Transcobalamin receptor binding conjugates useful for treating abnormal cellular proliferation

• US 20060166862A1
• Filed: 02/13/2006
• Published: 07/27/2006
• Est. Priority Date: 10/25/2000
• Status: Active Grant

• Current Assignee: Regents of The University of Minnesota (University of Minnesota)
• Original Assignee: Regents of The University of Minnesota (University of Minnesota)
• Inventors: Collins, Douglas, Hogenkamp, Henricus
• Granted Patent: US 7,531,162 B2
• Time in Patent Office: Days
• US Class Current: 514/52
• CPC Class Codes: A61K 47/551 one of the codrug's components being a vitamin, e.g. niacinamide, vitamin B3, cobalamin, vitamin B12, folate, vitamin A or retinoic acid
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07H 23/00 Compounds containing boron, silicon, or a metal, e.g. chelates, vitamin B12 esters with inorganic acids C07H11/00; metal salts, see parent compounds

Abstract

An agent, composition and method for the treatment, prophylaxis and/or diagnosis of proliferative disorders, which is highly and efficiently absorbed at the site of abnormal cellular proliferation is disclosed.

Claims

1. A compound of the formula (I):

2. The compound of claim 1, wherein at least one T is selected from the group consisting of cisplatin, taxol, taxotere (docetaxel), daunorubicin (daunomycin;

rubidomycin), doxorubicin, rubidazone and idarubicin (idamycin;

4-demethoxy-daunorubicin).

3. The compound of claim 1, wherein at least one T is a detectable and/or therapeutic radionuclide.

4. The compound of any one of claims 1-3, wherein at least one L is independently an amine, a polyamine, an amino acid, a poly(amino acid) or peptide linker;

5. The compound of any one of claims 1-3, wherein at least one -L-T is independently a poly(amino acid) residue bound to one or more T.

6. The compound of claim 5, wherein at least one -L-T is independently a poly-L-lysine-NR′

(CH((CH₂)₄—

NHR′

)CONR′

)_mR′

, wherein each R′

is independently hydrogen, lower alkyl or T; and

m is 2-20.

7. The compound of any one of claims 1-3, wherein at least one -L-T is independently a polyamine residue of the formula —

NR′

(alkylene-NR′

)_nalkyleneNR′

R′

, wherein each R′

is independently hydrogen, lower alkyl or T and n is 1-20.

8. The compound of claim 7, wherein —

NR′

(alkylene-NR′

)_nalkyleneNR′

is selected from the group consisting of —

NR′

(CH₂)₃NR′

(CH₂)₄NR′

(CH₂)₃NR′

R′

(spermine);

—

NR′

(CH₂)₃NR′

(CH₂)₄NR′

R′

(spermidine);

decamethylene tetraamine and pentamethylene hexamine.

9. The compound of any one of claims 1-3, wherein at least one -L-T is independently a diamine residue of the formula —

NR′

(alkylene)_xNR′

R′

, wherein each R′

is independently hydrogen, lower alkyl or T and x is 2-20.

10. The compound of claim 9, wherein —

NR′

(alkylene)_xNR′

R′

is selected from the group consisting of 1,6-diaminohexane, 1,5-diaminopentane, 1,4-diaminobutane and 1,3-diaminopropane.

11. The compound of claim 1, wherein T is not a residue of a therapeutic agent selected from the group consisting of hormone, growth factor, interleukin, cytokines, lymphokines, GCSF, EPO, interferon (α

, β

, γ

), calcitonin, TRH, vasopressin, desmopressin [Folia Endocrinologica Japonica 54, No. 5, p. 676-691 (1978)], oxytocin, insulin, Growth Hormone, testosterone, somatotrophin, somatostatin (U.S. Pat. Nos. 4,087,390 and 4,100,117), SCGF, (stem cell growth factor), CGRP, Erythropoietin, Colony Stimulating factors (GCSF, GM-CSF, CSF), pregnant mare serum gonadotrophin (PMSG), human. chorionic gonadotrophin (HCG), Inhibin, PAI-2;

neomycin, salbutamol, pyrimethamine, penicillin G, methicillin, carbenicillin, pethidine, xylazine, ketamine, mephenesin, GABA, iron dextran, nucleotide analogues or ribozyme, prolactin, adrenocorticotropic hormone (ACTH), melanocyte stimulating hormone (MSH), thyroid hormone releasing hormone (TRH) (U.S. Pat. No. 4,100,152), thyroid stimulating hormone (TSH), luteinizing hormone (LH), luteinizing hormone releasing hormone (LHRH), follicle stimulating hormone (FSH), oxytocin, calcitonin, parathyroid hormone, glucagon, gastrin, secretin, pancreozymin, cholecystokinin angiotensin, human placental lactogen, human chorionic gonadotropin (HCG), enkephalin [U.S. Pat. No. 4,277,394, European patent application Publication No. 31567], endorphin, kyotorphin, interleukins (I, II, and III), tuftsin, thymopoietin, thymosin, thymostimulin, thymic humoral factor (TFH), serum thymic factor (FTS) (U.S. Pat. No. 4,229,438), thymic factors [Medicine in Progress 125, No. 10, p. 835-843 (1983)], tumor necrosis factor (TNF), colony stimulating factor (CSF), motilin, dinorphin, bombesin, neurotensin, cerulein, bradykinin, urokinase, asparaginase, kallikrein, substance P analogue and antagonist, nerve growth factor, blood coagulation factors VIII and IX, lysozyme chloride, polymixin B, colistin, gramicidin, bacitracin, protein synthesis stimulating peptides (British patent No.

     8232082), gastric inhibitory polypeptide (GIP), vasoactive intestinal polypeptide (VIP), platelet-derived growth factor (PDGF), growth hormone factor (GRF, somatocrinin), bone morphogenetic protein (BMP), epidermal growth factor (EGF), bleomycin, methotrexate, actinomycin D, mitomycin C, vinblastine sulfate, vincristine sulfate, daunorubicin, adriamycin, neocarzinostatin, cytosine arabinoside, fluorouracil, tetrahydrofuryl-5-fluorouracil, krestin, picibanil, lentinan, levamisole, bestatin, azimexon, glycyrrhizin, poly I;

C, poly A;

U and poly ICLC, gentamicin, dibekacin, kanendomycin, lividomycin, tobramycin, amikacin, fradiomycin, sisomicin, tetracycline hydrochloride, oxytetracycline hydrochloride, rolitetracycline, doxycycline hydrochloride, ampicillin, piperacillin, ticarcillin, cephalothin, cephaloridine, cefotiam, cefsulodin, cefmenoxime, cefmetazole, cefazolin, cefotaxime, cefoperazone, ceftizoxime, moxolactam, latamoxef, thienamycin, sulfazecin, azthreonam, sodium salicylate, sulpyrine, sodium flufenamate, sodium diclofenac, sodium indomethacin, morphine hydrochloride, pethidine, levorphanol tartrate, oxymorphone, ephedrine, methylephedrine, noscapine, codeine phosphate, dihydrocodeine, phosphate, alloclamide, chlophedianol, picoperidamine, cloperastine, protokylol, isoproterenol, salbutamol, terbutaline sulfate, chlorpromazine, prochlorperazine, trifluoperazine, atropine sulfate, scopolamine methylbromide, pridinol methanesulfonate, tubocurarine chloride and pancuronium bromide, sodium phenytoin, ethosuximide, sodium acetazolamide, chlordiazepoxide hydrochloride, metoclopramide and L-histidine monohydrochloride, imipramine, clomipramine, noxiptiline, phenelzine sulfate, diphenhydramine, chlorpheniramine maleate, tripelenamine, methdilazine, clemizole, diphenylpyraline, methoxyphenamine, trans-p-oxocamphor, theophyllol, aminophylline, etilefrine, propranolol, alprenolol, bufetolol, oxyprenolol, oxyfedrine, diltiazem, tolazoline, hexobendine, bamethan sulfate, hexamethonium bromide, pentolinium, mecamlamine, ecarazine, clonidine, sodium glymidine, glypizide, phenformin, buformin, metformin, sodium heparin, sodium citrate, thromboplastin, thrombin, menadione sodium bisulfite, acetomenaphthone, .epsilon.-amino-caproic acid, tranexamic acid, carbazochrome sodium sulfonate, adrenochrome monoaminoguanidine methanesulfonate, isoniazid, ethambutol, sodium p-aminosalicylate, prednisolone succinate, prednisolone sodium phosphate, dexamethasone sodium sulfate, betamethasone sodium phosphate, hexestrol phosphate, hexestrol·

acetate, methimazole, levallorphan tartrate, nalorphine hydrochloride and naloxone hydrochloride;

a protein derived from or immunogens against influenza, measles, Rubella, smallpox, yellow fever, diphtheria, tetanus, cholera, plague, typhus, BCG, tuberculosis causing agents, Haemophilus influenzae, Neisseria catarrhalis, Klebsiella pneumoniae, pneumococci, streptococci;

a secretory product derived from diphtheria, tetanus, cholera, plague, typhus, tuberculosis causing agents, Haemophilus influenzae, Neisseria catarrhalis, Klebsiella pneumoniae, pneumococci, streptococci, Streptococcus mutans, or is derived from a malarial parasite or the causative agent of coccidiosis in chickens.

12. A pharmaceutical composition for the treatment, prophylaxis and/or diagnosis of a proliferative disorder in a host comprising a compound of any one of claims 1-11, or the pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier.

13. A pharmaceutical composition for the treatment, prophylaxis and/or diagnosis of a proliferative disorder in a host comprising a compound of any one of claims 1-11, or the pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier, in combination with one or more other therapeutic and/or diagnostic agent(s).

14. The pharmaceutical composition of claim 12 or 13, wherein the host is a human.

15. A method for the treatment, prophylaxis and/or diagnosis of a proliferative disorder in a host comprising administering an effective amount of a compound of any one of claims 1-11, or the pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier.

16. A method for the treatment, prophylaxis and/or diagnosis of a proliferative disorder in a host comprising administering an effective amount of a compound of any one of claims 1-11, or the pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier, in combination or alternation with one or more other effective therapeutic and/or diagnostic agent.

17. The method of claim 15 or 16, wherein the host is a human.

18. A method for the treatment, prophylaxis and/or diagnosis of a proliferative disorder other than neoplasms in a host comprising administering an effective amount of a compound of the formula (I):

19. A method for the treatment, prophylaxis and/or diagnosis of a proliferative disorder other than neoplasms in a host comprising administering an effective amount of a compound of claim 18, optionally in a pharmaceutically acceptable carrier, in combination or alternation with one or more other effective therapeutic and/or diagnostic agent(s).

20. The method of claim 18 or 19, wherein at least one L is a linker of singular molecular weight.

21. The method of claim 18 or 19, wherein at least one L is independently an amine, a polyamine, an amino acid, a poly(amino acid) or peptide linker.

22. The method of claim 18 or 19, wherein at least one -L-T is independently a poly(amino acid) residue bound to one or more T.

23. The method of claim 22, wherein at least one -L-T is independently a poly-L-lysine-NR′

(CH((CH₂)₄—

NHR′

)CONR′

)_mR′

, wherein each R′

is independently hydrogen, lower alkyl or T; and

m is 2-20.

24. The method of claim 18 or 19, wherein at least one -L-T is independently a polyamine residue of the formula —

NR′

(alkylene-NR′

)_naIkyleneNR′

R′

, wherein each R′

is independently hydrogen, lower alkyl or T and n is 1-20.

25. The method of claim 24, wherein —

NR′

(alkylene-NR′

)_n-alkyleneNR′

is selected from the group consisting of —

NR′

(CH₂)₃NR′

(CH₂)₄NR′

—

(CH₂)₃NR′

R′

(spermine);

—

NR′

(CH₂)₃NR′

(CH₂)₄—

NR′

R′

(spermidine);

deca-methylene tetraamine and pentamethylene hexamine.

26. The method of claim 18 or 19, wherein at least one -L-T is independently a diamine residue of the formula —

NR′

(alkylene)_xNR′

R′

, wherein each R′

is independently hydrogen, lower alkyl or T and x is 2-20.

27. The method of claim 26, wherein —

NR′

(alkylene)_xNR′

R′

is selected from the group consisting of 1,6-diaminohexane, 1,5-diaminopentane, 1,4-diaminobutane and 1,3-diaminopropane.

28. The method of any one of claims 18-27, wherein the host is a human.