PYRROLOBENZODIAZEPINES AND CONJUGATES THEREOF

• US 20140120118A1
• Filed: 10/11/2013
• Published: 05/01/2014
• Est. Priority Date: 10/12/2012
• Status: Active Grant

• Current Assignee: MedImmune Ltd. (Astrazeneca PLC)
• Original Assignee: Spirogen SARL (Astrazeneca PLC)
• Inventors: HOWARD, Philip Wilson
• Granted Patent: US 9,415,117 B2
• Time in Patent Office: Days
• US Class Current: 424/178.1
• CPC Class Codes: A61K 47/68035 the drug being a pyrrolobenzodiazepine
• CPC Class Codes: A61K 47/6855 the tumour determinant being from breast cancer cell
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 39/00 General protective or antinoxious agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 487/04 Ortho-condensed systems
• CPC Class Codes: C07D 519/00 Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Abstract

A compound which is selected from A:

B:

and C:

and salts and solvates thereof, as well as conjugates thereof with cell binding agent.

Claims

1. A compound which is selected from A:

15. A method of preparing a conjugate according to claim 2, the method comprising the step of reacting a cell binding agent with compound A, B or C as defined in claim 1.

2. A conjugate of formula ConjA:

3. The conjugate according to claim 2, wherein the cell binding agent is an antibody or an active fragment thereof.

4. The conjugate according to claim 3, wherein the antibody or antibody fragment is an antibody or antibody fragment for a tumour-associated antigen.

5. The conjugate of claim 3 wherein the antibody or antibody fragment is an antibody which binds to one or more tumor-associated antigens or cell-surface receptors selected from (1)-(88):

(1) BMPR1B;

(2) E16;

(3) STEAP1;

(4) 0772P;

(5) MPF;

(6) Napi3b;

(7) Sema 5b;

(8) PSCA hIg;

(9) ETBR;

(10) MSG783;

(11) STEAP2;

(12) TrpM4;

(13) CRIPTO;

(14) CD21;

(15) CD79b;

(16) FcRH2;

(17) HER2;

(18) NCA;

(19) MDP;

(20) IL20R-alpha;

(21) Brevican;

(22) EphB2R;

(23) ASLG659;

(24) PSCA;

(25) GEDA;

(26) BAFF-R;

(27) CD22;

(28) CD79a;

(29) CXCR5;

(30) HLA-DOB;

(31) P2X5;

(32) CD72;

(33) LY64;

(34) FcRH1;

(35) IRTA2;

(36) TENB2;

(37) PSMA—

FOLH1;

(38) SST;

(38.1) SSTR2;

(38.2) SSTR5;

(38.3) SSTR1;

(38.4) SSTR3;

(38.5) SSTR4;

(39) ITGAV;

(40) ITGB6;

(41) CEACAM5;

(42) MET;

(43) MUC1;

(44) CA9;

(45) EGFRvIII;

(46) CD33;

(47) CD19;

(48) IL2RA;

(49) AXL;

(50) CD30—

TNFRSF8;

(51) BCMA—

TNFRSF17;

(52) CT Ags—

CTA;

(53) CD174 (Lewis Y)—

FUT3;

(54) CLEC14A;

(55) GRP78—

HSPA5;

(56) CD70;

(57) Stem Cell specific antigens;

(58) ASG-5;

(59) ENPP3;

(60) PRR4;

(61) GCC—

GUCY2C;

(62) Liv-1—

SLC39A6;

(63) 5T4;

(64) CD56—

NCMA1;

(65) CanAg;

(66) FOLR1;

(67) GPNMB;

(68) TIM-1—

HAVCR1;

(69) RG-1/Prostate tumor target Mindin—

Mindin/RG-1;

(70) B7-H4—

VTCN1;

(71) PTK7;

(72) CD37;

(73) CD138—

SDC1;

(74) CD74;

(75) Claudins—

CLs;

(76) EGFR;

(77) Her3;

(78) RON—

MST1R;

(79) EPHA2;

(80) CD20—

MS4A1;

(81) Tenascin C—

TNC;

(82) FAP;

(83) DKK-1;

(84) CD52;

(85) CS1—

SLAMF7;

(86) Endoglin—

ENG;

(87) Annexin A1—

ANXA1;

(88) V-CAM (CD106)—

VCAM1.

6. The conjugate of claim 2 wherein the antibody or antibody fragment is a cysteine-engineered antibody.

7. The conjugate according to claim 2 wherein the drug loading (p) of drugs (D) to antibody (Ab) is an integer from 1 to about 8.

8. The conjugate according to claim 7, wherein p is 1, 2, 3, or 4.

9. The conjugate according to claim 7 comprising a mixture of the antibody-drug conjugate compounds, wherein the average drug loading per antibody in the mixture of antibody-drug conjugate compounds is about 2 to about 5.

10. A pharmaceutical composition comprising the conjugate of claim 2 and a pharmaceutically acceptable diluent, carrier or excipient.

11. The pharmaceutical composition of claim 10 further comprising a therapeutically effective amount of a chemotherapeutic agent.

12. Use of a conjugate according to claim 2 in the preparation of a medicament for use in the treatment of a proliferative disease in a subject.

13. A method of treating cancer comprising administering to a patient the pharmaceutical composition of claim 11.

14. The method of claim 13 wherein the patient is administered a chemotherapeutic agent, in combination with the conjugate.