Triglyceride and triglyceride-like prodrugs of glycogen phosphorylase inhibiting compounds

• US 7,098,235 B2
• Filed: 11/13/2003
• Issued: 08/29/2006
• Est. Priority Date: 11/14/2002
• Status: Active Grant

• Current Assignee: Bristol-Myers Squibb Company
• Original Assignee: Bristol-Myers Squibb Company
• Inventors: Ellsworth, Bruce A., Sher, Philip M.
• Primary Examiner(s): Wilson, James O.
• Assistant Examiner(s): Ward, Paul V.
• Application Number:
  US10/712,823
• Publication Number:
  US 20040142938A1
• Time in Patent Office: 1,020 Days
• Field of Search: 548/452, 548/469, 548/470, 514/416, 514/415
• US Class Current: 514/416
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/496 Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: C07K 5/06139 with the first amino acid being heterocyclic
• CPC Class Codes: C07K 5/06191 containing heteroatoms different from O, S, or N
• CPC Class Codes: C07K 5/0821 with the first amino acid being heterocyclic, e.g. His, Pro, Trp
• CPC Class Codes: C07K 5/0827 containing heteroatoms different from O, S, or N

Abstract

Prodrugs of glycogen phosphorylase inhibiting compounds are provided which are useful in treating diabetes, having the formula I
G(—O₂CR′)_m(—OH)_n(—O₂C(CH₂)_pCH₃)_qI
wherein G is a C₃ to C₅ branched or straight carbon chain and (—O₂CR′), (—OH) and (—O₂C(CH₂)_pCH₃) are attached to any available carbon atom along G;

• • —O₂CR′ is a fragment of a compound of formula Ib

where W is a bicyclic heteroaryl; m, n, p, q, X, Y, Z, R₁ and R₂ are as defined herein, as exemplified by

Further provided are pharmaceutical compositions and methods for treating diabetes and related diseases employing the above compounds above, either alone or in combination with another therapeutic agent.

Claims

1. A compound of the formula I

G(—

O₂CR′

)_m(—

OH)_n(—

O₂C(CH₂)_pCH₃)_q 

 

I

wherein

G is a C₃ to C₅ branched or straight carbon chain and (—

O₂CR′

), (—

OH) and (—

O₂C(CH₂)_pCH₃) are attached to any available carbon atom along G;

m is an integer from 1 to 4;

n is an integer from 0 to 3;

p is integer from 0 to 16;

q is an integer from 0 to 3;

where the sum of m, n and q is 3 or 4; and

—

O₂CR′

is a fragment of a compound of formula

2. The compounds as defined in claim 1 wherein Z is an aryl or heteroaryl group of the structure

3. The compound as defined in claim 1 wherein said hydrogen bonding group is selected from the group consisting of OR^9A, OCO₂R¹⁰, OCONR^9AR^9B, CN, NO₂, CN₄R^9A (tetrazole), COCF₃, COR^9A, CO₂R^9A, CONR^9AR^9B, CONR^9AOR^9B, C(NR^9A)NR^9BR^9C, CONR^9ASO₂R^9B, SOR¹⁰, SO₂R¹⁰, SO₃H, SO₂NR^9AR^9B, SO₂NR^9ACOR^9B, SO₂NR^9ACONR^9BR^9C, POR^9AR^9B, PO₂R^9AR^9B, PO₂R^9ANR^9BR^9C, NR^9AR^9B, NR^9ACOR^9B, NR^9AC(NR^9B)R^9C, NR^9ACO₂R^9B, NR^9ACONR^9BR^9C, NR^9AC(NR^9B)NR^9CR^9D, NR^9ASO₂R^9B, NR^9ACONR^9BSO₂R^9C, NR^9ASO₂NR^9BR^9C, NR^9APOR^9BR^9C, NR^9APO₂R^9BR^9C, NR^9APO₃R^9BR^9C and NR^9APO₂R^9BNR^9CR^9D;

wherein

R^9C and R^9D are each independently hydrogen, alkyl, arylalkyl, heteroarylalkyl or aryl; and

R¹⁰ is independently alkyl, arylalkyl, heteroarylalkyl, or aryl;

wherein R^9A, R^9B, R^9C, R^9D or R¹⁰ may further be substituted with one to three additional hydrogen bonding groups; and

wherein two of R^9A, R^9B, R^9C or R^9D within the same hydrogen bonding group may optionally be cyclized together to form a ring, wherein said ring may further be substituted with one to three additional hydrogen bonding groups.

4. The compound as defined in claim 1 where (—

O₂CR′

) represents a fragment of compounds of formula Ib wherein R⁵ or R⁶ is CO₂—

, or wherein one or more of R¹, R², R⁵, R⁶, R⁷ and R⁸ is alkyl, aryl, alkenyl, arylalkyl, heteroarylalkyl, alkoxy or aryloxy, and one of R¹, R², R⁵, R⁶, R⁷ and R⁸ is substituted with or contains a fragment of structure CO₂—

.

5. The compound as defined in claim 1 wherein R¹ is hydrogen;

Z is

6. The compound as defined in claim 1 wherein R¹ is hydrogen;

Z is

7. The compound as defined in claim 1 wherein W is 5-chloroindol-2-yl.

8. The compound as defined in claim 1 where (—

O₂CR′

) represents a fragment of compounds of formula Ib wherein

X is —

CHR⁵—

or —

CH₂CHR⁵—

;

Y is —

CHR⁶—

; and

R⁵ or R⁶ is CO₂—

.

9. The compound as defined in claim 1 wherein W is

10. The compound as defined in claim 1 having the structure

11. A pharmaceutical composition comprising a compound as defined in claim 1 and a pharmaceutically acceptable carrier.