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1. AU1998081018 - Fused 1,2,4-thiadiazine derivatives, their preparation and use

Note: Texte fondé sur des processus automatiques de reconnaissance optique de caractères. Seule la version PDF a une valeur juridique

[ EN ]
CLAIMS
1.          A compound of the general formula I
(D
wherein
B represents >NR 5 or >CR SR 6, wherein R 5 and R 6 independently are hydrogen; hydroxy; C,. 6-alkoxy; or C^-alkyl, C^-cycloalkyl, C 2.6-alkenyl or C 2.6-alkynyl optionally mono- or polysubstituted with halogen; or R 5 and R 4 together represent one of the bonds in a double bond between the atoms 2 and 3 of formula I;
D represents - S(=0) 2- or -S(=0)-; or
D-B represents -S(=0)(R 7)=N-
wherein R 7 is C^-alkyl; or aryl or heteroaryl optionally mono- or polysubstituted with halogen, hydroxy, C^-alkoxy, aryloxy, arylalkoxy, nitro, amino, C 1-6-monoalkyl- or dialkylamino, cyano, acyl, or C,. 6-alkoxycarbonyl;
R 1 is hydrogen; hydroxy; C 1-6-alkoxy; or C,. 6-alkyl, C^-cycloalkyl, C 2.6- alkenyl or C 2.6-alkynyl Optionally mono- or polysubstituted with halogen and R 4 is hydrogen; or R 4 together with R 5 represent one of the bonds in a double bond between the atoms 2 and 3 of formula I; or R 1 together with R 4 Represent one of the bonds in a double bond between the atoms 3 and 4 of formula I;
R 2 is hydrogen; hydroxy; C^-alkoxy; or C 1-6-alkyl, C^-cycloalkyi, C 2.e- alkenyl or C 2^-alkynyl optionally mono- or polysubstituted with halogen;
R 3 is R a; -OR 8; -C(=X)R 8; -NR 8R 9; bicycloalkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl optionally mono- or polysubstituted with halogen, hydroxy, C,. 6-alkoxy, aryioxy, arylalkoxy, nitro, amino, C^-monoalkyl- or dialkylamino, cyano, oxo, acyl or C^-alkoxycarbonyl; or aryl substituted with C 1-6-alkyl;
wherein R 8 is hydrogen; C^-cycloalkyl or (C^-cycloalkyl)C^-alkyl, the C^-cycloalkyl group optionally being mono- or polysubstituted with C,. 6-alkyl, halogen, hydroxy or C,. 6-alkoxy; a 3-6 membered saturated ring system comprising one or more nitrogen-, oxygenor sulfur atoms; or straight or branched C^^-alkyl optionally mono- or polysubstituted with halogen, hydroxy, C 6-alkoxy, C 1-6-alkylthio, C^-cycloalkyl, aryl, aryioxy, arylalkoxy, nitro, amino, C^- monoalkyl- or dialkylamino, cyano, oxo, formyl, acyl, carboxy, C,. 6-alkoxycarbonyl, or carbamoyl;
X is O or S;
R 9 is hydrogen; C^-alkyl; C 2.6-alkenyl; C^-cycloalkyl optionally mono- or polysubstituted with C 1-6-alkyl, halogen, hydroxy or C^-alkoxy; or
R 8 and R 9 together with the nitrogen atom form a 3-12 membered mono- or bicyc!ic system, in which one or more of the carbon atoms may be exchanged with nitrogen, oxygen or sulfur, each of these ring systems optionally being mono- or polysubstituted with halogen, C 1-6-alkyl, hydroxy, C^-alkoxy, C^-alkoxy-C^-alkyl, nitro, amino, cyano, trifluoromethy!, C^-monoalkyl- or dialkylamino, oxo; or R 3 is
wherein n,m,p independently are 0,1, 2, 3 and R 10 is hydrogen; hydroxy; C^-alkoxy; C M-cycloalkyl optionally mono- or polysubstituted with C^-alkyl, halogen, hydroxy or C^-alkoxy; C 1-6-alkyl, C^-alkenyl or C 2.6-alkynyl optionally mono- or polysubstituted with halogen; or
R 2 and R 3 together with the nitrogen atom forms a 3-12 membered mono- or bicyclic system, in which one or more of the carbon atoms may be exchanged with nitrogen, oxygen or sulfur, each of these ring systems optionally being mono- or polysubstituted with halogen, C 1-6-aikyl, hydroxy, C^e-alkoxy, C^-alkoxy-C^-alkyl, nitro, amino, cyano, trifluoromethyl, C^-monoalkyl- or dialkylamino or oxo;
A together with carbon atoms 5 and 6 of formula I represents a 5 or 6 membered heterocyclic system comprising one or more nitrogen-, oxygen- or sulfur atoms, the heterocyclic systems optionally being mono- or polysubstituted with halogen; C n.12-alkyl; C^-cycloalkyl; hydroxy; C,. s-alkoxy; C^-alkoxy-C^-alkyl; nitro; amino; cyano; cyanomethyl; perhalomethyl; C^-monoalkyl- or dialkylamino; sulfamoyl; C^-alkylthio; C^-alkylsulfonyl; C^-alkylsulfinyl; C,. 6-alkylcarbonylamino; arylthio, arylsu!finyl, arylsulfonyl, the aryl group optionally being mono- or polysubstituted with C^-alkyl, halogen, hydroxy or C 1-6-alkoxy; C,. 6-alkoxycarbonyl; C^-alkoxycarbonyl-C^-alkyl; carbamyl; carbamyl- methyl; C,. 6-monoalkyl- or dialkylaminocarbonyl; C^-monoalkyl- or dialkylaminothiocarbonyl; ureido; •''..la-monoalkyl- or dialky!aminocarbonylamino, thioureido; C^-monoalkyl- or dialkylaminothiocarbonyl- amino; C 1-6-monoalkyl- or dialkylaminosulfonyl; carboxy; carboxy-C,. e-alkyl; acyl; aryl, arylalkyl, aryloxy, the aryl group optionally being mono- or polysubstituted with C^-alkyi, halogen, hydroxy or C 1-6-alkoxy; (1 ,2,4-oxadiazol-5-yl)- or (1 ,2,4-oxadia ol ycloa!kyl; or a 5 - 6 membered nitrogen containing ring, optionally substituted with phenyl r C 1-6-alkyl;
provided that A together with carbon atoms 5 and 6 of formula I do not form a pyridine ring and that the following compounds 3-aminoimidazo[4,5-e]-1,2,4-thiadiazine 1,1-dioxide and 3- (benzoylamino)imidazo[4,5-e]-1,2,4-thiadiazine 1,1-dioxide are not included;
or a salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric form.
2, A compound according to claim 1 , wherein R 2 is hydrogen or C^-alkyl.
3. A compound according to claim 1 or 2 wherein R 3 is R 8, -OR 8, NR 8R 9 or aryl, the aryl groups optionally being substituted with C 1-6-alkyi; wherein
R 8 is hydrogen; C^-cycloalkyl; (C^-cycloalky C^g-alkyl; a 3 - 6 membered saturated ring system comprising one, two or three nitrogen-, oxygen- or sulfur atoms; or straight or branched C 18-alkyl optionally substituted with halogen, hydroxy, C^ s-alkoxy, C^-alkylthio, C^-cycioalkyl or aryl,
R 9 is hydrogen, C 1-6-alkyl or C^-cycloalkyl; or
R 8 and R 9 together with the nitrogen atom form a 4 - 6 membered ring.
4. A compound according to any one of the preceding claims wherein R 3 is secondary C^-alkyl, tertiary C^-alkyl, C^-cycloa!kyl or (C 3.6-cycloalkyl)methy!.
5 . A compound according to any one of the preceding claims wherein A together with carbon atoms 5 and 6 of formula I forms a 5 membered heterocyclic system containing one hetero atom selected from nitrogen and sulfur, the heterocyclic system optionally being mono- or disubstituted with halogen; C^^-alkyl; C^-cycloalkyl; cyano; cyanomethyl; pe h l ethyl; lf i C lk lthi C ik I lf I C lk l lfi ! arylthio, arylsulfinyl, arylsulfonyl, the aryl group optionally being mono- or polysubstituted with C 1-6-alkyl, halogen, hydroxy or C 1-6-alkoxy; C^g-alkoxycarbonyl-Cvg-alkyl; carbamyimethyl; carboxy-C^-alkyl; aryloxy; (1 ,2,4-oxadiazol-5-yl)- or (1 ,2,4-oxadiazol-3-yl)C 1-6-alkyl, the oxadiazolyl group optionally being substituted with C 1-6-alkyl or C^-cycloalkyl; acyl or a 5 - 6 membered nitrogen containing ring, optionally substituted with phenyl or C^-alkyl.
6. A compound according to any one of the preceding claims wherein A together with carbon atoms 5 and 6 of formula I forms a 5 membered heterocyclic system containing two hetero atoms selected from nitrogen, oxygen and sulfur, the heterocyclic system optionally being substituted with halogen; C 1-12-alkyl; C^-cycloalkyl; cyano; cyanomethyl; perhalomethyl; sulfamoyl; C^-alkylsuifonyl; C 1-6-alkylsulfinyl; arylthio, arylsulfinyl, arylsulfonyl, the aryl group optionally being mono- or polysubstituted with Ο,. Β-alkyl, halogen, hydroxy or C^ g-alkoxy; C^-alkoxycarbonyl-C^g-alkyl; carbamyimethyl; carboxy-C^-alkyl; aryloxy; (1,2,4-oxadiazol-5-yl)- or (l^^-oxadiazol-S-yl)C^-alkyl, the oxadiazolyl group optionally being substituted with C^-alkyi or C^-cycloalkyl; acyl; or a 5 -6 membered nitrogen containing ring, optionally substituted with phenyl or C^-alkyl.
7. A compound according to any one of the preceding claims wherein A together with carbon atoms 5 and 6 of formula I forms a 6 membered aromatic heterocyclic system containing two or three nitrogen atoms, the heterocyclic system optionally being substituted with halogen; C 1.12-alkyl; C^g-cycloalkyi; cyano; cyanomethyl; perhalomethyl; sulfamoyl; C^ g-alkylthio; C^alkylsulfonyl; C^-aikylsulfmyl; arylthio, arylsulfinyl, arylsulfonyl, the aryll group optionally being mono- or polysubstituted with C 1-e-alkyl, halogen, hydroxy or C^g-alkoxy; C^-alkoxycarbonyl-C^ g-alkyl; carbamyimethyl; carboxy-C^g-alkyl: aryloxy; (1 ,2,4-oxadiazol-5-yl)- or (l^^-oxadiazol-S-yl)C^g-alkyi, the oxadiazolyl group optionally being substituted with C 1-6-alkyl or C^ g-cycloa!kyl; acyl; or a 5 - 6 membered nitrogen containing ring, optionally substituted with phenyl or C,. 6-alkyl.
0  8. A compound according to any one of the preceding claims wherein A together With carbon atoms 5 and 6 of formula I forms a 6 membered non-aromatic heterocyclic system containing one or twd hetero atoms selected from nitrogen, oxygen and sulfur, the heterocyclic system optionally being substituted with halogen; C 1-12-alkyl; C 3.6-cycloalkyl; cyano; cyanomethyl; perhalomethyl; sulfamoyl; C,. 6-alkylthio; C^alkylsulfonyl; C^-alkylsulfmyl; arylthio, arylsulfinyl, arylsulfonyl, the aryll group optionally being mono- or polysubstituted with C^-alkyl, halogen, hydroxy or C^-alkoxy; C^-alkoxycarbonyl-C^-alkyl; carbamylmethyl; carboxy-C^-alkyl: aryloxy; (1 ,2,4-oxadiazol-5-yl)- or (1,2,4-oxadiazol-S-y alkyl, the oxadiazolyl group optionally being substituted with C 1-6-alkyl or C^-cycloalkyl; acyl; or a 5 - 6 membered nitrogen containing ring, optionally substituted with phenyl or C 1.6-alkyl.
9. A compound according to any one of the claims 1 - 8, wherein the genera! formula I is
wherein
R 1 and R 5 independently are hydrogen; hydroxy; C^-alkoxy; or C^-alkyl, C^-cycloalkyl, C 2.6-alkenyl or C 2.6-alkynyl optionally mono- or polysubstituted with halogen and R 4 is hydrogen; or
R 4 together with R 5 represent one of the bonds in a double bond between the atoms 2 and 3 of formula I and R 1 Is as defined above; or
R 4 together With R 1 represent one of the bonds in a double bond between the atoms 3 and 4 of formula I and R 5 is as defined above;
D represents -S(=0) 2- or S<=0)-; and 
A, R 2 and R 3 are as defined above.
10. A compound according to claim 9 wherein R 1 and R 5 independently are hydrogen or C^-aikyl.
1 1. A compound according to claims 9 or 10 wherein R 1 together with R 4 represent one of the bonds in a double bond between the atoms 3 and 4 of formula I.
12. A compound according to any one of the claims 9 - 11, wherein R 4 together with R 5 represent one of the bonds in a double bond between the atoms 2 and 3 of formula I.
13. A compound according to any one of the claims 9 - 12 wherein D is -S(=0) 2-.
14. A compound according to any one of the claims 1 - 8 wherein the general formula I is
wherein
R 1 is hydrogen; hydroxy; C^-alkoxy; or C 1-6-alkyl, C^-cycloalkyl, C 2.6-alkenyl or C M-aikynyl optionally mono- or polysubstituted with halogen and R 4 is hydrogen; or
R 4 together with R 1 represent one of the bonds in a double bond between the atoms 3 and D represents -S(=0)R 7=
wherein R 7 is C^-alkyl; or aryl or heteroaryl optionally mono- or polysubstituted with halogen, hydroxy, C 1-6-alkoxy, aryloxy, arylalkoxy, nitro, amino, C^-monoalkyl- or dialkylamino, cyano, acyl or C s-alkoxycarbonyl; and
A, R 2 and R 3 are as defined above.
15. A compound according to claim 14 wherein R 1 is hydrogen or C 1-6-alkyl.
16. A compound according to claim 14 or 15 wherein R 1 together with R 4 represent one of the bonds in a double bond between the atoms 3 and 4 of formula I.
17. A compound according to any one of the claims 14 - 16 wherein R 7 is C 1-6-aikyl, phenyl or pyridyl.
18. A compound according to any one of the claims 1 - 8 wherein the general formula I is
wherein
R 1, R 5 and R 6 independently are hydrogen; hydroxy; C,. 6-a!koxy; or C^e-alkyl, C^-cycloalkyl, C 2.6-alkeny! or C 2.6-alkynyl optionally mono- or polysubstituted with halogen and together with R 5 represent one of the bonds in a double bond between the atoms 2 and of formula I and R 1 and R 6 are as defined above; or
together with R 1 represent one of the bonds in a double bond between the atoms 3 and of formula I and R 5 and R 6 are as defined above;
represents -S(=0) 2- or -S(=0)-; and
R 2, R 3 are as defined above.
9. A compound according to claim 18 wherein R 1 , R 5 and R 6 independently are ydrogen or C^-alkyl.
0. A compound according claim 18 or 19 wherein R 1 together with R 4 represent one f the bonds in a double bond between the atoms 3 and 4 of formula I.
1 . A compound according to any one of the claims 18 - 20 wherein R 4 together with s represent one of the bonds in a double bond between the atoms 2 and 3 of formula I.
22.        A compound according to any one of the claims 18 - 21 wherein D is -S(=0) 2-.
3. A compound selected from the following:
-Cyano-3-isopropylamino-6-methyl-4H-thieno{2,3-e]-1 ,2,4-thiadiazine 1 ,1-dioxide 7-Cyano-6-methyI-3-propylamino-4H-thieno[2,3-e]-1,2,4-thiadiazine 1,1 -dioxide
6-Chloro-3-isopentylamino-4H-thieno[3,2-e]-1 ,2,4-thiadiazine 1 , 1 -dioxide
6-Chloro-3-(1-methylhepty!)amino-4H-thieno[3,2-e]-1 ,2,4-thiadiazine 1,1 -dioxide
6-Chloro-3-(1-ethylpentyl)amino-4H-thieno[3,2-e]-1 ,2,4-thiadiazine 1 , 1 -dioxide
6-Chloro-3-(2-methylbutyl)amino- 4H-thieno[3,2-e]-1 ,2,4-thiadiazine 1 ,1 -dioxide
6-Chloro-3-(1-methylhexy!)amino-4H-thieno[3,2-e]-1 ,2,4-thiadiazine 1 ,1-dioxide  -Chloro-3-cyclohexylmethylamino-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1 -dioxide thyl 3-(6-chloro-1,4-dihydro-1,1-dioxothieno[3,2-e]-1 6,2,4-thiadiazin-3-lamino)butanoate
3-(6-Chloro-1,4-dihydro-1,1-dioxothieno[3,2-e]-^ 6,2,4-thiadiazin-3-ylamino)butanoic acid 6-Chloro-3-(3-hydroxy-1-methylpropyl)amino-4H-thieno[3,2-e]-1,2,4-thiadiazine 1 ,1-ioxide
(R)-6-Chloro-3-(1-pheny!ethy!)amino-4H-thieno[3,2-e]-1 ,2,4-thiadiazine 1 ,1-dioxide (S)-3-sec-Butylamin 'o-6-chloro-4H-thieno[3,2-e]-1 ,2,4-thiadiazine 1 , 1 -dioxide
6-Chloro-3-isopropylamino-4H-thieno[2, 3-e]-1 ,2,4-thiadiazine 1 , 1 -dioxide
6-Chloro-3-cyclopentylamino-4H-thieno[2,3-e]-1 ,2,4-thiadiazine 1,1 -dioxide
6-Bromo-3-isopropylamino-4H-thieno[3,2-e]-1 ,2,4-thiadiazine 1 ,1 -dioxide
3-lsopropylamino-4H-thieno[3,2-e]-1 ,2,4-thiadiazine 1 ,1-dioxide
6-Fluoro-3-isopropylamino-4H-thieno[3,2-e]-1 ,2,4-thiadiazine 1 , 1 -dioxide
3-Cyclobutylamino-5,6-dimethyl-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1 -dioxide
3-Cyciopentylamino-5,6-dimethyl-4H-thieno[3,2-e]-1 ,2,4-thiadiazine 1,1 -dioxide 3-!sopropylamino-6,7-di ethyl-4H-thieno[2,3-e]- ,2,4-thiadiazine 1 ,1 -dioxide
3-Cyclobutylamino-6,7-dimethyl-4H-thieno[2,3-e]-1 ,2,4-thiadiazine 1 ,1-dioxide
3-Cyc!opentylamino -6,7-dimethyl-4H-thieno[2,3-e]-1 ,2,4-thiadiazine 1 ,1-dioxide 5-Chloro-3-isopropy!amino-4H-thieno[3,2-e]-1 ,2,4-thiadiazine 1 ,1 -dioxide
5-Ch!oro-3-propylamino-4H-thieno[3,2-e]-1 ,2,4-thiadiazine 1 ,1-dioxide
5-Chloro-3-cyclopentylamino-4H-thieno[3,2-e]-1 ,2,4-thiadiazine 1 ,1-dioxide
5-Chloro-6-methy!-3-isepropytamino-4H-thieno[3,2-e]-1 ,2,4-thiadiazine 1 ,1-dioxide 6-chloro-3-isopropylamino-5-methyl-4H-thieno[3,2-e]-1 ,2,4-thiadiazine 1 ,1 -dioxide 6-chlero-3-cyclopentylamino-5-methyl-4H-thieno[3,2-e]-1 ,2,4-thiadiazine 1 ,1-dioxide 6-Fluoro-3-propyiamino-4H-thieno[3,2-e]-1 ,2,4-thiadiazine 1 ,1-dioxide
6-Fluoro-3-cyclopentylamino-4H-thieno[3,2-e]-1 ,2,4-thiadiazine 1 ,1-dioxide
5-F!uoro-3-propy!amino-4H-thieno[3,2-e]-1 ,2,4-thiadiazine 1 ,1-dioxide or
5-Fluoro-3-isopropylamino-4H-thieno[3,2-e]-1 ,2,4-thiadiazine 1 ,1 -dioxide.
3-lsopropyiamino-7-methyl-4H-thieno[2,3-e]-1 ,2,4-thiadiazine 1 ,1 -dioxide
6-Chloro-3-cyclobutylamino-4H-thieno[3,2-e]-1 ,2,4-thiadiazine 1 , 1 -dioxide
6-Chloro-3-(2-hydroxyethyl)amino-4H-thieno[3,2-e]-1 ,2,4-thiadiazine 1 ,1 -dioxide (±)-3-exo-Bicyc!o[2.2.1]hept-2-ylamino-6-chioro-4H-thieno[3,2-e]-1 ,2,4-thiadiazine 1,1ioxide
R)-6-Ch!oro-3-(2-hydroxypropy!)amino-4H-thieno[3,2-e]-1 ,2,4-thiadiazine 1 ,1-dioxide -Bromo-3-isopropylamino-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide
, 6-Dibromo-3-isopropylamino-4H-thieno[3,2-e]-1 ,2,4-thiadiazine 1,1-dioxide6-Chloro-3-yclohexylamino-4H-thieno[3,2-e]-1 ,2,4-thiadiazine 1 ,1-dioxide
-Chloro-3-(furan-2-ylmethyl)amino-4H-thieno[3,2-e]-1 ,2,4-thiadiazine 1 ,1-dioxide -Chloro-3-(1-ethylpropyl)amino-4H-thieno[3,2-e]-1 ,2,4-thiadiazine 1 ,1-dioxide
-Bromo-3-cyclopentylamino-4H-thieno[3,2-e]-1 ,2,4-thiadiazine 1,1 -dioxide
6-Chloro-3-(2-methyIallyl)amino-4H-thieno[3,2-e]-1 ,2,4-thiadiazine 1,1-dioxide or 6-Cyano-3-isopropylamino-4H-thieno[3,2-e]-1 ,2,4-thiadiazine 1 , 1 -dioxide.
24.      Compounds according to any one of the preceding claims which acts as openers of the K ATP-regulated potassium channels.
25.        A method of preparing a compound of formula I, characterized in
a) reacting a compound of formula II:
(ID
wherein A, B, D, R 1 and R 4 are as defined above and Z is a leaving group such as alkoxy, alky!thio, halogen, preferentially chloro, bromo, iodo, trimethylamino, or methylsu!fonyl with a compound of formula III:
/ R2
HN
R 3 (III)
wherein R 2 and R 3 are defined above to form a compound of the general formula I;
b) reacting a compound of formula IV:
wherein R 1 is hydrogen and A, B, D and X are as defined above, or B is NH and R 1, A, D
and X are as defined above, with the compound of formula ill, or a suitable salt thereof in
the presence of P 2O s and a high boiiing tertiary amine or a suitable salt thereof, to form a
compound of the general formula I;
c) reacting a compound of the formula IV:
R 1
N X
A Y . B
D (IV)
wherein R 1 is hydrogen and A, B, D and X are as defined above or B is NH and R\ A, D and X are as defined above, with a compound of the formula 111, or a suitable sr!t thereof in the presence of titanium tetrachloride and a solvent with which it may form a complex, like e.g. tetrahydrofuran, or a mixture of toluene and anisole, to form a compound of the general formula I;
d) reacting a compound of formula V
wherein R 1 and A are as defined above, with a compound of formula VI
R 3NCO (VI)
wherein R 3 is as defined above, to form a compound of the general formula I wherein D is SO 2, B is >NR S, R 2 is H, and R 4 and R 5 together form a bond;
e) reacting a compound of the formula V
NHR
A
5                                                              SO 2NH 2
(V)
wherein R 1 and A are as defined above, with a compound of formula VII
R 3NHC(=0)CI (VII)
wherein R 3 is as defined, to form a compound of the general formula I wherein D is SO 2, B is >NR 5, R 2 is H, and R 4 and R 5 together form a bond;
f) reacting a compound of the formula V
wherein R 1 and A are defined as above, with a compound of formula VIII
wherein Y is NH or S, or a suitable salt thereof, to form a compound of the general formula I, wherein D is SO 2, B is >NR 5 , R 4 and R 5 together form a bond, and R 2 and R 3 are H;
g)  reacting in the presence of a base a compound of formula IX 
or a suitable salt thereof, wherein R 11 is R 1 or Et0C(=0), wherein R 1 and A are defined as above, with a compound of formula X
R 3N=C=S (X)
wherein R 3 is as defined above, to form an adduct which may have either of the two structures XI or XII or be a mixture of the two
either of which by ring-closure, e.g. by treatment with phosgene in a suitable solvent, forms a compound of the general formula I, if R 11 is R 1 , wherein D is S(=0) 2 , B is >NR 5 , R 2 is H, and R 4 and R 5 together form a bond, and a compound of the general formula Xlll if R 11 is Et0C(=0);
0 V.
. N. /.NH-R
A       N    T
S -N
O 0 (Xlll)
h) hydrolyzing and subsequently decarboxylating a compound of the general formula Xlll
to form a compound of the general formula I, wherein D is S(=0) 2 , B is >NR 5 , R 1 and R 2 are H, and R 4 and R 5 together form a bond, e.g. by heating the starting compound in aqueous base.
26.        A pharmaceutical composition comprising a compound according to any of the claim 1 - 24 or a or a pharmaceutical acceptable salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric form together with one or more pharmaceutically acceptable carriers or diluents.
27. A pharmaceutical composition for use in the treatment of diseases of the endocrinological system such as hyperinsulinaemia and diabetes comprising a compound according to any of the claims 1 - 24 or a pharmaceutical acceptable salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric form together with one or more pharmaceutically acceptable carriers or diluents.
28. The pharmaceutical composition according to claim 26 or 27 in the form of an oral dosage unit or parenteral dosage unit.
29. A pharmaceutical composition according to claim 26 or 27 wherein said compound is administered as a dose in a range from about 0.05 to 1000, preferably from about 0.1 to 500 and especially in the range from 50 to 200 mg per day.
30. A compound according to any one of the claims 1 - 24 or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric form for therapeutical use.
31. A compund according to any one of the claims 1 - 24 or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric form for therapeutical use in the treatment or prevention of diseases of the endocrinological system, such as hyperinsulinaemia and diabetes.
32.         The use of a compound according to any one of the claims 1 - 24 or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric form as a medicament.
33. The use of a compound according to any of the claims 1 - 24 for preparing a medicament.
34. The use of a compound according to any one of the claims 1 - 24 or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric form for the preparation of a medicament for the treatment or prevention of diseases of the endocrinological system, such as hyperinsulinaemia and diabetes.
35. A method of treating or preventing diseases of the endocrinological system, such as hyperinsulinaemia and diabetes in a subject in need thereof comprising administering an effective amount of a compound according to any of the claims 1 - 24 to said subject.
36. A process for the manufacture of a medicament, particular to be used in the treatment or prevention of diseases of the endocrinological system, such as hyperinsulinaemia and diabetes which process comprising bringing a compound of formula 1 according to any of the claims 1 - 24 or a pharmaceutically acceptable salt thereof into a galenic dosage form.
37.         Any  novel feature  or combination  of features  as described  herein.