US20040259922A1 - Epothilone derivatives, a process for their production thereof and their use - Google Patents

Epothilone derivatives, a process for their production thereof and their use Download PDF

Info

Publication number
US20040259922A1
US20040259922A1 US10/780,181 US78018104A US2004259922A1 US 20040259922 A1 US20040259922 A1 US 20040259922A1 US 78018104 A US78018104 A US 78018104A US 2004259922 A1 US2004259922 A1 US 2004259922A1
Authority
US
United States
Prior art keywords
compound
formula
group
alkyl
alkyl group
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
US10/780,181
Inventor
Gerhard Hoefle
Thomas Leibold
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Individual
Original Assignee
Individual
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Individual filed Critical Individual
Priority to US10/780,181 priority Critical patent/US20040259922A1/en
Publication of US20040259922A1 publication Critical patent/US20040259922A1/en
Abandoned legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates generally to epothilon derivatives, to processes for their production and to their use in the manufacture of medicaments and plant protection agents.
  • the invention relates especially to epothilon derivatives of the general formulae 2 to 6 shown below and to their use as medicaments and plant protection agents.
  • R 1 a H atom or a C 1 - to C 8 -alkyl group, preferably a C 1 - to C 6 -alkyl group, especially preferably a C 1 - to C 4 -alkyl group, especially a methyl, ethyl, propyl or butyl group,
  • R 2 a monocyclic aromatic group, such as a 5- or 6-membered aromatic group (such as a phenyl ring) or a vinyl group, each of which may be substituted in the ortho- and/or meta- and/or para-position(s) by one, two, three, four or five, especially one or two, halogen atoms and/or OR 4 and/or NR 5 R 6 groups and/or alkyl and/or alkenyl and/or alkynyl groups, wherein R 4 , R 5 and R 6 each independently of the others have the same meanings as R 1 , but are independent of R 1 , or
  • R 2 a monocyclic 5- or 6-membered heteroaromatic group which may have one or more, especially one or two, O and/or N and/or S atoms in the ring and/or may have OR 4 and/or NR 5 R 6 groups and/or alkyl and/or alkenyl and/or alkynyl groups as substituents, wherein R 4 , R 5 and R 6 are as defined above.
  • R 2 there are especially preferred C 1 -C 6 -alkyl or C 2 -C 6 -alkenyl and -alkynyl groups, especially C 1 -C 4 -alkyl or C 2 -C 4 -alkenyl and -alkynyl groups.
  • alkyl groups there are especially preferred methyl, ethyl, propyl and butyl groups and as heteroaromatic groups 6-membered heteroaromatic groups,
  • Hal a halogen atom, such as Br or I
  • X-Y a group of the formula —CH 2 CH—OP or —CH ⁇ CH—
  • P a protecting group, such as TMS.
  • the compounds according to the invention may be produced as follows:
  • Compounds of the formula (2) may be produced by reacting compounds of the formula (1)
  • Compounds of the formula (3) are obtainable by reacting a compound of the formula (2) with a compound of the formula HC[B(OR) 2 ] 3 , such as tris(ethylenedioxyboryl)methane; R may be an alkyl or alkenyl group as defined above.
  • a strong base such as a C 1 -C 4 -alkyl-Li compound (such as butyllithium) or a di-C 1 -C 4 -alkylamine-Li compound (such as a dimethylamine-lithium compound).
  • the reaction is generally carried out at low temperatures, such as, for example, at temperatures of less than ⁇ 30° C., preferably at temperatures of less than ⁇ 50° C., especially preferably at temperatures of at least ⁇ 78° C. Further reaction conditions may be found in D. Schummer, G. Höfle in Tetrahedron 1995, 51, 11219.
  • a compound of the formula (2) is reacted with tris(ethylenedioxyboryl)methane and butyllithium at ⁇ 78° C. to form a compound of the formula (3).
  • a compound of the formula (4) may be produced from a compound of the formula (3) by reaction with N-iodo- or N-bromo-succinimide, optionally in a polar solvent, such as acetonitrile. Further reaction conditions may be found in the following literature reference: N. A. Petasis, I. A. Zavialor, Tetrahedron Lett. 1996, 37, 567.
  • a compound of the formula (3) may be reacted within the framework of a Suzuki coupling with a compound of the formula R 2 -Z, wherein R 2 has the meanings given above and Z may be a halogen atom or a group of the formula —OSO 2 CF 3 , —CH ⁇ CHI, —CH ⁇ CHOSO 2 CF 3 .
  • the group R 2 -Z may especially have the following structures:
  • a 1 represents O, S, N or C atoms and the substituents O—, N— and C— correspond to the above-described groups OR 4 , NR 5 R 6 and alkyl, alkenyl and/or alkynyl groups.
  • substituents “C” are C 1 -C 6 -alkyl or C 2 -C 6 -alkenyl and/or -alkynyl groups, especially C 1 -C 4 -alkyl or C 2 -C 4 -alkenyl and/or -alkynyl groups.
  • alkyl groups there are especially preferred methyl, ethyl, propyl and butyl groups.
  • a compound of the formula (5) may be produced by reacting a compound of the formula (4) by means of a Stille coupling with R 2 —SnR 3 3 , wherein R 2 is as defined above and R 3 is a C 1 - to C 6 -alkyl group, preferably a C 1 - to C 4 -alkyl group and especially preferably a methyl, ethyl, propyl or butyl group.
  • R 2 —SnR 3 3 may have one of the following structures:
  • a compound of the formula (6) may be produced by removing the protecting group from the compound of the formula (5), for example with a weak acid, such as citric acid, or compounds such as TBAF, pyridine ⁇ HF.
  • a weak acid such as citric acid
  • compounds such as TBAF, pyridine ⁇ HF.
  • an alcohol such as methanol, may be used as solvent, the temperature preferably being adjusted to values of, for example, from 40 to 60° C., preferably about 50° C.
  • the compound of the formula (6) may be produced by the above-described steps (epothilon A or B ⁇ (2) ⁇ (3) ⁇ (4) ⁇ (5) ⁇ (6) or epothilon A or B ⁇ (2) ⁇ (3) ⁇ (5) ⁇ (6)).
  • medicaments that contain at least one of the compounds (2), (3), (4), (5) or (6) and optionally customary carriers, diluents and adjuvants.
  • Such compounds may especially be used also as cytostatic agents and for plant protection in agriculture and/or forestry and/or in horticulture, the compounds optionally being used together with one or more customary carriers, adjuvants and/or diluents.
  • N-iodosuccinimide (6.0 mg, 27 ⁇ mol) was added under inert gas and with the exclusion of light to a solution of alkenylboronic acid 3 (12 mg, 21 ⁇ mol; E/Z 9:1) in CH 3 CN (150 ⁇ l) and stirred for 3 hours. After concentration, the residue was purified by means of preparative thin-layer chromatography (SiO 2 , CH 2 Cl 2 /MeOH 95:5). 9 mg (66%) of the iodovinyl derivative 4 were isolated in the form of an E/Z-isomeric mixture (9:1).

Abstract

The present invention relates to epothilon derivatives, processes for their production and their use in the manufacture of medicaments and plant protection agents.

Description

  • The present invention relates generally to epothilon derivatives, to processes for their production and to their use in the manufacture of medicaments and plant protection agents. The invention relates especially to epothilon derivatives of the general formulae 2 to 6 shown below and to their use as medicaments and plant protection agents. [0001]
    Figure US20040259922A1-20041223-C00001
  • In the above formulae: [0002]
  • R[0003] 1=a H atom or a C1- to C8-alkyl group, preferably a C1- to C6-alkyl group, especially preferably a C1- to C4-alkyl group, especially a methyl, ethyl, propyl or butyl group,
  • R[0004] 2=a monocyclic aromatic group, such as a 5- or 6-membered aromatic group (such as a phenyl ring) or a vinyl group, each of which may be substituted in the ortho- and/or meta- and/or para-position(s) by one, two, three, four or five, especially one or two, halogen atoms and/or OR4 and/or NR5R6 groups and/or alkyl and/or alkenyl and/or alkynyl groups, wherein R4, R5 and R6 each independently of the others have the same meanings as R1, but are independent of R1, or
  • R[0005] 2=a monocyclic 5- or 6-membered heteroaromatic group which may have one or more, especially one or two, O and/or N and/or S atoms in the ring and/or may have OR4 and/or NR5R6 groups and/or alkyl and/or alkenyl and/or alkynyl groups as substituents, wherein R4, R5 and R6 are as defined above. In the definition of R2 there are especially preferred C1-C6-alkyl or C2-C6-alkenyl and -alkynyl groups, especially C1-C4-alkyl or C2-C4-alkenyl and -alkynyl groups. As alkyl groups there are especially preferred methyl, ethyl, propyl and butyl groups and as heteroaromatic groups 6-membered heteroaromatic groups,
  • Hal=a halogen atom, such as Br or I, [0006]
  • X-Y=a group of the formula —CH[0007] 2CH—OP or —CH═CH—, and
  • P=a protecting group, such as TMS. [0008]
  • The compounds according to the invention may be produced as follows: [0009]
  • Compounds of the formula (2) may be produced by reacting compounds of the formula (1) [0010]
    Figure US20040259922A1-20041223-C00002
  • as described in DE 195 42 986, the radicals being as defined above. In that reaction, especially the following conditions (i), (iii) and optionally (after (i)) also (ii) may be used: [0011]
  • (i) [0012]
  • (a) O[0013] 3 in a solvent, such as CH2Cl2, and
  • (b) reductive working-up, for example with Me[0014] 2S;
  • (ii) [0015]
  • (a) (CH[0016] 3CO)2O, HCO2H, NEt3, DMAP;
  • (b) DBU; and [0017]
  • (c) MeOH, NH[0018] 3; and
  • (iii) Me[0019] 3SiCl, NEt3.
  • Compounds of the formula (3) are obtainable by reacting a compound of the formula (2) with a compound of the formula HC[B(OR)[0020] 2]3, such as tris(ethylenedioxyboryl)methane; R may be an alkyl or alkenyl group as defined above.
  • In the reaction there is optionally used a strong base, such as a C[0021] 1-C4-alkyl-Li compound (such as butyllithium) or a di-C1-C4-alkylamine-Li compound (such as a dimethylamine-lithium compound). The reaction is generally carried out at low temperatures, such as, for example, at temperatures of less than −30° C., preferably at temperatures of less than −50° C., especially preferably at temperatures of at least −78° C. Further reaction conditions may be found in D. Schummer, G. Höfle in Tetrahedron 1995, 51, 11219.
  • For example, a compound of the formula (2) is reacted with tris(ethylenedioxyboryl)methane and butyllithium at −78° C. to form a compound of the formula (3). [0022]
  • A compound of the formula (4) may be produced from a compound of the formula (3) by reaction with N-iodo- or N-bromo-succinimide, optionally in a polar solvent, such as acetonitrile. Further reaction conditions may be found in the following literature reference: N. A. Petasis, I. A. Zavialor, [0023] Tetrahedron Lett. 1996, 37, 567.
  • For the production of a compound of the formula (5), a compound of the formula (3) may be reacted within the framework of a Suzuki coupling with a compound of the formula R[0024] 2-Z, wherein R2 has the meanings given above and Z may be a halogen atom or a group of the formula —OSO2CF3, —CH═CHI, —CH═CHOSO2CF3. The group R2-Z may especially have the following structures:
    Figure US20040259922A1-20041223-C00003
  • wherein A[0025] 1 represents O, S, N or C atoms and the substituents O—, N— and C— correspond to the above-described groups OR4, NR5R6 and alkyl, alkenyl and/or alkynyl groups.
  • Especially preferred as substituents “C” are C[0026] 1-C6-alkyl or C2-C6-alkenyl and/or -alkynyl groups, especially C1-C4-alkyl or C2-C4-alkenyl and/or -alkynyl groups. As alkyl groups there are especially preferred methyl, ethyl, propyl and butyl groups.
  • Alternatively, a compound of the formula (5) may be produced by reacting a compound of the formula (4) by means of a Stille coupling with R[0027] 2—SnR3 3, wherein R2 is as defined above and R3 is a C1- to C6-alkyl group, preferably a C1- to C4-alkyl group and especially preferably a methyl, ethyl, propyl or butyl group. In addition, the compound R2—SnR3 3 may have one of the following structures:
    Figure US20040259922A1-20041223-C00004
  • wherein the radicals and substituents are as defined above. [0028]
  • Furthermore, according to the invention, a compound of the formula (6) may be produced by removing the protecting group from the compound of the formula (5), for example with a weak acid, such as citric acid, or compounds such as TBAF, pyridine×HF. Optionally an alcohol, such as methanol, may be used as solvent, the temperature preferably being adjusted to values of, for example, from 40 to 60° C., preferably about 50° C. [0029]
  • In summary, the compound of the formula (6) may be produced by the above-described steps (epothilon A or B→(2)→(3)→(4)→(5)→(6) or epothilon A or B→(2)→(3)→(5)→(6)). [0030]
  • According to the invention there are also disclosed medicaments that contain at least one of the compounds (2), (3), (4), (5) or (6) and optionally customary carriers, diluents and adjuvants. [0031]
  • Such compounds may especially be used also as cytostatic agents and for plant protection in agriculture and/or forestry and/or in horticulture, the compounds optionally being used together with one or more customary carriers, adjuvants and/or diluents.[0032]
    • EXAMPLES
  • Synthesis of the Ketone Derivatives 2 [0033]
  • For a detailed description see DE 195 42 986 A1. [0034]
  • Synthesis of the Alkenylboronic Acid Derivatives 3 [0035]
  • (see also D. Schummer, G. Höfle, [0036] Tetrahedron 1995, 51, 11219)
  • Typical Example (R[0037] 1=H, X-Y=CH2CHOTMS):
  • A solution of tris(ethylenedioxyboryl)methane (0.30 g, 1.5 mmol) in CH[0038] 2Cl2/THF (1:1; 4 ml) was prepared and cooled under inert gas to −78° C. At that temperature, butyllithium (1.6M solution in hexane; 0.73 ml, 1.2 mmol) was added drop-wise in the course of 10 minutes. After 2 hours, ketone 2 (81 mg, 0.15 mmol) in CH2Cl2/THF (1:1, 2 ml) was added, heated to room temperature and stirred for 17 hours. After the addition of MeOH (2 ml), the clear reaction solution was purified by means of preparative HPLC (Lichroprep RP-18, CH3CN/H2O 75:25). 57 mg (65%) of alkenylboronic acid 3 were obtained in the form of an E/Z-isomeric mixture (6:4).
  • Selected typical data: LC-MS (ESI-MS): 585 (M[0039] ++H); 1H-NMR: (300 MHz, CD3OD): E-isomer: 1.91 (S, 3H), 5.16 (d, 1H, 10 Hz), 5.49 (s, 1H), Z-isomer; 1.85 (d, 3H, 1.1 Hz), 4.93 (s, 1H), 5.26 (d, 1H, 9.6 Hz).
  • Synthesis of the Iodovinyl Derivatives 4 [0040]
  • (see also N. A. Petasis, I. A. Zavialor, [0041] Tetrahedron Lett. 1996, 37, 567)
  • Typical Example (R[0042] 1=H, X-Y=CH2CHOTMS):
  • At room temperature, N-iodosuccinimide (6.0 mg, 27 μmol) was added under inert gas and with the exclusion of light to a solution of alkenylboronic acid 3 (12 mg, 21 μmol; E/Z 9:1) in CH[0043] 3CN (150 μl) and stirred for 3 hours. After concentration, the residue was purified by means of preparative thin-layer chromatography (SiO2, CH2Cl2/MeOH 95:5). 9 mg (66%) of the iodovinyl derivative 4 were isolated in the form of an E/Z-isomeric mixture (9:1).
  • Selected typical data: LC-MS (ESI-MS): 667 (M[0044] ++H); 1H-NMR: (300 MHz, CDCl3); E-isomer: 1.82 (d, 3H, 1.1 Hz), 5.36 (d, 1H, 11 Hz), 6.43 (s, 1H), Z-isomer: 1.84 (d, 3H, 1.1 Hz), 5.54 (d, 1H, 10.5 Hz), 6.09 (s, 1H).
  • Suzuki Coupling of the Alkenylboronic Acid 3 [0045]
  • (see also A. Suzuki, [0046] Acc. Chem. Res. 1982, 15, 178; A. Torrado, S. Lopez, R. Alvarez, A. R. De Lera Synthesis, 1995, 285)
  • Typical Example (R[0047] 1=H, X-Y=CH2CHOTMS, R2=Ph):
  • A solution of alkenylboronic acid 3 (12 mg, 21 μmol; E/Z 2:8) and thallium ethanolate (2M solution in EtOH; 12 μl, 24 μmol) in THF (150 μl) was stirred at room temperature for 15 minutes, then a solution of phenyl iodide (4.0 μl, 6.0 mg, 29 μmol) and tetrakis(triphenylphosphino)-palladium (7.1 mg, 6.2 μmol) in THF (150 μl) was added drop-wise in 30 minutes and again stirred for 30 minutes. After purification by means of preparative thin-layer chromatography (SiO[0048] 2, CH2Cl2/Et2O 95:5) the phenyl-analogous epothilon 5 (10 mg, 79%, E/Z 2:8) was obtained in the form of a colourless solid.
  • Selected typical data: LC-MS (ESI-MS): 617 (M[0049] ++H); 1H-NMR: (300 MHz, CDCl3): E-isomer: 1.87 (d, 3H, 1.4 Hz), 5.35 (d, 1H, 10.7 Hz), 6.54 (s, 1H), Z-isomer: 1.80 (d, 3H, 1.5 Hz), 5.61 (d, 1H, 10.2 Hz), 6.41 (s, 1H).
  • Stille Coupling of the Iodovinyl Derivatives 4 [0050]
  • (see also K. C. Nicolaou, Y. He, F. Roschangar, N. P. King, D. Vourloumis, T. Li [0051] Angew. Chem. 1998, 110, (1/2), 89)

Claims (14)

1-17. (cancelled)
18. A compound of formula:
Figure US20040259922A1-20041223-C00005
wherein
R1 is a H atom or a C1- to C8-alkyl group,
X-Y is a group of the formula —CH2CH(OP)— or —CH═CH—,
P is a protecting group, and
each R is independently a C1- to C8-alkyl group or a C2- to C6-alkenyl group.
19. The compound of claim 18 wherein at least one R is a C1- to C6-alkyl group.
20. The compound of claim 18 wherein at least one R is a C1- to C4-alkyl group.
21. The compound of claim 18 wherein at least one R is a C2- to C6-alkenyl group.
22. The compound of claim 18 wherein at least one R is a C2- to C4-alkenyl group.
23. The compound of claim 18 wherein R1 is a H atom or a C1- to C6-alkyl group.
24. The compound of claim 18 wherein R1 is a H atom or a methyl group.
25. A process for preparing a compound of the formula
Figure US20040259922A1-20041223-C00006
wherein
R1 is a H atom or a C1- to C8-alkyl group,
X-Y is a group of the formula —CH2CH(OP)— or —CH═CH—,
P is a protecting group, and
each R is independently a C1- to C8-alkyl group or a C2- to C6-alkenyl group;
comprising: reacting a compound of the formula 2:
Figure US20040259922A1-20041223-C00007
with a compound of the formula HC[B(OR)2]3.
26. The process according to claim 25 wherein the compound of the formula HC[B(OR)2]3 is tris(ethylenedioxyboryl)methane.
27. The process according to claim 25 wherein the compound of the formula 2 and the compound of the formula HC[B(OR)2]3 are reacted in the presence of a strong base.
28. The process according to claim 27 wherein the strong base is a C1-C4-alkyl lithium compound or a di-C1-C4-alkylamine lithium compound.
29. The process according to claim 28 wherein the strong base is butyllithium or dimethylamine lithium compound.
30. The process according to claim 25 wherein the compound of the formula II and the compound of the formula HC[B(OR)2]3 are reacted at a temperature of less than about −30° C.
US10/780,181 1998-05-08 2004-02-17 Epothilone derivatives, a process for their production thereof and their use Abandoned US20040259922A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US10/780,181 US20040259922A1 (en) 1998-05-08 2004-02-17 Epothilone derivatives, a process for their production thereof and their use

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
DE19820599A DE19820599A1 (en) 1998-05-08 1998-05-08 New epothilone derivatives useful as pharmaceuticals and in plant protection
DE19820599.6 1998-05-08
US09/674,877 US6982280B1 (en) 1998-05-08 1999-05-07 Epothilone derivatives, a method for the production thereof, and their use
US10/780,181 US20040259922A1 (en) 1998-05-08 2004-02-17 Epothilone derivatives, a process for their production thereof and their use

Related Parent Applications (2)

Application Number Title Priority Date Filing Date
US09/674,877 Division US6982280B1 (en) 1998-05-08 1999-05-07 Epothilone derivatives, a method for the production thereof, and their use
PCT/EP1999/003159 Division WO1999058534A2 (en) 1998-05-08 1999-05-07 Epothilone derivatives, a method for the production thereof, and their use

Publications (1)

Publication Number Publication Date
US20040259922A1 true US20040259922A1 (en) 2004-12-23

Family

ID=7867085

Family Applications (2)

Application Number Title Priority Date Filing Date
US09/674,877 Expired - Fee Related US6982280B1 (en) 1998-05-08 1999-05-07 Epothilone derivatives, a method for the production thereof, and their use
US10/780,181 Abandoned US20040259922A1 (en) 1998-05-08 2004-02-17 Epothilone derivatives, a process for their production thereof and their use

Family Applications Before (1)

Application Number Title Priority Date Filing Date
US09/674,877 Expired - Fee Related US6982280B1 (en) 1998-05-08 1999-05-07 Epothilone derivatives, a method for the production thereof, and their use

Country Status (14)

Country Link
US (2) US6982280B1 (en)
EP (1) EP1077980B1 (en)
JP (1) JP2002514649A (en)
KR (1) KR20010052325A (en)
AR (1) AR018344A1 (en)
AT (1) ATE234842T1 (en)
AU (1) AU754212B2 (en)
CA (1) CA2330812A1 (en)
DE (2) DE19820599A1 (en)
ES (1) ES2195577T3 (en)
HU (1) HUP0102283A3 (en)
IL (1) IL139480A0 (en)
TW (1) TW568910B (en)
WO (1) WO1999058534A2 (en)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8008256B2 (en) 2006-05-01 2011-08-30 University Of Southern California Combination therapy for treatment of cancer
US8685668B2 (en) 2005-02-11 2014-04-01 University Of Southern California Method of expressing proteins with disulfide bridges
US8802394B2 (en) 2008-11-13 2014-08-12 Radu O. Minea Method of expressing proteins with disulfide bridges with enhanced yields and activity

Families Citing this family (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0977563B1 (en) 1996-12-03 2005-10-12 Sloan-Kettering Institute For Cancer Research Synthesis of epothilones, intermediates thereto, analogues and uses thereof
GB9810659D0 (en) 1998-05-18 1998-07-15 Ciba Geigy Ag Organic compounds
US6518421B1 (en) 2000-03-20 2003-02-11 Bristol-Myers Squibb Company Process for the preparation of epothilone analogs
EP1483251B1 (en) 2002-03-12 2009-12-23 Bristol-Myers Squibb Company C3-cyano epothilone derivatives
DE10355223A1 (en) 2003-11-26 2005-06-30 Institut für Pflanzenbiochemie (IPB) New macrocycles for the treatment of cancer
EP1674098A1 (en) 2004-12-23 2006-06-28 Schering Aktiengesellschaft Stable and tolerable parental formulations of highly reactive organic drug substances with low or no solubility in water
EP1994412A2 (en) 2006-03-31 2008-11-26 Brystol-Myers Squibb Company Biomarkers and methods for determining sensitivity to microtubule-stabilizing agents
EP2065054A1 (en) 2007-11-29 2009-06-03 Bayer Schering Pharma Aktiengesellschaft Combinations comprising a prostaglandin and uses thereof
DE102007059752A1 (en) 2007-12-10 2009-06-18 Bayer Schering Pharma Aktiengesellschaft Functionalized solid polymer nanoparticles containing epothilones
EP2070521A1 (en) 2007-12-10 2009-06-17 Bayer Schering Pharma Aktiengesellschaft Surface-modified nanoparticles
EP2210584A1 (en) 2009-01-27 2010-07-28 Bayer Schering Pharma Aktiengesellschaft Stable polymeric composition comprising an epothilone and an amphiphilic block copolymer
EP2793947B1 (en) 2011-12-23 2021-02-03 Innate Pharma Enzymatic conjugation of polypeptides
US10132799B2 (en) 2012-07-13 2018-11-20 Innate Pharma Screening of conjugated antibodies
EP3564259A3 (en) 2012-11-09 2020-02-12 Innate Pharma Recognition tags for tgase-mediated conjugation
WO2014140300A1 (en) 2013-03-15 2014-09-18 Innate Pharma Solid phase tgase-mediated conjugation of antibodies
EP3010547B1 (en) 2013-06-20 2021-04-21 Innate Pharma Enzymatic conjugation of polypeptides
EP3010548A1 (en) 2013-06-21 2016-04-27 Innate Pharma Enzymatic conjugation of polypeptides
WO2019092148A1 (en) 2017-11-10 2019-05-16 Innate Pharma Antibodies with functionalized glutamine residues

Citations (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5351146A (en) * 1993-03-01 1994-09-27 At&T Bell Laboratories All-optical network architecture
US5781537A (en) * 1995-07-07 1998-07-14 International Business Machines Corporation Setting up, taking down and maintaining connections in a communications network
US6304349B1 (en) * 1998-06-30 2001-10-16 Lucent Technologies Inc. WDM optical communications networks and methods for provisioning
US6380394B1 (en) * 1996-12-13 2002-04-30 The Scripps Research Institute Epothilone analogs
US20020097671A1 (en) * 2000-12-21 2002-07-25 At&T Corp. Method for selecting a restoration path in a mesh network
US6445844B1 (en) * 1999-09-15 2002-09-03 Xros, Inc. Flexible, modular, compact fiber optic switch
US20020126343A1 (en) * 2000-11-14 2002-09-12 Andrea Fumagalli System and method for configuring optical circuits
US20020154357A1 (en) * 2001-03-29 2002-10-24 Cuneyt Ozveren Methods and apparatus for reconfigurable WDM lightpath rings
US20020194339A1 (en) * 2001-05-16 2002-12-19 Lin Philip J. Method and apparatus for allocating working and protection bandwidth in a telecommunications mesh network
US20020196808A1 (en) * 2001-02-21 2002-12-26 Ramesh Karri Signaling for reserving a communications path
US20030009582A1 (en) * 2001-06-27 2003-01-09 Chunming Qiao Distributed information management schemes for dynamic allocation and de-allocation of bandwidth

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE4138042C2 (en) * 1991-11-19 1993-10-14 Biotechnolog Forschung Gmbh Epothilones, their production processes and agents containing these compounds
DE19542986A1 (en) * 1995-11-17 1997-05-22 Biotechnolog Forschung Gmbh New epothilone derivatives useful as cytostatics
DK1186606T4 (en) 1995-11-17 2011-12-05 Biotechnolog Forschung Gmbh Epothilone derivatives, their preparation and use
KR100538095B1 (en) 1996-11-18 2005-12-21 게젤샤프트 퓌어 비오테크놀로기쉐 포르슝 엠베하(게베에프) Epothilone c, d, e and f, production process, and their use as cytostatic as well as phytosanitary agents

Patent Citations (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5351146A (en) * 1993-03-01 1994-09-27 At&T Bell Laboratories All-optical network architecture
US5781537A (en) * 1995-07-07 1998-07-14 International Business Machines Corporation Setting up, taking down and maintaining connections in a communications network
US6380394B1 (en) * 1996-12-13 2002-04-30 The Scripps Research Institute Epothilone analogs
US6304349B1 (en) * 1998-06-30 2001-10-16 Lucent Technologies Inc. WDM optical communications networks and methods for provisioning
US6445844B1 (en) * 1999-09-15 2002-09-03 Xros, Inc. Flexible, modular, compact fiber optic switch
US20020126343A1 (en) * 2000-11-14 2002-09-12 Andrea Fumagalli System and method for configuring optical circuits
US20020097671A1 (en) * 2000-12-21 2002-07-25 At&T Corp. Method for selecting a restoration path in a mesh network
US20020196808A1 (en) * 2001-02-21 2002-12-26 Ramesh Karri Signaling for reserving a communications path
US20020154357A1 (en) * 2001-03-29 2002-10-24 Cuneyt Ozveren Methods and apparatus for reconfigurable WDM lightpath rings
US20020194339A1 (en) * 2001-05-16 2002-12-19 Lin Philip J. Method and apparatus for allocating working and protection bandwidth in a telecommunications mesh network
US20030009582A1 (en) * 2001-06-27 2003-01-09 Chunming Qiao Distributed information management schemes for dynamic allocation and de-allocation of bandwidth

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8685668B2 (en) 2005-02-11 2014-04-01 University Of Southern California Method of expressing proteins with disulfide bridges
US8008256B2 (en) 2006-05-01 2011-08-30 University Of Southern California Combination therapy for treatment of cancer
US8802394B2 (en) 2008-11-13 2014-08-12 Radu O. Minea Method of expressing proteins with disulfide bridges with enhanced yields and activity

Also Published As

Publication number Publication date
EP1077980A2 (en) 2001-02-28
CA2330812A1 (en) 1999-11-18
HUP0102283A2 (en) 2001-10-28
KR20010052325A (en) 2001-06-25
IL139480A0 (en) 2001-11-25
JP2002514649A (en) 2002-05-21
AR018344A1 (en) 2001-11-14
AU754212B2 (en) 2002-11-07
EP1077980B1 (en) 2003-03-19
ES2195577T3 (en) 2003-12-01
AU4361199A (en) 1999-11-29
DE19820599A1 (en) 1999-11-11
HUP0102283A3 (en) 2002-03-28
ATE234842T1 (en) 2003-04-15
DE59904632D1 (en) 2003-04-24
TW568910B (en) 2004-01-01
WO1999058534A2 (en) 1999-11-18
US6982280B1 (en) 2006-01-03
WO1999058534A3 (en) 2000-01-13

Similar Documents

Publication Publication Date Title
US20040259922A1 (en) Epothilone derivatives, a process for their production thereof and their use
MXPA06000951A (en) Regioselective synthesis of cci-779.
KR102621941B1 (en) Method for the synthesis of rapamycin derivatives
HU203555B (en) Process for producing glycero-phospho-colin- and glycero-phospho-etanol-amine derivatives
US6008363A (en) Process for producing guanidine derivatives, intermediates therefor and their production
KR101728443B1 (en) Method for Producing Benzyl Ester 2-aminonicotinicotinate Derivative
CN110950836B (en) Preparation method of benzodithiol heterocyclic alkene skeleton compound
Reddy et al. Chemo‐and regioselective allylic oxidation: Oxo‐derivatives of 2‐phospholene sugar analogs
CN105037428A (en) Preparation method for coumarin-3-phosphonate derivative
US4927943A (en) Substituted 7-oxomitosanes
JP5270549B2 (en) Method for producing HI-6 dimethanesulfonate
US5654429A (en) Method for the preparation of 3-amino-2-chloro-4-alkylpyridines
KR0145402B1 (en) Process for preparing of (+)2-benzoyl-3-c silyloxyprop-2(s)-yl) aminoacrylatederivatives
US5233045A (en) Process for the preparation of imidazothiazolone derivatives
CA2508341A1 (en) Processes for preparing quinolonecarboxylate derivatives
Bradbury et al. Synthesis of analogs of prostacyclin containing a thiazone ring
SE411120B (en) PROCEDURE FOR THE PREPARATION OF 2-HYDRAZINOBENSOTIAZOLES BY OMAMINATION
JP4016098B2 (en) Novel 1,3-selenazoline derivative and method for producing the same
KR20080047315A (en) Process for producing tricyclic ketone
CS235986B2 (en) Method of 1,1-dioxopenicilanoyloxy-methyl-6-beta-amino- penicilanate production
JP2023023286A (en) Method for manufacturing silafluorene derivative
KR100449310B1 (en) preparation method of 2-deoxy-L-ribose
US5097036A (en) Substituted 7-oxomitosanes
KR20220033267A (en) Method of manufacturing alkyl-D-alaninate
MXPA00010953A (en) Epothilone derivatives, a method for the production thereof, and their use

Legal Events

Date Code Title Description
STCB Information on status: application discontinuation

Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION