Stable analogues of ribose-1-phosphate and methods for treating diabetes and other metabolic disorders

• US 20070099851A1
• Filed: 12/29/2005
• Published: 05/03/2007
• Est. Priority Date: 12/30/2004
• Status: Abandoned Application

• Current Assignee: Gregory Linn
• Original Assignee: Gregory Linn
• Inventors: Linn, Gregory
• Application Number:
  US11/321,570
• Publication Number:
  US 20070099851A1
• Time in Patent Office: Days
• US Class Current: 514/25
• CPC Class Codes: C07H 19/04 Heterocyclic radicals containing only nitrogen atoms as ring hetero atom

Abstract

Novel D-ribose-1-phosphate analogue compounds of formula I, pharmaceutically acceptable prodrugs and salts thereof, and their use as hypoglycemic agents and anticancer agents and regulators of carbohydrate metabolism are useful for the treatment of diabetes in humans and for the treatment of various metabolic disorders that involve the regulation of cellular metabolism, e.g. cancer

Claims

1. A compound having the formula as shown:

where X is selected from the group consisting of —

CH₂, CHF, CF₂, S NH, alkyl, alkenyl, alkynyl, alkyl(carboxyl), alkyl(hydroxy), alkyl(phosphonate), alkyl(sulfonate, aryl, alkylaminoalkyl, alkoxyalkyl, alkylthioalkyl, alkylthio, alicyclic, 1-monohaloalkyl, 1,1 dihaloalkyl, carbonylalkyl, aminocarbonylamino, alkylaminocarbonyl, alkylcarbonylamino, aralkyl and alkylaryl, all optionally substituted;

A is (CH₂)_n-A′

where n is from 1-4 and A′

is hydroxy, halogen, OPO(OH)₂, alkyl, alkoxy, amino, azido or alkenyl;

R1 is independently selected from the group consisting of alkyl, aryl, heteroalicyclic where the cyclic moiety contains a carbonate or thiocarbonate, —

C(R²)₂-aryl, -alk-aryl, —

C(R²)₂OC(O)NR²₂, —

NR²—

C(O)—

R³, —

C(R²)₂—

OC(O)R³, —

C(R²)₂—

O—

C(O)OR³, —

C(R²)₂OC(O)SR³, -alk-S—

C(O)R³, -alk-S—

S-alkylhydroxy, and -alk-S—

S—

S-alkylhydroxy, or together R1 and R1 are -alk-S—

S-alk- to form a cyclic group, wherein each “

alk”

is an independently selected alkylene, or together R1 and R1 are

wherein

V and W are independently selected from the group consisting of hydrogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl, 1-alkynyl, and —

R⁹;

or

together V and Z are connected via a chain of 3-5 atoms, only one of which can be a heteroatom, to form part of a cyclic group substituted with hydroxy, acyloxy, alkoxycarboxy, or aryloxycarboxy attached to a carbon atom that is three atoms from an oxygen attached to the phosphorus;

or

together V and W are connected via a chain of 3 carbon atoms to form part of a cyclic group substituted with hydroxy, acyloxy, alkoxycarboxy, alkylthiocarboxy, hydroxymethyl, or aryloxycarboxy attached to a carbon atom that is three atoms from an oxygen attached to the phosphorus;

Z is selected from the group consisting of —

CH₂ OH, —

CH₂ OCOR³, —

CH₂OC(O)R³, —

CH₂OC(O)SR³, —

CH₂OCO₂R³, —

SR³, —

S(O)R³, —

CH₂ N₃, —

CH₂ NR²₂, —

CH₂AR, —

CH(Ar)OH, —

CH(CH═

CR²R²)OH, —

CH(C═

CR²)OH, and —

R²;

with the provisos that;

a) V, Z, W are not all —

H; and

b) when Z is —

R², then at least one of V and W is not —

H or —

R⁹;

R² is selected from the group consisting of R³ and —

H;

R³ is selected from the group consisting of alkyl aryl, alicyclic, heteroalicyclic, and aralkyl;

R⁴ is independently selected from the group consisting of —

H, lower alkyl, lower alicyclic, lower heteroalicyclic, lower aralkyl, and lower aryl;

R⁵ is selected from the group consisting of lower alkyl, lower aryl, lower aralkyl, lower alicyclic, and lower heteroalicyclic;

R⁶ is independently selected from the group consisting of —

H, and lower alkyl;

R⁷ is independently selected from the group consisting of —

H, lower alkyl, lower alicyclic, lower heteroalicyclic, lower aralkyl, lower aryl, and —

C(O)R¹⁰;

R⁸ is independently selected from the group consisting of —

H, lower alkyl, lower aralkyl, lower aryl, lower alicyclic, —

(O)R¹⁰, or together said R⁸ groups form a bidendate alkylene;

R⁹ is selected from the group consisting of alkyl, aralkyl, alicyclic, and heteroalicyclic;

R¹⁰ is selected from the group consisting of —

H, lower alkyl, —

NH₂, lower aryl, and lower perhaloalkyl;

R¹¹ is selected from the group consisting of alkyl, aryl, —

OH, —

NH₂ and —

OR³; and

pharmaceutically acceptable prodrugs and salts thereof.

4. A method for treating hyperglycemia in an animal, which comprises administering to the animal, the pharmaceutical composition of claim 1.

6. A pharmaceutical composition, which comprises the compounds of claim 1 in association with pharmaceutically acceptable diluent or carrier.

9. A method for treating cancer in an animal, which comprises administering to the animal a pharmaceutical composition of claim 1.

11. A method for killing cancer cells, which comprises administering to the cells the compound of claim 1.

14. A compound as in claim 1 which can be phosphorylated at the C(5) position.

2. A compound having formula I

where X is selected from the group consisting of CHF, CF₂, S, NH, alkyl, alkenyl, alkynyl, alkyl(carboxyl), alkyl(hydroxy), alkyl(phosphonate), alkyl(sulfonate, aryl, alkylaminoalkyl, alkoxyalkyl, alkylthioalkyl, alkylthio, alicyclic, 1-monohaloalkyl, 1,1 dihaloalkyl, carbonylalkyl, aminocarbonylamino, alkylaminocarbonyl, alkylcarbonylamino, aralkyl and alkylaryl, all optionally substituted;

A is (CH₂)_n-A′

where n is from 1-4 and A′

is hydroxy, halogen, OPO(OH)₂, alkyl, alkoxy, amino, azido or alkenyl;

B is OH or F;

R1 is independently selected from the group consisting of H, alkyl, aryl, heteroalicyclic where the cyclic moiety contains a carbonate or thiocarbonate, —

C(R²)₂-aryl, -alk-aryl, —

C(R²)₂ OC(O)NR²₂, —

NR²—

C(O)—

R³, —

C(R²)₂—

OC(O)R³, —

C(R²)₂—

O—

C(O)OR³, —

C(R²)₂ OC(O)SR³, -alk-S—

C(O)R³, -alk-S—

S-alkylhydroxy, and -alk-S—

S—

S-alkylhydroxy, or together R1 and R1 are -alk-S—

S-alk- to form a cyclic group, wherein each “

alk”

is an independently selected alkylene, or together R1 and R1 are

wherein

V and W are independently selected from the group consisting of hydrogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl, 1-alkynyl, and —

R⁹;

or

together V and Z are connected via a chain of 3-5 atoms, only one of which can be a heteroatom, to form part of a cyclic group substituted with hydroxy, acyloxy, alkoxycarboxy, or aryloxycarboxy attached to a carbon atom that is three atoms from an oxygen attached to the phosphorus;

or

together V and W are connected via a chain of 3 carbon atoms to form part of a cyclic group substituted with hydroxy, acyloxy, alkoxycarboxy, alkylthiocarboxy, hydroxymethyl, or aryloxycarboxy attached to a carbon atom that is three atoms from an oxygen attached to the phosphorus;

Z is selected from the group consisting of —

CH₂OH, —

CH₂OCOR³, —

CH₂OC(O)R³, —

CH₂OC(O)SR³, —

CH₂OCO₂R³, —

SR³, —

S(O)R³, —

CH₂N₃, —

CH₂NR²₂, —

CH₂Ar, —

CH(Ar)OH, —

CH(CH═

CR²R²)OH, —

CH(C═

CR²)OH, and —

R²;

with the provisos that;

a) V, Z, W are not all —

H; and

b) when Z is —

R², then at least one of V and W is not —

H or —

R⁹;

R² is selected from the group consisting of R³ and —

H;

R³ is selected from the group consisting of alkyl aryl, alicyclic, heteroalicyclic, and aralkyl;

R⁴ is independently selected from the group consisting of —

H, lower alkyl, lower alicyclic, lower heteroalicyclic, lower aralkyl, and lower aryl;

R⁵ is selected from the group consisting of lower alkyl, lower aryl, lower aralkyl, lower alicyclic, and lower heteroalicyclic;

R⁶ is independently selected from the group consisting of —

H, and lower alkyl;

R⁷ is independently selected from the group consisting of —

H, lower alkyl, lower alicyclic, lower heteroalicyclic, lower aralkyl, lower aryl, and —

C(O)R¹⁰;

R⁸ is independently selected from the group consisting of —

H, lower alkyl, lower aralkyl, lower aryl, lower alicyclic, —

(O)R¹⁰, or together said R⁸ groups form a bidendate alkylene;

R⁹ is selected from the group consisting of alkyl, aralkyl, alicyclic, and heteroalicyclic;

R¹⁰ is selected from the group consisting of —

H, lower alkyl, —

NH₂, lower aryl, and lower perhaloalkyl;

R¹¹ is selected from the group consisting of alkyl, aryl, —

OH, —

NH₂ and —

OR³; and

pharmaceutically acceptable prodrugs and salts thereof.

5. A method for treating hyperglycemia in an animal, which comprises administering to the animal, the pharmaceutical composition of claim 2.

8. A pharmaceutical composition, which comprises the compound of claim 2 in association with a pharmaceutically acceptable diluent or carrier.

10. A method for treating cancer in an animal, which comprises administering to the animal, the pharmaceutical composition of claim 2.

12. A method for killing cancer cells, which comprises administering to the cells, the compound of claim 2.

15. A compound as in claim 2 which can be phosphorylated at the C(5) position.

3. A method of treating hyperglycemia in an animal, which comprises administering to the animal a pharmaceutical composition of a compound having the formula

where X is selected from the group consisting of CH₂ CHF, CF₂, S, NH, alkyl, alkenyl, alkynyl, alkyl(carboxyl), alkyl(hydroxy), alkyl(phosphonate), alkyl(sulfonate, aryl, alkylaminoalkyl, alkoxyalkyl, alkylthioalkyl, alkylthio, alicyclic, 1-monohaloalkyl, 1,1 dihaloalkyl, carbonylalkyl, aminocarbonylamino, alkylaminocarbonyl, alkylcarbonylamino, aralkyl and alkylaryl, all optionally substituted;

A is (CH₂)_n-A′

where n is from 1-4 and A′

is hydroxy, halogen, OPO(OH)₂, alkyl, alkoxy, amino, azido or alkenyl;

B is OH or F;

R1 is independently selected from the group consisting of H, alkyl, aryl, heteroalicyclic where the cyclic moiety contains a carbonate or thiocarbonate, —

C(R²)₂-aryl, -alk-aryl, —

C(R²)₂ OC(O)NR²₂, —

NR²—

C(O)—

R³, —

C(R²)₂—

OC(O)R³, —

C(R²)₂—

0—

C(O)OR³, —

C(R²)₂ OC(O)SR³, -alk-S—

C(O)R³, -alk-S—

S-alkylhydroxy, and -alk-S—

S—

S-alkylhydroxy, or together R1 and R1 are -alk-S—

S-alk- to form a cyclic group, wherein each “

alk”

is an independently selected alkylene, or together R1 and R1 are

wherein

V and W are independently selected from the group consisting of hydrogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl, 1-alkynyl, and —

R⁹;

or

together V and Z are connected via a chain of 3-5 atoms, only one of which can be a heteroatom, to form part of a cyclic group substituted with hydroxy, acyloxy, alkoxycarboxy, or aryloxycarboxy attached to a carbon atom that is three atoms from an oxygen attached to the phosphorus;

or

together V and Z are connected via a chain of 3-5 atoms, only one of which can be a heteroatom, to form part of a cyclic group substituted with hydroxy, acyloxy, alkoxycarboxy, or aryloxycarboxy attached to a carbon atom that is three atoms from an oxygen attached to the phosphorus;

or

together V and W are connected via a chain of 3 carbon atoms to form part of a cyclic group substituted with hydroxy, acyloxy, alkoxycarboxy, alkylthiocarboxy, hydroxymethyl, or aryloxycarboxy attached to a carbon atom that is three atoms from an oxygen attached to the phosphorus;

Z is selected from the group consisting of —

CH₂ OH, —

CH₂ OCOR³, —

CH₂OC(O)R³, —

CH₂OC(O)SR³, —

CH₂OCO₂R³, —

SR³, —

S(O)R³, —

CH₂ N₃, —

CH₂ NR²₂, —

CH₂Ar, —

CH(Ar)OH, —

CH(CH═

CR²R²)OH, —

CH(C═

CR²)OH, and —

R²;

with the provisos that;

a) V, Z, W are not all —

H; and

b) when Z is —

R², then at least one of V and W is not —

H or —

R⁹;

R² is selected from the group consisting of R³ and —

H;

R³ is selected from the group consisting of alkyl aryl, alicyclic, heteroalicyclic, and aralkyl;

R⁴ is independently selected from the group consisting of —

H, lower alkyl, lower alicyclic, lower heteroalicyclic, lower aralkyl, and lower aryl;

R⁵ is selected from the group consisting of lower alkyl, lower aryl, lower aralkyl, lower alicyclic, and lower heteroalicyclic;

R⁶ is independently selected from the group consisting of —

H, and lower alkyl;

R⁷ is independently selected from the group consisting of —

H, lower alkyl, lower alicyclic, lower heteroalicyclic, lower aralkyl, lower aryl, and —

C(O)R¹⁰;

R⁸ is independently selected from the group consisting of —

H, lower alkyl, lower aralkyl, lower aryl, lower alicyclic, —

(O)R¹⁰, or together said R⁸ groups form a bidendate alkylene;

R⁹ is selected from the group consisting of alkyl, aralkyl, alicyclic, and heteroalicyclic;

R¹⁰ is selected from the group consisting of —

H, lower alkyl, —

NH₂, lower aryl, and lower perhaloalkyl;

R¹¹ is selected from the group consisting of alkyl, aryl, —

OH, —

NH₂ and —

OR³; and

pharmaceutically acceptable prodrugs and salts thereof.

7. A pharmaceutical composition, which comprises the compounds of claim 3 in association with pharmaceutically acceptable diluent or carrier.

13. A method for killing cancer cell, which comprises administering to the cells the compound of claim 3.