1. A compound of formula I (tubulysin):
wherein R, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, S, T, U, V, W, X, Y and Z have the following meanings:
R=H, alkyl, aryl, OR1, NR1R2 or
R1=H, alkyl or aryl
R2=H, alkyl or aryl
S=H, Hal, NO2 or NHR3
U=H, Hal, NO2 or NHR3
R3=H, HCO or alkyl-CO
T=H or OR4
R4=H, alkyl, aryl, COR5, P(O)(OR6)2 or SO3R6
R5=alkyl, alkenyl, aryl or heteroaryl
R6=H, alkyl or a metal ion
V=H, OR7, Hal or (with W=O) O
R7=H, alkyl or COR8
R8=alkyl, alkenyl or aryl
W=H or alkyl or (with V) O
X=H, alkyl, alkenyl or CH2OR9
R9=H, alkyl, alkenyl, aryl or COR10
R10=alkyl, alkenyl, aryl or heteroaryl
Y=(for Z=CH3 or COR11) free electron pair or (for Z=CH3) O
R11=alkyl, CF3 or aryl andor
Z=(for Y=O or free electron pair) CH3 or (for Y=free electron pair) COR11.
2. The compound according to claim 1, wherein
R, R1, R4, R5, R8, R9, R10 andor R11=unsubstituted or substituted phenyl, especially
C1-4alkyl-substituted phenyl
R5=C1-4alkyl, C2-6alkenyl or pyridyl
R5 andor X=C2-4alkenyl
R6=an alkali metal ion, especially the Na ion, or an alkaline earth metal ion
R8 andor R9=C2-4alkenyl andor
R10=C2-6alkenyl, especially C2-4alkenyl, or pyridyl.
3. A process for the preparation of a compound of formula I (type 7)
wherein R, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, S, T, U, V, W, X, Y and Z have the following meanings:
R=H, alkyl, aryl, OR1, NR1R2 or
R1=H, alkyl or aryl
R2=H, alkyl or aryl
S=H, Hal, NO2 or NHR3
U=H, Hal, NO2 or NHR3
R3=H, HCO or alkyl-CO
T=H or OR4
R4=H, alkyl, aryl, COR5, P(O)(OR6), or SO3R6
R5=alkyl, alkenyl, aryl or heteroaryl
R6=H, alkyl or a metal ion
V=H, OR7, Hal or (with W=O) O
R7=H, alkyl or COR8
R=alkyl, alkenyl or aryl
W=H or alkyl or (with V) O
X=H alkyl alkenyl or CH2OR9
R9=H alkyl alkenyl, aryl or COR10
R10=alkyl alkenyl, aryl or heteroaryl
Y=(for Z=CH3 or COR11) free electron pair or (for Z=CH3) O
R11=alkyl, CF3 or aryl andor
Z=(for Y=O or free electron pair) CH3 or (for Y=free electron pair) COR11
wherein R=OR1, R1=H, S=U=H, T=H or OH, V=OR7, R7=COR8, R8=alkyl, preferably C1-4alkyl, especially methyl, W=H, X=CH2OR9, R9=H, Y=free electron pair and Z=CH3, wherein a compound of formula II (type 1, 2, 3, 4, 5 or 6):
wherein X=CH2OR9, R9=COR10, R10=alkyl, especially Cl 6alkyl, and which otherwise has the meanings indicated above is subjected to ester cleavage in an acidic medium, thereby preparing the compound of the general formula I having the indicated meanings is obtained.
4. The process according to claim 3, wherein the ester cleavage is carried out in an organic solvent, especially dioxane, in the presence of an acid, especially hydrogen chloride, andor at elevated temperature.
5. A process for the preparation of a compound of formula I (type 8)
wherein R, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, S, T, U, V, W, X, Y and Z have the following meanings:
R=H, alkyl aryl OR1, NR1R2 or
R1=H, alkyl or aryl
R2=H, alkyl or aryl
S=H Hal, NO2 or NHR3
U=H Hal, NO2 or NHR3
R3=H, HCO or alkyl-CO
T=H or OR4
R4=H, alkyl, aryl, COR5, P(O)(OR6)2 or SO3R6
R5=alkyl, alkenyl, aryl or heteroaryl
R6=H, alkyl or a metal ion
V=H, OR7 Hal or (with W=O) O
R7=H alkyl or COR8
R8=alkyl alkenyl or aryl
W=H or alkyl or (with V) O
X=H alkyl alkenyl or CH2OR9
R9=H alkyl, alkenyl, aryl or COR10
R10=alkyl, alkenyl, aryl or heteroaryl
Y=(for Z=CH3 or COR11) free electron pair or (for Z=CH3) O
R11=alkyl, CF3 or aryl andor
Z=(for Y=O or free electron pair) CH3 or (for Y=free electron pair) COR11
wherein R=OR1, R1=H, S=U=H, T=H or OH, V=OR7, R7=COR8, R8=alkyl, preferably C1-4alkyl, especially methyl, W=H, X=H, Y=free electron pair and Z=CH3, wherein a compound of formula II (type 1, 2, 3, 4, 5 or 6)
wherein X=CH2OR9, R9=COR10, R10=alkyl, preferably C1-6alkyl, and which otherwise has the meanings indicated above is subjected to acetal cleavage thereby preparing the compound of formula I having the indicated meanings.
6. The process according to claim 5, wherein the acetal cleavage is carried out in an acidic medium, especially in the presence of hydrochloric acid, andor at elevated temperature.
7. A process for the preparation of a compound of formula I (type 9)
wherein R, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, S, T, U, V, W, X, Y and Z have the following meanings:
R=H, alkyl, aryl, OR1, NR1R2 or
R1=H, alkyl or aryl
R2=H, alkyl or aryl
S=H, Hal, NO2 or NHR3
U=H, Hal, NO2 or NHR3
R3=H, HCO or alkyl-CO
T=H or OR4
R4=H, alkyl aryl COR5, P(O)(OR6)2 or SO3R6
R5=alkyl, alkenyl, aryl or heteroaryl
R6=H, alkyl or a metal ion
V=H, OR7, Hal or (with W=O) O
R7=H, alkyl or COR8
R8=alkyl, alkenyl or aryl
W=H or alkyl or (with V) O
X=H alkyl, alkenyl or CH2OR9
R9=H, alkyl, alkenyl, aryl or COR10
R10=alkyl, alkenyl, aryl or heteroaryl
Y=(for Z=CH3 or COR11) free electron pair or (for Z=CH3) O
R11=alkyl, CF3 or aryl andor
Z=(for Y=O or free electron pair) CH3 or (for Y=free electron pair) COR11
wherein R=OR1, R1=H, S=U=H, T=H or OH, V=OR7, R7=H, W=H, X=CH2OR9, R9=COR10, R10=alkyl, especially C1-6alkyl, Y=free electron pair and Z=CH3, wherein a compound of formula II (type 1, 2, 3, 4, 5 or 6)
wherein V=OR7, R7=COR8, R8=alkyl, preferably C1-4alkyl, especially methyl, and which otherwise has the meanings indicated above is subjected to ester cleavage in a weakly alkaline medium, thereby preparing the compound of formula I having the indicated meanings.
8. The process according to claim 7, wherein the ester cleavage is carried out in an organic medium, especially a hydrophilic organic solvent, preferably an alcohol, especially methanol, in the presence of a weak base, especially NH3.
9. A process for the preparation of a compound of the general formula I (type 10)
wherein R, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, S, T, U, V, W, X, Y and Z have the following meanings:
R=H, alkyl, aryl, OR1, NR1R2 or
R1=H, alkyl or aryl
R2=H, alkyl or aryl
S=H, Hal, NO2 or NHR3
U=H, Hal, NO2 or NHR3
R3=H, HCO or alkyl-CO
T=H or OR4
R4=H, alkyl, aryl, COR5, P(O)(OR6)2 or SO3R6
R5=alkyl, alkenyl, aryl or heteroaryl
R6=H, alkyl or a metal ion
V=H, OR7, Hal or (with W=O) O
R7=H, alkyl or COR8
R8=alkyl, alkenyl or aryl
W=H or alkyl or (with V) O
X=H, alkyl, alkenyl or CH2OR9
R9=H, alkyl, alkenyl, aryl or COR10
R10=alkyl, alkenyl, aryl or heteroaryl
Y=(for Z=CH3 or COR11) free electron pair or (for Z=CH3) O
R11=alkyl, CF3 or aryl andor
Z=(for Y=O or free electron pair) CH3 or (for Y=free electron pair) COR11
wherein R=OR1, R1=H, S=U=H, T=H or OH, V=OR7, R7=H, W=H, X=H, Y=free electron pair and Z=CH3, wherein a compound of the general formula II (type 1, 2, 3, 4, 5 or 6)
wherein V=OR7, R7=COR8, R8=alkyl, preferably C1-4alkyl, especially methyl, X=CH2OR9, R9=COR10, R10=alkyl, especially C1-6alkyl, and which otherwise has the meanings indicated above is subjected to double ester cleavage in a strongly alkaline medium, thereby preparing the compound of formula I having the indicated meanings.
10. The process according to claim 9, wherein the double ester cleavage is carried out in an organic medium, especially in a hydrophilic organic solvent, preferably an alcohol, especially methanol, in the presence of a strong base, especially an alkali metal hydroxide, preferably sodium hydroxide.
11. A process for the preparation of a compound of formula III (type 11)
wherein R=OR1, R1=H, S=U=H, T=H or OR4, R4=H, V with X=CH2O bridge, W=H, Y=free electron pair and Z=CH3 in the general formula according to claim 1, wherein a compound of the general formula II (type 1, 2, 3, 4, 5 or 6)
wherein X=CH2OR9, R9=COR10, R10=alkyl, especially C1-6alkyl, V=OR7, R7=COR8, R8=alkyl, preferably C1-4alkyl, especially methyl, and which otherwise has the meanings indicated above is subjected to ring formation with double ester cleavage in an acidic medium, thereby preparing the compound of formula III having the indicated meanings.
12. The process according to claim 11, wherein the ring formation is carried out in an aqueous medium, in the presence of an inorganic acid, preferably hydrochloric acid, and with heating.
13. A process for the preparation of a compound of formula I (type 12)
wherein R, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, S, T, U, V, W, X, Y and Z have the following meanings:
R=H, alkyl, aryl, OR1, NR1R2 or
R1=H, alkyl or aryl
R2=H, alkyl or aryl
S=H, Hal, NO2 or NHR3
U=H, Hal, NO2 or NHR3
R3=H, HCO or alkyl-CO
T=H or OR4
R4=H, alkyl, aryl, COR5, P(O)(OR6)2 or SO3R6
R5=alkyl, alkenyl, aryl or heteroaryl
R6=H, alkyl or a metal ion
V=H, OR7, Hal or (with W=O) O
R7=H, alkyl or COR8
R8=alkyl, alkenyl or aryl
W=H or alkyl or (with V) O
X=H, alkyl, alkenyl or CH2OR9
R9=H, alkyl, alkenyl, aryl or COR10
R10=alkyl, alkenyl, aryl or heteroaryl
Y=(for Z=CH3 or COR11) free electron pair or (for Z=CH3) O
R11=alkyl, CF3 or aryl andor
Z=(for Y=O or free electron pair) CH3 or (for Y=free electron pair) COR11
wherein R=OR1, R1=H, S=U=H, T=H or OR4, R4=COR5, R5=alkyl, especially C1-6alkyl, alkenyl, especially C2-6alkenyl, aryl or heteroaryl, V=OR7, R7=COR8, R8=alkyl, preferably C1-4alkyl, especially methyl, W=H, X=CH2OR9, R9=COR10, R10=R5, Y=free electron pair and Z=CH3, wherein a compound of formula IV (type 7):
wherein X=CH2OR9, R9=H and which otherwise has the meanings indicated above is subjected to acylation, thereby preparing the compound of formula I having the indicated meanings.
14. The process according to claim 13, wherein the acylation is carried out using an acyl halide, especially an acyl chloride, andor in the presence of a weak base, especially a weak organic base, preferably a tertiary amine, especially triethylamine.
15. A process for the preparation of a compound of formula I (type 13)
wherein R, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, S, T, U, V, W, X, Y and Z have the following meanings:
R=H, alkyl, aryl, OR1, NR1R2 or
R1=H, alkyl or aryl
R2=H, alkyl or aryl
S=H, Hal, NO2 or NHR3
U=H, Hal, NO2 or NHR3
R3=H, HCO or alkyl-CO
T=H or OR4
R4=H, alkyl, aryl, COR5, P(O)(OR6)2 or SO3R6
R5=alkyl, alkenyl, aryl or heteroaryl
R6=H, alkyl or a metal ion
V=H, OR7, Hal or (with W=O) O
R7=H, alkyl or COR8
R8=alkyl, alkenyl or aryl
W=H or alkyl or (with V) O
X=H, alkyl, alkenyl or CH2OR9
R9=H, alkyl, alkenyl, aryl or COR10
R10=alkyl, alkenyl, aryl or heteroaryl
Y=(for Z=CH3 or COR11) free electron pair or (for Z=CH3) O
R11=alkyl, CF3 or aryl andor
Z=(for Y=O or free electron pair) CH3 or (for Y=free electron pair) COR11
wherein R=OR1, R1=H, S=U=H, T=H or OR4, R4=H, V=OR7, R7=COR8, R8=alkyl, preferably C1-4alkyl, especially methyl, W H, X=CH2OR9, R9=COR10, R10=alkyl, especially C1-6alkyl, alkenyl, especially C2-6alkenyl, aryl or heteroaryl, Y=free electron pair and Z=CH3, wherein hydrolysis is carried out in an alkaline medium on the compound of Formula I wherein T=OR4, R4=COR5 and R5=alkyl, especially C1-6alkyl, alkenyl, especially C2-6alkenyl, aryl or heteroaryl and which otherwise has the meanings indicated above, thereby preparing a compound of formula I having the indicated meanings.
16. The process according to claim 15, wherein the hydrolysis is carried out using ammonia.
17. A process for the preparation of a compound of formula I (type 14)
wherein R, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, S, T, U, V, W, X, Y and Z have the following meanings:
R=H, alkyl, aryl, OR1, NR1R2 or
R1=H, alkyl or aryl
R2=H, alkyl or aryl
S=H, Hal, NO2 or NHR3
U=H, Hal, NO2 or NHR3
R3=H, HCO or alkyl-CO
T=H or OR4
R4=H, alkyl, aryl, COR5, P(O)(OR6)2 or SO3R6
R5=alkyl, alkenyl, aryl or heteroaryl
R6=H, alkyl or a metal ion
V=H, OR7, Hal or (with W=O) O
R7=H, alkyl or COR8
R8=alkyl, alkenyl or aryl
W=H or alkyl or (with V) O
X=H, alkyl, alkenyl or CH2OR9
R9=H, alkyl, alkenyl, aryl or COR10
R10=alkyl, alkenyl, aryl or heteroaryl
Y=(for Z=CH3 or COR11) free electron pair or (for Z=CH3) O
R11=alkyl, CF3 or aryl andor
Z=(for Y=O or free electron pair) CH3 or (for Y=free electron pair) COR11
wherein R=OR1, R1=H, S=U=H, T=H or OH, V=OR7, R7=COR8, R8=alkyl, preferably C1-4alkyl, especially methyl, W=H, X=CH2OR9, R9=alkyl, especially C1-4alkyl, alkenyl or aryl, Y=free electron pair and Z=CH3, wherein a starting compound of formula II (type 1, 2, 3, 4, 5 or 6)
is subjected to ester cleavage and is alkylated, thereby preparing the compound of formula I having the indicated meanings.
18. The process according to claim 17, wherein the reaction is carried out using an alkylating agent of formula R9OH wherein R9=alkyl, especially C1-4alkyl, alkenyl or aryl.
19. The process according to claim 17, wherein the reaction is carried out in the presence of p-CH3-C6H4SO2OH in tetrahydrofuran (THF) at elevated temperature.
20. A Process for the preparation of a compound of formula I (type 15)
wherein R, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, S, T, U, V, W, X, Y and Z have the following meanings:
R=H, alkyl, aryl, OR1, NR1R2 or
R1=H, alkyl or aryl
R2=H, alkyl or aryl
S=H, Hal, NO2 or NHR3
U=H, Hal, NO2 or NHR3
R3=H, HCO or alkyl-CO
T=H or OR4
R4=H, alkyl, aryl, COR5, P(O)(OR6)2 or SO3R6
R5=alkyl, alkenyl, aryl or heteroaryl
R6=H, alkyl or a metal ion
V=H, OR7, Hal or (with W=O) O
R7=H, alkyl or COR8
R8=alkyl, alkenyl or aryl
W=H or alkyl or (with V) O
X=H, alkyl, alkenyl or CH2OR9
R9=H, alkyl, alkenyl, aryl or COR10
R10=alkyl, alkenyl, aryl or heteroaryl
Y=(for Z=CH3 or COR11) free electron pair or (for Z=CH3) O
R11=alkyl, CF3 or aryl andor
Z=(for Y=O or free electron pair) CH3 or (for Y=free electron pair) COR11
wherein R=OR1, R1=H, S=U=H, T=H or OR4, R4=HV=OR7, R7=H or COR8, R8=alkyl, preferably C1-4alkyl, especially methyl, W=H, X=CH3, Y=free electron pair and Z=CH3, wherein a compound of Formula I (type 7) wherein X=CH2, OR9, R9=H and which otherwise has the meanings indicated above is subjected to reduction, thereby preparing the compound of formula I having the indicated meanings.
21. The process according to claim 20, wherein the reduction is carried out using NaCNBH3 and trifluoroacetic acid in methanol (MeOH).
22. A process for the preparation of a compound of formula I (type 15)
wherein R, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, S, T, U, V, W, X, Y and Z have the following meanings:
R=H, alkyl, aryl, OR1, NR1R2 or
R1=H, alkyl or aryl
R2=H, alkyl or aryl
S=H, Hal, NO2 or NHR3
U=H, Hal, NO2 or NHR3
R3=H, HCO or alkyl-CO
T=H or OR4
R4=H, alkyl, aryl, COR5, P(O)(OR6)2 or SO3R6
R5=alkyl, alkenyl, aryl or heteroaryl
R6=H, alkyl or a metal ion
V=H, OR7, Hal or (with W=O) O
R7=H, alkyl or COR8
R8=alkyl, alkenyl or aryl
W=H or alkyl or (with V) O
X=H, alkyl, alkenyl or CH2OR9
R9=H, alkyl, alkenyl, aryl or COR10
R10=alkyl, alkenyl, aryl or heteroaryl
Y=(for Z=CH3 or COR11) free electron pair or (for Z=CH3) O
R11=alkyl, CF3 or aryl andor
Z=(for Y=O or free electron pair) CH3 or (for Y=free electron pair) COR11
wherein R=OR1, R1=H, S=U=H, T=H or OR4, R4=H V=OR7, R7=H or COR8, R8=alkyl, especially C1-4alkyl, especially methyl, W=H, X=CH3, Y=free electron pair and Z=CH3, wherein a compound of formula III (type 11)
is subjected to ring opening with reduction or to reduction with ring opening, thereby preparing the compound of formula I having the indicated meanings.
23. The process according to claim 22, wherein the reaction is carried out in the presence of NaCNBH3 and Me3SiCl in acetonitrile (CH3CN).
24. A process for the preparation of a compound of formula I (type 16)
wherein R, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, S, T, U, V, W, X, Y and Z have the following meanings:
R=H, alkyl, aryl, OR1, NR1R2 or
R1=H, alkyl or aryl
R2=H, alkyl or aryl
S=H, Hal, NO2 or NHR3
U=H, Hal, NO2 or NHR3
R3=H, HCO or alkyl-CO
T=H or OR4
R4=H, alkyl, aryl, COR5, P(O)(OR6)2 or SO3R6
R5=alkyl, alkenyl, aryl or heteroaryl
R6=H, alkyl or a metal ion
V=H, OR7, Hal or (with W=O) O
R7=H, alkyl or COR8
R8=alkyl, alkenyl or aryl
W=H or alkyl or (with V) O
X=H, alkyl, alkenyl or CH2OR9
R9=H, alkyl, alkenyl, aryl or COR10
R10=alkyl, alkenyl, aryl or heteroaryl
Y=(for Z=CH3 or COR11) free electron pair or (for Z=CH3) O
R11=alkyl, CF3 or aryl andor
Z=(for Y=O or free electron pair) CH3 or (for Y=free electron pair) COR11
wherein R=OR1, R1=H, S=U=H, T=H or OH, V=OR7, R7=COR8, R8=alkyl, especially C1-4alkyl, alkenyl or aryl, W=H, X=CH2, OR9, R9=COR10, R10=alkyl, especially C1-6alkyl, or alkenyl, Y=free electron pair and Z=CH3, wherein the compound of Formula I (type 9) wherein V=OR7 and R7=H and which otherwise has the meanings indicated above is subjected to acylation, thereby preparing the compound of formula I having the indicated meanings.
25. The process according to claim 24, wherein the acylation is carried out using an acyl halide of formula R8COCI wherein R8=alkyl, especially C1-4alkyl, alkenyl or aryl, especially an acyl chloride, andor in the presence of a base, especially an organic base, preferably a trialkylamine, especially triethylamine.
26. A process for the preparation of a compound of formula I (type 17)
wherein R, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, S, T, U, V, W, X, Y and Z have the following meanings:
R=H, alkyl, aryl, OR1, NR1R2 or
R1=H, alkyl or aryl
R2=H, alkyl or aryl
S=H, Hal, NO2 or NHR3
U=H, Hal, NO2 or NHR3
R3=H, HCO or alkyl-CO
T=H or OR4
R4=H, alkyl, aryl, COR5, P(O)(OR6)2 or SO3R6
R5=alkyl, alkenyl, aryl or heteroaryl
R6=H, alkyl or a metal ion
V=H, OR7, Hal or (with W=O) O
R7=H, alkyl or COR8
R8=alkyl, alkenyl or aryl
W=H or alkyl or (with V) O
X=H, alkyl, alkenyl or CH2OR9
R9=H, alkyl, alkenyl, aryl or COR10
R10=alkyl, alkenyl, aryl or heteroaryl
Y=(for Z=CH3 or COR11) free electron pair or (for Z=CH3) O
R11=alkyl, CF3 or aryl andor
Z=(for Y=O or free electron pair) CH3 or (for Y=free electron pair) COR11
wherein R=OR1, R1=H, S=U=H, T=H or OR4, R4=H, V=H or F, W=H, X=CH2OR9, R9=COR10, R10=alkyl, especially C1-6alkyl, or alkenyl, Y=free electron pair and Z=CH3, wherein the compound of Formula I (type 9) wherein V=OR7 and R7=H and which otherwise has the meanings indicated above is subjected to catalytic hydrogenation or fluorination, thereby preparing the compound of formula I having the indicated meanings.
27. The process according to claim 26, wherein, for V=H, the hydrogenation is carried out using palladium-on-carbon in the presence of acetic acid and, for V=F, the fluorination is carried out using DAST in tetrahydrofuran.
28. A process for the preparation of a compound of formula (type 18)
wherein R, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, S, T, U, V, W, X, Y and Z have the following meanings:
R=H, alkyl, aryl, OR1, NR1R2 or
R1=H, alkyl or aryl
R2=H, alkyl or aryl
S=H, Hal, NO2 or NHR3
U=H, Hal, NO2 or NHR3
R3=H, HCO or alkyl-CO
T=H or OR4
R4=H, alkyl, aryl, COR5, P(O)(OR6)2 or SO3R6
R5=alkyl, alkenyl, aryl or heteroaryl
R6=H, alkyl or a metal ion
V=H, OR7, Hal or (with W=O) O
R7=H, alkyl or COR8
R8=alkyl, alkenyl or aryl
W=H or alkyl or (with V) O
X=H, alkyl, alkenyl or CH2OR9
R9=H, alkyl, alkenyl, aryl or COR10
R10=alkyl, alkenyl, aryl or heteroaryl
Y=(for Z=CH3 or COR11) free electron pair or (for Z=CH3) O
R11=alkyl, CF3 or aryl andor
Z=(for Y=O or free electron pair) CH3 or (for Y=free electron pair) COR11
wherein R=OR1, R1=H, S=U=H, T=H or OR4, R4=H, V with W=O, X=CH2OR9, R9=COR10, R10=alkyl, especially C1-6alkyl, or alkenyl, Y=free electron pair and Z=CH3, wherein the compound of Formula I (type 9) wherein V=OR7 and R7=H and which otherwise has the meanings indicated above is subjected to oxidation with formation of a ketones, thereby preparing a the compound of formula I having the indicated meanings.
29. The process according to claim 28, wherein the oxidation is carried out in the presence of TPAP and NMO in dichloromethane.
30. A process for the preparation of a compound of formula I (type 19)
wherein R, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, S, T, U, V, W, X, Y and Z have the following meanings:
R=H, alkyl, aryl, OR1, NR1R2 or
R1=H, alkyl or aryl
R2=H, alkyl or aryl
S=H, Hal, NO2 or NHR3
U=H, Hal, NO2 or NHR3
R3=H, HCO or alkyl-CO
T=H or OR4
R4=H, alkyl, aryl, COR5, P(O)(OR6)2 or SO3R6
R5=alkyl, alkenyl, aryl or heteroaryl
R6=H, alkyl or a metal ion
V=H, OR7, Hal or (with W=O) O
R7=H, alkyl or COR8
R8=alkyl, alkenyl or aryl
W=H or alkyl or (with V) O
X=H, alkyl, alkenyl or CH2OR9
R9=H, alkyl, alkenyl, aryl or COR10
R10=alkyl, alkenyl, aryl or heteroaryl
Y=(for Z=CH3 or COR11) free electron pair or (for Z=CH3) O
R11=alkyl, CF3 or aryl andor
Z=(for Y=O or free electron pair) CH3 or (for Y=free electron pair) COR11
wherein R=OR1, R1=H, S=U=H, T=H or OH, V=OR7, R7=H, W=alkyl, especially C1-4alkyl, X=CH2OR9, R9=COR10, R10=alkyl, especially C1-6alkyl, or alkenyl, Y=free electron pair and Z=CH3, wherein the compound of Formula I (type 18) is reacted with a Grignard compound to form the compound of formula I having the indicated meanings.
31. The process according to claim 30, wherein the reaction is carried out using an organomagnesium compound of formula WMgHaI wherein W=alkyl and especially C1-4alkyl.
32. A process for the preparation of a compound of formula I (type 19)
wherein R, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, S, T, U, V, W, X, Y and Z have the following meanings:
R=H, alkyl, aryl, OR1, NR1R2 or
R1=H, alkyl or aryl
R2=H, alkyl or aryl
S=H, Hal, NO2 or NHR3
U=H, Hal, NO2 or NHR3
R3=H, HCO or alkyl-CO
T=H or OR4
R4=H, alkyl, aryl, COR5, P(O)(OR6)2 or SO3R6
R5=alkyl, alkenyl, aryl or heteroaryl
R6=H, alkyl or a metal ion
V=H, OR7, Hal or (with W=O) O
R7=H, alkyl or COR8
R8=alkyl, alkenyl or aryl
W=H or alkyl or (with V) O
X=H, alkyl, alkenyl or CH2OR9
R9=H, alkyl, alkenyl, aryl or COR10
R10=alkyl, alkenyl, aryl or heteroaryl
Y=(for Z=CH3 or COR11) free electron pair or (for Z=CH3) O
R11=alkyl, CF3 or aryl andor
Z=(for Y=O or free electron pair) CH3 or (for Y=free electron pair) COR11
wherein R=OR1, R1=H, S=U=H, T=H or OH, V=OR7, R7=H, W=alkyl and especially C1-4alkyl, X=CH2OR9, R9=COR10, R10=alkyl, especially C1-6alkyl, or alkenyl, Y=free electron pair and Z=CH3, wherein
(i) in a first step a process according to claim 28 is carried out and then
(ii) in a second step a process according to claim 30 is carried out, thereby preparing the compound of formula I having the indicated meanings.
33. A process for the preparation of a compound of formula I (type 20)
wherein R, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, S, T, U, V, W, X, Y and Z have the following meanings:
R=H, alkyl, aryl, OR1, NR1R2 or
R1=H, alkyl or aryl
R2=H, alkyl or aryl
S=H, Hal, NO2 or NHR3
U=H, Hal, NO2 or NHR3
R3=H, HCO or alkyl-CO
T=H or OR4
R4=H, alkyl, aryl, COR5, P(O)(OR6)2 or SO3R6
R5=alkyl, alkenyl, aryl or heteroaryl
R6=H, alkyl or a metal ion
V=H, OR7, Hal or (with W=O) O
R7=H, alkyl or COR8
R8=alkyl, alkenyl or aryl
W=H or alkyl or (with V) O
X=H, alkyl, alkenyl or CH2OR9
R9=H, alkyl, alkenyl, aryl or COR10
R10=alkyl, alkenyl, aryl or heteroaryl
Y=(for Z=CH3 or COR11) free electron pair or (for Z=CH3) O
R11=alkyl, CF3 or aryl andor
Z=(for Y=O or free electron pair) CH3 or (for Y=free electron pair) COR11
wherein R=OR1, R1=alkyl, especially C1-4alkyl, or alkenyl, S=U=H, T=H or OR4, R4=H, V=OR7, R7=COR8, R8=alkyl, preferably C1-4alkyl, especially methyl, W=H, X=CH2OR9, R9=COR10, R10=alkyl, especially C2-6alkyl, alkenyl, especially C2-6alkenyl, aryl or heteroaryl, Y=free electron pair and Z=CH3, wherein a compound of Formula II (type 1, 2, 3, 4, 5 or 6)
or the compound of Formula I (type 13) is subjected to alkylation or alkenylation, thereby preparing the compound of formula I having the indicated meanings.
34. The process according to claim 33, wherein the alkylation or alkenylation is carried out in the presence of EDC, R1OH wherein R1=alkyl, especially C1-4alkyl, or alkenyl, and DMAP in methylene chloride.
35. A process for the preparation of a compound of formula I (type 21)
wherein R, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, S, T, U, V, W, X, Y and Z have the following meanings:
R=H, alkyl, aryl, OR1, NR1R2 or
R1=H, alkyl or aryl
R2=H, alkyl or aryl
S=H, Hal, NO2 or NHR3
U=H, Hal, NO2 or NHR3
R3=H, HCO or alkyl-CO
T=H or OR4
R4=H, alkyl, aryl, COR5, P(O)(OR6)2 or SO3R6
R5=alkyl, alkenyl, aryl or heteroaryl
R6=H, alkyl or a metal ion
V=H, OR7, Hal or (with W=O) O
R7=H, alkyl or COR8
R8=alkyl, alkenyl or aryl
W=H or alkyl or (with V) O
X=H, alkyl, alkenyl or CH2OR9
R9=H, alkyl, alkenyl, aryl or COR10
R10=alkyl, alkenyl, aryl or heteroaryl
Y=(for Z=CH3 or COR11) free electron pair or (for Z=CH3) O
R11=alkyl, CF3 or aryl andor
Z=(for Y=O or free electron pair) CH3 or (for Y=free electron pair) COR11
wherein R=NHR1, NH-NR1R2, NHOR1 or NH((CH2)2-4NR1R2, R1 and R2, each independently of the other=H, alkyl, especially C1-6alkyl, or aryl, S=U=H, T=H or OR4, R4=H, V=OR7, R7=COR8, R8=alkyl, preferably C1-4alkyl, especially methyl, W=H, X=CH2OR9, R9=COR10, R10=alkyl, especially C1-6alkyl, alkenyl, especially C2-6alkenyl, aryl or heteroaryl, Y=free electron pair and Z=CH3, wherein a compound of Formula II (type 1, 2, 3, 4, 5 or 6)
or the compound of Formula I (type 13) is subjected to amination using a compound of formula RH, R having the indicated meanings, thereby preparing the compound of formula I having the indicated meanings.
36. The process according to claim 35, wherein the reaction is carried out
(i) in the presence of EDC in methylene chloride or
(ii) in the presence of isobutyl chloroformate and triethylamine in THF.
37. A process for the preparation of a compound of formula (type 22)
wherein R, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, S, T, U, V, W, X, Y and Z have the following meanings:
R=H, alkyl, aryl, OR1, NR1R2 or
R1=H, alkyl or aryl
R2=H, alkyl or aryl
S=H, Hal, NO2 or NHR3
U=H, Hal, NO2 or NHR3
R3=H, HCO or alkyl-CO
T=H or OR4
R4=H, alkyl, aryl, COR5, P(O)(OR6)2 or SO3R6
R5=alkyl, alkenyl, aryl or heteroaryl
R6=H, alkyl or a metal ion
V=H, OR7, Hal or (with W=O) O
R7=H, alkyl or COR8
R8=alkyl, alkenyl or aryl
W=H or alkyl or (with V) O
X=H, alkyl, alkenyl or CH2OR9
R9=H, alkyl, alkenyl, aryl or COR10
R10=alkyl, alkenyl, aryl or heteroaryl
Y=(for Z=CH3 or COR11) free electron pair or (for Z=CH3) O
R11=alkyl, CF3 or aryl andor
Z=(for Y=O or free electron pair) CH3 or (for Y=free electron pair) COR11
wherein R=alkyl, especially C1-4alkyl, or alkenyl, S=U=H, T=H or OR4, R4=H, V=OR7, R7=COR8, R8=alkyl, preferably C1-4alkyl, especially methyl, W=H, X=CH2OR9, R9=COR10, R10=alkyl, especially C1-6alkyl, alkenyl, especially C2-6alkenyl, aryl or heteroaryl, Y=free electron pair and Z=CH3, wherein a compound of Formula II (type 1, 2 3, 4, 5 or 6)
or the compound of Formula I (type 13) is reacted with an organolithium compound of formula RLi having the indicated meaning for R, thereby preparing the compound of formula I having the indicated meanings.
38. A process for the preparation of a compound of formula I (type 23)
wherein R, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, S, T, U, V, W, X, Y and Z have the following meanings:
R=H, alkyl, aryl, OR1, NR1R2 or
R1=H, alkyl or aryl
R2=H, alkyl or aryl
S=H, Hal, NO2 or NHR3
U=H, Hal, NO2 or NHR3
R3=H, HCO or alkyl-CO
T=H or OR4
R4=H, alkyl, aryl, COR5, P(O)(OR6)2 or SO3R6
R5=alkyl, alkenyl, aryl or heteroaryl
R6=H, alkyl or a metal ion
V=H, OR7, Hal or (with W=O) O
R7=H, alkyl or COR8
R8=alkyl, alkenyl or aryl
W=H or alkyl or (with V) O
X=H, alkyl, alkenyl or CH2OR9
R9=H, alkyl, alkenyl, aryl or COR10
R10=alkyl, alkenyl, aryl or heteroaryl
Y=(for Z=CH3 or COR11) free electron pair or (for Z=CH3) O
R11=alkyl, CF3 or aryl andor
Z=(for Y=O or free electron pair) CH3 or (for Y=free electron pair) COR11
wherein R=amino radical of 1-(2-amino-C2-4alkyl)-pyrrole -2, 5-dione, S=U=H, T=H or OR4, R4=H, V=OR7, R7=COR8, R8=alkyl, preferably C1-4alkyl, especially methyl, W=H, X=CH2OR9, R9=COR10, R10=alkyl, especially C1-6alkyl, alkenyl, especially C2-6alkenyl, aryl or heteroaryl, Y=free electron pair and Z=CH3, wherein a compound of Formula II (type 1, 2, 3, 4, 5 or 6)
or the compound of Formula I (type 13) is subjected to amination using 1-(2-amino-C2-4alkyl)-pyrrole-2,5-dione, thereby preparing the compound of formula I having the indicated meanings.
39. The process according to claim 38, wherein the amination is carried out in the presence of EDC in methylene chloride.
40. A process for the preparation of a compound of formula I (type 24)
wherein R, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, S, T, U, V, W, X, Y and Z have the following meanings:
R=H, alkyl, aryl, OR1, NR1R2 or
R1=H, alkyl or aryl
R2=H, alkyl or aryl
S=H, Hal, NO2 or NHR3
U=H, Hal, NO2 or NHR3
R3=H, HCO or alkyl-CO
T=H or OR4
R4=H, alkyl, aryl, COR5, P(O)(OR6)2 or SO3R6
R5=alkyl, alkenyl, aryl or heteroaryl
R6=H, alkyl or a metal ion
V=H, OR7, Hal or (with W=O) O
R7=H, alkyl or COR8
R8=alkyl, alkenyl or aryl
W=H or alkyl or (with V) O
X=H, alkyl, alkenyl or CH2OR9
R9=H, alkyl, alkenyl, aryl or COR10
R10=alkyl, alkenyl, aryl or heteroaryl
Y=(for Z=CH3 or COR11) free electron pair or (for Z=CH3) O
R11=alkyl, CF3 or aryl andor
Z=(for Y=O or free electron pair) CH3 or (for Y=free electron pair) COR11
wherein R=OR1, R1=H, S=U=H, T=OR4, R4=P(O)(OR6)2 wherein R6=H or alkyl, especially C1-4alkyl, or R4=SO3R6 wherein R6=H. V=OR7, R7=COR8, R8=alkyl, preferably C1-4alkyl, especially methyl, W=H X==CH2OR9, R9=COR10, R10=alkyl, especially C1-6alkyl, alkenyl, especially C2-6alkenyl, aryl or heteroaryl, Y=free electron pair and Z=CH3, wherein
(i) a compound of Formula II (type 1, 2 or 3)
or
(ii) the compound of Formula I (type 13) is reacted with
(a) a compound of formula P(O)(OR6)2OH wherein R6=H or alkyl, especially C1-4alkyl, or
(b) SO3
thereby preparing the compound of formula I having the indicated meanings.
41. The process according to claim 40, wherein the variant (a) is carried out in the presence of I2 and pyridine in methylene chloride.
42. The process according to claim 40, wherein the variant (b) is carried out using pyridine SO3.
43. A process for the preparation of a compound of formula I (type 25)
wherein R, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, S, T, U, V, W, X, Y and Z have the following meanings:
R=H, alkyl, aryl, OR1, NR1R2 or
R1=H, alkyl or aryl
R2=H, alkyl or aryl
S=H, Hal, NO2 or NHR3
U=H, Hal, NO2 or NHR3
R3=H, HCO or alkyl-CO
T=H or OR4
R4=H, alkyl, aryl, COR5, P(O)(OR6)2 or SO3R6
R5=alkyl, alkenyl, aryl or heteroaryl
R6=H, alkyl or a metal ion
V=H, OR7, Hal or (with W=O) O
R7=H, alkyl or COR8
R8=alkyl, alkenyl or aryl
W=H or alkyl or (with V) O
X=H, alkyl, alkenyl or CH2OR9
R9=H, alkyl, alkenyl, aryl or COR10
R10=alkyl, alkenyl, aryl or heteroaryl
Y=(for Z=CH3 or COR11) free electron pair or (for Z=CH3) O
R11=alkyl, CF3 or aryl andor
Z=(for Y=O or free electron pair) CH3 or (for Y=free electron pair) COR11
wherein R=OR1, R1=H, S=U=H, T=OR4, R4=COR5, R5=alkyl, especially C1-4alkyl, alkenyl or N(R12)2, R12,=alkyl, V=OR7, R7==COR8, R8=alkyl, preferably C1-4alkyl, especially methyl, W=H, X=CH2OR9, R9=COR10 R10=alkyl, especially C1-6alkyl, alkenyl, especially C2-6alkenyl, aryl or heteroaryl, in which process
(i) a compound of Formula II (type 1, 2 or 3)
or
(ii) the compound of Formula II (type 13) is subjected to acylation, thereby preparing the compound of formula I having the indicated meanings.
44. The process according to claim 43, wherein the acylation is carried out using an acyl halide of formula R5COCI wherein R5=alkyl, especially C1-4alkyl, alkenyl or N(R12)2 and R12=alkyl, especially using an acyl chloride, in the presence of an organic base, especially a trialkylamine, preferably triethylamine, in an organic solvent, especially THF.
45. A process for the preparation of a compound of formula I (type 26)
wherein R, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, S, T, U, V, W, X, Y and Z have the following meanings:
R=H, alkyl, aryl, OR1, NR1R2 or
R1=H, alkyl or aryl
R2=H, alkyl or aryl
S=H, Hal, NO2 or NHR3
U=H, Hal, NO2 or NHR3
R3=H, HCO or alkyl-CO
T=H or OR4
R4=H, alkyl, aryl, COR5, P(O)(OR6)2 or SO3R6
R5=alkyl, alkenyl, aryl or heteroaryl
R6=H, alkyl or a metal ion
V=H, OR7, Hal or (with W=O) O
R7=H, alkyl or COR8
R8=alkyl, alkenyl or aryl
W=H or alkyl or (with V) O
X=H, alkyl, alkenyl or CH2OR9
R9=H, alkyl, alkenyl, aryl or COR10
R10=alkyl, alkenyl, aryl or heteroaryl
Y=(for Z=CH3 or COR11) free electron pair or (for Z=CH3) O
R11=alkyl, CF3 or aryl andor
Z=(for Y=O or free electron pair) CH3 or (for Y=free electron pair) COR11
wherein R=OR1, R1=alkyl, especially C1-4alkyl, or alkenyl, S=U=H, T=OR4, R4=alkyl, especially C1-4alkyl, or alkenyl, V=OR7, R7=COR8, R8=alkyl, preferably C1-4alkyl, especially methyl, W=H, X=CH2OR9, R9=COR10, R10=alkyl, especially C1-6alkyl, alkenyl, especially C2-6alkenyl, aryl or heteroaryl, Y=free electron pair and Z=CH3, wherein
(i) a compound of Formula II (type 1, 2 or 3)
or
(ii) the compound of Formula I (type 13) is subjected to alkylation, thereby preparing the compound of formula I having the indicated meanings.
46. The process according to claim 45, wherein the alkylation is carried out using an alkyl iodide of formula R4I wherein R4=alkyl, especially C1-4alkyl, or alkenyl in the presence of a weak base, especially Ag2O, in an organic solvent, especially methylene chloride.
47. The process according to claim 45, wherein methylation is carried out using diazomethane in an organic solvent, especially methanol.
48. A process for the preparation of a compound of formula I (type 27)
wherein R, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, S, T, U, V, W, X, Y and Z have the following meanings:
R=H, alkyl, aryl, OR1, NR1R2 or
R1=H, alkyl or aryl
R2=H, alkyl or aryl
S=H, Hal, NO2 or NHR3
U=H, Hal, NO2 or NHR3
R3=H, HCO or alkyl-CO
T=H or OR4
R4=H, alkyl, aryl, COR5, P(O)(OR6)2 or SO3R6
R5=alkyl, alkenyl, aryl or heteroaryl
R6=H, alkyl or a metal ion
V=H, OR7, Hal or (with W=O) O
R7=H, alkyl or COR8
R8=alkyl, alkenyl or aryl
W=H or alkyl or (with V) O
X=H, alkyl, alkenyl or CH2OR9
R9=H, alkyl, alkenyl, aryl or COR10
R10=alkyl, alkenyl, aryl or heteroaryl
Y=(for Z=CH3 or COR11) free electron pair or (for Z=CH3) O
R11=alkyl, CF3 or aryl andor
Z=(for Y=O or free electron pair) CH3 or (for Y=free electron pair) COR11
wherein R=OR1, R1=H, S=U=H, T=OR4, R4=alkyl, especially C1-4alkyl, or alkenyl, V=OR7, R7=COR8, R8=alkyl, preferably C1-4alkyl, especially methyl, W=H, X=CH2OR9, R9=COR10, R10=alkyl, especially C1-6alkyl, alkenyl, especially C2-6alkenyl, aryl or heteroaryl, Y=free electron pair and Z=CH3, wherein the compound of Formula I (type 26) is subjected to partial dealkylation or dealkenylation enzymatically, thereby preparing the compound of formula I having the indicated meanings.
49. The process according to claim 48, wherein an esterase, especially pig liver esterase, is used as the enzyme.
50. A process for the preparation of a compound of formula I (type 27)
wherein R, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, S, T, U, V, W, X, Y and Z have the following meanings:
R=H, alkyl, aryl, OR1, NR1R2 or
R1=H, alkyl or aryl
R2=H, alkyl or aryl
S=H, Hal, NO2 or NHR3
U=H, Hal, NO2 or NHR3
R3=H, HCO or alkyl-CO
T=H or OR4
R4=H, alkyl, aryl, COR5, P(O)(OR6)2 or SO3R6
R5=alkyl, alkenyl, aryl or heteroaryl
R6=H, alkyl or a metal ion
V=H, OR7, Hal or (with W=O) O
R7=H, alkyl or COR8
R8=alkyl, alkenyl or aryl
W=H or alkyl or (with V) O
X=H, alkyl, alkenyl or CH2OR9
R9=H, alkyl, alkenyl, aryl or COR10
R10=alkyl, alkenyl, aryl or heteroaryl
Y=(for Z=CH3 or COR11) free electron pair or (for Z=CH3) O
R11=alkyl, CF3 or aryl andor
Z=(for Y=O or free electron pair) CH3 or (for Y=free electron pair) COR11
wherein R=OR1, R1=H, S=U=H, T=OR4, R4=alkyl, especially C1-4alkyl, or alkenyl, V=OR7, R7=COR8, R8=alkyl, preferably C1-4alkyl, especially methyl, W=H, X=CH2OR9, R9=COR10, R10=alkyl, especially C1-6alkyl, alkenyl, especially C2-6alkenyl, aryl or heteroaryl, wherein
(a) in a first step
(i) a compound of Formula II (type 1, 2 or 3)
or
(ii) the compound of Formula I (type 13) is subjected to a process according to claim 45, and
(b) in a second step a process according to claim 48 is carried out, thereby preparing the compound of formula I having the indicated meanings.
51. A process for the preparation of a compound of formula I (type 28 and 29)
wherein R, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, S, T, U, V, W, X, Y and Z have the following meanings:
R=H, alkyl, aryl, OR1, NR1R2 or
R1=H, alkyl or aryl
R2=H, alkyl or aryl
S=H, Hal, NO2 or NHR3
U=H, Hal, NO2 or NHR3
R3=H, HCO or alkyl-CO
T=H or OR4
R4=H, alkyl, aryl, COR5, P(O)(OR6)2 or SO3R6
R5=alkyl, alkenyl, aryl or heteroaryl
R6=H, alkyl or a metal ion
V=H, OR7, Hal or (with W=O) O
R7=H, alkyl or COR8
R8=alkyl, alkenyl or aryl
W=H or alkyl or (with V) O
X=H, alkyl, alkenyl or CH2OR9
R9=H, alkyl, alkenyl, aryl or COR10
R10=alkyl, alkenyl, aryl or heteroaryl
Y=(for Z=CH3 or COR11) free electron pair or (for Z=CH3) O
R11=alkyl, CF3 or aryl andor
Z=(for Y=O or free electron pair) CH3 or (for Y=free electron pair) COR11
wherein R=OR1, R1=H, S=H or Hal, T=OR4, R4=H, U=Hal, V=OR7, R7=COR8, R8=alkyl, preferably C1-4alkyl, especially methyl, W=H, X=CH2OR9, R9=COR10, R10=alkyl, especially C1-6alkyl, alkenyl, especially C2-6alkenyl, aryl or heteroaryl, wherein
(i) a compound of Formula II (type 1, 2, 3, 4, 5 or 6)
or
(ii) the compound of Formula I (type 13) is subjected to halogenation or dihalogenation in the position ortho to the T substituent, thereby preparing the compound of formula I having the indicated meanings.
52. The process according to claim 51, wherein the halogenation is carried out in the presence of C5CI5NF-triflate, SO2, CI2, NBS and ICI.
53. A process for the preparation of a compound of formula I (type 30)
wherein R, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, S, T, U, V, W, X, Y and Z have the following meanings:
R=H, alkyl, aryl, OR1, NR1R2 or
R1=H, alkyl or aryl
R2=H, alkyl or aryl
S=H, Hal, NO2 or NHR3
U=H, Hal, NO2 or NHR3
R3=H, HCO or alkyl-CO
T=H or OR4
R4=H, alkyl, aryl, COR5, P(O)(OR6)2 or SO3R6
R5=alkyl, alkenyl, aryl or heteroaryl
R6=H, alkyl or a metal ion
V=H, OR7, Hal or (with W=O) O
R7=H, alkyl or COR8
R8=alkyl, alkenyl or aryl
W=H or alkyl or (with V) O
X=H, alkyl, alkenyl or CH2OR9
R9=H, alkyl, alkenyl, aryl or COR10
R10=alkyl, alkenyl, aryl or heteroaryl
Y=(for Z=CH3 or COR11) free electron pair or (for Z=CH3) O
R11=alkyl, CF3 or aryl andor
Z=(for Y=O or free electron pair) CH3 or (for Y=free electron pair) COR11
wherein R=OR1, R1=H, S=H, T==OR4, R4=H, U=NO2, V=OR7, R7=COR8, R8=alkyl, preferably C1-4alkyl, especially methyl, W=H, X=CH2, OR9, R9=COR10, R10=alkyl, especially C1-6alkyl, alkenyl, especially C2-6alkenyl, aryl or heteroaryl, Y=free electron pair and Z=CH3, wherein
(i) a compound of Formula II (type 1, 2, 3, 4, 5 or 6)
or
(ii) the compound of Formula I (type 13) is subjected to nitration in the position ortho to the T substituent, thereby preparing the compound of formula I having the indicated meanings.
54. The process according to claim 53, wherein the nitration is carried out using an alkali metal nitrite, especially sodium nitrite, and acetic acid in the presence of an organic solvent, especially ethanol.
55. A process for the preparation of a compound of formula I (type 31)
wherein R, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, S, T, U, V, W, X, Y and Z have the following meanings:
R=H, alkyl, aryl, OR1, NR1R2 or
R1=H, alkyl or aryl
R2=H, alkyl or aryl
S=H, Hal, NO2 or NHR3
U=H, Hal, NO2 or NHR3
R3=H, HCO or alkyl-CO
T=H or OR4
R4=H, alkyl, aryl, COR5, P(O)(OR6)2 or SO3R6
R5=alkyl, alkenyl, aryl or heteroaryl
R6=H, alkyl or a metal ion
V=H, OR7, Hal or (with W=O) O
R7=H, alkyl or COR8
R8=alkyl, alkenyl or aryl
W=H or alkyl or (with V) O
X=H, alkyl, alkenyl or CH2OR9
R9=H, alkyl, alkenyl, aryl or COR10
R10=alkyl, alkenyl, aryl or heteroaryl
Y=(for Z=CH3 or COR11) free electron pair or (for Z=CH3) O
R11=alkyl, CF3 or aryl andor
Z=(for Y=O or free electron pair) CH3 or (for Y=free electron pair) COR11
wherein R=OR1, R1=H, S=H, T=OR4, R4=H, U=NH2, V=OR7, R7=COR8, R8=alkyl, preferably C1-4alkyl, especially methyl, W=: H, X=CH2OR9, R9=COR10, R10=alkyl, especially C1-6alkyl, alkenyl, especially C2-6alkenyl, aryl or heteroaryl, Y=free electron pair and Z=CH3, wherein the compound of Formula I (type 30) is subjected to catalytic reductions, thereby preparing the compound of formula I having the indicated meanings.
56. The process according to claim 55, wherein the reduction is carried out using elemental hydrogen in the presence of palladium on activated carbon, especially in an organic solvent, preferably ethanol.
57. A process for the preparation of a compound of formula I (type 31)
wherein R, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, S, T, U, V, W, X, Y and Z have the following meanings:
R=H, alkyl, aryl, OR1, NR1R2 or
R1=H, alkyl or aryl
R2=H, alkyl or aryl
S=H, Hal, NO2 or NHR3
U=H, Hal, NO2 or NHR3
R3=H, HCO or alkyl-CO
T=H or OR4
R4=H, alkyl, aryl, COR5, P(O)(OR6)2 or SO3R6
R5=alkyl, alkenyl, aryl or heteroaryl
R6=H, alkyl or a metal ion
V=H, OR7, Hal or (with W=O) O
R7=H, alkyl or COR8
R8=alkyl, alkenyl or aryl
W=H or alkyl or (with V) O
X=H, alkyl, alkenyl or CH2OR9
R9=H, alkyl, alkenyl, aryl or COR10
R10=alkyl, alkenyl, aryl or heteroaryl
Y=(for Z=CH3 or COR11) free electron pair or (for Z=CH3) O
R11=alkyl, CF3 or aryl andor
Z=(for Y=O or free electron pair) CH3 or (for Y=free electron pair) COR11
wherein R=OR1, R1=H, S=H, T=OR4, R4=H, U=NH2, V=OR7, R7=COR8, R8=alkyl, preferably C1-4alkyl, especially methyl, W=H, X=CH2OR9, R9=COR10, R10=alkyl, preferably C1-6alkyl, alkenyl, especially C2-6alkenyl, aryl or heteroaryl, Y=free electron pair and Z=CH3, wherein
(a) in a first step
(i) a compound of the Formula II (type 1, 2, 3, 4, 5 or 6)
or
(ii) the compound of Formula I (type 13) is subjected to a process according to claim 53 and
(b) in a second step the resulting product (type 30) is subjected to a process according to claim 55, an thereby preparing the compound of formula I having the indicated meanings.
58. A process for the preparation of a compound of formula I (type 32)
wherein R, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, S, T, U, V, W, X, Y and Z have the following meanings:
R=H, alkyl, aryl, OR1, NR1R2 or
R1=H, alkyl or aryl
R2=H, alkyl or aryl
S=H, Hal, NO2 or NHR3
U=H, Hal, NO2 or NHR3
R3=H, HCO or alkyl-CO
T=H or OR4
R4=H, alkyl, aryl, COR5, P(O)(OR6)2 or SO3R6
R5=alkyl, alkenyl, aryl or heteroaryl
R6=H, alkyl or a metal ion
V=H, OR7, Hal or (with W=O) O
R7=H, alkyl or COR8
R8=alkyl, alkenyl or aryl
W=H or alkyl or (with V) O
X=H, alkyl, alkenyl or CH2OR9
R9=H, alkyl, alkenyl, aryl or COR10
R10=alkyl, alkenyl, aryl or heteroaryl
Y=(for Z=CH3 or COR11) free electron pair or (for Z=CH3) O
R11=alkyl, CF3 or aryl andor
Z=(for Y=O or free electron pair) CH3 or (for Y=free electron pair) COR11
wherein R=OR1, R1=H, S=H, T=OR4, R4=H, U=NHR3, R3=alkyl-CO, especially C1-4alkyl-CO, V=OR7, R7=COR8, R8=alkyl, preferably C1-4alkyl, especially methyl, W=H, X=CH2OR9, R9=COR10, R10=alkyl, especially C1-6alkyl, alkenyl, especially C2-6alkenyl, aryl or heteroaryl, Y=free electron pair and Z=CH3, wherein the compound of Formula I (type 31) is subjected to alkylation, thereby preparing the compound of formula I having the indicated meanings.
59. The process according to claim 58, wherein the alkylation is carried out using an acid anhydride of formula (R3)2O wherein R3=alkyl-CO, especially C1-4alkyl-CO.
60. A process for the preparation of a compound of formula I (type 32)
wherein R, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, S, T, U, V, W, X, Y and Z have the following meanings:
R=H, alkyl, aryl, OR1, NR1R2 or
R1=H, alkyl or aryl
R2=H, alkyl or aryl
S=H, Hal, NO2 or NHR3
U=H, Hal, NO2 or NHR3
R3=H, HCO or alkyl-CO
T=H or OR4
R4=H, alkyl, aryl, COR5, P(O)(OR6)2 or SO3R6
R5=alkyl, alkenyl, aryl or heteroaryl
R6=H, alkyl or a metal ion
V=H, OR7, Hal or (with W=O) O
R7=H, alkyl or COR8
R8=alkyl, alkenyl or aryl
W=H or alkyl or (with V) O
X=H, alkyl, alkenyl or CH2OR9
R9=H, alkyl, alkenyl, aryl or COR10
R10=alkyl, alkenyl, aryl or heteroaryl
Y=(for Z=CH3 or COR11) free electron pair or (for Z=CH3) O
R11=alkyl, CF3 or aryl andor
Z=(for Y=O or free electron pair) CH3 or (for Y=free electron pair) COR11
wherein R=OR1, R1=H, S=H, T=OR4, R4=H, U=NHR3, R3=alkyl-CO, especially C1-4alkyl-CO, V=OR7, R7=COR8, R8=alkyl, preferably C1-4alkyl, especially methyl, W=H, X=CH2OR9, R9=COR10, R10=alkyl, especially C1-6alkyl, alkenyl, especially C2-6alkenyl, aryl or heteroaryl, wherein
(a) in an optional first step
(i) a compound of Formula II (type 1, 2, 3, 4, 5 or 6)
or
(ii) the compound of Formula I (type 13) is subjected to a process according to claim 53,
(b) in a second step the resulting product (type 30) is subjected to a process according to claim 55 and
(c) in a third step a process according to claim 58 is carried out, thereby preparing the compound of formula I having the indicated meanings.
61. A process for the preparation of a compound of formula I (type 33)
wherein R, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, S, T, U, V, W, X, Y and Z have the following meanings:
R=H, alkyl, aryl, OR1, NR1R2 or
R1=H, alkyl or aryl
R2=H, alkyl or aryl
S=H, Hal, NO2 or NHR3
U=H, Hal, NO2 or NHR3
R3=H, HCO or alkyl-CO
T=H or OR4
R4=H, alkyl, aryl, COR5, P(O)(OR6)2 or SO3R6
R5=alkyl, alkenyl, aryl or heteroaryl
R6=H, alkyl or a metal ion
V=H, OR7, Hal or (with W=O) O
R7=H, alkyl or COR8
R8=alkyl, alkenyl or aryl
W=H or alkyl or (with V) O
X=H, alkyl, alkenyl or CH2OR9
R9=H, alkyl, alkenyl, aryl or COR10
R10=alkyl, alkenyl, aryl or heteroaryl
Y=(for Z=CH3 or COR11) free electron pair or (for Z=CH3) O
R11=alkyl, CF3 or aryl andor
Z=(for Y=O or free electron pair) CH3 or (for Y=free electron pair) COR11
wherein R=OR1, R1=H, S=U=H, T=OR4, R4=H, V=OR7, R7=COR8, R8=alkyl, preferably C1-4alkyl, especially methyl, W=H, X=CH2OR9, R9=COR10, R10=alkyl, especially C1-6alkyl, alkenyl, especially C2-6alkenyl, aryl or heteroaryl, Y=O and Z=CH3, wherein
(i) a compound of Formula II (type 1, 2, 3, 4, 5 or 6)
or
(ii) the compound of Formula I (type 13) is subjected to a reaction for formation of an N-oxide, thereby preparing the compound of formula I having the indicated meanings.
62. The process according to claim 61, wherein the N-oxide formation is carried out using mCPBA in an organic solvent, especially methylene chloride.
63. A process for the preparation of a compound of formula (type 34)
wherein R, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, S, T, U, V, W, X, Y and Z have the following meanings:
R=H, alkyl, aryl, OR1, NR1R2 or
R1=H, alkyl or aryl
R2=H, alkyl or aryl
S=H, Hal, NO2 or NHR3
U=H, Hal, NO2 or NHR3
R3=H, HCO or alkyl-CO
T=H or OR4
R4=H, alkyl, aryl, COR5, P(O)(OR6)2 or SO3R6
R5=alkyl, alkenyl, aryl or heteroaryl
R6=H, alkyl or a metal ion
V=H, OR7, Hal or (with W=O) O
R7=H, alkyl or COR8
R8=alkyl, alkenyl or aryl
W=H or alkyl or (with V) O
X=H, alkyl, alkenyl or CH2OR9
R9=H, alkyl, alkenyl, aryl or COR10
R10=alkyl, alkenyl, aryl or heteroaryl
Y=(for Z=CH3 or COR11) free electron pair or (for Z=CH3) O
R11=alkyl, CF3 or aryl andor
Z=(for Y=O or free electron pair) CH3 or (for Y=free electron pair) COR11
wherein R=OR1, R1=H, S=U=H, T=OR4, R4=H, V=OR7, R7=COR8, R8=alkyl, preferably C1-4alkyl, especially methyl, W=H, X=CH2OR9, R9=COR10, R10=alkyl, especially C1-6alkyl, alkenyl, especially C2-6alkenyl, aryl or heteroaryl, Y=free electron pair, Z=COR11 and R11=alkyl, preferably C1-4alkyl, especially methyl, the compound of Formula I (type 33) is reacted with an acylating agent, thereby preparing the compound of formula I having the indicated meanings.
64. The process according to claim 63, wherein the acylation is carried out using an acid anhydride, especially acetic anhydride, preferably at elevated temperature.
65. A process for the preparation of a compound of formula I (type 34)
wherein R, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, S, T, U, V, W, X, Y and Z have the following meanings:
R=H, alkyl, aryl, OR1, NR1R2 or
R1=H, alkyl or aryl
R2=H, alkyl or aryl
S=H, Hal, NO2 or NHR3
U=H, Hal, NO2 or NHR3
R3=H, HCO or alkyl-CO
T=H or OR4
R4=H, alkyl, aryl, COR5, P(O)(OR6)2 or SO3R6
R5=alkyl, alkenyl, aryl or heteroaryl
R6=H, alkyl or a metal ion
V=H, OR7, Hal or (with W=O) O
R7=H, alkyl or COR8
R8=alkyl, alkenyl or aryl
W=H or alkyl or (with V) O
X=H, alkyl, alkenyl or CH2OR9
R9=H, alkyl, alkenyl, aryl or COR10
R10=alkyl, alkenyl, aryl or heteroaryl
Y=(for Z=CH3 or COR11) free electron pair or (for Z=CH3) O
R11=alkyl, CF3 or aryl andor
Z=(for Y=O or free electron pair) CH3 or (for Y=free electron pair) COR11
wherein R=OR1, R1=H, S=U=H, T=OR4, R4=H, V=OR7, R7=COR8, R8=alkyl, preferably C1-4alkyl, especially methyl, W=H, X==CH2OR9, R9=COR10, R10=alkyl, especially C1-6alkyl, alkenyl, especially C2-6alkenyl, aryl or heteroaryl, Y=free electron pair, Z=COR11and R11=alkyl, preferably C 14alkyl, especially methyl, wherein
(a) in a first step
(i) a compound of Formula II (type 1, 2, 3, 4, 5, or 6)
or
(ii) the compound of Formula I (type 13) is subjected to a process according to claim 61 or and
(b) in a second step the resulting product (type 33) is subjected to a process according to claim 63,
thereby preparing the compound of formula I having the indicated meanings.
66. A therapeutic preparation, especially a cytostatic agent, comprising one or more compounds or as active ingredient in addition to one or more optional customary carriers andor one or more optional customary diluents.
67. A therapeutic preparation, especially a cytostatic agent, comprising one or more products of a process according to claim 3 as active ingredient in addition to one or more optional customary carriers andor one or more optional customary diluents.
68. The compound according to claim 1, wherein alkyl is branched, unbranched or cyclic C1-20alkyl, especially C1-7alkyl, preferably C1-8alkyl and more preferably C1-4alkyl, especially methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, and cycloalkyl having preferably from 3 to 8 carbon atoms in the ring.
69. The compound according to claim 1, wherein alkenyl is branched, unbranched or cyclic C2-20alkenyl, especially C2-7alkenyl, preferably C2-6alkenyl and more preferably C2-4alkenyl, especially vinyl, allyl propen-1-yl, propen-2-yl, but-1 -en-1-yl, but-1-en-2-yl, but-1-en-3-yl, but-1-en-4-yl, but-2-en- 1 -yl, but-2-en-2-yl, 2methyl-propen-1-yl, 2-methyl-propen-3-yl, and cycloalkenyl having preferably from 3 to 8 carbon atoms in the ring and the number of double bonds in the alkenyl groups being from 1 to 3.
70. The compound according to claim 1, wherein aryl is phenyl, naphthyl and biphenylyl.
71. The compound according to claim 1, wherein heteroaryl is furyl, thienyl, imidazolyl, indolyl, pyridyl, pyridinyl, pyrrolyl, thiazolyl, oxazolyl or pyrimidinyl.
72. The compound according to claim 1, wherein alkyl, alkenyl, aryl and heteroaryl are unsubstituted or substituted and, especially, carry, in any position, from 1 to 3 substituents from the group formed by C1-3alkyl, C1-3alkoxy, hydroxy, amino (NH2) and nitro (NO2).
The claims below are in addition to those above.
All refrences to claim(s) which appear below refer to the numbering after this setence.
1. A card-shaped device to be used by an electronic device having a card interface, comprising:
a connector having connector pins that include data pins, a command pin, and a power signal pin, the connector being connectable to the electronic device via the card interface;
a register file pre-storing operation mode information of the card-shaped device, the operation mode information indicating one of first and second operation modes;
a transmitter configured to transmit the operation mode information stored in the register file to the electronic device via one of the connector pins, when a first command that requests reading of the operation mode information is received from the electronic device via the command pin; and
a data transfer unit configured to execute data transfer between the card-shaped device and the electronic device, the data transfer unit transferring data using the data pins to which signal assignment was performed by the electronic device according to the operation mode information, wherein:
the data transfer unit uses all of the data pins for data transfer in the first operation mode;
the data transfer unit uses one of the data pins for data transfer in the second operation mode;
the register file stores an operation voltage information indicating an operation voltage of the card-shaped device; and
the transmitter transmits the operation voltage information stored in the register file to the electronic device via the command pin, when a second command that requests reading of the operation voltage information is received from the electronic device via the command pin.
2. The card-shaped device according to claim 1, wherein the connector receives a power voltage information indicating a power voltage supplied from the electronic device via the power signal pin.
3. The card-shaped device according to claim 2, wherein the transmitter transmits a response indicating a ready state if the card-shaped device can be operated by the power voltage.
4. The card-shaped device according to claim 3, wherein:
the register file stores a card address pre-assigned to the card-shaped device; and
the transmitter transmits the card address stored in the register file to the electronic device, via the command pin, when a third command that requests reading of the card address is received from the electronic device via the command pin.
5. The card-shaped device according to claim 4, wherein:
the connector receives a fourth command for selecting the card-shaped device, the fourth command including a card address indicating a card-shaped device to be selected; and
the card-shaped device shifts to a selected state if the card address included in the fourth command is identical to the card address stored in the register file.
6. The card-shaped device according to claim 5, wherein:
the register file stores a card ID, the card ID identifying data peculiar to the card-shaped device; and
the transmitter transmits the card ID stored in the register file to the electronic device via the command pin, when a fifth command that requests reading of the card ID is received from the electronic device via the command pin.
7. The card-shaped device according to claim 6, wherein the card-shaped device shifts from a Ready State to an Identification State after the transmitter transmits the card ID to the electronic device.
8. The card-shaped device according to claim 3, wherein the transmitter transmits a response indicating a busy state if the card-shaped device can not be operated by the power voltage.
9. The card-shaped device according to claim 6, further comprising a non-volatile programmable memory.
10. The card-shaped device according to claim 6, wherein the data transfer unit uses at least one of the data pins for informing a state of the electronic device in the second mode.
11. The card-shaped device according to claim 7, wherein the connector pins further include a plurality of ground signal pins for transferring ground voltage from the electronic device to the card-shaped device.
12. The card-shaped device according to claim 11, wherein the connector pins further include a clock pin for transferring a clock signal from the electronic device to the card-shaped device.