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1. WO1999003861 - DERIVES DE 1,2,4-THIADIAZINE FUSIONNEE, LEUR PREPARATION ET UTILISATION

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


wherein
B represents >NR5 or >CR5R6, wherein R5 and R6 independently are hydrogen; hydroxy;

C1-6-alkoxy; or C1-6-alkyl, C^-cycloalkyl, C2.6-alkenyl or C2.6-alkynyl optionally mono- or polysubstituted with halogen; or R5 and R4 together represent one of the bonds in a double bond between the atoms 2 and 3 of formula I;

D represents - S(=O)2- or -S(=O)-; or

D-B represents -S(=O)(R7)=N- wherein R7 is C,.6-alkyl; or aryl or heteroaryl optionally mono- or polysubstituted with halogen, hydroxy, C^-alkoxy, aryloxy, arylalkoxy, nitro, amino, C1-6-monoalkyl- or dialkylamino, cyano, acyl, or CLe-alkoxycarbonyl;

R1 is hydrogen; hydroxy; C1-6-alkoxy; or C1-6-alkyl, C^-cycloalkyl, C2-6- alkenyl or C2.6- alkynyl optionally mono- or polysubstituted with halogen and R4 is hydrogen; or R4 together with R5 represent one of the bonds in a double bond between the atoms 2 and 3 of formula I; or R1 together with R4 represent one of the bonds in a double bond between the atoms 3 and 4 of formula I;

R2 is hydrogen; hydroxy; C1-6-alkoxy; or C1-6-alkyl, C^-cycloalkyl, C2-6- alkenyl or C2^-alkynyl optionally mono- or polysubstituted with halogen;

R3 is R8; -OR8; -C(=X)R8; -NR8R9; bicycloalkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl optionally mono- or polysubstituted with halogen, hydroxy, C1-6-alkoxy, aryloxy, arylalkoxy, nitro, amino, CLβ-monoalkyl- or dialkylamino, cyano, oxo, acyl or C1-6-alkoxycarbonyl; or aryl substituted with C1-6-alkyl;

wherein R8 is hydrogen; C^-cycloalkyl or (C^-cycloalkyOC^-alkyl, the C^-cycloalkyl group optionally being mono- or polysubstituted with C1-6-alkyi, halogen, hydroxy or C1-6-alkoxy; a 3-6 membered saturated ring system comprising one or more nitrogen-, oxygen-or sulfur atoms; or straight or branched C1-18-alkyl optionally mono- or polysubstituted with halogen, hydroxy, C1-6-alkoxy, C1-6-alkylthio, C^-cycloalkyl, aryl, aryloxy, arylalkoxy, nitro, amino, C1-6- monoalkyl- or dialkylamino, cyano, oxo, formyl, acyl, carboxy, C,.6-alkoxy-carbonyl, or carbamoyl;

X is O or S;

R9 is hydrogen; C1-6-alkyl; C2.6-alkenyl; C^-cycloalkyl optionally mono- or polysubstituted with C^-alkyl, halogen, hydroxy or C1-6-alkoxy; or

R8 and R9 together with the nitrogen atom form 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,
nitro, amino, cyano, trifluoromethyl, C^-monoalkyl- or dialkylamino, oxo; or R3 is

wherein n,m,p independently are 0,1 ,2,3 and R10 is hydrogen; hydroxy;

cycloalkyl optionally mono- or polysubstituted with C1-6-alkyl, halogen, hydroxy or C1-6-alkoxy; C1-6-alkyl, C2-6-alkenyl or C2.6-alkynyl optionally mono- or polysubstituted with halogen; or

R2 and R3 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,
nitro, amino, cyano, trifluoromethyl, CLs-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; C1-12-alkyl; C^-cycloalkyl; hydroxy; C1-6-alkoxy;
nitro; amino; cyano; cyanomethyl; perhalomethyl; C1-6-monoalkyl- or dialkylamino; suifamoyl; C^-alkylthio; C1-6-alkylsulfonyl; C1-6- alkylsulfinyl; CLβ-alkylcarbonylamino; arylthio, arylsulfinyl, arylsulfonyl, the aryl group optionally being mono- or polysubstituted with C^-alkyl, halogen, hydroxy or C1-6-alkoxy; C,.6-alkoxycarbonyl; C^-alkoxycarbonyl-C^-alkyl; carbamyl; carbamyl- methyl; C1-6- monoalkyl- or dialkylaminocarbonyl; C1-6-monoalkyl- or dialkylaminothiocarbonyl; ureido; CLfs-monoalkyl- or dialkylaminocarbonylamino, thioureido; C^-monoalkyl- or dialkylami- nothiocarbonyl- amino; C1-6-monoalkyl- or dialkylaminosulfonyl; carboxy; carboxy-C1-6- alkyl; acyl; aryl, arylalkyl, aryloxy, the aryl group optionally being mono- or polysubstituted with C1-6-alkyl, halogen, hydroxy or C1-6-alkoxy; (1 ,2,4-oxadiazol-5-yl)- or (1 ,2,4-oxadiazol- 3-yl)-C1-6-alkyl the oxadiazolyl group optionally being substituted with C1-6-alkyl or C^- cycloalkyl; or a 5 - 6 membered nitrogen containing ring, optionally substituted with phenyl or C1-6-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 R2 is hydrogen or C1-6-alkyl.

3. A compound according to claim 1 or 2 wherein R3 is R8, -OR8, NR8R9 or aryl, the aryl groups optionally being substituted with C1-6-alkyl; wherein

R8 is hydrogen; C^-cycloalkyl; (C3.6-cycloalkyl)C1.6-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, C1-6-alkoxy, C1-6-alkylthio,
or aryl,

R9 is hydrogen, C1-6-alkyl or C^-cycloalkyl; or

R8 and R9 together with the nitrogen atom form a 4 - 6 membered ring.

4. A compound according to any one of the preceding claims wherein R3 is secondary C^-alkyl, tertiary C^-alkyl, C^-cycloalkyl or (C^-cycloalky methyl.

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; C1-12-alkyl; C^-cycloalkyl; cyano; cyanomethyl; perhalomethyl; suifamoyl; C1-6-alkylthio; C^-alkylsulfonyl; C1-6-alkylsulfinyl;

arylthio, arylsulfinyl, arylsulfonyl, the aryl group optionally being mono- or polysubstituted with C^-alkyl, halogen, hydroxy or C1-6-alkoxy; C^-alkoxycarbonyl-C^-alkyl;
carbamylmethyl; carboxy-C1-6-alkyl; aryloxy; (1 ,2,4-oxadiazol-5-yl)- or (1 ,2,4-oxadiazol-3-yI)C1.6-alkyl, the oxadiazolyl group optionally being substituted with C1-6-alkyl or C^-cycloalkyl; acyl or a 5 - 6 membered nitrogen containing ring, optionally substituted with phenyi or C1-6-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^-alkyl; C^-cycloalkyl; cyano;
cyanomethyl; perhalomethyl; suifamoyl; CLe-alkylsulfonyl; C^-alkylsulfinyi; arylthio, arylsulfinyl, arylsulfonyl, the aryl group optionally being mono- or polysubstituted with C1-6- alkyl, halogen, hydroxy or C1-6-alkoxy;
carbamylmethyl; carboxy-CLβ-alkyl; aryloxy; (1 ,2,4-oxadiazol-5-yl)- or (l ^^-oxadiazol-S-y C^-alkyl, the oxadiazolyl group optionally being substituted with C1-6-alkyl or C3_6-cycloalkyl; acyl; or a 5 - 6 membered nitrogen containing ring, optionally substituted with phenyl or C^-alky!.

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; C1-12-alkyl; C^-cycloalkyl; cyano; cyanomethyl; perhalomethyl; suifamoyl; C1-6-alkylthio; C^alkylsulfonyl; C1-6-alkylsulfinyl; arylthio, arylsulfinyl,
arylsulfonyl, the aryll group optionally being mono- or polysubstituted with C1-6-alkyl, halogen, hydroxy or C1-6-alkoxy; C^-alkoxycarbonyl-C^-alkyl; carbamylmethyl; carboxy- C^-alkyl: aryloxy; (1 ,2,4-oxadiazol-5-yl)- or (l ^^-oxadiazol-S-y C^-alkyl, the oxadiazolyl group optionally being substituted with C1-6-alkyl or C^-cycloalkyl; acyl; or a 5 - 6 membered nitrogen containing ring, optionally substituted with phenyl or C^-alky!.

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 two hetero atoms selected from nitrogen, oxygen and sulfur, the heterocyclic system optionally being substituted with halogen; C1-12-alkyl; C3.6-cycloalkyl; cyano; cyanomethyl; perhalomethyl; suifamoyl; C1-6-alkylthio; C1-6alkylsulfonyl; C1-6-alkylsulfinyl; arylthio, arylsulfinyl, arylsulfonyl, the aryll group optionally being mono- or polysubstituted with C^-alkyl, halogen, hydroxy or C1-6-alkoxy; C^-alkoxycarbonyl-C s-alkyl; carbamylmethyl; carboxy-C^-alkyl: aryloxy; (1 ,2,4-oxadiazol-5-yl)- or (1,2,4-oxadiazol-3-yl)C1-6-alkyl, the oxadiazolyl group optionally being substituted with C,.6-alkyl or
acyl; or a 5 - 6 membered nitrogen containing ring, optionally substituted with phenyl or C1-6-alkyl.

9. A compound according to any one of the claims 1 - 8, wherein the general formula I is


wherein
R1 and R5 independently are hydrogen; hydroxy; C1-6-alkoxy; or C^-alky!, C^-cycioalkyl, C2.6-alkenyl or C2.6-alkynyl optionally mono- or polysubstituted with halogen and R4 is hydrogen; or

R4 together with R5 represent one of the bonds in a double bond between the atoms 2 and

3 of formula I and R1 is as defined above; or

R4 together with R1 represent one of the bonds in a double bond between the atoms 3 and

4 of formula I and R5 is as defined above;

D represents -S(=O)2- or S(=O)-; and A, R2 and R3 are as defined above.

10. A compound according to claim 9 wherein R1 and R5 independently are hydrogen 5 or C1-6-alkyl.

1 1 . A compound according to claims 9 or 10 wherein R1 together with R4 represent one of the bonds in a double bond between the atoms 3 and 4 of formula I.

10 1 2. A compound according to any one of the claims 9 - 11 , wherein R4 together with R5 represent one of the bonds in a double bond between the atoms 2 and 3 of formula I.

1 3. A compound according to any one of the claims 9 - 12 wherein D is -S(=O)2-.

15 14. A compound according to any one of the claims 1 - 8 wherein the general formula Ms



20

wherein

R1 is hydrogen; hydroxy; C1-6-alkoxy; or C1-6-alkyl, C^-cycloalkyl, C2-6-alkenyl or C2-6- 25 alkynyl optionally mono- or polysubstituted with halogen and R4 is hydrogen; or

R4 together with R1 represent one of the bonds in a double bond between the atoms 3 and 4 of formula I;

D represents -S(=O)R - wherein R7 is C -6-alkyi; or aryl or heteroaryl optionally mono- or polysubstituted with 5 halogen, hydroxy, C1-6-alkoxy, aryloxy, arylalkoxy, nitro, amino, C^e-monoalkyl- or dialkylamino, cyano, acyl or C1-6-alkoxycarbonyl; and

A, R2 and R3 are as defined above.

10 1 5. A compound according to claim 14 wherein R1 is hydrogen or C1-6-alkyl.

1 6. A compound according to claim 14 or 15 wherein R1 together with R4 represent one of the bonds in a double bond between the atoms 3 and 4 of formula I.

15 1 7. A compound according to any one of the claims 14 - 16 wherein R7 is C1-6-alkyl, phenyl or pyridyl.

1 8. A compound according to any one of the claims 1 - 8 wherein the general formula I is
20


25 wherein
R1, R5 and R6 independently are hydrogen; hydroxy; Cj.e-alkoxy; or C1-6-alkyl, C^- cycloalkyl, C2.6-alkenyl or C2-6-alkynyl optionally mono- or polysubstituted with halogen and R4 is hydrogen; or R4 together with R5 represent one of the bonds in a double bond between the atoms 2 and

3 of formula I and R1 and R6 are as defined above; or

5 R4 together with R represent one of the bonds in a double bond between the atoms 3 and

4 of formula I and R5 and R6 are as defined above;

D represents -S(=O)2- or -S(=O)-; and

0 A, R2, R3 are as defined above.

1 9. A compound according to claim 18 wherein R1, R5 and R6 independently are hydrogen or C1-β-alkyl.

15 20. A compound according claim 18 or 19 wherein R1 together with R4 represent one of the bonds in a double bond between the atoms 3 and 4 of formula I.

21 . A compound according to any one of the claims 18 - 20 wherein R4 together with R5 represent one of the bonds in a double bond between the atoms 2 and 3 of formula I.

20
22. A compound according to any one of the claims 18 - 21 wherein D is -S(=O)2-.

23. A compound selected from the following:

25 7-Cyano-3-isopropylamino-6-methyl-4H-thieno[2,3-e]-1 ,2,4-thiadiazine 1 , 1 -dioxide 7-Cyano-6-methyl-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-methylheptyl)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
30 6-Chloro-3-(2-methylbutyl)amino- 4H-thieno[3,2-e]-1 ,2,4-thiadiazine 1 , 1 -dioxide
6-Chloro-3-(1-methylhexyl)amino-4H-thieno[3,2-e]-1 ,2,4-thiadiazine 1 ,1-dioxide
6-Chloro-3-cyclopentylamino-4H-thieno[3,2-e]-1 ,2,4-thiadiazine 1 , 1 -dioxide 6-Chloro-3-cyclohexylmethylamino-4H-thieno[3,2-e]-1 ,2,4-thiadiazine 1 , 1 -dioxide Ethyl 3-(6-chloro-1 ,4-dihydro-1 ,1-dioxothieno[3,2-e]-1λ6,2,4-thiadiazin-3-ylamino)butanoate
3-(6-Chloro-1 ,4-dihydro-1 ,1-dioxothieno[3,2-e]-1λ6,2,4-thiadiazin-3-ylamino)butanoic acid 6-Chloro-3-(3-hydroxy-1-methylpropyl)amino-4H-thieno[3,2-e]-1 ,2,4-thiadiazine 1 ,1-dioxide
(R)-6-Chloro-3-(1 -phenylethyl)amino-4H-thieno[3,2-e]-1 ,2,4-thiadiazine 1 , 1 -dioxide (S)-3-sec-Butylamino-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-isopropyiamino-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-Cyclopentylamino-5,6-dimethyl-4H-thieno[3,2-e]-1 ,2,4-thiadiazine 1 , 1 -dioxide
3-lsopropylamino-6,7-dimethyl-4H-thieno[2,3-e]-1 ,2,4-thiadiazine 1 , 1 -dioxide
3-Cyclobutylamino-6,7-dimethyl-4H-thieno[2,3-e]-1 ,2,4-thiadiazine 1 , 1 -dioxide
3-Cyclopentylamino -6,7-dimethyl-4H-thieno[2,3-e]-1 ,2,4-thiadiazine 1 ,1-dioxide 5-Chloro-3-isopropylamino-4H-thieno[3,2-e]-1 ,2,4-thiadiazine 1 ,1-dioxide
5-Chloro-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-methyl-3-isopropylamino-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-chloro-3-cyclopentylamino-5-methyl-4H-thieno[3,2-e]-1 ,2,4-thiadiazine 1 ,1-dioxide 6-Fluoro-3-propylamino-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-Fluoro-3-propylamino-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-cycIobutylamino-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-Bicyclo[2.2.1]hept-2-ylamino-6-chloro-4H-thieno[3,2-e]-1 ,2,4-thiadiazine 1 ,1- dioxide
(R)-6-Chloro-3-(2-hydroxypropyl)amino-4H-thieno[3,2-e]-1 ,2,4-thiadiazine 1 , 1 -dioxide 6-Bromo-3-isopropylamino-4H-thieno[3,2-e]-1 ,2,4-thiadiazine 1 , 1 -dioxide
5,6-Dibromo-3-isopropylamino-4H-thieno[3,2-e]-1 ,2,4-thiadiazine 1 ,1-dioxide6-Chloro-3-cyclohexylamino-4H-thieno[3,2-e]-1 ,2,4-thiadiazine 1 ,1-dioxide
6-Chloro-3-(furan-2-ylmethyl)amino-4H-thieno[3,2-e]-1 ,2,4-thiadiazine 1 , 1 -dioxide
6-Chloro-3-(1-ethylpropyl)amino-4H-thieno[3,2-e]-1 ,2,4-thiadiazine 1 ,1-dioxide
6-Bromo-3-cyclopentylamino-4H-thieno[3,2-e]-1 ,2,4-thiadiazine 1 , 1 -dioxide
6-Chloro-3-(2-methylallyl)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 KATP-regulated potassium channels.

25. A method of preparing a compound of formula I, characterized in
a) reacting a compound of formula II:


wherein A, B, D, R1 and R4 are as defined above and Z is a leaving group such as alkoxy, alkylthio, halogen, preferentially chloro, bromo, iodo, trimethylamino, or methylsulfonyl with a compound of formula III:

R'
/
HN

RJ
(III)

wherein R and R3 are defined above to form a compound of the general formula

b) reacting a compound of formula IV:

R1


(IV)

wherein R1 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 the compound of formula III, or a suitable salt thereof in the presence of P2O5 and a high boiling tertiary amine or a suitable salt thereof, to form a compound of the general formula I;

c) reacting a compound of the formula IV:


wherein R1 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 III, or a suitable salt 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

NHR

A
S02NH2
(V)

wherein R1 and A are as defined above, with a compound of formula VI

R3NCO (VI)

wherein R3 is as defined above, to form a compound of the general formula I wherein D is SO2, B is >NR5, R2 is H, and R4 and R5 together form a bond;

e) reacting a compound of the formula V

NHR

S02NH2
(V) wherein R1 and A are as defined above, with a compound of formula VII

R3NHC(=O)CI (VII)

wherein R3 is as defined, to form a compound of the general formula I wherein D is SO2, B is >NR5, R2 is H, and R4 and R5 together form a bond;

f) reacting a compound of the formula V

NHR

A
S02NH2
(V)

wherein R1 and A are defined as above, with a compound of formula VIII

H2N- ~NH,
(VIII)

wherein Y is NH or S, or a suitable salt thereof, to form a compound of the general formula I, wherein D is SO2, B is >NR5 , R4 and R5 together form a bond, and R2 and R3 are H;

g) reacting in the presence of a base a compound of formula IX 11
R

A

S NH.
0 o (IX)

or a suitable salt thereof, wherein R11 is R1 or EtOC(=O), wherein R1 and A are defined as above, with a compound of formula X

R3N=C=S (X)

wherein R3 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 R11 is R1 , wherein D is S(=O)2 , B is >NR5 , R2 is H, and R4 and R5 together form a bond, and a compound of the general formula XIII if R11 is EtOC(=O);


h) hydrolyzing and subsequently decarboxylating a compound of the general formula XIII


to form a compound of the general formula I, wherein D is S(=O)2 , B is >NR5 , R1 and R2 are H, and R4 and R5 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

5 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 0 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.

15 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

20 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

25 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

30 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.
5
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
0 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.

15 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 20 treatment or prevention of diseases of the endocrinological system, such as
hyperinsulinaemia and diabetes which process comprising bringing a compound of formula I according to any of the claims 1 - 24 or a pharmaceutically acceptable salt thereof into a galenic dosage form.

25 37. Any novel feature or combination of features as described herein.