Benzodiazepine derivatives

• US 8,809,320 B2
• Filed: 02/22/2013
• Issued: 08/19/2014
• Est. Priority Date: 02/05/2009
• Status: Active Grant

• Current Assignee: ImmunoGen Incorporated (Abbvie Incorporated)
• Original Assignee: ImmunoGen Incorporated (Abbvie Incorporated)
• Inventors: Li, Wei, Fishkin, Nathan Elliott, Zhao, Robert Yongxin, Miller, Michael Louis, Chari, Ravi V. J.
• Primary Examiner(s): Kifle, Bruck
• Application Number:
  US13/774,059
• Publication Number:
  US 20130266596A1
• Time in Patent Office: 543 Days
• Field of Search: 514/219, 540/494
• US Class Current: 514/219
• CPC Class Codes: A61K 31/5517 condensed with five-membered rings having nitrogen as a ring hetero atom, e.g. imidazobenzodiazepines, triazolam
• CPC Class Codes: A61K 38/07 Tetrapeptides
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 47/60 the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
• CPC Class Codes: A61K 47/6835 the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
• CPC Class Codes: A61K 47/6849 the antibody targeting a receptor, a cell surface antigen or a cell surface determinant
• CPC Class Codes: A61K 47/6863 the tumour determinant being from stomach or intestines cancer cell
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07D 487/04 Ortho-condensed systems
• CPC Class Codes: C07D 498/04 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
• CPC Class Codes: C07K 16/2803 against the immunoglobulin superfamily
• CPC Class Codes: C07K 16/2896 against molecules with a "CD"-designation, not provided for elsewhere
• CPC Class Codes: C07K 16/46 Hybrid immunoglobulins hybrids of an immunoglobulin with a peptide not being an immunoglobulin C07K19/00
• CPC Class Codes: C07K 19/00 Hybrid peptides , i.e. peptides covalently bound to nucleic acids, or non-covalently bound protein-protein complexes
• CPC Class Codes: C07K 5/0202 containing the structure -NH-X-X-C(=0)-, X being an optionally substituted carbon atom or a heteroatom, e.g. beta-amino acids
• CPC Class Codes: C07K 5/1008 the side chain containing 0 or 1 carbon atoms, i.e. Gly, Ala

Abstract

The invention relates to novel benzodiazepine derivatives with antiproliferative activity and more specifically to novel benzodiazepines of formula (I) and (II), in which the diazepine ring (B) is fused with a heterocyclic ring (CD), wherein the heterocyclic ring is bicyclic or a compound of formula (III), in which the diazepine ring (B) is fused with a heterocyclic ring (C), wherein the heterocyclic ring is monocyclic. The invention provides cytotoxic dimers of these compounds. The invention also provides conjugates of the monomers and the dimers. The invention further provides compositions and methods useful for inhibiting abnormal cell growth or treating a proliferative disorder in a mammal using the compounds or conjugates of the invention. The invention further relates to methods of using the compounds or conjugates for in vitro, in situ, and in vivo diagnosis or treatment of mammalian cells, or associated pathological conditions.

Claims

1. A conjugate comprising a cell binding agent (CBA) covalently linked, through a linking group, to a compound represented by formula (IV) or (V):

2. The conjugate of claim 1, wherein:

Y is selected from the group consisting of —

OR, —

NR′

R″

, —

SO₃, and —

OSO₃, wherein R is selected from the group consisting of —

H, a linear, branched or cyclic alkyl, alkenyl or alkynyl having from 1 to 10 carbon atoms, a polyethylene glycol unit (—

OCH₂CH₂)_n, wherein n is an integer from 1 to 2000, an aryl having from 6 to 10 carbon atoms, and a heterocyclic ring having from 3 to 10 carbon atoms;

W is C═

O;

R₁, R₂, R₃, R₄, R₁′

, R₂′

, R₃′ and

R₄′

are each independently selected from —

H, —

NO₂ or the linking group;

R₆ is —

OR₁₈, wherein R₁₈ has the same definition as R;

Z is CH₂;

A and A′

are each O;

D and D′

are the same or different and are independently a linear, branched or cyclic alkyl, alkenyl or alkynyl having from 1 to 10 carbon atoms;

L is absent, or is a phenyl group or a heterocyclic ring having from 3 to 10 carbon atoms, wherein said phenyl group or heterocyclic ring represented by L is optionally linked to the linking group, or is a linear, branched or cyclic alkyl, alkenyl or alkynyl having from 1 to 10 carbon atoms, optionally substituted with any one of halogen, —

OR₇, —

NR₈R₉, —

NO₂, —

NRCOR′

, —

SR₁₀, —

SOR′

, —

SO₂R′

, —

SO₃, —

OSO₃, —

SO₂NRR′

, a cyano, an azido, —

COR₁₁, —

OCOR₁₁ or and —

OCONR₁₁R₁₂, or a polyethylene glycol unit (—

OCH₂CH₂)_n, wherein n is an integer from 1 to 2000;

optionally, L itself is the linking group.

3. The conjugate of claim 1, selected from formulae (XII) and (XIII):

4. The conjugate of claim 1, selected from formulae (XIV) and (XV):

5. The conjugate of claim 1, wherein one of R₁, R₂, R₃, R₄, R₁′

, R₂′

, R₃′

, R₄′

, L′

, L″

, L′

″

is covalently linked to the CBA, and is selected from the group consisting of;

—

O(CR₂₀R₂₁)_m(CR₂₂R₂₃)_n(OCH₂CH₂)_p(CR₄₀R₄₁)_p″

Y″

(CR₂₄R₂₅)_q(CO)_tX″

,

—

O(CR₂₀R₂₁)_m(CR₂₆═

CR₂₇)_m′

(CR₂₂R₂₃)_n(OCH₂CH₂)_p(CR₄₀R₄₁)_p″

Y″

(CR₂₄R₂₅)_q(CO)_tX″

,

—

O(CR₂₀R₂₁)_m(alkynyl)_n′

(CR₂₂R₂₃)_n(OCH₂CH₂)_p(CR₄₀R₄₁)_p″

Y″

(CR₂₄R₂₅)_q(CO)_tX″

,

—

O(CR₂₀R₂₁)_m(piperazino)_t′

(CR₂₂R₂₃)_n(OCH₂CH₂)_p(CR₄₀R₄₁)_p″

Y″

(CR₂₄R₂₅)_q(CO)_tX″

,

—

O(CR₂₀R₂₁)_m(pyrrolo)_t′

(CR₂₂R₂₃)_n(OCH₂CH₂)_p(CR₄₀R₄₁)_p″

Y″

(CR₂₄R₂₅)_q(CO)_tX″

,

—

O(CR₂₀R₂₁)_mA″

_m″

(CR₂₂R₂₃)_n(OCH₂CH₂)_p(CR₄₀R₄₁)_p″

Y″

(CR₂₄R₂₅)_q(CO)_tX″

,

—

S(CR₂₀R₂₁)_m(CR₂₂R₂₃)_n(OCH₂CH₂)_p(CR₄₀R₄₁)_p″

Y″

(CR₂₄R₂₅)_q(CO)_tX″

,

—

S(CR₂₀R₂₁)_m(CR₂₆═

CR₂₇)_m′

(CR₂₂R₂₃)_n(OCH₂CH₂)_p(CR₄₀R₄₁)_p″

Y″

(CR₂₄R₂₅)_q(CO)_tX″

,

—

S(CR₂₀R₂₁)_m(alkynyl)_n′

(CR₂₂R₂₃)_n(OCH₂CH₂)_p(CR₄₀R₄₁)_p″

Y″

(CR₂₄R₂₅)_q(CO)_tX″

,

—

S(CR₂₀R₂₁)_m(piperazino)_t′

(CR₂₂R₂₃)_n(OCH₂CH₂)_p(CR₄₀R₄₁)_p″

Y″

(CR₂₄R₂₅)_q(CO)_tX″

,

—

S(CR₂₀R₂₁)_m(pyrrolo)_t′

(CR₂₂R₂₃)_n(OCH₂CH₂)_p(CR₄₀R₄₁)_p″

Y″

(CR₂₄R₂₅)_q(CO)_tX″

,

—

S(CR₂₀R₂₁)_mA″

_m″

(CR₂₂R₂₃)_n(OCH₂CH₂)_p(CR₄₀R₄₁)_p″

Y″

(CR₂₄R₂₅)_q(CO)_tX″

,

—

NR₃₃(C═

O)_p″

(CR₂₀R₂₁)_m(CR₂₂R₂₃)_n(OCH₂CH₂)_p(CR₄₀R₄₁)_p″

Y″

(CR₂₄R₂₅)_q(CO)_tX″

,

—

NR₃₃(C═

O)_p″

(CR₂₀R₂₁)_m(CR₂₆═

CR₂₇)_m′

(CR₂₂R₂₃)_n(OCH₂CH₂)_p(CR₄₀R₄₁)_p″

Y″

(CR₂₄R₂₅)_q(CO)_tX″

,

—

NR₃₃(C═

O)_p″

(CR₂₀R₂₁)_m(alkynyl)_n′

(CR₂₂R₂₃)_n(OCH₂CH₂)_p(CR₄₀R₄₁)_p″

Y″

(CR₂₄R₂₅)_q(CO)_tX″

,

—

NR₃₃(C═

O)_p″

(CR₂₀R₂₁)_m(piperazino)_t′

(CR₂₂R₂₃)_n(OCH₂CH₂)_p(CR₄₀R₄₁)_p″

Y″

(CR₂₄R₂₅)_q(CO)_tX″

,

—

NR₃₃(C═

O)_p″

(CR₂₀R₂₁)_mA″

_m″

(CR₂₂R₂₃)_n(OCH₂CH₂)_p(CR₄₀R₄₁)_p″

Y″

(CR₂₄R₂₅)_q(CO)_tX″

,

—

(CR₂₀R₂₁)_m(CR₂₂R₂₃)_n(OCH₂CH₂)_p(CR₄₀R₄₁)_p″

Y″

(CR₂₄R₂₅)_q(CO)_tX″

,

—

(CR₂₀R₂₁)_m(CR₂₆═

CR₂₇)_m′

(CR₂₂R₂₃)_n(OCH₂CH₂)_p(CR₄₀R₄₁)_p″

Y″

(CR₂₄R₂₅)_q(CO)_tX″

,

—

(CR₂₀R₂₁)_m(alkynyl)_n′

(CR₂₂R₂₃)_n(OCH₂CH₂)_p(CR₄₀R₄₁)_p″

Y″

(CR₂₄R₂₅)_q(CO)_tX″

,

—

(CR₂₀R₂₁)_m(piperazino)_t′

(CR₂₂R₂₃)_n(OCH₂CH₂)_p(CR₄₀R₄₁)_p″

Y″

(CR₂₄R₂₅)_q(CO)_tX″

,

—

(CR₂₀R₂₁)_mA″

_m″

(CR₂₂R₂₃)_n(OCH₂CH₂)_p(CR₄₀R₄₁)_p″

Y″

(CR₂₄R₂₅)_q(CO)_tX″

,

—

(CR₂₀R₂₁)_m(CR₂₉N—

NR₃₀)_n″

(CR₂₂R₂₃)_n(OCH₂CH₂)_p(CR₄₀R₄₁)_p″

Y″

(CR₂₄R₂₅)_q(CO)_tX″

,

—

(CR₂₀R₂₁)_m(CR₂₉═

N—

NR₃₀)_n″

(CR₂₆═

CR₂₇)_m′

(CR₂₂R₂₃)_n(OCH₂CH₂)_p(CR₄₀R₄₁)_p″

Y″

(CR₂₄R₂₅)_q(CO)_tX″

,

—

(CR₂₀R₂₁)_m(CR₂₉═

N—

NR₃₀)_n″

(alkynyl)_n′

(CR₂₂R₂₃)_n(OCH₂CH₂)_p(CR₄₀R₄₁)_p″

Y″

(CR₂₄R₂₅)_q(CO)_tX″

, and

—

(CR₂₀R₂₁)_m(CR₂₉═

N—

NR₃₀)_n″

A″

_m″

(CR₂₂R₂₃)_n(OCH₂CH₂)_p(CR₄₀R₄₁)_p″

Y″

(CR₂₄R₂₅)_q(CO)_tX″

,

wherein;

m, n, p, q, m′

, n′

, t′

are integer from 1 to 10, or are optionally 0;

m″

, n″ and

p″

are 0 or 1;

X″

is covalently linked to the CBA, and when Y″

is not S—

S and t=0, X″

is

6. The conjugate of claim 1, wherein the cell-binding agent binds to target cells selected from tumor cells, virus infected cells, microorganism infected cells, parasite infected cells, autoimmune cells, activated cells, myeloid cells, activated T-cells, B cells, or melanocytes;

cells expressing the CD4, CD6, CD19, CD20, CD22, CD30, CD33, CD37, CD38, CD40, CD44, CD56, EpCAM, CanAg, CALLA, or Her-2 antigens;

Her-3 antigens or cells expressing insulin growth factor receptor, epidermal growth factor receptor, and folate receptor.

7. The conjugate of claim 6, wherein the tumor cells are selected from breast cancer cells, prostate cancer cells, ovarian cancer cells, colorectal cancer cells, gastric cancer cells, squamous cancer cells, small-cell lung cancer cells, and testicular cancer cells.

8. The conjugate of claim 1, wherein the cell-binding agent is an antibody, a single chain antibody, an antibody fragment that specifically binds to the target cell, a monoclonal antibody, a single chain monoclonal antibody, or a monoclonal antibody fragment that specifically binds the a target cell, a chimeric antibody, a chimeric antibody fragment that specifically binds to the target cell, a domain antibody, a domain antibody fragment that specifically binds to the target cell, a lymphokine, a hormone, a vitamin, a growth factor, a colony stimulating factor, or a nutrient-transport molecule.

9. The conjugate of claim 8, wherein the antibody is a resurfaced antibody, a resurfaced single chain antibody, or a resurfaced antibody fragment.

10. The conjugate of claim 8, wherein the antibody is a monoclonal antibody, a single chain monoclonal antibody, or a monoclonal antibody fragment thereof.

11. The conjugate of claim 8, wherein the antibody is a chimeric antibody, a chimeric antibody fragment, a domain antibody, or a domain antibody fragment.

12. The conjugate of claim 8, wherein the antibody is a humanized antibody, a humanized single chain antibody, or a humanized antibody fragment.

13. The conjugate of claim 8, wherein the antibody is humanized or resurfaced MY9, humanized or resurfaced anti-B4, or humanized or resurfaced C242.

14. The conjugate of claim 1, wherein the compound is selected from the group consisting of:

15. A pharmaceutical composition comprising a conjugate of claim 1, and a pharmaceutically acceptable carrier.

16. The pharmaceutical composition of claim 15, further comprising a second compound, which is a chemotherapeutic agent.

17. A method of treating a cancer in a mammal, comprising administering to said mammal a therapeutically effective amount of the conjugate of claim 1, wherein the cancer is selected from the group consisting of lymphoma, leukemia, colon cancer, cervical cancer, epidermoid carcinoma, sarcoma, breast cancer, multiple myeloma, and melanoma.

18. The method of claim 17, further comprising administering to said mammal a second compound, which is a chemotherapeutic agent.

19. The method of claim 18, wherein said chemotherapeutic agent is administered to said mammal sequentially.

20. The method of claim 17, wherein the proliferative disorder is Burkitt'"'"'s lymphoma, colon cancer, rhabdomyosarcoma, acute promyelocytic leukemia, cervical cancer, epidermoid carcinoma, multiple myeloma, breast cancer, acute lymphoblastic leukemia (ALL), or melanoma.

21. The method of claim 20, wherein the colon cancer is a multi-drug resistant (MDR) colon cancer.

22. The method of claim 20, wherein the Burkitt'"'"'s lymphoma is a multi-drug resistant (MDR) Burkitt'"'"'s lymphoma.