US2009018342A1PendingUtilityA1
New epothiolone derivatives, process for their production, and their pharmaceutical use
Est. expiryAug 9, 2017(expired)· nominal 20-yr term from priority
C07D 307/33C07D 417/14A61P 43/00C07D 405/14Y02P20/55C07C 45/673C07C 49/355C07D 405/06C07D 319/08C07C 49/337C07C 59/185C07D 407/04C07F 7/1804C07C 45/56C07D 277/24C07D 263/22C07D 213/55C07C 45/29C07D 309/12C07D 417/12C07D 407/12C07D 319/14C07D 417/06A61P 35/00C07D 405/12C07C 49/185C07D 319/06C07D 493/04C07D 213/50
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Claims
Abstract
This invention relates to the new epothilone derivatives of general formula I, in which substituents Y, Z, R 2a , R 2b , R 3 , R 4a , R 4b , D-E, R 5 , R 6 , R 7 , R 8 and X 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 are suitable for treating malignant tumors, for example, ovarian, stomach, colon, adeno-, breast, lung, head and neck carcinomas, malignant melanomas, acute lymphocytic and myelocytic leukemia. In addition, they are suitable for anti-angiogenesis therapy as well as for treatment of chronic inflammatory diseases (psoriasis, arthritis). To avoid uncontrolled proliferation of cells and for better compatibility of medical implants, they can be applied or introduced into polymer materials. The compounds according to the invention can be used alone or to achieve additive or synergistic actions in combination with other principles and classes of substances that can be used in tumor therapy.
Claims
exact text as granted — not AI-modified1 - 30 . (canceled)
31 . An epothilone compound of formula I,
in which
R 1a , R 1b are the same or different and mean hydrogen, C 1 -C 10 alkyl, aryl, C 7 -C 20 aralkyl, or together a —(CH 2 ) m — group with m=2, 3, 4 or 5,
R 2a , R 2b are the same or different and mean hydrogen, C 1 -C 10 alkyl, aryl, C 7 -C 20 aralkyl or together a —(CH 2 ) n — group with n=2, 3, 4 or 5, whereby, if -D-E- stands for —CH 2 —CH 2 — and Y stands for an oxygen atom, at least one of R 2a and R 2b is not hydrogen or methyl,
R 3 means hydrogen, C 1 -C 10 alkyl, aryl, C 7 -C 20 aralkyl,
R 4a , R 4b are the same or different and mean hydrogen, C 1 -C 10 alkyl aryl, C 7 -C 20 aralkyl or together a —(CH 2 ) p — group with p=2, 3, 4 or 5, D-E means a group
R 5 means hydrogen, C 1 -C 10 alkyl, aryl, C 7 -C 20 aralkyl,
R 6 , R 7 each mean a hydrogen atom, together an additional bond or an oxygen atom,
R 8 means hydrogen, C 1 -C 20 alkyl, aryl, C 7 -C 20 aralkyl, which can all be substituted,
X means an oxygen atom, two alkoxy groups OR 23 , a C 2 -C 10 alkylene-α,ω-dioxy group, which is straight-chain or branched, H/OR 9 or a grouping CR 10 R 11 ,
whereby
R 23 stands for a C 1 -C 20 alkyl radical,
R 9 stands for hydrogen or a protective group PG X ,
R 10 , R 11 are the same or different and stand for:
hydrogen;
a C 1 -C 20 alkyl radical;
a substituted or unsubstituted phenyl, naphthyl, furyl, thienyl, pyridyl, pyrazolyl, pyrimidinyl, oxazolyl, pyridazinyl, pyrazinyl, quinolyl or thiazolyl radical; or
a C 7 -C 20 aralkyl radical; or
R 10 and R 11 together with the methylene carbon atom together stand for a 5- to 7-membered carbocyclic ring,
Y means an oxygen atom or two hydrogen atoms,
Z means an oxygen atom or H/OR 12 ,
whereby
R 12 means hydrogen or a protective group PG Z .
32 . An epothilone compound of claim 31 which is of formula Ia
in which
R 1a , R 1b are the same or different and mean hydrogen, C 1 -C 10 alkyl, aryl, C 7 -C 20 aralkyl, or together a —(CH 2 ) m — group with m=2, 3, 4 or 5,
R 2a , R 2b are the same or different and mean hydrogen, C 1 -C 10 alkyl, aryl, C 7 -C 20 aralkyl or together a —(CH 2 ) n — group with n=2, 3, 4 or 5, whereby, if Y stands for an oxygen atom, at least one of R 2a and R 2b is not hydrogen or methyl,
R 5 is H or CH 3
Y means an oxygen atom or two hydrogen atoms, and
Z means an oxygen atom or H/OR 12 .
33 . An epothilone compound of claim 31 which is of formula Ib
in which
R 1a , R 1b are the same or different and mean hydrogen, C 1 -C 10 alkyl aryl, C 7 -C 20 aralkyl, or together a —(CH 2 ) m — group with m=2, 3, 4 or 5,
R 2a , R 2b are the same or different and mean hydrogen, C 1 -C 10 alkyl aryl, C 7 -C 20 aralkyl or together a —(CH 2 ) n — group with n=2, 3, 4 or 5, whereby, if -D-E- stands for —CH 2 —CH 2 — and Y stands for an oxygen atom, at least one of R 2a and R 2b is not hydrogen or methyl,
R 3 means hydrogen, C 1 -C 10 alkyl, aryl, C 7 -C 20 aralkyl,
R 4a , R 4b are the same or different and mean hydrogen, C 1 -C 10 alkyl, aryl, C 7 -C 20 aralkyl or together a —(CH 2 ) p — group with p=2, 3, 4 or 5,
D-E means a group
R 5 means hydrogen, C 1 -C 10 alkyl, aryl, C 7 -C 20 aralkyl,
R 6 , R 7 each mean a hydrogen atom, together an additional bond or an oxygen atom,
Y means an oxygen atom or two hydrogen atoms, and
Z means an oxygen atom or H/OR 12 .
34 . An epothilone compound of formula I according to claim 31 , in which Y,
Z, R 1a , R 1b , R 2a , R 2b , R 6 , R 7 , R 8 and X all have the meanings that are indicated in formula I, and R 3 is H, one R 4a and R 4b is H and the other is methyl, R 5 is H or methyl and D-E is H 2 C—CH 2 .
35 . A process for the production of an epothilone compound according to claim 31 , comprising:
reacting a fragment of formula A
in which
R 1a′ , R 1b′ , R 2a′ and R 2b′ have the meanings already mentioned for R 1a , R 1b , R 2a and R 2b ,
R 1 means CH 2 OR 13a , CH 2 -Hal, CHO, CO 2 R 13b , COHal,
R 1 means hydrogen, OR 14a , Hal, OSO 2 R 14b ,
R 13a , R 14a mean hydrogen, SO 2 -alkyl, SO 2 -aryl, SO 2 -aralkyl or together a —(CH 2 ) o group or together a CR 15a R 15b group,
R 13b , R 14b mean hydrogen, C 1 -C 20 alkyl, aryl, C 1 -C 20 aralkyl,
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,
Hal means halogen,
o means 2 to 4,
q means 3 to 6,
including all stereoisomers as well as their mixtures, and
free hydroxyl groups in R 13 and R 14 is etherified or esterified, free carbonyl groups are ketalized in A and R 13 , converted into an enol ether or reduced, and free acid groups in A are converted into their salts with bases,
with a fragment of formula B
in which
R 3′ , R 4a′ , R 4b′ and R 5′ have the meanings already mentioned for R 3 , R 4a , R 4b and R 5 ,
V means an oxygen atom, two alkoxy groups OR 17 , a C 2 -C 10 alkylene-α,ω-dioxy group, which is straight-chain or branched or H/OR 16 ,
W means an oxygen atom, two alkoxy groups OR 19 , a C 2 -C 10 alkylene-α,ω-dioxy group, which is straight-chain or branched or H/OR 18 ,
R 16 , R 18 , independently of one another, mean hydrogen or a protective group PG 1
R 17 , R 19 , independently of one another, mean C 1 -C 20 alkyl, to a form a compound of partial fragment of formula AB
in which R 1a′ , R 1b′ , R 2a′ , R 2b′ , R 3 , R 4a , R 4b , R 5 , R 13 , R 14 , D, E, V and Z have the meanings already mentioned, and PG 14 represents a hydrogen atom or a protective group PG,
and
reacting this compound of partial fragment AB is reacted with a fragment of formula C
in which
R 8′ has the meaning already mentioned in formula I for R 8 , and
R 7′ means a hydrogen atom,
R 20 means a hydrogen atom or a protective group PG 2 ,
R 21 means a hydroxy group, halogen, a protected hydroxy group OPG 3 , a phosphonium halide radical PPh 3 + Hal − (Ph=phenyl; Hal=F, Cl, Br, I), a phosphonate radical P(O)(OQ) 2 (Q=C 1 -C 10 alkyl or phenyl) or a phosphine oxide radical P(O)Ph 2 (Ph=phenyl),
U means an oxygen atom, two alkoxy groups OR 23 , a C 2 -C 10 alkylene-α,ω-dioxy group, which is straight-chain or branched, H/OR 9 or a grouping CR 10 R 11 ,
whereby
R 23 stands for a C 1 -C 20 alkyl radical,
R 9 stands for hydrogen or a protective group PG 3 ,
R 10 , R 11 are the same or different and stand for
hydrogen;
a C 1 -C 20 alkyl radical;
a substituted or unsubstituted phenyl, naphthyl, furyl, thienyl, pyridyl, pyrazolyl, pyrimidinyl, oxazolyl, pyridazinyl, pyrazinyl, quinolyl or thiazolyl radical; or
a C 7 -C 20 aralkyl radical or
R 10 and R 11 together with the methylene carbon atoms together stand for a 5- to 7-membered carbocyclic ring,
to obtain a compound of a partial fragment of formula ABC
in which R 1a′ , R 1b′ , R 2a′ , R 2b′ , R 3 , R 4a , R 4b , R 5 , R 6 , R 7 , R 8 , R 13 , R 14 , D, E, U and Z have the meanings already mentioned, and this compound of partial fragment of formula ABC is cyclized to an epothilone derivative of formula I.
36 . A pharmaceutical composition comprising a therapeutically effective amount of at least one compound of formula I according to claim 31 , as well as a pharmaceutically compatible vehicle.
37 . A method for the production of a pharmaceutical agent comprising mixing a therapeutically effective amount of a compound of formula I according to claim 31 , together with a pharmaceutically compatible vehicle.
38 . A process for the production of a compound of formula A
in which
R 2 means CH 2 OR 2a , CHO, CO 2 R 2b , COX,
R 2a , R 2b mean hydrogen, C 1 -C 20 alkyl, aryl, C 7 -C 20 aralkyl,
R 3 means hydrogen, OR 3a , X, OSO 2 R 3b ,
R 3a means hydrogen or together with R 2a a —(CH 2 ) n — group or a CR 6a R 6B group,
R 3b means C 1 -C 4 alkyl, aryl,
X means halogen,
n means 2 to 4,
R 6a , R 6b are the same or different and mean C 1 -C 8 alkyl C 6 -C 10 aryl
or together a —(CH 2 ) 0 — group,
o means 3 to 6,
R 6a additionally can assume the meaning of hydrogen,
R 4a , R 4b are the same or different and mean hydrogen, C 1 -C 10 alkyl C 7 -C 20 aralkyl
or together a —(CH 2 ) m — group,
m means 2 to 5
R 5a , R 5b are the same or different and mean hydrogen, C 1 -C 10 alkyl, C 7 -C 20 aralkyl
or together a —(CH 2 ) p — group,
p means 2 to 5
R 5c means hydrogen,
including all steroisomers and mixtures thereof, and
free hydroxyl groups are etherified or esterified in R 2 and R 3 , free carbonyl groups are ketalized in A and R 2 , converted into an enol ether or reduced, and free acid groups in A are converted into their salts with bases, wherein
a) a pantolactone of formula IIa or
in which
R 4a and R 4b in each case are methyl groups or
b) a malonic acid dialkyl ester of formula XXVIII
in which
R 4a , R 4b , which have the meaning that is indicated in formula A, and alkyl, independently of one another, mean a C 1 -C 20 alkyl, C 3 -C 10 cycloalkyl or C 4 -C 20 alkylcycloalkyl radical, is used as a starting product.
39 . A compound of claim 31 , in which
R 2a , R 2b are the same or different and mean hydrogen, C 1 -C 10 alkyl aryl, C 7 -C 20 aralkyl or together a —(CH 2 ) n — group with n=2, 3, 4 or 5, whereby, if -D-E- stands for
—CH 2 —CH 2 — or Y stands for an oxygen atom, then R 2a and R 2b cannot be hydrogen or C 1 -C 10 alkyl.
40 . A compound of formula A′
in which
R 2 means CH 2 OR 2a , CHO, CO 2 R 2b , COX,
R 2a , R 2b mean hydrogen, C 1 -C 20 alkyl, aryl, C 7 -C 20 aralkyl,
R 3 means hydrogen, OR 3a , X, OSO 2 R 3b ,
R 3a means hydrogen or together with R 2a a —(CH 2 ) n group or a CR 6a R 6b group,
R 3b means C 1 -C 4 alkyl, aryl,
X means halogen,
n means 2 to 4,
R 6a , R 6b are the same or different and mean C 1 -C 8 alkyl, C 6 -C 10 aryl or together a —(CH 2 ) o group,
or R 6 , may be hydrogen,
o means 3 to 6,
R 4a , R 4b are the same or different and mean hydrogen, C 1 -C 10 alkyl, C 7 -C 20 aralkyl or together a —(CH 2 ) m group,
m means 2 to 5,
R 5a , R 5b are the same or different and mean hydrogen, C 1 -C 10 alkyl, C 7 -C 20 aralkyl or together a —(CH 2 ) p group,
p means 2 to 5,
R 5c means hydrogen,
including all stereoisomers and mixtures thereof,
and
free hydroxyl groups are etherified or esterified in R 2 and R 3 , free carbonyl groups are ketalized in A and R 2 , converted into an enol ether or reduced, and free acid groups in A are converted into their salts with bases, excluding the compounds
41 . A process for the production of compounds of formula A″
in which
R 3 means OR 3a and
R 3a means hydrogen or a protective group PG
R 4a , R 4b are the same or different and mean hydrogen, C 1 -C 10 -alkyl,
C 7 -C 20 -aralkyl, or together a —(CH 2 ) m group,
m means 2-5,
R 5a , R 5b are the same or different and mean hydrogen, C 1 -C 10 -alkyl,
C 7 -C 20 -aralkyl, or together a —(CH 2 ) p group,
p means 2-5,
including a stereoisomer or a mixture thereof,
and
free carbonyl groups are ketalized in A″,
wherein a compound of formula II
in which
X is a chlorine or bromine atom, and the 2-oxazolidinone ring has either a (4R,5S) or a (4S,5R) conformation,
is reacted with a compound of formula III
in which
R 4a , R 4b are the same or different and mean hydrogen, C 1 -C 10 -alkyl,
C 7 -C 20 -aralkyl, or together a —(CH 2 ) m group,
m means 2-5,
R 5a , R 5b are the same or different and mean hydrogen,
C 1 -C 10 -alkyl, C 7 -C 20 -aralkyl, or together a —(CH 2 ) p group,
p means 2-5,
to a compound of formula IV
in which
the 2-oxazolidinone ring (4R,5S) and the 3′-carbon atom have an R conformation, or
the 2-oxazolidinone ring (4S,5R) and the 3′-carbon atom have an S conformation,
the 3′-hydroxy group in IV is protected by a protective group PG,
the oxazolidinone ring is cleaved, and protective group PG is optionally cleaved.
42 . A process according to claim 41 , wherein the compound of formula II is reacted in the presence of chromium(II) chloride with a compound of formula III.
43 . A process according to claim 41 , wherein the cleaved oxazolidinone ring is recovered in an enantiomer-pure manner.
44 . A compound of formula C
in which
R 1 means hydrogen, C 1 -C 20 alkyl, aryl, C 7 -C 20 aralkyl, which can all be substituted,
R 2 means hydrogen or a protective group PG 1 ,
R 3 means a hydroxy group, halogen, a protected hydroxy group OPG 2 , a phosphonium halide radical Pph 3 + Hal − (Ph=phenyl; Hal=F, Cl, Br, I), a phosphate radical P(O)(OQ) 2 , (Q=C 1 -C 10 alkyl or phenyl) or a posphine oxide radical P(O)Ph 2 (Ph=phenyl),
X means an oxygen atom, two alkoxy groups OR 4 , a C 2 -C 10 alkylene-α,ω-dioxy group, which is straight-chain or branched, H/OR 5 or a group CR 6 R 7 ,
whereby
R 4 stands for a C 1 -C 20 alkyl radical,
R 5 stands for hydrogen or a protective group PG 3 ,
R 6 , R 7 are the same or different and stand for hydrogen, a C 1 -C 20 alkyl, aryl, C 7 -C 20 aralkyl radical or R 6 and R 7 together with the methylene carbon atom together stand for a 5- to 7-membered carboncyclic ring,
whereby not simultaneously
R 1 is a methyl group, R 2 is a tertbutyldimethylsilyl or benzyl radical, R 3 is an O-ter-butyldimethylisyl radical and X is a (2-methylthiazol-4-yl)methylene radical or R 1 is a methyl group, R 2 is a tertbutyldimethylsilyl radical, R 3 is a triphenylphosphonium iodide radical and X is a (2-methylthiazol-4-yl)methylene radical.
45 . A compound of formula C according to claim 44 , wherein R 1 stands for a hydrogen atom, an optionally substituted C 1 -C 4 alkyl radical, a phenyl radical that is optionally substituted with 1 to 3 radicals, that are halogen, a free hydroxy group or a protected hydroxy group OPG 4 , C 1 -C 4 alkyl, azido, nitro, nitrile or amino (NH 2 ).
46 . A compound of formula C according to claim 44 , wherein X stands for an oxygen atom.
47 . A compound of formula C according to claim 44 , wherein R 6 and/or R 7 stand for phenyl optionally substituted with 1 to 3 radicals, that are halogen, free hydroxy group or protected hydroxy group OPG 5 , C 1 -C 4 , alkyl, azido, nitro, nitrile, or amino (NH 2 ),
or R 6 and/or R 7 stand for a 5- or 6-membered heteroaryl radical that is optionally substituted with 1 to 2 C 1 -C 4 alkyl radicals.
48 . A compound of formula C according to claim 47 , R 6 and/or R 7 stand for 2-, 3-furanyl; 2-, 3-, 4-pyridinyl; 2-, 4-, 5-thiazollyl; 2-, 4- or 5-imdiazolyl radical, which isoptionally substituted by 1 or 2 C 1 -C 4 alkyl radicals.
49 . A compound of formula C according to claim 45 , wherein protective groups PG 1 , PG 2 , and PG 3 are methoxymethyl, methoxyethyl, ethoxyethyl, tetrahydropranyl, tetrahydrofuranyl, trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, tribenzylsilyl, triisopropylsilyl, benzyl, para-nitrobenzyl, para-methoxybenzyl, formyl, acetyl, propionyl, isopropionyl, pivalyl, butyryl or benzoyl radical.
50 . A compound according to claim 45 wherein protective group PG 4 is methoxymethyl, methoxyethyl, ethoxyethyl, tetrahydropranyl, tetrahydrofuranyl, trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, tribenzylsilyl, triisopropylsilyl, benzyl, para-nitrobenzyl, para-methoxybenzyl, formyl, acetyl, propionyl, isopropionyl, pivalyl, butyryl or a benzoyl radical.
51 . A compound according to claim 47 , wherein protective group PG 5 is methoxymethyl, methoxyethyl, ethoxyethyl, tetrahydropranyl, tetrahydrofuranyl, trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, tribenzylsilyl, triisopropylsilyl, benzyl, para-nitrobenzyl, para-methoxybenzyl, formyl, acetyl, propionyl, isopropionyl, pivalyl, butyryl or benzoyl radical.
52 . A compound according to claim 49 , wherein protective group PG 1 is a tert-butyldiphenylsilyl, tert-butyldimethylsilyl or triisopropylsilyl radical.
53 . A compound according to claim 49 , wherein protective group PG 2 is a tert-butyldimethylsilyl, acteyl, benzoyl, benzyl or tetrahydropyranyl radical.
54 . A process for the production of a compound of formula C′
in which
R 1 means hydrogen, C 1 -C 20 alkyl, aryl, C 7 -C 20 aralkyl, which can all be substituted,
R 2 means hydrogen or a protective group PG 1 ,
R 3 means a hydroxy group, halogen, a protected hydroxy group OPG 2 , a phosphonium halide radical PPh 3 + Hal − (Ph=phenyl; Hal=F, Cl, Br, I), a phosphonate radical P(O)(OQ) 2 (Q=C 1 -C 10 alkyl or phenyl) or a phosphine oxide radical P(O)Ph 2 (Ph=phenyl),
X means an oxygen atom, two alkoxy groups OR 4 , a C 2 -C 10 alkylene-αα, ω -dioxy group, which is straight-chain or branched, H/OR 5 or a grouping CR 6 R 7 ,
whereby
R 4 stands for C 1 -C 20 alkyl radical
R 5 stands for hydrogen or a protective group PG 3 ,
R 6 , R 7 are the same or different and stand for hydrogen, a C 1 -C 20 alkyl, aryl, C 7 -C 20 aralkyl radical or R 6 and R 7 together with the methylene carbon atom together stand for a 5- to 7-membered carbocyclic ring,
wherein L-(−)-malic acid, D-(+)-malic acid or racemic malic acid is used as a starting product.
55 . A process according to claim 54 , wherein L-(−)-malic acid or D-(+)-malic acid is used.
56 . An intermediate compound of formula VI″
in which,
R 1 , PG 1 and R 5 have the meaning that is indicated in formula C, and
PG 2+H stands for a hydrogen atom or a protective group PG 2 .
57 . A process for the production of a compound of formula VI″ according to claim 56 , wherein an organometal compound of formula
R 1 Y in which R 1 has the meaning and that is indicated in formula C′, and Y stands for an alkali metal atom or MZ, whereby M is a divalent metal atom and Z is a halogen atom, is added to a compound of Formula IV
in which,
PG 1 has the meaning that is indicated in formula C, while the lactol ring is opened, and then optionally the primary hydroxy group is protected with a protective group PG 2 and optionally the secondary group is protected with a protective group PG 3 .Cited by (0)
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