6-alkenyl-, 6-alkinyl- and 6-epoxy-epothilone derivatives, process for their production, and their use in pharmaceutical preparations
View Patent ↗This invention describes the new 6-alkenyl- and 6-alkinyl-epothilone derivatives of general formula (I) in which R 1a , R 1b , R 2b , R 3a , R 3b , R 4 , R 5 , R 6 , R 7 , A, Y, D, E, G, Y and Z have the meanings that are indicated in the description. The new compounds interact with tubulin by stabilizing microtubuli that are formed. They are able to influence the cell-splitting in a phase-specific manner and thus find use in treating diseases or conditions associated with the need for cell growth, division and/or proliferation. Thus the compounds are suitable for treating malignant tumors, for example, ovarian, stomach, colon, adeno-, breast, lung, head and neck carcinomas, malignant melanoma, acute lymphocytic and myelocytic leukemia. In addition, they are suitable for anti-angiogenesis therapy as well as for treatment of chronic inflammatory diseases (such as psoriasis, arthritis). Methods of use and preparation of the compounds are also described.
1. A compound of the formula A-1 or A-2:
wherein
R 1a′ , R 1b′ are the same or different and mean C 1 -C 10 alkyl, C 6 -C 12 aryl, or C 7 -C 20 aralkyl, each optionally substituted; or taken together a —(CH 2 ) m — group, with m=1, 2, 3, 4 or 5, or a —(CH 2 )—O—(CH 2 )— group;
R 2a′ means hydrogen, C 1 -C 10 alkyl, C 6 -C 12 aryl or C 7 -C 20 aralkyl, each optionally substituted; —(CH 2 ) ra —C≡C—(CH 2 ) pa —R 26a ; —(CH 2 ) ra —CH═CH—(CH 2 ) pa —R 26a ;
R 2b′ means —(CH 2 ) rb —C≡C—(CH 2 ) pb —R 26b ; —(CH 2 ) rb —CH═CH—(CH 2 ) pb —R 26b ;
n means 0 to 5,
ra, rb are the same or different and mean 0 to 4,
pa, pb are the same or different and mean 0 to 3,
R 26a , R 26b are the same or different and mean hydrogen; C 1 -C 10 alkyl, C 6 -C 12 aryl or C 7 -C 20 aralkyl, each optionally substituted; C 1 -C 10 acyl, or, if pa or pb>0, additionally a group OR 27 ,
provided:
that, when R 2a′ is hydrogen, R 2b′ is —(CH 2 ) rb —C≡—(CH 2 ) pb —R 26b , rb is 2, and pb is 0, R 26b is not hydrogen,
R 27 means hydrogen or a protective group,
R 13 means CH 2 OR 13a , CH 2 -Hal, CHO, CO 2 R 13b or COHal, where Hal means a halogen atom,
R 13a means hydrogen, SO 2 -alkyl, SO 2 -aryl, SO 2 -aralkyl or together with R 14a a —(CH 2 ) o — group or a CR 15a R 15b group,
R 13b means hydrogen, C 1 -C 20 alkyl, C 6 -C 12 aryl, C 7 -C 20 aralkyl, each optionally substituted,
R 15a , R 15b are the same or different and mean hydrogen, C 1 -C 10 alkyl, aryl, C 7 -C 20 aralkyl or together a —(CH 2 ) q — group,
o means 2 to 4,
q means 3 to 6,
R 14′ means hydrogen, OR 14a , Hal, OSO 2 R 14b ,
R 14a means hydrogen, SO 2 -alkyl, SO 2 -aryl, SO 2 -aralkyl or together with R 13a a —(CH 2 ) o — group or a CR 15a R 15b group,
R 14b means hydrogen, C 1 -C 20 alkyl, C 6 -C 12 aryl, C 7 -C 20 aralkyl, each optionally substituted,
R 30 means hydrogen,
R 31 means hydroxyl, or
R 30 , R 31 together mean an oxygen atom or a C 2 -C 10 alkylene-α,ω-dioxy group, which can be straight-chain or branched,
or
R 30 , R 31 independently mean a C 1 -C 10 alkoxy group.
2. A compound of claim 1 , wherein R 14′ or R 31 is OH, R 1a′ and R 1b′ are both methyl and one of R 2a′ and R 2b′ is hydrogen and the other is prop-2-en-1-yl.
3. A compound of claim 1 , which is of formula A-1, wherein: R 13 is CH 2 OR 13a and R 14′ is OR 14a , where R 13a and R 14a together are a CR 15a R 15b group; R 1a′ and R 1b′ are both methyl; and one of R 2a′ and R 2b′ is hydrogen and the other is prop-2-en-1-yl.
4. A compound of claim 1 , which is (4S)-4-(2-methyl-3-oxo-hept-6-en-2-yl)-2,2-dimethyl-[1,3]-dioxane.
5. A compound of claim 1 , wherein:
R 2b′ means —(CH 2 ) rb —CH═CH—(CH 2 ) pb —R 26b ;