl;

R 9 is hydrogen or C 1-6 alkyl;

x is a number from zero to six; and

y is zero;

or a pharmaceutically acceptable salt thereof;

formula (I-2) is represented by:

wherein

R 1 is hydrogen or C 1-6 alkyl;

R 2 and R 3 are independently hydrogen or C 1-6 alkyl;

R 4 , R 5 , R 6 , and R 7 are independently selected from hydrogen, C 1-6 alkyl, C 1-6 alkoxy, —OCH 2 C 6 H 5 , halogen, —CHO, and —(CH 2 ) x —COOH; and

x is a number from zero to six;

or a pharmaceutically acceptable salt thereof;

provided that at least one of R 4 , R 5 , R 6 , and R 7 is —CHO or —(CH 2 ) x —COOH; and

formula (I-3) is represented by:

wherein

R 1 is hydrogen or C 1-6 alkyl;

R 2 is hydrogen or C 1-6 alkyl;

R 3 is —(CH 2 ) x —COOH;

R 4 , R 5 , R 6 , and R 7 are independently selected from hydrogen, C 1-6 alkyl, C 1-6 alkoxy, halogen, —(CH 2 ) x —OH, and —OCH 2 C 6 H 5 ; and

x is a number from zero to six;

or a pharmaceutically acceptable salt thereof.

3. A method selected from:

(i) a method for treating an adipose tissue disorder or an adipose tissue tumor in a subject comprising locally administering to the subject a compound of Formula (I-1), Formula (I-2), or Formula (I-3), wherein Formula (I-1) is represented by:

wherein

R 1 is hydrogen or C 1-6 alkyl;

R 4 , R 5 , R 6 , and R 7 are independently selected from hydrogen, C 1-6 alkyl, C 1-6 alkoxy, halogen, and —OCH 2 C 6 H 5 ;

R 2 and R 3 , together with the atoms they attach to, form

wherein R 8 , R 10 , and R 11 are independently selected from hydrogen, halogen, —(CH 2 ) x —C(O)—OC 1-6 alkyl, —(CH 2 ) x —OH, —(CH 2 ) x —CN, —OCH 2 C 6 H 5 , —OCOCH 3 , —(CH 2 ) x —CONH 2 , —CHO, —(CH 2 ) x —COOH, —(CH 2 ) y —CO—COOH, —(CH 2 ) y —C(H)(OH)—COOH, phenyl, and substituted phenyl; wherein the substituted phenyl is substituted with 1-4 substituents selected from hydroxyl, C 1-6 alkoxy, and C 1-6 alkyl;

R 9 is hydrogen or C 1-6 alkyl;

x is a number from zero to six; and

y is zero;

or a pharmaceutically acceptable salt thereof;

Formula (I-2) is represented by:

wherein

R 1 is hydrogen or C 1-6 alkyl;

R 2 and R 3 are independently hydrogen or C 1-6 alkyl;

R 4 , R 5 , R 6 , and R 7 are independently selected from hydrogen, C 1-6 alkyl, C 1-6 alkoxy, —OCH 2 C 6 H 5 , halogen, —CHO, and —(CH 2 ) x —COOH; and

x is a number from zero to six;

or a pharmaceutically acceptable salt thereof;

provided that at least one of R 4 , R 5 , R 6 , and R 7 is —CHO or —(CH 2 ) x —COOH; and

Formula (I-3) is represented by:

wherein

R 1 is hydrogen or C 1-6 alkyl;

R 2 is hydrogen or C 1-6 alkyl;

R 3 is —(CH 2 ) x —COOH;

R 4 , R 5 , R 6 , and R 7 are independently selected from hydrogen, C 1-6 alkyl, C 1-6 alkoxy, halogen, —(CH 2 ) x —OH, and —OCH 2 C 6 H 5 ; and

x is a number from zero to six;

or a pharmaceutically acceptable salt thereof; and

(ii) a method for decreasing a submental fat deposit under a skin area in a subject comprising administering to a target site in the fat deposit a compound of Formula (I-1), Formula (I-2), or Formula (I-3), wherein Formula (I-1) is represented by:

wherein

R 1 is hydrogen or C 1-6 alkyl;

R 4 , R 5 , R 6 , and R 7 are independently selected from hydrogen, C 1-6 alkyl, C 1-6 alkoxy, halogen, and —OCH 2 C 6 H 5 ;

R 2 and R 3 , together with the atoms they attach to, form

wherein R 8 , R 10 , and R 11 are independently selected from hydrogen, halogen, —(CH 2 ) x —C(O)—OC 1-6 alkyl, —(CH 2 ) x —OH, —(CH 2 ) x —CN, —OCH 2 C 6 H 5 , —OCOCH 3 , —(CH 2 ) x —CONH 2 , —CHO, —(CH 2 ) x —COOH, —(CH 2 ) y —CO—COOH, —(CH 2 ) y —C(H)(OH)—COOH, phenyl, and substituted phenyl; wherein the substituted phenyl is substituted with 1-4 substituents selected from hydroxyl, C 1-6 alkoxy, and C 1-6 alkyl;

R 9 is hydrogen or C 1-6 alkyl;

x is a number from zero to six; and

y is zero;

or a pharmaceutically acceptable salt thereof;

Formula (I-2) is represented by:

wherein

R 1 is hydrogen or C 1-6 alkyl;

R 2 and R 3 are independently hydrogen or C 1-6 alkyl;

R 4 , R 5 , R 6 , and R 7 are independently selected from hydrogen, C 1-6 alkyl, C 1-6 alkoxy, —OCH 2 C 6 H 5 , halogen, —CHO, and —(CH 2 ) x —COOH; and

x is a number from zero to six;

or a pharmaceutically acceptable salt thereof;

provided that at least one of R 4 , R 5 , R 6 , and R 7 is —CHO or —(CH 2 ) x —COOH; and

Formula (I-3) is represented by:

wherein

R 1 is hydrogen or C 1-6 alkyl;

R 2 is hydrogen or C 1-6 alkyl;

R 3 is —(CH 2 ) x —COOH;

R 4 , R 5 , R 6 , and R 7 are independently selected from hydrogen, C 1-6 alkyl, C 1-6 alkoxy, halogen, —(CH 2 ) x —OH, and —OCH 2 C 6 H 5 ; and

x is a number from zero to six;

or a pharmaceutically acceptable salt thereof.

4. The method of claim 3 , wherein the method is for decreasing a submental fat deposit under a skin area in a subject comprising administering to a target site in the fat deposit a compound of Formula (I-1), Formula (I-2), or Formula (I-3), wherein Formula (I-1) is represented by:

wherein

R 1 is hydrogen or C 1-6 alkyl;

R 4 , R 5 , R 6 , and R 7 are independently selected from hydrogen, C 1-6 alkyl, C 1-6 alkoxy, halogen, and —OCH 2 C 6 H 5 ;

R 2 and R 3 , together with the atoms they attach to, form

wherein R 8 , R 10 , and R 11 are independently selected from hydrogen, halogen, —(CH 2 ) x —C(O)—OC 1-6 alkyl, —(CH 2 ) x —OH, —(CH 2 ) x —CN, —OCH 2 C 6 H 5 , —OCOCH 3 , —(CH 2 ) x —CONH 2 , —CHO, —(CH 2 ) x —COOH, —(CH 2 ) y —CO—COOH, —(CH 2 ) y —C(H)(OH)—COOH, phenyl, and substituted phenyl; wherein the substituted phenyl is substituted with 1-4 substituents selected from hydroxyl, C 1-6 alkoxy, and C 1-6 alkyl;

R 9 is hydrogen or C 1-6 alkyl;

x is a number from zero to six; and

y is zero;

or a pharmaceutically acceptable salt thereof;

Formula (I-2) is represented by:

wherein

R 1 is hydrogen or C 1-6 alkyl;

R 2 and R 3 are independently hydrogen or C 1-6 alkyl;

R 4 , R 5 , R 6 , and R 7 are independently selected from hydrogen, C 1-6 alkyl, C 1-6 alkoxy, —OCH 2 C 6 H 5 , halogen, —CHO, and —(CH 2 ) x —COOH; and

x is a number from zero to six;

or a pharmaceutically acceptable salt thereof;

provided that at least one of R 4 , R 5 , R 6 , and R 7 is —CHO or —(CH 2 ) x —COOH; and

Formula (I-3) is represented by:

wherein

R 1 is hydrogen or C 1-6 alkyl;

R 2 is hydrogen or C 1-6 alkyl;

R 3 is —(CH 2 ) x —COOH;

R 4 , R 5 , R 6 , and R 7 are independently selected from hydrogen, C 1-6 alkyl, C 1-6 alkoxy, halogen, —(CH 2 ) x —OH, and —OCH 2 C 6 H 5 ; and

x is a number from zero to six;

or a pharmaceutically acceptable salt thereof.

5. The method of claim 1 , wherein the compound is of Formula (II):

wherein

R 1 is hydrogen or C 1-6 alkyl;

R 2 and R 3 are independently hydrogen or C 1-6 alkyl;

R 4 is —CHO or —(CH 2 ) x —COOH;

R 5 , R 6 , and R 7 are independently selected from hydrogen, C 1-6 alkyl, C 1-6 alkoxy, halogen, and —OCH 2 C 6 H 5 ; and

x is a number from zero to six;

or a pharmaceutically acceptable salt thereof.

6. The method of claim 1 , wherein the compound is of Formula (IV):

wherein

R 1 is hydrogen or C 1-6 alkyl;

R 2 and R 3 are independently hydrogen or C 1-6 alkyl;

R 4 , R 6 , and R 7 are independently selected from hydrogen, C 1-6 alkyl, C 1-6 alkoxy, halogen, and —OCH 2 C 6 H 5 ,

R 5 is —CHO or —(CH 2 ) x —COOH; and

x is a number from zero to six;

or a pharmaceutically acceptable salt thereof.

7. The method of claim 1 , wherein the compound is of Formula (V):

wherein

R 1 is hydrogen or C 1-6 alkyl;

R 2 is hydrogen or C 1-6 alkyl;

R 3 is —(CH 2 ) x —COOH;

R 4 , R 5 , R 6 , and R 7 are independently selected from hydrogen, C 1-6 alkyl, C 1-6 alkoxy, —OCH 2 C 6 H 5 , and halogen; and

x is a number from zero to six;

or a pharmaceutically acceptable salt thereof.

8. The method of claim 1 , wherein the compound is of Formula (VI):

wherein

R 1 is hydrogen or C 1-6 alkyl;

R 4 , R 5 , R 6 , and R 7 are independently selected from hydrogen, C 1-6 alkyl, C 1-6 alkoxy, halogen, and —OCH 2 C 6 H 5 ;

R 8 , R 10 , and R 11 are independently selected from hydrogen, halogen, —(CH 2 ) x —C(O)—OC 1-6 alkyl, —OCH 2 C 6 H 5 , —OCOCH 3 , —(CH 2 ) x —CONH 2 , —CHO, —(CH 2 ) x —COOH, phenyl, and substituted phenyl; wherein the substituted phenyl is substituted with 1-4 substituents selected from hydroxyl, C 1-6 alkoxy, and C 1-6 alkyl;

R 9 is hydrogen or C 1-6 alkyl; and

x is zero;

or a pharmaceutically acceptable salt thereof.

9. The method of claim 1 , wherein the compound is a compound in Table 1A below, or a pharmaceutically acceptable salt thereof:

TABLE 1A

Com-

pound

Structure

Chemical Name

10

4-(1H-indol-3- yl)butanoic acid

30

1H-indole-2- carboxylic acid.

10. The method of claim 1 , wherein the compound is a compound in Table 1B below, or a pharmaceutically acceptable salt thereof:

TABLE 1B

3

1H-indole-5-carbaldehyde

4

1H-indole-7-carbaldehyde

5

1H-indole-4-carbaldehyde

6

1H-indole-6-carbaldehyde

27

1H-indole-4-carboxylic acid

28

1H-indole-5-carboxylic acid.

11. The method of claim 1 , wherein the compound is a compound in Table 1C below, or a pharmaceutically acceptable salt thereof:

TABLE 1C

78

(1R,3R)-1-(2,4- dihydroxyphenyl)- 2,3,4,9-tetrahydro- 1H-pyrido[3,4-b] indole-3-carboxylic acid.

12. The method of claim 1 , wherein the administering step is by injection, transdermal pump, transdermal patch, or a subdermal depot.

13. The method of claim 1 , wherein the administering step is by subcutaneous injection or intradermal injection.

14. The method of claim 1 , wherein the subject is a mammal.

15. The method of claim 1 , wherein the subject is a human.

16. The method of claim 1 , further comprising administering to the subject a second therapeutic agent.

17. The method of claim 1 , wherein the compound is of Formula (IV-1):

wherein

R 1 is hydrogen or C 1-6 alkyl;

R 2 and R 3 are independently hydrogen or C 1-6 alkyl; and

R 4 , R 5 , R 6 , and R 7 are independently selected from hydrogen, C 1-6 alkyl, C 1-6 alkoxy, halogen, —OCH 2 C 6 H 5 , and —CHO;

or a pharmaceutically acceptable salt thereof;

provided that at least one of R 4 , R 5 , R 6 , and R 7 is —CHO.

18. The method of claim 1 , wherein the compound is of Formula (IV-2):

wherein

R 1 is hydrogen or C 1-6 alkyl;

R 2 and R 3 are independently hydrogen or C 1-6 alkyl;

R 4 , R 5 , R 6 , and R 7 are independently selected from hydrogen, C 1-6 alkyl, C 1-6 alkoxy, halogen, —OCH 2 C 6 H 5 , and —(CH 2 ) x —COOH; and

x is a number from zero to six;

or a pharmaceutically acceptable salt thereof;

provided that at least one of R 4 , R 5 , R 6 , and R 7 is —(CH 2 ) x —COOH.

19. The method of claim 1 , wherein the compound is a compound in Table 1D below, or a pharmaceutically acceptable salt thereof:

TABLE 1D

3

1H-indole-5-carbaldehyde

4

1H-indole-7-carbaldehyde

5

1H-indole-4-carbaldehyde

6

1H-indole-6-carbaldehyde.

20. The method of claim 1 , wherein the compound is a compound in Table 1E below, or a pharmaceutically acceptable salt thereof:

TABLE 1E

27

1H-indole-4-carboxylic acid

28

1H-indole-5-carboxylic acid.