US2015057221A1PendingUtilityA1
Prodrug comprising a drug linker conjugate
Est. expiryFeb 1, 2028(~1.6 yrs left)· nominal 20-yr term from priority
A61P 43/00A61K 47/65A61K 47/542A61K 47/60A61K 47/545A61K 47/54A61K 38/1709A61K 38/18A61K 38/26A61K 31/553A61K 47/48023A61K 47/48061A61K 47/48215C07D 207/46A61K 47/50
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Claims
Abstract
The present invention relates to a prodrug or a pharmaceutically acceptable salt thereof comprising a drug linker conjugate D-L, wherein -D is an amine containing biologically active moiety; and -L is a non-biologically active linker moiety -L 1 represented by formula (I): wherein the dashed line indicates the attachment to the amine of the biologically active moiety and wherein R 1 , R 1a , R 2 , R 2a , R 3 , R 3a , X, X 1 , X 2 , X 3 have the meaning as indicated in the description and the claims and wherein L 1 is substituted with one to four groups L 2 -Z and optionally further substituted, provided that the hydrogen marked with the asterisk in formula (I) is not replaced by a substituent; wherein L 2 is a single chemical bond or a spacer; and Z is a carrier group. The invention also relates to A-L, wherein A is a leaving group, pharmaceutical composition comprising said prodrugs and their use as medicaments.
Claims
exact text as granted — not AI-modified1 . A prodrug or a pharmaceutically acceptable salt thereof comprising:
a drug-linker conjugate D-L; wherein:
-D is a nitrogen containing biologically active moiety;
-L is a non-biologically active linker moiety -L 1 ; and
-L 1 comprises an amine-containing nucleophile, and is represented by formula (I):
wherein:
the dashed line indicates the attachment to the nitrogen of the biologically active moiety by forming an amide bond;
X is C(R 4 R 4a ), N(R 4 ), O, C(R 4 R 4a )—C(R 5 R 5a ), C(R 5 R 5a )—C(R 4 R 4a ), C(R 4 R 4a )—N(R 6 ), N(R 6 )—C(R 4 R 4a ), C(R 4 R 4a )—O, or O—C(R 4 R 4a );
X 1 is C, or S(O);
X 2 is C(R 7 R 7a , or C(R 7 R 7a )—C(R 8 R 8a );
X 3 is O, S, or N—CN;
R 1 , R 1a , R 2 , R 2a , R 3 , R 3a , R 4 , R 4a , R 5 , R 5a , R 6 , R 7 , R 7a , R 8 , R 8a are independently selected from the group consisting of H, and C 1-4 alkyl;
optionally, one or more of the pairs R 1a /R 4a , R 1a /R 5a , R 4a /R 5a , and R 7a /R 8a form a chemical bond;
optionally, one or more of the pairs R 1 /R 1a , R 2 /R 2a , R 4 /R 4a , R 5 /R 5a , R 7 /R 7a , R 8 /R 8a are joined together with the atom to which they are attached to form a C 3-7 cycloalkyl; or 4 to 7 membered heterocyclyl;
optionally, one or more of the pairs R 1 /R 4 , R 1 /R 5 , R 1 /R 6 , R 4 /R 5 , R 4 /R 6 , R 7 /R 8 , R 2 /R 3 are joined together with the atoms to which they are attached to form a ring A;
optionally, R 3 /R 3a are joined together with the nitrogen atom to which they are attached to form a 4 to 7 membered heterocycle;
A is selected from the group consisting of:
phenyl, naphthyl, indenyl, indanyl, tetralinyl, C 3-10 cycloalkyl, 4 to 7 membered heterocyclyl, and 9 to 11 membered heterobicyclyl; and
—N(R 3 R 3a ) is the amine-containing nucleophile;
wherein L 1 is substituted with one to four groups L 2 -Z and optionally further substituted, provided that the hydrogen marked with the asterisk in formula (I) is not replaced by a substituent;
wherein L 2 is a single chemical bond or a spacer; and
wherein Z is a carrier group.
2 . The prodrug of claim 1 ;
wherein X 3 is O.
3 . The prodrug of claim 1 ;
wherein:
X is N(R 4 );
X 1 is C; and
X 3 is O.
4 . The prodrug of claim 1 ;
wherein X 2 is C(R 7 R 7a ).
5 . The prodrug of claim 1 ;
wherein L 1 is selected from the group consisting of:
wherein:
R is H, or C 1-4 alkyl; and
Y is NH, O, or S.
6 . The prodrug of claim 1 ;
wherein L 1 is selected from the group consisting of:
wherein R is H, or C 1-4 alkyl.
7 . The prodrug of claim 1 ;
wherein:
L 2 is a single chemical bond; or
L 2 -Z is selected from the group consisting of:
COOR 9 , OR 9 , C(O)R 9 , C(O)N(R 9 R 9a ), S(O) 2 N(R 9 R 9a ), S(O)N(R 9 R 9a ), S(O) 2 R 9 , S(O)R 9 , N(R 9 )S(O) 2 N(R 9a R 9b ), SR 9 , N(R 9 R 9a ), OC(O)R 9 , N(R 9 )C(O)R 9a , N(R 9 )S(O) 2 R 9a , N(R 9 )S(O)R 9a , N(R 9 )C(O)OR 9a , N(R 9 )C(O)N(R 9a R 9b , OC(O)N(R 9 R 9a ), T, C 1-50 alkyl, C 2-50 alkenyl, and C 2-50 alkynyl;
wherein T, C 1-50 alkyl, C 2-50 alkenyl, and C 2-50 alkynyl are optionally substituted with one or more R 10 , which are the same or different; and
wherein C 1-50 alkyl, C 2-50 alkenyl, and C 2-50 alkynyl are optionally interrupted by one or more groups selected from the group consisting of
-T-, —C(O)O—, —O—, —C(O)—, —C(O)N(R 11 )—, —S(O) 2 N(R 11 )—, —S(O)N(R 11 )—, —S(O) 2 —, —S(O)—, —N(R 11 )S(O) 2 N(R 11a )—, —S—, —N(R 11 )—, —OC(O)R 11 , —N(R 11 )C(O)—, —N(R 11 )S(O) 2 —, —N(R 11 )S(O)—, —N(R 11 )C(O)O—, —N(R 11 )C(O)N(R 11a )—, and —OC(O)N(R 11 R 11a ); and
wherein:
R 9 , R 9a , and R 9b are independently selected from the group consisting of H, Z, T, C 1-50 alkyl, C 2-50 alkenyl, and C 2-50 alkynyl;
wherein T, C 1-50 alkyl, C 2-50 alkenyl, and C 2-50 alkynyl are optionally substituted with one or more R 10 , which are the same or different; and
wherein C 1-50 , alkyl, C 2-50 alkenyl, and C 2-50 alkynyl are optionally interrupted by one or more groups selected from the group consisting of:
T, —C(O)O—, —O—, —C(O)—, —C(O)N(R 11 )—, —S(O) 2 N(R 11 )—, —S(O)N(R 11 )—, —S(O) 2 —, —S(O)—, —N(R 11 )S(O)N(R 11 )—, —S—, —N(R 11 )—, —OC(O)R 11 , —N(R 11 )C(O)—, —N(R 11 )S(O) 2 —, —N(R 11 )S(O)—, —N(R 11 )C(O)O—, —N(R 11 )C(O)N(R 11a )—, and —OC(O)N(R 11 R 11a );
T is selected from the group consisting of:
phenyl, naphthyl, indenyl, indanyl, tetralinyl, C 3-10 cycloalkyl, 4 to 7 membered heterocyclyl, and 9 to 11 membered heterobicyclyl;
wherein T is optionally substituted with one or more R 10 , which are the same or different;
R 10 is selected from the group consisting of:
Z, halogen, CN, oxo (═O), COOR 12 , OR 12 , C(O)R 12 , C(O)N(R 12 R 12a ), S(O) 2 N(R 12 R 12a ), S(O)N(R 12 R 12a ), S(O) 2 R 12 , S(O)R 12 , N(R 12 )S(O) 2 N(R 12 R 12b ), SR 12 , N(R 12 R 12a ), NO 2 ; OC(O)R 12 , N(R 12 )C(O)R 12a , N(R 12 )S(O) 2 R 12a , N(R 12 )S(O)R 12a , N(R 12 )C(O)OR 12a , N(R 12 )C(O)N(R 12a R 12b ), OC(O)N(R 12 R 12a ), and C 1-6 alkyl;
wherein C 1-6 alkyl is optionally substituted with one or more halogen, which are the same or different; and
R 11 , R 11a , R 12 , R 12a , and R 12b are independently selected from the group consisting of:
H, Z, or C 1-6 alkyl;
wherein C 1-6 alkyl is optionally substituted with one or more halogen, which are the same or different;
provided that one of R 9 , R 9a , R 9b , R 10 , R 11 , R 11a , R 12 , R 12a , and R 12b is Z.
8 . The prodrug of claim 1 ;
wherein L 2 is a C 1-20 alkyl chain, which is:
optionally interrupted by one or more groups independently selected from —O— and C(O)N(R 3aa ); and
optionally substituted with one or more groups independently selected from OH and C(O)N(R 3aa R 3aaa ); and
wherein R 3aa and R 3aaa are independently selected from the group consisting of H, and C 1-4 alkyl.
9 . The prodrug of claim 1 ;
wherein L 2 has a molecular weight in the range of from 14 g/mol to 750 g/mol.
10 . The prodrug of claim 1 ;
wherein L 2 is attached to Z via a terminal group selected from the group consisting of:
11 . The prodrug of claim 1 ;
wherein L is represented by formula (Ia):
wherein R 3aa and R 3aaa :
are independently selected from the group consisting of H and C 1-4 alkyl; or
are joined together with the nitrogen atom to which they are attached to form a 4 to 7 membered heterocycle.
12 . The prodrug of claim 1 ;
wherein L is represented by formula (Ib):
wherein R 3aa is H or C 1-4 alkyl.
13 . The prodrug of claim 1 ;
wherein R 1 in formula (I) is L 2 -Z.
14 . The prodrug of claim 1 ;
wherein R 3 in formula (I) is L 2 -Z.
15 . The prodrug of claim 1 ;
wherein R 3 and R 3a in formula (I) are joined together with the nitrogen atom to which they are attached to form a 4 to 7 membered heterocycle which is substituted with L 2 -Z.
16 . The prodrug of claim 1 ;
wherein D-H is a small molecule bioactive agent or a biopolymer.
17 . The prodrug of claim 1 ;
wherein D-H is a biopolymer selected from the group of biopolymers consisting of proteins, polypeptides, oligonucleotides, and peptide nucleic acids.
18 . The prodrug of claim 1 ;
wherein D-H is a polypeptide selected from the group of polypeptides consisting of:
ACTH, adenosine deaminase, agalsidase, alfa-1 antitrypsin (AAT), alfa-1 proteinase inhibitor (API), alteplase, amylins (amylin, symlin), anistreplase, anerod serine protease, antibodies (monoclonal or polyclonal, and fragments or fusions), antithrombin III, antitrypsins, aprotinin, asparaginases, atosiban, biphalin, bivalirudin, bone-morphogenic proteins, bovine pancreatic trypsin inhibitor (BPTI), cadherin fragments, calcitonin (salmon), collagenase, complement C1 esterase inhibitor, conotoxins, cytokine receptor fragments, DNase, dynorphine A, endorphins, enfuvirtide, enkephalins, erythropoietins, exendins, factor VII, factor VIIa, factor VIII, factor VIIIa, factor IX, fibrinolysin, fibroblast growth factor (FGF), growth hormone releasing peptide 2 (GHRP2), fusion proteins, follicle-stimulating hormones, gramicidin, ghrelin, desacyl-ghrelin, granulocyte colony stimulating factor (G-CSF), galactosidase, glucagon, glucagon-like peptides, glucocerebrosidase, granulocyte macrophage colony stimulating factor (GM-CSF), human heat shock proteins (HSP), phospholipase-activating protein (PLAP), gonadotropin chorionic (hCG), hemoglobins, hepatitis B vaccines, hirudin, human serine protease inhibitor, hyaluronidases, idurnonidase, immune globulins, influenza vaccines, interleukins (1 alfa, 1 beta, 2, 3, 4, 6, 10, 11, 12, 13, 21), IL-1 receptor antagonist (rhIL-1ra), insulins, insulin like growth factors, insulin-like growth factor binding protein (rhIGFBP), interferons (alfa 2a, alfa 2b, alfa 2c, beta 1a, beta 1b, gamma 1a, gamma 1b), intracellular adhesion molecule, keratinocyte growth factor (KGF), P-selectin glycoprotein ligand (PSGL), transforming growth factors, lactase, leptin, leuprolide, levothyroxine, luteinizing hormone, lyme vaccine, natriuretic peptides (ANP, BNP, CNP and fragments), neuropeptide Y, pancrelipase, pancreatic polypeptide, papain, parathyroid hormone, PDGF, pepsin, peptide YY, platelet activating factor acetylhydrolase (PAF-AH), prolactin, protein C, thymalfasin, octreotide, secretin, sermorelin, soluble tumor necorsis factor receptor (TNFR), superoxide dismutase (SOD), somatropins (growth hormone), somatoprim, somatostatin, streptokinase, sucrase, terlipressin, tetanus toxin fragment, tilactase, thrombins, thymosin, thyroid stimulating hormone, thyrotropin, tumor necrosis factor (TNF), TNF receptor-IgG Fc, tissue plasminogen activator (tPA), TSH, urodilatin, urate oxidase, urokinase, vaccines, vascular endothelial growth factor (VEGF), vasoactive intestinal peptide, vasopressin, ziconotide, lectin, and ricin.
19 . The prodrug of claim 1 ;
wherein D-H is a protein prepared by recombinant DNA technologies.
20 . The prodrug of claim 1 ;
wherein D-H is a protein selected from the group of proteins consisting of:
antibody fragments, single chain antigen binding proteins, catalytic antibodies, and fusion proteins.
21 . The prodrug of claim 1 ;
wherein D-H is a small molecule bioactive agent selected from the group of agents consisting of:
central nervous system-active agents, anti-infective, anti-allergic, immunomodulating, anti-obesity, anticoagulants, antidiabetic, anti-neoplastic, antibacterial, anti-fungal, analgesic, contraceptive, anti-inflammatory, steroidal, vasodilating, vasoconstricting, and cardiovascular agents with at least one primary or secondary amino group.
22 . The prodrug of claim 1 ;
wherein D-H is a small molecule bioactive agent selected from the group of agents consisting of:
acarbose, alaproclate, alendronate, amantadine, amikacin, amineptine, aminoglutethimide, amisulpride, amlodipine, amotosalen, amoxapine, amoxicillin, amphetamine, amphotericin B, ampicillin, amprenavir, amrinone, anileridine, apraclonidine, apramycin, articaine, atenolol, atomoxetine, avizafone, baclofen, benazepril, benserazide, benzocaine, betaxolol, bleomycin, bromfenac, brofaromine, carvedilol, cathine, cathinone, carbutamid, cefalexine, clinafloxacin, ciprofloxacin, deferoxamine, delavirdine, desipramine, daunorubicin, dexmethylphenidate, dexmethylphenidate, diaphenylsulfon, dizocilpine, dopamin, dobutamin, dorzolamide, doxorubicin, duloxetine, eflornithine, enalapril, epinephrine, epirubicin, ergoline, ertapenem, esmolol, enoxacin, ethambutol, fenfluramine, fenoldopam, fenoterol, fingolimod, flecaimide, fluvoxamine, fosamprenavir, frovatriptan, furosemide, fluoexetine, gabapentin, gatifloxacin, gemiflocacin, gentamicin, grepafloxacin, hexylcaine, hydralazine, hydrochlorothiazide, icofungipen, idarubicin, imiquimod, inversine, isoproterenol, isradipine, kanamycin A, ketamin, labetalol, lamivudine, levobunolol, levodopa, levothyroxine, lisinopril, lomefloxacin, loracarbef, maprotiline, mefloquine, melphalan, memantine, meropenem, mesalazine, mescaline, methyldopa, methylenedioxymethamphetamine, metoprolol, milnacipran, mitoxantron, moxifloxacin, norepinephrine, norfloxacin, nortriptyline, neomycin B, nystatin, oseltamivir, pamidronic acid, paroxetine, pazufloxacin, pemetrexed, perindopril, phenmetrazine, phenelzine, pregabalin, procaine, pseudoephedrine, protriptyline, reboxetine, ritodrine, sabarubicin, salbutamol, serotonin, sertraline, sitagliptin, sotalol, spectinomycin, sulfadiazin, sulfamerazin, sertraline, sprectinomycin, sulfalen, sulfamethoxazol, tacrine, tarnsulosin, terbutaline, timolol, tirofiban, tobramycin, tocainide, tosufloxacin, trandolapril, tranexamic acid, tranylcypromine, trimerexate, trovafloxacin, valaciclovir, valganciclovir, vancomycin, viomycin, viloxazine, and zalcitabine.
23 . The prodrug of claim 1 ;
wherein Z is a polymer of at least 500 Da or a C 8-18 alkyl group.
24 . The prodrug of claim 1 ;
wherein Z is selected from the group of optionally crosslinked polymers consisting of:
poly(propylene glycol), poly(ethylene glycol), dextran, chitosan, hyaluronic acid, alginate, xylan, mannan, carrageenan, agarose, cellulose, starch, hydroxyalkyl starch (HAS), poly(vinyl alcohols), poly(oxazolines), poly(anhydrides), poly(ortho esters), poly(carbonates), poly(urethanes), poly(acrylic acids), poly(acrylamides), poly(acrylates), poly(methacrylates), poly(organophosphazenes), polyoxazoline, poly(siloxanes), poly(amides), poly(vinylpyrrolidone), poly(cyanoacrylates), poly(esters), poly(iminocarbonates), poly(amino acids), collagen, gelatin, hydrogel, a blood plasma protein, and copolymers thereof.
25 . The prodrug of claim 1 ;
wherein Z is a protein.
26 . The prodrug of claim 1 ;
wherein Z is a protein selected from the group consisting of albumin, transferrin, and immunoglobulin.
27 . The prodrug of claim 1 ;
wherein Z is a linear or branched poly(ethylene glycol) with a molecular weight from 2,000 Da to 150,000 Da.
28 . The prodrug of claim 1 ;
wherein:
D-H is a GLP-1 receptor agonist; and
Z is a hydrogel.
29 . The prodrug of claim 28 ;
wherein the GLP-1 receptor agonist is Exendin-4.
30 . The prodrug of claim 28 ;
wherein in formula (I):
X is N(R 4 );
X 1 is C; and
X 3 is O.
31 . The prodrug of claim 1 ;
wherein D-H is a GLP-1 receptor agonist; and wherein:
L is represented by formula (Ia):
wherein R 3aa and R 3aaa :
are independently selected from the group consisting of H and C 1-4 alkyl; or
are joined together with the nitrogen atom to which they are attached to form a 4 to 7 membered heterocycle; and
wherein Z is a hydrogel; or
L is represented by formula (Ib):
wherein R 3aa is H or C 1-4 alkyl.
32 . A prodrug precursor comprising:
a compound of formula Act-L; wherein:
Act is a leaving group; and
L is a non-biologically active linker moiety L 1 which comprises an amine-containing nucleophile, and which is represented by formula (I):
wherein:
the dashed line indicates the attachment to the nitrogen of the biologically active moiety by forming an amide bond;
X is C(R 4 R 4a ), N(R 4 ), O, C(R 4 R 4a )—C(R 5 R 5a ), C(R 5 R 5a )—C(R 4 R 4a ), C(R 4 R 4a )—N(R 6 ), N(R 6 )—C(R 4 R 4a ), C(R 4 R 4a )—O, or O—C(R 4 R 4a );
X 1 is C; or S(O);
X 2 is C(R 7 R 7a ; or C(R 7 R 7a )—C(R 8 R 8a );
X 3 is O; S; or N—CN;
R 1 , R 1a , R 2 , R 2a , R 3 , R 3a , R 4 , R 4a , R 5 , R 5a , R 6 , R 7 , R 7a , R 8 , R 8a are independently selected from the group consisting of H, and C 1-4 alkyl;
optionally, one or more of the pairs R 1a /R 4a , R 1a /R 5a , R 4a /R 5a , and R 7a /R 8a form a chemical bond;
optionally, one or more of the pairs R 1 /R 1a , R 2 /R 2a , R 4 /R 4a , R 5 /R 5a , R 7 /R 7a , and R 8 /R 8a are joined together with the atom to which they are attached to form a C 3-7 cycloalkyl, or 4 to 7 membered heterocyclyl;
optionally, one or more of the pairs R 1 /R 4 , R 1 /R 5 , R 1 /R 6 , R 4 /R 5 , R 4 /R 6 , R 7 /R 8 , and R 2 /R 3 are joined together with the atoms to which they are attached to form a ring A;
optionally, R 3 /R 3a are joined together with the nitrogen atom to which they are attached to form a 4 to 7 membered heterocycle;
A is selected from the group consisting of:
phenyl, naphthyl, indenyl, indanyl, tetralinyl, C 3-10 cycloalkyl, 4 to 7 membered heterocyclyl, and 9 to 11 membered heterobicyclyl; and
—N(R 3 R 3a ) is the amine-containing nucleophile;
wherein L 1 is substituted with one to four groups L 2 -Z and optionally further substituted, provided that the hydrogen marked with the asterisk in formula (I) is not replaced by a substituent;
wherein L 2 is a single chemical bond or a spacer, and
wherein Z is a carrier group.
33 . The prodrug precursor of claim 32 ;
wherein Act is chloride, bromide, fluoride, nitrophenoxy, imidazolyl, N-hydroxysuccinimidyl, N-hydroxybenzotriazolyl, N-hydroxyazobenzotriazolyl, pentafluorophenoxy, 2-thiooxo-thiazolidinyl, or N-hydroxysulfosuccinimidyl.
34 . A pharmaceutical composition comprising:
a prodrug of claim 1 or a pharmaceutical salt thereof; and a pharmaceutically acceptable excipient.
35 . A method comprising:
administering the prodrug of claim 1 .
36 . A method comprising:
administering the pharmaceutical composition of claim 34 .
37 . The prodrug of claim 1 ;
wherein D-H is a GLP-1 receptor agonist; and wherein L is represented by formula (Ib):
wherein:
R 3aa is H or C 1-4 alkyl; and
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