NZ767751B2 - Targeted delivery of tertiary amine-containing drug substances - Google Patents
Targeted delivery of tertiary amine-containing drug substancesInfo
- Publication number
- NZ767751B2 NZ767751B2 NZ767751A NZ76775115A NZ767751B2 NZ 767751 B2 NZ767751 B2 NZ 767751B2 NZ 767751 A NZ767751 A NZ 767751A NZ 76775115 A NZ76775115 A NZ 76775115A NZ 767751 B2 NZ767751 B2 NZ 767751B2
- Authority
- NZ
- New Zealand
- Prior art keywords
- hydrogen
- alkyl
- formula
- optionally substituted
- subscript
- Prior art date
Links
- 150000003512 tertiary amines Chemical class 0.000 title claims abstract 7
- 229940088679 drug related substance Drugs 0.000 title 1
- 239000003446 ligand Substances 0.000 claims abstract 42
- 229940079593 drug Drugs 0.000 claims abstract 35
- 239000003814 drug Substances 0.000 claims abstract 35
- 239000000203 mixture Substances 0.000 claims abstract 30
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract 20
- 150000001875 compounds Chemical class 0.000 claims abstract 17
- 230000002159 abnormal effect Effects 0.000 claims abstract 4
- 239000003937 drug carrier Substances 0.000 claims abstract 2
- 230000008685 targeting Effects 0.000 claims abstract 2
- 229910052739 hydrogen Inorganic materials 0.000 claims 84
- 239000001257 hydrogen Substances 0.000 claims 82
- 125000000217 alkyl group Chemical group 0.000 claims 60
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 56
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 32
- 229910052799 carbon Inorganic materials 0.000 claims 24
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims 21
- 150000002431 hydrogen Chemical class 0.000 claims 20
- 125000000753 cycloalkyl group Chemical group 0.000 claims 18
- 229910052717 sulfur Inorganic materials 0.000 claims 16
- 239000000562 conjugate Substances 0.000 claims 13
- 125000004434 sulfur atom Chemical group 0.000 claims 12
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims 11
- 125000001424 substituent group Chemical group 0.000 claims 10
- DLKUYSQUHXBYPB-NSSHGSRYSA-N (2s,4r)-4-[[2-[(1r,3r)-1-acetyloxy-4-methyl-3-[3-methylbutanoyloxymethyl-[(2s,3s)-3-methyl-2-[[(2r)-1-methylpiperidine-2-carbonyl]amino]pentanoyl]amino]pentyl]-1,3-thiazole-4-carbonyl]amino]-2-methyl-5-(4-methylphenyl)pentanoic acid Chemical compound N([C@@H]([C@@H](C)CC)C(=O)N(COC(=O)CC(C)C)[C@H](C[C@@H](OC(C)=O)C=1SC=C(N=1)C(=O)N[C@H](C[C@H](C)C(O)=O)CC=1C=CC(C)=CC=1)C(C)C)C(=O)[C@H]1CCCCN1C DLKUYSQUHXBYPB-NSSHGSRYSA-N 0.000 claims 9
- 125000001072 heteroaryl group Chemical group 0.000 claims 9
- 125000000623 heterocyclic group Chemical group 0.000 claims 9
- 229930184737 tubulysin Natural products 0.000 claims 9
- 125000006582 (C5-C6) heterocycloalkyl group Chemical group 0.000 claims 8
- 125000003118 aryl group Chemical group 0.000 claims 8
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims 8
- 229910052757 nitrogen Inorganic materials 0.000 claims 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 7
- 108091005804 Peptidases Proteins 0.000 claims 7
- 239000004365 Protease Substances 0.000 claims 7
- 239000002253 acid Substances 0.000 claims 7
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims 7
- 210000004027 cell Anatomy 0.000 claims 6
- 102000005744 Glycoside Hydrolases Human genes 0.000 claims 5
- 108010031186 Glycoside Hydrolases Proteins 0.000 claims 5
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 claims 5
- 125000003342 alkenyl group Chemical group 0.000 claims 5
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims 5
- 125000004433 nitrogen atom Chemical group N* 0.000 claims 5
- 125000000547 substituted alkyl group Chemical group 0.000 claims 5
- 108010016626 Dipeptides Proteins 0.000 claims 4
- 238000003776 cleavage reaction Methods 0.000 claims 4
- 230000007062 hydrolysis Effects 0.000 claims 4
- 238000006460 hydrolysis reaction Methods 0.000 claims 4
- 229910052760 oxygen Inorganic materials 0.000 claims 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims 4
- 230000001105 regulatory effect Effects 0.000 claims 4
- 150000003839 salts Chemical class 0.000 claims 4
- 230000007017 scission Effects 0.000 claims 4
- 125000003107 substituted aryl group Chemical group 0.000 claims 4
- -1 -NO Chemical group 0.000 claims 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims 3
- 239000000611 antibody drug conjugate Substances 0.000 claims 3
- 229940049595 antibody-drug conjugate Drugs 0.000 claims 3
- 150000001720 carbohydrates Chemical class 0.000 claims 3
- 125000006575 electron-withdrawing group Chemical group 0.000 claims 3
- 229910052736 halogen Inorganic materials 0.000 claims 3
- 230000003834 intracellular effect Effects 0.000 claims 3
- 210000002966 serum Anatomy 0.000 claims 3
- KZNICNPSHKQLFF-UHFFFAOYSA-N succinimide Chemical group O=C1CCC(=O)N1 KZNICNPSHKQLFF-UHFFFAOYSA-N 0.000 claims 3
- 150000008575 L-amino acids Chemical class 0.000 claims 2
- 102000035195 Peptidases Human genes 0.000 claims 2
- 102000004243 Tubulin Human genes 0.000 claims 2
- 108090000704 Tubulin Proteins 0.000 claims 2
- 125000002947 alkylene group Chemical group 0.000 claims 2
- 125000000304 alkynyl group Chemical group 0.000 claims 2
- 150000001412 amines Chemical class 0.000 claims 2
- 239000000427 antigen Substances 0.000 claims 2
- 102000036639 antigens Human genes 0.000 claims 2
- 108091007433 antigens Proteins 0.000 claims 2
- 108010044540 auristatin Proteins 0.000 claims 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims 2
- 125000002228 disulfide group Chemical group 0.000 claims 2
- AMRJKAQTDDKMCE-UHFFFAOYSA-N dolastatin Chemical compound CC(C)C(N(C)C)C(=O)NC(C(C)C)C(=O)N(C)C(C(C)C)C(OC)CC(=O)N1CCCC1C(OC)C(C)C(=O)NC(C=1SC=CN=1)CC1=CC=CC=C1 AMRJKAQTDDKMCE-UHFFFAOYSA-N 0.000 claims 2
- 229930188854 dolastatin Natural products 0.000 claims 2
- RWSXRVCMGQZWBV-WDSKDSINSA-N glutathione Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 claims 2
- 125000005843 halogen group Chemical group 0.000 claims 2
- 125000005842 heteroatom Chemical group 0.000 claims 2
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims 2
- 125000004430 oxygen atom Chemical group O* 0.000 claims 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims 2
- 108090000765 processed proteins & peptides Proteins 0.000 claims 2
- 125000006239 protecting group Chemical group 0.000 claims 2
- OFDNQWIFNXBECV-UHFFFAOYSA-N Dolastatin 10 Natural products CC(C)C(N(C)C)C(=O)NC(C(C)C)C(=O)N(C)C(C(C)CC)C(OC)CC(=O)N1CCCC1C(OC)C(C)C(=O)NC(C=1SC=CN=1)CC1=CC=CC=C1 OFDNQWIFNXBECV-UHFFFAOYSA-N 0.000 claims 1
- LQKSHSFQQRCAFW-UHFFFAOYSA-N Dolastatin 15 Natural products COC1=CC(=O)N(C(=O)C(OC(=O)C2N(CCC2)C(=O)C2N(CCC2)C(=O)C(C(C)C)N(C)C(=O)C(NC(=O)C(C(C)C)N(C)C)C(C)C)C(C)C)C1CC1=CC=CC=C1 LQKSHSFQQRCAFW-UHFFFAOYSA-N 0.000 claims 1
- 108010024636 Glutathione Proteins 0.000 claims 1
- 241000124008 Mammalia Species 0.000 claims 1
- 102000012750 Membrane Glycoproteins Human genes 0.000 claims 1
- 108010090054 Membrane Glycoproteins Proteins 0.000 claims 1
- 102000018697 Membrane Proteins Human genes 0.000 claims 1
- 108010052285 Membrane Proteins Proteins 0.000 claims 1
- 101000977048 Streptomyces cinnamonensis Uncharacterized protein in mutB 3'region Proteins 0.000 claims 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims 1
- LQKSHSFQQRCAFW-CCVNJFHASA-N [(2s)-1-[(2s)-2-benzyl-3-methoxy-5-oxo-2h-pyrrol-1-yl]-3-methyl-1-oxobutan-2-yl] (2s)-1-[(2s)-1-[(2s)-2-[[(2s)-2-[[(2s)-2-(dimethylamino)-3-methylbutanoyl]amino]-3-methylbutanoyl]-methylamino]-3-methylbutanoyl]pyrrolidine-2-carbonyl]pyrrolidine-2-carboxyl Chemical compound C([C@@H]1N(C(=O)C=C1OC)C(=O)[C@@H](OC(=O)[C@H]1N(CCC1)C(=O)[C@H]1N(CCC1)C(=O)[C@H](C(C)C)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)C)C(C)C)C(C)C)C1=CC=CC=C1 LQKSHSFQQRCAFW-CCVNJFHASA-N 0.000 claims 1
- 238000005903 acid hydrolysis reaction Methods 0.000 claims 1
- 230000002378 acidificating effect Effects 0.000 claims 1
- 125000004450 alkenylene group Chemical group 0.000 claims 1
- 125000003545 alkoxy group Chemical group 0.000 claims 1
- 125000005360 alkyl sulfoxide group Chemical group 0.000 claims 1
- 125000004414 alkyl thio group Chemical group 0.000 claims 1
- 150000001413 amino acids Chemical class 0.000 claims 1
- 125000003277 amino group Chemical group 0.000 claims 1
- 125000005362 aryl sulfone group Chemical group 0.000 claims 1
- 125000005361 aryl sulfoxide group Chemical group 0.000 claims 1
- 125000005110 aryl thio group Chemical group 0.000 claims 1
- 125000000732 arylene group Chemical group 0.000 claims 1
- 125000004104 aryloxy group Chemical group 0.000 claims 1
- 125000004429 atom Chemical group 0.000 claims 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims 1
- 210000004899 c-terminal region Anatomy 0.000 claims 1
- 239000003795 chemical substances by application Substances 0.000 claims 1
- OFDNQWIFNXBECV-VFSYNPLYSA-N dolastatin 10 Chemical compound CC(C)[C@H](N(C)C)C(=O)N[C@@H](C(C)C)C(=O)N(C)[C@@H]([C@@H](C)CC)[C@H](OC)CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@H](C=1SC=CN=1)CC1=CC=CC=C1 OFDNQWIFNXBECV-VFSYNPLYSA-N 0.000 claims 1
- 108010045524 dolastatin 10 Proteins 0.000 claims 1
- 108010045552 dolastatin 15 Proteins 0.000 claims 1
- 239000003623 enhancer Substances 0.000 claims 1
- 150000002148 esters Chemical class 0.000 claims 1
- 125000004428 fluoroalkoxy group Chemical group 0.000 claims 1
- 125000003709 fluoroalkyl group Chemical group 0.000 claims 1
- 239000012634 fragment Substances 0.000 claims 1
- 229960003180 glutathione Drugs 0.000 claims 1
- 229930182470 glycoside Natural products 0.000 claims 1
- 125000001188 haloalkyl group Chemical group 0.000 claims 1
- 150000002367 halogens Chemical class 0.000 claims 1
- 125000004404 heteroalkyl group Chemical group 0.000 claims 1
- 230000002209 hydrophobic effect Effects 0.000 claims 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims 1
- 125000005647 linker group Chemical group 0.000 claims 1
- 210000003712 lysosome Anatomy 0.000 claims 1
- 230000001868 lysosomic effect Effects 0.000 claims 1
- NSPJNIDYTSSIIY-UHFFFAOYSA-N methoxy(methoxymethoxy)methane Chemical group COCOCOC NSPJNIDYTSSIIY-UHFFFAOYSA-N 0.000 claims 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims 1
- 238000006467 substitution reaction Methods 0.000 claims 1
- 239000011593 sulfur Substances 0.000 claims 1
- 125000003396 thiol group Chemical group [H]S* 0.000 claims 1
- 208000023275 Autoimmune disease Diseases 0.000 abstract 1
- 206010028980 Neoplasm Diseases 0.000 abstract 1
- 201000011510 cancer Diseases 0.000 abstract 1
- 201000010099 disease Diseases 0.000 abstract 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract 1
Abstract
Compounds and compositions are disclosed in which a quaternized drug unit is linked to a targeting ligand unit from which a tertiary amine-containing drug is released at the targeted site of action. Methods for treating diseases characterized by the targeted abnormal cells, such as cancer or an autoimmune disease using the compounds and compositions of the invention are also disclosed. Pharmaceutical compositions of the ligand drug composition (LDC) and a pharmaceutically acceptable carrier are claimed, where the LDC compound has the structure of formula 1.
Claims (19)
1. A pharmaceutical composition comprising a Ligand Drug Conjugate (LDC) compound and a pharmaceutically acceptable carrier, wherein the LDC compound is represented by 5 the structure of Formula 1: (Formula 1) wherein 10 “Ligand” is a Ligand Unit (L), wherein L is capable of selectively binding to a target moiety, and L is an antibody or fragment thereof to define an antibody drug conjugate (ADC), wherein the target moiety is an antigen capable of selectively binding to the ADC, and wherein the antigen is an extracellularly accessible cell-surface protein, glycoprotein or carbohydrate displayed preferentially by abnormal cells in comparison to normal cells, 15 wherein the abnormal and normal cells are cells in a mammal, wherein the abnormal cells are hyper-proliferating cells; L is a primary linker; Q is A -W , wherein A is an optional Stretcher unit so that subscript a is 0 when A is absent or 1 when A is present and is optionally comprised of two, three or four subunits; 2 2 1 2 3 20 Q is W' -E-, wherein Q , when present, is bonded to V, Z , Z or Z ; W and W are cleavable units, wherein W of Q is capable of selective cleavage by an intracellular or regulatory protease in comparison to serum proteases, or by glutathione through disulfide exchange, or is more reactive to hydrolysis under more acidic conditions present in lysosomes in 25 comparison to physiological pH of serum, W'-E of Q provides a glycosidic bond cleavable by a glycosidase located intracellularly, and subscript w is 0 or 1 so that W is absent when w is 0 or W is present when w is 1, and subscript w' is 0 or 1, wherein W'-E is absent when w' is 0 or W’-E is present when w' is 1, and wherein w + w' is 1 so that one and only one of W, W' is present; 1 2 3 24 24 V, Z , Z and Z are =N- or =C(R )-, wherein R is hydrogen or alkyl, alkenyl or 5 alkynyl, optionally substituted, or halogen, -NO , -CN or other electron withdrawing 2 8 9 + group, an electron donating group, or the -Q or the –C(R )(R )-D substituent of Formula 1 2 3 24 1, wherein at least one of V, Z , Z and Z is =C(R )- when w is 1, and at least two of V, 1 2 3 24 Z , Z and Z are =C(R )- when w' is 1, 2 24 8 9 + provided that when w is 1, Q is absent and one and only one R is –C(R )(R )-D so 8 9 + 1 2 3 24 10 that –C(R )(R )-D is bonded to one of V, Z , Z , Z when that variable group is =C(R )- 1 8 9 + and the Q -J- and –C(R )(R )-D substituents are ortho or para to each other, 24 8 9 + 8 9 provided that when w' is 1, one and only one R is –C(R )(R )-D so that –C(R )(R )- + 1 2 3 24 D is bonded to one of V, Z , Z , Z when that variable group is =C(R )- and one and only 24 2 2 1 2 3 one other R is Q so that Q is bonded to another one of V, Z , Z , Z when that variable 24 2 8 9 + 15 group is =C(R )-, and the Q and –C(R )(R )-D substituents are ortho or para to each other; R and R independently are hydrogen, alkyl, alkenyl or alkynyl, optionally substituted, or aryl or heteroaryl, optionally substituted; R’ is hydrogen or is halogen, -NO , -CN or other electron withdrawing group, or is an 20 electron donating group; 33 33 E and J independently are –O-, -S- or –N(R )-, wherein R is hydrogen or optionally substituted alkyl; D represents a structure of a quaternized tertiary amine-containing drug; subscript p is an average drug loading having a number ranging from 1 to 24; 25 wherein said protease cleavage, disulfide exchange, acid hydrolysis or glycosidase cleavage results in release of tertiary amine containing drug (D) from a Ligand Drug Conjugate compound of the composition; wherein, as used herein, “optionally substituted” moieties refer to moieties wherein one H atom is replaced by a moiety selected from the group consisting of halogen, -CN, - 30 NH , -OH, -CH , -CH , -CF , -OCH , -OCF , amino, including mono-, di- and tri- 2 3 3 3 3 3 substituted amino groups, -NH(CH ), -N(CH ) , alkyl, nitro, fluoroalkyl, heteroalkyl, 3 3 2 cycloalkyl, heterocycloalkyl, aryl, heteroaryl, haloalkyl, alkoxy, fluoroalkoxy, aryloxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, arylsulfone, -C(=O)OH, - C(=O)O-alkyl, -C(=O)NH , -C(=O)NH(alkyl), -C(=O)N(alkyl) , -S(=O) NH , - 2 2 2 2 S(=O) NH(alkyl), -S(=O) N(alkyl) , -S-alkyl and -S(=O) alkyl, and wherein an optionally 2 2 2 2 substituted moiety may be substituted one or more times.
2. The pharmaceutical composition of claim 1, wherein the structure of the 5 composition is represented by the structure of Formula 2A or Formula 2B: (Formula 2A) (Formula 2B)
3. The pharmaceutical composition of claim 1, wherein the structure of the composition is represented by the structure of Formula 3A, Formula 3B, Formula 3C, 15 Formula 3D, Formula 3E, or Formula 3F: (Formula 3A) (Formula 3B) 5 (Formula 3C) Ligand L A J (Formula 3D) (Formula 3E) (Formula 3F) 5 4. The pharmaceutical composition of claim 2, wherein W of Q is comprised or consists of a peptide moiety having a peptide bond to J that is selectively cleavable by an intracellular or regulatory protease in comparison to serum proteases wherein action of the regulatory protease on W causes release of tertiary amine-containing drug (D) from a Ligand Drug Conjugate compound of the composition, 10 particularly wherein the peptide moiety of W is comprised or consists of a dipeptide moiety having the structure of Formula 6: (Formula 6), 15 wherein R is benzyl, methyl, isopropyl, isobutyl, sec-butyl, -CH(OH)CH or has the structure of and R is methyl, –(CH ) -NH , -(CH ) NH(C=O)NH , - 2 4 2 2 3 2 (CH ) NH(C=NH)NH , or -(CH ) CO H, 2 3 2 2 2 2 wherein the wavy bond to the dipeptide’s C-terminus indicates covalent bonding to J of the arylene moiety of Formula 2A or 2B and the wavy bond to the dipeptide’s N- 20 terminus indicates covalent bonding to the remainder of W, if any such remainder is present, or to A, or a subunit thereof, when a is 1 or to L when subscript a is 0, and wherein the dipeptide’s bond to J is cleavable by an intracellular or regulatory protease, particularly wherein the structure of the composition is represented by the structure of Formula 9: 5 (Formula 9) wherein Ab is an antibody Ligand Unit; R’ is hydrogen or an electron donating group; R is hydrogen; R is hydrogen, optionally substituted C -C alkyl, or optionally substituted phenyl; 10 R is methyl, isopropyl or -CH(OH)CH ; R is methyl, -(CH ) NH(C=O)NH or -(CH ) CO H; 2 3 2 2 2 2 33 33 J is –N(R )-, wherein R is hydrogen or methyl; and V and Z independently are =CH- or =N-, particularly wherein the structure of the composition is represented by the structure of 15 Formula 10: (Formula 10) wherein 20 S is a sulfur atom of an antibody Ligand Unit (Ab-); the asterisk (*) designates chirality or absence thereof at the indicated carbon; b1 b1
4.A is an optional subunit of A, wherein –[C(R )(R )] -[HE]- is A when A is absent o m o and is A when A is present so A becomes -A -A -; 1 o 1 o R is –H; a1 22 23 R is –H or a basic unit (BU), wherein BU has the structure of –CH -N(R )(R ), 22 23 wherein R and R independently are hydrogen, methyl or ethyl or both together with the nitrogen atom to which they are attached comprise a 5- or 6-membered heterocycloalkyl; R is hydrogen; 5 subscript m is an integer ranging from 0 to 5 when HE is present or from 1 to 5 when HE is absent; each R independently is hydrogen or optionally substituted C -C alkyl; HE is absent or is –C(=O)-; R is methyl, isopropyl or -CH(OH)CH ; 10 R is -(CH ) NH(C=O)NH or -(CH ) CO H; 2 3 2 2 2 2 J is –NH-; V, Z and Z are each =CH-; R’ is hydrogen or an electron donating group; R is hydrogen; and 15 R is hydrogen or methyl.
5. The pharmaceutical composition of claim 3, wherein W’ of Q is a glycoside- bonded carbohydrate, wherein the glycoside bond W’-E of Q provides for a cleavage site for a glycosidase located intracellularly wherein action of the glycosidase on W’-E causes 20 release of tertiary amine-containing drug (D) from a Ligand Drug Conjugate compound of the composition, particularly wherein W’ of Q is a carbohydrate moiety that is glycoside-bonded to E, wherein the glycosidic bond is cleavable by a glycosidase located intracellularly, and wherein W’-E has the structure of Formula 7: (Formula 7), 1 2 3 wherein the wavy line represents E bonded to one of V, Z , Z , or Z when that 24 33 33 variable group is =C(R ), wherein E is –O-, -S- , or –N(R )-, wherein R is hydrogen or methyl; and wherein R is –CH OH or –CO H, 5 particularly wherein the structure of the composition is represented by the structure of Formula 11: (Formula 11) 10 wherein wherein Ab is an antibody Ligand Unit; A and A are independently selected subunits of A, wherein A is an optional subunit 1 o o of A so that A becomes A when A is absent and A is -A -A - when A is present; 1 o 1 o o E is –O- or –NH-; 33 33 15 J is –N(R )-, wherein R is hydrogen or methyl; V and Z independently are =CH- or =N-; R’ is hydrogen or an electron withdrawing group; R is hydrogen; R is hydrogen, optionally substituted C -C alkyl or optionally substituted phenyl; 20 R is –CO H; and subscript p is a number ranging from 1 to 8, particularly wherein the structure of the composition is represented by the structure of Formula 12: (Formula 12) wherein wherein S is a sulfur atom of antibody Ligand Unit Ab; 5 the asterisk (*) designates chirality or absence thereof at the indicated carbon, that is predominantly in the same absolute configuration as the alpha carbon of an L-amino acid when that indicated carbon has chirality; A and A are independently selected subunits of A, wherein A is an optional subunit 1 o o b1 b1 of A, wherein–[C(R )(R )] -[HE]- is A when A is absent and is A when A is present m o 1 o 10 so that A becomes A -A ; wherein A when present corresponds in structure to an amine- 1 o o containing acid bonded to J through the C-terminal carbonyl of the amine-containing acid; R is hydrogen; R’ is hydrogen or an electron withdrawing group; a1 a1 R is hydrogen or R is a basic unit (BU) that participates in base-assisted hydrolysis 22 23 15 of the succinimide ring, wherein BU has the structure of –CH -N(R )(R ), or an acid 22 23 addition salt thereof, wherein R and R independently are hydrogen, methyl or ethyl or both together with the nitrogen atom to which they are attached comprise a 5- or 6- membered heterocycloalkyl; R is hydrogen; 20 subscript m is an integer ranging from 0 to 5 when HE is present or 1 to 5 when HE is absent; each R independently is hydrogen or optionally substituted C -C alkyl; HE is absent or is –C(=O)-; R is –CO H; E is –O-; J is –NH-; V and Z are each =CH-; 5 R is hydrogen; R is hydrogen or methyl; and subscript p is a number ranging from 1 to 8, or wherein A , when present, has the structure of Formula 13 or Formula 14: (Formula 13) (Formula 14) wherein the wavy line to the carbonyl moiety of either structure represents the point of attachment of A to W and wherein the wavy line to the amino moiety of either 15 structure represents the point of attachment of A to A , wherein K and L independently are C, N, O or S, provided that when K or L is O or S, 41 42 43 44 41 42 R and R to K or R and R to L are absent, and when K or L are N, one of R , R to 43 44 K or one of R , R to L are absent, and provided that no two adjacent L are independently selected as N, O, or S; 20 wherein q is an integer ranging from 0 to 12, and r is an integer ranging from 1 to 12; wherein G is hydrogen, optionally substituted C -C alkyl, -OH, -OR , -CO H, 1 6 2 G G PR CO R , wherein R is C -C alkyl, aryl or heteroaryl, optionally substituted, or R , 2 1 6 PR G G G wherein R is a suitable protecting group, -NH , or -N(R )(R ), wherein R independently selected is as previously defined or both R together with the nitrogen to 25 which they are attached comprises a 5- or 6-membered heterocycloalkyl or both R together form a suitable protecting group; 38 39 44 wherein R is hydrogen or optionally substituted C -C alkyl; R -R independently are hydrogen, optionally substituted C -C alkyl, optionally substituted, or optionally 39 40 substituted heteroaryl, or both R , R together with the carbon to which they are attached 41 42 30 comprise a C -C cycloalkyl, or R , R together with K to which they are attached when 43 44 K is C, or R , R together with L to which they are attached when L is C, comprise a C - 40 41 40 43 41 43 C cycloalkyl, or R and R , or R and R , or R and R together with the carbon or heteroatom to which they are attached and atoms intervening between those carbon and/or heteroatoms comprise a 5- or 6-membered cycloalkyl or heterocycloalkyl, 5 or wherein A has a structure corresponding to alpha-amino, beta-amino or another amine-containing acid.
6. The pharmaceutical composition of any one of claims 1-5, wherein subscript a is 10 wherein –L -A in Formula 1 is –L -A when A is absent or –L -A is -L -A -A when b a b o b b 1 O A is present so that A becomes A -A O 1 o wherein L -A - has the structure of Formula 8: (Formula 8) 15 wherein b1 b1 the -[C(R )(R )] -[HE]- moiety is A or A ; R and R independently are hydrogen or methyl; R is hydrogen, methyl, ethyl or R is a Basic Unit (BU) that participates in base- assisted hydrolysis of the succinimide ring; 20 HE is an optional Hydrolysis Enhancer (HE) Unit; subscript m is an integer ranging from 0 to 6; each R independently is hydrogen, optionally substituted C -C alkyl, optionally substituted aryl or optionally substituted heteroaryl, or two R together with the carbon(s) to which they are attached comprise a C -C cycloalkyl or one R and HE together with 25 the carbon to which they are attached comprise a 5 or 6-membered cycloalkyl or a 5- or 6- membered heterocycloalkyl and the other R is hydrogen, optionally substituted C -C alkyl, optionally substituted aryl or optionally substituted heteroaryl; 1 1 2 2 22 23 BU has the structure of –[C(R )(R )]-[C(R )(R )] -N(R )(R ), wherein subscript n is 0, 1, 2 or 3; each R independently is hydrogen or C -C alkyl or two R together with the carbon to which they are attached comprise a C -C cycloalkyl, and each R independently is hydrogen, optionally substituted C -C alkyl, optionally substituted aryl or optionally substituted heteroaryl, or two R together with the carbon(s) to 5 which they are attached and any intervening carbons define a C -C cycloalkyl, or one R and one R together with the carbons to which they are attached and any intervening carbons comprise a 5- or 6-membered cycloalkyl and the remaining R and R are as defined; 22 23 R and R independently are hydrogen or optionally substituted C -C alkyl 10 or together with the nitrogen to which they are attached comprise a 5- or 6-membered heterocycloalkyl; and wherein the wavy line to the succinimide ring of L indicates covalent bonding of sulfur derived from a sulfhydryl group of a targeting moiety and the other wavy line indicates covalent bonding of A (or A ) to the remainder of the composition structure.
7. The pharmaceutical composition of claim 1, wherein the Ligand Drug Conjugate compounds of the composition are represented by the structures of Formula 16A and Formula 16B: 20 (Formula 16A) (Formula 16B) wherein Ab is an antibody Ligand Unit; S is a sulfur atom of the antibody Ligand Unit; 5 the asterisk (*) designates chirality or absence thereof at the indicated carbon; 1’ 1’ Q is A -W , wherein A is an optional subunit of A so that -Q - is –W - when A is o w o w o absent, or is –A -W - when A is present, o W o wherein –[C(R )(R )] -[HE]- becomes A when A is absent or is A when A is m o 1 o present, and 10 wherein subscript w is 1 when Q is absent or w is 0 so that W is absent and Q is present; R is hydrogen; a1 22 23 R is BU wherein BU has the structure of –CH -N(R )(R ), or an acid addition salt 22 23 thereof, wherein R and R independently are hydrogen or methyl or both together with 15 the nitrogen atom to which they are attached comprise a 5- or 6-membered heterocycloalkyl; R is hydrogen; subscript m is an integer ranging from 0 to 5 when HE is present or from 1 to 5 when HE is absent ; 20 each R independently is hydrogen or optionally substituted C -C alkyl; HE is absent or is –C(=O)-; J is –O- or –NH-; Q when present is W-E, wherein E is –O- or –NH-; and subscript p’ is an integer ranging from 1 to 8.
8. The pharmaceutical composition of claim 7, wherein the Ligand Drug Conjugate compounds of the composition have the structures of Formula 17A and Formula 17B: (Formula 17A) 5 (Formula 17B) wherein J is –NH-; 1 24 24 one of V or Z is =C(R )-, wherein R is hydrogen, -Cl, or –NO , and the others of V, Z and Z are each =CH-; 10 R is hydrogen; R is hydrogen or methyl; and subscript p’ is an integer ranging from 1 to 8.
9. The pharmaceutical composition of claim 7, wherein the Ligand Drug Conjugate 15 compounds of the composition have the structures of Formula 18A and Formula 18B: (Formula 18A) (Formula 18B) b1 b1 5 wherein A is an optional subunit of A, wherein the –[C(R )(R )] -[HE]- moiety is A when A is absent or the moiety is A when A is present so that A becomes -A -A -; o 1 o 1 O R is –H; 22 23 R is a Basic Unit (BU), wherein BU has the structure of –CH -N(R )(R ), or an 22 23 acid addition salt thereof, wherein R and R independently are hydrogen or methyl or 10 both together with the nitrogen atom to which they are attached comprise a 5- or 6- membered heterocycloalkyl; R is hydrogen; subscript m is an integer ranging from 0 to 5 when HE is present or 1 to 5 when HE is absent; 15 each R independently is hydrogen or optionally substituted C -C alkyl; HE is absent or is –C(=O)-; and R is hydrogen; and R is hydrogen, optionally substituted C -C alkyl or optionally substituted phenyl; particularly wherein the Ligand Drug Conjugate compounds of the composition have 20 the structures of Formula 19A and Formula 19B: (Formula 19A) (Formula 19B) wherein R is hydrogen; 22 23 10 R is a Basic Unit (BU), wherein BU has the structure of –CH -N(R )(R ), or an 22 23 acid addition salt thereof, wherein R and R independently are hydrogen or methyl or both together with the nitrogen atom to which they are attached comprise a 5- or 6- membered heterocycloalkyl; R is hydrogen; subscript m is an integer ranging from 0 to 5 when HE is present or 1 to 5 when HE is 5 absent; each R independently is hydrogen or optionally substituted C -C alkyl; HE is absent or is –C(=O)-; R is –CO H; E is –O-; 10 J is –NH-; V and Z are each =CH-; R is hydrogen; R is hydrogen or methyl; and the indicated (*) carbon is predominantly in the same absolute configuration as the 15 alpha carbon of an L-amino acid when that indicated carbon has chirality.
10. The pharmaceutical composition of any one of claims 1-9, wherein –D is a quaternized tertiary amine-containing tubulin disrupting agent, particularly wherein the quaternized tubulin disrupting Drug Unit –D is a quaternized 20 tubulysin Drug Unit, particularly wherein the quaternized tubulysin Drug Unit –D has the structure of Formula D or Formula D ’: G-1 H-1 (Formula D G-1 ) 25 (Formula D ) wherein the circle represents an 5-membered nitrogen-heteroaryl and wherein the indicated required substituents to that heteroaryl are in a 1,3-relationship with each other with optional substitution at the remaining positions; 2A 2A R is hydrogen or optionally substituted alkyl or R along with the oxygen atom to 5 which it is attached defines an O-linked substituent other than -OH; R is hydrogen or optionally substituted alkyl; 4 4A 4B 5 6 R , R , R , R and R are optionally substituted alkyl, independently selected; R is optionally substituted aryl or optionally substituted heteroaryl; R is hydrogen or optionally substituted alkyl; and 10 m is 0 or 1, wherein the wavy line indicates covalent bonding of D to the remainder of the composition structure.
11. The pharmaceutical composition of claim 10, wherein the quaternized tubulysin 15 Drug Unit –D has the structure of: wherein Z is an optionally substituted C -C alkylene or an optionally substituted C - 1 4 2 C alkenylene; subscript q, indicating the number of R substituents, is 1, 2 or 3; 20 wherein each R is independently selected from the group consisting of hydrogen and an O-linked substituent; and wherein the wavy line indicates covalent bonding of D to the remainder of the composition structure, or wherein the quaternized tubulysin Drug Unit –D has the structure of: wherein R is hydrogen or optionally substituted C -C alkyl or R along with the oxygen atom to which it is attached defines an O-linked substituent other than -OH; R is optionally substituted C -C alkyl; R and R are the side chain residues of natural hydrophobic amino acids; 5 –N(R )(R ) is –NH(C -C alkyl) or -NH–N(C -C alkyl) , wherein one and only one 1 6 1 6 2 C -C alkyl is optionally substituted by –CO H, or an ester thereof, or by an optionally 1 6 2 substituted phenyl; and wherein the wavy line indicates covalent bonding of D to the remainder of the composition structure, 10 particularly wherein –N(R )(R ) is selected from the group consisting of –NH(CH ), - NHCH CH Ph, and –NHCH -CO H, -NHCH CH CO H and –NHCH CH CH CO H, 2 2 2 2 2 2 2 2 2 2 2 2A 2A particularly wherein the O-linked substituent –OR is other than –OH so that R is not hydrogen, particularly wherein R is –CH CH .
12. The pharmaceutical composition of claim 11, wherein the quaternized tubulysin Drug Unit –D has the structure of: 20 particularly wherein the quaternized tubulysin Drug Unit –D has the structure of: wherein R is methyl; 3 3A 3B 3A R is H, methyl, ethyl, propyl, -CH -OC(O)R , -CH CH(R )C(O)R , or – 3B 3A 3A 3B CH(R )C(O)NHR , wherein R is C -C alkyl and R is H or C -C alkyl, 1 6 1 6 25 independently selected from R ; and 2A 2B -OR is an O-linked substituent selected from the group consisting of –OCH R , - 2B 2B 2C 2B 2C OC(O)R and –OC(O)N(R )(R ), wherein R and R are independently selected from the group consisting of H, C -C alkyl and C -C alkenyl; and 1 6 2 6 R is hydrogen or –OH, 5 particularly wherein R is –CH CH .
13. The pharmaceutical composition of claim 12, wherein the quaternized tubulysin Drug Unit –D has the structure of: 10 wherein subscript m is 1; R is –CH , -CH CH , -CH(CH ) , -C(CH ) , or –CH=CH ; 3 2 3 3 2 3 3 2 R is methyl, ethyl or propyl; and R is hydrogen or –OH, or wherein the quaternized tubulysin Drug Unit –D has the structure of: wherein subscript m is 1; R is –H, –CH , -CH CH , or –OCH ; 3 2 3 3 R is methyl, ethyl or propyl; and R is hydrogen or –OH, 20 or wherein the quaternized tubulysin Drug Unit –D has the structure of: wherein R is –CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH(CH3)2, or – 5 CH C(CH ) , 2 3 3 2B 2B 10 wherein R is hydrogen, methyl or –OCH so that -OCH R is a methyl ethyl, methoxymethyl ether substituent, particularly wherein R is methyl.
14. The pharmaceutical composition of claim 1, wherein the composition is 15 represented by the structure of: wherein Ab is an antibody Ligand Unit; S is a sulfur atom of the antibody Ligand Unit; 34 35 5 R is isopropyl and R is –CH3, isopropyl, –CH2CH2CH2NH(C=O)NH2 or – CH CH CO H; 2 2 2 R is hydrogen or –OH; 2A 2B 2B 2B R is C -C alkyl, C -C alkenyl, -OCH OR , –C(=O)R or –C(=O)NHR , 1 6 2 6 2 wherein R is hydrogen, or C -C alkyl; and 10 subscript p is a number ranging from 1 to 8, particularly wherein 34 35 R is isopropyl and R is –CH , or –CH CH CH NH(C=O)NH ; 3 2 2 2 2 R is hydrogen or –OH; and 2A 2B 2B 2B R is lower alkyl, –C(=O)R or –C(=O)NHR , wherein R is lower alkyl, 15 particularly wherein A is –CH2(CH2)4(C=O)- or – CH (CH ) (C=O)NHCH CH (C=O)-, 2 2 4 2 2 particularly wherein the structure of the composition is represented by the structure wherein Ab is an antibody Ligand Unit; S is a sulfur atom of the antibody Ligand Unit; subscript p is a number ranging from 1 to 8; and 5 subscript m is 4, particularly wherein R is –C(O)CH , methyl, ethyl or propyl.
15. The pharmaceutical composition of claim 1, wherein the composition is represented by the structure of: wherein Ab is an antibody Ligand Unit; S is a sulfur atom of the antibody Ligand Unit; R is hydrogen or –OH; 2A 2B 2B 2B 2B R is C -C alkyl, -OCH OR –C(=O)R or –C(=O)NHR , wherein R is C -C 1 6 2 1 6 15 alkyl or C -C alkenyl; and subscript p is a number ranging from 1 to 8, particularly wherein R is hydrogen or –OH; and 2A 2B 2B 2B R is lower alkyl, –C(=O)R or –C(=O)NHR , wherein R is lower alkyl, 20 particularly wherein A is –CH (CH ) (C=O)- or – 2 2 4 CH (CH ) (C=O)NHCH CH (C=O)-, 2 2 4 2 2 particularly wherein the structure of the composition is represented by the structure wherein Ab is an antibody Ligand Unit; 5 S is a sulfur atom of the antibody Ligand Unit; subscript p is a number ranging from 1 to 8; and subscript m is 4, particularly wherein R is –C(O)CH , methyl, ethyl or propyl. 10
16. The pharmaceutical composition of claim 1, wherein each Ligand Drug Conjugate compound of the composition is represented by the structure of: wherein Ab is an antibody Ligand Unit; 15 S is a sulfur atom of the antibody Ligand Unit; the Ab-S- moiety is bonded to the carbon a or ß to the carboxylic acid; 34 35 R is isopropyl and R is –CH or –CH CH CH NH(C=O)NH ; 3 2 2 2 2 R is hydrogen or –OH; 2A 2B 2B 2B R is lower alkyl, –C(=O)R or –C(=O)NHR , wherein R is lower alkyl; and subscript p’ is an integer ranging from 1 to 8, particularly wherein A is –CH (CH ) (C=O)- or – 2 2 4 5 CH (CH ) (C=O)NHCH CH (C=O)-, 2 2 4 2 2 particularly wherein each Ligand Drug Conjugate compound of the composition is represented by the structure of: wherein Ab is an antibody Ligand Unit; S is a sulfur atom of the antibody Ligand Unit; the Ab-S- moiety is bonded to the carbon a or ß to the M carboxylic acid; subscript p’ is an integer ranging from 1 to 8; and 15 subscript m is 4, particularly wherein R is –C(O)CH , methyl, ethyl or propyl.
17. The pharmaceutical composition of claim 1, wherein each Ligand Drug Conjugate compound of the composition is represented by the structure of: wherein Ab is an antibody Ligand Unit; S is a sulfur atom of the antibody Ligand Unit; 5 the Ab-S- moiety is bonded to the carbon a or ß to the M carboxylic acid; R is hydrogen or –OH; 2A 2B 2B 2B R is lower alkyl, –C(=O)R or –C(=O)NHR , wherein R is lower alkyl; and subscript p’ is an integer ranging from 1 to 8, particularly wherein A is –CH (CH ) (C=O)- or – 2 2 4 10 CH (CH ) (C=O)NHCH CH (C=O)-, 2 2 4 2 2 particularly wherein each Ligand Drug Conjugate compound of the composition is represented by the structure of: wherein Ab is an antibody Ligand Unit; S is a sulfur atom of the antibody Ligand Unit; 5 the Ab-S- moiety is bonded to the carbon a or ß to the M carboxylic acid; subscript p’ is an integer ranging from 1 to 8; and subscript m is 4, particularly wherein R is –C(O)CH , methyl, ethyl or propyl. 10
18. The pharmaceutical composition of claim 1, wherein –D is a quaternized auristatin Drug Unit or a quaternized dolastatin Drug Unit, particularly wherein the quaternized dolastatin Drug Unit is quaternized dolastatin 10 or quaternized dolastatin 15, particularly wherein the quaternized auristatin Drug unit –D has the structure of D ’ 15 or D ’: (D ’) 20 (D ’) 10 11 wherein R and R are independently C -C alkyl; 12 1 1 R is hydrogen, C -C alkyl, C -C cycloalkyl, aryl, -X -aryl, -X -(C -C cycloalkyl), 1 8 3 8 3 8 C -C heterocycle or -X -(C -C heterocycle); 3 8 3 8 13 1 1 R is hydrogen, C -C alkyl, C -C cycloalkyl, aryl, -X -aryl, -X -(C -C cycloalkyl), 1 8 3 8 3 8 C -C heterocycle and -X -(C -C heterocycle); 3 8 3 8 5 R is hydrogen or methyl; 13 14 or R and R taken together with the carbon to which they are attached comprise a C -C cycloalkyl; R is hydrogen or C -C alkyl; 16 1 1 R is hydrogen, C -C alkyl, C -C cycloalkyl, aryl, -X -aryl, -X -(C -C cycloalkyl), 1 8 3 8 3 8 10 C -C heterocycle and -X -(C -C heterocycle); 3 8 3 8 R independently are hydrogen, -OH, C -C alkyl, C -C cycloalkyl and O-(C -C 1 8 3 8 1 8 alkyl); R independently are hydrogen or C -C alkyl; 19 19A 19A 19A 19A R is -C(R ) -C(R ) -aryl, -C(R ) -C(R ) -(C -C heterocycle) or 2 2 2 2 3 8 19A 19A 21 19A 15 -C(R ) -C(R ) -(C -C cycloalkyl); R is aryl or C -C heterocycle; wherein R is 2 2 3 8 3 8 hydrogen, C -C alkyl or –OH; 20 47 48 47 R is hydrogen, C -C alkyl, aryl, C -C heterocycle, -(R O) -R , and -(R O) - 1 20 3 8 m m CH(R ) ; subscript m is an integer ranging from 1-1000; 20 R is C -C alkyl; R is hydrogen or C -C alkyl; 49 50 R independently are -COOH, -(CH ) -N(R ) , -(CH ) -SO H, or -(CH ) -SO -C - 2 n 2 2 n 3 2 n 3 1 C alkyl; R independently are C -C alkyl, or -(CH ) -COOH; 1 8 2 n 46 46 25 Z is O, S, NH, or NR , wherein R is C -C alkyl; X is C -C alkylene; and subscript n is an integer ranging from 0 to 6; wherein the wavy line indicates covalent bonding of D to the remainder of the composition structure, 30 particularly wherein each Ligand Drug Conjugate compound of the composition is represented by the structure of: 5 wherein Ab is an antibody Ligand Unit; S is a sulfur atom of the antibody Ligand Unit; the Ab-S- moiety is bonded to the carbon a or ß to the M carboxylic acid; and subscript p’ is an integer ranging from 1 to 8. 10
19. The pharmaceutical composition of claim 1 substantially as herein described with reference to any example thereof.
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
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US201462049206P | 2014-09-11 | 2014-09-11 | |
US201462087218P | 2014-12-03 | 2014-12-03 | |
US201462087755P | 2014-12-04 | 2014-12-04 | |
NZ730552A NZ730552A (en) | 2014-09-11 | 2015-09-10 | Targeted delivery of tertiary amine-containing drug substances |
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NZ767751B2 true NZ767751B2 (en) | 2024-03-26 |
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