Hypoglycemic and hypolipidemic compounds

• US 6,121,282 A
• Filed: 12/18/1998
• Issued: 09/19/2000
• Est. Priority Date: 07/01/1996
• Status: Expired due to Fees

• Current Assignee: Eli Lilly and Company
• Original Assignee: Eli Lilly and Company
• Inventors: Gritton, William Harlan, Dominianni, Samuel James
• Primary Examiner(s): NORTHINGTON DAVIS, ZINNA
• Application Number:
  US09/216,470
• Time in Patent Office: 641 Days
• Field of Search: 546/147, 374/307
• US Class Current: 514/307
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/06 Antihyperlipidemics
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: C07D 413/12 linked by a chain containing hetero atoms as chain links

Abstract

This invention provides 1,2,3,4-tetrahydroisoquinoline compounds and their pharmaceuticallyacceptable salts, pharmaceutical formulations of said compounds, and methods for treating hyperglycemia associated with non-insulin dependent diabetes and for treating hyperlipidemia.

Claims

1. A 1,2,3,4-tetrahydroisoquinoline compound of Formula I:

##STR49## wherein;

R⁰ is selected from the group consisting of ##STR50## and R² is hydrogen, C_1-4 acyl, C_1-4 alkyloxycarbonyl, C_1-4 alkylaminocarbonyl, arylcarbonyl, aryloxycarbonyl, aryloxy C_1-4 alkylcarbonyl, arylaminocarbonyl, aryl C_1-4 acyl, aryl C_1-4 alkyloxycarbonyl, aryl C_1-4 alkylaminocarbonyl, aryl C_1-4 alkylsulfonyl, or an amino-protecting group;

R⁴ is hydrogen, or C_1-4 alkyl;

R⁵ is --COOH, --CONR¹⁰ R¹¹, --CN, --CONHOH, or ##STR51## R⁶ is hydrogen, C_1-4 alkyl, aryl, or aryl C_1-4 alkyl;

R⁷ is hydrogen, halogen, or C_1-4 alkyl;

R⁹ is hydrogen, C_1-4 alkyl, or aryl;

R¹⁰ and R¹¹ are independently hydrogen, C_1-4 alkyl, or aryl;

W is --(CH₂)n--;

Y is attached at position 6 or at position 7 of the 1,2,3,4-tetrahydroisoquinoline moiety, and is --O--, --S--, --SO--, --SO₂ --, --NH--, --CONR⁹ --, --NR⁹ --SO₂ --, or --SO₂ --NR⁹ --; and

n is 1 to 4;

or a pharmaceutically-acceptable salt thereof.

2. The compound of claim 1, wherein:

R⁰ is ##STR52## or ##STR53## R² is hydrogen, C_1-4 alkyloxycarbonyl, arylcarbonyl, aryloxycarbonyl, arylaminocarbonyl, aryl C_1-4 alkyloxycarbonyl, aryloxy C_1-4 alkylcarbonyl, aryl C_1-4 alkylsulfonyl, or an amino-protecting group;

R⁴ is hydrogen or methyl;

R⁵ is --COOH, --CONR⁹ R¹⁰, or ##STR54## R⁶ is aryl;

R⁷ is hydrogen, halogen, or methyl;

R⁹ and R¹⁰ are hydrogen; and

Y is --O-- or --S--,

or a pharmaceutically-acceptable salt thereof.

3. The compound of claim 2, wherein:

##STR55## R⁰ is R² is arylcarbonyl, aryloxycarbonyl, aryl C_1-4 alkyloxycarbonyl, aryl C_1-4 alkylsulfonyl, or an amino-protecting group;

R⁵ is --COOH;

Y is --O--; and

n is 1 or 2;

or a pharmaceutically-acceptable salt thereof.

4. The compound of claim 3, wherein:

##STR56## R⁰ is R² is hydrogen, benzyloxycarbonyl, phenylcarbonyl, benzylcarbonyl, methylbenzylcarbonyl, phenyloxycarbonyl, para-chlorophenylcarbonyl, benzylsulfonyl, para-bromophenyloxycarbonyl, para-trifluoromethylphenyloxycarbonyl, para-methoxyphenyloxycarbonyl, para-n-butylphenyloxycarbonyl, phenyloxymethylcarbonyl, benzylaminocarbonyl, or ethoxycarbonyl;

R⁶ is phenyl;

R⁷ is hydrogen;

Y is attached at the 7 position; and

n is 2;

or a pharmaceutically-acceptable salt thereof.

6. The compound of claim 1, wherein Y is attached at the 7 position of the 1,2,3,4-tetrahydroisoquinoline moiety.

7. The compound of claim 1, wherein Y is attached at the 6 position of the 1,2,3,4-tetrahydroisoquinoline moiety.

8. The compound of claim 1, which is the R enantiomer.

9. The compound of claim 1, which is the S enantiomer.

10. The compound of claim 1, which is the racemate.

11. A pharmaceutical formulation comprising as a active ingredient a compound of formula (I), as claimed in claim 1, together with one or more pharmaceutically-acceptable excipients.

13. A method of treating hyperglycemia comprising administering to a mammal an effective dose of the compound of claim 1.

15. A method of treating hyperlipidemia comprising administering to a mammal an effective dose of the compound of claim 1.

5. The compound of the formula:

##STR57## or a pharmaceutically-acceptable salt thereof.

12. A pharmaceutical formulation comprising the compound of claim 5, or a pharmaceutically-acceptable salt thereof, together with one or more pharmaceutically-acceptable excipients.

14. A method of treating hyperglycemia comprising administering to a mammal an effective dose of the compound of claim 5.

16. A method of treating hyperlipidemia comprising administering to a mammal an effective dose of the compound of claim 5.

17. A process for preparing a 1,2,3,4-tetrahydroisoquinoline compound of Formula I:

##STR58## wherein;

R⁰ is selected from the group consisting of ##STR59## and R² is hydrogen, C_1-4 acyl, C_1-4 alkyloxycarbonyl, C_1-4 alkylaminocarbonyl, arylcarbonyl, aryloxycarbonyl, aryloxy C_1-4 alkylcarbonyl, arylaminocarbonyl, aryl C_1-4 acyl, aryl C_1-4 alkyloxycarbonyl, aryl C_1-4 alkylaminocarbonyl, aryl C_1-4 alkylsulfonyl, or an amino-protecting group;

R⁴ is hydrogen, or C_1-4 alkyl;

R⁵ is --COOH, --CONR¹⁰ R¹¹, --CN, --CONHOH, or ##STR60## R⁶ is hydrogen, C_1-4 alkyl, aryl, or aryl C_1-4 alkyl;

R⁷ is hydrogen, halogen, or C_1-4 alkyl;

R⁹ is hydrogen, C_1-4 alkyl, or aryl;

R¹⁰ and R¹¹ are independently hydrogen, C_1-4 alkyl, or aryl;

W is --(CH₂)n--;

Y is attached at position 6 or at position 7 of the 1,2,3,4-tetrahydroisoquinoline moiety, and is --O--, --S--, --SO--, --SO₂ --, --NH--, --CONR⁹ --, --NR⁹ --SO₂ --, or --SO₂ --NR⁹ --; and

n is 1 to 4;

or a pharmaceutically-acceptable salt thereof, comprising;

A. A. reacting a compound of the formula ##STR61## wherein Z3 is --OH, --SO₂ Cl, a halogen leaving group, --NHR⁹, or --COCl, with a compound of the formula ##STR62## wherein Z4 is --OH, --SH, --NH₂, or --SO₂ Cl, to form a compound of formula (I);

or

B. deprotecting a compound of the formula ##STR63## wherein R is a carboxy protecting group, to form a compound of formula (I) wherein R⁵ is a free carboxy group.