WO1999001423A1 - Glucagon antagonists/inverse agonists - Google Patents

Glucagon antagonists/inverse agonists Download PDF

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Publication number
WO1999001423A1
WO1999001423A1 PCT/DK1998/000287 DK9800287W WO9901423A1 WO 1999001423 A1 WO1999001423 A1 WO 1999001423A1 DK 9800287 W DK9800287 W DK 9800287W WO 9901423 A1 WO9901423 A1 WO 9901423A1
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WO
WIPO (PCT)
Prior art keywords
lower alkyl
γçö
aryl
hydrogen
compound according
Prior art date
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PCT/DK1998/000287
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English (en)
French (fr)
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WO1999001423A8 (en
Inventor
Anthony Ling
Vlad Gregor
Javier Gonzales
Yufeng Hong
Dan Kiel
Atsuo Kuki
Shenghua Shi
Lars Naerum
Peter Madsen
Christian Sams
Jesper Lau
Michael Bruno Plewe
Jun Feng
Min Teng
Michael David Johnson
Kimberly Ann Teston
Ulla Grove Sidelmann
Lotte Bjerre Knudsen
Original Assignee
Novo Nordisk A/S
Agouron Pharmaceuticals, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Publication date
Application filed by Novo Nordisk A/S, Agouron Pharmaceuticals, Inc. filed Critical Novo Nordisk A/S
Priority to BR9810378-4A priority Critical patent/BR9810378A/pt
Priority to AU79083/98A priority patent/AU749271B2/en
Priority to CA002294046A priority patent/CA2294046A1/en
Priority to JP50616099A priority patent/JP2003514508A/ja
Priority to HU0002373A priority patent/HUP0002373A3/hu
Priority to EP98929244A priority patent/EP0994848A1/en
Priority to IL13337798A priority patent/IL133377A0/xx
Publication of WO1999001423A1 publication Critical patent/WO1999001423A1/en
Publication of WO1999001423A8 publication Critical patent/WO1999001423A8/en
Priority to NO996550A priority patent/NO996550L/no

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Definitions

  • the present invention relates to agents that act to antagonize the action of the giucagon peptide hormone. It relates particularly to non-peptide giucagon antagonists or inverse agonists.
  • Giucagon is a key hormonal agent that, in cooperation with insulin, mediates homeostatic regulation of the amount of glucose in the blood. Giucagon primarily acts by stimulating certain cells (mostly liver cells) to release glucose when blood glucose levels fall. The action of giucagon is opposed by insulin which stimulates cells to take up and store glucose whenever blood glucose levels rise. Both giucagon and insulin are peptide hormones.
  • Giucagon is produced in the alpha islet cells and insulin in the beta islet cells of the pancreas.
  • Diabetes mellitus the common disorder of glucose metabolism, is characterized by hypergly- cemia, and can present as type I, insulin-dependent, or type II, a form that is non-insulin- dependent in character.
  • Subjects with type I diabetes are hyperglycemic and hypoinsulinemic, and the conventional treatment for this form of the disease is to provide insulin.
  • absolute or relative elevated giucagon levels have been shown to contribute to the hyperglycemic state.
  • giucagon can be suppressed by providing an antagonist or an inverse agonist, substances that inhibit or prevent giucagon induced response.
  • the antagonist can be peptide or non-peptide in nature.
  • Native giucagon is a 29 amino acid- containing peptide having the sequence: His-Ser-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-Ser-Arg-Arg-Ala-Gln-Asp- Phe-Val-Gln-Trp-Leu-Met-Asn-Thr-NH 2 .
  • Giucagon exerts its action by binding to and activating its receptor, which is part of the Glu- cagon-Secretin branch of the 7-transmembrane G-protein coupled receptor family (Jelinek et al. Science 259, 1614, (1993)).
  • the receptor functions by activation of the adenylyl cyclase second messenger system and the result is an increase in cA P levels.
  • Peptide antagonists of peptide hormones are often quite potent; however, they are defective as drugs because of degradation by physiological enzymes, and poor biodistribution. Therefore, non-peptide antagonists of the peptide hormones are preferred.
  • non-peptide glu- cagon antagonists a quinoxaline derivative, (2-styryl-3-[3-(dimethylamino)propylmethyl- amino]-6,7-dichloroquinoxaline was found to displace giucagon from the rat liver receptor (Collins, J.L. et al. (1992) Bioorganic and Medicinal Chemistry Letters 2(9):915-918). West, R.R.- et al.
  • WO 94/14426 discloses use of skyrin, a natural product comprising a pair of linked 9,10-anthracenedione groups, and its synthetic analogues, as giucagon antagonists.
  • Anderson, P.L., U.S. Patent No. 4,359,474 discloses the giucagon antagonistic properties of 1- phenyl pyrazole derivatives.
  • Barcza, S., U.S. Patent No. 4,374,130 discloses substituted disi- lacyclohexanes as giucagon antagonists.
  • WO 98/04528 (Bayer Corporation) discloses substituted pyridines and biphenyls as giucagon antagonists.
  • WO 97/16442 discloses substituted pyridyl pyrroles as giucagon antagonists
  • WO 98/21957 discloses 2,4-diaryl-5-pyridylimidazoles as giucagon antagonists. These giucagon antagonists differ structurally from the present compounds. Description of the invention
  • Halogen designates an atom selected from the group consisting of F, Cl, Br or I.
  • alkyl in the present context designates a hydrocarbon chain or a ring that is either saturated or unsaturated (containing one or more double or triple bonds where feasible) of from 1 to 10 carbon atoms in either a linear or branched or cyclic configuration.
  • alkyl includes for example n-octyl, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, allyl, propargyl, 2- hexynyl, cyclopropyl, cyclopropylmethyl, cyclopentyl, cyclohexyl, cyclooctyl, 4-cyclohexylbutyl, and the like.
  • non-limiting examples are sec-butyl, n-pentyl, isopentyl, neopentyl, te/ ⁇ -pentyl, n- hexyl, isohexyl, n-heptyl, n-nonyl, n-decyl, vinyl, 1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-1-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 3-met.hyl-2-but.enyl, 1- hexenyl, 3-hexenyl, 2,4-hexadienyl, 5-hexenyl, 1-heptenyl, 2,4-heptadienyl, 1-octenyl, 2,4- octadienyi, ethynyl, 1-propynyl, 1-butynyl, 2-butyn
  • lower alkyl designates a hydrocarbon moiety specified above, of from 1 to 6 carbon atoms.
  • Aryl means an aromatic ring moiety, for example: phenyl, naphthyl, furyl, thienyl, pyrrolyl, pyridyl, pyrimidinyl, pyrazolyl, imidazolyl, pyrazinyl, pyridazinyl, 1 ,2,3-triazinyl, 1 ,2,4-triazinyl, oxazolyl, isoxazolyl, 1 ,2,3-oxadiazolyl, 1 ,2,4-oxadiazolyl, 1 ,3,4-oxadiazolyl, 1 ,2,3-thiadiazolyl, 1 ,2,4-thiadiazolyl, 1 ,3,4-thiadiazolyl, thiazolyl, isothiazolyl, tetrazolyl, 1-H-tetrazol-5-yl, indolyl, quinolyl, quinazolinyl, benzofuryl, be
  • Non-limiting examples are biphenyl, anthracenyl, phenanthrenyl, fluorenyl, indenyl, 1 ,2,3,4-tetrahydronaphthyl, 2,3-dihydrobenzofuryl, triazolyl, pyranyl, thiadiazinyl, isoindolyl, in- dazolyl, 1 ,2,5-oxadiazolyl, 1 ,2,5-thiadiazolyl, benzothienyl, benzimidazolyl, benzthiazolyl, ben- maiothiazolyl, benzoxazolyl, benzisoxazolyl, purinyl, quinolizinyl, isoquinolyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, pyrrolinyl, pyrazolinyl, indolinyl, pyrrolidinyl
  • the aryl moieties are optionally substituted by one or more substituents, for example selected from the group consisting of F, Cl, I, and Br; lower alkyl; lower alkanoyl such as formyl, acetyl, propionyl, butyryl, valeryl, hexanoyl and the like; -OH; -NO 2 ; -CN; -CO 2 H; -O-lower alkyl; aryl; aryl-lower alkyl; -CO 2 CH 3 ; -CONH 2 ; -OCH 2 CONH 2 ; -NH 2 ; -N(CH 3 ) 2 ; -SO 2 NH 2 ; -OCHF 2 ; -CF 3 ; -OCF 3 and the like.
  • Such aryl moieties may also be substituted by two substituents forming a bridge, for example -OCH 2 O-.
  • Aryl-lower alkyl means a lower alkyl as defined above, substituted by an aryl, for example:
  • the aryl group is optionally substituted as described above.
  • the present invention is based on the unexpected observation that compounds having a selected nitrogen-bearing central motif and the general structural features disclosed below antagonize the action of giucagon. Accordingly, the invention is concerned with compounds of the general formula
  • R 1 and R 2 independently are hydrogen or lower alkyl or together form a valence bond
  • R 3 and R 4 independently are hydrogen or lower alkyl
  • n 0, 1, 2 or 3;
  • n 0 or 1 ;
  • R 5 is hydrogen, lower alkyl, aryl-lower alkyl or -OR 6 ;
  • R 6 is hydrogen, lower alkyl, aryl or aryl-lower alkyl
  • R 7 is hydrogen, halogen, -CN, -CF 3 , -OCF 3 , -OCH 2 CF 3 , -NO 2 , -OR 11 , -NR 11 R 12 , lower alkyl, aryl, aryl-lower alkyl, -SCF 3 , -SO 2 NR 11 R 12 , -SR 11 , -CHF 2 , -OCHF 2 , -OSO 2 R 11 , -CONR 11 R 12 , -OCH 2 CONR 11 R 12 , -CH 2 OR 11 , -CH 2 NR 11 R 12 , -OCOR 11 , -CO 2 R 13 or -OSO 2 CF 3 ;
  • R 8 and R 9 independently are hydrogen, halogen, -CN, -CF 3 , -OCF 3 , -OCH 2 CF 3 , -NO 2 , -OR 11 , -NR 11 R 12 , lower alkyl, aryl, -SCF 3 , -SR 11 , -CHF 2 , -OCHF 2 , -OSO 2 R 11 , -CONR 11 R 12 , -CH 2 OR 11 , -CH 2 NR 11 R 12 , -OCOR 11 , -CO 2 R 13 or -OSO 2 CF 3 , or R 8 and R 9 together form a bridge -OCH 2 O- or -OCH 2 CH 2 O-;
  • R 11 and R 12 independently are hydrogen, -COR 13 , -SO 2 R 13 , lower alkyl or aryl;
  • R 13 is hydrogen, lower alkyl, aryl-lower alkyl or aryl
  • R 10 is hydrogen, lower alkyl, aryl-lower alkyl or aryl;
  • R 14 and R 15 independently are hydrogen, halogen, -CN, -CF 3 , -OCF 3> -O(CH 2 ) ! CF 3 , -NO 2 , -OR 16 , -NR 16 R 17 , lower alkyl, aryl, aryl-lower alkyl, -SCF 3 , -SR 16 , -CHF 2 , -OCHF 2 , -OCF 2 CHF 2 , -OSO 2 CF 3 , -CONR 16 R 17 , -(CH 2 ),CONR 16 R 17 , -O(CH 2 ),CONR 16 R 17 , -(CH 2 ),COR 16 , -(CH 2 ),COR 16 , -(CH 2 ),COR 16 , -(CH 2 ),OR 16 , -O(CH 2 ),OR 16 , -(CH 2 ),NR 16 R 17 , -O(CH 2 ),NR 16 R 17 ,
  • I is 1 , 2, 3 or 4;
  • R 16 and R 17 independently are hydrogen, -COR 18 , -SO 2 R 18 , lower alkyl, aryl, or R 16 and R 17 together form a cyclic alkyl bridge containing from 2 to 7 carbon atoms;
  • R 18 is hydrogen, lower alkyl, aryl or aryl-lower alkyl
  • Q is -NR 23 -, -O- or -S-;
  • R 19 , R 20 , R 21 and R 22 independently are hydrogen, halogen, -CN, -CF 3 , -OCF 3 , -OCH 2 CF 3 , -NO 2 , -OR 24 , -NR 24 R 25 , lower alkyl, aryl, aryl-lower alkyl, -SCF 3 , -SR 24 , -CHF 2 , -OCHF 2 , -OCF 2 CHF 2 , -OSO 2 CF 3 , -CONR 24 R 25 , -CH 2 CONR 24 R 25 , -OCH 2 CONR 24 R 25 , -CH 2 OR 24 , -CH 2 NR 4 R 25 , -OCOR 24 or -CO 2 R 24 , or R 19 and R 20 , R 20 and R 21 , or R 21 and R 22 together form a bridge -OCH 2 O-; wherein R 24 and R 25 independently are hydrogen, -COR 26 , -SO
  • R 26 is hydrogen, lower alkyl, aryl or aryl-lower alkyl
  • R 23 is hydrogen, lower alkyl, aryl or aryl-lower alkyl
  • R 3a , R 3b , R 4a and R 4b independently are hydrogen, halogen, -CN, -CF 3 , -OCF 3 , -OCH 2 CF 3 , -NO 2 , -OR 24a , -NR 24a R 25a , lower alkyl, aryl, aryl-lower alkyl, -SCF 3 , -SR 24a , -CHF 2 , -OCHF 2 , -OCF 2 CHF 2, -OSO 2 CF 3 , -CONR 24a R 25a , -CH 2 CONR 24a R 25a , -OCH 2 CONR 24a R 5a , -CH 2 OR 24a , -CH 2 NR 24a R 25a , -OCOR 24a or -CO 2 R 24a ;
  • R 24a and R 25a independently are hydrogen, -COR 26a , -SO 2 R 26a , lower alkyl, aryl or aryl-lower alkyl;
  • R 26a is hydrogen, lower alkyl, aryl or aryl-lower alkyl
  • R 3a and R 3b , R 4a and R 4b , or R 3a and R 4b together form a bridge -(CH 2 ) r ;
  • 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 0, 1 or 2;
  • R 5a and R 5b independently are hydrogen, lower alkyl, -OH, -(CH 2 ) k -OR 6a , -COR 6a , -(CH 2 ) k -CH(OR 6a ) 2 , -(CH 2 ) k -CN, -(CH 2 ) k -NR 6a R 6b , aryl, aryl-lower alkyl, -(CH 2 ) g -COOR 43 or (CH 2 ) g -CF 3 ;
  • k is 1 , 2, 3 or 4;
  • R 6a and R 6b independently are hydrogen, lower alkyl, aryl or aryl-lower alkyl
  • g 0, 1 , 2, 3 or 4;
  • R 43 is hydrogen or lower alkyl
  • G" is -OCH 2 CO-, -CH 2 CO-, -CO- or a valence bond
  • F' is >CR 38 - or >N-;
  • Q' is -NR 36 -, -O- or -S-;
  • R 27 , R 28 , R 32 , R 33 , R ⁇ and R 35 independently are hydrogen, halogen, -CN, -CF 3 , -O(CH 2 ) y CF 3 , -(CH 2 ) y NHCOCF 3 , -NO 2 , lower alkyl, aryl, aryl-lower alkyl, -SCF 3 , -SR 29 , -CHF 2 , -OCHF 2 , -OCF 2 CHF 2 , -OSO 2 R 29 , -OSO 2 CF 3 , -(CH 2 ) y CONR 29 R 30 , -O(CH 2 ) y CONR 29 R 30 , -(CH 2 ) y OR 29 , -(CH 2 ) y NR 29 R 30 , -OCOR 29 , -COR 29 or -CO 2 R 29 ;
  • R 27 and R 28 , R 32 and R 33 , R 33 and R 34 , or R 34 and R 35 together form a bridge -O(CH 2 ) y O-;
  • y is 0, 1 , 2, 3 or 4;
  • R 29 and R 30 independently are hydrogen, -COR 31 , -CO 2 R 31 , -SO 2 R 31 , lower alkyl, aryl or aryl-lower alkyl; wherein R 31 is hydrogen, lower alkyl, aryl or aryl-lower alkyl;
  • R 36 and R 39 independently are hydrogen, lower alkyl, aryl or aryl-lower alkyl
  • R 38 is hydrogen, -OR 40 , -NR 40 R 41 , lower alkyl, aryl, aryl-lower alkyl, -SCF 3 , -SR 40 , -CHF 2 , -OCHF 2 , -OCF 2 CHF 2 , -CONR 40 R 41 , -(CH 2 ) X CONR 40 R 41 , -O(CH 2 ) X CONR 40 R 41 , -(CH 2 ) x OR 40 , -(CH 2 ) X NR 40 R 41 , -OCOR 40 or -C0 2 R 40 ;
  • x is 1 , 2, 3 or 4;
  • R 40 and R 41 independently are hydrogen, -COR 42 , -SO 2 R 42 , lower alkyl, aryl or aryl-lower alkyl;
  • R 42 is hydrogen, lower alkyl, aryl or aryl-lower alkyl
  • R 19 , R 20 , R 21 , R 22 and R 23 may alternatively be re- placed by R 14 or R 1S , respectively.
  • R 32 , R 33 , R 34 , R 35 , R 36 , R 38 and R 39 may alternatively be replaced by R 27 or R 28 , respectively.
  • R 3 is preferably hydrogen.
  • R 4 is preferably hydrogen.
  • A is preferably selected from the group consisting of:
  • R 7 , R 8 , R 9 and R 10 are as defined for formula I.
  • A is more preferably
  • R 7 , R 8 and R are as defined for formula I.
  • R 7 is preferably halogen, lower alkyl, -OH, -NO 2 , -CN, -CO 2 H, -O-lower alkyl, aryl, aryl-lower alkyl, -CO 2 CH 3 , -CONH 2 , -OCH 2 CONH 2 , -NH 2 , -N(CH 3 ) 2 , -SO 2 NH 2 , -OCHF 2 , -CF 3 or -OCF 3 .
  • R 8 and R 9 are independently hydrogen, halogen, -OH, -NO 2 , -NH 2 , -CN, -OCF 3 , -SCF 3 , -CF 3 , -OCH 2 CF 3 , -O-lower alkyl such as methoxy and ethoxy, lower alkyl such as methyl and ethyl, or phenyl, and R 10 is hydrogen, lower alkyl or phenyl.
  • R 8 and R 9 are independently selected from hydrogen, halogen such as -F and -Cl, -O-lower alkyl such as methoxy and ethoxy, -NH 2 , -CNor -NO 2 , and R 10 is hydrogen.
  • R 8 and R 9 independently are hydrogen, halogen, -OH, -NO 2 , -NH 2 , -CN, -OCF 3 , -SCF 3 , -CF 3 , -OCH 2 CF 3 , -O-lower alkyl such as methoxy and ethoxy, lower alkyl such as methyl and ethyl, or phenyl, preferably hydrogen, halogen such as -F and -Cl, -O-lower alkyl such as methoxy and ethoxy, -NH 2 , -CNor -NO 2 .
  • R 8 is hydrogen, halogen such as -F or -Cl, -O-lower alkyl such as -OCH 3 or -OC 2 H 5 , -NH 2 , -CN or -NO 2 ; and R 9 is hydrogen or halogen such as -F or -Cl.
  • R 8 is halogen and R 9 is hydrogen.
  • R 4 , B, K, D and m are as defined for formula I and R 8 and R 9 are as defined for formula I and preferably as defined for the preferred embodiments of A above.
  • B is preferably:
  • V, W, Z, Y and Q are as defined for formula I;
  • R 14 and R 15 independently are hydrogen, halogen, -CF 3 ⁇ -OCF 3 , -OR 16 , -NR 16 R 17 , lower alkyl, aryl, aryl-lower alkyl, -OSO 2 CF 3 , -CONR 16 R 17 , -CH 2 OR 16 , -CH 2 NR 6 R 17 , -OCOR 16 or -CO 2 R 18 ; or R 14 and R 15 together form a bridge -OCH 2 O- or -(CH 2 ) r ;
  • Q is preferably -O- or -NH-.
  • V, W, Z, Y and Q are as defined for formula I;
  • R 14 and R 15 independently are hydrogen, halogen, -CF 3, -OCF 3 , -OR 16 , -NR 16 R 17 , lower alkyl, aryl, aryl-lower alkyl, -OS0 2 CF 3 , -CONR 16 R 17 , -CH 2 OR 16 , -CH 2 NR 6 R 17 , -OCOR 16 or -CO 2 R 18 ; or R 14 and R 15 together form a bridge -OCH 2 O- or -(CH 2 ) r ;
  • R 14 and R 15 independently are hydrogen, halogen, -CF 3, -OCF 3 , -OR 16 , -NR 16 R 17 , lower alkyl, aryl, aryl-lower alkyl, -OSO 2 CF 3 , -CONR 16 R 17 , -CH 2 OR 16 , -CH 2 NR 16 R 17 , -OCOR 16 or -CO 2 R 18 ; or R 14 and R 15 together form a bridge -OCH 2 O- or -(CH 2 ) r ;
  • I, R 6 , R 17 and R 18 are as defined for formula I; K, D and m are as defined for formula I; and
  • R 8 and R 9 are as defined for formula I and preferably as defined for the preferred embodiments of A above.
  • R 14 and R 15 are preferably independently hydrogen, halogen, lower alkyl, aryl such as phenyl, or -O-lower alkyl such as methoxy.
  • K is preferably bound in para-position and in the above formulae Villa and Vlllb, K is preferably bound at the nitrogen atom of the indole group.
  • K is preferably selected from the group consisting of:
  • R 3a , R 3 , R 4a , R 4b , R 5a , R 5b , a, b, c, d, p and q are as defined for formula I.
  • K is selected from the group consisting of:
  • R 3a , R 3b , R 4a , R 4b , R 5a , R 5b , a, b, c, d, p and q are as defined for formula I.
  • R 3a , R 3b , R 4a , R 4b , R 5a , R 5b , b, c, d, p and q are as defined for formula I.
  • R 5a and R 5 are preferably independently hydrogen, lower alkyl, -OH, -(CH 2 ) k OR 6a , aryl, aryl-lower alkyl, -CH 2 CF 3> -(CH 2 ) g -COOR 43 , -COOR 43 , -(CH 2 ) k - CN or -(CH 2 ) k -NR 6a R 6b wherein g, k, R 43 , R 6a and R 6 are as defined for formula I.
  • g and k are independently 1 , 2 or 3
  • R 6a and R 6b are independently hydrogen, lower alkyl such as methyl or ethyl, or aryl such as phenyl,
  • R 3a and R 3b are preferably independently hydrogen, halogen, -OH, -O-iower alkyl, -COO-lower alkyl, lower alkyl or aryl-lower alkyl.
  • R a and R b are preferably independently hydrogen, -CN, -CONH 2 , -(CH 2 )-N(CH 3 ) 2 , -O-lower alkyl, -CH 2 OH, -CH 2 O-aryl, -N(CH 3 ) 2 , -OH, -CO 2 -lower alkyl or lower alkyl.
  • D is preferably hydrogen
  • D is hydrogen
  • D is more preferably hydrogen
  • E and E' independently are >CHR 38 , >NR 39 or -O-;
  • F' is >CR 38 - or >N-; and
  • s, r, R 27 , R 28 , R 38 , R 39 , V, Y', Z', Q' and W * are as defined for formula I.
  • R 27 and R 28 are preferably independently hydrogen; halogen such as -Cl, -Br or -F; -CF 3 ; -OCF 3; -OCHF 2 ; -OCH 2 CF 3 ; -(CH 2 ) y NHCOCF 3 ; -NHCOCF 3 ; -CN; -NO 2 ; -COR 29 , -COOR 29 , -(CH 2 ) y OR 29 or -OR 29 wherein R 29 is hydrogen, aryl or lower alkyl and y is 1 , 2, 3 or 4; lower alkyl such as methyl, ethyl, 2-propenyl, isopropyl, tert-butyl or cyclohexyl; lower alkylthio; -SCF 3 ; aryl such as phenyl; -(CH 2 ) y NR 29 R 30 or -NR 29 R 30 wherein R 29 and R 30 independently are hydrogen, -COO-
  • R 1 and R 2 independently are hydrogen or lower alkyl or together form a valence bond
  • R 3 and R 4 independently are hydrogen or lower alkyl
  • n 0, 1 , 2 or 3;
  • n 0 or 1 ;
  • R 5 is hydrogen, lower alkyl, aryl-lower alkyl, or -OR 6 ;
  • R 6 is hydrogen, lower alkyl, aryl or aryl-lower alkyl
  • R 7 is hydrogen, halogen, -CN, -CF 3 , -OCF 3 , -OCH 2 CF 3 , -NO 2 , -OR 11 , -NR 11 R 12 , lower alkyl, aryl, -SCF 3 , -SR 11 , -CHF 2 , -OCHF 2 , -OSO 2 R 11 , -CONR 11 R 12 , -CH 2 OR 11 , -CH 2 NR 1 R 12 , -OCOR 11 , -CO 2 R 13 , -OSO 2 CF 3 .
  • R 8 and R 9 independently are hydrogen, halogen, -CN, -CF 3 , -OCF 3 , -OCH 2 CF 3 , -NO 2 , -OR 11 , -NR 11 R 12 , lower alkyl, aryl, -SCF 3 , -SR 11 , -CHF 2 , -OCHF 2 , -OSO 2 R 11 , -CONR 11 R 12 , -CH 2 OR 11 , -CH 2 NR 1 R 12 , -OCOR 11 , -CO 2 R 13 , -OSO 2 CF 3 , or R 8 and R 9 together form a bridge -OCH 2 O-;
  • R 1 and R 12 independently are hydrogen, -COR 13 , -SO 2 R 13 , lower alkyl or aryl;
  • R 13 is hydrogen, lower alkyl, aryl-lower alkyl or aryl;
  • R 10 is hydrogen, lower alkyl, aryl-lower alkyl or aryl;
  • R 14 and R 15 independently are hydrogen, halogen, -CN, -CF 3 , -OCF 3 , -O(CH 2 )
  • R 14 and R 5 preferably independently representing hydrogen, halogen, -CF 3, -OCF 3 , -OR 16 , -NR 16 R 17 , lower alkyl, aryl, aryl-lower alkyl, -OSO 2 CF 3 , -CONR 16 R 17 , -CH 2 OR 16 , -CH 2 NR 16 R 17 , -OCOR 16 or -CO 2 R 18 ; or together forming a bridge -OCH 2 O-;
  • I is 1 , 2, 3 or 4;
  • R 16 and R 17 independently are hydrogen, -COR 18 , -SO 2 R 18 , lower alkyl, aryl, or R 16 and R 17 together form a cyclic alkyl bridge containing from 2 to 7 carbon atoms;
  • R 18 is hydrogen, lower alkyl, aryl or aryl-lower alkyl
  • Q is -NR 23 -, -O- or -S-;
  • R 19 , R 20 , R 2 and R 22 independently are hydrogen, halogen, -CN, -CF 3 , -OCF 3 , -OCH 2 CF 3 , -NO 2 , -OR 24 , -NR 24 R 25 , lower alkyl, aryl, aryl-lower alkyl, SCF 3 , -SR 24 , -CHF 2 , -OCHF 2 , OCF 2 CHF 2 , -OSO 2 CF 3 , -CONR 24 R 25 , -CH 2 CONR 24 R 25 , -OCH 2 CONR 24 R 2 VCH 2 OR 24 , - CH 2 NR 24 R 25 , -OCOR 24 or -CO 2 R 24 , or R 19 and R 20 , R 20 and R 21 or R 21 and R 22 together form a bridge -OCH 2 O-;
  • R 24 and R 25 independently are hydrogen, -COR 26 , -SO 2 R 26 , lower alkyl, aryl or aryl-lower alkyl;
  • R 26 is hydrogen, lower alkyl, aryl or aryl-lower alkyl
  • R 23 is hydrogen, lower alkyl, aryl or aryl-lower alkyl
  • R 3a , R 3b , R 4a and R 4b independently are hydrogen, halogen, -CN, -CF 3 , -OCF 3 , -OCH 2 CF 3 , -NO 2 , -OR 24a , -NR 24a R 25a , lower alkyl, aryl, aryl-lower alkyl, SCF 3 , -SR 24a , -CHF 2 2 ,, -O v_/Cv_#H ⁇ ⁇ F 22 ,, -CONR 24a R 25a , -CH 2 CONR 24a R 25a , -OCH 22 CCOONNRR 44aa RR 2255aa ,, --CCHH 22 OORR 2244aa ,, --CCHH 22 IN,R ⁇ 24a ,R ⁇ 25a ,, --OCO.RX 24a U o,r -- W CO 22 .RX 24a - , wherein R 2 a and R 25a independently are hydrogen
  • R 26a is hydrogen, lower alkyl, aryl or aryl-lower alkyl
  • R 3a and R 3b , R 4a and R 4b or R 3a and R 4b together form a bridge -(CH 2 ) r , wherein
  • i 1 , 2, 3 or 4;
  • a, b, c and d independently are 0, 1 , 2, 3 or 4;
  • e, f, p and q independently are 0 or 1 ;
  • R 5a and R 5b independently are hydrogen, lower alkyl, -(CH 2 ) k -OH, -(CH 2 ) k - NR 6a R 6b , aryl or aryl-lower alkyl;
  • k is 2, 3 or 4;
  • R 6a and R 6b independently are hydrogen, lower alkyl or aryl-lower alkyl
  • K preferably representing — (CH 2 ) b -0— (CH 2 ) d , (CH2 j_ CH - CH _ (CH2)d
  • r and s independently are 1 or 2;
  • Q' is -NR 36 -, -O- or -S-;
  • R 27 , R 28 , R 32 , R 33 , R 34 and R 35 are independently hydrogen, halogen, -CN, -CF 3 , -OCF 3> _O(CH 2 ) y CF 3 , -NO 2 , -OR 29 , -NR 29 R 30 , lower alkyl, aryl, aryl-lower alkyl, -SCF 3 , -SR 29 , -CHF 2 , -OCHF 2 , -OCF 2 CHF 2> -OSO 2 R 29 , -OSO 2 CF 3 , -CONR 29 R 30 , -(CH 2 ) y CONR 29 R 30 , -O(CH 2 ) y CONR 29 R 30 , -(CH 2 ) y OR 29 , -(CH 2 ) y NR 29 R 30 , -OCOR 29 , -CO 2 R 29; or R 27 and R 28 , R 32 and R 33 ,
  • R 27 and R 28 preferably independently representing hydrogen, halogen,-CF 3 , -OCF 3 , -OCH 2 CF 3 , -OR 29 , lower alkyl, aryl or aryl-lower alkyl, or together forming a bridge -OCH 2 O-;
  • y is 1 , 2, 3 or 4;
  • R 29 and R 30 independently are hydrogen, -COR 31 , -SO 2 R 31 , lower alkyl, aryl or aryl-lower alkyl;
  • R 31 is hydrogen, lower alkyl, aryl or aryl-lower alkyl
  • R 36 and R 39 independently are hydrogen, lower alkyl, aryl or aryl-lower alkyl
  • R 38 is hydrogen, -OR 40 , -NR 40 R 41 , lower alkyl, aryl, aryl-lower alkyl, -SCF 3 , -SR 40 , -CHF 2 , - OCHF 2 , -OCF 2 CHF 2 , -CONR 40 R 41 , -(CH 2 ) X CONR 40 R 41 , -O(CH 2 ) X CONR 40 R 41 , -(CH 2 ) x OR 40 , -(CH 2 ) X NR 40 R 41 , -OCOR 40 or -CO 2 R 40 ; x is 1 , 2, 3 or 4;
  • R 40 and R 41 independently are hydrogen, -COR 42 , -SO 2 R 42 , lower alkyl, aryl or aryl-lower alkyl;
  • R 42 is hydrogen, lower alkyl, aryl or aryl-lower alkyl.
  • R 1 and R 2 independently are hydrogen or lower alkyl or together form a valence bond
  • R 3 and R 4 independently are hydrogen or lower alkyl
  • n 0, 1 , 2 or 3;
  • n 0 or 1 ;
  • R 5 is hydrogen, lower alkyl, aryl-lower alkyl or -OR 6 ;
  • R 6 is hydrogen, lower alkyl, aryl or aryl-lower alkyl
  • R 7 is hydrogen, halogen, -CN, -CF 3 , -OCF 3 , -OCH 2 CF 3 , -NO 2 , -OR 11 , -NR 11 R 12 , lower alkyl, aryl, -SCF 3 , -SR 11 , -CHF 2 , -OCHF 2 , -OSO 2 R 11 , -CONR 11 R 12 , -CH 2 OR 11 , -CH 2 NR 11 R 12 ,
  • R 8 and R 9 independently are hydrogen, halogen, -CN, -CF 3 , -OCF 3 , -OCH 2 CF 3> -NO 2 , -OR 11 , -NR 11 R 12 , lower alkyl, aryl, -SCF 3 , -SR 11 , -CHF 2) -OCHF 2 , -OSO 2 R 11 , -CONR 1 R 12 , -CH 2 OR 11 , -CH 2 NR 11 R 12 , -OCOR 11 , -CO 2 R 13 or -OSO 2 CF 3> or R 8 and R 9 together form a bridge -OCH 2 O- or - OCH 2 CH 2 O-;
  • R 11 and R 12 independently are hydrogen, -COR 13 , -SO 2 R 13 , lower alkyl or aryl;
  • R 13 is hydrogen, lower alkyl, aryl-lower alkyl or aryl
  • R 10 is hydrogen, lower alkyl, aryl-lower alkyl or aryl;
  • R 14 and R 15 independently are hydrogen, halogen, -CN, -CF 3 , -OCF 3 , -O(CH 2 ),CF 3 , -NO 2 , -OR 16 , -NR 16 R 17 , lower alkyl, aryl, aryl-lower alkyl, -SCF 3 , -SR 16 , -CHF 2 , -OCHF 2 , -OCF 2 CHF 2 , -OSO 2 CF 3 , -CONR 16 R 17 , -(CH 2 ),CONR 16 R 17 , -O(CH 2 ),CONR 16 R 17 , -(CH 2 ),COR 16 , -(CH 2 ),COR 16 , -(CH 2 ),COR 16 , -(CH 2 ),OR 16 , -O(CH 2 ),OR 16 , -(CH 2 ),NR 16 R 17 , -0(CH 2 ),NR 16 R 17 , -
  • R 14 andR 15 preferably independently representing hydrogen, halogen, -CF 3 , -OCF 3 , -OR 16 , -NR 16 R 17 , lower alkyl, aryl, aryl-lower alkyl, -OSO 2 CF 3 , -CONR 6 R 17 , -CH 2 OR 16 , -CH 2 NR 16 R 17 , -OCOR 16 or -CO 2 R 18 ; or together forming a bridge -OCH 2 O-;
  • I is 1 , 2, 3 or 4;
  • R 16 and R 17 independently are hydrogen, -COR 18 , -SO 2 R 18 , lower alkyl, aryl, or R 16 and R 17 together form a cyclic alkyl bridge containing from 2 to 7 carbon atoms;
  • R 18 is hydrogen, lower alkyl, aryl or aryl-lower alkyl
  • Q is -NR 23 -, -O- or -S-;
  • R 19 , R 20 , R 21 and R 22 independently are hydrogen, halogen, -CN, -CF 3 , -OCF 3 , -OCH 2 CF 3 , -NO 2 , -OR 24 , -NR 24 R 25 , lower alkyl, aryl, aryl-lower alkyl, SCF 3 , -SR 24 , -CHF 2 , -OCHF 2 , -OCF 2 CHF 2 , -OSO 2 CF 3 , -CONR 24 R 25 , -CH 2 CONR 24 R 25 , -OCH 2 CONR 24 R 25 , -CH 2 OR 24 , -CH 2 NR 24 R 25 , -OCOR 24 or -CO 2 R 24 , or R 19 and R 20 , R 20 and R 21 or R 21 and R 22 together form a bridge -OCH 2 O-;
  • R 24 and R 25 independently are hydrogen, -COR 26 , -SO 2 R 26 , lower alkyl, aryl or aryl-lower alkyl;
  • R 26 is hydrogen, lower alkyl, aryl or aryl-lower alkyl
  • R 23 is hydrogen, lower alkyl, aryl or aryl-lower alkyl
  • R 3a , R 3 , R 4a and R 4b independently are hydrogen, halogen, -CN, -CF 3 , -OCF 3 , -OCH 2 CF 3 , -NO 2 , -OR 24a , -NR 24a R 25a , lower alkyl, aryl, aryl-lower alkyl, SCF 3 , -SR 24a , -CHF 2 , -OCHF 2 , -OCF 2 CHF 2, -OSO 2 CF 3 , -CONR 24a R 25a , -CH 2 CONR 24a R 25a , -OCH 2 CONR 24a R 25a , -CH 2 OR 24a , -CH 2 NR 24a R 25a , -OCOR 24a or -CO 2 R 24a ; wherein R 24a and R 25a independently are hydrogen, -COR 26a , -SO 2 R 26a , lower alkyl, aryl or ary
  • R 6a is hydrogen, lower alkyl, aryl or aryl-lower alkyl
  • R 3a and R 3b , R 4a and R 4b or R 3a and R 4b together form a bridge -(CH 2 ) r ;
  • 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 0,1 or 2;
  • R 5a and R 5b independently are hydrogen, lower alkyl, -(CH 2 ) k -OH, -(CH 2 ) k - NR 6a R 6 , aryl or aryl-lower alkyl;
  • k is 2, 3 or 4;
  • R 6a and R 6b independently are hydrogen, lower alkyl or aryl-lower alkyl
  • K preferably representing -(CH 2 )- -N- -O— (CH 2 ) 2 -N— (CH H 2' ⁇
  • r and s independently are 0, 1 or 2;
  • F' is >CR 38 - or >N
  • Q' is -NR 36 -, -O- or -S-;
  • R 27 , R 28 ,R 32 , R 33 , R 34 and R 35 are independently hydrogen, halogen, -CN, -CF 3 , -OCF 3 , -O(CH 2 ) y CF 3 , -NO 2 , -OR 29 , -NR 29 R 30 , lower alkyl, aryl, aryl-lower alkyl, -SCF 3 , -SR 29 , -CHF 2 , -OCHF 2 , -OCF 2 CHF 2 , -OSO 2 R 29 , -OSO 2 CF 3 , -CONR 29 R 30 , -(CH 2 ) y CONR 29 R 30 , -O(CH 2 ) y CONR 29 R 30 , -(CH 2 ) y OR 29 , -(CH 2 ) y NR 9 R 30 , -OCOR 29 or -CO 2 R 29 ;
  • R 27 and R 28 , R 3 and R 33 , R 33 and R M or R ⁇ and R 35 together form a bridge -OCH 2 O-;
  • R 27 and R 28 preferably independently representing hydrogen; halogen such as -Cl or -F; -CF 3 ; -OCF 3 . -OCHF 2 ; -OCH 2 CF 3 ; -OR 29 wherein R 29 is hydrogen or lower alkyl; lower alkyl such as methyl, isopropyl or tert-butyl; lower alkylthio; -SCF 3 ; -CH 2 OH; -COO-lower alkyl; aryl or -CONH 2 ; or together forming a bridge -OCH 2 O-;
  • y is 1 , 2, 3 or 4;
  • R 29 and R 30 independently are hydrogen, -COR 31 , -SO 2 R 31 , lower alkyl, aryl or aryl-lower alkyl;
  • R 31 is hydrogen, lower alkyl, aryl or aryl-lower alkyl
  • R 36 and R 39 independently are hydrogen, lower alkyl, aryl or aryl-lower alkyl
  • R 38 is hydrogen, -OR 40 , -NR 40 R 41 , lower alkyl, aryl, aryl-lower alkyl, -SCF 3 , -SR 40 , -CHF 2 , -OCHF 2 , -OCF 2 CHF 2 , -CONR 40 R 41 , -(CH 2 ) X CONR 40 R 41 , -O(CH 2 ) X CONR 40 R 41 , -(CH 2 ) x OR 40 , -(CH 2 ) X NR 40 R 41 , -OCOR 40 or -CO 2 R 40 ; wherein x is 1 , 2, 3 or 4;
  • R 40 and R 41 independently are hydrogen, -COR 42 , -SO 2 R 42 , lower alkyl, aryl or aryl-lower alkyl;
  • R 42 is hydrogen, lower alkyl, aryl or aryl-lower alkyl.
  • Preferred specific compounds represented by the formulae VI and VII are the following:
  • Especially preferred according to the present invention are the following compounds which show a particularly high affinity to the human giucagon receptor:
  • the compounds of the present invention may have one or more asymmetric centres and it is intended that any optical isomers, as separated, pure or partially purified optical isomers or racemic mixtures thereof are included in the scope of the invention.
  • one or more carbon-carbon or carbon-nitrogen double bonds may be present in the compounds which brings about geometric isomers. It is intended that any geometric isomers, as separated, pure or partially purified geometric isomers or mixtures thereof are included in the scope of the invention.
  • the compounds of the present invention may exist in different tautomeric forms, eg the following tautomeric forms:
  • any tautomeric forms which the compounds are able to form are included in the scope of the present invention. Owing to their efficacy in antagonizing the giucagon receptor the present compounds may be suitable for the treatment and/or prevention of any glucagon-mediated conditions and diseases.
  • the present compounds may be applicable for the treatment of hyperglycemia associated with diabetes of any cause or associated with other diseases and conditions, eg impaired glucose tolerance, insulin resistance syndromes, syndrome X, type I diabetes, type II diabetes, hyperlipidemia, dyslipidemia, hypertriglyceridemia, glucagonomas, acute pancreatitis, cardiovascular diseases, cardiac hypertrophy, gastrointestinal disorders, diabetes as a consequence of obesity etc.
  • diseases and conditions eg impaired glucose tolerance, insulin resistance syndromes, syndrome X, type I diabetes, type II diabetes, hyperlipidemia, dyslipidemia, hypertriglyceridemia, glucagonomas, acute pancreatitis, cardiovascular diseases, cardiac hypertrophy, gastrointestinal disorders, diabetes as a consequence of obesity etc.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising, as an active ingredient, at least one compound according to the present invention together with one or more pharmaceutically acceptable carriers or excipients.
  • the present invention furthermore relates to methods of treating type I or type II diabetes or hyperglycemia which methods comprise administering to a subject in need thereof an effective amount of a compound according to the invention.
  • the present invention relates to a method of lowering blood glucose in a mammal, comprising administering to said mammal an effective amount of a compound according to the invention.
  • the present invention is also concerned with the use of a compound according to the invention for the manufacture of a medicament for treating type I or type II diabetes or hyperglycemia, or for lowering blood glucose in a mammal.
  • Pharmaceutical formulations and administration methods are also concerned with the use of a compound according to the invention for the manufacture of a medicament for treating type I or type II diabetes or hyperglycemia, or for lowering blood glucose in a mammal.
  • the compounds according to the invention may be administered for therapy by any suitable route including oral, rectal, nasal, pul- monal, topical (including buccal and sublingual), transdermal, vaginal and parenteral (including subcutaneous, intramuscular, intravenous and intradermal), the oral route being preferred. It will be appreciated that the preferred route will vary with the condition and age of the recipient, the nature of the condition to be treated, and the chosen active ingredient.
  • a typical dosage is in the range of from 0.05 to about 1000 mg, preferably of from about 0.1 to about 500 mg, such as of from about 0.5 mg to about 250 mg for administration one or more times per day such as 1 to 3 times per day. It should be understood that the exact dosage will depend upon the frequency and mode of administration, the sex, age, weight and general condition of the subject treated, the nature and severity of the condition treated and any concomitant diseases to be treated as well as other factors evident to those skilled in the art.
  • formulations may conveniently be presented in unit dosage form by methods known to those skilled in the art.
  • parenteral routes such as intravenous, intrathecal, intramuscular and similar administration
  • typically doses are on the order of about 1/2 the dose employed for oral administration.
  • the compounds of this invention are generally utilized as the free substance or as a pharmaceutically acceptable salt thereof.
  • One example is an acid addition salt of a compound having the utility of a free base.
  • a compound of formula I contains a free base such salts are prepared in a conventional manner by treating a solution or suspension of a free base of formula I with a chemical equivalent of a pharmaceutically acceptable acid, for example, inorganic and organic acids, for example: maleic, fumaric, benzoic, ascorbic, pamoic, succinic, bis- methylene salicylic, methanesulfonic, ethanedisulfonic, acetic, oxalic, propionic, tartaric, sali- cylic, citric, pyruvic, gluconic, lactic, malic, mandelic, cinnamic, citraconic, aspartic, stearic, palmitic, EDTA, glycolic, p-aminobenzoic, glutamic, benz
  • the compounds of the invention may be administered alone or in combination with pharma- ceutically acceptable carriers, in either single or multiple doses.
  • solutions of the novel compounds of formula I in sterile aqueous solution, aqueous propylene glycol or sesame or peanut oil may be employed.
  • aqueous solutions should be suitable buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose.
  • the aqueous solutions are particularly suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration.
  • the sterile aqueous media employed are all readily available by standard techniques known to those skilled in the art.
  • Suitable pharmaceutical carriers include inert solid diluents or fillers, sterile aqueous solution and various organic solvents.
  • solid carriers are lactose, terra alba, sucrose, cy- clodextrin, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid or lower alkyl ethers of cellulose.
  • liquid carriers are syrup, peanut oil, olive oil, phospholipids, fatty acids, fatty acid amines, polyoxyethylene or water.
  • the carrier or diluent may include any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax.
  • the pharmaceutical compositions formed by combining the novel compounds of formula I and the pharmaceutically acceptable carriers are then readily administered in a variety of dosage forms suitable for the disclosed routes of administration.
  • the formulations may conveniently be presented in unit dosage form by methods known in the art of pharmacy.
  • Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules or tablets, each containing a predetermined amount of the active ingredient, and which may include a suitable excipient. These formulations may be in the form of powder or granules, as a solution or suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oii liquid emulsion.
  • the preparation may be tabletted, placed in a hard gelatin capsule in powder or pellet form or it can be in the form of a troche or lozenge.
  • the amount of solid carrier will vary widely but will usually be from about 25 mg to about 1 g.
  • the preparation may be in the form of a syrup, emulsion, soft gelatin capsule or sterile injectable liquid such as an aqueous or non-aqueous liquid suspension or solution.
  • a typical tablet which may be prepared by conventional tabletting techniques may contain:
  • Active compound (as free compound or salt 100 mg thereof)
  • the preparation may contain a compound of formula I dissolved or suspended in a liquid carrier, in particular an aqueous carrier, for aerosol application.
  • a liquid carrier in particular an aqueous carrier
  • the carrier may contain additives such as solubilizing agents, e.g. propylene glycol, surfactants, absorption enhancers such as lecithin (phosphatidylcholine) or cyclodextrin, or preservatives such as parabenes.
  • the pharmaceutical composition of the invention may comprise a compound of formula I combined with one or more other pharmacologically active compounds, e.g. an an- tidiabetic or other pharmacologically active material, including compounds for the treatment and/or prophylaxis of insulin resistance and diseases wherein insulin resistance is the pato- physiological mechanism.
  • Suitable antidiabetics comprise insulin, GLP-1 derivatives such as those disclosed in WO 98/08871 (Novo Nordisk A S) which is incorporated herein by refer- ence as well as orally active hypoglycaemic agents such as sulphonylureas, e.g. glibencla- mide and glipizide; biguanides, e.g.
  • metformin metformin
  • benzoic acid derivatives e.g. repaglinide
  • thiazolidinediones e.g. troglitazone and ciglitazone, as well as PPAR and RXR agonists.
  • Giucagon Binding Assay (I) Binding of compounds to the giucagon receptor was determined in a competition binding assay using the cloned human giucagon receptor.
  • antagonism was determined as the ability of the compounds to inhibit the amount of cAMP formed in the presence of 5 nM giucagon.
  • antagonism was determined in a functional assay, measured as the ability of the compounds to right-shift the giucagon dose-response curve. Using at least 3 different antagonist concentrations, the K, was calculated from a Schild plot. Receptor binding was assayed using cloned human receptor (Lok et al, Gene 140, 203-209 (1994)). The receptor inserted in the pLJ6' expression vector using EcoRI/SSt1 restriction sites (Lok et al) was expressed in a baby hamster kidney cell line (A3 BHK 570-25). Clones were selected in the presence of 0.5 mg/ml G-418 and were shown to be stable for more than 40 passages. The « ⁇ , was shown to be 0.1 nM.
  • Plasma membranes were prepared by growing cells to confluence, detaching them from the surface and resuspending the cells in cold buffer (10 mM tris/HCI), pH 7.4 containing 30 mM NaCl, 1 mM dithiothreitol, 5 mg/l leupeptin (Sigma), 5 mg/l pepstatin (Sigma), 100 mg/l baci- tracin (Sigma) and 15 mg/l recombinant aprotinin (Novo Nordisk)), homogenization by two 10-s bursts using a Polytron PT 10-35 homogenizer (Kinematica), and centrifugation upon a layer of 41 w/v% sucrose at 95.000 * g for 75 min. The white band located between the two layers was diluted in buffer and centrifuged at 40.000 * g for 45 min. The precipitate containing the plasma membranes was suspended in buffer and stored at -80°C until required.
  • Giucagon was iodinated according to the chloramine T method (Hunter and Greenwood, Na- ture 194, 495 (1962)) and purified using anion exchange chromatography (J ⁇ rgensen et al, Hormone and Metab. Res. 4, 223-224 (1972). The specific activity was 460 ⁇ Ci/ ⁇ g on day of iodination. Tracer was stored at -18°C in aliquots and were used immediately after thawing.
  • Binding assays were carried out in triplicate in filter microtiter plates (MADV N65, Millipore).
  • the buffer used in this assay was 25 mM HEPES pH 7.4 containing 0.1% human serum albumin (Sigma, grade V).
  • Giucagon was dissolved in 0.05 M HCI, added equal amounts(w/w) of HSA and freeze-dried. On the day of use, it was dissolved in water and diluted in buffer to the desired concentrations. 175 ⁇ l of sample (giucagon or test compounds) was added to each well. Tracer (50.000 cpm) was diluted in buffer and 15 ⁇ l was added to each well. 0.5 ⁇ g freshly thawed plasma membrane protein diluted in buffer was then added in 15 ⁇ l to each well.
  • the functional assay was carried out in 96 well microtiter plates (tissue culture plates, Nunc).
  • the resulting buffer concentrations in the assay were 50 mM tris/HCI, 1 mM EGTA, 1.5 mM MgSO 4 , 1.7 mM ATP, 20 ⁇ M GTP, 2 mM IBMX, 0.02% tween-20 and 0.1% HSA.
  • pH was 7.4 Giucagon and proposed antagonist were added in 35 ⁇ l diluted in 50 mM tris/HCI, 1 mM EGTA, 1.85 mM MgSO 4 , 0.0222 % tween-20 and 0.111 % HSA, pH 7.4.
  • the total assay volume was 140 ⁇ l.
  • the assay was incubated for 2 hours at 37°C with continuous shaking. Reaction was terminated by addition of 25 ⁇ l 0.5 N HCI.
  • cAMP was measured by the use of a scintillation proximity kit (Amersham).
  • Giucagon Binding Assay (lh Receptor binding was assayed using the cloned human receptor (Lok et al, Gene 140, 203- 209 (1994)). The receptor inserted in the pLJ6' expression vector using EcoRI/SSt1 restriction sites (Lok et al) was expressed in a baby hamster kidney cell line (A3 BHK 570-25). Clones were selected in the presence of 0.5 mg/ml G-418 and were shown to be stable for more than 40 passages. The Kd was shown to be 0.1 nM.
  • Plasma membranes were prepared by growing cells to confluence, detaching them from the surface and resuspending the cells in cold buffer (10 mM tris/HCI), pH 7.4 containing 30 mM NaCl, 1 mM dithiothreitol, 5 mg/l leupeptin Sigma), 5 mg/l pepstatin (Sigma), 100 mg/l baci- tracin (Sigma) and 15 mg/l recombinant aprotinin (Novo Nordisk)), homogenization by two 10-s bursts using a Polytron PT 10-35 homogenizer (Kinematica), and centrifugation. The ho- mogenate was resuspended and centrifuged again. The final precipitate containing the plasma membranes was suspended in buffer and stored at -80 C C until required.
  • cold buffer 10 mM tris/HCI
  • pH 7.4 containing 30 mM NaCl, 1 mM dithiothreitol, 5 mg/l le
  • Binding assays were carried out in duplicate in polypropylene tubes or microtiter plates.
  • the buffer used in this assay was 25 mM HEPES pH 7.4 containing 0.1 % bovine serum albumin
  • the functional assay determined the ability of the compounds to antagonize glucagon- stimulated formation of cAMP in a whole-cell assay.
  • the assay was carried out in borosilicate glass 12 x 75 tubes.
  • the buffer concentrations in the assay were 10 mM HEPES, 1 mM EGTA, 1.4 mM MgCI 2t 0.1 mM IBMX, 30 mM NaCl, 4.7 mM KCI, 2.5 mM NaH 2 PO 4 , 3mM glucose and 0.2% BSA.
  • the pH was 7.4. Loose whole cells (0.5 ml, 10 6 /ml) were pretreated with various concentrations of compounds for 10 min at 37°C, then challenged with giucagon for 20 min.
  • the compounds of general formula I may be prepared according to one embodiment of the invention, the alkylidene hydrazides of general formula II, as indicated in Scheme I, that is, by converting an ester of a carboxylic acid, for example, an aromatic acid to a hydrazide derivative and further reacting that product compound with a substituted aldehyde or ketone to yield a substituted alkylidene hydrazide.
  • HN-N r— (CH 2 ) n — B-(K)— D
  • A, B, K, D, m, n and R 4 are as defined for formula I and R a is lower alkyl.
  • the reactions are performed between 0°C to 130°C, preferably between 20°C to 100°C, most preferably at or about the reflux temperature of the solvent.
  • the reactions are preferably con- ducted under an inert atmosphere such as N 2 or Ar.
  • the solvent may be removed by concentration at atmospheric or reduced pressure.
  • the product can be further purified by either recrystallization from a solvent such as ethyl alcohol, methyl alcohol, isopropyl alcohol, toluene, xylene, hexane, tetrahydrofuran, diethyl ether, dibutyl ether, water or a mixture of two or more of the above.
  • the product can be purified by column chromatography using dichloromethane/methanol or chloroform/methanol or isopropyl alcohol as eluent.
  • the corresponding fractions are concentrated either at atmospheric pressure or in vacuo to provide the pure aroyl hydrazide.
  • aromatic acid hydrazides The methyl or ethyl ester of the corresponding aromatic acid, such as for example a substituted benzoic acid ester, is dissolved in ethanol and hydrazine (5 eq) is added. The reaction is refluxed overnight under nitrogen. Upon cooling the substituted hydrazide derivative usually precipitates. After filtration the product is usually recrystallized from hot methanol, ethanol or isopropyl alcohol. In cases where the hydrazide does not precipitate, the reaction is concen- trated under vacuo and chromatographed over silica gel using dichloromethane/methanol as the eluent. Specific examples illustrating the preparation of aromatic hydrazides are provided below.
  • step D Preparation of 2.3-Dichloro-4-hydroxybenzoic acid hydrazide and 2.5-dichloro-4- hydroxybenzoic acid hydrazide
  • 2,5-dichloro-4-hydroxybenzoic acid hydrazide was prepared in a similar way starting from 2,5-dichloro-4-hydroxybenzoate.
  • the product was purified via silica gel column chromatography using CH2Cl2/MeOH ( 95/5 to 80/20) to afford the title compound.
  • Methyl-4-hydroxybenzoate (35.5 g, 0.233 mol) was dissolved in 200 mL of warm (65 °C) acetic acid. A solution of iodine monochloride (37.8 g, 0.233 mol) in 50 mL of acetic acid was added slowly (40 minutes) to the methyl-4-hydroxybenzoate solution, while maintaining a temperature of 65 °C and vigorous stirring. The product crystallizes from solution upon cooling to room temperature and standing overnight. The crystals were collected on a filter, washed with water, then dried under vacuum. Methyl-4-hydroxy-3-iodobenzoate was obtained as white crystals (28.6 g, 44%).
  • Methyl-4-hydroxy-3-iodobenzoate (2.00 g, 7.2 mmol) was dissolved into 5 mL of dry DMF. Copper(l) cyanide (0.72 g, 8.0 mmol) and a small crystal of sodium cyanide was added. The mixture was flushed with nitrogen, placed in an oil heating bath (100-110 °C), and stirred overnight. TLC indicated nearly complete reaction. The mixture was cooled and the solids removed by filtration. The solids were extracted with DMF (3 mL). The filtrate and washings were taken up in 100 mL of ethyl acetate, then washed with 3 portions of saturated sodium chloride solution.
  • Methyl-3-cyano-4-hydroxybenzoate (2.71 g, 15.3 mmol) was dissolved in 50 mL of THF. The solution was chilled in an ice bath, and 2.0M potassium hydroxide (17 mL, 34 mmol) was added dropwise. The resulting mixture was stirred at room temperature overnight. TLC indicated complete reaction. The THF was removed by rotary evaporation. The aqueous re- sidue was acidified with aqueous trifluoroacetic acid and purified by reverse-phase HPLC (C- 18, 0.1 % TFA in water and acetonitrile). 3-Cyano-4-hydroxybenzoic acid was obtained as a white powder (2.1g, 84%) after lyophilization.
  • Step E The Boc-hydrazide (1.8g, 6.5 mmol) was suspended in 50 mL of chloroform and cooled in an ice-bath. Trifluoroacetic acid was added with stirring, and the resulting solution stood for 4 hours at 0 °C. TLC indicated complete reaction. Solvent and excess TFA were removed by rotary evaporation. The remaining oil was purified by reverse-phase liquid chromatography (Aquasil C-18 column, water/acetonitrile/0.1 % TFA). The title compound was obtained as a white solid (0.24 g, 13%).
  • Step A Silver nitrate (17 g, 0.1 mol) was dissolved in water (10 mL) and treated with 1 N NaOH (300 mL, 0.3 mol). The brown precipitate which was formed was stirred for 30 minutes and the supernatant was decanted. The brown silver oxide was washed with additional volumes of water (3x). To the silver oxide above was added 1N NaOH (150 mL) and 4-hydroxynaphthaldehyde (1 g, 6 mmol)). The mixture was heated to 70 °C for 10 minutes after which additional amounts of 4-hydroxynaphthaldehyde (5.5 g, 32 mmol) was added in portions. The mixture was kept at 80 °C for 16 hours. TLC analysis indicated incomplete conversion.
  • the ether-linked aldehydes may be prepared by 0-alkylation of the corresponding phenolic compounds using various electrophilic alkylating agents that introduce the -(K) m -D moiety as defined above in a reaction generally known as Williamson ether synthesis (H. Feuer, J. Hooz in The Chemistry of the Ether Linkage, S. Patai Ed., Wiley, New York 1967, p. 446-460).
  • Lx is a leaving group such as -Cl, -Br, -I, -OSO 2 CH 3 , -OSO 2 p-tolyl or -OSO 2 CF 3 ;
  • an ether-substituted aryl-aldehyde can be prepared by stirring hy- droxybenzaldehydes or hydroxynaphthaldehydes in an organic solvent such as acetone, meth- ylethyl ketone, dimethylformamide, dioxane, tetrahydrofuran, toluene, ethylene glycol dimethyl ether, sulfolane, diethylether, water or a compatible mixture of two or more of the above solvents with an equimolar amount of an alkyl halide or an aryl-lower alkyl halide and in the pres- ence of 1 to 15 equivalents (preferably 1 to 5 equivalents) of a base such as sodium hydride, potassium hydride, sodium or potassium methoxide, ethoxide or tej -butoxide, sodium, potassium or cesium carbonate, potassium or cesium fluoride, sodium or potassium hydroxide or organic bases
  • the reaction can be performed at 0°C to 150°C, preferably at 20°C to 100°C and preferably in an inert atmosphere of N 2 or Ar.
  • the reaction is complete the mixture is filtered, concentrated in vacuo and the resulting product optionally purified by column chromatography on silica gel using ethyl acetate/hexane as eluent.
  • the compound can also (when appropriate) be purified by recrystallization from a suitable solvent such as ethyl alcohol, ethyl acetate, isopropyl alcohol, water, hexane, toluene or their compatible mixture. Specific examples illustrating the preparation of ether-substituted aryl-aldehydes are provided below.
  • the crude syrup was heated neat in an oil bath at 200 °C for 6 h.
  • the crude material was dissolved in chloroform and filtered through a pack of silica gel.
  • the crude product (yield 72%) was used as is in the next step for O-alkylation.
  • a small portion was purified using prep-TLC to give a pure sample of 3-allyl-4-hydroxy-5-methoxy-benzaldehyde.
  • step D This type of aldehydes can be coupled to hydrazides using the methodology as described in step D to give a compound of formula IXa.
  • these compounds can undergo rearrangement by treatment with base as described below (step C), followed by coupling to a hydrazide (step D) to give a compound of formula IXb.
  • the resulting carbonyl compounds are treated with the corresponding acylhydrazide in a solvent.
  • the solvent may be one of the following: ethyl alcohol, methyl alcohol, isopropyl alcohol, tert-butyl alcohol, dioxane, tetrahydrofuran, toluene, chlorobenzene, anisole, benzene, chloroform, dichloromethane, DMSO, acetic acid, water or a compatible mixture of two or more of the above solvents.
  • a catalyst such as acetic acid can be added.
  • a dehydrating reagent such as triethylorthoformate can also be added to the reaction mixture.
  • the reaction is performed by stirring the reaction mixture preferably under an inert atmosphere of N 2 or Ar at temperatures between 0°C to 140°C, preferably between 10°C to 80°C.
  • the product simply crystallizes out when the reaction is completed and is isolated by suction filtration. It can be further recrystallized if necessary from a solvent such as the above described reaction sol- vents.
  • the product can also be isolated by concentration of the reaction mixture in vacuo, followed by column chromatography on silica gel using a solvent system such as chloroform/methanol or dichloromethane/methanol or chloroform/ethyl acetate to give a compound of formula IXb.
  • the acylhydrazides are treated with the corresponding carbonyl compounds, such as aldehydes or ketones, in a solvent.
  • the solvent may be one of the following: ethyl alcohol, methyl alcohol, isopropyl alcohol, te/ ⁇ f-butyl alcohol, dioxane, tetrahydrofuran, toluene, chlorobenzene, anisole, benzene, chloroform, dichloromethane, DMSO, acetic acid, water or a compatible mixture of two or more of the above solvents.
  • the reaction is performed by stirring the reaction mixture preferably under an inert atmosphere of N 2 or Ar at temperatures between 0°C to 140°C, preferably between 10°C to 80°C.
  • the product simply crystallizes out when the reaction is completed and is isolated by suction filtration. It can be further recrystal- lized if necessary from a solvent such as the above described reaction solvents.
  • the product can also be isolated by concentration of the reaction mixture in vacuo. followed by column chromatography on silica gel using a solvent system such as chloroform/-methanol or dichloromethane/methanol or chloroform/ethyl acetate. The product is isolated by concentration in vacuo of the appropriate fractions. Specific examples illustrating the preparation of compounds according to the invention are provided below. EXAMPLE 6:

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BR9810378A (pt) 2000-08-29

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