US2014308342A1PendingUtilityA1
Reprogramming urokinase into an antibody-recruiting anticancer agent
Est. expiryNov 11, 2031(~5.2 yrs left)· nominal 20-yr term from priority
C07D 493/10C07D 491/107C07K 5/06026A61K 38/482C12N 9/96C07C 279/12A61K 38/05A61K 45/06A61K 31/165A61K 31/365A61K 47/60A61K 47/54A61K 31/352
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Claims
Abstract
The present invention relates to chimeric (preferably, bifunctional) compounds, compositions comprising those compounds and methods of treating cancer in a patient or subject, especially including metastatic cancer where cancer cells exhibit overexpression (heightened expression) of cell surface urokinase-type plasminogen activator receptor (urokinase receptor) compared to normal (non-cancerous) cells. The compounds preferably covalently bind to the urokinase receptor and recruit native antibodies of the patient or subject where the antibodies can selectively degrade and/or deactivate targeted cancer cells through antibody-dependent cellular phagocytosis and/or antibody-dependent cellular cytotoxicity (ADCC) against a large number and variety of cancers, thus providing cancer cell death and/or an inhibition of growth, elaboration and/or metastasis of the cancer, including remission and cure of the patient's cancer.
Claims
exact text as granted — not AI-modified1 . A compound according to the chemical formula:
Where
is a moiety which non-covalent or covalently binds to an active site of urokinase-type plasminogen activator (uPA);
is an antibody binding moiety comprising a hapten which is capable of binding to an antibody in said patient or subject;
L1 is a linker molecule which chemically links
to CT, L2 or
in said compound;
L2 is a linker molecule which chemically links
to CT, L1 or
in a molecule;
CT is a bond or a connector molecule which links L1 and/or L2 to
and/or
Each j is independently 0, 1, 2, 3, 4 or 5;
Each k is independently 0, 1, 2, 3, 4 or 5, with the proviso that k and/or j are other than 0 when CT is a bond; and
Each m and n is independently an integer from 1 to 15, or
a pharmaceutically acceptable salt, stereoisomer, solvate or polymorph thereof.
2 . The compound according to claim 1 which further comprises urokinase-type plasminogen activator (uPA) bound to said
group.
3 . The compound according to claim 1 wherein
is covalently bound to uPA, m is 1 and n is 1.
4 . The compound according to claim 1 wherein
is a group according to the chemical formula:
Where T is a group R e group or an amino acid group according to the chemical structure:
R AA is a sidechain of an amino acid;
R e is H or an electrophilic group which is reactive with a nucleophile in the active site of uPA to produce a covalent bond;
p1 is an integer from 0 to 25 and
Each (AA) is independently a single amino acid residue, or
a pharmaceutically acceptable salt, stereoisomer, solvate or polymorph thereof.
5 . The compound according to claim 4 wherein R e is an electrophilic group according to the chemical formula:
Where X e is O, S, or N—R Xe ;
R Xe is H or a C 1 -C 3 alkyl or alkanol group;
R P1 is any group which forms a stable linkage with phosphorous in the phosphonate moiety;
R P2 is a halogen (preferably F);
Each e is independently 0, 1, 2, 3, 4, 5 or 6;
Each f is independently 0 or 1 (often 0); and
Each g is 0, 1, 2, 3, 4, 5 or 6 (often 1);
Each h is independently 0 or 1; and
Each q is independently 1, 2, 3, 4, 5, or 6, or
a pharmaceutically acceptable salt, enantiomer, solvate or polymorph thereof.
6 . The compound according to claim 4 wherein p 1 is an integer from 1 to 10.
7 . The compound according to claim 4 wherein p1 is an integer from 1 to 3.
8 . The compound according to claim 4 wherein p 1 is 2 and each (AA) is an amino acid residue independently selected from the group consisting of glycine, alanine, leucine, isoleucine and threonine, glutamic acid, aspartic acid, serine and lysine.
9 . The compound according to claim 4 wherein R AA is a side chain of arginine or lysine.
10 . The compound according to claim 4 wherein R AA is arginine.
11 . The compound according to claim 4 wherein R e is
Where e, f and h are 0.
12 . The compound according to claim 4 wherein R e is
Where g is an integer from 0 to 6;
R P1 is an optionally substituted hydrocarbyl group or an optionally substituted aromatic or heterocyclic group; and
R P2 is fluorine.
12 . (canceled)
13 . (canceled)
14 . A compound
of claim 1 according to the chemical formula:
Where R e is H or an electrophilic group which is reactive with a nucleophile in the active site of uPA to produce a covalent bond;
R S is S or a group
R S1 is S or a group
Y P is N or CH 2 ;
X a is H, a halogen, a C 1 -C 3 alkyl group or a O—(C 1 -C 3 alkyl group);
X b is H, a halogen, a C 1 -C 3 alkyl group or a O—(C 1 -C 3 alkyl group);
X c and X d are each independently H, a halogen, a C 1 -C 3 alkyl group or a O—(C 1 -C 3 alkyl group;
R 4a and R 5a are each independently H, a halogen, a C 1 -C 3 alkyl group or a O—(C 1 -C 3 alkyl group; and
S is
Where
is an antibody binding moiety comprising a hapten which is capable of binding to an antibody in a patient or subject;
L1 is a linker molecule which chemically links
to CT, L2 or
in said compound;
L2 is a linker molecule which chemically links
to CT, L1 or
in a molecule;
CT is a bond or a connector molecule which links L1 and/or L2 to
and/or
Each j is independently 0, 1, 2, 3, 4 or 5;
Each k is independently 0, 1, 2, 3, 4 or 5, with the proviso that k and/or j are other than 0 when CT is a bond; and
n is independently an integer from 1 to 15, or
a pharmaceutically acceptable salt, stereoisomer, solvate or polymorph thereof.
15 . A compound according to claim 14 wherein R e is an electrophilic group according to the chemical structure:
Where X e is O, S, or N—R Xe ;
R Xe is H or a C 1 -C 3 alkyl or alkanol group;
R P1 is any group which forms a stable linkage with phosphorous in the phosphonate moiety;
R P2 is a halogen (preferably F);
Each e is independently 0, 1, 2, 3, 4, 5 or 6;
Each f is independently 0 or 1 (often 0); and
Each g is 0, 1, 2, 3, 4, 5 or 6 (often 1);
Each h is independently 0 or 1; and
Each q is independently 1, 2, 3, 4, 5, or 6, or
a pharmaceutically acceptable salt, enantiomer, solvate or polymorph thereof.
16 . A compound according to claim 1 wherein said
group is a hapten group according to the chemical formula:
Where X″ is O, CH 2 , NR 1 , S; and
R 1 is H, a C 1 -C 3 alkyl group or a —C(O)(C 1 -C 3 ) group; or
Where X b is a bond, O, CH 2 or NR 1 or S; and
R 1 is the same as above; or
a group according to the chemical structure:
Where R N02 is a nitro group or a dinitrophenyl group optionally linked through CH 2 , S(O), S(O) 2 , —S(O) 2 O, —OS(O) 2 , or OS(O) 2 O;
a dinitrophenyl group according to the chemical structure:
Where Y′ is H or NO 2 (preferably H);
X is O, CH 2 , NR 1 , S(O), S(O) 2 , —S(O) 2 O, —OS(O) 2 , or OS(O) 2 O; and
R 1 is H, a C 1 -C 3 alkyl group, or a —C(O)(C 1 -C 3 ) group; or
a fluorescein group according to the chemical structure:
17 . The compound according to claim 1 wherein said
group is a dinitrophenyl group or a fluorescein group.
18 . A compound according to claim 1 wherein L 1 and/or L 2 is a group according to the chemical structure:
or a a group according to the chemical structure:
or
a polypropylene glycol or polypropylene-co-polyethylene glycol linker containing between 1 and 100 alkyleneglycol units;
Where R a is H, C 1 -C 3 alkyl or alkanol or forms a cyclic ring with R 3 when R 3 is a sidechain of proline and R 3 is a side chain derived from an amino acid;
Each m is independently an integer from 1 to 100; and
Each n is independently an integer from 1 to 100.
19 . A compound according to claim 1 wherein L 1 and/or L 2 is a polyethylene glycol linker containing from 1 to 100 ethylene glycol units.
20 . A compound according to claim 1 wherein L 1 and/or L 2 is a linker according to the chemical structure:
Where Z and Z′ are each independently a bond, —(CH 2 ) i —O, —(CH 2 ) i —S, —(CH 2 ) i —N—R,
wherein said —(CH 2 ) i group, if present in Z or Z′, is bonded to a connector (CT), A B M and/or U k BM;
Each R is H, or a C 1 -C 3 alkyl or alkanol group;
Each R 2 is independently H or a C 1 -C 3 alkyl group;
Each Y is independently a bond, O, S or N—R;
Each i is independently 0 to 100, 0 to 75, 1 to 60, 1 to 55, 1 to 50, 1 to 45, 1 to 40, 2 to 35, 3 to 30, 1 to 15, 1 to 10, 1 to 8, 1 to 6, 0, 1, 2, 3, 4 or 5;
D is
or
a bond, with the proviso that Z, Z′ and D are not each simultaneously bonds;
j is 1 to 100;
n is 1 to 100;
X 1 is O, S or N—R; and
R is as described above,
or a pharmaceutically acceptable salt, stereoisomer, solvate or polymorph thereof.
21 . A compound according to claim 1 wherein said connector group CT is a group according to the chemical structure:
Where X 2 is O, S, NR 4 , S(O), S(O) 2 , —S(O) 2 O, —OS(O) 2 , or OS(O) 2 O;
X 3 is O, S, NR 4 ; and
R 4 is H, a C 1 -C 3 alkyl or alkanol group, or a —C(O)(C 1 -C 3 ) group.
22 . The compound according to claim 21 wherein CT is a triazole group.
23 . A compound according to the chemical structure:
or an alternative pharmaceutically acceptable salt thereof.
24 . A compound according to the chemical structure:
or an alternative pharmaceutically acceptable salt thereof.
25 . A composition comprising a compound according to claim 1 in an aqueous solvent or buffer.
26 . A composition comprising a compound according to claim 1 bound to urokinase-type plasminogen activator (uPA).
27 . The composition according to claim 26 wherein said uPA is human recombinant uPA.
28 . A pharmaceutical composition comprising an effective amount of a composition according to claim 1 in combination with a pharmaceutically acceptable carrier, additive or excipient.
29 . A pharmaceutical composition according to claim 28 further in combination with an additional anticancer agent.
30 . The composition according to claim 29 wherein said additional anticancer agent is an antimetabolite, an inhibitor of topoisomerase I and II, an alkylating agent, a microtubule inhibitor or a mixture thereof.
31 . The composition according to claim 29 wherein said additional anticancer agent is a FLT-3 inhibitor, a VEGFR inhibitor, an EGFR TK inhibitor, an aurora kinase inhibitor, a PIK-1 modulator, a Bcl-2 inhibitor, an HDAC inhbitor, a c-MET inhibitor, a PARP inhibitor, a Cdk inhibitor, an EGFR TK inhibitor, an IGFR-TK inhibitor, an anti-HGF antibody, a PI3 kinase inhibitors, an AKT inhibitor, a JAK/STAT inhibitor, a checkpoint-1 or 2 inhibitor, a focal adhesion kinase inhibitor, a Map kinase kinase (mek) inhibitor, a VEGF trap antibody or a mixture thereof.
32 . The composition according to claim 29 wherein said additional anticancer agent is eyerolimus, trabectedin, abraxane, TLK 286, AV-299, DN-101, pazopanib, GSK690693, RTA 744, ON 0910.Na, AZD 6244 (ARRY-142886), AMN-107, TK1-258, GSK461364, AZD 1152, enzastaurin, vandetanib, ARQ-197, MK-0457, MLN8054, PHA-739358, R-763, AT-9263, pemetrexed, erlotinib, dasatanib, nilotinib, decatanib, panitumumab, amrubicin, oregovomab, Lep-etu, nolatrexed, azd2171, batabulin, ofatumumab, zanolimtunab, edotecarin, tetrandrine, rubitecan, tesmilifene, oblimersen, ticilimumab, ipilimumab, gossypol, Bio 111, 131-I-TM-601, ALT-110, BIO 140, CC 8490, cilengitide, gimatecan, IL13-PE38QQR, INO 1001, IPdR 1 KRX-0402, lucanthone, LY 317615, neuradiab, vitespan, Rta 744, Sdx 102, talampanel, atrasentan, Xr 311, romidepsin, ADS-100380, sunitinib, 5-fluorouracil, vorinostat, etoposide, gemcitabine, doxorubicin, liposomal doxorubicin, 5′-deoxy-5-fluorouridine, vincristine, temozolomide, ZK-304709, seliciclib; PD0325901, AZD-6244, capecitabine, L-Glutamic acid, N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-, disodium salt, heptahydrate, camptothecin, PEG-labeled irinotecan, tamoxifen, toremifene citrate, anastrazole, exemestane, letrozole, DES (diethylstilbestrol), estradiol, estrogen, conjugated estrogen, bevacizumab, IMC-1C11, CHIR-258,); 3-[5-(methylsulfonylpiperadinemethyl)-indolylj-quinolone, vatalanib, AG-013736, AVE-0005, the acetate salt of [D-Ser(Bu t) 6, Azgly 10](pyro-Glu-His-Trp-Ser-Tyr-D-Ser(Bu t)-Leu-Arg-Pro-Azgly-NH 2 acetate [C 9 H 84 N N Oi 4 -(C 2 H 4 O 2 )x where x=1 to 2.4], goserelin acetate, leuprolide acetate, triptorelin pamoate, medroxyprogesterone acetate, hydroxyprogesterone caproate, megestrol acetate, raloxifene, bicalutamide, flutamide, nilutamide, megestrol acetate, CP-724714; TAK-165, HKI-272, erlotinib, lapatanib, canertinib, ABX-EGF antibody, erbitux, EKB-569, PKI-166, GW-572016, Ionafamib, BMS-214662, tipifarnib; ainifostine, NVP-LAQ824, suberoyl analide hydroxamic acid, valproic acid, trichostatin A, FK-228, SU11248, sorafenib, KRN951, aminoglutethimide, amsacrine, anagrelide, L-asparaginase, Bacillus Calmette-Guerin (BCG) vaccine, bleomycin, buserelin, busulfan, carboplatin, carmustine, chlorambucil, cisplatin, cladribine, clodronate, cyproterone, cytarabine, dacarbazine, dactinomycin, daunorubicin, diethylstilbestrol, epirubicin, fludarabine, fludrocortisone, fluoxymesterone, flutamide, gemcitabine, hydroxyurea, idarubicin, ifosfamide, imatinib, leuprolide, levamisole, lomustine, 6-mechlorethamine, melphalan, mercaptopurine, mesna, methotrexate, mitomycin, mitotane, mitoxantrone, nilutamide, octreotide, oxaliplatin, pamidronate, pentostatin, plicamycin, porfimer, procarbazine, raltitrexed, rituximab, streptozocin, teniposide, testosterone, thalidomide, thioguanine, thiotepa, tretinoin, vindesine, 13-cis-retinoic acid, phenylalanine mustard, uracil mustard, estramustine, altretamine, floxuridine, 5-deooxyuridine, cytosine arabinoside, 6-mecaptopurine, deoxycoformycin, calcitriol, valrubicin, mithramycin, vinblastine, vinorelbine, topotecan, razoxin, marimastat, COL-3, neovastat, BMS-275291, squalamine, endostatin, SU541.6, SU6668, EMD1.21974, interleukin-12, IM862, angiostatin, vitaxin, droloxifene, idoxyfene, spironolactone, finasteride, cimitidine, trastuzumab, denileukin diftitox, gefitinib, bortezimib, paclitaxel, cremophor-free paclitaxel, docetaxel, epithilone B, BMS-247550, BMS-310705, droloxifene, 4-hydroxytamoxifen, pipendoxifene, ERA-923, arzoxifene, fulvestrant, acolbifene, lasofoxifene, idoxifene, TSE-424, HMR-3339, ZK186619, topotecan, PTK787/ZK 222584, VX-745, PD 184352, rapamycin, 40-O-(2-hydroxyethyl)-rapamycin, temsirolimus, AP-23573, RAD001, ABT-578, BC-210, LY294002, LY292223, LY292696, LY293684, LY293646, wortmannin, ZM336372, L-779,450, PEG-filgrastim, darbepoetin, erythropoietin, granulocyte colony-stimulating factor, zolendronate, prednisone, cetuximab, granulocyte macrophage colony-stimulating factor, histrelin, pegylated interferon alfa-2a, interferon alfa-2a, pegylated interferon alfa-2b, interferon alfa-2b, azacitidine, PEG-L-asparaginase, lenalidomide, gemtuzumab, hydrocortisone, interleukin-11, dexrazoxane, alemtuzumab, all-transretinoic acid, ketoconazole, interleukin-2, megestrol, immune globulin, nitrogen mustard, methylprednisolone, ibritgumomab tiuxetan, androgens, decitabine, hexamethylmelamine, bexarotene, tositumomab, arsenic trioxide, cortisone, editronate, mitotane, cyclosporine, liposomal daunorubicin, Edwina-asparaginase, strontium 89, casopitant, netupitant, an NK-1 receptor antagonists, palonosetron, aprepitant, diphenhydramine, hydroxyzine, metoclopramide, lorazepam, alprazolam, haloperidol, droperidol, dronabinol, dexamethasone, methylprednisolone, prochlorperazine, granisetron, ondansetron, dolasetron, tropisetron, pegfilgrastim, erythropoietin, epoetin alfa, darbepoetin alfa or a mixture thereof.
33 . A method of treating cancer in a patient in need comprising administered to said patient an effective amount of a composition according to claim 28 .
34 . The method according to claim 33 wherein said cancer is carcinoma, leukemia, lymphoma, melanoma; myeloproliferative disease; sarcoma, a tumor of the central nervous system, a germ-line tumor, a mixed type of neoplasia or a tumor of mixed origin.
35 . The method according to claim 33 wherein said cancer is squamous-cell carcinoma, adenocarcinoma, hepatocellular carcinoma, renal cell carcinoma, leukemia; Burkitt's lymphoma, Non-Hodgkin's lymphoma, melanoma; myeloproliferative disease; Ewing's sarcoma, hemangiosarcoma, Kaposi's sarcoma, liposarcoma, myosarcomas, peripheral neuroepithelioma, synovial sarcoma, glioma, astrocytoma, oligodendroglioma, ependymoma, gliobastoma, neuroblastoma, ganglioneuroma, ganglioglioma, medulloblastoma, a pineal cell tumor, meningioma, meningeal sarcoma, neurofibroma, Schwannoma, bowel cancer, breast cancer, prostate cancer, cervical cancer, uterine cancer, lung cancer, ovarian cancer, testicular cancer, thyroid cancer, astrocytoma, esophageal cancer, pancreatic cancer, stomach cancer, liver cancer, colon cancer, a mixed cancer of carcinosarcoma and Hodgkin's disease; and a mixed origin tumor Wilms' tumor and teratocarcinomas.
36 . The method according to claim 33 wherein said cancer is cancer of the prostate, stomach, colon, rectal, liver, pancreatic, lung, breast, cervix uteri, corpus uteri, ovary, testis, bladder, renal, brain/CNS, head and neck or throat, Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, leukemia, melanoma, non-melanoma skin cancer, acute lymphocytic leukemia, acute myelogenous leukemia, Ewing's sarcoma, small cell lung cancer, choriocarcinoma, rhabdomyosarcoma, Wilms' tumor, neuroblastoma, hairy cell leukemia, mouth/pharynx, oesophagus, larynx, kidney cancer or lymphoma.
37 . The method according to claim 33 wherein said cancer is metastatic cancer.
38 . A method of reducing the likelihood that a cancer in a patient will metastasize comprising administering to a cancer patient in need an effective amount of a composition according to claim 28 .
39 . The method according to claim 38 wherein said cancer is carcinoma, leukemia, lymphoma, melanoma; myeloproliferative disease; sarcoma, a tumor of the central nervous system, a germ-line tumor, a mixed type of neoplasia or a tumor of mixed origin.
40 . The method according to claim 38 wherein said cancer is squamous-cell carcinoma, adenocarcinoma, hepatocellular carcinoma, renal cell carcinoma, leukemia; Burkitt's lymphoma, Non-Hodgkin's lymphoma, melanoma; myeloproliferative disease; Ewing's sarcoma, hemangiosarcoma, Kaposi's sarcoma, liposarcoma, myosarcomas, peripheral neuroepithelioma, synovial sarcoma, glioma, astrocytoma, oligodendroglioma, ependymoma, gliobastoma, neuroblastoma, ganglioneuroma, ganglioglioma, medulloblastoma, a pineal cell tumor, meningioma, meningeal sarcoma, neurofibroma, Schwannoma, bowel cancer, breast cancer, prostate cancer, cervical cancer, uterine cancer, lung cancer, ovarian cancer, testicular cancer, thyroid cancer, astrocytoma, esophageal cancer, pancreatic cancer, stomach cancer, liver cancer, colon cancer, a mixed cancer of carcinosarcoma and Hodgkin's disease; and a mixed origin tumor Wilms' tumor and teratocarcinomas.
41 . The method according to claim 38 wherein said cancer is cancer of the prostate, stomach, colon, rectal, liver, pancreatic, lung, breast, cervix uteri, corpus uteri, ovary, testis, bladder, renal, brain/CNS, head and neck or throat, Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, leukemia, melanoma, non-melanoma skin cancer, acute lymphocytic leukemia, acute myelogenous leukemia, Ewing's sarcoma, small cell lung cancer, choriocarcinoma, rhabdomyosarcoma, Wilms' tumor, neuroblastoma, hairy cell leukemia, mouth/pharynx, oesophagus, larynx, kidney cancer or lymphoma.
42 . (canceled)
43 . (canceled)
44 . A method of making a pharmaceutical composition comprising exposing a compound according to claim 1 to an effective amount of urokinase-type plasminogen activator (uPA) in an aqueous solvent at a temperature and for a time sufficient to form an ARM-U compound.
45 . (canceled)
46 . (canceled)
47 . (canceled)
48 . The compound according to claim 11 wherein R P1 is an optionally substituted C 1 -C 12 alkyl group.
49 . The compound according to claim 12 wherein R P1 is a methyl group.Join the waitlist — get patent alerts
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