Effector conjugates, process for their production and their pharmaceutical use

• US 7,129,254 B2
• Filed: 07/31/2003
• Issued: 10/31/2006
• Est. Priority Date: 07/31/2002
• Status: Expired due to Fees

• Current Assignee: Bayer Schering Pharma AG (Bayer AG)
• Original Assignee: Schering Ag (Merck & Co., Inc.)
• Inventors: Berger, Markus, Bosslet, Klaus, Klar, Ulrich, Siemeister, Gerhard, Menrad, Andreas, Willuda, Jorg
• Primary Examiner(s): SOLOLA, TAOFIQ A
• Application Number:
  US10/631,011
• Publication Number:
  US 20050026971A1
• Time in Patent Office: 1,188 Days
• Field of Search: 514/340, 514/365, 514/374, 514/378, 514/372, 546/268.1, 548/146, 548/206, 548/215, 548/240, 549/357
• US Class Current: 514/340
• CPC Class Codes: A61K 47/6809 Antibiotics, e.g. antitumor antibiotics anthracyclins, adriamycin, doxorubicin or daunomycin
• CPC Class Codes: A61K 47/6851 the antibody targeting a determinant of a tumour cell
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07D 405/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 413/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 413/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 417/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 417/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 417/14 containing three or more hetero rings
• CPC Class Codes: C07D 493/04 Ortho-condensed systems

Abstract

Conjugates of epothilones and epothilone derivatives (as effectors) with suitable biomolecules (as recognition units) are described. Their production is carried out by the effectors being reacted with suitable linkers, and the compounds that are produced are conjugated to the recognition units. The pharmaceutical use of the conjugates for treating proliferative or angiogenesis-associated processes is described.

Claims

1. An effector recognition unit conjugate of formula (I),

2. An effector recognition unit conjugate according to claim 1, wherein the effector element is

(4S,7R,8S,9S,13Z,16S)-4,8-Dihydroxy-7-allyl-5,5,9,13-tetramethyl-16-(2methyl-benzothiazol-5-yl)-oxacyclohexadec-13-ene-2,6-dione;

(4S,7R,8S,9S,13Z,16S)-4,8-Dihydroxy-16-(2-hydroxymethyl-benzothiazol-5-yl)-7-allyl-5,5,9,13-tetramethyl-oxacyclohexadec-13-ene-2,6-dione;

(4S,7R,8S,9S,13Z,16S)-16-(2-Aminomethyl-benzothiazol-5-yl)-4,8-dihydroxy-7-allyl-5,5,9,13-tetramethyl-oxacyclohexadec-13-ene-2,6-dione;

(1S,3S,7S,10R,11S,12S,16R)-7,11-Dihydroxy-10-allyl-8,8,12,16-tetramethyl-3-(2-methyl-benzothiazol-5-yl)-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dione;

(1S,3S,7S,10R,11S,12S,16R)-7,11-Dihydroxy-3-(2-hydroxymethyl-benzothiazol-5-yl)-10-allyl-8,8,12,16-tetramethyl-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dione;

(1S,3S,7S,10R,11S,12S,16R)-3-(2-Aminomethyl-benzothiazol-5-yl)-7,11-dihydroxy-10-allyl-8,8,12,16-tetramethyl-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dione;

(4S,7R,8S,9S,13Z,16S)-4,8-Dihydroxy-7-allyl-5,5,9,13-tetramethyl-16-(2methyl-benzoxazol-5-yl)-oxacyclohexadec-13-ene-2,6-dione;

(4S,7R,8S,9S,13Z,16S)-4,8-Dihydroxy-16-(2-hydroxymethyl-benzoxazol-5-yl)-7-allyl-5,5,9,13-tetramethyl-oxacyclohexadec-13-ene-2,6-dione;

(4S,7R,8S,9S,13Z,16S)-16-(2-Aminomethyl-benzoxazol-5-yl)-4,8-dihydroxy-7-allyl-5,5,9,13-tetramethyl-oxacyclohexadec-13-ene-2,6-dione;

(1S,3S,7S,10R,11S,12S,16R)-7,11-Dihydroxy-10-allyl-8,8,12,16-tetramethyl-3-(2-methyl-benzoxazol-5-yl)-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dione;

(1S,3S,7S,10R,11S,12S,16R)-7,11-Dihydroxy-3-(2-hydroxymethyl-benzoxazol-5-yl)-10-allyl-8,8,12,16-tetramethyl-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dione;

(1S,3S,7S,10R,11S,12S,16R)-3-(2-Aminomethyl-benzoxazol-5-yl)-7,11-dihydroxy-10-allyl-8,8,12,16-tetramethyl-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dione;

wherein the hydrogen atoms in the above-mentioned effector elements are replaced in the positions indicated in formula (I) by radicals L¹–

L³.

3. An effector recognition unit conjugate according to claim 1, wherein the linker is a compound of formula (III), wherein

V represents a bond or an aryl radical,

o is zero, and

T is an oxygen atom.

4. An effector recognition unit conjugate according to claim 1, wherein the linker is a compound of formula (III), wherein

V represents a bond or an aryl radical or a group

5. An effector recognition unit conjugate according to claim 4, wherein

V is a bond or a group

6. An effector recognition unit conjugate according to claim 1, wherein the linker is a compound of formula (IV), wherein

o is 0 to 4, and

q is 0 to 3.

7. An effector recognition unit conjugate according to claim 6, wherein

o is 0, 2 or 3,

W¹ is oxygen,

q is 0,

R²² is hydrogen, C₁–

C₃ alkyl or aralkyl,

R²³ is hydrogen or C₁–

C₃ alkyl,

R^24a is hydrogen or C₁–

C₃ alkyl,

R²⁷ is fluorine, chlorine, CN, NO₂, CO₂R²⁸ or OR²⁸,

R²⁸ is hydrogen or C₁–

C₅ alkyl, and

U is oxygen, CHR²², or CHR²²—

NR²³—

C(═

O)—

.

8. An effector recognition unit conjugate according to claim 1, wherein the conjugate contains more than one recognition unit, and wherein the recognition units are identical.

9. An effector recognition unit conjugate according to claim 1, wherein the recognition unit is an antibody, or an antigen-binding fragment thereof, which is specific for an antigen that is selected from OC 125, OC 133, OMI, Mo v1, Mo v2, 3C2, 4C7, ID3, DU-PAN-2, F 36/22, 4F7/7A 10, OV-TL3, B72.3, DF3, 2C8/2F7, MF 116, Mov18, CEA 11-H5, CA 19-9, (1116NS 19-9), H17-E2, 791T/36, NDOG2, H317, 4D5, 3H4, 7C2, 6E9, 2C4, 7F3, 2H11, 3E8, 5B8, 7D3, SB8, HMFG2, 3.14.A3, DF3, NCRC-11, 3C6F9, MBE6, CLNH5, MAC 40/43, EMA, HMFG1 HFMG2, 3.15.C3, M3, M8, M24, M18, 67-D-11, D547Sp, D75P3, H222, Anti EGF, LR-3, TA1, H59, 10-3D-2, HmAB1,2, MBR 1,2,3, 24-17-1, 24-17-2 (3E1-2), F36/22, M7/105, C11, G3, H7, B6-2, B1-1, Cam 17-1, SM3, SM4, C-Mul (566), 4D5 3H4, 7C2, 6E9, 2C4, 7F3, 2H11, 3E8, 5B8, 7D3, 5B8, OC 125, MO v2, DU-PAN-2, 4F7/7A10, DF3, B72-3, cccccCEA 11, H17-E2, 3-14-A3, FO23C5, B72-3, (17-1A) 1038-17-1A, CO17-1A, ZCE-025, AB2, HT-29-15, 250-30.6, 44X14, A7, GA73-3, 791T/36, 28A32, 28.19.8, X MMCO-791, DU-PAN-2, ID3, CEA, 11-H5, 2C8/2F7, CA-19-9 (1116NS 19-9), PR5C5, PR4D2, PR4D1, 4-1, 8-2 M17, 96-5, 118-1, 133-2, (113-2), L1, L10, R10 (R19), I12, K5, 6-1, R24, 5-1, 225.28S, 465.12S, 9-2-27, F11, 376.96S, 465.12S, 15-75, 15-95, Mel-14, Mel-12, Me3-TB7, 225.28SD, 763.24TS, 705F6, 436910, M148, ID3, DU-PAN-2, OV-TL3, B72-3, CEA 11-H5, 3-14-A3,C COLI, CA-19-9, 1116NS 19-9) and CA50, OC125, 4D5, 3H4, 7C2, 6E9, 2C4, 7F3, 2H11, 3E8, 5B8, 7D3, SB8, MC v2, B72-3, DU-PAN-2, CEA 11-H5, MUG 8-22, MUG 2-63, MUC 2-39, MUG 7-39, PAb 240, PAb 246, PAb 1801, ERIC-1, M148, FMH25, 6-1, CA1, 3F8, 4F7/7A10, 2C8/2F7, CEA, 11-H5, 2H8, 10G6, CD19, CD20, CD40, CD22, CD25, CD5, CD52, CD10, CD2, CD7, CD33, CD38, CD40, CD72, CD4, CD21, CD37, CD30, VCAM, CD31, ELAM, endoglin, VEGFRI/II, α

_vβ

₃, Tie1/2, TES23 (CD44ex6), phosphatidylserine, PSMA, VEGFR/VEGF complex and ED-B-fibronectin.

10. An effector recognition unit conjugate according to claim 1, wherein Z is oxygen.

11. A method for preparing an effector recognition unit conjugate according to claim 1 comprising reacting an effector conjugate of formula (I) with at least one recognition unit selected from peptides, soluble receptors, cytokines, lymphokines, aptamers, spiegelmers, recombinant proteins, new framework structures, monoclonal antibodies and fragments of monoclonal antibodies.

12. A method according to claim 11, wherein the effector conjugate of formula (I), is prepared by reacting a compound of formula (I), wherein at least one substituent L¹, L² or L⁴ represent a linker of formula (III) or (IV), and at least one substituent L¹, L² or L⁴ represents hydrogen, a group C(═

O)Cl, or a group C(═

S)Cl,

with a linker that is selected from a linker of formula (III¹), (III²), (III³), (IV¹), (IV²) and (IV³),

13. A method according to claim 11, wherein in the effector conjugate of formula (I) at least one substituent L¹, L² or L⁴ represent a linker of formula (III) or (IV), and at least one substituent L¹, L² or L⁴ represents hydrogen, a group C(═

O)Cl, or a group C(═

S)Cl.

14. A pharmaceutical composition comprising an effector recognition unit conjugate according to claim 1 and a pharmaceutically acceptable carrier.

15. A method for treating a tumor comprising administering to a patient in need thereof an effective amount of a pharmaceutical composition according to claim 14.