Glucagon antagonists/inverse agonists

• US 6,613,942 B1
• Filed: 12/23/1998
• Issued: 09/02/2003
• Est. Priority Date: 07/01/1997
• Status: Expired due to Fees

• Current Assignee: Novo Nordisk A/S, Agouron Pharmaceuticals Incorporated (Pfizer Inc.)
• Original Assignee: Novo Nordisk A/S
• Inventors: Feng, Jun, Kiel, Dan, Gonzalez, Javier, Plewe, Michael Bruno, Gregor, Vlad, Kuki, Atsuo, Teston, Kimberly Ann, Madsen, Peter, Lau, Jesper, Hong, Yufeng, Shi, Shenghua, Johnson, Michael David, Teng, Min, Knudsen, Lotte Bjerre, Sams, Christian, Naerum, Lars, Sidelmann, Ulla Grove, Ling, Anthony
• Primary Examiner(s): Padmanabhan, Sreeni
• Assistant Examiner(s): Witherspoon, Sikarl A.
• Application Number:
  US09/220,003
• Time in Patent Office: 1,714 Days
• Field of Search: 564/161, 564/251, 514/482, 514/488, 514/647, 514/651
• US Class Current: 564/161
• CPC Class Codes: A61P 1/18 for pancreatic disorders, e.g. pancreatic enzymes
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/06 Antihyperlipidemics
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: C07C 251/86 having doubly-bound carbon atoms of hydrazone groups bound to carbon atoms of six-membered aromatic rings
• CPC Class Codes: C07C 255/29 containing cyano groups and acylated amino groups bound to the carbon skeleton
• CPC Class Codes: C07C 2601/02 with a three-membered ring
• CPC Class Codes: C07C 2601/08 the ring being saturated
• CPC Class Codes: C07C 2601/14 The ring being saturated
• CPC Class Codes: C07C 271/12 to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
• CPC Class Codes: C07C 271/22 to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
• CPC Class Codes: C07C 271/24 with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a ring other than a six-membered aromatic ring
• CPC Class Codes: C07C 271/28 to a carbon atom of a non-condensed six-membered aromatic ring
• CPC Class Codes: C07C 309/65 of a saturated carbon skeleton
• CPC Class Codes: C07C 311/16 having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
• CPC Class Codes: C07C 311/20 having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring
• CPC Class Codes: C07C 311/49 to nitrogen atoms
• CPC Class Codes: C07C 317/28 with sulfone or sulfoxide groups bound to acyclic carbon atoms of the carbon skeleton
• CPC Class Codes: C07C 323/45 : having at least one of the nitrogen atoms doubly-bound to the carbon skeleton
• CPC Class Codes: C07C 323/60 : with the carbon atom of at least one of the carboxyl groups bound to nitrogen atoms
• CPC Class Codes: C07D 209/08 : with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
• CPC Class Codes: C07D 209/48 : with oxygen atoms in positions 1 and 3, e.g. phthalimide
• CPC Class Codes: C07D 209/86 : with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the ring system
• CPC Class Codes: C07D 213/30 : Oxygen atoms
• CPC Class Codes: C07D 213/80 : in position 3
• CPC Class Codes: C07D 215/12 : with substituted hydrocarbon radicals attached to ring carbon atoms
• CPC Class Codes: C07D 215/26 : Alcohols; Ethers thereof
• CPC Class Codes: C07D 231/12 : with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 295/135 : with the ring nitrogen atoms and the substituent nitrogen atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
• CPC Class Codes: C07D 295/185 : from aliphatic carboxylic acids
• CPC Class Codes: C07D 295/192 : from aromatic carboxylic acids
• CPC Class Codes: C07D 295/26 : Sulfur atoms
• CPC Class Codes: C07D 307/12 : Radicals substituted by oxygen atoms
• CPC Class Codes: C07D 307/52 : Radicals substituted by nitrogen atoms not forming part of a nitro radical
• CPC Class Codes: C07D 307/84 : Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
• CPC Class Codes: C07D 309/06 : Radicals substituted by oxygen atoms
• CPC Class Codes: C07D 317/58 : Radicals substituted by nitrogen atoms nitro radicals C07D317/52
• CPC Class Codes: C07D 333/24 : Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 401/06 : linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 405/06 : linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 409/06 : linked by a carbon chain containing only aliphatic carbon atoms

Abstract

Non-peptide compounds comprising a central hydrazide motif and methods for the synthesis thereof are disclosed. The compounds act to antagonize the action of the glucagon peptide hormone.

Claims

1. A compound of formula I:

wherein;

R¹ and R² together form a valence bond;

R³ is hydrogen or lower alkyl and R⁴ is hydrogen;

n is 0, 1, 2 or 3;

m is 0 or 1;

X is >

C═

O,

A is

wherein;

R⁸ is halogen, —

CN, —

F₃, —

OCF₃, —

OCH₂CF₃, —

NO₂, —

OCOR¹³, —

OSO₂R¹³, -Olower alkyl, —

Oaryl, —

NR¹¹R¹², lower alkyl, aryl, —

SCF₃, —

SR¹¹, —

CHF₂, —

OCHF₂, —

OSO₂R¹¹, —

CONR¹¹R¹², —

CH₂OR¹¹, —

CH₂NR¹¹R¹², —

OCOR¹¹, —

CO₂R¹³ or —

OSO₂CF₃, and R⁹ is hydrogen, halogen, —

CN, —

CF₃, —

OCF₃, —

OCH₂CF₃, —

NO₂, —

OR¹¹, —

NR¹¹R¹², lower alkyl, aryl, —

SCF₃, —

SR¹¹, —

CHF₂, —

OCHF₂, —

OSO₂R¹¹, —

CONR¹¹R¹², —

CH₂OR¹¹, —

CH₂NR¹¹R¹², —

OCOR¹¹, —

CO₂R¹³ or —

OSO₂CF₃, or R⁸ and R⁹ together form a bridge —

OCH₂O—

or —

OCH₂CH₂O—

;

wherein R¹¹ and R¹² independently are hydrogen, —

COR¹³, —

SO₂R¹³, lower alkyl or aryl;

wherein R¹³ is hydrogen, lower alkyl, aryl-lower alkyl or aryl; and

R¹⁰ is hydrogen, lower alkyl, aryl-lower alkyl or aryl;

B is

wherein;

R¹⁴ and R¹⁵ independently are hydrogen, halogen, —

CN, —

CF₃, —

OCF₃, —

O(CH₂)_lCF₃, —

NO₂, —

OR¹⁶, —

NR¹⁶R¹⁷, lower alkyl, aryl, aryl-lower alkyl, —

SCF₃, —

SR¹⁶, —

CHF₂, —

OCHF₂, —

OCF₂CHF₂, —

OSO₂CF₃, —

CONR¹⁶R¹⁷, —

(CH₂)_lCONR¹⁶R¹⁷, —

O(CH₂)_lCONR¹⁶R¹⁷, —

(CH₂)_lCOR¹⁶, —

(CH₂)_lCOR¹⁶, —

(CH₂)_lOR¹⁶, —

O(CH₂)_lOR¹⁶, —

(CH₂)_lNR¹⁶R¹⁷, —

O(CH₂)_lNR¹⁶R¹⁷, —

OCOR¹⁶, —

CO₂R¹⁸, —

O(CH₂)_lCO₂R¹⁸, —

O(CH₂)_lCN, —

O(CH₂)_lCl, or R¹⁴ and R¹⁵ together form a bridge —

O(CH₂)_lO—

or —

(CH₂)_l—

;

wherein l is 1, 2, 3 or 4;

R¹⁶ and R¹⁷ independently are hydrogen, —

COR¹⁸, —

SO₂R¹⁸, lower alkyl, aryl, or R¹⁶ and R¹⁷ together form a cyclic alkyl bridge containing from 2 to 7 carbon atoms;

wherein R¹⁸ is hydrogen, lower alkyl, aryl or aryl-lower alkyl;

W is CR¹⁹═

;

Y is —

CR²⁰═

;

Z is —

CR²¹═

; and

V is —

CR²²═

;

wherein;

R¹⁹, R²⁰, R²¹ and R²² independently are hydrogen, halogen, —

CN, —

CF₃, —

OCF₃, —

OCH₂CF₃, —

NO₂, —

OR²⁴, —

NR²⁴R²⁵, lower alkyl, aryl, aryl-lower alkyl, —

SCF₃, —

SR²⁴, —

CHF₂, 13 OCHF₂, —

OCF₂CHF₂, —

OSO₂CF₃, —

CONR²⁴R²⁵, —

CH₂CONR²⁴R²⁵, —

OCH₂CONR²⁴R²⁵, —

CH₂OR²⁴, —

CH₂NR²⁴R²⁵, —

OCOR²⁴ or —

COR²R²⁴, or R¹⁹ and R²⁰, R²⁰ and R²¹, or R²¹ and R²² together form a bridge —

OCH₂O—

;

wherein R²⁴ and R²⁵ independently are hydrogen, —

COR²⁶, —

SO₂R²⁶, lower alkyl, aryl or aryl-lower alkyl; and

wherein R²⁶ is hydrogen, lower alkyl, aryl or aryl-lower alkyl;

K is

wherein;

R^3a, R^3b, R^4a and R^4b independently are hydrogen, halogen, —

CN, —

CF₃, —

OCF₃, —

OCH₂CF₃, —

NO₂, —

OR²⁴ⁿ, —

NR²⁴ⁿR^25a, lower alkyl, aryl, aryl-lower alkyl, —

SCF₃, —

SR²⁴ⁿ, —

CHF₂, —

OCH₂, —

OCF₂CHF₂, —

OSO₂CF₃, —

CONR²⁴ⁿR^25a, —

CH₂CONR^24aR²⁵ⁿ, —

OCH₂CONR^24aR²⁵ⁿ, —

CH₂OR²⁴ⁿ, —

CH₂NR^24aR²⁵ⁿ, —

OCOR²⁴ⁿ or —

CO₂R²⁴ⁿ;

wherein R²⁴ⁿ and R^25a independently are hydrogen, —

COR²⁶ⁿ, —

SO₂R^26a, lower alkyl, aryl or aryl-lower alkyl;

wherein R^26a is hydrogen, lower alkyl, aryl or aryl-lower alkyl;

or

R³ⁿ and R^3b, R⁴ⁿ and R^4b, or R³ⁿ and R^4b together form a bridge —

(CH₂)_i—

;

wherein i is 1, 2, 3 or 4;

a, b, c and d independently are 0, 1, 2, 3 or 4;

e, f and p independently are 0 or 1;

q is 0, 1 or 2; and

L and M independently are —

O—

, —

S—

, —

CH═

CH—

, —

C≡

C—

, —

NR^5a—

, —

CH₂NR^5a—

, —

CO—

, —

OCO—

, —

COO—

, —

CONR^5a—

, —

CONR^5b—

, —

NR⁵ⁿCO—

, —

SO—

, —

SO₂—

, —

OSO₂—

, —

SO₂NR^5a—

, —

NR⁵ⁿSO₂—

, —

NR^5aCON^5b—

, —

CONR^5aNR^5b—

, —

NR^5aCSNR^5b—

, —

OCONR^5b—

, —

CH₂CONR^5b—

, —

OCH₂CONR^5b, —

P(O)(OR^5a)O—

, —

NR^5aC(O)O—

or

wherein R^5a and R^5b independently are hydrogen, lower alkyl, —

OH, —

(CH₂)_kOR⁶ⁿ, —

COR⁶ⁿ, —

(CH₂)_k—

CH(OR⁶ⁿ)_z, —

(CH₂)_k—

CN, —

(CH₂)_k—

NR^6aR^6b, aryl, aryl-lower alkyl, —

(CH₂)_E—

COOR⁴³ or —

(CH₂)_E—

CF₃;

wherein k is 1, 2, 3 or 4;

R^6a and R^6b independently are hydrogen, lower alkyl, aryl or aryl-lower alkyl;

g is 0, 1, 2, 3 or 4;

R⁴³ is hydrogen or lower alkyl;

G″

is —

OCH₂CO—

, —

CH₂CO—

, —

CO—

or a valence bond; and

E″

is —

CH₂—

, —

CH₂CH₂—

, —

CH═

CH—

, —

CH₂NH—

or —

CH₂CH₂NH—

;

D is hydrogen,

wherein;

r is 0 or 1;

s is 0, 1, 2 or 3;

E, E′

, F, G and G′

independently are —

CHR³⁸—

, >

C═

O, >

NR³⁹, —

O—

or —

S—

;

F′

is >

CR³⁸—

or >

N—

;

Y′

is —

N═

or —

CR³²═

;

Z′

is —

N═

or CR³³═

;

V′

is —

N═

or —

CR³⁴═

;

W′

is —

N═

or —

CR³⁵═

; and

Q′

is —

NR³⁶—

, —

O—

or —

S—

;

wherein;

R²⁷, R²⁸, R³², R³³, R³⁴ and R³⁵ independently are hydrogen, halogen, —

CN, —

CF₃, —

O(CH₂)_yCF₃, —

(CH₂)_yNHCOCF₃, —

NO₂, lower alkyl, aryl aryl-lower alkyl, —

SCF₃, —

SR²⁹, —

CHF₂, —

OCHF₂, —

OCF₂CHF₂, —

OSO₂R²⁹, —

OSO₂CF₃, —

(CH₂)_yCONR²⁹R³⁰, —

O(CH₂)_yCONR²⁹R³⁰, —

(CH₂)_yOR²⁹, —

(CH₂)_yNR²⁹R³⁰, —

OCOR²⁹, —

COR²⁹ or —

CO₂R²⁹;

or

R²⁷ and R²⁸, R³² and R³³, R³³ and R³⁴, or R³⁴ and R³⁵ together form a bridge —

O(CH₂)_yO—

;

wherein y is 0, 1, 2, 3 or 4; and

R²⁹ and R³⁰ independently are hydrogen, —

COR³¹, —

CO₂R³¹, —

SO₂R³¹, lower alkyl, aryl or aryl-lower alkyl;

wherein R³¹ is hydrogen, lower alkyl, aryl or aryl-lower alkyl;

R³⁶ and R³⁹ independently are hydrogen, lower alkyl, aryl or aryl-lower alkyl; and

R³⁸ is hydrogen, —

OR⁴⁰, —

NR⁴⁰R⁴¹, lower alkyl, aryl, aryl-lower alkyl, —

SCF₃, —

SR⁴⁰, —

CHF₂, —

OCHF₂, —

OCF₂CHF₂, —

CONR⁴⁰R⁴¹, —

(CH₂)_xCONR⁴⁰R⁴¹, —

O(CH₂)_xCONR⁴⁰R⁴¹, —

(CH₂)_xOR⁴⁰, —

(CH₂)_xNR⁴⁰R⁴¹, —

OCOR⁴⁰ or —

CO₂R⁴⁰;

wherein x is 1, 2, 3 or 4;

R⁴⁰ and R⁴¹ independently are hydrogen, —

COR⁴², —

SO₂R⁴², lower alkyl, aryl or aryl-lower alkyl;

wherein R⁴² is hydrogen, lower alkyl, aryl or aryl-lower alkyl;

as well as any optical or geometric isomer or tautomeric form thereof including mixtures of these or a pharmaceutically acceptable salt thereof.

2. A compound according to claim 1, wherein R³ is hydrogen.

3. A compound according to claim 1, wherein R⁸ is halogen, —

NO₂, —

NH₂, —

CN, —

OCF₃, —

SCF₃, —

CF₃, —

OCH₂CF₃, —

O-lower alkyl, lower alkyl or phenyl and R⁹ is hydrogen, halogen, —

OH, —

NO₂, —

NH₂, —

CN, —

OCF₃, —

SCF₃, —

CF₃, —

OCH₂CF₃, —

O-lower alkyl, lower alkyl or phenyl.

4. A compound according to claim 3, wherein R⁸ is halogen, —

O-lower alkyl, —

NH₂, —

CN or —

NO₂ and R⁹ is hydrogen, halogen, —

O-lower alkyl, —

NH₂, —

CN or —

NO₂.

5. A compound according to claim 1, wherein R⁸ is halogen, —

O-lower alkyl, —

NH₂, —

CN or —

NO₂; and

R⁹ is hydrogen or halogen.

6. A compound according to claim 1, wherein B is

wherein R¹⁴ and R¹⁵ independently are hydrogen, halogen, — CF₃, —

OCF₃, —

OR¹⁶, —

NR¹⁶R¹⁷, lower alkyl, aryl, aryl-lower alkyl, —

OSO₂CF₃, —

CONR¹⁶R¹⁷, —

CH₂OR¹⁶, —

CH₂NR¹⁶R¹⁷, —

OCOR¹⁶ or —

CO₂R¹⁸;

or R¹⁴ and R¹⁵ together form a bridge —

OCH₂O—

or —

(CH₂)₁—

.

7. A compound according to claim 6 wherein B is

wherein R¹⁴ and R¹⁵ are as defined in claim 6.

8. A compound according to claim 6, wherein R¹⁴ and R¹⁵ independently are hydrogen, halogen, lower alkyl, —

O-lower alkyl or aryl.

9. A compound according to claim 1, wherein K is selected from the group consisting of

10. A compound according to claim 9, wherein K is selected from the group consisting of

11. A compound according to claim 10, wherein K is selected from the group consisting of

12. A compound according to claim 9, wherein R^5a and R^5b independently are hydrogen, lower alkyl, —

OH, —

(CH₂)_kOR^6a, aryl, aryl-lower alkyl, —

CH₂CF₃, —

(CH₂)_g—

COOR⁴³, —

COOR⁴³, —

(CH₂)_k—

CN or —

(CH₂)_k—

NR^6aR^6b.

13. A compound according to claim 12, wherein g and k independently are 1, 2 or 3, R^6a and R^6b independently are hydrogen, lower alkyl or aryl.

14. A compound according to claim 9, wherein R^3a and R^3b independently are hydrogen, halogen, —

OH, —

O-lower alkyl, —

COO-lower alkyl, lower alkyl or aryl-lower alkyl.

15. A compound according to claim 9, wherein R^4a and R^4b independently are hydrogen, —

CN, —

CONH₂, —

(CH₂)—

N(CH₃)₂, —

O-lower alkyl, —

CH₂OH, —

CH₂O-aryl, —

N(CH₃)₂, —

OH, —

CO₂-lower alkyl or lower alkyl.

16. A compound according to claim 1, wherein D is hydrogen,

17. A compound according to claim 16, wherein D is hydrogen,

18. A compound according to claim 16, wherein D is hydrogen,

wherein E and E′

independently are >

CHR³⁸, >

NR³⁹ and/or —

O—

;

F, G and G′

independently are >

CHR³⁸, >

C═

O or >

NR³⁹;

F′

is >

CR³⁸—

or >

N.

19. A compound according to claim 16, wherein R²⁷ and R²⁸ independently are hydrogen;

halogen —

CF₃;

—

OCF₃;

—

OCHF₂;

—

OCH₂CF₃;

—

(CH₂)_yNHCOCF₃;

—

NHCOCF₃;

—

CN;

—

NO₂;

—

COR²⁹;

—

COOR²⁹, —

(CH₂)_yOR²⁹ or —

OR²⁹ wherein R²⁹ is hydrogen, aryl or lower alkyl and y is 1, 2, 3 or 4;

lower alkyl lower alkylthio;

—

SCF₃;

aryl —

(CH₂)_yNR²⁹R³⁰ or —

NR²⁹R³⁰ wherein R²⁹ and R³⁰ independently are hydrogen, —

COO-lower alkyl or lower alkyl and y is 1, 2, 3 or 4;

or —

CONH₂;

or R²⁷ and R²⁸ together form a bridge —

OCH₂O—

;

R³⁸ is hydrogen;

—

OCHF₂;

—

OR⁴⁰ wherein R⁴⁰ is hydrogen or lower alkyl;

lower alkyl lower alkylthio;

—

SCF₃;

—

CH₂OH;

—

COO-lower alkyl or —

CONH₂; and

R³⁹ is hydrogen, lower alkyl, aryl or aryl-lower alkyl.

20. A pharmaceutical composition comprising, as an active ingredient a compound according to claim 1 together with one or more pharmaceutically acceptable carriers or excipients.

21. A pharmaceutical composition according to claim 20 in unit dosage form, comprising from about 0.05 mg to about 1000 mg, of the compound.

22. A method of treating type I or type II diabetes, comprising administering to a subject in need thereof an effective amount of a compound according to claim 1.

23. A method of treating hyperglycemia, comprising administering to a subject in need thereof an effective amount of a compound according to claim 1.

24. A method of lowering blood glucose in a mammal, comprising administering to said mammal an effective amount of a compound according to claim 1.

25. The method according to claim 22 comprising administering to a subject in need thereof an amount of the compound as defined in claim 1 to 33 in the range of from about 0.05 mg to about 1000 mg, one or more times per day.

26. A compound according to claim 1 characterized by having a glucagon antagonistic activity as determined by the Glucagon Binding Assay I or Glucagon By Binding Assay II corresponding to an IC₅₀ value of less than 1 μ

M.

27. A compound of formula (XVI):

wherein

R⁸ is chloro, fluoro, nitro or cyano; and

D is C_1-6-alkyl, C_3-8-cycloalkyl,

 

wherein R²⁷ and R²⁸ independently are hydrogen, halogen, cyano, nitro, acetoxy, C_1-6-alkoxy, benzyloxy, trifluoromethyl, methylsulfonyl or C_1-6-alkyl;

Q′

is —

O—

or —

S—

; and

R⁴³ is hydrogen, C_1-6-alkyl, C_1-6-alkylene-NH₂, C_1-6-alkylene-NH(C_1-3-alkyl) or C_1-6-alkylene-N(C_1-3-alkyl)₂;

as well as any optical or geometric isomer or tautomeric form thereof including mixtures of these or a pharmaceutically acceptable salt thereof.

28. A compound according to claim 27 wherein D is

29. A compound according to claim 27 wherein R⁸ is chloro.

30. A compound according to claim 27 wherein R⁸ is cyano.

31. A pharmaceutical composition comprising, as an active ingredient, a compound according to claim 27 together with one or more pharmaceutically acceptable carriers or excipients.

32. A pharmaceutical composition according to claim 31 in unit dosage form, comprising from about 0.05 mg to about 1000 mg of the compound according to claim 29.

33. A method of treating type I or type II diabetes, comprising administering to a subject in need thereof an effective amount of a compound according to claim 29.

34. A method of treating hyperglycemia, comprising administering to a subject in need thereof an effective amount of a compound according to claim 29.

35. A method of lowering blood glucose in a mammal, comprising administering to said mammal an effective amount of a compound according to claim 29.

36. The method according to claim 33 comprising administering to a subject in need thereof an amount of the compound as defined in claim 27 in the range of from about 0.05 mg to about 1000 mg, one or more times per day.

45. A method of treating type I or type II diabetes, comprising administering to a subject in need thereof an effective amount of a composition according to claim 31.

46. A method of treating hyperglycemia, comprising administering to a subject in need thereof an effective amount of a composition according to claim 31.

47. A method of lowering blood glucose in a mammal, comprising administering to said mammal an effective amount of a composition according to claim 31.

37. A compound selected from the group consisting of:

N-(4-[(3-chloro-4-hydroxybenzoyl)hydrazonomethyl]-3-methoxyphenyl)-2-(2-trifluoromethylphenyl)acetamide as well as any optical or geometric isomer or tautomeric form thereof including mixtures of these or a pharmaceutically acceptable salt thereof;

3-phenylpropynoic acid {4-[(3-chloro-4-hydroxybenzoyl)hydrazonomethyl]-3-methoxyphenyl}amide as well as any optical or geometric isomer or tautomeric form thereof including mixtures of these or a pharmaceutically acceptable salt thereof;

N-{4-[(3-chloro-4-hydroxybenzoyl)hydrazonomethyl]-3-methoxyphenyl}-2-(4-chlorophenyl)-acetamide as well as any optical or geometric isomer or tautomeric form thereof including mixtures of these or a pharmaceutically acceptable salt thereof;

N-{4-[(3-chloro-4-hydroxybenzoyl)hydrazonomethyl]-3-methoxyphenyl}-2-(3-chlorophenyl)acetamide as well as any optical or geometric isomer or tautomeric form thereof including mixtures of these or a pharmaceutically acceptable salt thereof;

N-{4-[(3-chloro-4-hydroxybenzoyl)hydrazonomethyl]-3-methoxyphenyl}-2-(4-trifluoromethylphenylsulfanyl)acetamide as well as any optical or geometric isomer or tautomeric form thereof including mixtures of these or a pharmaceutically acceptable salt thereof;

5-methoxybenzofuran-2-carboxylic acid {4-[(3-chloro-4-hydroxybenzoyl)hydrazonomethyl]-3-methoxyphenyl)amide as well as any optical or geometric isomer or tautomeric form thereof including mixtures of these or a pharmaceutically acceptable salt thereof;

2-benzo[b]thiophen-3-yl-N-{4-[(3-chloro-4-hydroxybenzoyl)hydrazonomethyl]-3-methoxyphenyl}acetamide as well as any optical or geometric isomer or tautomeric form thereof including mixtures of these or a pharmaceutically acceptable salt thereof;

N-(4-[(3-chloro-4-hydroxybenzoyl)hydrazonomethyl]-3-methoxyphenyl}-2-(3,4-difluorophenyl)acetamide as well as any optical or geometric isomer or tautomeric form thereof including mixtures of these or a pharmaceutically acceptable salt thereof;

N-{4-[(3-chloro-4-hydroxybenzoyl)hydrazonomethyl]-3-methoxyphenyl}-2-(4-chlorophenylsulfanyl)acetamide as well as any optical or geometric isomer or tautomeric form thereof including mixtures of these or a pharmaceutically acceptable salt thereof;

N-{4-[(3-chloro-4-hydroxybenzoyl)hydrazonomethyl]-3-methoxyphenyl}-3-(4-chlorophenyl)propionamide as well as any optical or geometric isomer or tautomeric form thereof including mixtures of these or a pharmaceutically acceptable salt thereof; and

N-{4-[(3-chloro-4-hydroxybenzoyl)hydrazonomethyl]-3-methoxyphenyl}-3-(4-cyanophenoxy)acetamide as well as any optical or geometric isomer or tautomeric form thereof including mixtures of these or a pharmaceutically acceptable salt thereof.

39. A pharmaceutical composition comprising, as an active ingredient a compound according to claim 37 together with one or more pharmaceutically acceptable carriers or excipients.

40. A pharmaceutical composition according to claim 39 in unit dosage form, comprising from about 0.05 mg to about 1000 mg of the compound according to claim 37.

41. A method of treating type I or type II diabetes, comprising administering to a subject in need thereof an effective amount of a compound according to claim 37.

42. A method of treating hyperglycemia, comprising administering to a subject in need thereof an effective amount of a compound according to claim 37.

43. A method of lowering blood glucose in a mammal, comprising administering to said mammal an effective amount of a compound according to claim 37.

44. The method according to claim 41 comprising administering to a subject in need thereof an amount of the compound as defined in claim 37 in the range of from about 0.05 mg to about 1000 mg.

48. A method of treating type I or type II diabetes, comprising administering to a subject in need thereof an effective amount of a composition according to claim 39.

49. A method of treating hyperglycemia, comprising administering to a subject in need thereof an effective amount of a composition according to claim 39.

50. A method of lowering blood glucose in a mammal, comprising administering to said mammal an effective amount of a composition according to claim 39.

38. A compound selected from the group consisting of:

N-{4-[(3-cyano-4-hydroxybenzoyl)hydrazonomethyl]-3-methoxyphenyl}-2-(2-trifluoromethylphenyl)acetamide as well as any optical or geometric isomer or tautomeric form thereof including mixtures of these or a pharmaceutically acceptable salt thereof;

3-phenylpropynoic acid {4-[(3-cyano-4-hydroxybenzoyl)hydrazonomethyl]-3-methoxyphenyl}amide as well as any optical or geometric isomer or tautomeric form thereof including mixtures of these or a pharmaceutically acceptable salt thereof;

N-{4-[(3-cyano-4-hydroxybenzoyl)hydrazonomethyl]-3-methoxyphenyl}-2-(4-chlorophenyl)acetamide as well as any optical or geometric isomer or tautomeric form thereof including mixtures of these or a pharmaceutically acceptable salt thereof;

N-{4-[(3-cyano-4-hydroxybenzoyl)hydrazonomethyl]-3-methoxyphenyl}-2-(3-chlorophenyl)acetamide as well as any optical or geometric isomer or tautomeric form thereof including mixtures of these or a pharmaceutically acceptable salt thereof;

N-{4-[(3-cyano-4-hydroxybenzoyl)hydrazonomethyl]-3-methoxyphenyl}-2-(4-trifluoromethylphenylsulfanyl)acetamide as well as any optical or geometric isomer or tautomeric form thereof including mixtures of these or a pharmaceutically acceptable salt thereof;

5-methoxybenzofuran-2-carboxylic acid {4-[(3-cyano-4-hydroxybenzoyl)hydrazonomethyl]-3-methoxyphenyl)amide as well as any optical or geometric isomer or tautomeric form thereof including mixtures of these or a pharmaceutically acceptable salt thereof;

2-benzo[b]thiophen-3-yl-N-{4-[(3-cyano-4-hydroxybenzoyl)hydrazonomethyl]-3-methoxyphenyl}acetamide as well as any optical or geometric isomer or tautomeric form thereof including mixtures of these or a pharmaceutically acceptable salt thereof;

N-{4-[(3-cyano-4-hydroxybenzoyl)hydrazonomethyl]-3-methoxyphenyl)-2-(3,4-difluorophenyl)acetamide as well as any optical or geometric isomer or tautomeric form thereof including mixtures of these or a pharmaceutically acceptable salt thereof;

N-{4-[(3-cyano-4-hydroxybenzoyl)hydrazonomethyl]-3-methoxyphenyl}-2-(3-trifluoromethylphenyl)acetamide as well as any optical or geometric isomer or tautomeric form thereof including mixtures of these or a pharmaceutically acceptable salt thereof;

N-{4-[(3-cyano-4-hydroxybenzoyl)hydrazonomethyl]-3-methoxyphenyl}-3-(4-trifluoromethylphenyl)propionamide as well as any optical or geometric isomer or tautomeric form thereof including mixtures of these or a pharmaceutically acceptable salt thereof;

N-{4-[(3-cyano-4-hydroxybenzoyl)hydrazonomethyl]-3-methoxyphenyl}-2-(4-chlorophenylsulfanyl)acetamide as well as any optical or geometric isomer or tautomeric form thereof including mixtures of these or a pharmaceutically acceptable salt thereof;

N-(4-[(3-cyano-4-hydroxybenzoyl)hydrazonomethyl]-3-methoxyphenyl}-3-(4-chlorophenyl)propionamide as well as any optical or geometric isomer or tautomeric form thereof including mixtures of these or a pharmaceutically acceptable salt thereof; and

N-{4-[(3-cyano-4-hydroxybenzoyl)hydrazonomethyl]-3-methoxyphenyl}-3-(4-cyanophenoxy)acetamide as well as any optical or geometric isomer or tautomeric form thereof including mixtures of these or a pharmaceutically acceptable salt thereof.