| Epothilone derivatives, process for their production, and their pharmaceutical use -> Monitor Keywords |
|
|
  Epothilone derivatives, process for their production, and their pharmaceutical useUSPTO Application #: 20060040990Title: Epothilone derivatives, process for their production, and their pharmaceutical use Abstract: which are useful as pharmaceutical compounds for treating, for example, malignant tumors and chronic inflammatory diseases and are useful in anti-angiogenesis therapy.
Disclosed are epothilone compounds of formula I, (end of abstract)
Agent: Millen, White, Zelano & Branigan, P.C. - Arlington, VA, US Inventors: Ulrich Klar, Werner Skuballa, Bernd Buchmann, Wolfgang Schwede, Michael Schirner USPTO Applicaton #: 20060040990 - Class: 514337000 (USPTO) Related Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Designated Organic Active Ingredient Containing (doai), Heterocyclic Carbon Compounds Containing A Hetero Ring Having Chalcogen (i.e., O,s,se Or Te) Or Nitrogen As The Only Ring Hetero Atoms Doai, Hetero Ring Is Six-membered Consisting Of One Nitrogen And Five Carbon Atoms, Additional Hetero Ring Containing, The Additional Hetero Ring Is One Of The Cyclos In A Polycyclo Ring System The Patent Description & Claims data below is from USPTO Patent Application 20060040990. Brief Patent Description - Full Patent Description - Patent Application Claims
[0001] Hofle et al. describe the cytotoxic action of the natural substances epothilone A (R=hydrogen) and epothilone B (R=methyl) [0002] Epothilone A (R=H), Epothilone B (R=CH.sub.3) in, e.g., Angew. Chem. [Applied Chem.], 1996, 108, 1671-1673. Because of their in-vitro selectivity for breast cell lines and intestinal cell lines and their significantly higher activity against P-glycoprotein-forming multiresistant tumor lines in comparison to taxol as well as their physical properties that are superior to those of taxol, e.g., a water solubility that is higher by factor of 30, this novel structural class is especially advantageous for the development of a pharmaceutical agent for treating malignant tumors. [0003] The natural substances are not sufficiently stable either chemically or metabolically for the development of a pharmaceutical agents. To eliminate these drawbacks, modifications to the natural substance are necessary. Such modifications are possible only with a total-synthesis approach and require synthesis strategies that make possible a broad modification of the natural substance. The purpose of the structural changes is also to increase the therapeutic range. This can be done by improving the selectivity of the action and/or increasing the active strength and/or reducing undesirable toxic side-effects, as they are described in Proc. Natl. Acad. Sci. USA 1998, 95, 9642-9647. [0004] The total synthesis of epothilone A is described by Schinzer et al. in Chem. Eur. J. 1996, 2, No. 11, 1477-1482 and in Angew. Chem. 19977, 109, No. 5, pp. 543-544). Epothilone derivatives were already described by Hofle et al. in WO 97/19086. These derivatives were produced starting from natural epothilone A or B. [0005] Another synthesis of epothilone and epothilone derivatives was described by Nicolaou et al., in Angew. Chem. 1997, 109, No. 1/2, pp. 170-172. The synthesis of epothilone A and B and several epothilone analogs was described in Nature, Vol. 387, 1997, pp. 268-272; and the synthesis of epothilone A and its derivatives was described in J. Am. Chem. Soc., Vol. 119, No. 0.34, 1997, pp. 7960-7973 as well as the synthesis of epothilone A and B and several epothilone analogs in J. Am. Chem. Soc., Vol. 119, No. 34, 1997, pp. 7974-7991 also by Nicolaou et al. [0006] Nicolaou et al. also describe in Angew. Chem. 1997, 109, No. 19, pp. 2181-2187 the production of epothilone A analogs using combinatory solid-phase synthesis. Several epothilone B analogs are also described there. [0007] The object of this invention consists in making available new epothilone derivatives, which are both chemically and metabolically stable enough for the development of pharmaceutical agents and which are superior to natural derivatives in terms of their therapeutic range, their selectivity of action and/or undesirable toxic side-effects and/or their active strength. [0008] This invention describes the new epothilone derivatives of general formula I, in which [0009] R.sup.4 means hydrogen, C.sub.1-C.sub.10 alkyl, aryl, C.sub.7-C.sub.20 aralkyl, [0010] R.sup.5 means hydrogen, C.sub.1-C.sub.10 alkyl, arly, C.sub.7-C.sub.20 aralkyl, [0011] R.sup.6, R.sup.7 each mean a hydrogen atom, together an additional bond or an oxygen atom, [0012] R.sup.8 means a methyl group or hydrogen, [0013] and at the same time, R.sup.1a and R.sup.1b together stand for a trimethylene croup, R.sup.2 stands for a phenyl or benzyl radical, and X stands for a 2-pyridyl, 2-methyl-4-thiazolyl or 2-methyl-4-oxazolyl radical or [0014] at the same time R.sup.1a and R.sup.1b together stand for a trimethylene group, R.sup.2 stands for a methyl, ethyl or propyl group and X stands for a 2-pyridyl, 2-methyl-4-thiazolyl or 2-methyl-4-oxazolyl radical or [0015] at the same time R.sup.1a and R.sup.1b in each case stand for a methyl group, R.sup.2 stands for a methyl, ethyl or propyl radical, and X stands for 2-pyridyl, 2-methyl-4-thiazolyl or 2-methyl-4-oxazolyl radical, [0016] whereby the nitrogen atom and/or the sulfur atom in X can be present in oxidized form, and whereby, if R.sup.2 and R.sup.8 in each case mean a methyl radical, X can be only one 2-pyridyl radical that is optionally oxidized on the nitrogen atom, including all possible stereoisomers as well as their mixtures. [0017] Substituents in the compounds of general formula I: [0018] As alkyl groups R.sup.4 and R.sup.5, straight-chain or branched-chain alkyl groups with 1-20 carbon atoms can be considered such as, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, heptyl, hexyl, and decyl. [0019] Alkyl groups R.sup.4 and R.sup.5 can be perfluorinated or substituted by 1-5 halogen atoms, hydroxy groups, C.sub.1-C.sub.4 alkoxy groups, C.sub.6-C.sub.12 aryl groups (which can be substituted by 1-3 halogen atoms). [0020] As aryl radicals R.sup.4 and R.sup.5, substituted and unsubstituted carbocyclic or heterocyclic radicals with one or more heteroatoms, such as, e.g., phenyl, naphthyl, furyl, thienyl, pyridyl, pyrazolyl, pyrimidinyl, oxazolyl, pyridazinyl, pyrazinyl, quinolyl, thiazolyl, which can be substituted in one or more places by halogen, OH, O-alkyl, CO.sub.2H, CO.sub.2-alkyl, --NH.sub.2, --NO.sub.2, --N.sub.3, --CN, C.sub.1-C.sub.20 alkyl, C.sub.1-C.sub.20 acyl, C.sub.1-C.sub.20 acyloxy groups, are suitable. Heteroatoms in the heteroaryl radicals can be oxidized; thus, for example, the thiazole ring can be present in the form of N-oxide. [0021] The nitrogen atom in the 2-pyridyl radical, 2-methyl-4-thiazolyl radical or 2-methyl-4-oxazolyl radical standing for X can also be present in the form of the N-oxide. [0022] The aralkyl groups in R.sup.4 and R.sup.5 can contain in the ring up to 14 C atoms, preferably 6 to 10, and in the alkyl chain 1 to 8, preferably 1 to 4 atoms. As aralkyl radicals, for example, benzyl, phenylethyl, naphthylmethyl, naphthylethyl, furylmethyl, thienylethyl, and pyridylpropyl are suitable. The rings can be substituted in one or more places by halogen, OH, O-alkyl, CO.sub.2H, CO.sub.2-alkyl, --NO.sub.2, --N.sub.3, --CN, C.sub.1-C.sub.20 alkyl, C.sub.1-C.sub.20 acyl, C.sub.1-C.sub.20 acyloxy groups. [0023] The representation of the new epothilone derivatives is based on the linkage of three partial fragments A, B and C (DE 197 51 200.3, date of application Nov. 13, 1997 as well as the corresponding PCT/EP98/05064). The interfaces are as indicated in general formula I' (Y and Z=oxygen). [0024] A means a C1-C6 fragment (epothilone numbering system) of general formula in which [0025] R.sup.1a', R.sup.1b' are the same or different and mean hydrogen, C.sub.1-C.sub.10 alkyl, aryl, C.sub.7-C.sub.20 aralkyl, or together a --(CH.sub.2).sub.m group with m=2, 3, 4 or 5, [0026] R.sup.2a', R.sup.2b' are the same or different and mean hydrogen, C.sub.1-C.sub.10 alkyl, aryl, C.sub.7-C.sub.20 aralkyl or together a --(CH.sub.2).sub.n group with n=2, 3, 4 or 5, [0027] R.sup.13 means CH.sub.2OR.sup.13a, CH.sub.2-Hal, CHO, CO.sub.2R.sup.13b, COHal, [0028] R.sup.14 means hydrogen, OR.sup.14a, Hal, OSO.sub.2R.sup.14b, [0029] R.sup.13a, R.sup.14a mean hydrogen, SO.sub.2-alkyl, SO.sub.2-aryl, SO.sub.2-aralkyl or together a --(CH.sub.2).sub.o a group or together a CR.sup.15aR.sup.15b group, [0030] R.sup.13b, R.sup.14b mean hydrogen, C.sub.1-C.sub.20 alkyl, aryl, C.sub.7-C.sub.20 aralkyl, [0031] R.sup.15a, R.sup.15b are the same or different and mean hydrogen, C.sub.1-C.sub.10 alkyl, aryl, C.sub.7-C.sub.20 aralkyl or together a --(CH.sub.2).sub.q group, [0032] Hal means halogen, [0033] o means 2 to 4, [0034] q means 3 to 6, [0035] including all stereoisomers as well as their mixtures, and [0036] free hydroxyl a groups can be etherified or esterified in R.sup.13 and R.sup.14, free carbonyl groups can be ketalized in A and R.sup.13, converted into an enol ether or reduced, and free acid groups in A can be converted into their salts with bases. [0037] B stands for a C7-C12 fragment (epothilone numbering system) of general formula in which [0038] R.sup.3' means hydrogen, C.sub.1-C.sub.10 alkyl, aryl, C.sub.7-C.sub.20 aralkyl, [0039] R.sup.4a', R.sup.4b' are the same or different and mean hydrogen, C.sub.1-C.sub.10 alkyl, aryl, C.sub.7-C.sub.20 aralkyl or together a --(CH.sub.2).sub.p group with p=2, 3, 4, or 5, [0040] R.sup.5' means hydrogen, C.sub.1-C.sub.10 alkyl, aryl, C.sub.7-C.sub.20 aralkyl, [0041] D-E means a group [0042] V means an oxygen atom, two alkoxy groups OR.sup.17, a C.sub.2-C.sub.10 alkylene-.alpha.,.omega.-dioxy group, which can be straight-chain or branched or H/OR.sup.16, [0043] W means an oxygen atom, two alkoxy groups OR.sup.19, a C.sub.2-C.sub.10 alkylene-.alpha.,.omega.-dioxy group, which can be straight-chain or branched or H/OR.sup.18, [0044] R.sup.16, R.sup.18, independently of one another, mean hydrogen or a protective group PG.sup.1 [0045] R.sup.17, R.sup.19, independently of one another, mean C.sub.1-C.sub.20 alkyl. [0046] C stands for a C13-C16 fragment (epothilone numbering system) of general formula in which [0047] R.sup.8' means hydrogen, C.sub.1-C.sub.20 alkyl, aryl, C.sub.7-C.sub.20 aralkyl, which can all be substituted, and [0048] R.sup.7' means a hydrogen atom, [0049] R.sup.20 means a hydrogen atom or a protective group PG.sup.2, [0050] R.sup.21 means a hydroxy group, halogen, a protected hydroxy group OPG.sup.3, a phosphonium halide radical PPh.sub.3*Hal* (Ph=phenyl; Hal=F, Cl, Br, I), a phosphonate radical P(O)(OQ).sub.2 (Q=C.sub.1-C.sub.10 alkyl or phenyl) or a phosphine oxide radical P(O)Ph.sub.2 (Ph=phenyl) [0051] U means an oxygen atom, two alkoxy groups OR.sup.23, a C.sub.2-C.sub.10 alkylene-.alpha.,.omega.-dioxy group, which can be straight-chain or branched, H/OR.sup.9 or a grouping --CR.sup.10R.sup.11. [0052] whereby [0053] R.sup.23 stands for a C.sub.1-C.sub.20 alkyl radical, [0054] R.sup.9 stands or hydrogen or a protective group PG.sup.3, [0055] R.sup.10, R.sup.11 are the same or different and stand for hydrogen, ac C.sub.1-C.sub.20 alkyl, aryl, C.sub.7-C.sub.20 aralkyl radical or --R.sup.10 and R.sup.11 together with the methylene carbon atom commonly stand for a 5- to 7-membered carbocyclic ring. [0056] Substituents in Partial Fragments A, B, C: [0057] As alkyl groups R.sup.1a', R.sup.1b', R.sup.2a', R.sup.2b', R.sup.3', R.sup.4'. R.sup.5', R.sup.8', R.sup.9, R.sup.10, R.sup.11, R.sup.12, R.sup.13b, R.sup.14b, R.sup.15a, R.sup.15b, R.sup.17 and R.sup.23, straight-chain or branched-chain alkyl groups with 1-20 carbon atoms can be considered, such as, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, heptyl, hexyl, decyl. [0058] Alkyl groups R.sup.1a', R.sup.1b', R.sup.2a', R.sup.2b', R.sup.3', R.sup.4', R.sup.5', R.sup.8', R.sup.9, R.sup.10, R.sup.11, R.sup.12, R.sup.13b, R.sup.14b, R.sup.15a, R.sup.15b, R.sup.17 and R.sup.23 can be perfluorinated or substituted by 1-5 halogen atoms, hydroxy groups, C.sub.1-C.sub.4 alkoxy groups, C.sub.6-C.sub.12 aryl groups (which can be substituted by 1-3 halogen atoms). [0059] As aryl radicals R.sup.1a', R.sup.1b', R.sup.2a', R.sup.2b', R.sup.3', R.sup.4', R.sup.5', R.sup.8', R.sup.9, R.sup.10, R.sup.11, R.sup.12, R.sup.13b, R.sup.14b, R.sup.15a and R.sup.15b, substituted and unsubstituted carbocyclic or heterocyclic radicals with one or more heteroatoms, such as, e.g., phenyl, naphthyl, furyl, thienyl, pyridyl, pyrazolyl, pyrimidinyl, oxazolyl, pyridazinyl, pyrazinyl, quinolyl, thiazolyl, which can be substituted in one or more places by halogen, OH, O-alkyl, CO.sub.2H, CO.sub.2-alkyl, --NH.sub.2, --NO.sub.2, --N.sub.3, --CN, C.sub.1-C.sub.20 alkyl, C.sub.1-C.sub.20 acyl, C.sub.1-C.sub.20 acyloxy groups, are suitable. Heteroatoms in the heteroaryl radicals can be oxidized; thus, for example, the thiazole ring can be present in the form of N-oxide. [0060] The aralkyl groups in R.sup.1a', R.sup.1b', R.sup.2a', R.sup.2b', R.sup.3', R.sup.4', R.sup.5', R.sup.8', R.sup.9, R.sup.10, R.sup.11, R.sup.12, R.sup.13b, R.sup.14b, R.sup.15a and R.sup.15b can contain in the ring up to 14 C atoms, preferably 6 to 10, and in the alkyl chain 1 to 8, preferably 1 to 4 atoms. As aralkyl radicals, for example, benzyl, phenylethyl, naphthylmethyl, naphthylethyl, furylmethyl, thienylethyl, and pyridylpropyl are suitable. The rings can be substituted in one or more places by halogen, OH, O-alkyl, CO.sub.2H, CO.sub.2-alkyl, --NO.sub.2, --N.sub.3, --CN, C.sub.1-C.sub.20 alkyl, C.sub.1-C.sub.20 acyl, C.sub.1-C.sub.20 acyloxy groups. [0061] As representatives of protective groups PG, alkyl- and/or aryl-substituted silyl, C.sub.1-C.sub.20 alkyl, C.sub.4-C.sub.7 cycloalkyl, which in addition in the ring can contain ar oxygen atom, aryl, C.sub.7-C.sub.20 aralkyl, C.sub.1-C.sub.20 acyl and aroyl can be mentioned. [0062] As alkyl, silyl and acyl radicals for protective groups PG, the radicals that are known to one skilled in the art are suitable. Preferred are alkyl or silyl radicals that can be easily cleaned from the corresponding alkyl and silyl ethers, such as, for example, the methoxymethyl, methoxyethyl, ethoxyethyl, tetrahydropyranyl, tetrahydrofuranyl, trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl- , tert-butyldiphenylsilyl, tribenzylsilyl, triisopropylsilyl, benzyl, para-nitrobenzyl, para-methoxybenzyl radical as well as alkylsulfonyl and arylsulfonyl radicals. As acyl radicals, e.g., formyl, acetyl, propionyl, isopropionyl, pivalyl, butyryl or benzoyl, which can be substituted with amino and/or hydroxy groups, are suitable. Continue reading... Full patent description for Epothilone derivatives, process for their production, and their pharmaceutical use Brief Patent Description - Full Patent Description - Patent Application Claims Click on the above for other options relating to this Epothilone derivatives, process for their production, and their pharmaceutical use patent application. ###  How KEYWORD MONITOR works... a FREE service from FreshPatents1. Sign up (takes 30 seconds). 2. Fill in the keywords to be monitored. 3. Each week you receive an email with patent applications related to your keywords. Start now! - Receive info on patent apps like Epothilone derivatives, process for their production, and their pharmaceutical use or other areas of interest. ### Previous Patent Application: N-aryl piperidine substituted biphenylcarboxamides as inhibitors of apolipoprotein b secretion Next Patent Application: Pharmaceutical presentation form for oral administration of a poorly soluble active compound, process for its preparation and kit Industry Class: Drug, bio-affecting and body treating compositions ### FreshPatents.com Support Thank you for viewing the Epothilone derivatives, process for their production, and their pharmaceutical use patent info. IP-related news and info Results in 0.89552 seconds Other interesting Feshpatents.com categories: Accenture , Agouron Pharmaceuticals , Amgen , AT&T , Bausch & Lomb , Callaway Golf |
||
