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Title:
SALTS AND SOLVATES OF GLUCAGON ANTAGONISTS
Document Type and Number:
WIPO Patent Application WO/2004/063147
Kind Code:
A1
Abstract:
The invention provides salts and solvated of glucagon antagonists.

Inventors:
Horvath, Karol (Fornhöjdsvägen 56, Södertälje, S-152 58, SE)
Jensen, Anette Frost (Lyngbyvej 32B, 7tv, Copenhagen Ø, DK-2100, DK)
Rasmussen, Kaare Gyberg (Trepkasgade 8, 1th, Copenhagen Ø, DK-2100, DK)
Junager, Finn Broni (Efterårsvej 7, Charlottenlund, DK-2920, DK)
Ekelund, Ole (Skovsvinget 4B, Kgs. Lyngby, DK-2800, DK)
Christophersen, Claus (Benløseparken 21, 1.th, Ringsted, DK-4100, DK)
Kornø, Hanne Tøfting (Trongårdsvej 27A, Lyngby, DK-2800, DK)
Application Number:
PCT/DK2004/000013
Publication Date:
July 29, 2004
Filing Date:
January 12, 2004
Export Citation:
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Assignee:
Novo, Nordisk A/s (Novo Allé, Bagsværd, DK-2880, DK)
Horvath, Karol (Fornhöjdsvägen 56, Södertälje, S-152 58, SE)
Jensen, Anette Frost (Lyngbyvej 32B, 7tv, Copenhagen Ø, DK-2100, DK)
Rasmussen, Kaare Gyberg (Trepkasgade 8, 1th, Copenhagen Ø, DK-2100, DK)
Junager, Finn Broni (Efterårsvej 7, Charlottenlund, DK-2920, DK)
Ekelund, Ole (Skovsvinget 4B, Kgs. Lyngby, DK-2800, DK)
Christophersen, Claus (Benløseparken 21, 1.th, Ringsted, DK-4100, DK)
Kornø, Hanne Tøfting (Trongårdsvej 27A, Lyngby, DK-2800, DK)
International Classes:
A61K31/15; A61K31/166; A61K31/197; A61K31/404; A61K31/426; A61P3/04; A61P3/10; C07C275/30; C07D277/42; C07D319/08; C07D333/68; (IPC1-7): C07C275/42; C07C211/27; C07C211/07; C07C279/14; A61K31/17; A61K31/13; A61P3/10; A61P3/04; C07C229/26; C07C215/08; C07C31/02
Domestic Patent References:
WO2002040446A12002-05-23
WO2002040445A12002-05-23
WO2002040444A12002-05-23
WO2002000612A12002-01-03
WO2003051357A12003-06-26
WO2003053938A12003-07-03
WO1998022109A11998-05-28
Foreign References:
US20020187982A12002-12-12
US5380838A1995-01-10
Attorney, Agent or Firm:
Novo, Nordisk A/s (Corporate Patents, Novo Allé, Bagsværd, DK-2880, DK)
Download PDF:
Claims:
CLAIMS
1. A composition comprising a salt of a glucagon antagonist and a pharmaceutical accept able base.
2. The composition of claim 1, wherein the pharmaceutically acceptable basic counter ion is derived from ammonium or imidazole or the metal ions of lithium, sodium, potassium, mag nesium, calcium, zinc, or the basic amino acids Larginine, Llysine, Lhistidine, and L ornithine; or alkylated ammonium derivatives such as diethylamine, tertbutylamine (erbu mine), 1, 2ethylenediamine, N (phenylmethyl)benzeneethaneamine (benethamine) or N, N' dibenzylethylenediamine (benzathine); or hydroxyalkylated ammonium derivatives trishy droxymethylaminomethane (tris, tromethamine), NmethylDglucamine (meglumine), cho line, monoethanolamine (2aminoethanol, lamine), diethanolamine (2,2'iminobis (ethanol)), triethanolamine (2, 2', 2"nitrilotris (ethanol), trolamine), 2diethylaminoethanol.
3. A composition according to claims 12, wherein the compound is represented by the general formula (I) below : wherein A is X is a valence bond,CR'R2orNR', Y is >CR3or >N, R', R2 and R3 independently are hydrogen or C, 4alkyl, or R'and R3 on adjacent atoms may be combined to form a double bond, E is C1, 0alkyl or C210alkenyl, # C310cycloalkyl, C310cycloalkenyl, C710bicycloalkyl, C310cycloalkylC16alkyl, C31ocycloalkenylC, 6alkyl or C710bicycloalkylC16alkyl, wherein the rings may optionally be substituted with one or more substituents selected from halogen, C16alkyl, C26alkenyl, C16alkoxy, C16thioalkyl, CF3, OCF3, SCF3, OCHF2 and SCHF2, # aryl, aryloxy, arylthio, heteroaryl, arylC16alkyl, aryloxyC16alkyl, arylthioC16alkyl, heteroarylC16alkyl, diarylC14alkyl or (C16alkyl)(aryl)C17alkyl, wherein the nonaromatic and aromatic rings may optionally be substituted with one or more substituents selected from halogen, C16alkyl, C26alkenyl, C16alkoxy, C16thioalkyl, CF3, OCF3, SCF3, CHF2, SCHF2, C310cycloalkyl and C310cycloalkenyl, or with two substitu ents on adjacent positions which are combined to form a bridge C16alkylene, C26alkenylene or OC16alkyleneO, B is R8 is hydrogen, Cl6alkyl or aryl, wherein aryl is optionally substituted with one or two sub stituents selected from halogen, C16alkyl, C16alkoxy, C16thioalkyl, CF3, OCF3, SCF3, OCHF2, SCHF2, SO2CF3 and SO2C16alkyl, R9 is hydrogen or C16alkyl, D is aryl or heteroaryl, which may optionally be substituted with one or more substituents selected from halogen,CF3,OCF3,SCF3,CN,NO2, C110alkyl, C26alkenyl, C16alkoxy, C, 6alkylthio, amino, C16alkylamino, diC16alkylamino, SO2CF3 and SO2C16alkyl, # C38cycloalkyl, C38cycloalkenyl, aryl and arylC16alkoxy, wherein the nonaromatic and aromatic rings optionally may be substituted with one to three substituents selected from halogen,CF3,OCF3,SCF3,CN,N02, C,, 0alkyl, C24alkenyl, C16alkoxy and C, 4alkylthio, or with two substituents on adjacent positions which are com bined to form a bridge O(CH2)mO(CH2)p or O(CF2)mO(CF2)p, wherein m is an integer of from 1 to 6, and p is 0 or 1, or with two substituents on adjacent positions which are combined to form a bridge O(CH2) mO(CH2) porO(CF2) mO(CF2) p, wherein m is an integer of from 1 to 6, and p is 0 or 1, or a substituent on B may be combined with a substiuent on D to form aC (=O) bridge, as well as any diastereomer or enantiomer or tautomeric form thereof including mixtures of these.
4. A compound according to claim 3, wherein B is wherein X'and Y'are as defined in claim 3.
5. A compound according to claim 4, wherein B is wherein R8 is as defined in claim 3.
6. A compound according to claims 35, wherein E is C,, 0alkyl C310cycloalkyl, which may optionally be substituted as defined in claim 3, wherein R4 and R5 are as defined in claim 3.
7. A compound according to claim 6 wherein E is wherein R4 is hydrogen and R5 is C16alkyl, C16alkoxy, cyclohexyl, halogen, CF3 or cyclo hex1enyl, or R4 and R5 on adjacent positions may be combined to form a bridge C16alkylene.
8. A compound according to claims 37, wherein D is wherein R10, R11, R12, R15, R16, R17 and R18 are as defined in claim 3.
9. A compound according to claim 8, wherein D is wherein R'°, R"and R12 are as defined in claim 3.
10. A compound according to claim 8 or 9, wherein R'°, R"and R12 independently are hy drogen, halogen,OCF3,CF3,NO2, diC16alkylamino, C110alkyl, C16alkoxy orCN, phenyl or phenylC16alkoxy, or two of R'°, R"and R12 in adjacent positions form a bridge0CH20,0CH2CH20or OCH2CH2CH2O.
11. A compound of claim 10 wherein one of R'°, R"and R12 represent hydrogen.
12. A compound according to claim 11, wherein one or two of R'°, R"and R12 is hydrogen, and the remaining is independently selected from halogen,OCF3,CF3,N02, di C16alkylamino, C110alkyl, C16alkoxy or CN.
13. A compound according to any one of the previous claims 312, wherein the compounds is selected from 3(4{[[4(4Chlorophenyl)thiazol2yl](4trifluoromethylphenyl amino] methyl} benzoylamino) propionic acid, 3(4{[[4(3,4Dichlorophenyl)thiazol2yl](5, 6,7, 8tetrahydronaphthalen2yl) amino] methyl} benzoylamino) propionic acid 3[4({(4Chlorophenyl)[4(4trifluoromethoxyphenyl)thiazol2yl]amino}methyl)benzoyl amino] propionic acid, <BR> <BR> <BR> <BR> <BR> 3 [4 ( ( (4Chlorophenyl) [4 (4trifluoromethylphenyl) thiazol2yl] amino) methyl) benzoylamino] propionic acid or 3[4({(4Trifluoromethoxyphenyl)[4(4trifluoromethylphenyl)thiazol2yl]amino}methyl) benzoylamino] propionic acid,.
14. The composition according to any one of claims 113, comprising 3(4{[[4(3,4Dichlorophenyl)thiazol2yl](5, 6,7, 8tetrahydronaphthalen2yl) amino] methyl} benzoylamino) propionic acid as a salt with tertbutylamine.
15. The composition according to any one of claims 113 comprising 3(4{[[4(4chlorophenyl)thiazol2yl](4trifluoromethylphenyl) amino] methyl} benzoylamino) propionic acid as a salt with Llysine.
16. The composition according to any one of claims 113, comprising 3(4{[[4(4chlorophenyl)thiazol2yl](4trifluoromethylphenyl) amino] methyl} benzoylamino) propionic acid as a salt with Lhistidine.
17. The composition according to any one of claims 113, comprising 3(4{[[4(4chlorophenyl)thiazol2yl](4trifluoromethylphenyl) amino] methyl} benzoylamino) propionic acid as a salt with monoethanolamine.
18. The composition according to any one of claims 113, comprising 3(4{[[4(4chlorophenyl)thiazol2yl](4trifluoromethylphenyl) amino] methyl} benzoylamino) propionic acid as a salt with tertbutylamine.
19. The composition according to any one of claims 113, comprising3 (4 { [ [4 chlorophenyl) thiazol2yl] (4trifluoromethylphenyl) amino] methyl} benzoylamino) propionic acid as a salt with 1, 2ethylenediamine.
20. The composition according to any one of claims 113, comprising 3(4{[[4(4chlorophenyl)thiazol2yl](4trifluoromethylphenyl) amino] methyl} benzoylamino) propionic acid as a salt with N, N'dibenzylethylenediamine.
21. A composition according to claims 12 comprising a compound represented by the gen eral formula (I) : wherein wherein R2 and R3 independently are hydrogen or C16alkyl, R4 is hydrogen, halogen,CN,CF3,OCF3,N02,OR5,NR5R6 or C16alkyl, wherein R5 and R5 independently are hydrogen or C16alkyl, A is wherein b is 0 or 1, n is 0, 1, 2 or 3, R7 is hydrogen, C16alkyl or C38cycloalkylC16alkyl, R8 and R9 independently are hydrogen or C16alkyl, Y isC (O),S (O) 2,0or a valence bond, Z is phenylen or a divalent radical derived from a 5 or 6 membered heteroaromatic ring con taining 1 or 2 heteroatoms selected from nitrogen, oxygen and sulfur, which may optionally be substituted with one or two groups R46 and R47 selected from hydro gen, halogen,CN,CF3,OCF3,N02,OR'°,NR'°R"and C16alkyl, wherein R'° and R"independently are hydrogen or C16alkyl, orAYZtogether are R'is hydrogen or C16alkyl, X is wherein r is 0 or 1, q and s independently are 0,1, 2 or 3, R'2, R'3, R'4 and R'5 independently are hydrogen or C16alkyl, D is wherein W is O, S, S (0) 2 orNR, W' is = CR20' or =N, R'6, R17, R'8 and R'9 independently are # hydrogen, halogen, CN, CH2CN, CHF2, CF3, OCF3, OCHF2, OCH2CF3, OCF2CHF2, OS(O)2CF3, SCF3, NO2, OR21, NR21R22, SR21, NR21S(O)2R22, S(O)2NR21R22, S(O)NR21R22, S(O)R21, S(O)2R21, OS(O)2R21, C(O)NR21R22, OC(O)NR21R22, <BR> <BR> <BR> NR2'C (O) Ræ,CH2C (O) NR2'R22,OCH2C (O) NR2'R22,CH20R2',CH2NR2'R22,<BR> <BR> <BR> <BR> <BR> OC (O) RC (O) R orC (O) OR<BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> # C16alkyl, C26alkenyl or C26alkynyl, which may optionally be substituted with one or more substituents selected fromCHF2,CF3, <BR> <BR> <BR> OCF3,OCHF2,OCH2CF3,OCF2CHF2,SCF3,OR,NR'R22,SR,S (O) R,S (0) 2R, C(O)NR21R22, C(O)NR21R22, NR21C(O)R22, OCH2C(O)NR21R22, C(O)R21 and C(O)OR21, # C38cycloalkyl, C48cycloalkenyl, heterocyclyl, C38cycloalkylC16alkyl, C38cyclo alkylC16alkoxy, C38cycloalkyloxy, C38cycloalkylC16alkylthio, C38cycloalkylthio, C38cycloalkylC26alkenyl, C38cycloalkylC26alkynyl, C48cycloalkenylC16alkyl, C48 cycloalkenylC26alkenyl, C48cycloalkenylC26alkynyl, heterocyclylC16alkyl, heterocy clylC26alkenyl or heterocyclylC26alkynyl, of which the cyclic moieties optionally may be substituted with one or more substituents se lected from <BR> <BR> <BR> <BR> <BR> CHF2,CF3,OCF3,OCHF2,OCH2CF3,OCF2CHF2,SCF3,OR,NR'R,SR<BR> <BR> <BR> <BR> S (O) R2',S (0) 2R2',C (O) NR2'R22,OC (O) NR2'Rz2,NR2'C (O) R22,OCH2C (O) NR2'R22,<BR> <BR> <BR> <BR> C (O) R' andC (O) OR, C, 4alkyl, C24alkenyl and C24alkynyl, which may optionally be substituted with one or more substituents selected fromCHF2,CF3, OCF3, OCHF2, OCH2CF3, OCF2CHF2, SCF3, OR21, NR21R22, SR21, S(O)R21, S(O)2R21, <BR> <BR> C (O) NR2'R22,OC (O) NR2'R22,NR2'C (O) R22,OCH2C (O) NR2'R22,C (O) R2'andC (O) OR2', # aryl, aryloxy, aryloxycarbonyl, aroyl, arylC16alkoxy, arylC16alkyl, arylC26alkenyl, aryl C26alkynyl, heteroaryl, heteroarylC16alkyl, heteroarylC26alkenyl or heteroaryl C2alkynyl, of which the aryl and heteroaryl moieties optionally may be substituted with one or more sub stituents selected from halogen,CN,CH2CN,CHF2,CF3,OCF3,OCHF2,OCH2CF3,OCF2CHF2,OS (0) 2CF3, SCF3, NO2, OR21, NR21R22, SR21, NR21S(O)2R22, S(O)2NR21R22, S(O)NR21R22, S(O)R21, <BR> <BR> <BR> S (0) 2R2'OS (0) 2R2'C (O) NR2'R22,OC (O) NR2'R22,NR2'C (O) R22,CH2C (O) NR2'R22,<BR> <BR> <BR> <BR> OCH2C (O) NR2'R22,CH2OR2',CH2NR2'R22,OC (O) R2',C (O) R2'andC (O) OR2', C16alkyl, C26alkenyl and C26alkynyl, which may optionally be substituted with one or more substituents selected fromCHF2,CF3, <BR> <BR> <BR> OCF3,OCHF2,OCH2CF3,OCF2CHF2,SCF3,OR21,NR2'R22,SR2',S (O) R2',S (0) 2R2', C(O)NR21R22, OC(O)NR21R22, NR21C(O)R22, OCH2C(O)NR21R22, C(O)R21 and C(O)OR21, wherein R 21 and R22 independently are hydrogen,CF3, C16alkyl, triC16alkylsilyl, C38cyclo alkyl, C38cycloalkylC16alkyl, aryl, arylC, 4alkyl or heteroaryl, or R2'and R22 when attached to the same nitrogen atom together with the said nitrogen atom may form a 3 to 8 membered heterocyclic ring optionally containing one or two further het eroatoms selected from nitrogen, oxygen and sulfur, and optionally containing one or two double bonds, or two of the groups R16 to R'9 when placed in adjacent positions together may form a bridge (CR16'R17')aO(CR18'R19')cO, wherein a is 0, 1 or 2, cis 1 or 2, R16', R17', R18' and R19' independently are hydrogen, C16alkyl or halogen, R20 and R20 independently are hydrogen, C16alkyl, C38cycloalkyl or C38cycloalkylC16 alkyl, E is a 3 to 9 membered monoor bicyclic ring which may optionally contain one or two dou ble bonds and which may optionally contain one or two heteroatoms selected from nitrogen, oxygen and sulfur, wherein one or two groups R23 and R24 may be attached to the same or different ring carbon atoms and wherein a group R3'may be attached to a ring nitrogen atom when present, or wherein m and p independently are 0,1, 2,3 or 4, with the proviso that when both m and p are pre sent in the same formula at least one of m and p is different from 0, R23 and R24 independently are hydrogen, CHF2, CF3, OCF3, OCHF2, OCH2CF3, OCF2CHF2, SCF3, OR36, NR36R37, SR36, S(O)R36, S(O)2R36, C(O)NR36R37, OC(O)NR36R37, NR36C(O)R37, OCH2C(O)NR36R37, C(O)R36 orC (O) OR C16alkyl, C26alkenyl or C26alkynyl, which may optionally be substituted with one or more substituents selected fromCHF2,CF3, OCF3, OCHF2, OCH2CF3, OCF2CHF2, SCF3, OR36, NR36R37, SR36, S(O)R36, S(O)2R36, C(O)NR36R37, OC(O)NR36R37, NR36C(O)R37, OCH2C(O)NR36R37, C(O)R36 andC (O) OR, # C38cycloalkyl, C38cycloalkylidene, C48cycloalkenyl, heterocyclyl, C38cycloalkyl C16alkyl, C38cycloalkylC26alkenyl, C38cycloalkylC26alkynyl, C48cycloalkenyl C16alkyl, C48cycloalkenylC26alkenyl, C48cycloalkenylC26alkynyl, heterocyclyl C16alkyl, heterocyclylC26alkenyl or heterocyclylC26alkynyl, of which the cyclic moieties optionally may be substituted with one or more substituents se lected from CHF2, CF3, OCF3, OCHF2, OCH2CF3, OCF2CHF2, SCF3, OR36, NR36R37, SR36, S(O)R36, S(O)2R36, C(O)NR36R37, OC(O)NR36R37, NR36C(O)R37, OCH2C(O)NR36R37, C (O) R andC (O) OR C, 6alkyl, C24alkenyl and C26alkynyl, which may optionally be substituted with one or more substituents selected fromCHF2,CF3, OCF3, OCHF2, OCH2CF3, OCF2CHF2, SCF3, OR36, NR36R37, SR36, S(O)R36, S(O)2R36, C(O)NR36R37, OC(O)NR36R37, NR36C(O)R37, OCH2C(O)NR36R37, C(O)R36 andC (O) OR, # aryl, aryloxy, aroyl, arylC16alkoxy, arylC16alkyl, arylC26alkenyl, arylC26alkynyl, het eroaryl, heteroarylC14alkyl, heteroarylC26alkenyl or heteroarylC24alkynyt, of which the aryl and heteroaryl moieties optionally may be substituted with one or more sub stituents selected from <BR> <BR> <BR> <BR> halogen,CN,CH2CN,CHF2,CF3,OCF3,OCHF2,OCH2CF3,OCF2CHF2,OS (0) 2CF3, SCF3, NO2, OR36, NR36R37, SR36, NR36S(O)2R37, S(O)2NR36R37, S(O)NR36R37, S(O)R36, S(O)2R36, OS(O)2R36, C(O)NR36R37, OC(O)NR36R37, NR36C(O)R37, CH2C(O)NR36R37, CH2C(O)NR36R37, CH2OR36, CH2NR36R37, OC(O)R36, C(O)R36 and C(O)OR36, C16alkyl, C26alkenyl and C26alkynyl, which may optionally be substituted with one or more substituents selected fromCHF2,CF3, OCF3, OCHF2, OCH2CF3, OCF2CHF2, SCF3, OR36, NR36R37, SR36, S(O)R36, S(O)2R36, C(O)NR36R37, OC(O)NR36R37, NR36C(O)R37, OCH2C(O)NR36R37, C(O)R36 andC (O) OR, wherein R36 and R37 independently are hydrogen, C »alkyl or aryl, of which the aryl moiety optionally may be substituted with one or more substituents selected from halogen,CN,CF3,OCF3,N02,OR38,NR38R39 and C16alkyl, wherein R38 and R39 independently are hydrogen or C16alkyl, or R36 and R37 when attached to the same nitrogen atom together with the said nitrogen atom may form a 3 to 8 membered heterocyclic ring optionally containing one or two further het eroatoms selected from nitrogen, oxygen and sulfur, and optionally containing one or two double bonds, or R23 and R24 when attached to the same ring carbon atom or different ring carbon atoms together may form a radicalO(CH2),CR4°R4'(CH2) 1O,(CH2),CR4°R4'(CH2) lor S(CH2)tCR40R41(CH2)@s, wherein t and I independently are 0,1, 2,3, 4 or 5, R40 and R4'independently are hydrogen or C16alkyl, R25 to R30 independently are hydrogen, halogen, CN, CF3, NO2, OR42, NR42R43, C16alkyl, C34cycloalkyl or C44cycloalkenyl, wherein R42 and R43 independently are hydrogen or C16alkyl, or R42 and R43 when attached to the same nitrogen atom together with the said nitrogen atom may form a 3 to 8 membered heterocyclic ring optionally containing one or two further het eroatoms selected from nitrogen, oxygen and sulfur, and optionally containing one or two double bonds, R3', R32 and R33 independently are hydrogen or C16alkyl, R34 and R35 independently are hydrogen, C16alkyl, C16alkoxy, C16alkanoyl, C(O)NR44R45 orS (O) 2R45, # aryl, aroyl, arylC16alkoxy, arylC16alkanoyl or arylC16alkyl, of which the aryl moieties optionally may be substituted with one or more substituents se lected from halogen, CN, CF3, OCF3, OR44, NR44R45 and C16alkyl, wherein R44 and R45 independently are hydrogen or C, $alkyl, or R34 and R35 when attached to a carbon atom together with the said carbon atom may form a 3 to 8 membered cyclic ring optionally containing one or two heteroatoms selected from ni trogen, oxygen or sulfur, and optionally containing one or two double bonds, or R34 and R35 when attached to a nitrogen atom together with the said nitrogen atom may form a 3 to 8 membered heterocyclic ring optionally containing one or two further heteroatoms se lected from nitrogen, oxygen or sulfur, and optionally containing one or two double bonds, as well as any optical or geometric isomer or tautomeric form thereof including mixtures of these.
22. A compound according to claim 21, wherein V isC (O) OH or 5tetrazolyl.
23. A compound according to claim 21 or 22, wherein A is.
24. A compound according to any one of the claims 2123, wherein Y isC (O), or Y is a valence bond.
25. A compound according to any one of the claims 21 to 24, wherein Z is.
26. A compound according to claims 2125, wherein R'is hydrogen or methyl.
27. A compound according to claims 2126, wherein X isC (O) NH,C (O) NHCH2,C (O) NHCH (CH3),C (O) NHCH2CH2, C (O) CH2,CH2,C (O) orNHC (O) .
28. A compound according to claims 2327, wherein D is wherein one or two of R'5, R", and R13 are hydrogen and the remaining is independently se lected fromOCF3,SCF3CF3,S (O) 2CH3, phenyl, halogen, C16alkyl, nitro, SC16alkyl or S(O)2NR21R22, wherein R21 is C16alkyl and R22 is phenyl.
29. A compound according to claim 2128, wherein E is wherein R23 is hydrogen and R24 is C16alkyl such as tertbutyl or C38cycloalkyl such as cyclohexyl, wherein R23 and R24 are both C16alkyl or wherein R23 and R24 together form the radical (CH2) 5.
30. A compound according to claims 2128, wherein E is wherein R25 is OCF3, CF3, C16alkyl such as tertbutyl, phenyl, piperidyl, C38cycloalkyl such as cyclohexyl or C48cycloalkenyl such as cyclohexenyl.
31. The compound according to any one of the claims 2130 wherein the compound is any of the following 3 {4 [1 (4Cyclohex1enylphenyl)3 (3, 5dichlorophenyl) ureidomethyl] benzoylamino} propionic acid, <BR> <BR> <BR> <BR> 4 [3 (3, 5Bistrifluoromethylphenyl)1 (4tertbutylcyclohexyl) ureidomethyl]N (2Htetrazol5 yl) benzamide, (S)4 [3 [1 (4Chlorophenyl) ethyl]1 (4cyclohexylphenyl) ureidomethyl]N (2Htetrazol5 yl) benzamide, 4[1(4Cyclohexylphenyl)3(3fluoro5trifluoromethylphenyl)ureidomethyl]N(2Htetrazol5 yl) benzamide <BR> <BR> <BR> <BR> <BR> 4 [3 (3Bromo5trifluoromethylphenyl)1 (4tertbutylphenyl) ureidomethyl]N (2Htetrazol5 yl) benzamide, <BR> <BR> <BR> <BR> <BR> 4 [3 (3Bromo5trifluoromethylphenyl)1 (4cyclohexylphenyl) ureidomethyl]N (2Htetrazol5 yl) benzamide, 4 [3 (3Bromophenyl)1 (4cyclohex1enylphenyl) ureidomethyl]N (2Htetrazol5yl) benzamide.
32. The composition according to any one of the claims 12 and 2131 comprising N [4 { {4 (lcyclohexen1yl) [ (3, 5 dichloroanilino)carbonyl[anilino}methyl)benzoyl]ßalanine and tertbutylamine.
33. The composition according to any one of the claims 12 and 2131 comprising N [4 ( {4 (lcyclohexen1yl) [ (3, 5 dichloroanilino) carbonyl] anilino} methyl) benzoyl]ßalanine and Larginine.
34. A composition according to claims 12 comprising a compound represented by the gen eral formula (I) : wherein R', R2, R3, R4 and R5 independently are hydrogen or C16alkyl, A isC (O),CH (OR6) or CHF, wherein R5 is hydrogen or C16alkyl, Z is arylene or a divalent radical derived from a 5 or 6 membered heteroaromatic ring con taining 1 or 2 heteroatoms selected from nitrogen, oxygen and sulfur, which may optionally be substituted with one or two groups R7 and R8 selected from halogen, CN, CF3, OCF3, NO2, OR9, NR9R10 and C16alkyl, wherein R9 and R'° independently are hydrogen or C, 4alkyl, X is wherein r is 0 or 1, q and s independently are 0,1, 2 or 3, R", R12, R13 and R'4 independently are hydrogen, C16alkyl or C38cycloalkyl, D is wherein R15, pie R'7 and R13 independently are hydrogen, halogen,CN,CHF2,CF3,OCF3,OCHF2,OCH2CF3,OCF2CHF2, S(O)2CF3, SCF3, NO2, OR21, NR21R22, SR21, NR21S(O)2R22, S(O)2NR21R22, S(O)NR21R22, S(O)R21, S(O)2R21, C(O)NR21R22, OC(O)NR21R22, NR21C(O)R22, CH2C(O)NR21R22, OCH2C(O)NR21R22, OC(O)R21, C(O)R21 or C(O)OR21, # C16alkyl, C26alkenyl or C26alkynyl, which may optionally be substituted with one or more substituents selected from halogen, CN,CF3,OCF3,N02,OR2',NR2'R22 and C16alkyl, # C38cycloalkyl, C48cycloalkenyl, heterocyclyl, C38cycloalkylC16alkyl, C38cyclo alkylC16alkoxy, C38cycloalkyloxy, C38cycloalkylC16alkylthio, C38cycloalkylthio, C38cycloalkylC26alkenyl, C38cycloalkylC26alkynyl, C48cycloalkenylC16alkyl, C48cycloalkenylC26alkenyl, C48cycloalkenylC26alkynyl, heterocyclylC16alkyl, heterocyclylC2alkenyl, heterocyclylC26alkynyl, aryl, aryloxy, aryloxycarbonyl, aroyl, arylC16alkoxy, arylC16alkyl, arylC26alkenyl, arylC26alkynyl, heteroaryl, heteroarylC, 4alkyl, heteroarylC24alkenyl or heteroarylC24alkynyl, of which the cyclic moieties optionally may be substituted with one or more substituents se lected from halogen (O) OR21, CN, CF3, OCF3, NO2, OR21, NR21R22 and C16alkyl, wherein R2'and RZ independently are hydrogen, C16alkyl, arylC16alkyl or aryl, or R2'and RZ when attached to the same nitrogen atom together with the said nitrogen atom may form a 3 to 8 membered heterocyclic ring optionally containing one or two further het eroatoms selected from nitrogen, oxygen and sulfur, and optionally containing one or two double bonds, or two of the groups R'5 to R'8 when placed in adjacent positions together may form a bridge (CR23R24)aO(CR25R26)cO, wherein a is 0,1 or 2, c is 1 or 2, R23, R24,R25 and R26 independently are hydrogen, C16alkyl or fluorine, R'9 and R20 independently are hydrogen, C16alkyl, C38cycloalkyl or C38cyclo alkylC16alkyl, E is R30 R30 R30 Rzi R \ Ra'Rzs \ Ra' \ Ra I HZ (I Hz) z ? R30 R30 R27% R R r, 30 i \ i \ Rza 2, CH2 (CH2) 2 R f WR28 Rz'H C CH H3C CH C, _ealkyl\'C_e alkyl 28 28 Or ", CH2 R , CHz wherein R27 and R28 independently are hydrogen, halogen, CN, CF3, OR32, NR32R33, C16alkyl, C38cycloalkyl, C48cycloalkenyl or aryl, wherein the aryl group optionally may be substituted with one or more substituents selected from halogen,CN,CF3,N02,OR32,NR3zR33 and C16alkyl, wherein R32 and R33 independently are hydrogen or C16alkyl, or R32 and R when attached to the same nitrogen atom together with the said nitrogen atom may form a 3 to 8 membered heterocyclic ring optionally containing one or two further het eroatoms selected from nitrogen, oxygen and sulfur, and optionally containing one or two double bonds, R29, R30 and R3'independently are hydrogen, halogen, CHF2, CF3, OCF3, OCHF2, OCH2CF3, OCF2CHF2, SCF3, OR34, NR34R35, SR3, S(O)R34, S(O)2R34, C(O)NR34R35, OC(O)NR34R35, NR34C(O)R35, OCH2C(O)NR34R35, C(O)R34 or C(O)OR34, # C16alkyl, C26alkenyl or C26alkynyl, which may optionally be substituted with one or more substituents selected from halogen, <BR> <BR> <BR> CN,CF3,OCF3,NO2,oR34,NR34R35 and C, 6alkyl<BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> # C38cycloalkyl, C48cycloalkenyl, heterocyclyl, C38cyclaolkylC16alkyl, C38cyclo alkylC26alkenyl, C38cycloalkylC26alkynyl, C48cycloalkenylC16alkyl, C48cyclo alkenylC26alkenyl, C48cycloalkenylC24alkynyl, heterocyclylC, 6alkyl, heterocy clylC26alkenyl, heterocyclylC26alkynyl, aryl, aryloxy, aroyl, arylC16alkoxdy, aryl C16alkyl, arylC26alkenyl, arylC26alkynyl, heteroaryl, heteroarylC16alkyl, hetero arylC26alkenyl or heteroarylC26alkynyl, of which the cyclic moieties optionally may be substituted with one or more substituents se lected from halogen,CN,CF3,OCF3,NO2,oR34,NR34R35 and C16alkyl, wherein R34 and R35 independently are hydrogen, C, 6alkyl or aryl, or R34 and R35 when attached to the same nitrogen atom together with the said nitrogen atom may form a 3 to 8 membered heterocyclic ring optionally containing one or two further het eroatoms selected from nitrogen, oxygen and sulfur, and optionally containing one or two double bonds, or two of the groups R29, R30 and R3'when attached to the same ring carbon atom or differ ent ring carbon atoms together may form a radical O(CH2)tCR36R37(CH2)lO, (CH2)tCR36R37(CH2)l or S(CH2)tCR36R37(CH2)lS, wherein t and I independently are 0,1, 2,3, 4 or 5, R36 and R37 independently are hydrogen or C, 4alkyl, as well as any optical or geometric isomer or tautomeric form thereof including mixtures of these.
35. A compound according to claim 34, wherein R', R2, R3i R4 and R5 are hydrogen.
36. A compound according to claim 34 or 35, wherein A isCHF.
37. A compound according to claim 34 or 35, wherein A isCH (OR6), wherein R6 is as de fined in claim 34.
38. A compound according to claim 37, wherein A isCH (OH).
39. A compound according to any of the claims 3438, wherein Z is wherein R7 and R8 are as defined in claim 34.
40. A compound according to claim 39, wherein Z is.
41. A compound according to claims 3440, wherein X isC (O) NH, C (O) NHCH2, C(O) NHCH (CH3),C (O) CH2 or C (O) .
42. A compound according to claim 41, wherein X isC (O) NH.
43. A compound according to claims 3442, wherein D is wherein R15, R'6 and R17 independently are hydrogen, halogen,CN,CF3,OCF3 or Cl6 alkoxy.
44. A compound according to claims 3443, wherein E is wherein R29 and R3'are both hydrogen, and R30 is cyclohexenyl, which may optionally be substituted with one or more substituents selected from halogen,CN,CF3,OCF3,NOz,OR,NR34R35 and C16alkyl, wherein R34 and R35 independently are hydrogen, C16alkyl or aryl, # or R34 and R35 when attached to the same nitrogen atom together with the said nitro gen atom may form a 3 to 8 membered heterocyclic ring optionally containing one or two further heteroatoms selected from nitrogen, oxygen and sulfur, and optionally containing one or two double bonds.
45. A compound according to claim 44, wherein R29, R30 and R3'independently are hydro gen, C18alkyl, phenyl, C38cycloalkyl or C48cycloalkenyl.
46. A compound according to claim 45, wherein R29 and Rare both hydrogen and R30 is C16alkyl, C38cycloalkyl or C4. 8cycloalkenyl.
47. A compound according to any one of the claims 3446 wherein the compound is se lected from the following : <BR> <BR> <BR> <BR> (R)3 {4 [1 (4Cyclohexylphenyl)3 (3methoxy5trifluoromethylphenyl) ureidomethyl] benzoyl amino}2hydroxypropionic acid (R)3 {4 [3 (3, 5Bis (trifluoromethyl) phenyl)1 (4cyclohexylphenyl) ureidomethyl] benzoyl amino}2hydroxypropionic acid <BR> <BR> <BR> <BR> (R)3 {4 [3 (3Bromophenyl)1 (4cyclohexylphenyl) ureidomethyl] benzoylamino}2hydroxy propionic acid (R)3 {4 [l (4Cyclohexylphenyl)3 (4trifluoromethoxyphenyl) ureidomethyl] benzoylaminol2 hydroxypropionic acid <BR> <BR> <BR> <BR> <BR> (R)3 (4 [l (4Cyclohexylphenyl)3 (3trifluoromethylphenyl) ureidomethyl] benzoylamino)2 hydroxypropionic acid <BR> <BR> <BR> <BR> <BR> (R)3 {4 [1 (4Cyclohexylphenyl)3 (3fluoro5trifluoromethylphenyl) ureidomethyl] benzoyl amino}2hydroxypropionic acid (R)3 {4 [3 (3Cyano5trifluoromethylphenyl)1 (4cyclohex1enylphenyl) ureidomethyl] benzoylamino}2hydroxypropionic acid <BR> <BR> <BR> <BR> <BR> (R)3 {4 [3 (3Cyano5trifluoromethylphenyl)1 (4cyclohexylphenyl) ureidomethyl] benzoyl amino}2hydroxypropionic acid (R)3 {4 [3 (3Bromo5trifluoromethylphenyl)1 (4cyclohex1enylphenyl) ureidomethyl] benzoylamino}2hydroxypropionic acid <BR> <BR> <BR> <BR> <BR> (R)3 {4 [l (4Cyclohexlenylphenyl)3 (3methoxy5trifluoromethylphenyl) ureidomethyl] benzoylamino}2hydroxypropionic acid (R)3 {4 [3 (3Bromophenyl)1 (4cyclohex1enylphenyl) ureidomethyl] benzoylamino}2 hydroxypropionic acid (R)3{4[3(3Bromo5trifluoromethylphenyl)1(4cyclohexylphenyl)ureidomethyl]benzoyl amino} 2hydroxypropionic acid (S)Trans3 {4 [3 (3, 5Bis (trifluoromethyl) phenyl)1 (4tertbutylcyclohexyl) ureidomethyl] benzoylamino}2hydroxypropionic acid (R)Trans3 {4 [3 (3, 5bis (trifluoromethyl) phenyl)1 (4tertbutylcyclohexyl) ureidomethyl] benzoylamino}2hydroxypropionic acid <BR> <BR> <BR> <BR> <BR> Trans (R)3 {4 [3 (3methyl5trifluoromethylphenyl)1 (4tertbutylcyclohexyl) ureidomethyl] benzoylamino}2hydroxypropionic acid <BR> <BR> <BR> <BR> <BR> (RS)3 {4 [1 (4tertButylphenyl)3 (4trifluoromethoxyphenyl) ureidomethyl] benzoylamino}2 hydroxypropionic acid <BR> <BR> <BR> <BR> <BR> (RS)3 {4 [1 (4Cyclohex1enylphenyl)3 (3, 5dichlorophenyl) ureidomethyl] benzoylamino} 2hydroxypropionic acid <BR> <BR> <BR> <BR> <BR> (S)3 {4 [1 (4Cyclohex1enylphenyl)3 (3, 5dichlorophenyl) ureidomethyl] benzoylamino}2 hydroxypropionic acid (R)3 {4 [1 (4Cyclohex1enylphenyl)3 (3, 5dichlorophenyl) ureidomethyl] benzoylamino}2 hydroxypropionic acid (R)3 {4 [3 (3Chlorophenyl)1 (4cyclohex1enylphenyl) ureidomethyl] benzoylamino}2 hydroxypropionic acid (R)3 {4 [1 (4Cyclohex1enylphenyl)3phenylureidomethyl] benzoylamino}2hydroxy propionic acid (R)3 {4 [3Benzyl1 (4cyclohex1enylphenyl) ureidomethyl] benzoylamino}2hydroxy propionic acid <BR> <BR> <BR> <BR> <BR> (RS)3 {4 [1 (4Cyclohex1enylphenyl) 3 (3, 5dichlorophenyl) ureidomethyl] benzoylamino}2 fluoropropionic acid (R)3 {4 [1 (4Cyclohexylphenyl)3 (4trifluoromethylsulfanylphenyl) ureidomethyl] benzoyl amino}2hydroxypropionic acid (R)3 {4 [1 (4Cyclohexen1ylphenyl)3 (3methanesulfonyl4trifluoromethoxyphenyl) ureidomethyl] benzoylamino}2hydroxypropionic acid Trans (R)3 {4 [3 (3, 5bis (methyl) phenyl)l (4tertbutylcyclohexyl) ureidomethyl] benzoyl amino}2hydroxypropionic acid (R)3 {4 [l (4Cyclohexylphenyl)3 (3, 5dichlorophenyl) ureidomethyl] benzoylamino)2 hydroxypropionic acid (R) (3 {4 [1 (4Cyclohex1enylphenyl)3 (3fluoro5trifluoromethylphenyl) ureidomethyl] benzoylamino}2hydroxypropionic acid <BR> <BR> <BR> <BR> <BR> (R)3 {4 [1 (4Cyclohexylphenyl)3 (3methylsulfanylphenyl) ureidomethyl] benzoylamino}2 hydroxypropionic acid (R)3 {4 [1 (4Cyclohex1enylphenyl)3 (2, 2, 4, 4tetrafluoro4Hbenzo [1,3] dioxin6yl) ureido methyl] benzoylamino}2hydroxypropionic acid 3 {4 [1 (4Cyclohex1enylphenyl)3 (3, 5dichlorophenyl) ureidomethyl] benzoylamino}2 (R) methoxypropionic acid : 3 (4 {3 (3, 5Dichlorophenyl)1 [4 (2methylcyclohex1enyl) phenyl] ureidomethyl} benzoyl amino)2 (R)hydroxypropionic acid and (R, S)3 (4 {3 (3, 5dichlorophenyl)1 [4 (6 <BR> <BR> <BR> <BR> methylcyclohex1enyl) phenyl] ureidomethyl} benzoylamino)2(R)hydroxypropionic acid<BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> 3 {4 [1 [4 (4tertButylcyclohex1enyl) phenyl]3 (3, 5dichlorophenyl) ureidomethyl] benzoyl<BR> <BR> <BR> <BR> <BR> <BR> amino}2(R)hydroxypropionic acid (R, S)3 (4 (3 (3, 5dichlorophenyl)1 (4 (3methylcyclohex1 enyl) phenyl) ureidomethyl) benzoylamino)2hydroxypropionic acid 3 {4 [3 [1 (S) (4Chlorophenyl) ethyl]1 (4cyclohexylphenyl) ureidomethyl] benzoylamino}2 (R) hydroxypropionic acid 3 {4 [3Biphenyl2ylmethyl1 (4cyclohexylphenyl) ureidomethyl] benzoylamino}2 (R) hydroxypropionic acid <BR> <BR> <BR> <BR> <BR> (R)3 {4 [3 (4Cyano3trifluoromethylphenyl)1 (4cyclohexylphenyl) ureidomethyl] benzoyl amino}2hydroxypropionic acid (R)3{4[3(3tertButylphenyl)1(4cyclohexylphenyl)ureidomethyl]benzoylamino}2 hydroxypropionic acid (R)3 {4 [1 (4Cyclohexylphenyl)3 (3hydroxymethyl4trifluoromethoxyphenyl) ureido methyl] benzoylamino}2hydroxypropionic acid (R)3 {4 [1 (4tertButylphenyl)3 (3, 4dichlorophenyl) ureidomethyl] benzoylamino}2 hydroxypropionic acid (R)3 {4 [1 (4tertButylcyclohexyl)3 (3, 4dichlorophenyl) ureidomethyl] benzoylamino}2 hydroxypropionic acid (R)3 {4 [l (4Cyclohexylphenyl)3 (3, 4dichlorophenyl) ureidomethyl] benzoylamino)2 hydroxypropionic acid (R)3 {4 [1 (4Cyclohexylphenyl)3 (2, 2,4, 4tetrafluoro4Hbenzo [1,3] dioxin6yl) ureido methyl] benzoylamino}2hydroxypropionic acid (R)3 {4 [1 (4tertButylphenyl)3 (2, 2,4, 4tetrafluoro4Hbenzo [1,3] dioxin6yl) ureidomethyl] benzoylamino}2hydroxypropionic acid (R)3 {4 [1 (4tertButylcyclohexyl)3 (2, 2,4, 4tetrafluoro4Hbenzo [1,3] dioxin6yl) ureido methyl] benzoylamino}2hydroxypropionic acid <BR> <BR> <BR> <BR> <BR> (R)3 {4 [1 (4tertButylphenyl)3 (3, 4difluorophenyl) ureidomethyl] benzoylamino}2hydroxy propionic acid (R)3 {4 (1 (4Cyclohexylphenyl)3 (3, 4difluorophenyl) ureidomethyl] benzoylamino}2 hydroxypropionic acid <BR> <BR> <BR> <BR> <BR> (R)3 {4 [l (4Cyclohexlenylphenyl)3 (3, 4difluorophenyl) ureidomethyl] benzoylamino)2 hydroxypropionic acid (R)3 {4 [3 (4Chloro3trifluoromethylphenyl)1 (4cyclohexylphenyl) ureidomethyl] benzoyl amino}2hydroxypropionic acid (R)3 {4 [l (4Cyclohexylphenyl)3 (4fluoro3nitrophenyl) ureidomethyl] benzoylamino)2 hydroxypropionic acid (R)3 {4 [l (4Cyclohexylphenyl)3 (4isopropylphenyl) ureidomethyl] benzoylamino)2 hydroxypropionic acid <BR> <BR> <BR> <BR> <BR> (R)3 {4 (1 (4Cyclohex1enylphenyl)3 (3, 4dichlorophenyl) ureidomethyl] benzoylamino}2 hydroxypropionic acid <BR> <BR> <BR> <BR> <BR> <BR> (R)3 {4 [3 (4Acetylphenyl)1 (4cyclohexylphenyl) ureidomethyl] benzoylamino}2hydroxy propionic acid <BR> <BR> <BR> <BR> <BR> <BR> 3 {4 [3 [1 (RS) (4Bromophenyl) ethyl]1 (4cyclohexylphenyl) ureidomethyl] benzoylamino} 2 (R) hydroxypropionic acid (R)3 {4 [1 (4Cyclohexylphenyl)3 (3, 5difluorophenyl) ureidomethyl] benzoylamino}2 hydroxypropionic acid (R)3[4({(4tertButylcyclohexyl)[2(4trifluoromethoxyphenyl)acetyl]amino}methyl)benzoyl amino] 2hydroxypropionic acid <BR> <BR> <BR> <BR> <BR> <BR> (R)3 [4 ( { (4tertButylcyclohexyl) [2 (3fluoro5trifluoromethylphenyl) acetyl] amino} methyl) benzoylamino]2hydroxypropionic acid (R)3 [4 ( { (2, 2Diphenylethyl) [2 (3fluoro5trifluoromethylphenyl) acetyl] amino} methyl) benzoylamino]2hydroxypropionic acid (R)3(4{[(5Chlorobenzo[b]thiophene3carbonyl)(2,2diphenylethyl) amino] methyl} benzoyl amino) 2hydroxypropionic acid (R)3 [4 ( { (2, 2Diphenylethyl) [2 (4trifluoromethoxyphenyl) acetyl] amino} methyl) benzoyl amino]2hydroxypropionic acid (R)3(4{[(4tertButylcyclohexyl)(5chlorobenzo[b]thiophene3carbonyl) amino] methyl} benzoylamino)2hydroxypropionic acid (R)3 (4 { [ (2, 2Diphenylethyl) (5trifluoromethoxy1 Hindole2carbonyl) amino] methyl} benzoylamino)2hydroxypropionic acid (R)3[4({(4Cyclohexylphenyl)[(4trifluoromethoxyphenyl)acetyl]amino}methyl)benzoyl amino] 2hydroxypropionic acid (R)3[3({(4Cyclohexylphenyl)[(3trifluoromethoxyphenyl)acetyl]amino}methyl)benzoyl amino] 2hydroxypropionic acid (R)3 [4 ( { (4Cyclohexylphenyl) [ (3fluoro5trifluoromethylphenyl) acetyl] amino} methyl) benzoylamino]2hydroxypropionic acid (R)3 (4 { ( [ (3, 5Bis (trifluoromethyl) phenyl) acetyl] (4cyclohexylphenyl) amino) methyl} benzoyl amino) 2hydroxypropionic acid <BR> <BR> <BR> <BR> <BR> (R)3 [4 ( { (4Cyclohexylphenyl) [ (3trifluoromethylphenyl) acetyl] amino} methyl) benzoylamino] 2hydroxypropionic acid <BR> <BR> <BR> <BR> <BR> (R)3 [4 ( { (4Cyclohexylphenyl) [ (3, 4dichlorophenyl) acetyl] amino} methyl) benzoylamino]2 hydroxypropionic acid (R)3(4{[[(3Bromophenyl)acetyl](4cyclohexylphenyl) amino] methyl} benzoylamino)2 hydroxypropionic acid (R)3 (4 { [ (Biphenyl4ylacetyl) (4cyclohexylphenyl) amino] methyl} benzoylamino)2hydroxy propionic acid (R)3(4{[(4Cyclohexylphenyl)(2naphthylacetyl) amino] methyl} benzoylamino)2hydroxy propionic acid (R)3 (4 { [ (3 (3, 5Bis (trifluoromethyl) phenyl) propionyl) (4cyclohexylphenyl) amino] methyl} benzoylamino)2hydroxypropionic acid (R)3[4({(4Cyclohexylphenyl)[3(3nitrophenyl)propionyl]amino}methyl)benzoylamino]2 hydroxypropionic acid (2R)N[4({4cyclohexyl[(3,5dichloroanilino)carbonyl]anilino}methyl)benzoyl]2hydroxyß alanine (2R)N[4({[1,1'biphenyl]4 yl[(3,5dichloroanilino)carbonyl]amino}methyl)benzoyl]2 hydroxyßalanine.
48. The composition according to any one of the claims 12 and 3447, comprising <BR> <BR> <BR> <BR> <BR> (R) [3 {4 (1 (4Cyclohex1enylphenyl)3 (3, 5dichlorophenyl) ureidomethyl] benzoylamino} 2Rhydroxypropionic acid as a tertbutylamine salt.
49. The composition according to any one of the claims 12 and 3447, comprising <BR> <BR> <BR> <BR> <BR> (R) [3 {4 [1 (4Cyclohex1enylphenyl)3 (3, 5dichlorophenyl) ureidomethyl] benzoylamino} 2Rhydroxypropionic acid as an Larginine salt.
50. The composition according to any one of the claims 12 and 3447, comprising (R) [3 {4 [1 (4Cyclohex1enylphenyl)3 (3, 5dichlorophenyl) ureidomethyl] benzoylamino}2R hydroxypropionic acid as a salt with N, N'dibenzylethylenediamine.
51. The composition according to claim 50 comprising (R) [3 {4 [1 (4Cyclohex1 <BR> <BR> <BR> <BR> enylphenyl)3 (3, 5dichlorophenyl) ureidomethyl] benzoylamino}2Rhydroxypropionic acid as a salt with N, N'dibenzylethylenediamine as a 2: 1 ratio between compound and N, N' dibenzylethylenediamine.
52. The composition according to any one of the claims 12 and 3447 comprising (2R)N [4 <BR> <BR> <BR> <BR> ({[1, 1'biphenyl] 4yl [(3, 5dichloroanilino) carbonyl] amino} methyl) benzoyl]2hydroxyßalanine and benzathine.
53. The composition according to claim 52 comprising (2R)N[4({[1,1'biphenyl]4yl[(3, 5 dichloroanilino) carbonyl] amino} methyl) benzoyl]2hydroxyßalanine and benzathine as a 2: 1 ratio between compound and N, N'dibenzylethylenediamine.
54. The composition according to any one of the claims 12 and 3447 comprising ( (2R)N [4({4cyclohexyl[(3,5dichloroanilino)carbonyl]anilino}methyl)benzoyl]2hydroxyßalanine as a salt with N, N'dibenzylethylenediamine.
55. The composition according to claim 54 comprising ( (2R)N [4 ( {4cyclohexyl [ (3, 5 dichloroanilino) carbonyl] anilino} methyl) benzoyl]2hydroxyßalanine as a salt with N, N' dibenzylethylenediamine in a 2: 1 ratio of compound to N, N'dibenzylethylenediamine.
56. A composition according to claims 12 comprising a compound represented by the gen eral formula (I) : wherein R2 is hydrogen or C1alkyl, Z is arylene or a divalent radical derived from a 5 or 6 membered heteroaromatic ring con taining 1 or 2 heteroatoms selected from nitrogen, oxygen and sulfur, which may optionally be substituted with one or two groups R 7and R8 selected from halogen, CN,CF3,OCF3,N02,OR9,NR9R'° and C16alikyl, wherein R9 and R'° independently are hydrogen or C16alkyl, X is wherein ris0 or 1, q and s independently are 0,1, 2 or 3, R", R12,R13 and R'4 independently are hydrogen or C16alkyl, D is wherein pi5 R'6, R17 and R18 independently are hydrogen, halogen,CN,CH2CN,CHF2,CF3,OCF3,OCHF2,OCH2CF3, OCF2CHF2, S(O)2CF3, SCF3, NO2, OR21, NR21R22, SR21, NR21S(O)2R22, S(O)2NR21R22, S(O)NR21R22, S(O)R21, S(O)2R21, C(O)NR21R22, OC(O)NR21R22, NR21C(O)R22, CH2C(O)NR21R22, OCH2C(O)NR21R22, CH2OR21, CH2NR21R22, OC (O) R,C (O) R orC (O) OR, # C16alkyl, C26alkenyl or C26alkynyl, which may optionally be substituted with one or more substituents selected from halogen, CN, CF3, OCF3, NO2, OR21, NR21R22 and C16alkyl, # C38cycloalkyl, C48cycloalkenyl, heterocyclyl, C38cycloalkylC16alkyl, C38cyclo alkylC16alkoxy, C38cycloalkloxy, C38cycloalkylC16alkylthio, C38cycloalkylthio, C38cycloalkylC26alkenyl, CmcycloalkylC26alkynyl, C"cycloalkenylCI6alkyl, C48cycloalkenylC26alkenyl, C48cycloalkenylC26alkynyl, heterocyclylC16alkyl, heterocyclylC26alkenyl, heterocyclylC26alkynyl, aryl, aryloxy, aryloxycarbonyl, aroyl, arylC16alkoxy, arylC16alkyl, arylC26alkenyl, arylC26alkynyl, heteroaryl, heteroarylC16alkyl, heteroarylC26alkenyl or heteroarylC26alkynyl, of which the cyclic moieties optionally may be substituted with one or more substituents se lected from halogen, CN, CF3, OCF3, NO2, OR21, NR21R22 and C16alkyl, wherein R21 and R22 independently are hydrogen, C, $alkyl or aryl, or R21 and R22 when attached to the same nitrogen atom together with the said nitrogen atom may form a 3 to 8 membered heterocyclic ring optionally containing one or two further het eroatoms selected from nitrogen, oxygen and sulfur, and optionally containing one or two double bonds, or two of the groups R'5 to R18 when placed in adjacent positions together may form a bridge (CR23R24)aO(CR25R26)cO. wherein a is 0, 1 or 2, cis 1 or 2, R23, R24, R25 and R26 independently are hydrogen, C16alkyl or fluorine, R'9 and R20 independently are hydrogen, C16alkyl, C38cycloalkyl or C3. 8cyclo alkylC16alkyl, E is wherein R27 and R28 independently are hydrogen, halogen, CN, CF3, OCF3, OR32, NR32R33, C16alkyl, C38cycloalkyl, C48cyclo alkenyl or aryl, wherein the cyclic moieties optionally may be substituted with one or more substituents se lected from halogen,CN,CF3,OCF3,NO2,OR32,NR32R33 and C16alkyl, wherein R32 and R33 independently are hydrogen or C16alkyl, or R32 and R33 when attached to the same nitrogen atom together with the said nitrogen atom may form a 3 to 8 membered heterocyclic ring optionally containing one or two further het eroatoms selected from nitrogen, oxygen and sulfur, and optionally containing one or two double bonds, R29, R30 and R3'independently are hydrogen, halogen,CHF2,CF3,OCF3,OCHF2,OCH2CF3,OCF2CHF2,SCF3, OR34, NR34R35, SR34, S(O)R34, S(O)2R34, C(O)NR34R35, OC(O)NR34R35, NR34C(O)R35, OCH2C(O)NR34R35, C(O)R34 orC (O) OR34, # C16alkyl, C26alkenyl or C26alkynyl, which may optionally be substituted with one or more substituents selected from halogen, CN,CF3,OCF3,N02,OR34,NR34R35 and C16alkyl # C38cycloalkyl, C48cycloalkenyl, heterocyclyl, C38cycloalkylC16alkyl, C38cyclo alkylC26alkenyl, C38cycloalkylC26alkynyl, C48cycloalkenylC16alkyl, C48cyclo alkenylC24alkenyl, C48cycloalkenylC24alkynyl, heterocyclylC16alkyl, heterocy clylC26alkenyl, heterocyclylC26alkynyl, aryl, aryloxy, aroyl, arylC16alkoxy, aryl C16alkyl, arylC26alkenyl, arylC26alkynyl, heteroaryl, heteroarylC16alkyl, hetero arylC26alkenyl or heteroarylC24alkynyl, of which the cyclic moieties optionally may be substituted with one or more substituents se lected from halogen,CN,CF3,OCF3,N02,OR34,NR34R35 and C16alkyl, wherein R34 and R35 independently are hydrogen, C, $alkyl or aryl, or R34 and R35 when attached to the same nitrogen atom together with the said nitrogen atom may form a 3 to 8 membered heterocyclic ring optionally containing one or two further het eroatoms selected from nitrogen, oxygen and sulfur, and optionally containing one or two double bonds, or two of the groups R29, R30 and When attached to the same ring carbon atom or differ ent ring carbon atoms together may form a radicalo(CH2) tCR36R37(CH2),o, (CH2)tCR36R37(CH2)l or S(CH2)tCR36R37(CH2)lS, wherein t and I independently are 0,1, 2,3, 4 or 5, R36 and R37 independently are hydrogen or C16alkyl, as well as any optical or geometric isomer or tautomeric form thereof including mixtures of these.
57. A compound according to claim 56, wherein R2 is hydrogen.
58. A compound according to any of the claims 56 or 57, wherein Z is wherein R7 and R8 are as defined in claim 56.
59. A compound according to claim 58, wherein Z is.
60. A compound according to claims 5659, wherein X is wherein q is 0 or 1, r is 0 or 1, s is 0, 1 or 2, and R12 and R'3 independently are hydrogen or C16alkyl.
61. A composition according to claims 12 comprising a compound represented by the gen eral formula (l) : wherein A is m is 0 or 1, n is 0, 1,2 or 3, with the proviso that m and n must not both be 0, R'is hydrogen, fluoro or (CH2)oOR2, o is 0 or 1, R is hydrogen, C16alkyl, C16alkanoyl, aryl or arylC16alkyl, X isN= orCH=, B is V and W independently areCH= orN=, Y isO,SorNH, R3, R4 and R5 independently are <BR> <BR> <BR> <BR> <BR> <BR> hydrogen, halogen,CN,CHF2,CF3,OCF3,OCHF2,OCH2CF3,OCF2CHF2,<BR> <BR> <BR> <BR> S (O) zCF3,SCF3,N02,ORs,NR6R',SRs,NR6S (O) 2R',S (O) 2NReR', S(O)NR6R7, S(O)R6, S(O)2R6, C(O)NR6R7, OC(O)NR6R7, NR6C(O)R7, CH2C(O)NR6R7, OCH2C(O)NR6R7, OCH2C(O)OR6, OC(O)R6, C(O)R6 or <BR> <BR> <BR> ~C (O) OR6w<BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> # C16alkyl, C26alkenyl or C26alkynyl, which may optionally be substituted with one or more substituents selected from fluoro,CN, CF3, OCF3, OR6 and NR6R7, # C38cycloalkyl, C48cycloalkenyl, heterocyclyl, C38cycloalkylC16alkyl, C38cyclo alkylC18alkoxy, C38cycloalkyloxy, C38cycloalkylC16alkylthio, C38cycloalkylthio, C38cycloalkylC26alkenyl, C38cycloalkylC26alkynyl, C48cycloalkenylC16alkyl, C48cycloalkenylC26alkenyl, C48cycloalkenylC26alkynyl, heterocyclylC18alkyl, heterocyclylC26alkenyl, heterocyclylC26alkynyl, of which the cyclic moieties may optionally be substituted with one or more substituents se lected from fluoro, C(O)OR6, NR, CF3, OCF3, OR7, NR6R7 and C16alkyl, # aryl, arylthio, arylC16alkylthio, aryloxy, aryloxycarbonyl, aroyl, arylC16alkoxy, aryl C16alkyl, arylC26alkenyl, arylC26alkynyl, heteroaryl, heteroarylC16alkyl, het eroarylC26alkenyl or heteroarylC26alkynyl, of which the cyclic moieties may optionally be substituted with one or more substituents se lected from halogen (O) OR6, CN, CF3, OCF3, NO2, OR7, NR6R7 and C16alkyl, R6 and R7 independently are hydrogen or C16alkyl, or R6 and R7 when attached to the same nitrogen atom together with the said nitrogen atom may form a 3 to 8 membered heterocyclic ring optionally containing one or two further het eroatoms selected from nitrogen, oxygen and sulfur, and optionally containing one or two double bonds, or two of the groups R3 to R5 when placed in adjacent positions together may form a bridge (CR8R9)sO(CR10R11)tO, s is 0, 1 or 2, t is 1 or 2, R8, R9, R'° and R"independently are hydrogen, C, 6alkyl or fluoro, pis0, 1,2, 3 or 4, E is X', Z'and W'independently areCH= orN=, Y'isO,SorNH, Q1 is CH2 or NH, q is 2,3, 4,5 or 6, r is 1, 2,3, 4 or 5, R'2, R'3 and R'4 independently are # hydrogen, halogen, CN, CHF2, CF3, OCF3, OCHF2, OCH2CF3, OCF2CHF2, S(O)2CF3, SCF3, NO2, OR17, NR17R18, SR17, NR17S(O)2R18, S(O)2NR17R18, S(O)NR17R18, S(O)R17, S(O)2R17, C(O)NR17R18, OC(O)NR17R18, NR17C(O)R18, CH2C(O)NR17R18, OCH2C(O)NR17R18, OC(O)R17, C(O)R17 orC (O) OR # C16alkyl, C26alkenyl or C24alkynyl, which may optionally be substituted with one or more substituents selected from fluoro,CN, <BR> <BR> andNR'7R'8,<BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> # C38cycloakyl, C48cycloalkenyl, heterocyclyl, C38cycloalkylC16alkyl, C38cyclo alkylC16alkoxy, C38cycloalkyloxy, C38cycloalkylC16alkylthio, C38cycloalkylthio, C38cycloalylC26alkenyl, C38cycloalkylC26alkynyl, C48cycloalkenylC16alkyl, C48cycloalkenylC26alkenyl, C48cycloalkenylC26alkynyl, heterocyclylC16alkyl, heterocyclylC24alkenyl, heterocyclylC24alkynyl, of which the cyclic moieties may optionally be substituted with one or more substituents se lected from fluoro,C (O) OR17, CN, CF3, OCF3, OR17 and NR17R18, # aryl, aryloxy, aryloxycarbonyl, aroyl, arylC16alkoxy, arylC16alkyl, arylC26alkenyl, arylC26alkynyl, heteroaryl, heteroarylC16alkyl, heteroarylC26alkenyl or heteroaryl C24alkynyl, of which the cyclic moieties may optionally be substituted with one or more substituents se lected from halogen (O) OR17, CN, CF3, OCF3, NO2, OR17, NR17R18 and C16alkyl, R17 and R18 independently are hydrogen or C16alkyl, or R'7 and R18 when attached to the same nitrogen atom together with the said nitrogen atom may form a 3 to 8 membered heterocyclic ring optionally containing one or two further het eroatoms selected from nitrogen, oxygen and sulfur, and optionally containing one or two double bonds, or two of the groups R12 to R'4 when placed in adjacent positions together may form a bridge (CR19R20)xO(CR21R22)yO, x is 0, 1 or 2, y is 1 or 2, R'9, R20, R21 and R22 independently are hydrogen, C16alkyl or fluoro, R"5 and R16 independently are hydrogen, halogen, CN, CF3, OR23, NR23R24, C16alkyl, C38cycloalkyl, C48cycloalkenyl, aryl or arylC16alkyl, wherein the cyclic moieties may optionally be substituted with one or more substituents se lected from halogen,CN,CF3,NO2,OR23,NR23R24 and C16alkyl, R23 and R24 independently are hydrogen or C16alkyl, or R23 and R24 when attached to the same nitrogen atom together with the said nitrogen atom may form a 3 to 8 membered heterocyclic ring optionally containing one or two further het eroatoms selected from nitrogen, oxygen and sulfur, and optionally containing one or two double bonds, or E is C16alkyl, C26alkenyl or C26alkynyl, which may optionally be substituted with one or more substituents selected from halogen, CN,CF3,OCF3,N02,OR25,SR25,NR25R26 and C16aikyl R25 and R26 independently are hydrogen or C1. 6alkyl, or R25 and R26 when attached to the same nitrogen atom together with the said nitrogen atom may form a 3 to 8 membered heterocyclic ring optionally containing one or two further het eroatoms selected from nitrogen, oxygen and sulfur, and optionally containing one or two double bonds, Z is (CR27R28)v(O)w(CR29R30)z, v and z independently are 0,1 or 2, w is 0 or 1, R27, R28, R29 and R3. independently are hydrogen or CI6alkyl, as well as any diastereomer or enantiomer or tautomeric form thereof including mixtures of these.
62. A compound according to claim 61, wherein A is wherein n is as defined in claim 61.
63. A compound according to claim 61, wherein A is.
64. A compound according to claim 61, wherein A is.
65. A compound according to any of the claims 6164, wherein B is wherein R3 to R5 are as defined in claim 61.
66. A composition according to claims 12 comprising a compound represented by the gen eral formula (I) : wherein A is m is 0 or 1, n is 0, 1, 2 or 3, with the proviso that m and n must not both be 0, R4 is hydrogen, halogen or (CH2)oOR5, o is 0 or 1, R5 is hydrogen, C16alkyl, C16alkanoyl, aryl or arylC16alkyl, R1 and R2 independently are hydrogen, halogen or C16alkyl, or R'and R2 are combined to form a double bond, R3 is hydrogen, C16alkyl or halogen, or R3 and R2 are combined to form a double bond to oxygen, X is arylene or heteroarylene, which may optionally be substituted with one or two groups R5 and R7 selected from halogen, CN, CF3, OCF3, OCHF2, NO2, OR8, NR8R9 and C16alkyl, R8 and R9 independently are hydrogen or C16alkyl, Y isC (O),O,NR'°,S,S (O),S (O) 2 or CR11R12, R'° is hydrogen or C16alkyl, R11 and R12 independently are hydrogen, C16alkyl or hydroxy, or R"is combined with R'to form a double bond, and R12 is hydrogen, C, $alkyl or hydroxy, Z isC (O)(CR13R14)p, O(CR13R14)p, S(CR13R14)p, S(O)(CR13R14)p, S(O)2(CR13R14)p, NR15(CR13R14)p or (CR13R14)p, p is 0,1 or 2, R'3 and R'4 independently are selected from hydrogen,CF3,OCF3,OCHF2 and C, $alkyl, R'5 is hydrogen or C16alkyl, D is aryl or heteroaryl, which may optionally be substituted with one or more substituents R'6, R17, R18, R19, R20 and R21, wherein R16, R17, R18 and R'9 independently are <BR> <BR> <BR> hydrogen, halogen,CN,CH2CN,CHF2,CF3,OCF3,OCHF2,OCH2CF3,<BR> <BR> OCF2CHF2,S (O) 2CF3,SCF3,NO2,ORZ,NRZR23,SR22,NRZS (O) 2R23, S(O)2NR22R23, S(O)NR22R23, S(O)R22, S(O)2R22, C(O)NR22R23, OC(O)NR22R23, NR22C(O)R23, CH2C(O)NR22R23, OCH2C(O)NR22R23, CH2OR22, CH2NR22R23, OC(O)R22, C(O)R22 or C(O)OR22, # C16alkyl, C26alkenyl or C24alkynyl, which may optionally be substituted with one or more substituents selected from halogen, CN,CF3,OCHF2,OCF3,NO2,ORZ,NRZR23 and C16alkyl, # C38cycloalkyl, C48cycloalkenyl, heterocyclyl, C38cycloalkylC16alkyl, C38cyclo alkylC16alkoxy, C38cycloalkyloxy, C38cycloalkylC16alkylthio, C38cycloalkylthio, C38cycloalkylC26alkenyl, C38cycloalkylC26alkynyl, C48cycloalkenylC16alkyl, C48cycloalkynylC26alkenyl, C48cycloalkenylC26alkynyl, heterocyclylC16alkyl, heterocyclylC24alkenyl, heterocyclylC2alkynyl, aryl, aryloxy, aryloxycarbonyl, aroyl, arylC16alkoxy, arylC16alkyl, arylC26alkenyl, arylC26alkynyl, heteoraryl, heteroarylC16alkyl, heteroarylC26alkenyl or heteroarylC26alkynyl, of which the aromatic and nonaromatic ring systems optionally may be substituted with one or more substituents selected from halogen (O) ORZ,CN,CF3,OCF3,OCHF2,NO2, OR22, NR22R23 and Cl6alkyl, R22 and R23 independently are hydrogen, C16alkyl, arylC16alkyl or aryl, or R22 and R23 when attached to the same nitrogen atom together with the said nitrogen atom may form a 3 to 8 membered heterocyclic ring optionally containing one or two further heteroatoms se lected from nitrogen, oxygen and sulfur, and optionally containing one or two double bonds, or two of the groups R15 to R'9 when placed in adjacent positions together may form a bridge (CR24R25)aO(CR26R27)cO, a is 0, 1 or 2, c is 1 or 2, R 24, R25, R26 and R27 independently are hydrogen, C, $alkyl or fluoro, R20 and R21 independently are hydrogen, C16alkyl, C38cycloalkyl or Cmcyclo alkylC16alkyl, E is C34cycloalkyl or C48cycloalkenyl, which may optionally be substituted with one or two sub stituents R28 and R29, which are independently selected from # hydrogen, halogen, CN, CF3, OCF3, OCHF2, OR33, NR33R34, C16alkyl, C38 cycloalkyl, C48cycloalkenyl, heteroaryl and aryl, wherein the heteroaryl and aryl groups optionally may be substituted with one or more sub stituents selected from halogen,CN,CF3,OCF3,OCHF2,NO2,oR33,NR33R34 and C16alkyl, R33 and R34 independently are hydrogen or C16alkyl, or R33 and R34 when attached to the same nitrogen atom together with the said nitrogen atom may form a 3 to 8 membered heterocyclic ring optionally containing one or two further het eroatoms selected from nitrogen, oxygen and sulfur, and optionally containing one or two double bonds, aryl, heteroaryl, arylC24alkenyl or arylC26alkynyl, of which the aryl and heteroaryl moieties may optionally be substituted with one or more substitutents R, R, R3°, R3'and R32, wherein R23 and R29 are as defined above, and R30, R3'and R32 are independently selected from hydrogen, halogen,CHF2,CF3,OCF3,OCHF2,OCH2CF3,OCF2CHF2,SCF3, OR35, NR35R36, SR35, S(O)R35, S(O)2R35, C(O)NR35R36, OC(O)NR35R36, NR35C(O)R36, OCH2C(O)NR35R36, C(O)R35 andC (O) OR35, # C16alkyl, C26alkenyl and C24alkynyl, which may optionally be substituted with one or more substituents selected from halogen, CN, CF3, OCF3, OCHF2, NO2, OR35, NR35R36 and C16alkyl, # C38cycloalkyl, C48cycloalkenyl, heterocyclyl, C38cycloalkylC16alkyl, C38cyclo alkylC26alkenyl, C38cycloalkylC26alkynyl, C48cycloalkenylC16alkyl, C48cyclo alkenylC26alkenyl, C48cycloalkenylC26alkynyl, heterocyclylC16alkyl, heterocy clylC26alkenyl, heterocyclylC26alkynyl, aryl, aryloxy, aroyl, arylC16alkoxy, aryl C16alkyl, arylC26alkenyl, arylC26alkynyl, heteroaryl, heteroarylC16alkyl, hetero arylC26alkenyl and heteroarylC24alkynyl, of which the aromatic and nonaromatic ring systems optionally may be substituted with one or more substituents selected from halogen, CN, CF3, OCF3, OCH2F2, NO2, OR35, NR35R36 and C16alkyl, wherein R35 and R36 independently are hydrogen, Cl6alkyl or aryl, or R35 and R36 when attached to the same nitrogen atom together with the said nitrogen atom may form a 3 to 8 membered heterocyclic ring optionally containing one or two further het eroatoms selected from nitrogen, oxygen and sulfur, and optionally containing one or two double bonds, or two of the substituents R30, R3'and R32 when attached to the same ring carbon atom or adjacent ring carbon atoms together may form a bridge O(CH2)tCR37R38(CH2)lO, (CH2)tCR37R38(CH2)l or S(CH2)tCR37R38(CH2)lS, t and I independently are 0,1, 2,3, 4 or 5, R 37 and e independently are hydrogen or C16alkyl, as well as any diastereomer or enantiomer or tautomeric form thereof including mixtures of these.
67. A compound according to claim 66, wherein A is wherein m, n and R4 are as defined in claim 66.
68. A compound according to claim 66, wherein A is.
69. A compound according to claim 66, wherein A is.
70. A compound according to claim 66, wherein A is.
71. A compound according to any of the claims 6670, wherein X is monocyclic arylene or heteroarylene, which may optionally be substituted as defined in claim 66.
72. A compound according to any of the claim 71, wherein X is wherein Re and R7 are as defined in claim 66.
73. A compound according to claim 72, wherein X is wherein R 6 and R7 are as defined in claim 66.
74. A compound according to claims 6673 wherein E is wherein R3°, R3'and R32 are as defined in claim 66.
75. A compound according to claim 74, wherein R30, R31 and R32 independently are hydrogen, * halogen,OCF3,OCHF2 orSCF3, # C16alkyl, which may optionally be substituted with one or more substituents selected from fluoro, CN, CF3, OCF3, OR35 and NR35R36, # cyclohexyl or cyclohex1enyl, which may optionally be substituted with one or more substituents selected from fluoro, CN, CF3, OCF3, OR35, NR35R36 and C16alkyl, # phenyl which may optionally be substituted with one or more substitutents selected from halogen, CN, CF3, OCF3, NO2, OR35, NR35R36 and C16alkyl, phenoxy or benzyloxy, of which the phenyl moieties may optionally be substituted with one or more substituents selected from halogen,CN,CF3,OCF3,NO2,oR35, NR35R36 and C16alkyl, R35 and R36 independently are hydrogen or C16alkyl.
76. A compound according to claim 75, wherein E is.
77. A compound according to claims 6676, wherein R'and R2 are both hydrogen.
78. A compound according to claims 6676, wherein R'and R2 are combined to form a dou ble bond.
79. A compound according to claims 6678, wherein R3 is hydrogen.
80. A compound according to claim 6679, wherein Z is NH orC (O).
81. A compound according to claim 6680, wherein D is wherein R'6, R17 and R18 are as defined in claim 66.
82. A compound according to claim 81, wherein R16, R17 and R18 independently are # hydrogen, halogen, CF3, OCF3, SCF3, C16alkyl, C16alkoxy, phenyl, cyclopentyl, cyclohexyl or phenoxy, * or two of the groups R16 to R'8 when placed in adjacent positions together may form a bridgeO(CF2) 2O,CF2OCF2OorOCH2O.
83. A compound according to any one of the claims 6682 wherein the compound is one of the following : <BR> <BR> <BR> <BR> <BR> (Z)3 {4 [4Biphenyl4yl2 (4cyclohexylphenyl)4oxobut2enoyl] benzoylamino} propionic acid <BR> <BR> <BR> <BR> <BR> (Z)3 {4 [2Biphenyl4yl4 (4chlorophenyl)4oxobut2enoyl] benzoylamino} propionic acid (Z)3 {4 [4 (4tertButylphenyl)4oxo2 (4trifluoromethoxyphenyl) but2enoyl] benzoylamino} propionic acid <BR> <BR> <BR> <BR> 3 {4 [4 (3, 5Bistrifluoromethylphenyl)2 (4cyclohexylphenyl)4oxobutyryl] benzoylamino} propionic acid ( (R) 3 4 [4 (3, 5Bistrifluoromethylphenyl)2 (4cyclohexylphenyl)4oxo butyryl] benzoylamino}propionic acid (S) 3 {4 [4 (3, 5Bistrifluoromethylphenyl)2 (4cyclohexylphenyl)4oxo butyryl] benzoylamino}propionic acid.
84. A composition according to claims 12 comprising a compound represented by the gen eral formula (I) : wherein A is m is 0 or 1, n is 0,1, 2 or 3, with the proviso that m and n must not both be 0, R'is hydrogen, fluoro or (CH2)oOR2, o is 0 or 1, R2 is hydrogen, C16alkyl, C16alkanoyl, aryl or arylC, 4alkyl, X is N, CH or C with a double bond to one substituent, Z is CR3R4, (C=O)(NR5)(C16alkyl)K, (C=O)O(C16alkyl)K, (C=O)(C16alkyl) K, (C16alkyl) K (C=O)O (C=O)O(C24alkenyl) K,(C=O)(C24alkenyl) K, (C16alkenyl) K (C=O)O wherein k is 0 or 1, R3, R4 and R5 are independently selected from hydrogen, C16alkyl or aryl, Y is (C16alkyl)s(C=O)(C16alkyl)t, (C16alkenyl)s(C=O)(C16alkyl)t, C16alkyl, C26 alkenyl, orCR6R' wherein s and t independently are 0 or 1; wherein R6, R7and R8 independently are selected from hydrogen, C, $alkyl and aryl ; D is aryl or heteroaryl, which may optionally be substituted with one or more substituents R'6, R", R'8, R19, R20 and R2', wherein pie R'7, R18 and R'9 independently are hydrogen, halogen,CN,CH2CN,CHF2,CF3,OCF3,OCHF2,OCH2CF3, OCF2CHF2,S (0) 2CF3,SCF3,N02,OR22,NRR23,SR22,NR22S (0) 2R23, S(O)2NR22R23, S(O)NR22R23, S(O)R22, S(O)2R22, C(O)NR22R23, OC(O)NR22R23, NR22C(O)R23, CH2C(O)NR22R23, OCH2C(O)NR22R23, CH2OR22, CH2NR22R23, OC (O) R22,C (O) R22 orC (O) OR22 # C16alkyl, C26alkenyl or C26alkynyl, which may optionally be substituted with one or more substituents selected from halogen, CN, CF3, OCF3, NO2, OR22, NR22R23 and C16alkyl, # C38cycloalkyl, C48cycloalkenyl, heterocyclyl, C38cycloalkylC16alkyl, C38cyclo alkylC16alkoxy, C38cycloalkyloxy, C38cycloalkylC16alkylthio, C38cycloalkylthio, C38cycloalkylC26alkenyl, C38cycloalkylC26alkynyl, C48cycloalkenylC16alkyl, C48cycloalkenylC26alkenyl, C48cycloalkenylC26alkynyl, heterocyclylC16alkyl, heterocyclylC26alkenyl, heterocyclylC26alkynyl, aryl, aryloxy, aryloxycarbonyl, aroyl, arylC16alkoxy, arylC16alkyl, arylC26alkenyl, arylC26alkynyl, heteroaryl, heteroarylC16alkynyl, heteroarylC26alkenyl or heteroarylCz6alkynyl, of which the cyclic moieties optionally may be substituted with one or more substituents se lected from halogen (O) OR22, CN, CF3, OCF3, NO2, OR22, NR22R23 and C16alkyl, RZ and R23 independently are hydrogen, C16alkyl, arylC16alkyl or aryl, or R22 and R23 when attached to the same nitrogen atom together with the said nitrogen atom may form a 3 to 8 membered heterocyclic ring optionally containing one or two further heteroatoms se lected from nitrogen, oxygen and sulfur, and optionally containing one or two double bonds, or two of the groups R16 to R'9 when placed in adjacent positions together may form a bridge (CR24R25)aO(CR26R27)cO, a is 0, 1 or 2, c is 1 or 2, R24, R25, R26 and R27 independently are hydrogen, C, $alkyl or fluoro, R20 and R21 independently are hydrogen, C16alkyl, C38cycloalkyl or C34cyclo alkylC, 6alkyl, E is Cmcycloalkyl or C48cycloalkenyl, which may optionally be substituted with one or two sub stituents R28and R29, which are independently selected from # hydrogen, halogen, CN, CF3, OR33, NR33R34, C16alkyl, C38cycloalkyl, C48cyclo alkenyl, heteroaryl and aryl, wherein the heteroaryl and aryl groups optionally may be substituted with one or more sub stituents selected from halogen,CN,CF3,N02,OR33,NR33R34 and C16alkyl, R33 and R34 independently are hydrogen or C16alkyl, or R33 and R34 when attached to the same nitrogen atom together with the said nitrogen atom may form a 3 to 8 membered heterocyclic ring optionally containing one or two further het eroatoms selected from nitrogen, oxygen and sulfur, and optionally containing one or two double bonds, aryl, heteroaryl, arylC24alkenyl or arylC24alkynyl, of which the cyclic moieties may option ally be substituted with one to three substitutents R30, R3'and R32, which are independently selected from hydrogen, halogen,CHF2,CF3,OCF3,OCHF2,OCH2CF3,OCF2CHF2,SCF3, OR35, NR35R36, SR35, S(O)R35, S(O)2R35, C(O)NR35R36, OC(O)NR35R36, NR35C(O)R36, OCH2C(O)NR35R36, C(O)R35 andC (O) OR35, # C16alkyl, C26alkenyl and C24alkynyl, which may optionally be substituted with one or more substituents selected from halogen, CN, CF3, OCF3, SCF3, NO2, OR35, NR35R36 and C16alkyl, # C38cycloalkyl, C48cycloalkenyl, heterocyclyl, C38cycloalkylC16alkyl, C38cyclo alkylC24alkenyl, C38cycloalkylC26alkynyl, C48cycloalkenylC16alkyl, C48cyclo alkenylC26alkenyl, C48cycloalkenylC26alkynyl, heterocyclylC16alkyl, heterocy clylC26alkenyl, heterocyclylC26alkynyl, aryl, aryloxy, aroyl, arylC14alkoxy, aryl C16alkyl, arylC26alkenyl, arylC26alkynyl, heteroaryl, heteroarylC16alkyl, hetero arylC24alkenyl and heteroarylC26alkynyl, of which the cyclic moieties optionally may be substituted with one or more substituents se lected from halogen, CN, CF3, OCF3, SCF3, NO2, OR35, NR35R36 and C14alkyl, wherein R35 and R36 independently are hydrogen, C16alkyl or aryl, or R35 and R when attached to the same nitrogen atom together with the said nitrogen atom may form a 3 to 8 membered heterocyclic ring optionally containing one or two further het eroatoms selected from nitrogen, oxygen and sulfur, and optionally containing one or two double bonds, or two of the substituents R30, R3'and R32 when attached to the same ring carbon atom or different ring carbon atoms together may form a radical O(CH2)tCR37R38(CH2)iO, (CH2)tCR37R38(CH2)l or S(CH2)tCR37R38(CH2)lS, t and I independently are 0,1, 2,3, 4 or 5, R37 and R38 independently are hydrogen or Cl6alkyl, as well as any diastereomer or enantiomer or tautomeric form thereof including mixtures of these.
85. A compound according to claim 84, wherein A is wherein m, n and R4 are as defined in claim 84.
86. A compound according to claim 84, wherein A is.
87. A compound according to claim 84, wherein A is.
88. A compound according to any one of the preceding claims 8487, wherein D is wherein R'6, R'7 and R18 independently are hydrogen, halogen, CN, CF3, OCF3, SCF3, S(O) C16alkyl, C(O) C16alkyl, C16 alkyl, C16alkoxy, phenyl, cyclopentyl, cyclohexyl or phenoxy, # or two of the groups R16 to R'8 when placed in adjacent positions together may form a bridgeO (CF2) 2O,CF2OCF2Oor0CH2O.
89. A compound according to any one of the preceding claims 8488, wherein E is wherein R28, R29, R30, R31 and R32 are independently selected from hydrogen, halogen,OCF3,OCHF2,SCF3, orCF3, C16alkyl, which may optionally be substituted with one or more substituents selected from fluoro, CN, CF3, OCF3, OR35 and NR35R36, # cyclohexyl or cyclohex1enyl, which may optionally be substituted with one or more substituents selected from fluoro,CN,CF3,OCF3,oR35,NR35R36 and C16alkyl # phenyl which may optionally be substituted with one or more substitutents selected from halogen,CN,CF3,OCF3,N02,OR35,NR35R36 and C16alkyl, # phenoxy or benzyloxy, of which the phenyl moieties may optionally be substituted with one or more substituents selected from halogen, CN, CF3, OCF3, NO2, OR35, NR35R36 and C16alkyl, thiadiazolyl, R35 and R36 independently are hydrogen or C16alkyl.
90. A compound according to claims 8489, wherein Y isC=O,CH2.
91. A compound according to claims 8490, wherein Z isCH2, (C=O) (NH), (C=O)Oor (C=O)CH2.
92. The compound according to any one of the preceding claims 8491, wherein the com pound is 3 {4 [ (4Cyclohexylbenzyl) (4trifluoromethoxybenzyl) amino] benzoylamino} propionic acid.
93. The composition according to any one of the preceding claims, wherein the basic counter ion is N, N'dibenzylethylenediamine (benzathine).
94. The composition according to claim 93, wherein the ratio of compound to counter ion is 2: 1;.
95. A composition comprising a glucagon antagonist according to any one of the claims 394 as a solvate.
96. A composition according to claim 95 wherein the solvate is selected from ethanol, 2 propanol, 2methyl1propanol, nbutanol, 2butanol, 3methyllbutanol, diethyl ether, tert butylmethylether, tetrahydrofuran, anisol, acetone, 2butanon, methylacetate, ethylacetate, npropylacetate and toluene.
97. A composition according to any of the claims 9596 comprising 3 {4 [1 (4Cyclohex1 enylphenyl)3 (3, 5dichlorophenyl) ureidomethyl] benzoylamino}2Rhydroxypropionic acid in a solvate form.
98. A composition according to claim 97 comprising 3 {4 [1 (4Cyclohex1enylphenyl)3 (3, 5dichlorophenyl) ureidomethyl] benzoylamino}2Rhydroxypropionic acid as a solvate with one of the following solvents ethanol, 2propanol, 2methyl1propanol, nbutanol, 2butanol, 3methyl1butanol, diethyl ether, tertbutylmethylether, tetrahydrofuran, anisol, acetone, 2 butanon, methylacetate, ethylacetate, npropylacetate and toluene.
99. A composition according to any of the claim 98 comprising 3 {4 [1 (4Cyclohex1 enylphenyl)3 (3, 5dichlorophenyl) ureidomethyl] benzoylamino}2Rhydroxypropionic acid as a solvate with 2butanol, 3methyllbutanol and 2methyl1propanol.
100. A composition according to any of the claims 9596 comprising N[4({4(1cyclohexen 1yl) [(3, 5dichloroanilino) carbonyl] anilino} methyl) benzoyl]ßalanine as a solvate.
101. A composition according to any of the claim 100 comprising N [4 ( (4 (lcyclohexenl yl) [(3, 5dichloroanilino) carbonyl] anilino} methyl) benzoyl]ßalanine as a solvate with acetone, butanol, ethanol 2propanol or 1propanol.
102. A pharmaceutical composition comprising, as an active ingredient a compound accord ing to any of the claims 1101 together with pharmaceutical acceptable carriers and/or dilu ents.
103. A pharmaceutical composition according claim 102 in a unit dosage form comprising from about 0.05 to about 1000 mg, preferably from about 0.1 to about 500 mg compound.
104. The use of a composition according to any of the claims 1101 for the preparation of a medicament useful in the treatment and/or prevention of conditions mediated by glucagon receptors.
105. The invention provides the use of a composition according to claim 104 for the prepara tion of a medicament useful in the treatment and/or prevention of diabetes and/or obesity.
106. A method for the treatment and/or prevention of conditions mediated by glucagon re ceptors which method comprises administering to a subject in need thereof an effective amount of a composition according to claims 1101.
107. A method for the treatment and/or prevention of diabetes and/or obesity which method comprises administering to a subject in need thereof an effective amount of a composition according to claim 1101.
108. Use of a composition according to any of the claims 1101, for the preparation of a me dicament.
109. A process for the preparation a solvate of 3 {4 [1 (4Cyclohex1enylphenyl)3 (3, 5 dichlorophenyl) ureidomethyl] benzoylamino}2Rhydroxypropionic acid comprising the steps of: a) dissolving the parent compound as a free acid, an ester derivative or as a solvate of the parent compound, in same solvent as the solvate to be obtained or a different solvent or in a mixture of solvents b) optionally heating the mixture c) cooling the solution d) isolating the precipitate e) optionally drying the obtained solvate.
110. The process of claim 109, wherein the temperature in the optional step b) is below 150 °C, optionally below 85°C.
111. 106 A method for the treatment and/or prevention of conditions mediated by glucagon re ceptors which method comprises administering to a subject in need thereof an effective amount of a composition according to claims 1101.
112. 107 A method for the treatment and/or prevention of diabetes and/or obesity which method comprises administering to a subject in need thereof an effective amount of a composition according to claim 1101.
113. 108 Use of a composition according to any of the claims 1101, for the preparation of a me dicament.
114. 109 A process for the preparation a solvate of 3 {4 [1 (4Cyclohex1enylphenyl)3 (3, 5 dichlorophenyl) ureidomethyl] benzoylamino}2Rhydroxypropionic acid comprising the steps of: a) dissolving the parent compound as a free acid, an ester derivative or as a solvate of the parent compound, in same solvent as the solvate to be obtained or a different solvent or in a mixture of solvents b) optionally heating the mixture c) cooling the solution d) isolating the precipitate e) optionally drying the obtained solvate.
115. The process of claim 109, wherein the temperature in the optional step b) is below 150 °C, optionally below 85°C.
Description:
SALTS AND SOLVATES OF GLUCAGON ANTAGONISTS FIELD OF INVENTION The present invention relates to salts and solvates of glucagon antagonists.

BACKGROUND OF THE INVENTION The invention relates to glucagon antagonist as previously disclosed in published patent ap- plications WO 99/01423, WO 00/39088, WO00/42026, WO 00/69810, WO 02/00612, WO 02/40444, WO 02/40445 and WO 02/40446, W003/048109, W003/51357, W003/53938, W003/97619 (Novo Nordisk A/S) disclose glucagon antagonists and other glucagon antago- nists.

The compounds areuseful as glucagon antagonist and in the treatment of hyperglycemia, Type 1 diabetes, Type 2 diabetes, disorders of the lipid metabolism, such as dyslipidemia, and obesity as well as in treatment of other diseases.

For pharmaceutical and commercial use it is important to have an active compound with prop- erties such as for example good stability, non-hygroscopicity, high melting point, good bioavail- ability, good handling properties, high degree of crystallinity and a reproducible crystalline form.

The present invention thus provides suitable salts and solvates of the compounds of the in- vention. For example, the salts and solvates of the invention provide stable compounds un- der storage and accelerated storage conditions as a model for long term stability.

SUMMARY OF THE INVENTION The invention provides a composition comprising a salt or a solvate of a glucagon antagonist.

In an aspect of the invention a composition is provided comprising a salt of a glucagon antagonist and a pharmaceutical acceptable base

In an aspect of the invention the glucagon antagonists are described in the published applications WO 99/01423, WO 00/39088, WO00/42026, WO 00/69810, WO 02/00612, WO 02/40444, WO 02/40445 and WO 02/40446, W003/048109, W003/51357, W003/53938 and W003/97619 and as described in this application below.

In an embodiment of the invention the basic counter ion are derived from ammonium or imidazole or the metal ions of lithium, sodium, potassium, magnesium, calcium, zinc, or the basic amino acids L-arginine, L-lysine, L-histidine, and L-ornithine; or alkylated ammonium derivatives such as di-ethylamine, tert-butylamine (erbumine), 1, 2-ethylenediamine, N- (phenylmethyl)-benzeneethaneamine (benethamine) or N, N'-dibenzylethylenediamine (benzathine); or hydroxyalkylated ammonium derivatives trishydroxymethylaminomethane (tris, tromethamine), N-methyl-D-glucamine (meglumine), choline, monoethanolamine (2- aminoethanol, lamine), di-ethanolamine (2,2'-iminobis (ethanol)), tri-ethanolamine (2,2', 2"- nitrilotris (ethanol), trolamine), 2-diethylaminoethanol.

In an aspect of the invention a composition is provided comprising a solvate of a glucagon antagonist.

In one aspect of the invention the solvate is formed from a class III solvent (ICH Guidelines Q3C ;"Impurities : Guidelines for Residual Solvents", 1997).

In another aspect the solvate is formed from one of the solvents: ethanol, 2-propanol, 2- methyl-1-propanol, n-butanol, 2-butanol, 3-methyl-1-butanol, diethyl ether, tert-butyl- methylether, tetrahydrofuran, anisol, acetone, 2-butanon, methylacetate, ethylacetate, n- propylacetate and toluene.

The present invention also relates to a process for the preparation and pharmaceutical com- positions containing the compounds.

The present invention provides compounds as novel materials, in particular in pharmaceutically acceptable form.

Within another aspect of the present invention there is provided a method of using the compounds according to the invention for the treatment and/or prevention of diabetes and/or obesity.

DETAILED DESCRIPTION OF THE INVENTION The following is a detailed definition of the terms used to describe the compounds of the inven- tion: "Halogen"designates an atom selected from the group consisting of F, Cl, Br and 1.

The term"C,. 4-alkyl"or"lower alkyl"as used herein represents a saturated, branched or straight hydrocarbon group having from 1 to 6 carbon atoms. Representative examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, n- pentyl, isopentyl, neopentyl, tert-pentyl, n-hexyl, isohexyl and the like.

The term"C2-6-alkenyl"or"lower alkenyl"as used herein represents a branched or straight hydrocarbon group having from 2 to 6 carbon atoms and at least one double bond. Examples of such groups include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, iso-propenyl, 1,3- butadienyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-l-propenyl, 1-pentenyl, 2-pentenyl, 3- pentenyl, 4-pentenyl, 3-methyl-2-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 2, 4-hexadienyl, 5- hexenyl and the like.

The term"C2-6-alkynyl"or"lower alkynyl"as used herein represents a branched or straight hydrocarbon group having from 2 to 6 carbon atoms and at least one triple bond. Examples of such groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2- butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3- hexynyl, 4-hexynyl, 5-hexynyl, 2, 4-hexadiynyl and the like.

The term"C,. -alkoxy"or"lower alkoxy'as used herein refers to the radical-O-C, 4-alkyl, wherein Cl. 6-alkyl is as defined above. Representative examples are methoxy, ethoxy, n- propoxy, isopropoxy, butoxy, sec-butoxy, tert-butoxy, pentoxy, isopentoxy, hexoxy, isohexoxy and the like.

The temm"C, 4-alkanoyl"or"lower alkanoyl"as used herein denotes a group-C (O) H or-C (O)-C1- 5-alkyl. Representative examples are formyl, acetyl, propionyl, butyryl, valeryl, hexanoyl and the like.

The term"C38-cycloalkyl"or"cycloalkyl"as used herein represents a saturated, carbocyclic group having from 3 to 8 carbon atoms. Representative examples are cyclopropyl, cyclobu- tyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.

The temm"C48-cycloalkenyl"or"cycloalkenyl"as used herein represents a non-aromatic, carbo- cyclic group having from 4 to 8 carbon atoms containing one or two double bonds. Represen- tative examples are 1-cyclopentenyl, 2-cyclopentenyl, 3-cyclopentenyl, 1-cyclohexenyl, 2- cyclohexenyl, 3-cyclohexenyl, 2-cycloheptenyl, 3-cycloheptenyl, 2-cyclooctenyl, 1, 4-cyclo- octadienyl and the like.

The term"heterocyclyl"as used herein represents a non-aromatic 3 to 10 membered ring con- taining one or more heteroatoms selected from nitrogen, oxygen and sulfur and optionally con- taining one or two double bonds. Representative examples are pyrrolidinyl, piperidyl, piperaz- inyl, morpholinyl, thiomorpholinyl, aziridinyl, tetrahydrofuranyl and the like.

The term"aryl"as used herein is intended to include carbocyclic aromatic ring systems such as phenyl, biphenylyl, naphthyl, anthracenyl, phenanthrenyl, fluorenyl, indenyl, pentalenyl, azulenyl and the like. Aryl is also intended to include the partially hydrogenated derivatives of the carbocyclic systems enumerated above. Non-limiting examples of such partially hydro- genated derivatives are 1,2, 3, 4-tetrahydronaphthyl, 1, 4-dihydronaphthyl and the like.

The term"aroyl"as used herein denotes a group-C (0)-aryl, wherein aryl is as defined above.

The term"aryloxy"as used herein denotes a group-O-aryl, wherein aryl is as defined above.

The term"arylene"as used herein is intended to include divalent carbocyclic aromatic ring systems such as phenylen, biphenylylene, naphthylene, anthracenylene, phenanthrenylene, fluorenylene, indenylene, pentalenylene, azulenylene and the like. Arylene is also intended to include the partially hydrogenated derivatives of the carbocyclic systems enumerated above.

Non-limiting examples of such partially hydrogenated derivatives are 1,2, 3,4-tetrahydro- naphthylene, 1, 4-dihydronaphthylene and the like.

The term"heteroaryl"as used herein represents a heterocyclic aromatic ring system containing one or more heteroatoms selected from nitrogen, oxygen and sulfur such as furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, 1,2, 3-triazolyl,

1,2, 4-triazolyl, pyranyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1, 2, 3-triazinyl, 1,2, 4-triazinyl, 1,3, 5-triazinyl, 1,2, 3-oxadiazolyl, 1,2, 4-oxadiazolyl, 1,2, 5-oxadiazolyl, 1, 3, 4-oxadiazolyl, 1,2, 3- thiadiazolyl, 1,2, 4-thiadiazolyl, 1,2, 5-thiadiazolyl, 1,3, 4-thiadiazolyl, tetrazolyl, thiadiazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzothiophenyl (thianaphthenyl), indazolyl,<BR> benzimidazolyl, benzthiazolyl, benzisothiazolyl, benzoxazolyl, benzisoxazolyl, purinyl, quinazolinyl, quinolizinyl, quinolinyl, isoquinolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, azepinyl, diazepinyl, acridinyl and the like. Heteroaryl is also intended to include the partially hydrogenated derivatives of the heterocyclic systems enumerated above. Non- limiting examples of such partially hydrogenated derivatives are 2, 3-dihydrobenzofuranyl, pyrrolinyl, pyrazolinyl, indolinyl, oxazolidinyl, oxazolinyl, oxazepinyl and the like. <BR> <BR> <P>"Aryl-Cr4-alkyl","heteroaryl-C4-alkyl", Uaryl-C24-alkenyl"or"Aryl-lower alkyl","heteroaryl-lower alkyl","aryl-lower alkenyl"etc. mean C, 4-alkyl or C2-6-alkenyl as defined above, substituted by an aryl or heteroaryl as defined above, for example : The term"optionally substituted"as used herein means that the groups in question are either unsubstituted or substituted with one or more of the substituents specified. When the groups in question are substituted with more than one substituent the substituents may be the same or different.

Certain of the above defined terms may occur more than once in the structural formulae, and upon such occurrence each term shall be defined independently of the other.

Crystalline salts with a well defined structure are preferred salts due to their stability.

The salts may form in different ratios between compound and salt. The ratio depend on the nature of the basic counter ion and of the compound. In an aspect of the invention salts are formed in a 1: 1 ratio of compound to salt. In another aspect of the invention the salts are formed in a 2: 1 ratio of compound to salt.

The composition as above wherein the pharmaceutically acceptable basic counter ion are derived from ammonium or imidazole or the metal ions of lithium, sodium, potassium,

magnesium, calcium, zinc, or the basic amino acids L-arginine, L-lysine, L-histidine, and L- ornithine; or alkylated ammonium derivatives such as di-ethylamine, tert-butylamine (erbumine), 1, 2-ethylenediamine, N- (phenylmethyl)-benzeneethaneamine (benethamine) or N, N'-dibenzylethylenediamine (benzathine); or hydroxyalkylated ammonium derivatives trishydroxymethylaminomethane (tris, tromethamine), N-methyl-D-glucamine (meglumine), choline, monoethanolamine (2-aminoethanol, lamine), di-ethanolamine (2,2'- iminobis (ethanol)), tri-ethanolamine (2,2', 2"-nitrilotris (ethanol), trolamine), 2- diethylaminoethanol.

In an embodiment of the invention the basic counter ions are selected from calcium, zinc, the amino acids L-arginine, L-lysine, L-histidine, and L-ornithine; N-methyl-D-glucamine (meglu- mine), choline, monoethanolamine (lamine), di-ethanolamine, tri-ethanolamine (trolamine), 2-diethylaminoethanol, tri-ethylamine, trishydroxymethylaminomethane (tris, tromethamine), 1, 2-ethylenediamine or N, N'-dibenzylethylenediamine (benzathine).

In an embodiment of the invention the basic counter ion is selected from: L-lysine, L-arginine, L-histidine, tert-butylamine (erbumine), monoethanolamine (lamine), 1, 2-ethylenediamine or N, N'-dibenzylethylenediamine (benzathine).

In an embodiment of the invention the basic counter ion is selected from: L-arginine, tert- butylamine (erbumine), or N, N'-dibenzylethylenediamine (benzathine).

In an embodiment of the invention the basic counter ion is N, N'-dibenzylethylenediamine (benzathine).

In an embodiment the ratio of compound to counter ion is 2: 1 when the counter ion is N, N'- dibenzylethylenediamine (benzathine) or 1, 2-ethylenediamine.

In an embodiment of the invention is provided solvates as a novel materials, in particular in pharmaceutical acceptable form. Consequently, only solvates which are physiologically acceptable in the amount administered to the subject in need of treatment are within the scope of the invention. Solvates between the parent compound and the following solvents are to be considered as being administrable to subjects: pentane, heptane, cumene, 1-propanol, dimethylsulfoxide, ethanol, ethyl formiate, formic acid, acetic acid, methyl acetate, ethyl acetate, n-propyl acetate, isopropylacetate, n-butylacetate, iso-butylacetate, methyl-isobutyl- ketone, 1-butanol, 2-butanol, 2-propanol, 2-methyl-1-propanol, 3-methyl-1-butanol, 1-

pentanol, diethyl ether, tert-butyl methyl ether, tetrahydrofuran, anisol, acetone, 2-butanone or toluene.

Stable solvates are arranged in stable conformations of solvent and parent compound which can be defined as a ratio of the parent compound to the solvate. The specific ratio between the two components is in the context of this invention not a limiting feature.

The invention also encompasses prodrugs of the present compounds, which on administra- tion undergo chemical conversion by metabolic processes before becoming pharmacologi- cally active substances. In general, such prodrugs will be functional derivatives of the com- pounds of the general formula (I), which are readily convertible in vivo into the required com- pound of the formula (I). Conventional procedures for the selection and preparation of suit- able prodrug derivatives are described, for example, in"Design of Prodrugs", ed. H. Bund- gaard, Elsevier, 1985.

The invention also encompasses active metabolites of the present compounds.

The compounds according to the present invention act to antagonize the action of glucagon and are accordingly useful for the treatment and/or prevention of disorders and diseases in which such an antagonism is beneficial.

Accordingly, the present compounds may be applicable for the treatment and/or prevention of hyperglycemia, IGT (impaired glucose tolerance), insulin resistance syndromes, syndrome X, Type 1 diabetes, Type 2 diabetes, hyperlipidemia, dyslipidemia, hypertriglyceridemia, hyperlipo- proteinemia, hypercholesterolemia, arteriosclerosis including atherosclerosis, glucagonomas, acute pancreatitis, cardiovascular diseases, hypertension, cardiac hypertrophy, gastrointestinal disorders, obesity, diabetes as a consequence of obesity, diabetic dyslipidemia, etc.

Accordingly, in a further aspect the invention relates to a compound according to the inven- tion for use as a medicament.

The invention also relates to pharmaceutical compositions comprising, as an active ingredi- ent, at least one compound according to the invention together with one or more pharmaceu- tically acceptable carriers or excipients.

The pharmaceutical composition is preferably in unit dosage form comprising from about 0.05 mg to about 1000 mg, preferably from about 0.1 mg to about 500 mg and especially preferred from about 0.5 mg to about 200 mg of the compound according to the invention.

Furthermore, the invention relates to the use of a compound according to the invention for the preparation of a pharmaceutical composition for the treatment and/or prevention of a disorder or disease, wherein a glucagon antagonistic action is beneficial.

The invention also relates to a method for the treatment and/or prevention of disorders or diseases, wherein a glucagon antagonistic action is beneficial the method comprising admin- istering to a subject in need thereof an effective amount of a compound according to the in- vention.

In a preferred embodiment of the invention the present compounds are used for the prepara- tion of a medicament for the treatment and/or prevention of any glucagon-mediated conditions and diseases.

In a preferred embodiment of the invention the present compounds are used for the prepara- tion of a medicament for the treatment and/or prevention of hyperglycemia.

In yet a preferred embodiment of the invention the present compounds are used for the preparation of a medicament for lowering blood glucose in a mammal.

In another preferred embodiment of the invention the present compounds are used for the preparation of a pharmaceutical composition for the treatment and/or prevention of IGT.

In still another preferred embodiment of the invention the present compounds are used for the preparation of a pharmaceutical composition for the treatment and/or prevention of Type 2 diabetes.

In yet another preferred embodiment of the invention the present compounds are used for the preparation of a pharmaceutical composition for the delaying or prevention of the pro- gression from IGT to Type 2 diabetes.

In yet another preferred embodiment of the invention the present compounds are used for the preparation of a pharmaceutical composition for the delaying or prevention of the pro- gression from non-insulin requiring Type 2 diabetes to insulin requiring Type 2 diabetes.

In a further preferred embodiment of the invention the present compounds are used for the preparation of a pharmaceutical composition for the treatment and/or prevention of Type 1 diabetes. Such treatment and/or prevention is normally accompanied by insulin therapy.

In a further preferred embodiment of the invention the present compounds are used for the preparation of a pharmaceutical composition for the treatment and/or prevention of obesity.

In yet a further preferred embodiment of the invention the present compounds are used for the preparation of a pharmaceutical composition for the treatment and/or prevention of disor- ders of the lipid metabolism, such as dyslipidemia.

In still a further embodiment of the invention the present compounds are used for the prepa- ration of a pharmaceutical composition for the treatment and/or prevention of an appetite regulation or energy expenditure disorder.

In a further aspect of the invention the present compounds are combined with diet and/or ex- ercise.

In yet a further aspect of the invention the present compounds are administered in combina- tion with one or more further active substances in any suitable ratios. Such further active agents may be selected from antidiabetic agents, antihyperlipidemic agents, antiobesity agents, antihypertensive agents and agents for the treatment of complications resulting from or associated with diabetes.

Suitable antidiabetic agents comprise insulin, insulin analogues and derivatives such as those disclosed in EP 792 290 (Novo Nordisk A/S), eg NEB29-tetradecanoyl des (B30) human insulin, EP 214 826 and EP 705 275 (Novo Nordisk A/S), eg AspB28 human insulin, US 5, 504, 188 (Eli Lilly), eg LysB28 ProB29 human insulin, EP 368 187 (Aventis), eg Lantus, which are all incorporated herein by reference, GLP-1 derivatives such as those disclosed in WO 98/08871 (Novo Nordisk A/S), which is incorporated herein by reference, as well as orally active hypoglycaemic agents.

The orally active hypoglycaemic agents preferably comprise imidazolines, sulphonylureas, biguanides, meglitinides, oxadiazolidinediones, thiazolidinediones, glucosidase inhibitors, glucagon antagonists, GLP-1 agonists, agents acting on the ATP-dependent potassium channel of the (3-cells eg potassium channel openers such as those disclosed in WO 97/26265, WO 99/03861 and WO 00/37474 (Novo Nordisk A/S) which are incorporated herein by reference, or nateglinide or potassium channel blockers such as BTS-67582, insulin sensitizers, DPP-IV (dipeptidyl peptidase-IV) inhibitors, PTPase inhibitors, inhibitors of hepatic enzymes involved in stimulation of gluconeogenesis and/or glycogenolysis, glucose uptake modulators, GSK-3 (glycogen synthase kinase-3) inhibitors, compounds modifying the lipid metabolism such as antihyperlipidemic agents and antilipidemic agents, compounds lowering food intake, PPAR (peroxisome proliferator-activated receptor) and RXR (retinoid X receptor) agonists such as ALRT-268, LG-1268 or LG-1069.

In one embodiment of the invention the present compounds are administered in combination with insulin or an insulin analogue or derivative, such as NEB29-tetradecanoyl des (B30) human insulin, AspB28 human insulin, LysB28 ProB29 human insulin, Lantus, or a mix- preparation comprising one or more of these.

In a further embodiment of the invention the present compounds are administered in com- bination with a sulphonylurea eg tolbutamide, chlorpropamide, tolazamide, glibenclamide, glyburide, glipizide or glicazide.

In another embodiment of the invention the present compounds are administered in com- bination with a biguanide eg metformin.

In yet another embodiment of the invention the present compounds are administered in combination with a meglitinide eg repaglinide or nateglinide.

In still another embodiment of the invention the present compounds are administered in combination with a thiazolidinedione insulin sensitizer eg troglitazone, ciglitazone, pioglita- zone, rosiglitazone, isaglitazone, darglitazone, englitazone, CS-01 1/C1-1037 or T174 or the compounds disclosed in WO 97/41097, WO 97/41119, WO 97/41120, WO 00/41121 and WO 98/45292 (Dr. Reddy's Research Foundation).

In still another embodiment of the invention the present compounds may be administered in combination with an insulin sensitizer such as GI 262570, YM-440, MCC-555, JTT-501, AR-H039242, KRP-297, GW-409544, CRE-16336, AR-H049020, LY510929, MBX-102, CLX-0940, GW-501516 or the compounds disclosed in WO 99/19313, WO 00/50414, WO 00/63191, WO 00/63192, WO 00/63193 (Dr. Reddy's Research Foundation) and WO 00/23425, WO 00/23415, WO 00/23451, WO 00/23445, WO 00/23417, WO 00/23416, WO 00/63153, WO 00/63196, WO 00/63209, WO 00/63190 and WO 00/63189 (Novo Nord- isk A/S).

In a further embodiment of the invention the present compounds are administered in combi- nation with an a-glucosidase inhibitor eg voglibose, emiglitate, miglitol or acarbose.

In another embodiment of the invention the present compounds are administered in combination with an agent acting on the ATP-dependent potassium channel of the ß-cells eg tolbutamide, chlorpropamide, tolazamide, glibenclamide, glyburide, glipizide, glicazide, BTS- 67582, repaglinide or nateglinide.

In still another embodiment of the invention the present compounds are administered in combination with an antihyperlipidemic agent or antilipidemic agent eg cholestyramine, colestipol, clofibrate, gemfibrozil, lovastatin, pravastatin, simvastatin, probucol or dextrothy- roxine.

In another aspect of the invention, the present compounds are administered in combination with more than one of the above-mentioned compounds eg in combination with mefformin and a sulphonylurea such as glibenclamide or glyburide ; a sulphonylurea and acarbose; met- formin and a meglitinide such as repaglinide ; acarbose and mefformin ; a sulfonylurea, met- formin and troglitazone ; a sulfonylurea, mefformin and pioglitazone ; a sulfonylurea, met- formin and an insulin sensitizer such as disclosed in WO 00/63189 or WO 97/41097; a me- glitinide such as repaglinide, mefformin and troglitazone ; a meglitinide such as repaglinide, mefformin and pioglitazone ; a meglitinide such as repaglinide, mefformin and an insulin sen- sitizer such as disclosed in WO 00/63189 or WO 97/41097; insulin and a sulfonylurea ; insulin and a meglitinide such as repaglinide ; insulin and mefformin ; insulin, metformin and a meglit- inide such as repaglinide ; insulin, mefformin and a sulfonylurea ; insulin and troglitazone ; in- sulin and pioglitazone ; insulin and an insulin sensitizer such as such as disclosed in

WO 00/63189 or WO 97/41097; insulin and lovastatin ; an insulin analogue or derivative, met- formin and a meglitinide such as repaglinide ; an insulin analogue or derivative, mefformin and a sulfonylurea ; an insulin analogue or derivative and troglitazone ; an insulin analogue or derivative and pioglitazone ; an insulin analogue or derivative and an insulin sensitizer such as disclosed in WO 00/63189 or WO 97/41097; an insulin analogue or derivative and lovas- tatin; etc.

Furthermore, the compounds according to the invention may be administered in combination with one or more antiobesity agents or appetite regulating agents.

Such agents may be selected from the group consisting of CART (cocaine amphetamine regulated transcript) agonists, NPY (neuropeptide Y) antagonists, MC4 (melanocortin 4) agonists, orexin antagonists, TNF (tumor necrosis factor) modulators, CRF (corticotropin re- leasing factor) agonists, CRF BP (corticotropin releasing factor binding protein) antagonists, urocortin agonists, ß3 adrenergic agonists such as CL-316243, AJ-9677, GW-0604, LY362884, LY377267 orAZ-40140, MSH (melanocyte-stimulating hormone) agonists, MCH (melanocyte-concentrating hormone) antagonists, CCK (cholecystokinin) agonists, serotonin re-uptake inhibitors such as fluoxetine, seroxat or citalopram, serotonin and noradrenaline re- uptake inhibitors, 5HT (serotonin) agonists, bombesin agonists, galanin antagonists, growth hormone, growth hormone releasing compounds, TRH (thyreotropin releasing hormone) agonists, UCP 2 or 3 (uncoupling protein 2 or 3) modulators, leptin agonists, DA (dopamine) agonists (bromocriptin, doprexin), lipase/amylase inhibitors, PPAR modulators, RXR modula- tors or TR ß agonists.

In one embodiment of the invention the antiobesity agent is leptin.

In another embodiment of the invention the antiobesity agent is dexamphetamine or amphetamine.

In another embodiment of the invention the antiobesity agent is fenfluramine or dexfenfluramine.

In still another embodiment of the invention the antiobesity agent is sibutramine.

In a further embodiment of the invention the antiobesity agent is orlistat.

In another embodiment of the invention the antiobesity agent is mazindol or phentermine.

Furthermore, the present compounds may be administered in combination with one or more antihypertensive agents. Examples of antihypertensive agents are (3-blockers such as alprenolol, atenolol, timolol, pindolol, propranolol and metoprolol, ACE (angiotensin converting enzyme) inhibitors such as benazepril, captopril, enalapril, fosinopril, lisinopril, quinapril and ramipril, calcium channel blockers such as nifedipine, felodipine, nicardipine, isradipine, nimodipine, diltiazem and verapamil, and a-blockers such as doxazosin, urapidil, prazosin and terazosin. Further reference can be made to Remington: The Science and Practice of Pharmacy, 19th Edition, Gennaro, Ed. , Mack Publishing Co. , Easton, PA, 1995.

It should be understood that any suitable combination of the compounds according to the in- vention with diet and/or exercise, one or more of the above-mentioned compounds and op- tionally one or more other active substances are considered to be within the scope of the present invention.

PHARMACEUTICAL COMPOSITIONS The compounds of the invention may be administered alone or in combination with pharma- ceutically acceptable carriers or excipients, in either single or multiple doses. The pharmaceu- tical compositions according to the invention may be formulated with pharmaceutically ac- ceptable carriers or diluents as well as any other known adjuvants and excipients in accor- dance with conventional techniques such as those disclosed in Remington: The Science and Practice of Pharmacy, 19th Edition, Gennaro, Ed. , Mack Publishing Co. , Easton, PA, 1995.

The pharmaceutical compositions may be specifically formulated for administration by any suitable route such as the oral, rectal, nasal, pulmonary, topical (including buccal and sublin- gual), transdermal, intracisternal, intraperitoneal, vaginal and parenteral (including subcuta- neous, intramuscular, intrathecal, intravenous and intradermal) route, the oral route being preferred. It will be appreciated that the preferred route will depend on the general condition and age of the subject to be treated, the nature of the condition to be treated and the active ingredient chosen.

Pharmaceutical compositions for oral administration include solid dosage forms such as cap- sules, tablets, dragees, pills, lozenges, powders and granules. Where appropriate, they can

be prepared with coatings such as enteric coatings or they can be formulated so as to pro- vide controlled release of the active ingredient such as sustained or prolonged release ac- cording to methods well known in the art.

Liquid dosage forms for oral administration include solutions, emulsions, suspensions, syr- ups and elixirs.

Pharmaceutical compositions for parenteral administration include sterile aqueous and non- aqueous injectable solutions, dispersions, suspensions or emulsions as well as sterile pow- ders to be reconstituted in sterile injectable solutions or dispersions prior to use. Depot in- jetable formulations are also contemplated as being within the scope of the present inven- tion.

Other suitable administration forms include suppositories, sprays, ointments, cremes, gels, inhalants, dermal patches, implants etc.

A typical oral dosage is in the range of from about 0.001 to about 100 mg/kg body weight per day, preferably from about 0.01 to about 50 mg/kg body weight per day, and more preferred from about 0.05 to about 10 mg/kg body weight per day administered in one or more dos- ages such as 1 to 3 dosages. 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 and other factors evident to those skilled in the art.

The formulations may conveniently be presented in unit dosage form by methods known to those skilled in the art. A typical unit dosage form for oral administration one or more times per day such as 1 to 3 times per day may contain from 0.05 to about 1000 mg, preferably from about 0.1 to about 500 mg, and more preferred from about 0.5 mg to about 200 mg.

For parenteral routes such as intravenous, intrathecal, intramuscular and similar administration, typically doses are in the order of about half the dose employed for oral administration.

The compounds of this invention are generally utilized as the free substance or as a pharma- ceutically acceptable salt thereof. One example is a base addition salt of a compound having the utility of a free acid. When a compound of the formula (I) contains a free acid such salts are

prepared in a conventional manner by treating a solution or suspension of a free acid of the formula (I) with a chemical equivalent of a pharmaceutically acceptable base. Representative examples are mentioned above.

For parenteral administration, solutions of the novel compounds of the formula (I) in sterile aqueous solution, aqueous propylene glycol, aqueous vitamin E or sesame or peanut oil may be employed. Such aqueous solutions should be suitably buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose. The aqueous solutions are par- ticularly suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administra- tion. 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. Examples of solid carriers are lactose, terra alba, sucrose, cyclodextrin, talc, gelatine, agar, pectin, acacia, magnesium stearate, stearic acid and lower alkyl ethers of cellulose. Examples of liquid carriers are syrup, peanut oil, olive oil, phospho- lipids, fatty acids, fatty acid amines, polyoxyethylene and water. Similarly, the carrier or dilu- ent may include any sustained release material known in the art, such as glyceryl mono- stearate or glyceryl distearate, alone or mixed with a wax. The pharmaceutical compositions formed by combining the novel compounds of the formula (I) and the pharmaceutical accept- able 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 dis- crete units such as capsules or tablets, each containing a predetermined amount of the active ingredient, and which may include a suitable excipient. Furthermore, the orally available formu- lations may be in the form of a powder or granules, a solution or suspension in an aqueous or non-aqueous liquid, or an oil-in-water or water-in-oil liquid emulsion.

If a solid carrier is used for oral administration, the preparation may be tablette, placed in a hard gelatine 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.

If a liquid carrier is used, the preparation may be in the form of a syrup, emulsion, soft gela-

tine capsule or sterile injectable liquid such as an aqueous or non-aqueous liquid suspension or solution.

A typical tablet that may be prepared by conventional tabletting techniques may contain: Core: Active compound (as free compound or salt thereof) 5.0 mg Lactosum Ph. Eur. 67.8 mg Cellulose, microcryst. (Avicel) 31.4 mg AmberlitellRP88* 1.0 mg Magnesii stearas Ph. Eur. q. s.

Coating: Hydroxypropyl methylcellulose approx. 9 mg Mywacett 9-40 T** approx. 0.9 mg * Polacrillin potassium NF, tablet disintegrant, Rohm and Haas.

** Acylated monoglyceride used as plasticizer for film coating.

If desired, the pharmaceutical composition of the invention may comprise the compound of the formula (I) in combination with further pharmacologically active substances such as those described below.

In an aspect of the invention the compound is represented by the general formula (1)

X is a valence bond,-CR'R2-or-NR'-, Y is >CR3-or >N-, R', R2 and R3 independently are hydrogen or CI-6-alkyl, or R'and R3 on adjacent atoms may be combined to form a double bond, E is # C1-10-alkyl or C2-10-alkenyl, #C3-10-cycloalkyl, C3-10-cycloalkenyl, C7-10-bicycloalkyl, C3-10-cycloalkyl-C1-6-alkyl, C3-1o-cycloalkenyl-C$-alkyl or C7-10-bicycloalkyl-C1-6-alkyl, wherein the rings may optionally be substituted with one or more substituents se- lected from halogen, C1-6alkyl, C2-6-alkenyl, C1-6-alkoxy, C1-6-thioalkyl, -CF3, -OCF3, -SCF3, -OCHF2 and -SCHF2, # aryl, aryloxy, arylthio, heteroaryl, aryl-C1-6-alkyl, aryloxy-C1-6alkyl, arylthio-C1-6-alkyl, heteroaryl-C1-6-alkyl, diaryl-C1-6-alkyl or (C1-6-alkyl)(aryl)-C1-7-alkyl, wherein the non-aromatic and aromatic rings may optionally be substituted with one or more substituents selected from halogen, C1-6-alkyl, C2-6-alkenyl, C1-6-alkoxy, C1-6-thioalkyl, -CF3, -OCF3, -SCF3, -OCHF2, -SCHF2, C3-10-cycloalkyl and C3-10-cyclo- alkenyl, or with two substituents on adjacent positions which are combined to form a bridge C1-6-alkylene, C2-6-alkenylene or -O-C1-6-alkylene-O-, B is X'is-N= or-CR8=, Y'is-S-,-O-or-NR9-,

Ra is hydrogen, C, $-alkyl or aryl, wherein aryl is optionally substituted with one or two sub- stituents selected from halogen, C1-6-alkyl, C1-6-alkoxy, C1-6-thioalkyl, -CF3, -OCF3, -SCF3, -OCHF2,-SCHF2,-SO2CF3 and-SO2-C1 6-alkyl, R9 is hydrogen or C1-6-alkyl, D is aryl or heteroaryl, which may optionally be substituted with one or more substituents selected from #halogen, -CF3, -OCF3, -SCF3, -CN, -NO2, C1-10-alkyl, C2-6-alkyl, C1-6-alkoxy, C16-alkylthio, amino, C1-6-alkylamino, di-C1-6-alkylamino, -SO2CF3 and -SO2-C1-6-alkyl, #C3-8-cycloalkyl, C3-8-cycloalkenyl, aryl and aryl-C1-6-alkoxy, wherein the non-aromatic and aromatic rings optionally may be substituted with one to three substituents selected from halogen,-CF3,-OCF3,-SCF3,-CN,-N02, C1-10-alkyl, C2-6-alkenyl, C1-6-alkoxy and Cl-e-alkylthio, or with two substituents on ad- jacent positions which are combined to form a bridge-O-(CH2) m-O-(CH2) p-or -O-(CF2) m-O-(CF2) p-, wherein m is an integer of from 1 to 6, and p is 0 or 1, 'or with two substituents on adjacent positions which are combined to form a bridge -O-(CH2) m-O-(CH2) p-or-O-(CF2) m-O-(CF2) p-, wherein m is an integer of from 1 to 6, andpisOor1, or a substituent on B may be combined with a substiuent on D to form a-C (=O)- bridge, as well as any diastereomer or enantiomer or tautomeric form thereof including mixtures of these.

In one embodiment the invention provides the compounds as above, wherein B is wherein X'and Y'are as defined above.

In another embodiment the invention provides the compounds as above, wherein B is

wherein R8 is as defined above.

In another embodiment the invention provides the compounds as above, wherein E is C1-10-alkyl, C3-10-cycloalkyl, which may optionally be substituted as defined above.

wherein R4 and R5 are as defined above.

In another embodiment the invention provides the compounds as above, wherein E is

wherein R4 is hydrogen and R5 is C1-6-alkyl, C1-6-alkoxy, cyclohexyl, halogen, -CF3 or cyclo- hex-1-enyl, or R4 and R5 on adjacent positions may be combined to form a bridge C1-6-alkylene.

In another embodiment the invention provides the compounds as above, wherein D is

wherein R10, R11, R12, R15, R16, R17 and R18 are as defined above.

In another embodiment the invention provides the compounds as above, wherein D is wherein R'°, R"and R12 are as defined above.

In another embodiment the invention provides the compounds as above, wherein R10, R" and R12 independently are hydrogen, halogen,-OCF3,-CF3,-NO2, di-C1-6-alkylamino, C1-10-alkyl, C1-6-alkoxy or-CN, phenyl or phenyl-C1-6-alkoxy, or two of R'°, R11 and R12 in adjacent positions form a bridge -O-CH2-O-, -O-CH2-CH2-O- or -O-CH2-CH2-CH2-O- In another embodiment the invention provides the compounds as above, wherein one of R'°, R11 and R12 represent hydrogen.

In another embodiment the invention provides the compounds as above, wherein one or two of R'°, R11 and R12 is hydrogen, and the remaining is independently selected from halogen,- OCF3,-CF3,-N02, di-C1-6-alkylamino, C1-10-alkyl, C1-6-alkoxy or-CN.

In another embodiment the invention provides the compounds such as 3-(4-{[[4-(4-Chlorophenyl)thiazol-2-yl]-(4-trifluoromelthylp henyl) amino] methyl} benzoylamino)- propionic acid, 3-(4-{[[4-(3,4-Dichlorophenyl)thiazol-2-yl]-(5, 6,7, 8-tetrahydronaphthalen-2-yi) amino] methyl}- benzoylamino) propionic acid 3- [4- ( ( (4-Chlorophenyl)- [4- (4-trifluoromethoxyphenyl) thiazol-2-yl] amino} methyl) benzoyl- amino] propionic acid, 3-[4-({(4-Chlorophenyl)-[4-(4-trifluoromelthylphenyl)thiazol -2- yl] amino} methyl) benzoylamino] propionic acid or 3-[4-({(4-Trifluoromelthoxyphenyl)-[4-(4-trifluopromethylphe nyl)thiazol-2-yl)amino}methyl)- benzoylamino] propionic acid, In another embodiment the invention provides the compounds such as 3- (4- { [ [4- (3, 4-Dichlorophenyl) thiazol-2-yl]- (5, 6,7, 8-tetrahydronaphthalen-2-yl)amino]methyl}- benzoylamino) propionic acid as a salt with tert-butylamine.

In another embodiment the invention provides the compound 3- (4- { [ [4- (4- chlorophenyl) thiazol-2-yl]- (4-trifluoromethylphenyl) amino] methyl} benzoylamino) propionic acid as a salt with L-lysine.

In another embodiment the invention provides the compound3- (4- { [ [4- (4- chlorophenyl) thiazol-2-yl]- (4-trifluoromethylphenyl) amino] methyl} benzoylamino) propionic acid as a salt with L-histidine.

In another embodiment the invention provides the compound3-(4-{[[4-(4- chlorophenyl) thiazol-2-yl]- (4-trifluoromethylphenyl) amino] methyl} benzoylamino) propionic acid as a salt with monoethanolamine.

In another embodiment the invention provides the compound3-(4-{[[4-(4- chlorophenyl) thiazol-2-yl]- (4-trifluoromethylphenyl) amino] methyl} benzoylamino) propionic acid as a salt with tert-butylamine.

In another embodiment the invention provides the compound3-(4-{[[4-chlorophenyl)thiazol-2- yl]- (4-trifluoromethylphenyl) amino] methyl} benzoylamino) propionic acid as a salt with 1,2- ethylenediamine.

In another embodiment the invention provides the compound 3- (4- { [ [4- (4- chlorophenyl) thiazol-2-yi]- (4-trifluoromethylphenyl) amino] methyl} benzoylamino) propionic acid as a salt with N, N'-dibenzylethylenediamine.

In an embodiment the invention provides glucagon antagonists of the formula (I) :

wherein V is-C (O) OR2, -C(O)NR2R3, -C(O)NROR3, -S(O)2OR2,

wherein R2 and R3 independently are hydrogen or C1-6-alkyl, R4 is hydrogen, halogen, -CN, -CF3, -OCF3, -NO2, -OR5, -NR5R6 or C1-6-alkyl, wherein R5 and Re independently are hydrogen or C1-8-alkyl, A is wherein bis0 or1, n is 0, 1, 2 or 3, R7 is hydrogen, C1-6-alkyl or C3-8-cycloalkyl-C1-6-alkyl, R8 and R9 independently are hydrogen or C1-6-alkyl,

Y is-C (O)-,-S (O) 2-,-0-or a valence bond, Z is phenylen or a divalent radical derived from a 5 or 6 membered heteroaromatic ring con- taining 1 or 2 heteroatoms selected from nitrogen, oxygen and sulfur, which may optionally be substituted with one or two groups R and R47 selected from hydrogen, halogen, -CN, -CF3, -OCF3, -NO2, -OR10, -NR10R11 and C1-6-alkyl, wherein R'° and R"independently are hydrogen or C1-6-alkyl, or-A-Y-Z-together are

R'is hydrogen or C1-6-alkyl, wherein r is 0 or 1, q and s independently are 0,1, 2 or 3,

R'2, R'3, R'4 and R'5 independently are hydrogen or C1-6-alkyl, D is

wherein W is -O-, -S-, -S (0) 2- or -NR20-, W' is =CR20'-or = N-, R16, R17, R18 and R'9 independently are hydrogen, halogen, -CN, -CH2CN, -CHF2, -CF3, -OCF3, -OCHF2, -OCH2CF3, -OCF2CHF2, -OS(O)2CF3, -SCF3, -NO2, -OR21, -NR21R22, -SR21, -NR21S(O)2R22, -S(O)2NR21R22, -S(O)NR21R22, -S(O)R21, -S(O)2R21, -OS(O)2R21, -C(O)NR21R22, -OC(O)NR21R22, -NR21C(O)R22, -CH2C(O)NR21R22, -OCH2C(O)NR21R22, -CH2OR21, -CH2NR'R,-OC (O) R,-C (O) R or-C (O) OR

C, 6-alkyl, C24-alkenyl or C24-alkynyl, which may optionally be substituted with one or more substituents selected from- CHF2,-CF3,-OCF3,-OCHF2,-OCH2CF3,-OCF2CHF2,-SCF3,-OR,-NR'R -SR21, -S(O)R21, -S(O)2R21, -C(O)NR21R22, -OC(O)NR21R22, -NR21C(O)R22, - OCH2C (O) NR2'R22,-C (O) R2' and-C (O) OR2', C3-8-cycloalkyl, C4-8-cycloalkenyl, heterocyclyl, C3-8-cycloalkyl-C1-6-alkyl, C3-8-cyclo- alkyl-C1-6-alkoxy, C3-8-cycloalkyloxy, C3-8-cycloalkyl-C1-6-alkylthio, C3-8-cycloalkylthio, C3-8-cycloalkyl-C2-6-alkenyl, C3-8-cycloalkyl-C2-6-alkynyl, C4-8-cyc loalkenyl-C1-6-alkyl, C4-8- cycloalkenyl-C2-6-alkenyl, C4-8-cycloalkenyl-C2-6-alkynyl, heterocyclyl-C1-6-alkyl, heterocy- clyl-C24-alkenyl or heterocyclyl-C24-alkynyl, of which the cyclic moieties optionally may be substituted with one or more sub- stituents selected from -CHF2, -CF3, -OCF3, -OCHF2, -OCH2CF3, -OCF2CHF2, -SCF3, -OR21, -NR21R22, -SR21, -S(O)R21, -S(O)2R21, -C(O)NR21R22, -OC(O)NR21R22, -NR21C(O)R22, -OCH2C(O)NR21R22, -C(O)R21 and -C(O)OR21, C, 6-alkyl, C24-alkenyl and C24-alkynyl, which may optionally be substituted with one or more substituents se- lected from-CHF2,-CF3,-OCF3,-OCHF2,-OCH2CF3,-OCF2CHF2, -SCF3-oR2',-NR2'R22,-SR2',-S (O) R2',-S (O) 2R2',-C (O) NR2'R22,<BR> - OC (O) NR2'R22,-NR2'C (O) R22,-OCH2C (O) NR2'R22,-C (O) R2' and<BR> -C (O) OR<BR> <BR> # aryl, aryloxy, aryloxycarbonyl, aroyl, aryl-C1-6-alkoxy, aryl-C1-6-alkyl, aryl-C2-6-alkenyl, aryl-C24-alkynyl, heteroaryl, heteroaryl-C1-6-alkyl, heteroaryl-C2-6-alkenyl or heteroaryl- C2-6-alkynyl, of which the aryl and heteroaryl moieties optionally may be substituted with one or more substituents selected from

halogen,-CN,-CH2CN,-CHF2,-CF3,-OCF3,-OCHF2,-OCH2CF3,-OCF2CHF 2, -OS(O)2CF3, -SCF3, -NO2, -OR21, -NR21R22, -SR21R22, -SR21, -NR21S(O)2R22, -S(O)2NR21R22, -S(O)NR21R22, -S(O)R21, -S(O)2R21, -OS(O)2R21, -C(O)NR21R22, -OC(O)NR21R22, - NR21C (O) R,-CH2C (O) NR2'R22,-OCH2C (O) NR'R,-CH20R,-CH2NR'R -OC (O) R,-C (O) R2' and-C (O) OR, C1-6-alkyl, C2-6-alkenyl and C2--alkynyl, which may optionally be substituted with one or more substituents se- lected from-CHF2,-CF3,-OCF3,-OCHF2,-OCH2CF3,-OCF2CHF2, -SCF3, -OR21, -NR21R22, -SR21, -S(O)R21, -S(O)2R21, -C(O)NR21R22, -OC (O) NR2'R22,-NR2'C (O) R22,-OCH2C (O) NR2'R22,-C (O) R2'and<BR> -C (O) OR wherein R2'and R22 independently are hydrogen,-CF3, C1-6-alkyl, tri-C1-6-alkylsilyl, C3-8-cyclo- alkyl, C3-8-cycloalkyl-C1-6-alkyl, aryl, aryl-C1-6-alkyl or heteroaryl, or R2'and R22 when attached to the same nitrogen atom together with the said nitrogen atom may form a 3 to 8 membered heterocyclic ring optionally containing one or two further het- eroatoms selected from nitrogen, oxygen and sulfur, and optionally containing one or two double bonds, or two of the groups R16 to R19 when placed in adjacent positions together may form a bridge - (CR16'R17')a-O-(CR18'R19')c-O-, wherein a is 0, 1 or 2, cis 1 or 2, R16', R17', R18' and R19' independently are hydrogen, C1-6-alkyl or halogen, R20 and R20 independently are hydrogen, C1-6-alkyl, C3-8-cycloalkyl or C38-cycloalkyl-C, 4- alkyl,

E is a 3 to 9 membered mono-or bicyclic ring which may optionally contain one or two dou- ble bonds and which may optionally contain one or two heteroatoms selected from nitrogen, oxygen and sulfur, wherein one or two groups R23 and R24 may be attached to the same or different ring carbon atoms and wherein a group R3'may be attached to a ring nitrogen atom when present, or

wherein m and p independently are 0,1, 2,3 or 4, with the proviso that when both m and p are pre- sent in the same formula at least one of m and p is different from 0,

R23 and R24 independently are hydrogen,-CHF2,-CF3,-OCF3,-OCHF2,-OCH2CF3,-OCF2CHF2,-SCF3,-O R36, -NR NR36R37, -SR36, -S(O)R36, -S(O)2R36, -C(O)NR36R37, -OC(O)NR36R37, -NR36C(O)R37, -OCH2C(O)NR36R37, -C(O)R36 or-C (O) OR36, C, 4-alkyl, C2. 6-alkenyl or C24-alkynyl, which may optionally be substituted with one or more substituents selected from - 37, -SR36, -S(O)R36, -S(O)2R36, -C(O)NR36R37, -OC(O)NR36R37, -NR36C(O)R37, -OCH2C(O)NR36R37, -C(O)R36 and -C(O)OR36, # C3-8-cycloalkyl, C3-8-cycloalkylidene, C4-8-cycloalkenyl, heterocyclyl, C3-8-cycloalkyl- C1-6-alkyl, C3-8-cycloalkyl-C2-6-alkenyl, C3-8-cycloalkyl-C2-6-alkynyl, C4-8-cycloalkenyl- C1-6-alkyl, C4-8-cycloalkylenyl-C2-6-alkenyl, C4-8-cycloalkenyl-C2-6-alkynyl, heterocyclyl- C, 6-alkyl, heterocyclyl-C2-6-alkenyl or heterocyclyl-C2-6-alkynyl, of which the cyclic moieties optionally may be substituted with one or more sub- stituents selected from - R -SR36, -S(O)R36, -S(O)2R36, -C(O)NR36R37, -OC(O)NR36R37, -NR36C(O)R37, -OCH2C(O)NR36R37, -C(O)R36 and -C(O)OR36, C1-6-alkyl, C2-6-alkenyl and C2-6-alkynyl, which may optionally be substituted with one or more substituents se- lected from-CHF2,-CF3,-OCF3,-OCHF2,-OCH2CF3,-OCF2CHF2, -SCF3, -OR36, -NR36R37, -SR36, -S(O)R36, -S(O)2R36, -C(O)NR36R37, -OC(O)NR36R37, -NR36C(O)R37, -OCH2C(O)NR36R37, -C(O)R36 and -C (O) OR

# aryl, aryloxy, aroyl, aryl-C1-6-alkoxy, aryl-C1-6-alkyl, aryl-C2-6-alkenyl, aryl-C2-6-alkynyl, heteroaryl, heteroaryl-C, 6-alkyl, heteroaryl-C24-alkenyl or heteroaryl-C2-6-alkynyl, of which the aryl and heteroaryl moieties optionally may be substituted with one or more substituents selected from halogen,-CN,-CH2CN,-CHF2,-CF3,-OCF3,-OCHF2,-OCH2CF3,-OCF2CHF 2, -OS(O)2CF3, -SCF3, -NO2, -OR36, -NR36R37, -SR36, -NR36S(O)2R37, -S(O)2NR36R37, -S(O)NR36R37, -S(O)R36, -S(O)2R36, -OS(O)2R36, -C(O)NR36R37, -OC(O)NR36R37, -NR36C(O)R37, -CH2C(O)NR36R37, -CH2C(O)NR36R37, -CH2OR36, -CH2NR36R37, -oC (o) R36,-C (o) R36 and-C (O) OR36, C1-6-alkyl, C2-6-alkenyl and C2-6-alkynyl, which may optionally be substituted with one or more substituents se- lected from-CHF2,-CF3,-OCF3,-OCHF2,-OCH2CF3,-OCF2CHF2, -SCF3, -OR36, -NR36R37, -SR36, -S(O)R36, -S(O)2R36, -C(O)NR36R37, -OC(O)NR36R37, -NR36C(O)R37, -OCH2C(O)NR36R37, -C(O)R36 and -C (O) OR wherein R36 and R37 independently are hydrogen, C1-6-alkyl or aryl, of which the aryl moiety optionally may be substituted with one or more substitu- ents selected from halogen, -CN, -CF3, -OCF3, -NO2, -OR38, -NR38R39 and C1-6-alkyl, wherein R38 and R39 independently are hydrogen or C1-6-alkyl, or R36 and R37 when attached to the same nitrogen atom together with the said nitrogen atom may form a 3 to 8 membered heterocyclic ring optionally containing one or two further het- eroatoms selected from nitrogen, oxygen and sulfur, and optionally containing one or two double bonds, or R23 and R24 when attached to the same ring carbon atom or different ring carbon atoms together may form a radical -O-(CH2)t-CR40R41-(CH2)l-O-, -(CH2)t-CR40R41-(CH2)l- or

-S-(CH2)t-CR40R41-(CH2)l-S-, wherein t and I independently are 0,1, 2,3, 4 or 5, R40 and R4'independently are hydrogen or C, 4-alkyl, R25 to R30 independently are hydrogen, halogen, -CN, -CF3, -NO2, -OR42, -NR42R43, C1-6-alkyl, C3-8-cycloalkyl or C4-8-cycloalkenyl, wherein R42 and R43 independently are hydrogen or C, 4-alkyl, or R42 and R43 when attached to the same nitrogen atom together with the said nitrogen atom may form a 3 to 8 membered heterocyclic ring optionally containing one or two further het- eroatoms selected from nitrogen, oxygen and sulfur, and optionally containing one or two double bonds, R3', R32 and R33 independently are hydrogen or C1-6-alkyl, R34 and R35 independently are hydrogen, C1-6-alkyl, C1-6-alkoxy, C1-6-alkanoyl, -C(O)NR44R45 or-S (O) 2R45, # aryl, aroyl, aryl-C1-6-alkoxy, aryl-C1-6-alkanoyl or aryl-C1-6-alkyl, of which the aryl moieties optionally may be substituted with one or more sub- stituents selected from halogen, -CN, -CF3, -OCF3, -OR44, -NR44R45 and C1-6-alkyl, wherein R44 and R45 independently are hydrogen or C, 4-alkyl, or R34 and R35 when attached to a carbon atom together with the said carbon atom may form a 3 to 8 membered cyclic ring optionally containing one or two heteroatoms selected from ni- trogen, oxygen or sulfur, and optionally containing one or two double bonds, or

R34 and R35 when attached to a nitrogen atom together with the said nitrogen atom may form a 3 to 8 membered heterocyclic ring optionally containing one or two further heteroatoms se- lected from nitrogen, oxygen or sulfur, and optionally containing one or two double bonds, as well as any optical or geometric isomer or tautomeric form thereof including mixtures of these.

In an embodiment the invention provides compounds, wherein V is-C (O) OH or 5-tetrazolyl.

In an embodiment the invention provides compounds, wherein A is In an embodiment the invention provides compounds, wherein Y is-C (O)-, or Y is a valence bond.

In an embodiment the invention provides compounds, wherein Z is In an embodiment the invention provides compounds, wherein R'is hydrogen or methyl.

In an embodiment the invention provides compounds, wherein X is-C (O) NH-, -C (O) NHCH2-, -C(O) NHCH (CH3)-,-C (O) NHCH2CH2-, -C (O) CH2-,-CH2-,-C (O)- or-NHC (O) -.

In an embodiment the invention provides compounds, wherein D is wherein one or two of R16,R17, and R18 are hydrogen and the remaining is independently se- lected from-OCF3,-SCF3-CF3,-S (O) 2CH3, phenyl, halogen, C1-6-alkyl, nitro, -S-C1-6-alkyl or -S (O) 2NR2'R22, wherein R21 is C1-6-alkyl and R22 is phenyl.

In an embodiment the invention provides compounds, wherein E is wherein R23 is hydrogen and R24 is C1-6-alkyl such as tert-butyl or C38-cycloalkyl such as cyclohexyl, wherein R23 and R24 are both C1-6-alkyl or wherein R23 and R24 together form the radical- (CH2) 5-.

In an embodiment the invention provides compounds, wherein E is wherein R25 is-OCF3,-CF3, C, 4-alkyl such as tert-butyl, phenyl, piperidyl, C3-8-cycloalkyl such as cyclohexyl or C48-cycloalkenyl such as cyclohexenyl.

In an embodiment the invention provides compounds, wherein the compound is any of the following 3- {4- [1- (4-Cyclohex-1-enylphenyl)-3- (3, 5-dichlorophenyl) ureidomethyl] benzoylamino}- propionic acid,

4- [3- (3, 5-Bistrifluoromethylphenyl)-1- (4-tert-butylcyclohexyl) ureidomethyl]-N- (2H-tetrazol-5- yl) benzamide, (S)-4- [3- [1- (4-Chlorophenyl) ethyl]-1- (4-cyclohexylphenyl) ureidomethyl]-N- (2H-tetrazol-5- yl) benzamide, 4-[1-(4-Cyclohexylphenyl)-3-(3-fluoro-5-trifluoromethylpheny l)ureidomethyl]-N-(2H-tetrazol-5- yl) benzamide 4- [3- (3-Bromo-5-trifluoromethylphenyl)-l- (4-tert-butylphenyl) ureidomethyl]-N- (2H-tetrazol-5- yl) benzamide, 4- [3- (3-Bromo-5-trifluoromethylphenyl)-1- (4-cyclohexylphenyl) ureidomethyl]-N- (2H-tetrazol-5- yl) benzamide, 4- [3- (3-Bromophenyl)-1- (4-cyclohex-1-enylphenyl) ureidomethyl]-N (2H-tetrazol-5-yl)- benzamide.

In an embodiment the invention provides the compound N- [4- ( (4- (l-cyclohexen-1-yl) [ (3, 5- dichloroanilino) carbonyl] anilino} methyl) benzoyl]-ß-alanine as a salt with and tert-butylamine.

In an embodiment the invention provides the compound N-[4-({4-(1-cyclohexen-1-yl)[(3, 5- dichloroanilino) carbonyl] anilino} methyl) benzoyl]-ß-alanine as a salt with L-arginine.

In an embodiment the invention provides a glucagon antagonist represented by the general formula (I) : wherein R', R2, R3, R4 and R5 independently are hydrogen or C1-6-alkyl, A is-C (O)-,-CH (OR6)- or -CHF-, wherein R5 is hydrogen or C, 4-alkyl, Z is arylene or a divalent radical derived from a 5 or 6 membered heteroaromatic ring con- taining 1 or 2 heteroatoms selected from nitrogen, oxygen and sulfur,

which may optionally be substituted with one or two groups R7 and R3 selected from halogen, -CN, -CF3, -OCF3, -NO2, -OR9, -NR9R10 and C1-6-alkyl, wherein R9 and R'° independently are hydrogen or C1-6-alkyl, X is wherein r is 0 or 1, q and s independently are 0,1, 2 or 3, R", R12, R13 and R'4 independently are hydrogen, C1-6-alkyl or C3-8-cycloalkyl, D is

wherein pi5 R'6, R'7 and R18 independently are *hydrogen, halogen,-CN,-CHF2,-CF3,-OCF3,-OCHF2,-OCH2CF3,-OCF2CHF2, -S(O)2CF3, -SCF3, -NO2, OR21, -NR21R22, -SR21, -NR21S(O)2R22, -S(O)2NR21R22, -S(O)NR21R22, -S(O)R21, -S(O)2R21, -C(O)NR21R22, -OC(O)NR21R22, -NR21C(O)R22, <BR> <BR> <BR> -CH2C (O) NR2'R22,-OCH2C (O) NR2'R22,-OC (O) R2',-C (O) R2'or-C (O) OR2',<BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> C, 6-alkyl, C24-alkenyl or C26-alkynyl, which may optionally be substituted with one or more substituents selected from halogen,-CN,-CF3,-OCF3,-NO2,-OR2',-NR2'R22 and C1-6-alkyl, # C3-8-cycloalkyl, C4-8-cycloalkenyl, heterocyclyl, C3-8-cycloalkyl-C1-6-alkyl, C3-8-cyclo- alkyl-C1-6-alkoxy, C3-8-cycloalkyloxy, C3-8-cycloalkyl-C1-6-alkylthio, C3-8-cycloalkylthio, C3-8-cycloalkyl-C2-6-alkenyl, C3-8-cycloalkyl-C2-6-alkynyl, C4-8-cycloalkenyl-C1-6-alkyl,

C4-8-cycloalkenyl-C2-8-alkenyl, C4-8-cycloalkenyl-C2-6-alkynyl, heterocyclyl-C1-6-alkyl, heterocyclyl-C2-6-alkenyl, heterocyclyl-C2-6-alkynyl, aryl, aryloxy, aryloxycarbonyl, aroyl, aryl-C1-6-alkoxy, aryl-C1-6-alkyl, aryl-C2-6-alkenyl, aryl-C2-6-alkynyl, heteroaryl, heteroaryl-C1-6-alkyl, heteroaryl-C2-6-alkenyl or heteroaryl-C2-6-alkynyl, of which the cyclic moieties optionally may be substituted with one or more sub- stituents selected from halogen (O) OR21, -CN, -CF3, -OCF3, -NO2, -OR21, -NR21R22 and C1-6-alkyl, wherein R2'and R22 independently are hydrogen, C1-6-alkyl, aryl-C1-6-alkyl or aryl, or R21 and R22 when attached to the same nitrogen atom together with the said nitrogen atom may form a 3 to 8 membered heterocyclic ring optionally containing one or two further heteroatoms selected from nitrogen, oxygen and sulfur, and optionally containing one or two double bonds, or two of the groups R'5 to R18 when placed in adjacent positions together may form a bridge - (CR23R24)a-O-(CR25R26)c-O-, wherein a is 0,1 or 2, cis 1 or 2, R23, R24, R25 and R26 independently are hydrogen, C1-6-alkyl or fluorine, R'9 and R20 independently are hydrogen, C1-6-alkyl, C3-8-cycloalkyl or C34-cyclo- alkyl-C, 4-alkyl, E is

wherein R27 and R28 independently are hydrogen, halogen, -CN, -CF3, -OR32, -NR32R33, C1-6-alkyl, C3-8-cycloalkyl, C4-8-cycoalkenyl or aryl, wherein the aryl group optionally may be substituted with one or more substituents selected from halogen,-CN,-CF3,-N02,-OR32,-NR32R33 and C1-6-alkyl, wherein R32 and R33 independently are hydrogen or C1-6-alkyl, or R32 and R when attached to the same nitrogen atom together with the said nitrogen atom may form a 3 to 8 membered heterocyclic ring optionally containing one or two further heteroatoms selected from nitrogen, oxygen and sulfur, and optionally containing one or two double bonds,

R29, R30 and R3'independently are hydrogen, halogen,-CHF2,-CF3,-OCF3,-OCHF2,-OCH2CF3,-OCF2CHF2, -SCF3, -OR34, -NR34R35, -SR34, -S(O)R34, -S(O)2R34, -C(O)NR34R35, -OC(O)NR34R35, -NR34C(O)R35, -OCH2C(O)NR34R35, -C(O)R34 or-C (O) OR34, # C1-6-alkyl, C2-6-alkenyl or C2-6-alkynyl, which may optionally be substituted with one or more substituents selected from halogen,-CN,-CF3,-OCF3,-NO2,-oR34,-NR34R35 and C, 4-alkyl, # C3-8-cycloalkyl, C4-8-cycloalkenyl, heterocyclyl, C3-8-cycloalkyl-C1-6-alkyl, C3-8-cyclo- alkyl-C2-6-alkenyl, C3-8-cycloalkyl-C2-6-alkynyl, C4-8-cycloalkenyl-C1-6-alkyl, C4-8-cyclo- alkenyl-C2-6-alkenyl, C4-8-cycloalkenyl-C2-6-alkynyl, heterocyclyl-C1-6-alkyl, heterocy- clyl-C2-6-alkenyl, heterocyclyl-C2-6-alkynyl, aryl, aryloxy, aroyl, aryl-C1-6-alkoxy, aryl- C1-6-alkyl, aryl-C2-6-alkenyl, aryl-C2-6-alkynyl, heteroaryl, heteroaryl-C1-6-alkyl, hetero- aryl-C2-6-alkenyl or heteroaryl-C2-6-alkynyl, of which the cyclic moieties optionally may be substituted with one or more sub- stituents selected from halogen,-CN,-CF3,-OCF3,-NO2,-oR34,-NR34R35 and C, 6-alkyl, wherein R34 and R35 independently are hydrogen, C, 6-alkyl or aryl, or R34 and R35 when attached to the same nitrogen atom together with the said nitrogen atom may form a 3 to 8 membered heterocyclic ring optionally containing one or two further heteroatoms selected from nitrogen, oxygen and sulfur, and optionally containing one or two double bonds, or two of the groups R29, R30 and When attached to the same ring carbon atom or differ- ent ring carbon atoms together may form a radical -O-(CH2)t-CR36R37-(CH2)l-O-, -(CH2)t-CR36R37-(CH2)l- or -S-(CH2)t-CR36R37-(CH2)l-S-,

wherein t and I independently are 0,1, 2,3, 4 or 5, R36 and R37 independently are hydrogen or C, 4-alkyl, as well as any optical or geometric isomer or tautomeric form thereof including mixtures of these or a pharmaceutically acceptable salt thereof.

An embodiment of the invention provides compounds, wherein R', R2, R3, R4 and R5 are hy- drogen.

An embodiment of the invention provides compounds, wherein A is-CHF-.

An embodiment of the invention provides compounds, wherein A is-CH (OR6)-, wherein R5 is as defined above.

An embodiment of the invention provides compounds, wherein A is-CH (OH)-.

An embodiment of the invention provides compounds, wherein Z is wherein R 7and R8 are as defined above.

An embodiment of the invention provides compounds, wherein Z is An embodiment of the invention provides compounds, wherein X is-C (O) NH-, -C (O) NHCH2-, -C (O) NHCH (CH3)-,-C (O) CH2-or-C (O)-. An embodiment of the invention provides compounds, wherein X is-C (O) NH-.

An embodiment of the invention provides compounds, wherein D is

wherein R15, R16 and R17 independently are hydrogen, halogen,-CN,-CF3,-OCF3 or C14- alkoxy.

An embodiment of the invention provides compounds, wherein E is wherein R29 and R3'are both hydrogen, and R30 is cyclohexenyl, which may optionally be substituted with one or more substituents selected from halogen,-CN,-CF3,-OCF3,-NO2,-oR34,-NR34R35 and C1-6-alkyl, # wherein R34 and R35 independently are hydrogen, C1-6-alkyl or aryl, or R34 and R35 when attached to the same nitrogen atom together with the said ni- trogen atom may form a 3 to 8 membered heterocyclic ring optionally containing one or two further heteroatoms selected from nitrogen, oxygen and sulfur, and optionally containing one or two double bonds.

# An embodiment of the invention provides compounds, wherein R29, R30 and R3'independent- ly are hydrogen, C1-6-alkyl, phenyl, C3-8-cycloalkyl or C44-cycloalkenyl.

An embodiment of the invention provides compounds, wherein R29 and Rare both hydro- gen and R30 is C1-6-alkyl, C3-8-cycloalkyl or C44-cycloalkenyl In an embodiment the invention provides the compounds as below : (R)-3-{4-[1-(4-Cyclohexylphenyl)-3-(3-methoxy-5-trifluoromet hylphenyl)ureidomethyl]benzoyl- amino}-2-hydroxypropionic acid

(R)-3- {4- [3- (3, 5-Bis (trifluoromethyl) phenyl)-l- (4-cyclohexylphenyi) ureidomethyl] benzoyl- amino}-2-hydroxypropionic acid <BR> <BR> <BR> (R)-3- {4- [3- (3-Bromophenyl)-1- (4-cyclohexylphenyl) ureidomethyl] benzoylamino}-2-hydroxy- propionic acid <BR> <BR> <BR> <BR> (R)-3- {4- [1- (4-Cyclohexylphenyl)-3- (4-trifluoromethoxyphenyl) ureidomethyl] benzoylamino}-2- hydroxypropionic acid <BR> <BR> <BR> (R)-3- {4- [l- (4-Cyclohexylphenyl)-3- (3-trifluoromethylphenyl) ureidomethyl] benzoylamino)-2- hydroxypropionic acid <BR> <BR> <BR> (R)-3- {4- [l- (4-Cyclohexylphenyl)-3- (3-fluoro-5-trifluoromethylphenyi) ureidomethyI] benzoyl- amino}-2-hydroxypropionic acid <BR> <BR> <BR> (R)-3- {4- [3- (3-Cyano-5-trifluoromethylphenyl)-1- (4-cyclohex-1-enylphenyl) ureidomethyl]-<BR> <BR> <BR> <BR> <BR> <BR> benzoylamino}-2-hydroxypropionic acid<BR> <BR> <BR> <BR> <BR> (R)-3- {4- [3- (3-Cyano-5-trifluoromethylphenyl)-1- (4-cyclohexylphenyl) ureidomethyl] benzoyl- amino}-2-hydroxypropionic acid (R)-3- {4- [3- (3-Bromo-5-trifluoromethylphenyl)-1- (4-cyclohex-1-enylphenyl) ureidomethyl]- benzoylamino}-2-hydroxypropionic acid <BR> <BR> <BR> <BR> (R)-3- {4- [1- (4-Cyclohex-1-enylphenyl)-3- (3-methoxy-5-trifluoromethylphenyl) ureidomethyl]- benzoylamino}-2-hydroxypropionic acid (R)-3- {4- [3- (3-Bromophenyl)-1- (4-cyclohex-1-enylphenyl) ureidomethyl] benzoylamino}-2- hydroxypropionic acid <BR> <BR> <BR> <BR> (R)-3- {4- [3- (3-Bromo-5-trifluoromethylphenyl)-1- (4-cyclohexylphenyl) ureidomethyl] benzoyl- amino}-2-hydroxypropionic acid (S)-Trans-3- {4- [3- (3, 5-Bis (trifluoromethyl) phenyl)-1- (4-tert-butylcyclohexyl) ureidomethyl]- benzoylamino}-2-hydroxypropionic acid (R)-Trans-3- {4- [3- (3, 5-bis (trifluoromethyl) phenyl)-1-(4-tert-butylcyclohexyl)ureidomethyl]- benzoylamino}-2-hydroxypropionic acid <BR> <BR> <BR> <BR> Trans- (R)-3- {4- [3- (3-methyl-5-trifluoromethylphenyl)-1- (4-tert-butylcyclohexyl) ureidomethyl]- benzoylamino}-2-hydroxypropionic acid <BR> <BR> <BR> <BR> (RS)-3- {4- [1- (4-tert-Butylphenyl)-3- (4-trifluoromethoxyphenyl) ureidomethyl] benzoylamino}-2- hydroxypropionic acid <BR> <BR> <BR> (RS)-3- 4- [1- (4-Cyclohex-1-enylphenyl)-3- (3, 5-dichlorophenyl) ureidomethyl] benzoylamino}- 2-hydroxypropionic acid (S)-3-{4-[1-(4-Cyclohex-1-enylphenyl)-3-(3,5-dichlorophenyl) ureidomethyl]benzoylamino}-2- hydroxypropionic acid

(R)-3- {4- [1- (4-Cyclohex-1-enylphenyl)-3- (3, 5-dichlorophenyl) ureidomethyl] benzoylamino}-2- hydroxypropionic acid (R)-3- {4- [3- (3-Chlorophenyl)-1- (4-cyclohex-1-enylphenyl) ureidomethyl] benzoylamino}-2- hydroxypropionic acid (R)-3- {4- [1- (4-Cyclohex-1-enylphenyl)-3-phenylureidomethyl] benzoylamino}-2-hydroxy- propionic acid (R)-3- {4- [3-Benzyl-1- (4-cyclohex-1-enylphenyl) ureidomethyl] benzoylamino}-2-hydroxy- propionic acid <BR> <BR> <BR> (RS)-3- {4- [1- (4-Cyclohex-1-enylphenyl) 3- (3, 5-dichlorophenyl) ureidomethyl] benzoylamino}-2- fluoropropionic acid (R)-3- {4- [1- (4-Cyclohexylphenyl)-3- (4-trifluoromethylsulfanylphenyl) ureidomethyl] benzoyl- amino}-2-hydroxypropionic acid (R)-3- {4- [l- (4-Cyclohexen-1-ylphenyl)-3- (3-methanesulfonyl-4-trifluoromethoxyphenyl)- ureidomethyl] benzoylamino}-2-hydroxypropionic acid Trans- (R)-3- {4- [-3- (3, 5-bis (methyl) phenyl)-1- (4-tert-butylcyclohexyl) ureidomethyl] benzoyl- amino}-2-hydroxypropionic acid (R)-3- {4- [1- (4-Cyclohexylphenyl)-3- (3, 5-dichlorophenyl) ureidomethyl] benzoylamino}-2- hydroxypropionic acid (R)- (3- (4- [l- (4-Cyclohex-1-enylphenyl)-3- (3-fluoro-5-trifluoromethylphenyl) ureidomethyl]- benzoylamino}-2-hydroxypropionic acid <BR> <BR> <BR> (R)-3- {4- [1- (4-Cyclohexylphenyl)-3- (3-methylsulfanylphenyl) ureidomethyl] benzoylamino}-2- hydroxypropionic acid (R)-3- {4- [1- (4-Cyclohex-1-enylphenyl)-3- (2, 2,4, 4-tetrafluoro-4H-benzo [1,3] dioxin-6-yl) ureido- methyl] benzoylamino}-2-hydroxypropionic acid 3- {4- [1- (4-Cyclohex-1-enylphenyl)-3- (3, 5-dichlorophenyl) ureidomethyl] benzoylamino}-2 (R) - methoxypropionic acid : 3- (4- {3- (3, 5-Dichlorophenyl)-1- [4- (2-methylcyclohex-1-enyl) phenyl] ureidomethyl} benzoyl- amino)-2- (R)-hydroxypropionic acid and (R, S)-3- (4- {3- (3, 5-dichlorophenyl)-1- [4- (6- <BR> <BR> <BR> methylcyclohex-1-enyl) phenyl] ureidomethyl} benzoylamino)-2-(R)-hydroxypropionic acid<BR> <BR> <BR> <BR> <BR> 3- {4- [1- [4- (4-tert-Butylcyclohex-1-enyl) phenyl]-3- (3, 5-dichlorophenyl) ureidomethyl] benzoyl-<BR> <BR> <BR> <BR> <BR> amino}-2-(R)-hydroxypropionic acid (R, S)-3- (4- (3- (3, 5-dichlorophenyl)-1- (4- (3-methylcyclohex-1- enyl) phenyl) ureidomethyl) benzoylamino)-2-hydroxypropionic acid <BR> <BR> <BR> 3- {4- [3- [1 (S)- (4-Chlorophenyl) ethyl]-1- (4-cyclohexylphenyl) ureidomethyl] benzoylamino}-2 (R)- hydroxypropionic acid

3- {4- [3-Biphenyl-2-ylmethyl-1- (4-cyclohexylphenyl) ureidomethyl] benzoylamino}-2 (R)- hydroxypropionic acid <BR> <BR> <BR> (R)-3- {4- [3- (4-Cyano-3-trifluoromethylphenyl)-1- (4-cyclohexylphenyl) ureidomethyl] benzoyl- amino}-2-hydroxypropionic acid (R)-3- {4- [3- (3-tert-Butylphenyl)-1- (4-cyclohexylphenyl) ureidomethyl] benzoylamino}-2- hydroxypropionic acid (R)-3- {4- [1- (4-Cyclohexylphenyl)-3- (3-hydroxymethyl-4-trifluoromethoxyphenyl) ureido- methyl] benzoylamino}-2-hydroxypropionic acid (R)-3- {4- [1- (4-tert-Butylphenyl)-3- (3, 4-dichlorophenyl) ureidomethyl] benzoylamino}-2- hydroxypropionic acid (R)-3- (4- [l- (4-tert-Butylcyclohexyl)-3- (3, 4-dichlorophenyl) ureidomethyl] benzoylamino)-2- hydroxypropionic acid (R)-3- {4- [1- (4-Cyclohexylphenyl)-3- (3, 4-dichlorophenyl) ureidomethyl] benzoylamino}-2- hydroxypropionic acid (R)-3- {4- [1- (4-Cyclohexylphenyl)-3- (2, 2,4, 4-tetrafluoro-4H-benzo [1,3] dioxin-6-yl) ureido- methyl] benzoylamino}-2-hydroxypropionic acid (R)-3- {4- [1- (4-tert-Butylphenyl)-3- (2, 2,4, 4-tetrafluoro-4H-benzo [1,3] dioxin-6-yl) ureidomethyl]- benzoylamino}-2-hydroxypropionic acid (R)-3- {4- [1- (4-tert-Butylcyclohexyl)-3- (2, 2,4, 4-tetrafluoro-4H-benzo [1,3] dioxin-6-yl) ureido- methyl] benzoylamino}-2-hydroxypropionic acid <BR> <BR> <BR> (R)-3- {4- [1- (4-tert-Butylphenyl)-3- (3, 4-difluorophenyl) ureidomethyl] benzoylamino}-2-hydroxy- propionic acid (R)-3- {4- [1- (4-Cyclohexylphenyl)-3- (3, 4-difluorophenyl) ureidomethyl] benzoylamino}-2- hydroxypropionic acid <BR> <BR> <BR> (R)-3- {4- [1- (4-Cyclohex-1-enylphenyl)-3- (3, 4-difluorophenyl) ureidomethyl] benzoylamino}-2- hydroxypropionic acid <BR> <BR> <BR> (R)-3- {4- [3- (4-Chloro-3-trifluoromethylphenyl)-1- (4-cyclohexylphenyl) ureidomethyl] benzoyl- amino}-2-hydroxypropionic acid <BR> <BR> <BR> (R)-3- {4- [1- (4-Cyclohexylphenyl)-3- (4-fluoro-3-nitrophenyl) ureidomethyl] benzoylamino}-2- hydroxypropionic acid (R)-3- {4- [1- (4-Cyclohexylphenyl)-3- (4-isopropylphenyl) ureidomethyl] benzoylamino}-2- hydroxypropionic acid <BR> <BR> <BR> (R)-3- {4- [1- (4-Cyclohex-1-enylphenyl)-3- (3, 4-dichlorophenyl) ureidomethyl] benzoylamino}-2- hydroxypropionic acid

(R)-3- {4- [3- (4-Acetylphenyl)-1- (4-cyclohexylphenyl) ureidomethyl] benzoylamino}-2-hydroxy- propionic acid 3- {4- [3- [1 (RS)- (4-Bromophenyl) ethyl]-1- (4-cyclohexylphenyl) ureidomethyl] benzoylamino}- 2 (R) -hydroxypropionic acid (R)-3- (4- [l- (4-Cyclohexylphenyl)-3- (3, 5-difluorophenyl) ureidomethyl] benzoylamino)-2- hydroxypropionic acid (R)-3-[4-({(4-tert-Butylcyclohexyl)-[2-(4-trifluoromethoxyph enyl)acetyl]amino}methyl)benzoyl- amino] -2-hydroxypropionic acid <BR> <BR> <BR> <BR> (R)-3- [4- ( { (4-tert-Butylcyclohexyl)- [2- (3-fluoro-5-trifluoromethylphenyl) acetyl] amino} methyl)- benzoylamino]-2-hydroxypropionic acid (R)-3- [4- ( { (2, 2-Diphenylethyl)- [2- (3-fluoro-5-trifluoromethylphenyl) acetyl] amino} methyl)- benzoylamino]-2-hydroxypropionic acid (R)-3-(4-{[(5-Chlorobenzo[b]thiophene-3-carbonyl)-(2,2-diphe nylethyl) amino] methyl} benzoyl- amino) -2-hydroxypropionic acid (R)-3- [4- ( { (2, 2-Diphenylethyl)- [2- (4-trifluoromethoxyphenyl) acetyl] amino} methyl) benzoyl- amino]-2-hydroxypropionic acid (R)-3-(4-{[(4-tert-Butylcyclohexyl)-(5-chlorobenzo[b]thiophe ne-3-carbonyl) amino] methyl}- benzoylamino)-2-hydroxypropionic acid (R)-3-(4-{[(2,2-Diphenylethyl)-(5-trifluoromethoxy-1H-indole -2-carbonyl) amino] methyl}- benzoylamino)-2-hydroxypropionic acid (R)-3-[4-({(4-Cyclohexylphenyl)-[(4-trifluoromethoxyphenyl)a cetyl]amino}methyl)benzoyl- amino] -2-hydroxypropionic acid (R)-3- [4- ( { (4-Cyclohexylphenyl)- [ (3-trifluoromethoxyphenyl) acetyl] amino} methyl) benzoyl- amino]-2-hydroxypropionic acid (R)-3-[4-({(4-Cyclohexylphenyl)-[(3-fluoro-5-trifluoromethyl phenyl)acetyl]amino}methyl)- benzoylamino]-2-hydroxypropionic acid (R)-3- (4- { ( [ (3, 5-Bis (trifluoromethyl) phenyl) acetyl]- (4-cyclohexylphenyl) amino) methyl} benzoyl- amino) -2-hydroxypropionic acid <BR> <BR> <BR> <BR> (R)-3- [4- ( { (4-Cyclohexylphenyl)- [ (3-trifluoromethylphenyl) acetyl] amino) methyl) benzoylamino]- 2-hydroxypropionic acid (R)-3-[4-({(4-Cyclohexylphenyl)-[(3,4-dichlorophenyl)acetyl] amino}methyl)benzoylamino]-2- hydroxypropionic acid (R)-3-(4-{[[(3-Bromophenyl)acetyl]-(4-cyclohexylphenyl) amino] methyl} benzoylamino)-2- hydroxypropionic acid

(R)-3-(4-{[(Biphenyl4-ylacetyl)-(4-cycloheXylphenyl) amino] methyl} benzoylamino)-2-hydroxy- propionic acid (R)-3-(4-{[(4-Cyclohexylpheny)-(2-naphthylacetyl) amino] methyl} benzoylamino)-2-hydroxy- propionic acid (R)-3- (4- { [ (3- (3, 5-Bis (trifluoromethyl) phenyl) propionyl)- (4-cyclohexylphenyl) amino] methyl}- benzoylamino)-2-hydroxypropionic acid <BR> <BR> <BR> <BR> (R)-3- [4- ( { (4-Cyclohexylphenyl)- [3- (3-nitrophenyl) propionyl] amino} methyl) benzoylamino]-2- hydroxypropionic acid <BR> <BR> <BR> <BR> <BR> <BR> <BR> (2R)-N- [4- ( {4-cyclohexyl [ (3, 5-dichloroanilino) carbonyl] anilino} methyl) benzoyl]-2-hydroxy-- alanine (2R)-N- [4- ( { [1, 1'-biphenyl]-4-yl [ (3, 5-dichloroanilino) carbonyl] amino} methyl) benzoyl]-2- hydroxy-ß-alanineln an embodiment the invention provides the compound (R)- [3- {4- [1- (4- Cyclohex-1-enylphenyl)-3- (3, 5-dichlorophenyl) ureidomethyl] benzoylamino}-2R- hydroxypropionic acid as a tert-butylamine salt.

In an embodiment the invention provides the compound (R)- [3- {4- [1- (4-Cyclohex-1- enylphenyl)-3- (3, 5-dichlorophenyl) ureidomethyl] benzoylamino}-2R-hydroxypropionic acid as an L-arginine salt.

In an embodiment the invention provides the compound (R)- [3- {4- [1- (4-Cyclohex-1- enylphenyl)-3- (3, 5-dichlorophenyl) ureidomethyl] benzoylamino}-2R-hydroxypropionic acid as a salt with N, N'-dibenzylethylenediamine.

In an embodiment the invention provides the compound (R)- [3- {4- [1- (4-Cyclohex-1- <BR> <BR> <BR> <BR> enylphenyl)-3- (3, 5-dichlorophenyl) ureidomethyl] benzoylamino}-2R-hydroxypropionic acid as a salt with N, N'-dibenzylethylenediamine as a 2: 1 ratio between compound and N, N'- dibenzylethylenediamine.

In an embodiment the invention provides the compound (2R)-N-[4-({[1,1'-biphenyl]-4-yl[(3, 5- dichloroanilino) carbonyl] amino} methyl) benzoyl]-2-hydroxy-ß-alanine and benzathine.

In an embodiment the invention provides the compound (2R)-N-[4-({[1,1'-biphenyl]-4-yl[(3, 5- dichloroanilino) carbonyl] amino} methyl) benzoyl]-2-hydroxy-ß-alanine and benzathine as a 2: 1 ratio between compound and N, N'-dibenzylethylenediamine.

In an embodiment the invention provides the compound ( (2R)-N- [4- ( {4-cyclohexyl [ (3, 5- dichloroanilino)carbonyl]anilino}methyl)benzoyl]-2-hydroxy- -alanine as a salt with N, N'- dibenzylethylenediamine.

In an embodiment the invention provides the compound ( (2R)-N- [4- ( {4-cyclohexyl [ (3, 5- dichloroanilino) carbonyl] anilino} methyl) benzoyl]-2-hydroxy-ß-alanine as a salt with N, N'- dibenzylethylenediamine in a 2: 1 ratio of compound to N, N'-dibenzylethylenediamine.

In an embodiment the invention provides a glucagon antagonist represented by the general formula (I) : wherein R2 is hydrogen or C1-6-alkyl, Z is arylene or a divalent radical derived from a 5 or 6 membered heteroaromatic ring contai- ning 1 or 2 heteroatoms selected from nitrogen, oxygen and sulfur, which may optionally be substituted with one or two groups W and R8 selected from halogen,-CN,-CF3,-OCF3,-N02,-OR9,-NR9R'° and C1-6-alkyl, wherein R9 and R'° independently are hydrogen or C1-6-alkyl, wherein r is 0 or 1, q and s independently are 0,1, 2 or 3, R", R12, R13 and R'4 independently are hydrogen or C1-6-alkyl,

D is

wherein R'5, R'6, R'7 and R13 independently are hydrogen, halogen,-CN,-CH2CN,-CHF2,-CF3,-OCF3,-OCHF2,-OCH2CF3, -OCF2CHF2, -S(O)2CH3, -SCF3, -NO2, -OR21, -NR21R22, -SR21, -NR21S(O)2R22, -S(O)2NR21R22, -S(O)NR21R22, -S(O)R21, -S(O)2R21, -C(O)NR21R22, -OC(O)NR21R22, -NR21C(O)R22, -CH2C(O)NR21R22, -OCH2C(O)NR21R22, -CH2OR21, -CH2NR21R22, -OC (O) R,-C (O) R or-C (O) OR # C1-6-alkyl, C2-6-alkenyl or C2-6-alkynyl, which may optionally be substituted with one or more substituents selected from halogen,-CN,-CF3,-OCF3,-NO2,-oR2',-NR2'R22 and Cl-6-alkyl, # C3-8-cycloalkyl, C4-8-cycloalkenyl, heterocyclyl, C3-8-cycloalkyl-C1-6-alkyl, C3-8-cyclo- alkyl-C1-6-alkoxy, C3-8-cycloalkyloxy, C3-8-cycloalkyl-C1-6-alkylthio, C3-8-cycloalkylthio,

C3-8-cycloalkyl-C2-6-alkenyl, C3-8-cycloalkyl-C2-6-alkynyl, C4-8-cycloalkenyl-C1-6-alkyl, C4-8-cycloalkenyl-C2-6-alkenyl, C4-8-cycloalkenyl-C2-6-alkynyl, heterocyclyl-C1-6-alkyl, heterocyclyl-C26-alkenyl, heterocyclyl-C2. 6-alkynyl, aryl, aryloxy, aryloxycarbonyl, aroyl, aryl-C1-6-alkoxy, aryl-C1-6-alkyl, aryl-C2-6-alkenyl, aryl-C2-6-alkynyl, heteroaryl, heteroaryl-C16-alkyl, heteroaryl-C2-alkenyl or heteroaryl-C2-6-alkynyl, of which the cyclic moieties optionally may be substituted with one or more substituents selected from halogen,-CN,-CF3,-OCF3,-N02,-ORz',-NR2'R22 and C1-6-alkyl, wherein R21 and R22 independently are hydrogen, C1-6-alkyl or aryl, or R21 and R22 when attached to the same nitrogen atom together with the said nitrogen atom may form a 3 to 8 membered heterocyclic ring optionally containing one or two further heteroatoms selected from nitrogen, oxygen and sulfur, and optionally containing one or two double bonds, or two of the groups R'5 to R18 when placed in adjacent positions together may form a bridge - (CR23R24)a-O-(CR25R26)c-O-, wherein a is 0, 1 or 2, cis 1 or 2, R23, R24, R25 and R26 independently are hydrogen, C1. 6-alkyl or fluorine, R'9 and R20 independently are hydrogen, C1-6-alkyl, C3-8-cycloalkyl or C38-cyclo- alkyl-C1-6-alkyl, E is

wherein R27and R23 independently are hydrogen, halogen, -CN, -CF3, -OCF3, -OR32, -NR32R33, C1-6-alkyl, C3-8-cycloalkyl, C4-8-cyclo- alkenyl or aryl, wherein the cyclic moieties optionally may be substituted with one or more substituents se- lected from halogen,-CN,-CF3,-OCF3,-N02,-OR32,-NR32R33 and Cl-6-alkyl, wherein R32 and R33 independently are hydrogen or C1-6-alkyl, or R32 and R33 when attached to the same nitrogen atom together with the said nitrogen atom may form a 3 to 8 membered heterocyclic ring optionally containing one or two further heteroatoms selected from nitrogen, oxygen and sulfur, and optionally containing one or two double bonds, R29, R30 and R3'independently are hydrogen, halogen,-CHF2,-CF3,-OCF3,-OCHF2,-OCH2CF3,-OCF2CHF2, -SCF3, -OR34, -NR34R35, -SR34, -S(O)R34, -S(O)2R34, -C(O)NR34R35, -OC(O)NR34R35, -NR34C(O)R35, -OCH2C(O)NR34R35, -C(O)R34 or-C (O) OR34,

# C1-6-alkyl, C2-6-alkenyl or C2-6-alkynyl, which may optionally be substituted with one or more substituents selected from halogen,-CN,-CF3,-OCF3,-NO2,-oR34,-NR34R35 and C1-6-alkyl, # C3-8-cycloalkyl, C4-8-cycloalkenyl, heterocyclyl, C3-8-cycloalkyl-C1-6-alkyl, C3-8-cyclo- alkyl-C2-6-alkenyl, C3-8-cycloalkyl-C2-6-alkynyl, C4-8-cycloalkenyl-C1-6-alkyl, C4-8-cyclo- alkenyl-C2-6-alkenyl, C4-8-cycloalkenyl-C2-6-alkynyl, heterocyclyl-C1-6-alkyl, hetero- cyclyl-C2-6-alkenyl, heterocyclyl-C2-6-alkynyl, aryl, aryloxy, aroyl, aryl-C1-6-alkoxy, aryl- C1-6-alkyl, aryl-C2-6-alkenyl, aryl-C2-6-alkynyl, heteroaryl, heteroaryl-C1-6-alkyl, hetero- aryi-C2-e-alkenyl or heteroaryl-C26-alkynyl, of which the cyclic moieties optionally may be substituted with one or more sub- stituents selected from halogen,-CN,-CF3,-OCF3,-N02,-OR34,-NR34R35 and C1-6-alkyl, wherein R34 and R35 independently are hydrogen, C14-alkyl or aryl, or R34 and R35 when attached to the same nitrogen atom together with the said nitrogen atom may form a 3 to 8 membered heterocyclic ring optionally containing one or two further heteroatoms selected from nitrogen, oxygen and sulfur, and optionally containing one or two double bonds, or two of the groups R29, R30 and R3'when attached to the same ring carbon atom or diffe- rent ring carbon atoms together may form a radical -O-(CH2)t-CR36R37-(CH2)l-O-, -(CH2)t-CR36R37-(CH2)l- or -S-(CH2)t-CR36R37-(CH2)l-S-, wherein t and I independently are 0,1, 2,3, 4 or 5, R36 and R37 independently are hydrogen or Cl-6-alkyl,

as well as any optical or geometric isomer or tautomeric form thereof including mixtures of these.

In an embodiment the invention provides a compound, wherein R2 is hydrogen.

In an embodiment the invention provides a compound, wherein Z is wherein R7 and R3 are as defined as above.

In an embodiment the invention provides a compound, wherein Z is In an embodiment the invention provides a compound, wherein X is wherein q is 0 or 1, r is 0 or 1, s is 0, 1 or 2, and R12 and R'3 independently are hydrogen or C1-6-alkyl.

In an embodiment the invention provides a glucagon antagonist as represented by the gen- eral formula (I) :

wherein A is

mis0or1, n is 0, 1,2 or 3, with the proviso that m and n must not both be 0, R'is hydrogen, fluoro or -(CH2)o-OR2, ois0 or1, R2 is hydrogen, C1-6-alkyl, Cl-6-alkanoyl, aryl or aryl-C1-6-alkyl, X is-N= or-CH=, B is V and W independently are-CH= or-N=, Y is-O-,-S-or-NH-, R3, R4 and R5 independently are # hydrogen, halogen, -CN, -CHF2, -CF3, -OCF3, -OCHF2, -OCH2CF3, -OCF2CHF2, -S(O)2CF3, -SCF3, -NO2, -OR6, -NR6R7, -SR6, -NR6S(O)2R7, -S(O)2NR6R7, -S(O)NR6R7, -S(O)R6, -S(O)2R6, -C(O)NR6R7, -OC(O)NR6R7, -NR6C(O)R7,

- CH2C (O) NRgR',-OCH2C (O) NR6R7,-OCH2C (O) OR6,-OC (O) Re,-C (O) R6 or -C (O) OR, # C1-6-alkyl, C2-6-alkenyl or C24-alkynyl, which may optionally be substituted with one or more substituents selected from <BR> <BR> <BR> fluoro,-CN,-CF3,-OCF3,-OR6 and-NR6R',<BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> # C3-8-cycloalkyl, C4-8-cycloalkenyl, heterocyclyl, C3-8-cycloalkyl-C1-6-alkyl, C3-8-cyclo- alkyl-C1-6-alkoxy, C3-8-cycloalkyloxy, C3-8-cycloalkyl-C1-6-alkylthio, C3-8-cycloalkylthio, C3-8-cycloalkyl-C2-6-alkenyl, C3-8-cycloalkyl-C2-6-alkynyl, C4-8-cycloalkenyl-C1-6-alkyl, C4-8-cycloalkenyl-C2-6-alkenyl, C4-8-cycloalkenyl-C2-6-alkynyl, heterocyclyl-C1-6-alkyl, heterocyclyl-C2-6-alkenyl, heterocyclyl-C2-6-alkynyl, of which the cyclic moieties may optionally be substituted with one or more substitu- ents selected from fluoro,-C (O) OR6, -CN, -CF3, -OCF3, -OR7, -NR6R7 and C1-6-alkyl, # aryl, arylthio, aryl-C1-6-alkylthio, aryloxy, aryloxycarbonyl, aroyl, aryl-C1-6-alkoxy, aryl- C1-6-alkyl, aryl-C2-6-alkenyl, aryl-C2-6-alkynyl, heteroaryl, heteroaryl-C1-6-alkyl, het- eroaryl-C2-6-alkenyl or heteroaryl-C2-6-alkynyl, of which the cyclic moieties may optionally be substituted with one or more substitu- ents selected from halogen (O) OR6,-CN,-CF3,-OCF3,-NO2,-OR',-NRBR'and Cl-6-alkyl, R6 and R7 independently are hydrogen or C1-6-alkyl, or R6 and R7 when attached to the same nitrogen atom together with the said nitrogen atom may form a 3 to 8 membered heterocyclic ring optionally containing one or two further heteroatoms selected from nitrogen, oxygen and sulfur, and optionally contain- ing one or two double bonds, or two of the groups R3 to R5 when placed in adjacent positions together may form a bridge -(CR8R9)s-O-(CR10R11)t-O-,

s is 0,1 or 2, t is 1 or 2, R8, R9, R10 and R"independently are hydrogen, C1-6-alkyl or fluoro, p is 0, 1,2, 3 or 4, E is X1, Z'and W'independently are-CH= or-N=, Y'is-0-,-S-or-NH-, Q1 is -CH2- or -NH-, q is 2,3, 4,5 or 6, ris1, 2,3, 4 or 5, R12, R13 and R'4 independently are # hydrogen, halogen, -CN, -CHF2, -CF3, -OCF3, -OCHF2, -OCH2CF3, -OCF2CHF2, -S(O)2CF3, -SCF3, -NO2, -OR17, -NR17R18, -SR17, -NR17S(O)2R18, -S(O)2NR17R18, - S (O) NR"R'8,-S (O) R",-S (0) 2R",-C (O) NR"R'8,-OC (O) NR"R'8,-NR"C (O) R'8, -CH2C(O)NR17R18, -OCH2C(O)NR17R18, -OC(O)R17, -C(O)R17 or-C (O) OR # C1-6-alkyl, C2-6-alkenyl or C2-6-alkynyl,

which may optionally be substituted with one or more substituents selected from fluoro, -CN, -CF3, -OCF3, -OR17 and -NR17R18, #C3-8-cycloalkyl, C4-8-cycloalkenyl, heterocyclyl, C3-8-cycloalkyl-C1-6-alkyl, C3-8-cyclo- alkyl-C1-6-alkoxy, C3-8-cycloalkyloxy, C3-8-cycloalkyl-C1-6-alkylthio, C3-8-cycloalkylthio, <BR> <BR> <BR> C3-8-cycloalkyl-C2-6-alkenyl, Cm-cycloalkyl-C2-6-alkynyl, C"-cycloalkenyl-Cl-6-alkyl,<BR> <BR> <BR> <BR> C"-cycloalkenyl-C2-e-alkenyl, C"-cycloalkenyl-C2-6-alkynyl, heterocyclyl-Cl-6-alkyl, heterocyclyl-C2-6-alkenyl, heterocyclyl-C2-6-alkynyl, of which the cyclic moieties may optionally be substituted with one or more substitu- ents selected from fluoro,-C (O) OR17, -CN, -CF3, -OCF3, -OR17 and -NR17R18, #aryl, aryloxy, aryloxycarbonyl, aroyl, aryl-C1-6-alkoxy, aryl-C1-6-alkyl, aryl-C2-6-alkenyl, aryl-C2-6-alkynyl, heteroaryl, heteroaryl-C1-6-alkyl, heteroaryl-C2-6-alkenyl or heteroaryl- C24-alkynyl, of which the cyclic moieties may optionally be substituted with one or more substitu- ents selected from halogen (O) OR17, -CH, -CF3, -OCF3, -NO2, -OR17, -NR17R18 and C1-6-alkyl, R17 and R18 independently are hydrogen or C1-6-alkyl, or R17 and R'8 when attached to the same nitrogen atom together with the said nitro- gen atom may form a 3 to 8 membered heterocyclic ring optionally containing one or two further heteroatoms selected from nitrogen, oxygen and sulfur, and optionally containing one or two double bonds, or two of the groups R12 to R'4 when placed in adjacent positions together may form a bridge -(CR19R20)x-O-(CR21R22)y-O-, x is 0, 1 or 2, y is 1 or 2,

R'9, R20, R21 and R22 independently are hydrogen, C1-6-alkyl or fluoro, R'5 and R16 independently are hydrogen, halogen, -CN, -CF3, -OR23, -NR23R24, C1-6-alkyl, C3-8-cycloalkyl, C4-8-cycloalkyl, aryl or aryl-C1-6-alkyl, wherein the cyclic moieties may optionally be substituted with one or more substituents se- lected from halogen,-CN,-CF3,-NO2,-oR23,-NR23R24 and C1-6-alkyl, R23 and R24 independently are hydrogen or C1-6-alkyl, or R23 and R24 when attached to the same nitrogen atom together with the said nitrogen atom may form a 3 to 8 membered heterocyclic ring optionally containing one or two further het- eroatoms selected from nitrogen, oxygen and sulfur, and optionally containing one or two double bonds, or E is C1-6-alkyl, C1-6-alkenyl or C2-6-alkynyl, which may optionally be substituted with one or more substituents selected from halogen,- CN, -CF3, -OCF3, -NO2, -OR25, -SR25, -NR25R26 and C1-6-alkyl, R25 and R26 independently are hydrogen or C14-alkyl, or R25 and R26 when attached to the same nitrogen atom together with the said nitrogen atom may form a 3 to 8 membered heterocyclic ring optionally containing one or two further het- eroatoms selected from nitrogen, oxygen and sulfur, and optionally containing one or two double bonds, Z is -(CR27R28)v-(O)w-(CR29R30)z-, v and z independently are 0,1 or 2, w is 0 or 1,

R27, R28, R29 and R30 independently are hydrogen or C1-6-alkyl, as well as any diastereomer or enantiomer or tautomeric form thereof including mixtures of these.

In an embodiment the invention provides a compound, wherein A is wherein n is as defined above.

In an embodiment the invention provides a compound, wherein A is In an embodiment the invention provides a compound, wherein A is In an embodiment the invention provides a compound, wherein B is wherein R3 to R5 are as defined above.

In an embodiment the invention provides a glucagon antagonist as represented by the gen- eral formula (I) :

wherein A is m is 0 or 1, n is 0, 1, 2 or 3, with the proviso that m and n must not both be 0, is hydrogen, halogen or -(CH2)o-OR5, o is 0 or 1, R5 is hydrogen, C1-6-alkyl, C1-6-alkanoyl, aryl or aryl-C1-6-alkyl, R'and R2 independently are hydrogen, halogen or C1-6-alkyl, or R'and R2 are combined to form a double bond, R3 is hydrogen, C1-6-alkyl or halogen, or R3 and R2 are combined to form a double bond to oxygen, X is arylene or heteroarylene, which may optionally be substituted with one or two groups Ré and R7 selected from halogen,-CN,-CF3,-OCF3,-OCHFz,-NO2,-OR8,-NR8R9 and C1-6-alkyl,

R8 and R9 independently are hydrogen or C1-6-alkyl, Y is -C(O)-, -O-, -NR10-, -S-, -S(O)-, -S(O)2- or -CR11R12-, R'° is hydrogen or CI-6-alkyl, R11 and R12 independently are hydrogen, C, $-alkyl or hydroxy, or R"is combined with R1 to form a double bond, and R12 is hydrogen, CI-6-alkyl or hydroxy, Z is-C (O)-(CR13R14)p-, -O-(CR13R14)p-, -S(CR13R14)p-, -S(O)-(CR13R14)p-, -S(O)2-(CR13R14)p-, -NR15-(CR13R14)p- or -(CR13R14)p-, p is 0, 1 or 2, R'3 and R'4 independently are selected from hydrogen,-CF3,-OCF3,-OCHF2 and C1-6-alkyl, R'5 is hydrogen or C1-6-alkyl, D is aryl or heteroaryl, which may optionally be substituted with one or more substituents R16, R17, R18, R19, R20 and R21, wherein R16, R17, R18 and R19 independently are hydrogen, halogen,-CN,-CH2CN,-CHF2,-CF3,-OCF3,-OCHF2,-OCH2CF3, -OCF2CHF2, -S(O)2CF3, -SCF3, -NO2, -OR22, -NR22R23, -SR22, -NR22S(O)2R23, -S(O)2NR22R23, -S(O)NR22R23, -S(O)R22, -S(O)2R23, -C(O)NR22R23, -OC(O)NR22R23, -NR22C(O)R23, -CH2C(O)NR22R23, -OCH2C(O)NR22R23, -CH2OR22, -CH2NR22R23, -OC (O) R,-C (O) R or-C (O) OR #C1-6-alkyl, C2-6-alkenyl or C2 6-alkynyl, which may optionally be substituted with one or more substituents selected from halogen,-CN,-CF3,-OCHF2,-OCF3,-N02,-OR22,-NR22R23 and C1-6-alkyl,

C3-8-cycloalkyl, C4-8-cycloalkenyl, heterocyclyl, C3-8-cycloalkyl-C1-6-alkyl, C3-8-cyclo- arkyl-C1-6-alkoxy, C3-8-cycloalkyloxy, C3-8-cycloalkyl-C1-6-alkylthio, C3-8-cycloalkylthio, C3-8-cycloalkyl-C2-6-alkenyl, C3-8-cycloalkyl-C2-6-alkynyl, C4-8-cycloalkenyl-C1-6-alkyl, C4-8-cycloalkenyl-C2-6-alkenyl, C4-8-cycloalkenyl-C2-6-alkynyl, heterocyclyl-C1-6-alkyl, heterocyclyl-C2-6-alkenyl, heterocyclyl-C2-6-alkynyl, aryl, aryloxy, aryloxycarbonyl, aroyl, aryl-C1-6-alkoxy, aryl-C1-6-alkyl, aryl-C2-6-alkenyl, aryl-C2-6-alkynyl, heteroaryl heteroaryl-C, 6-alkyl, heteroaryl-C2-6-alkenyl or heteroaryl-C26-alkynyl, of which the aromatic and non-aromatic ring systems optionally may be substituted with one or more substituents selected from halogen,-C (O) OR,-CN,-CF3,-OCF3, -OCHF2, -NO2, -OR22, -NR22R23 and C1-6-alkyl, R22 and R23 independently are hydrogen, C1-6-alkyl, aryl-C1-6-alkyl or aryl, or R22 and R23 when attached to the same nitrogen atom together with the said nitrogen atom may form a 3 to 8 membered heterocyclic ring optionally containing one or two further heteroatoms selected from nitrogen, oxygen and sulfur, and optionally containing one or two double bonds, or two of the groups R16 to R'9 when placed in adjacent positions together may form a bridge -(CR24R25)a-O-(CR26R27)c-O-, a is 0, 1 or 2, c is 1 or 2, R24, R25, R26 and R27 independently are hydrogen, C, $-alkyl or fluoro, R20 and R21 independently are hydrogen, C1-6-alkyl, C3-8-cycloalkyl or Cm-cyclo- alkyl-C1-6-alkyl, E is Cm-cycloalkyl or C4. 8-cycloalkenyl, which may optionally be substituted with one or two sub- stituents R28 and R29, which are independently selected from

#hydrogen, halogen, -CN, -CF3, -OCF3, -OCHF2, -OR33, -NR33R34, C1-6-alkyl, C3-8- cycloalkyl, C"-cycloalkenyl, heteroaryl and aryl, wherein the heteroaryl and aryl groups optionally may be substituted with one or more substituents selected from halogen,-CN,-CF3,-OCF3,-OCHF2,-NO2,-OR33,- NR33R34 and C1-6-alkyl, R33 and R34 independently are hydrogen or C1-6-alkyl, or R33 and R34 when attached to the same nitrogen atom together with the said nitro- gen atom may form a 3 to 8 membered heterocyclic ring optionally containing one or two further heteroatoms selected from nitrogen, oxygen and sulfur, and optionally containing one or two double bonds, aryl, heteroaryl, aryl-C24-alkenyl or aryl-C24-alkynyl, of which the aryl and heteroaryl moieties may optionally be substituted with one or more substitutents R28, R29, R30, R3'and R32, wherein R28 and R29 are as defined above, and R30, R3'and R32 are independently selected from hydrogen, halogen,-CHF2,-CF3,-OCF3,-OCHF2,-OCH2CF3,-OCF2CHF2,-SCF3, -OR35, -NR35R36, -SR35, -S(O)R35, -S(O)2R35, -C(O)NR35R36, -OC(O)NR35R36, -NR35C(O)R36, -OCH2C(O)NR35R36, -C(O)R35 and-C (O) OR35, #C1-6-alkyl, C2-6-alkenyl and C24-alkynyl, which may optionally be substituted with one or more substituents selected from halogen,-CN,-CF3,-OCF3,-OCHF2,-NO2,-OR35,-NR35R3s and C1-6-alkyl, #C3-8-cycloalkyl, C4-8-cycloalkenyl, heterocyclyl, C3-8-cycloalkyl-C1-6-alkyl, C3-8-cyclo- alkyl-C2-6-alkenyl, C3-8-cycloalkyl-C2-6-alkynyl, C4-8-cycloalkenyl-C1-6-alkyl, C4-8-cyclo- alkenyl-C2-6-alkenyl, C4-8-cycloalkenyl-C2-6-alkynyl, heterocyclyl-C1-6-alkyl, heterocy- clyl-C2-6-alkenyl, heterocyclyl-C2$-alkynyl, aryl, aryloxy, aroyl, aryl-C14-alkoxy, aryl- C1-6-alkyl, aryl-C2-6-alkenyl, aryl-C2-6-alkynyl, heteroaryl, heteroaryl-C1-6-alkyl, hetero- aryl-C2-6-alkenyl and heteroaryl-C2-6-alkynyl,

of which the aromatic and non-aromatic ring systems optionally may be substituted with one or more substituents selected from halogen,-CN,-CF3,-OCF3,-OCHF2,- N02,-OR35,-NR35R38 and C1-6-alkyl, wherein R35 and R36 independently are hydrogen, Cl-6-alkyl or aryl, or R35 and R36 when attached to the same nitrogen atom together with the said nitro- gen atom may form a 3 to 8 membered heterocyclic ring optionally containing one or two further heteroatoms selected from nitrogen, oxygen and sulfur, and optionally containing one or two double bonds, or two of the substituents R30, R3'and R32 when attached to the same ring carbon atom or adjacent ring carbon atoms together may form a bridge -O- (CH2)t-CR37R38- (CH2) rO-,- (CH2)t-CR37R38-(CH2)@- or -S-(CH2)t-CR37R38-(CH2)@-S-, t and I independently are 0,1, 2,3, 4 or 5, R37 and R38 independently are hydrogen or Cl-6-alkyl, as well as any diastereomer or enantiomer or tautomeric form thereof including mixtures of these.

In an embodiment the invention provides compounds, wherein A is wherein m, n and R4 are as defined above.

In an embodiment the invention provides compounds, wherein A is In an embodiment the invention provides compounds, wherein A is In an embodiment the invention provides compounds, wherein A is

In an embodiment the invention provides compounds, wherein X is monocyclic arylene or heteroarylene, which may optionally be substituted as defined above.

In an embodiment the invention provides compounds, wherein X is

wherein Re and R7 are as defined above.

In an embodiment the invention provides compounds, wherein X is wherein R6 and R7 are as defined above.

In an embodiment the invention provides compounds, wherein E is

wherein R30, R3'and R32 are as defined above.

In an embodiment the invention provides compounds, wherein R30, R3'and R32 independ- ently are

# hydrogen, #halogen, -OCF3, -OCHF2 or -SCF3, #C1-6-alkyl, which may optionally be substituted with one or more substituents se- lected from fluoro,-CN,-CF3,-OCF3,-OR35 and-NR35R36, * cyclohexyl or cyclohex-1-enyl, which may optionally be substituted with one or more substituents selected from fluoro,-CN,-CF3,-OCF3,-oR35,-NR35R36 and Cl-6-alkyl, # phenyl which may optionally be substituted with one or more substitutents selected from halogen, -CN, -CF3, -OCF3, -NO2, -OR35, -NR35R36 and C1-6-alkyl, #phenoxy or benzyloxy, of which the phenyl moieties may optionally be substituted with one or more substituents selected from halogen, -CN, -CF3, -OCF3, -NO2, -OR35, -NR35R36 and C1-6-alkyl, R35 and R35 independently are hydrogen or C1-6-alkyl, In an embodiment the invention provides compounds, wherein E is In an embodiment the invention provides compounds, wherein R'and R2 are both hydrogen.

In an embodiment the invention provides compounds, wherein R'and R2 are combined to form a double bond.

In an embodiment the invention provides compounds, wherein R3 is hydrogen.

In an embodiment the invention provides compounds, wherein Z is NH or-C (O)-.

In an embodiment the invention provides compounds, wherein D is wherein R16, R17 and R18 are as defined above.

In an embodiment the invention provides compounds, wherein R'6, R'7 and R18 independ- ently are #hydrogen, halogen, -CF3, -OCF3, -SCF3, C1-6-alkyl, C1-6-alkoxy, phenyl, cyclopentyl, cyclohexyl or phenoxy, *or two of the groups R16 to R'8 when placed in adjacent positions together may form a bridge -O-(CF2)2-O-, -CF2-O-CF2-O- or -O-CH2-O-.

In an embodiment the invention provides compounds such as (Z)-3-{4-[4-Biphenyl-4-yl-2-(4-cyclohexylphenyl)-4-oxobut-2- enoyl]benzoylamino} propionic acid <BR> <BR> <BR> <BR> (Z)-3- {4- [2-Biphenyl-4-yl-4- (4-chlorophenyl)-4-oxobut-2-enoyl] benzoylamino} propionic acid<BR> <BR> <BR> <BR> <BR> (Z)-3- {4- [4- (4-tert-Butylphenyl)-4-oxo-2- (4-trifluoromethoxyphenyl) but-2-enoyl] benzoylamino}- propionic acid <BR> <BR> <BR> 3- {4- [4- (3, 5-Bis-trifluoromethylphenyl)-2- (4-cyclohexylphenyl)-4-oxo-butyryl] benzoylamino}- propionic acid ( (R) 3- {4- [4- (3, 5-Bis-trifluoromethylphenyl)-2- (4-cyclohexylphenyl)-4-oxo- butyryl] benzoylamino}-propionic acid (S) 3- {4- [4- (3, 5-Bis-trifluoromethylphenyl)-2- (4-cyclohexylphenyl)-4-oxo- butyryl] benzoylamino}-propionic acid In an embodiment the invention provides glucagon antagonists as represented by the gen- eral formula (I) :

wherein A is m is 0 or 1, n is 0, 1, 2 or 3, with the proviso that m and n must not both be 0, R'is hydrogen, fluoro or- (CH2) o-OR2, o is 0 or 1, R2 is hydrogen, C1-6-alkyl, C1-6-alkanoyl, aryl or aryl-C1-6-alkyl, X is N, CH or C with a double bond to one substituent, Z is -CR3R4-, -(C=O)-(NR5)-(C1-6-alkyl)K-, -(C=O)-O-(C1-6-alkyl)K-, -(C=O)-(C1-6-alkyl) K-, -(C1-6-alkyl)K(C=O)-O-, -(C=O)-O-(C2-6-alkenyl)K-, -(C=O)-C2-6-alkenyl) K-, -(C1-6-alkenyl) K (C=O)-O- wherein k is 0 or 1, R3, R4 and R5 are independently selected from hydrogen, C, $-alkyl or aryl,

Y is- (C1-6-alkyl)s-(C=O)-(C1-6-alkyl)t-, -(C1-6-alkenyl)s-(C=O)-(C1-6-alkyl)t-, -C1-6-alkyl-, -C2-6- alkenyl-, or-CR6R7- wherein s and t independently are 0 or 1; wherein R6, R7 and R8 independently are selected from hydrogen, C1-6-alkyl and aryl ; D is aryl or heteroaryl, which may optionally be substituted with one or more substituents R'6, R17, R R'9, R20 and R2', wherein pie R17, R'8 and R'9 independently are hydrogen, halogen,-CN,-CH2CN,-CHF2,-CF3,-OCF3,-OCHF2,-OCH2CF3, -OCF2CHF2, -S(O)2CF3, -SCF3, -NO2, -OR22, -NR22R23, -SR22, -NR22S(O)2R23, -S(O)2NR22R23, -S(O)NR22R23, -S(O)R22, -S(O)2R22, -C(O)NR22R23, -OC(O)NR22R23, -NR22C(O)R23, -CH2C(O)NR22R23, -OCH2C(O)NR22R23, -CH2OR22, -CH2NR22R23, -OC(O)R22, -C(O)R22 or -C(O)OR22, o CI-6-alkyl, C2-6-alkenyl orC2-6-alkynyl, which may optionally be substituted with one or more substituents selected from halogen,-CN,-CF3,-OCF3,-NO2,-OR22,-NR22R23 and C1-6-alkyl, #C3-8-cycloalkyl, C4-8-cycloalkenyl, heterocyclyl, C3-8-cycloalkyl-C1-6-alkyl, C3-8-cyclo- alkyl-C1-6-alkoxy, C3-8-cycloalkyloxy, C3-8-cycloalkyl-C1-6-alkylthio, C3-8-cycloalkylthio, C3-8-cycloalkyl-C2-6-alkenyl, C3-8-cycloalkyl-C2-6-alkynyl, C4-8-cycloalkenyl-C1-6-alkyl, C"-cycloalkenyl-C2-6-alkenyl, C"-cycloalkenyl-C2-6-alkynyl, heterocyclyl-Cl-6-alkyl, heterocyclyl-C2-6-alkenyl, heterocyclyl-C2-6-alkynyl, aryl, aryloxy, aryloxycarbonyl, aroyl, aryl-C1-6-alkoxy, aryl-C1-6-alkyl, aryl-C2-6-alkenyl, aryl-C2-6-alkynyl, heteroaryl, heteroaryl-C1-6-alkyl, heteroaryl-C2-6-alkenyl or heteroaryl-C2-6-alkynyl, of which the cyclic moieties optionally may be substituted with one or more substitu- ents selected from halogen (O) OR22,-CN,-CF3,-OCF3,-NO2,-OR22,-NR22R23 and C1-6-alkyl,

R22 and R23 independently are hydrogen, C1-6-alkyl, aryl-C1-6-alkyl or aryl, or R22 and R23 when attached to the same nitrogen atom together with the said nitrogen atom may form a 3 to 8 membered heterocyclic ring optionally containing one or two further heteroatoms selected from nitrogen, oxygen and sulfur, and optionally containing one or two double bonds, or two of the groups R16 to R'9 when placed in adjacent positions together may form a bridge -(CR24R25)A-O-(CR26R27)c-O-, a is 0, 1 or 2, cis 1 or 2, R24, R25, R26 and R27 independently are hydrogen, C1-6-alkyl or fluoro, R20 and R21 independently are hydrogen, C1-6-alkyl, C3-8-cycloalkyl or C3. 8-cyclo- alkyl-C1-6-alkyl, E is C3-8-cycloalkyl or C4-8-cycloalkenyl, which may optionally be substituted with one or two sub- stituents R and R, which are independently selected from #hydrogen, halogen, -CN, -CF3, -OR33, -NR33R34, C1-6-alkyl, C3-8-cycloalkyl, C4-8-cyclo- alkenyl, heteroaryl and aryl, wherein the heteroaryl and aryl groups optionally may be substituted with one or more substituents selected from halogen,-CN,-CF3,-NO2,-OR33,-NR33R34 and C1-6-alkyl, R33 and R34 independently are hydrogen or Cl-6-alkyl, or R33 and R34 when attached to the same nitrogen atom together with the said nitro- gen atom may form a 3 to 8 membered heterocyclic ring optionally containing one or two further heteroatoms selected from nitrogen, oxygen and sulfur, and optionally containing one or two double bonds,

aryl, heteroaryl, aryl-C24-alkenyl or aryl-C24-alkynyl, of which the cyclic moieties may option- ally be substituted with one to three substitutents R30, R3'and R32, which are independently selected from hydrogen, halogen,-CHF2,-CF3,-OCF3,-OCHF2,-OCH2CF3,-OCF2CHF2,-SCF3, -OR35, -NR35R36, -SR35, -S(O)R35, -S(O)2R35, -C(O)NR35R36, -OC(O)NR35R36, - NR35C (O) R36,-OCH2C (O) NR35R,-C (O) R35 and-C (O) OR35, #C1-6-alkyl, C2-6-alkenyl and C24-alkynyl, which may optionally be substituted with one or more substituents selected from halogen,-CN,-CF3,-OCF3,-SCF3,-N02,-OR35,-NR35R36 and C, 4-alkyl, #C3-8-cycloalkyl, C4-8-cycloalkenyl, heterocyclyl, C3-8-cycloalkyl-C1-6-alkyl, C3-8-cyclo- alkyl-C24-alkenyl, C3-8-cycloalkyl-C2-6-alkynyl, C4-8-cycloalkenyl-C1-6-alkyl, C4-8-cyclo- alkenyl-C24-alkenyl, C4-8-cycloalkenyl-C2-6-alkynyl, heterocyclyl-C1-6-alkyl, heterocy- clyl-C2-6-alkenyl, heterocyclyl-C2-6-alkynyl, aryl, aryloxy, aroyl, aryl-c1-6-alkoxy, aryl- C1-6-alkyl, aryl-C2-6-alkenyl, aryl-C2-6-alkynyl, heteroaryl, heteroaryl-C1-6-alkyl, hetero- aryl-C24-alkenyl and heteroaryl-C24-alkynyl, of which the cyclic moieties optionally may be substituted with one or more substitu- ents selected from halogen,-CN,-CF3,-OCF3,-SCF3,-N02,-OR35,-NR35R36 and C1-6-alkyl, wherein R35 and R36 independently are hydrogen, C1-6-alkyl or aryl, or R35 and R36 when attached to the same nitrogen atom together with the said nitro- gen atom may form a 3 to 8 membered heterocyclic ring optionally containing one or two further heteroatoms selected from nitrogen, oxygen and sulfur, and optionally containing one or two double bonds, or two of the substituents R30 R3'and R32 when attached to the same ring carbon atom or different ring carbon atoms together may form a radical -O-(CH2)t-CR37R38- (CH2) @-O-, -(CH2)t-CR37R38-(CH2)@- or -S-(CH2)t-CR37R38-(CH2)@-S-,

t and I independently are 0, 1,2, 3,4 or 5, R37 and R38 independently are hydrogen or C, $-alkyl, as well as any diastereomer or enantiomer or tautomeric form thereof including mixtures of these.

In an embodiment the invention provides compounds, wherein A is wherein m, n and R4 are as defined above.

In an embodiment the invention provides compounds, wherein A is In an embodiment the invention provides compounds, wherein A is In an embodiment the invention provides compounds, wherein D is wherein R'6, R'7 and R18 independently are #hydrogen, halogen, CN, -CF3, -OCF3, -SCF3, -S(O) C1-6-alkyl, -C(O) C1-6-alkyl-, C1-6- alkyl, C14-alkoxy, phenyl, cyclopentyl, cyclohexyl or phenoxy, #or two of the groups R16 to R13 when placed in adjacent positions together may form a bridge -O-(CF2)2-O-, -CF2-O-CF3-O- or -O-CH2-O-.

In an embodiment the invention provides compounds, wherein E is

wherein R28, R29, R30, R31 and R32 are independently selected from hydrogen, #halogen, -OCF3, -OCHF2, -SCF3, or -CF3, #C1-6-alkyl, which may optionally be substituted with one or more substituents se- lected from fluoro, -CN, -CF3, -OCF3, -OR35 and -NR35R36, cyclohexyl or cyclohex-1-enyl, which may optionally be substituted with one or more substituents selected from fluoro, -CN, -CF3, -OCF3, -OR35, -NR35R36 and C1-6-alkyl, # phenyl which may optionally be substituted with one or more substitutents selected from halogen,-CN,-CF3,-OCF3,-N02,-OR35,-NR35R36 and C16-alkyl, # phenoxy or benzyloxy, of which the phenyl moieties may optionally be substituted with one or more substituents selected from halogen,-CN,-CF3,-OCF3,-N02,-OR35, -NR35R36 and C1-6-alkyl, o thiadiazolyl,

R35 and R independently are hydrogen or Cl-6-alkyl.

In an embodiment the invention provides compounds, wherein Y is-C=O-,-CH2-.

In an embodiment the invention provides compounds, wherein Z is-CH2-,- (C=O)- (NH),- (C=O)-O-or-(C=O)-CH2-.

In an embodiment the invention provides a compound which is 3- {4- [ (4-Cyclohexylbenzyl)- (4-trifluoromethoxybenzyl) amino] benzoylamino} propionic acid.

In an embodiment the invention provides a glucagon antagonist represented by the general formula (I) : wherein R', R2, R3 and R4 independently are hydrogen, halogen,-CN,-CF3,-N02,-OR5, lower alkyl, -SR5, -S(O)2NR5R6, -S(O)NR5R6, -S(O)2R5, -S(O)R5, -C(O)NR5R6, -CH2OR5, -CH2NR5R6, - NR5R6,-C (O) R5 or-C (O) OR, wherein R5 and R6 independently are hydrogen, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, heteroaryl, cycloalkyl-lower alkyl, cycloalkyl-lower alkenyl, cycloalkyl-lower alkynyl, cycloalkenyl-lower alkyl, cycloalkenyl-lower alkenyl, cycloal- kenyl-lower alkynyl, aryl-lower alkyl, aryl-lower alkenyl, aryl-lower alkynyl, heterocyclyl-lower alkyl, heterocyclyl-lower alkenyl, heterocyclyl-lower alkynyl, heteroaryl-lower alkyl, heteroaryl- lower alkenyl or heteroaryl-lower alkynyl, or R5 and R6 together with the nitrogen atom to which they are bound form a 3 to 8 membered heterocyclic ring optionally containing one or more further heteroatoms selected from nitrogen, oxygen and sulfur and optionally containing one or more double bonds, in which the cycloalkyl, cycloalkenyl, heterocyclyl, aryl and heteroaryl rings may option- ally be substituted with one or more substituents independently selected from halogen, lower alkyl, lower alkanoyl, -OH, -CH2OH, -NO2, -CN, -C (O) OH,-O-lower alkyl,

-C (O) OCH3, -C (O) NH2,-OCH2C (O) NH2,-NH2,-N (CH3) 2,-CH2N (CH3) 2,-S02NH2,-OCHF2, -CF3 and -COF3, one of X and V is =N-, and the other is =CD-or =N-, wherein D is hydrogen, halogen,-CN,-CF3,-NO2,-OR',-NR7R8, lower alkyl, aryl, -C(O)NR7R8, -CH2OR7, -CH2NR7R8 or -C(O)OR7, wherein R7 and R8 independently are hydrogen, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, heteroaryl, cycloalkyl-lower alkyl, cycloalkyl-lower alkenyl, cycloalkyl-lower alkynyl, cycloalkenyl-lower alkyl, cycloalkenyl-lower alkenyl, cycloal- kenyl-lower alkynyl, aryl-lower alkyl, aryl-lower alkenyl, aryl-lower alkynyl, heterocyclyl-lower alkyl, heterocyclyl-lower alkenyl, heterocyclyl-lower alkynyl, heteroaryl-lower alkyl, heteroaryl- lower alkenyl or heteroaryl-lower alkynyl, or R7and R8 together with the nitrogen atom to which they are bound form a 3 to 8 membered heterocyclic ring optionally containing one or more further heteroatoms selected from nitrogen, oxygen and sulfur and optionally containing one or more double bonds, in which the cycloalkyl, cycloalkenyl, heterocyclyl, aryl and heteroaryl rings may option- ally be substituted with one or more substituents independently selected from halogen, lower alkyl, lower alkanoyl,-OH,-CH20H,-NO2,-CN,-C (O) OH,-O-lower alkyl, -C(O) OCH3, -C (O) NH2, -OCH2C (O) NH2, -NH2,-N (CH3) 2, -CH2N (CH3) 2,-S02NH2,-OCHF2, -CF3 and -OCF3, L and M independently are a valence bond,- (CH2) mS (CH2) n-,-(CH2) mO (CH2) n-, -(CH2)mS(O)CH2)n-, -(CH2)mS(O)2(CH2)n-, -(CH2)mCH=CH(CH2)n-, -(CH2)mC#C(CH2)n-, - (CH2) mCHR9 (CH2) n-,- (CH2) mNR9 (CH2) n-,- (CH2) mC (O) NR9 (CH2) n-, -(CH2)mC(O)O(CH2)n-, -S(CH2)mC(O)O (CH2) n-, -S(O) 2 (CH2) C (O) O (CH2) n,-S (O) 2 (CH2) mC (O) (CH2) zu -S (0) 2N R9 (CH2) mC (O) O (CH2) n-,-S (CH2) mC (O) NR9(CH2)n-, (CH2)mOC(O) (CH2) n-, - (CH2)mC(O)(CH2)n-, -(CH2)mC(NOR9) (CH2) n-,- (CH2) mNR9S (0) 2 (CH2) n-.

-(CH2)mS(O)2NR9(CH2)n-, -(CH2)mCHOR9 (CH2) n-,- (CH2)mP(O)(OR9)O(CH2)n-, -S(O) 2 (CH2) mCONR9 (CH2) n-,-S (0) 2 (CH2) mOC (O) NR9 (CH2) nC (O) O (CH2) r,-NR90 (CH2) n-, - NR9NR9aC (O) NR9b (CH2) n-,-NR9 (CH2) mNR9aC (O) (CH2) n- or-NR9 (CR9Rsd) n-, wherein R9, R9a and R9b independently are hydrogen, lower alkyl, lower alkenyl, lower al- kynyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, heteroaryl, cycloalkyl-lower alkyl, cycloalkyl-

lower alkenyl, cycloalkyl-lower alkynyl, cycloalkenyl-lower alkyl, cycloalkenyl-lower alkenyl, cycloalkenyl-lower alkynyl, aryl-lower alkyl, aryl-lower alkenyl, aryl-lower alkynyl, heterocy- clyl-lower alkyl, heterocyclyl-lower alkenyl, heterocyclyl-lower alkynyl, heteroaryl-lower alkyl, heteroaryl-lower alkenyl or heteroaryl-lower alkynyl, in which the cycloalkyl, cycloalkenyl, heterocyclyl, aryl and heteroaryl rings may option- ally be substituted with one or more substituents independently selected from halogen, lower alkyl, lower alkanoyl,-OH,-CH2OH,-N02,-CN,-C (O) OH,-O-lower alkyl, -C (O) OCH3, -C (O) NH2, -OCH2C (O) NH2,-NH2,-N (CH3) 2,-CH2N (CH3) 2, -S02NH2,-OCHF2, -CF3 and -OCF3, R9Cand R9d independently are hydrogen or lower alkyl, m, n and r independently are 0,1, 2,3 or 4, A and B independently are hydrogen, halogen,-CF3,-CF2CF3,-CN,-N02, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, hydroxy, in which the cycloalkyl ring may optionally be substituted with one or more substituents independently selected from halogen, lower alkyl, lower alkanoyl,-OH,-CH20H,-N02, -CN, -C(O)OH, -O-lower alkyl, -C(O) OCH3, -C (O) NH2, -OCH2C (O) NH2, -NH2, -N (CH3) 2, - CH2N (CH3) 2, -SO2NH2, -OCHF2, -CF3 and -OCF3, or A and B independently are

wherein <BR> <BR> <BR> <BR> <BR> <BR> pis1, 2or3,<BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> X'is-N= or-CR'4=, Y'is-N= or-CR <BR> <BR> <BR> <BR> <BR> <BR> Z'is-N= or-CR'6=,<BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> V'is-N=or-CR<BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> W'is-N= or-CR'8=, G is -CR18aR18b-, -N+O--, -NR19-, -O- or -S-, K is -CR18cR18d-, -N20, -O- or -S-, R10, R11, R12, R13, R14, R15, R16, R17, R18, R18a, R18b, R18c and R18d INDEPENDENTLY ARE hydro- gen, halogen, -CN, -CF3, -OCF3, -OCH2CF3, -OCF2CHF2, -NO2, -OR21, -NR21R22, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, heteroaryl, cycloalkyl- lower alkyl, cycloalkyl-lower alkenyl, cycloalkyl-lower alkynyl, cycloalkenyl-lower alkyl, cycloalkenyl-lower alkenyl, cycloalkenyl-lower alkynyl, aryl-lower alkyl, aryl-lower alkenyl, aryl-lower alkynyl, heterocyclyl-lower alkyl, heterocyclyl-lower alkenyl, heterocyclyl-lower al- kynyl, heteroaryl-lower alkyl, heteroaryl-lower alkenyl or heteroaryl-lower alkynyl,-SCF3, -SR21, -CHF2, -OCHF2, -OS(O)2CF3, -OS(O)2R21, -NR21S(O)2R22, -S(O)2NR21R22, -S(O)NR21R22, -S(O)2R21, -S(O)R21, -CH2C(O)NR21R22, -OCH2C(O)NR21R22, -CH2OR21, -CH2NR21R22, -OC(O)R21, -S(O)2NR21(CH2)sC(O)OR22, -C(O)NR21(CH)sC(O)OR22 or -C (O) NR2'R22 where R12 and R'3 furthermore independently may represent oxo, or two of the groups R'° to R'3d when defined in the same ring together may form a bridge-O (CH2) qO- or -CH2O(CH2)qO-, in which the cycloalkyl, cycloalkenyl, heterocyclyl, aryl and heteroaryl rings may option- ally be substituted with one or more substituents independently selected from halogen, lower alkyl, lower alkanoyl,-OH,-CH2OH,-NO2,-CN,-C (O) OH,-O-lower alkyl,

-C (O) OCH3,-C (O) NH2, -OCH2C (O) NH2,-NH2,-N (CH3) 2,-CH2N (CH3) 2,-SO2NH2,-OCHF2, - CF3 and-OCF3, wherein R2'and R22 independently are hydrogen, lower alkyl, lower alkenyl, lower alkynyl, <BR> <BR> <BR> cycloalkyl, cycloalkenyl, aryl, heterocyclyl, heteroaryl, cycloalkyl-lower alkyl, cycloalkyl-lower alkenyl, cycloalkyl-lower alkynyl, cycloalkenyl-lower alkyl, cycloalkenyl-lower alkenyl, cycloal- <BR> <BR> <BR> kenyl-lower alkynyl, aryl-lower alkyl, aryl-lower alkenyl, aryl-lower alkynyl, heterocyclyl-lower<BR> <BR> <BR> <BR> <BR> alkyl, heterocyclyl-lower alkenyl, heterocyclyl-lower alkynyl, heteroaryl-lower alkyl, heteroaryl- lower alkenyl or heteroaryl-lower alkynyl, or R2'and R22 together with the nitrogen atom to which they are bound form a 3 to 8 membered heterocyclic ring optionally containing one or more further heteroatoms selected from nitrogen, oxygen and sulfur and optionally containing one or more double bonds, in which the cycloalkyl, cycloalkenyl, heterocyclyl, aryl and heteroaryl rings may option- ally be substituted with one or more substituents independently selected from halogen, lower alkyl, lower alkanoyl,-OH,-CH20H,-N02,-CN,-C (O) OH,-O-lower alkyl, -C (O) OCH3, -C (O) NH2,-OCH2C (O) NH2,-NH2,-N (CH3) 2,-CH2N (CH3) 2,-SO2NH2,-OCHF2, - CF3 and-OCF3, R'9 and R independently are hydrogen,-OR23,-NR23R24, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, heteroaryl, cycloalkyl-lower alkyl, cycloal- kyl-lower alkenyl, cycloalkyl-lower alkynyl, cycloalkenyl-lower alkyl, cycloalkenyl-lower al- kenyl, cycloalkenyl-lower alkynyl, aryl-lower alkyl, aryl-lower alkenyl, aryl-lower alkynyl, het- <BR> <BR> <BR> erocyclyl-lower alkyl, heterocyclyl-lower alkenyl, heterocyclyl-lower alkynyl, heteroaryl-lower alkyl, heteroaryl-lower alkenyl or heteroaryl-lower alkynyl,-C (O) NR23R24 or-C (O) OR in which the cycloalkyl, cycloalkenyl, heterocyclyl, aryl and heteroaryl rings may option- ally be substituted with one or more substituents independently selected from halogen, lower alkyl, lower alkanoyl,-OH,-CH20H,-N02,-CN,-C (O) OH,-O-lower alkyl, -C (O) OCH3, -C (O) NH2,-OCH2C (O) NH2,-NH2,-N (CH3) 2,-CH2N (CH3) 2,-SO2NH2,-OCHF2, -CF3 and -OCF3, wherein R23 and R24 independently are hydrogen, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, heteroaryl, cycloalkyl-lower alkyl, cycloalkyl-lower alkenyl, cycloalkyl-lower alkynyl, cycloalkenyl-lower alkyl, cycloalkenyl-lower alkenyl, cycloal- kenyl-lower alkynyl, aryl-lower alkyl, aryl-lower alkenyl, aryl-lower alkynyl, heterocyclyl-lower alkyl, heterocyclyl-lower alkenyl, heterocyclyl-lower alkynyl, heteroaryl-lower alkyl, heteroaryl-

lower alkenyl or heteroaryl-lower alkynyl, or R23 and R24 together with the nitrogen atom to which they are bound form a 3 to 8 membered heterocyclic ring optionally containing one or more further heteroatoms selected from nitrogen, oxygen and sulfur and optionally containing one or more double bonds, in which the cycloalkyl, cycloalkenyl, heterocyclyl, aryl and heteroaryl rings may option- ally be substituted with one or more substituents independently selected from halogen, lower alkyl, lower alkanoyl,-OH,-CH2OH,-N02,-CN,-C (O) OH,-O-lower alkyl, -C (O) OCH3, -C (O) NH2,-OCH2C (O) NH2,-NH2,-N (CH3) 2,-CH2N (CH3) 2,-S02NH2,-OCHF2, -CF3 and-OCF3, q is 1,2 or 3, sis0, 1, 2or3, or A and B may be connected and together form a C23-alkylene radical, with the provisos that when L represents a group wherein n or r is 0, A is not halogen,-CN or-N02, and when M represents a group wherein n or r is 0, B is not halogen,-CN or-N02, as well as any optical or geometric isomer or tautomeric form thereof including mixtures of these.

(S)-3- {4- [1- (4-Cyclohex-1-enylphenyl)-3- (3, 5-dichlorophenyl) ureidomethyl] benzoylamino}-2- hydroxypropionic acid or (R)-3- {4- [1- (4-Cyclohex-1-enylphenyl)-3- (3, 5-dichlorophenyl) ureidomethyl] benzoylamino}-2- hydroxypropionic acid In an embodiment the invention provides glucagon antagonists represented by the general formula (I) :

wherein R'is chloro, fluoro, nitro or cyano; K is-C (O)-(CH2)d-, -CH2-CH2-O- or -CHR2-; wherein d is 0 or 1 ; R2 is hydrogen or C1-6-alkyl ; D is wherein Q is -O- or -S-; Y is-CH= or-N= ;

R3, R4, R5, R5 and R7 independently are hydrogen, C1-6-alkyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, halogen, carboxamido, hydroxymethyl, phenyl, dimethylamino, C,. 6-alkoxy or nitro ; as well as any optical or geometric isomer or tautomeric form thereof including mixtures of these.

In an embodiment, the invention provides a glucagon antagonist of the general formula (I) : wherein R2 is hydrogen or C, e-alkyl, B is R38 is hydrogen, -S (=O) 2-C1-6-alkyl or-C (=O)-C1-6-alkyl, A is a valence bond, -(CR3R4)-, or -(CR3R4)(CR5R6)-, R', R3, R4, R5 and R6 independently are hydrogen or C1-6-alkyl,

Z is arylene or a divalent radical derived from a 5 or 6 membered heteroaromatic ring con- taining 1 or 2 heteroatoms selected from nitrogen, oxygen and sulfur, which may optionally be substituted with one or two groups R'and R8 selected from halogen, -CN, -CF3, -OCF3, -NO2, -OR9, -NR9R10 and C1-6-alkyl, wherein R9 and R'° independently are hydrogen or C1-6-alkyl, X is wherein r is 0 or 1, q and s independently are 0,1, 2 or 3, R", R12, R'3 and R'4 independently are hydrogen or C1-6-alkyl, D is

wherein R'5, R'6, R'7 and R18 independently are hydrogen, halogen,-CN,-CH2CN,-CHF2,-CF3,-OCF3,-OCHF2,-OCH2CF3,-OCF2CHF 2, -S(O)2CF3, -SCF3, -NO2, -OR21, -NR21R22, -SR21, -NR21S(O)2R22, -S(O)2NR21R22, <BR> <BR> <BR> ) NR R,-S (O) R,-S (O) 2R21,-C (O) NR21 R22-OC (O) NR2'R22 NR21 C (O) R22<BR> <BR> <BR> <BR> <BR> -CH2C (O) NR2'R22,-OCH2C (O) NR2'R22,-CH2OR2',-CH2NR2'R22,-OC (O) R2',-C (O) R2'or<BR> <BR> <BR> <BR> <BR> -C (O) OR C1-6-alkyl, C2-6-alkenyl or C2-6-alkynyl, which may optionally be substituted with one or more substituents selected from halogen, -CN, -CF3, -OCF3, -NO2, -OR21, -NR21R22 and C1-6-alkyl, C3-8-cycloalkyl, C4-8-cycloalkenyl, heterocyclyl, C3-8-cycloalkyl-C1-6-alkyl, C3-8-cyclo- alkyl-C1-6-alkoxy, C3-8-cycloalkoxy, C3-8-cycloalkyl-C1-6-alkylthio, C3-8-cycloalkylthio,

C3-8-cycloalkyl-C2-6-alkenyl, C3-8-cycloalkyl-C2-6-alkynyl, C4-8-cycloalkenyl-C1-6-alkyl, C4-8-cyclo- alkenyl-C2-6-alkenyl, C4-8-cycloalkenyl-C2-6-alkynyl, heterocyclyl-C1-6-alkyl, heterocyclyl- C2-6-alkenyl, heterocyclyl-C2-6-alkynyl, aryl, aryloxy, aryloxycarbonyl, aroyl, aryl-C1-6-alkoxy, aryl-C1-6-alkyl, aryl-C2-6-alkenyl, aryl-C2-6-alkynyl, heteroaryl, heteroaryl-C1-6-alkyl, heteroaryl- C24-alkenyl or heteroaryl-C2-6-alkynyl, of which the cyclic moieties optionally may be substituted with one or more substituents se- lected from halogen,-CN,-CF3,-OCF3,-N02,-OR2',-NR2'R22 and C1-6-alkyl, wherein R21 and R22 independently are hydrogen, C1-6-alkyl or aryl, or R2'and R22 when attached to the same nitrogen atom together with the said nitrogen atom may form a 3 to 8 membered heterocyclic ring optionally containing one or two further het- eroatoms selected from nitrogen, oxygen and sulfur, and optionally containing one or two double bonds, or two of the groups R'5 to R'8 when placed in adjacent positions together may form a bridge - (CR23 O-(CR25R26)c-O-, wherein a is 0,1 or 2, c is 1 or 2, R23, R24, R25 and R26 independently are hydrogen, C1-6-alkyl or fluorine, R'9 and R20 independently are hydrogen, C1-6-alkyl, C3-8-cycloalkyl or C3$-cyclo- alkyl-C1-6-alkyl, E is

wherein R27 and R28 independently are hydrogen, halogen, -CN, -CF3, -OCF3, -OR32, -NR32R33, C1-6-alkyl, C3-8-cycloalkyl, C4-8cyclo- alkenyl or aryl, wherein the aryl group optionally may be substituted with one or more substituents selected from halogen,-CN,-CF3,-OCF3,-N02,-OR32,-NR32R33 and C, 4-alkyl, wherein R32 and R33 independently are hydrogen or C, 4-alkyl, or R32 and R33 when attached to the same nitrogen atom together with the said nitrogen atom may form a 3 to 8 membered heterocyclic ring optionally containing one or two further het- eroatoms selected from nitrogen, oxygen and sulfur, and optionally containing one or two double bonds, R29, R30 and R3'independently are hydrogen, halogen,-CHF2,-CF3,-OCF3,-OCHF2,-OCH2CF3,-OCF2CHF2,-SCF3,-OR , -NR34R35, -SR34, -S(O)R34, -S(O)2R34, -C(O)NR34R35, -OC(O)NR34R35, -NR34C(O)R35, -OCH2C(O)NR34R35, -C(O)R34 or -C(O)OR34,

C, e-alkyl, C2$-alkenyl or C26-alkynyl, which may optionally be substituted with one or more substituents selected from halogen, -CN, -CF3, -OCF3, -NO2, -OR34, -NR34R35 and C1-6-alkyl, C3-8-cycloalkyl, C4-8cycloalkenyl, heterocyclyl, C3-8-cycloalkyl-C1-6-alkyl, C3-8-cyclo- alkyl-C2-6-alkenyl, Cm-cycloalkyl-C2-6-alkynyl, C"-cycloalkenyl-Cl-6-alkyl, C"-cycloalkenyl- C2-6-alkenyl, C4-8-cycloalkenyl-C2-6-alkynyl, heterocyclyl-C1-6-alkyl, heterocyclyl-C2-6-alkenyl, heterocyclyl-C2-6-alkynyl, aryl, aryloxy,a royl, aryl-C1-6-alkoxy, aryl-C1-6-alkyl, aryl-C2-6-alkenyl, aryl-C2-6-alkynyl, heteroaryl, heteroaryl-C1-6-alkyl, heteroaryl-C2-6-alkenyl or heteroaryl-C24- alkynyl, of which the cyclic moieties optionally may be substituted with one or more substituents se- lected from halogen, -CN, -CF3, -OCF3, -NO2, -OR34, -NR34R35 and C1-6-alkyl, wherein R34 and R35 independently are hydrogen, C, 6-alkyl or aryl, or R34 and R35 when attached to the same nitrogen atom together with the said nitrogen atom may form a 3 to 8 membered heterocyclic ring optionally containing one or two further het- eroatoms selected from nitrogen, oxygen and sulfur, and optionally containing one or two double bonds, or two of the groups R29, R30 and R3'when attached to the same ring carbon atom or differ- ent ring carbon atoms together may form a radical -O-(CH2)t-CR36R37-(CH2)l-O-, -(CH2)t-CR36R37-(CH2)l- or -S-(CH2)t-CR36R37-(CH2)l-S-, wherein t and I independently are 0,1, 2, 3, 4 or 5, R36 and R37 independently are hydrogen or C1-6-alkyl, as well as any optical or geometric isomer or tautomeric form thereof including mixtures of these In an embodiment the invention provides glucagon antagonist of formula (I) :

wherein A is mis0or1, n is 0, 1, 2 or 3, with the proviso that m and n must not be 0 at the same time, R4 is hydrogen, fluoro or- (CH2) p-OR5, p is 0 or 1, R5 is hydrogen, C1-6-alkyl, C1-6-alkanoyl, aryl or aryl-C1-6-alkyl, R'and R2 independently are hydrogen, halogen, trifluoromethyl, trifluoromethoxy, cyano, trifluoromethylthio, nitro, C1-6-alkyl, C1-6-alkoxy, hydroxy, C1-6-alkylthio, C1-6-alkylsulfonyl, trifluoromethylsulfonyl or-NR6R7, Re and R7 independently are hydrogen or C1-6-alkyl, B is

R8, R9, R'3 and R'4 independently are hydrogen, halogen, trifluoromethyl, C1-6-alkyl or C1-6-alkoxy, R'° is hydrogen, halogen, trifluoromethyl, trifluoromethoxy, cyano, trifluoromethylthio, nitro, C1-6-alkyl, methylthio or C3-8-cyclcoalkyl, R"and R12 independently are hydrogen or C1-6-alkyl, q is 0,1, 2 or 3; R3 is hydrogen or C1-8-alkyl, X is =N-CN, =N-CH2R, =CH-N02or =CHR R'5 is hydrogen, cyano or trifluoromethyl, #C1-6-alkyl, which may optionally be substituted with fluoro, trifluoromethyl, trifluoromethoxy, cyano, trifluoromethylthio, C1-6-alkoxy, hy- droxy, C1-8-alkylthio, C1-6-alkylsulfonyl, trifluoromethylsulfonyl or -NR16R17, R15 and R17 independenly are hydrogen or C1-6-alkyl,

* aryl or heteroaryl, which may optionally be substituted with halogen, trifluoromethyl, trifluoromethoxy, cyano, trifluoromethylthio, nitro, C1-6-alkyl, C1-6-alkoxy, hydroxy, C1-6-alkylthio, C1-6-alkylsulfonyl, trifluoromethylsulfonyl or -NR'BR'g, R'8 and R'9 independenly are hydrogen or C, 4-alkyl, D is

R20 and R21 independently are hydrogen, halogen, trifluoromethyl, trifluoromethoxy, cyano, trifluoromethylthio, nitro, C1-6-alkyl, aryl, methylthio, methylsulfonyl, trifluoromethylsulfonyl, -NR23R24, C3 8-cycloalkyl or-S (0) 2-N (C1-6-alkyl)(aryl), R23 and R24 independently are hydrogen or C1-6-alkyl, R22 is hydrogen, C1-6-alkyl, C3-8-cycloalkyl or C3-8-cycloalkyl-C1-6-alkyl, as well as any diastereomer or enantiomer or tautomeric form thereof including mixtures of these In an embodiment the invention provides a compound, wherein A is

In an embodiment the invention provides a compound, wherein A is

In an embodiment the invention provides a compound, wherein R'and R2 are both hydrogen.

In an embodiment the invention provides a compound, wherein B is

wherein R8, R9, R"and R12 are as defined above.

In an embodiment the invention provides a compound, wherein R8 and R9 are both hydrogen.

In an embodiment the invention provides a compound, wherein B is

wherein R'° is as defined in above.

In an embodiment the invention provides a compound, wherein X is =N-CN, =CH-N02, =N- CH2-CF3 or =N-CH2-CN.

In an embodiment the invention provides a compound, wherein R3 is hydrogen.

In an embodiment the invention provides a compound, wherein D is wherein R20, R2'and R22 are as defined above.

In an embodiment the invention provides a compound, wherein R20 and R2'independently are hydrogen, halogen, trifluoromethyl or trifluoromethoxy, and R22 is C, 4-alkyl.

In an embodiment the invention provides solvates of compounds as described above.

In an embodiment the invention provides 3- {4- [1- (4-Cyclohex-1-enylphenyl)-3- (3, 5- dichlorophenyl) ureidomethyl] benzoylamino} propionic acid in a solvate form.

In an embodiment the invention provides 3- {4- [1- (4-Cyclohex-1-enylphenyl)-3- (3, 5- dichlorophenyl) ureidomethyl] benzoylamino}-2R-hydroxypropionic acid in a solvate form.

In an embodiment the invention provides 3- {4- [1- (4-Cyclohex-1-enylphenyl)-3- (3, 5- dichlorophenyl) ureidomethyl] benzoylamino}-2R-hydroxypropionic acid as a solvate with one of the following solvents ethanol, 2-propanol, 2-methyl-l-propanol, n-butanol, 2-butanol, 3- methyl-1-butanol, diethyl ether, tert-butyl-methylether, tetrahydrofuran, anisol, acetone, 2- butanon, methylacetate, ethylacetate, n-propylacetate and toluene.

In an embodiment the invention provides N-[4-({4-(1-cyclohexen-1-yl)[(3,5-dichloroanilino)- carbonyl] anilino} methyl) benzoyl]-ß-alanine as a solvate with acetone, butanol, ethanol or propanol.

In an embodiment the invention provides 3- {4- [1- (4-Cyclohex-1-enylphenyl)-3- (3, 5- dichlorophenyl) ureidomethyl] benzoylamino}-2R-hydroxypropionic acid as a solvate with 2- butanol, 3-methyl-1-butanol and 2-methyl-1-propanol.

In an embodiment the invention provides a process for the preparation a solvate of 3- {4- [1- (4-Cyclohex-1-enylphenyl)-3- (3, 5-dichlorophenyl) ureidomethyl] benzoylamino}-2R- hydroxypropionic acid comprising the steps of: a) dissolving the parent compound as a free acid, an ester derivative or as a solvate of the parent compound, in same solvent as the solvate to be obtained or a different solvent or in a mixture of solvents b) optionally heating the mixture c) cooling the solution

d) isolating the precipitate e) optionally drying the obtained solvate.

In an embodiment the invention provides the process of claim 4 wherein the temperature in the optional step b) is below 150 °C, optionally below 85°C.

In an embodiment the invention provides a pharmaceutical composition comprising, as an active ingredient a compound according to the invention as a solvate or as a salt as describedn above together with pharmaceutically acceptable carriers and/or diluents In an embodiment the invention provides a pharmaceutical composition according to the above in a unit dosage form comprising from about 0.05 to about 1000 mg, preferably from about 0.1 to about 500 mg compound as described above.

In an embodiment the invention provides a pharmaceutical composition useful in the treatment and/or prevention of conditions mediated by glucagon receptors, the composition comprising a compound as a salt or as a solvate according to the above together with a pharmaceutically acceptable carrier or diluent.

A method for the treatment and/or prevention of conditions mediated by glucagon receptors which method comprises administering to a subject in need thereof an an effective amount of a compounds according to the above as a solvate or as a salt.

A method for the treatment and/or prevention of diabetes and/or obesity which method comprises administering to a subject in need thereof an effective amount of a compound according to the above.

The invention provides the use of a compound according to the above as a salt or as a solvate for the preparation of a medicament useful in the treatment and/or prevention of conditions mediated by glucagon receptors.

The invention provides the use of a compound according to the above for the preparation of a medicament useful in the treatment and/or prevention of diabetes and/or obesity.

Examples : PXRD (Powder X-ray Diffraction)

The PXRD measurements were conducted on a Bruker D8 Advance powder diffractometer equipped with a multilayer mirror which selects the CuKa radiation ( ; = 1.5418 A). The sam- ple is mounted on a flat plate in reflection geometry in the center of a goniometer with a di- ameter of 435 mm. The diffracted beam from the sample is recorded stepwise with a scintilla- tion detector. All samples were ground in an agate mortar before measurement.

Scan range in 28 : 2°-30° Step size: 0. 03° Time per step: 10 sec Thermal Analysis Differential Scanning Analysis (DSC) was conducted on a MDSC 2920, TA Instruments.

Samples (approximately 3-6 mg) were heated in pinhole crimped aluminium pans from 25°C to 280°C at a rate of 10°C/min. The DSC measuring chamber was continuously purged with dry nitrogen during the runs and the instrument was routinely calibrated with indium and tin.

Thermo gravimetric Analysis (TGA) experiments were conducted on a TA Hi Res Thermo gravimetric Analyser, Model 2959. Samples (approximately 6-12 mg) were heated in an open platinum pan from 25°C to 250°C at a rate of 10°C/min. The TGA measuring chamber was continuously purged with dry nitrogen during the runs and the instrument was routinely calibrated with indium and aluminium.

Example 1: [3- 4- (1- (4-Cyclohex-1-enylphenyl)-3- (3, 5-dichlorophenyl) ureidomethyl]- benzoylamino}-2R-hydroxypropionic acid : N, M-dibenzylethylenediamine (1 : 0. 5)] 17.8g (0.03 mol) 3- {4- [l- (4-Cyclohex-l-enylphenyl)-3- (3, 5-dichlorophenyl) ureidomethyl]- benzoylamino}-2R-hydroxypropionic acid, 1, was dissolved in 350 mi ethyl acetate and 88 ml tetrahydrofurane under a nitrogen atmosphere. The solution was heated to 60°C. 3.68g

(0,015 mol) N, N'-dibenzyl-ethylenediamine was dissolved in 43 ml ethyl acetate, and added drop-wise to the hot solution over 20 minutes. When mixture became opaque, it was heated to 70°C and stirred at that temperature for 30 minutes. Then the mixture slowly cooled to room temperature, and the salt precipitated. The hemibenzathine salt was recovered and identified, after drying to constant weight.

Example 2 : [3- (4- [l- (4-Cyclohex-l-enylphenyl)-3- (3, 5-dichlorophenyl) ureidomethyl]- benzoylamino}-2R-hydroxypropionic acid : tert-butyl amine (1: 1) ]

1.3. 4 (0.582 g) was dissolved in acetone (8 ml) and tert-butylamine (105nul, 1.0 mmol in ace- tone) was added. More acetone was added (7 ml), and the solution was left to precipitate at room temperature. The suspension was cooled to 8°C over 2h, and the tert-butylamine salt <BR> <BR> of 3- {4- [1- (4-Cyclohex-1-enylphenyl)-3- (3, 5-dichlorophenyl) ureidomethyl] benzoylamino}-2R- hydroxypropionic acid was isolated. 0.51g was isolated after drying in vacuo.

Example 3: [3- (4- [1- (4-Cyclohex-1-enylphenyl)-3- (3, 5-dichlorophenyl) ureidomethyl]- benzoylamino}-2R-hydroxypropionic acid: L-arginine (1: 1) ]

1 (29.15 mg, 0.050 mmole) was dissolved in methanol (1.0 mL) by heating. 520 RL (0.052 mmole) of a 0.100 M solution of L-arginine in MilliQ water was added. A fine, white precipi- tate was observed. The solution was stored at 4°C for 2 days, after which an apparently crys- talline precipitate had formed. The mother liquor was filtered off and the precipitate was dried in a desiccator overnight. The precipitate had then become glass-like. This precipitate was analysed.

Example 4 : (2R)-N-[4-({4-cyclohexyl[ (3, 5-dichloroanilino)carbonyl]anilino}methyl)- benzoyl]-2-hydroxy-a-alanine : N, M-dibenzylethylenediamine (1: 0.5)]

(2.4 g) was dissolved in isopropyl acetate (37 ml) and N,N'-dibenzyl-ethylenediamine (1. 6 g, 6.5 mmol) in THF (18 ml) was added at elevated temperature. The solution was left to pre- cipitate at room temperature. The suspension was cooled to 5°C, and the hemibenzathine salt of (2R)-N- [4- ( {4-cyclohexyl [ (3, 5-dichloroanilino) carbonyl] anilino) methyl) benzoyl]-2- hydroxy-ß-alanine was isolated. 5.5 g was isolated after drying in vacuo.

Example 5 : (2R)-N-[4-({[1,1'-biphenyl]-4-yl[ (3, 5-dichloroanilino)- carbonyl] amino} methyl) benzoyl]-2-hydroxy-ß-alanine : N, M-dibenzylethylenediamine (1: 0.5)] (2R)-N- [4- ( { [1, 1'-biphenyl]-4-yl [ (3, 5-dichloroanilino) carbonyl] amino} methyl) benzoyl]-2- hydroxy-ß-alanine (5.5 g) was dissolved in ethyl acetate (100 ml) and THF (28 ml) N, N'- dibenzyl-ethylenediamine (1.1 g, 4.7 mmol) in ethyl acetate (22 ml) was added at elevated temperature. The solvent was removed under reduced pressure. To the material hot methyl tert butyl ether was added, and the hemibenzathine salt of (2R)-N-[4-({[1,1'-biphenyl]-4- yl [(3, 5-dichloroanilino) carbonyl] amino} methyl) benzoyl]-2-hydroxy-ß-alanine precipitated. 5.7 g was isolated after drying in vacuo.

Example 6: 3- {4- [1- (4-Cyclohex-1-enylphenyl)-3- (3, 5-dichlorophenyl) ureidomethyl]- benzoylamino} propionic acid: tert-butylamine : 582 mg 3- {4- [1- (4-Cyclohex-1-enylphenyl)-3- (3, 5-dichlorophenyl) ureidomethyl]- benzoylamino} propionic acid was dissolved in 20-25 ml acetone. 0.105 ml tert-butylamine (1 eq. ) was added slowly, and the reaction mixture was stirred at ambient temperature for 4 days. The suspension (Approx. 10-15 ml) was cooled 8°C over 2 hours and filtered. The crystals were washed with cold acetone and dried under vacuum. Yield : 78% Example 7: 3- 4- [1- (4-Cyclohex-1-enylphenyl)-3- (3, 5-dichlorophenyl) ureidomethyl]- benzoylamino} propionic acid: L-arginine: 566 mg. 3- {4- [1- (4-Cyclohex-1-enylphenyl)-3- (3, 5-dichlorophenyl) ureidomethyl]- benzoylamino} propionic acid was dissolved in 15 ml 1-propanol at reflux. 174 Mg. L-arginine was dissolved in 1 ml H20 by heating. The solution of L-arginine was slowly added to the so- lution of 3- {4- [1- (4-Cyclohex-1-enylphenyl)-3- (3, 5-dichlorophenyl) ureidomethyl]- benzoylamino} propionic acid. Seeding crystals were added until crystallization was observed (At ca. 60°C), and the reaction mixture was cooled to ambient temperature over 11/2 hour.

The crystals were isolated by filtration, washed with 1-propanol and dried under vacuum.

Yield : 73%.

Example 8 : N3- (4-{[[4-(3,4-Dichlorophenyl)thiazol-2-yl]-(5, 6,7, 8-tetrahydronaphthalen-2- yl) amino] methyl} benzoylamino) propionic acid : tert-butylamine (erbumine) (1: 1) 35.0 mg of 3-(4-{[[4-(3,4-Dichlorophenyl)thiazol-2-yl]-(5, 6,7, 8-tetrahydronaphthalen-2- yl) amino] methyl} benzoylamino) propionic acid was dissolved in 2 mL ethylacetate with light heating. When dissolved, 620 µL of 0.097 M tert-butylamine in ethylacetate was added in three portions. The solution was allowed stan- ding at room temperature a few days, during which an oily precipitate formed. This precipita- te was dissolved in 1 mL THF (tetrahydrofurane) and again allowed standing at room tempe- rature. After some days a crystalline precipitate formed.

Example 9: 3- {ll4-(4-Chlorophenyl) thiazol-2-yll-(4- trifluoromethylphenyl) amino] methyl} benzoylamino) propionic acid: L-lysine (1: 1) 33.7 mg of 3- (4- { ( [4- (4-Chlorophenyl) thiazol-2-yl]- (4-trifluoromethylphenyl) amino] methyl}- benzoylamino) propionic acid was dissolved in 1 mL of THF while shaking. 600 µL of 0.051 M

L-lysine in H20 was added in three portions. The solution was allowed standing at room tem- perature a few days during which the solvent evaporated and an oily precipitate formed. This was dissolved in 1 mL of absolute ethanol, and after some days a white precipitate in the so- lution was formed. This slurry was dried on the sample holder and analysed.

Example 10: 3- (4-{[[4-(4-Chlorophenyl)thiazol-2-yl]-(4-trifluoromethylphen yl) amino] - methyl} benzoylamino) propionic acid: L-histidine (1: 1) 33.7 mg of 3-(4-{[[4-(4-Chlorophenyl)thiazol-2-yl]-(4-trifluoromethylph enyl) amino] methyl}- benzoylamino) propionic acid was dissolved in 1 mL of THF while shaking. 600 µL of 0.050 M L-histidine in H20 was added in three portions. The solution was allowed standing at room temperature a few days during which the solvent evaporated and an oily precipitate formed.

This was dissolved in 1 mL of absolute ethanol, and after some days crystalline precipitate was formed on the side of the vial. The precipitate was analysed.

Example 11: 3- {1l4-(4-Chlorophenyl) thiazol-2-yl]-(4-trifluoromethylphenyl)- amino] methyl} benzoylamino) propionic acid: monoethanolamine (olamine) (1: 1) 33.7 mg of 3-(4-{[[4-(4-Chlorophenyl)thiazol-2-yl]-(4-trifluoromethylph enyl) amino] methyl}- benzoylamino) propionic acid was dissolved in 1 mL of ethylacetate while shaking. 575 gL of 0. 104 M monoethanolamine in ethylacetate was added in three portions. The solution was allowed standing at room temperature. After one day a white, gel-like precipitate formed. This was suspended in 300 ; j. L of ethylacetate. After some days a white precipitate was formed.

The precipitate was analysed.

Example 12 : 3- {1l4-(4-Chlorophenyl) thiazol-2-yl]-(4 trifluoromethylphenyl)- amino] methyl} benzoylamino) propionic acid: tert-butylamine (1: 1) 33.6 mg of 3- (4- { [ (4- (4-Chlorophenyl) thiazol-2-yl]- (4-trifluoromethylphenyl) amino] methyl}- benzoylamino) propionic acid was dissolved in 1 mL of THF while shaking. 300 pL of 0.201 M tert-butylamine in ethanol was added in three portions. The solution was allowed standing at room temperature. After a few days a transparent, oily precipitate formed. This was dissolved in 1 mL of absolute ethanol. After some days a crystalline precipitate was formed. The preci- pitate was analysed.

Example 13: 3- (4- { [ [4- (4-Chlorophenyl) thiazol-2-yl]- (4-trifluoromethylphenyl)- amino] methyl} benzoylamino) propionic acid: ethylenediamine (2: 1)

33.7 mg of 3- (4- { ( [4- (4-Chlorophenyl) thiazol-2-yl]- (4-trifluoromethylphenyl) amino] methyl}- benzoylamino) propionic acid was dissolved in 1 mL of ethylacetate while shaking. 510 IlL of 0.118 M ethylenediamine in ethylacetate was added in three portions, during which a precipi- tate formed. The solution was allowed standing at room temperature. After a few days a white voluminous precipitate formed. This was suspended in 300 iL of ethylacetate. After some days a white, solid precipitate was formed. The precipitate was analysed.

Example 14: 3-(4-{[[4-(4-Chlorophenyl)thiazol-2-yl]-(4-trifluoromethylph enyl)- amino] methyl} benzoylamino) propionic acid, dibenzylethylenediamine (benzathine) (2 : 1) 33.6 mg of 3- (4-f [ [4- (4-Chlorophenyl) thiazol-2-yl]- (4-trifluoromethylphenyl) amino] methyl}- benzoylamino) propionic acid was dissolved in 1 mL of THF while shaking. 290 pL of 0.104 M benzathine in ethanol was added in three portions. The solution was allowed standing at room temperature a few days during which the solvent evaporated and a solid, white precipi- tate formed. This was suspended in 1 mL of absolute ethanol, and after some days crystalli- ne precipitate was formed. The precipitate was analysed.

General procedure for the preparation of solvates of the invention: The parent compound as a free acid, an ester derivative or optionally as a solvate, was dis- solved in a suitable solvent. The solvent may the same solvent as the solvate to be obtained or it may be a different solvent. Optionally the temperature was elevated to dissolve the compound. Also the pH may be adjusted for ensuring the compound was dissolved. After- wards the solvent to form solvates with the compound as above was added in surplus amount and the formed solvate was isolated and dried, optionally in vacuo, at elevated tem- perature.

DSC method The following instrumentation was used: Mettler Toledo DSC module 822 Power Point Labplant RP 60 intra cooler Mettler Tolede DSC software STAR

A linear heating program from 25°C to 300°C with a heating rate of 10°C/min was used.

The DSC experiments were performed in open lid 40 pl aluminum crucibles.

PXRD (Powder X-ray Diffraction) The PXRD measurements were conducted on a Bruker D8 Advance powder diffractometer equipped with a multilayer mirror which selects the CuKa radiation (R = 1.5418 A). The sam- ple is mounted on a flat plate in reflection geometry in the center of a goniometer with a di- ameter of 435 mm. The diffracted beam from the sample is recorded stepwise with a scintilla- tion detector. All samples were ground in an agate mortar before measurement.

Scan range in 26 : 2°-30° Step size: 0. 03° Time per step: 10 sec Examples Example 1 <BR> <BR> <BR> <BR> <BR> [3- {4- [l- (4-Cyclohex-1-enylphenyl)-3- (3, 5-dichlorophenyl) ureidomethyl] benzoylamino)-2R- hydroxypropionic acid: ethyl acetate] To a solution of methyl 3- {4- [1- (4-Cyclohex-1-enylphenyl)-3- (3, 5-dichlorophenyl)- ureidomethyl] benzoylamino}-2R-hydroxypropionate (112 g) dissolved in THF (2800 ml) was added an aqueous solution of lithium hydroxide mono hydrate (10.2 g in 100 ml water). The mixture was stirred for 1 hour at room temperature. Phosphoric acid (3 M) was added to pH 2.4. Ethyl acetate (400 ml) was added to the solution and the two phases were separated.

The organic phase was washed with water (200 ml), and the organic solvent was removed under reduced pressure. The evaporation residue was added ethyl acetate (500 ml) and fur- ther stripping of water conducted by removal of the solvent under reduced pressure. The crude material was dissolved in ethyl acetate (500 ml) and heated to 40 °C for 1 hour. The

solution was cooled to room temperature. After stirring over night a precipitate was formed and the slurry was cooled to 0°C prior to filtration. The filter cake was washed with cooled (2 °C) ethyl acetate (100 ml) and dried in vacuo at 40 °C for 2 hours followed by drying at room temperature in the air. The title compound (92.8 g) was isolated in 91% yield.

Example 2 <BR> <BR> <BR> <BR> <BR> <BR> [3- {4- [1- (4-Cyclohex-1-enylphenyl)-3- (3, 5-dichlorophenyl) ureidomethyl] benzoylamino}-2R- hydroxypropionic acid: 2-butanol]

1 (11.7 g) was dissolved in 2-butanol (75 ml) by heating. The 2-butanol solvate of 3- {4- [1- (4- Cyclohex-1-enylphenyl)-3-(3, 5-dichlorophenyl) ureidomethyl] benzoylamino}-2R- hydroxypropionic acid precipitated by stirring the mixture at room temperature. 7.6 g was iso- lated after drying the material in vacuo at 40 °C.

Example 3 <BR> <BR> <BR> <BR> <BR> <BR> [3- {4- [1- (4-Cyclohex-1-enylphenyl)-3- (3, 5-dichlorophenyl) ureidomethyl] benzoylamino}-2R- hydroxypropionic acid: ethanol] 2 (5.0 g) was dissolved in ethanol (14 ml) by heating. Up on cooling to room temperature the ethanol solvate of 3- {4- [1- (4-Cyclohex-1-enylphenyl)-3- (3, 5- dichlorophenyl) ureidomethyl] benzoylamino}-2R-hydroxypropionic acid precipitated. The sus-

pension was filtered and washed with cold ethanol. After drying over night at room tempera- ture 2.6g (52%) was isolated after drying the material at room temperature over night.

Example 4 <BR> <BR> <BR> [3- {4- [1- (4-Cyclohex-1-enylphenyl)-3- (3, 5-dichlorophenyl) ureidomethyl] benzoylamino}-2R- hydroxypropionic acid: 2-propanol]

2 (5.0 g) was dissolved in 2-propanol (12 ml) by heating. The 2-propanol solvate of 3- {4- [1- (4-Cyclohex-1-enylphenyl)-3- (3, 5-dichlorophenyl) ureidomethyl] benzoylamino}-2R- hydroxypropionic acid precipitated by stirring the mixture at room temperature. 1.0 g was iso- lated after drying the material at room temperature over night.

Example 5 <BR> <BR> <BR> <BR> [3- {4- [1- (4-Cyclohex-1-enylphenyl)-3- (3, 5-dichlorophenyl) ureidomethyl] benzoylamino}-2R- hydroxypropionic acid: 1-butanol]

1 (5.0 g) was dissolved in 1-butanol (5 ml) by heating to 40 °C. n-Heptane (2.2 ml) was added and the 1-butanol solvate of 3- {4- [l- (4-Cyclohex-l-enylphenyl)-3- (3, 5- dichlorophenyl) ureidomethyl] benzoylamino}-2R-hydroxypropionic acid precipitated by cooling

to 20-25 °C. The suspension was filtered and washed with n-heptane (2 x 10 ml) followed by drying in vacuo at 40 °C for 5 days.

Example 6 <BR> <BR> [3- {4- [l- (4-Cyclohex-1-enylphenyl)-3- (3, 5-dichlorophenyl) ureidomethyl] benzoylamino)-2R- hydroxypropionic acid: 2-methyl-1-propanol]

1 (25.0 g) was dissolved in 2-methyl-1-propanol (50 ml) by heating to 40 °C. The 2-methyl-1- propanol solvate of 3- {4- [1- (4-Cyclohex-1-enylphenyl)-3- (3, 5-dichlorophenyl) ureidomethyl]- benzoylamino}-2R-hydroxypropionic acid precipitated by cooling to 20-25 °C. The suspen- sion was filtered and washed with 2-methyl-l-propanol (5 ml). Drying in vacuo at 40 °C for 2 days gave 21.4 g solvate.

Example 7 [3-{4-[1-(4-Cyclohex-1-enylphenyl)-3-(3,5-dichlorophenyl)ure idomethyl]benzoylamino}-2R- hydroxypropionic acid: 3-methyl-1-butanol]

1 (5.0 g) was dissolved in 3-methyl-1-butanol (20 ml) by heating to 40 °C. The 3-methyl-1- butanol solvate of 3- {4- [1- (4-Cyclohex-1-enylphenyl)-3- (3, 5-dichlorophenyl) ureidomethyl]- benzoylamino}-2R-hydroxypropionic acid precipitated by cooling to 20-25 OC. The suspen-

sion was filtered and washed with 3-methyl-1-butanol (10 ml) followed by drying in vacuo at 40 °C for 24 hours.

Example 8 <BR> <BR> <BR> [3- {4- [1- (4-Cyclohex-1-enylphenyl)-3- (3, 5-dichlorophenyl) ureidomethyl] benzoylamino}-2R- hydroxypropionic acid: diethyl ether]

1 (5.0 g) was partly dissolved in diethyl ether (15 ml) by heating. The diethyl ether solvate of 3- {4- [l- (4-Cyclohex-1-enylphenyl)-3- (3, 5-dichlorophenyl) ureidomethyl] benzoylamino)-2R- hydroxypropionic acid precipitated by cooling to 20-25 °C. After drying at room temperature for several days 4.3g was isolated.

Example 9 <BR> <BR> [3- {4- [1- (4-Cyclohex-1-enylphenyl)-3- (3, 5-dichlorophenyl) ureidomethyl] benzoylamino}-2R- hydroxypropionic acid : tert-butyl methyl ether]

1 (5.0 g) was dissolved in tert-butyl methyl ether (7 ml) by heating to 40 °C. The tert-butyl methyl ether solvate of 3- {4- [1- (4-Cyclohex-1-enylphenyl)-3- (3, 5-dichlorophenyl)- ureidomethyl] benzoylamino)-2R-hydroxypropionic acid precipitated by cooling to 20-25 °C.

The suspension was filtered and washed with n-heptane (2 x 10 ml) followed by drying in vacuo at 40 °C for 4 days.

Example 10 <BR> <BR> <BR> [3- {4- [1- (4-Cyclohex-1-enylphenyl)-3- (3, 5-dichlorophenyl) ureidomethyl] benzoylamino}-2R- hydroxypropionic acid: THF

1 (5.0 g) was dissolved in THF (5.0 ml) by heating to 35 °C. n-Heptane (8.0 ml) was added to the solution and the THF solvate of 3- {4- [1- (4-Cyclohex-1-enylphenyl)-3- (3, 5-dichlorophenyl)- ureidomethyl] benzoylamino}-2R-hydroxypropionic acid precipitated by cooling to 20-25 °C.

The suspension was filtered and the filter cake was dried at 20-25 °C for 6 days.

Example 11 <BR> <BR> <BR> <BR> <BR> <BR> [3- {4- [1- (4-Cyclohex-1-enylphenyl)-3- (3, 5-dichlorophenyl) ureidomethyl] benzoylamino}-2R- hydroxypropionic acid: anisole]

1 (5.0 g) was dissolved in a mixture of THF (10 ml) and anisole (90 ml) by heating to 40 °C.

The anisole solvate of 3- {4- [1- (4-Cyclohex-1-enylphenyl)-3- (3, 5-dichlorophenyl)- ureidomethyl] benzoylamino}-2R-hydroxypropionic acid precipitated by cooling to 20-25 °C.

The suspension was filtered and the product was washed with n-heptane (5 ml) followed by drying at 20-25 °C for 5 days.

Example 12 <BR> <BR> [3- {4- [l- (4-Cyclohex-l-enylphenyl)-3- (3, 5-dichlorophenyl) ureidomethyl] benzoylaminol-2R- hydroxypropionic acid: acetone]

1 (5.0 g) was dissolved in acetone (5.5 ml) by heating to 35 °C. n-Heptane (2.2 ml) was added to the solution and the acetone solvate of 3- {4- [1- (4-Cyclohex-1-enylphenyl)-3- (3, 5- dichlorophenyl) ureidomethyl] benzoylamino}-2R-hydroxypropionic acid precipitated by cooling to 20-25 °C. The suspension was filtered and the product was dried at 20-25 °C for 2 days.

Example 13 [3- {4- [1- (4-Cyclohex-1-enylphenyl)-3- (3, 5-dichlorophenyl) ureidomethyl] benzoylamino}-2R- hydroxypropionic acid: 2-butanone]

Methyl 3- {4- [1- (4-Cyclohex-1-enylphenyl)-3- (3, 5-dichlorophenyl) ureidomethyl] benzoylamino}- 2R-hydroxypropionate (9.0 g) dissolved in THF (80 ml) was hydrolysed with lithium hydroxide mono hydrate (0.75 g) dissolved in water (7.5 ml). The aqueous solution was added in 5 min, and the reaction mixture was stirred at room temperature for two hours. Hydrochloric acid (3

M) was added to pH 2.2 and ethyl acetate (50 ml) was added. The two phases were sepa- rated and the organic phase was washed with water (2 x 20 ml). The organic solvent was removed under reduced pressure. Water residues were removed by stripping with 2- butanone (2 x 50 ml). The crude material was dissolved in 2-butanone (90 ml) and heated to 50°C. The solution was added n-heptane (100 ml) and cooled to 5 °C. After stirring over night a precipitate was formed, and the title compound was isolated. The material was dried at 20 - 25 °C for 4 days.

Example 14 <BR> <BR> <BR> <BR> <BR> [3- {4- [1- (4-Cyclohex-1-enylphenyl)-3- (3, 5-dichlorophenyl) ureidomethyl] benzoylamino}-2R- hydroxypropionic acid: methyl acetate] 1 (5 g) was dissolved in methyl acetate (5 ml) at 40°C. At room temperature the methyl ace- tate solvate of 3- {4- [1- (4-Cyclohex-1-enylphenyl)-3- (3, 5-dichlorophenyl) ureidomethyl]- benzoylamino}-2R-hydroxypropionic acid precipitated. The mixture was diluted with methyl acetate (5 ml) prior to filtration. The solvate was identified after drying at room temperature for 18 hours.

Example 15 <BR> <BR> <BR> <BR> <BR> <BR> [3- {4- [1- (4-Cyclohex-1-enylphenyl)-3- (3, 5-dichlorophenyl) ureidomethyl] benzoylamino}-2R- hydroxypropionic acid: n-propyl acetate]

1 (5 g) was suspended in n-propyl acetate (15 ml). The material dissolved upon heating to 40°C to 45°C. The n-propyl acetate solvate of 3- {4- [1- (4-Cyclohex-1-enylphenyl)-3- (3, 5- dichlorophenyl) ureidomethyl] benzoylamino}-2R-hydroxypropionic acid precipitated by cooling to 0-5°C and was identified after drying at room temperature for 18 hours.

Example 16 <BR> <BR> <BR> <BR> <BR> <BR> [3- {4- [1- (4-Cyclohex-1-enylphenyl)-3- (3, 5-dichlorophenyl) ureidomethyl] benzoylamino}-2R- hydroxypropionic acid : toluene] To a solution of methyl 3- {4- [l- (4-Cyclohex-1-enylphenyl)-3- (3, 5-dichlorophenyl)- ureidomethyl] benzoylamino}-2R-hydroxypropionate (72 g) dissolved in ethanol (580 ml) and toluene (56 ml) was added an aqueous solution of lithium hydroxide mono hydrate (10.2 g in 100 ml water). The mixture was stirred for 1 hour at room temperature. Phosphoric acid (3 M) was added to adjust pH to 2.4. The mixture was heated to 40 °C for 1/2 hour. The solution was cooled to room temperature during 2 hours and kept at this temperature for 2 hours. Stir- ring over night at 10 °C resulted in formation of a white precipitate. The slurry was filtered and the filter cake was washed with cooled (10 °C) ethanol/water 1/1 (v/v) (2 x 70 ml) and dried in vacuo at 40 °C for 22 hours. The title compound (72.5 g) was isolated in 88% yield. Example 17: N-[4-({4-(1-cyclohexen-1-yl)[(3,5-dichloroanilino)carbonyl]a nilino}methyl)- benzoyl]-ß-alanine : acetone

N-[4-({4-(1-cyclohexen-1-yl)[(3,5-dichloroanilino)carbonyl]a nilino}methyl)benzoyl]-ß-alanine (1.0 g) was dissolved in acetone (44 ml) by heating. The acetone solvate of N-[4-({4-(1- cyclohexen-1-yl)[(e,t-dichloroanilino)carbonyl]anilino}methy l)benzoyl]-ß-alanine precipitated by stirring the mixture at room temperature. 0.62 g was isolated after drying the material.

Example 18: N-[4-({4-(1-cyclohexen-1-yl)[(3,5-dichloroaniliono)carbonyl] anilino}- methyl) benzoyl]-ß-alanine : 2-butanol]

N-[4-({4-(1-cyclohexen-1-yl)[(3,5-dichloroanilino)carbonyl]a nilino}methyl)benzoyl]-ß-alanine (1.0 g) was dissolved in 2-butanol (44 ml) by heating. Up on cooling to room temperature the 2-butanol solvate of N-[4-({4-(1-cyclohexen-1-yl) [(3, 5-dichloroanilino) carbonyl] anilino}- methyl) benzoyl]-ß-alanine precipitated. The material was collected by filtration. After drying at room temperature 0.98 g was isolated.

Example 19 : N-[4-({4-(1-cyclohexen-1-yl) [(3, 5-dichloroanilino) carbonyl] anilino} methyl)- benzoyl]-ß-alanine : ethanol]

N-[4-({4-(1-cyclohexen-1-yl)[(3,5-dichloroanilino)carbonyl]a nilino}methyl)benzoyl]-ß-alanine (1.0 g) was dissolved in ethanol (36 ml) by heating. Up on cooling to room temperature the ethanol solvate of N- [4- ( {4- (l-cyclohexen-1-yl) [ (3, 5-dichloroanilino) carbonyl] anilino)- methyl) benzoyl]-ß-alanine precipitated. The suspension was filtered and washed with cold ethanol. After drying for 2 days at room temperature 0.68g was isolated.

Example 20 : N-[4-({4-(1-cyclohexen-1-yl)[(3,5-dichloroanilino)carbonyl]a nilino}methyl)- benzoyl]-ß-alanine : 2-propanol]

N-[4-({4-(1-cyclohexen-1-yl)[(3,5-dichloroanilino)carbonyl]a nilino}methyl)benzoyl]-ß-alanine (1.0 g) was dissolved in 2-propanol (56 ml) by heating. The 2-propanol solvate of N-[4-({4-(1- cyclohexen-1-yl) [(3, 5-dichloroanilino) carbonyl] anilino} methyl) benzoyl]-ß-alanine precipitated by stirring the mixture at room temperature. 0.58 g was isolated after drying the material at room temperature over 3 days.

Example 21 : N- [4- ( {4- (1-cyclohexen-1-yl) [ (3, 5-dichloroanilino) carbonyl] anilino}- methyl) benzoyl]-ß-alanine : 1-propanol]

N-[4-({4-(1-cyclohexen-1-yl)[(3,5-dichloroanilino)carbonyl]a nilino}methyl)benzoyl]-ß-alanine (1.0 g) was dissolved in 1-propanol (44 ml) by heating. The 2-propanol solvate of N-[4-({4-(1- cyclohexen-1-yl) [(3, 5-dichloroanilino) carbonyl] anilino} methyl) benzoyl]-ß-alanine precipitated by stirring the mixture at room temperature. 0.63 g was isolated after drying the material at room temperature over 3 days.

Measurement of stability: The stability has been observed at accelerated as well as at long term storage conditions for a time period of 33 weeks. From the apparent degradation rates observed at the different storage conditions a retest time was estimated in the cases where a significant degradation was observed.

The experiment are measured at different temperatures and humidities for example: 25°C/60 % RH, 40°C/75% RH, 60°C/ambient humidity, or with light exposure in either open containers or bulk container.