CA2101104A1 - Amino acid linked nitrogen mustard derivatives and their use as prodrugs in the treatment of tumors - Google Patents
Amino acid linked nitrogen mustard derivatives and their use as prodrugs in the treatment of tumorsInfo
- Publication number
- CA2101104A1 CA2101104A1 CA002101104A CA2101104A CA2101104A1 CA 2101104 A1 CA2101104 A1 CA 2101104A1 CA 002101104 A CA002101104 A CA 002101104A CA 2101104 A CA2101104 A CA 2101104A CA 2101104 A1 CA2101104 A1 CA 2101104A1
- Authority
- CA
- Canada
- Prior art keywords
- group
- alkyl
- substituents
- halogen
- aryl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
- C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D257/04—Five-membered rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
- A61K47/6891—Pre-targeting systems involving an antibody for targeting specific cells
- A61K47/6899—Antibody-Directed Enzyme Prodrug Therapy [ADEPT]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
- C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
- C07C237/20—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton containing six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C271/06—Esters of carbamic acids
- C07C271/40—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of six-membered aromatic rings
- C07C271/42—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of six-membered aromatic rings with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C271/54—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of six-membered aromatic rings with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
- C07C275/04—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms
- C07C275/20—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms of an unsaturated carbon skeleton
- C07C275/24—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
- C07C275/28—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C275/40—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by nitrogen atoms not being part of nitro or nitroso groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
- C07C309/63—Esters of sulfonic acids
- C07C309/64—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms
- C07C309/65—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms of a saturated carbon skeleton
- C07C309/66—Methanesulfonates
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/50—Compounds containing any of the groups, X being a hetero atom, Y being any atom
- C07C311/51—Y being a hydrogen or a carbon atom
Abstract
Prodrugs, of generic formula I, are disclosed for use in antibody directed enzyme prodrug therapy (ADEPT). The prodrugs are substrates for carboxypeptidase G2 (CPG2) and yield more active cytotoxic drugs than known products of CPG2 catalysed reactions. Formula I is as follows:
(see formula I) wherein R1 and R2 each independently represents chlorine, bromine, iodine, OSO2Me, or OSO2phenyl (wherein phenyl is optionally substituted with 1,2,3,4 or 5 substituents independently selected from C1-4alkyl, halogen, -CN or -NO2);
R1a and R2a each independently represents hydrogen, C1-4alkyl or C1-4haloalkyl;
R3 and R4 each independently represents hydrogen, C1-4 alkyl or C1-4 haloalkyl;
R5a, R5b, R5c and R5d each independently represents hydrogen, C1-4 alkyl optionally containing one double bond or one triple bond, C1-4 alkoxy, halogen, cyano, -NH2, -CONR7R8 (wherein R7 and R8 are as defined below), -NH(C1-4-alkyl), -N(C1-4-alkyl)2 and C2-5alkanoyl; or R5a and R5b together represent a) C4 alkylene optionally having one double bond;
b) C3 alkylene ;or c) -CH=CH-CH=CH-, -CH=CH-CH2- or -CH2-CH=CH- each optionally substituted with 1, 2, 3 or 4 substituents said substituents each independently selected from the group consisting of C1-4 alkyl, C1-4 alkoxy, halogen, cyano, nitro, C2-5alkanoyl and -CONR7R8 (wherein R7 and R8 are as defined below);
X represents O, NH or -CH2-;
Y represents O;
2 represents -V-W where V is -CH2-T- in which T is -CH2-, -O-, -S-, -(SO)- or -(SO2)- (provided that when V has sulphur or oxygen as its second atom, W is other than -COON) and said group V optionally further carrying one or two substituents Q1 and/or Q2 on carbon;
wherein Q1 and Q2 each independently represents C1-4 alkyl or halogen; or, when Q1 and Q2 are bonded to adjacent carbon atoms, Q1 and Q2 together may additionally represent a C3-C4alkylene radical optionally substituted with 1, 2, 3 or 4 substituents independently selected from the group consisting of C1-4alkyl and halogen; and W represents (1) COON, (2) -(C=O)-O-R6 wherein R6 represents a C1-6alkyl, C3-6cycloalkyl or aryl (as defined in 3 below) group;
(3) -(C=O)-NR7R8 wherein R7 and R8 each independently represent hydrogen or a C1-6alkyl, C3-6cycloalkyl, aryl, heteroaryl linked to N
via carbon or C7-9aralkyl group wherein aryl is phenyl;
heteroaryl is a 5 or 6 membered ring containing 1 to 3 heteroatoms selected from the group consisting of nitrogen and sulphur;
the aryl moiety per se, the heteroaryl moiety and the aryl moiety of the aralkyl group may be substituted on carbon with 1-4 substituents selected from the group consisting of -COOH, -OH, -NH2, -CH2-NH2, -(CH2)1-4-COOH, tetrazol-5-yl and -SO3H and the alkyl moiety may optionally carry a methyl group;
(4) -SO2NHR9 wherein R9 is as defined for R7 but may additionally represent -CF3, -CH2CF3 or aryl as defined above;
(S) SO3R10 in which R10 represents H, C1-6alkyl or C3-6cycloalkyl, (6) PO3R10R10 (wherein the R10 radicals, which may be the same or different, are as herein defined) (7) a tetrazol-5-yl group;
(8) -CONH-SO2R11 in which R11 represents (a) C3-7cycloalkyl;
(b) C1-6-alkyl optionally substituted with substituents selected from the group consisting of aryl as defined below, C1-4-alkyl, CF3 or halogen; and (c) perfluoro-C1-6alkyl; wherein aryl is phenyl or phenyl having 1-5 substituents wherein the substituents are selected from the group consisting of halogen, -NO2, -CF3, C1-4alkyl, C1-4alkoxy, -NH2, -NHCOCH3, -CONH2, -OCH2COOH, -NH(C1-4-alkyl), -N(C1-4-alkyl)2, -NHCOOC1-4alkyl, -OH, -COOH, -CN and -COOC1-4alkyl; and (9)-M-Het wherein b represents S, SO or SO2 and Het represents a.5: or 6 membered heterocyclic aromatic ring linked to M via a carbon atom of the aromatic ring, said aromatic.ring containing 1, 2, 3 or 4-heteroatoms selected from the group consisting of O, N and S said aromatic ring optionally being substituted on carbon atoms of the ring with 1, 2, 3 or 4 substituents selected from the group consisting of -OH, -SH, -CN, -CF3, NH2 and halogen.
(see formula I) wherein R1 and R2 each independently represents chlorine, bromine, iodine, OSO2Me, or OSO2phenyl (wherein phenyl is optionally substituted with 1,2,3,4 or 5 substituents independently selected from C1-4alkyl, halogen, -CN or -NO2);
R1a and R2a each independently represents hydrogen, C1-4alkyl or C1-4haloalkyl;
R3 and R4 each independently represents hydrogen, C1-4 alkyl or C1-4 haloalkyl;
R5a, R5b, R5c and R5d each independently represents hydrogen, C1-4 alkyl optionally containing one double bond or one triple bond, C1-4 alkoxy, halogen, cyano, -NH2, -CONR7R8 (wherein R7 and R8 are as defined below), -NH(C1-4-alkyl), -N(C1-4-alkyl)2 and C2-5alkanoyl; or R5a and R5b together represent a) C4 alkylene optionally having one double bond;
b) C3 alkylene ;or c) -CH=CH-CH=CH-, -CH=CH-CH2- or -CH2-CH=CH- each optionally substituted with 1, 2, 3 or 4 substituents said substituents each independently selected from the group consisting of C1-4 alkyl, C1-4 alkoxy, halogen, cyano, nitro, C2-5alkanoyl and -CONR7R8 (wherein R7 and R8 are as defined below);
X represents O, NH or -CH2-;
Y represents O;
2 represents -V-W where V is -CH2-T- in which T is -CH2-, -O-, -S-, -(SO)- or -(SO2)- (provided that when V has sulphur or oxygen as its second atom, W is other than -COON) and said group V optionally further carrying one or two substituents Q1 and/or Q2 on carbon;
wherein Q1 and Q2 each independently represents C1-4 alkyl or halogen; or, when Q1 and Q2 are bonded to adjacent carbon atoms, Q1 and Q2 together may additionally represent a C3-C4alkylene radical optionally substituted with 1, 2, 3 or 4 substituents independently selected from the group consisting of C1-4alkyl and halogen; and W represents (1) COON, (2) -(C=O)-O-R6 wherein R6 represents a C1-6alkyl, C3-6cycloalkyl or aryl (as defined in 3 below) group;
(3) -(C=O)-NR7R8 wherein R7 and R8 each independently represent hydrogen or a C1-6alkyl, C3-6cycloalkyl, aryl, heteroaryl linked to N
via carbon or C7-9aralkyl group wherein aryl is phenyl;
heteroaryl is a 5 or 6 membered ring containing 1 to 3 heteroatoms selected from the group consisting of nitrogen and sulphur;
the aryl moiety per se, the heteroaryl moiety and the aryl moiety of the aralkyl group may be substituted on carbon with 1-4 substituents selected from the group consisting of -COOH, -OH, -NH2, -CH2-NH2, -(CH2)1-4-COOH, tetrazol-5-yl and -SO3H and the alkyl moiety may optionally carry a methyl group;
(4) -SO2NHR9 wherein R9 is as defined for R7 but may additionally represent -CF3, -CH2CF3 or aryl as defined above;
(S) SO3R10 in which R10 represents H, C1-6alkyl or C3-6cycloalkyl, (6) PO3R10R10 (wherein the R10 radicals, which may be the same or different, are as herein defined) (7) a tetrazol-5-yl group;
(8) -CONH-SO2R11 in which R11 represents (a) C3-7cycloalkyl;
(b) C1-6-alkyl optionally substituted with substituents selected from the group consisting of aryl as defined below, C1-4-alkyl, CF3 or halogen; and (c) perfluoro-C1-6alkyl; wherein aryl is phenyl or phenyl having 1-5 substituents wherein the substituents are selected from the group consisting of halogen, -NO2, -CF3, C1-4alkyl, C1-4alkoxy, -NH2, -NHCOCH3, -CONH2, -OCH2COOH, -NH(C1-4-alkyl), -N(C1-4-alkyl)2, -NHCOOC1-4alkyl, -OH, -COOH, -CN and -COOC1-4alkyl; and (9)-M-Het wherein b represents S, SO or SO2 and Het represents a.5: or 6 membered heterocyclic aromatic ring linked to M via a carbon atom of the aromatic ring, said aromatic.ring containing 1, 2, 3 or 4-heteroatoms selected from the group consisting of O, N and S said aromatic ring optionally being substituted on carbon atoms of the ring with 1, 2, 3 or 4 substituents selected from the group consisting of -OH, -SH, -CN, -CF3, NH2 and halogen.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB929215636A GB9215636D0 (en) | 1992-07-23 | 1992-07-23 | Chemical compounds |
| GB9215636.3 | 1992-07-23 | ||
| GB939310884A GB9310884D0 (en) | 1993-05-26 | 1993-05-26 | Chemical compounds |
| GB9310884.3 | 1993-05-26 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2101104A1 true CA2101104A1 (en) | 1994-01-24 |
| CA2101104C CA2101104C (en) | 2007-01-23 |
Family
ID=26301303
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002101104A Expired - Fee Related CA2101104C (en) | 1992-07-23 | 1993-07-22 | Amino acid linked nitrogen mustard derivatives and their use as prodrugs in the treatment of tumors |
Country Status (25)
| Country | Link |
|---|---|
| US (6) | US5405990A (en) |
| EP (1) | EP0651740B1 (en) |
| JP (1) | JP3541037B2 (en) |
| KR (1) | KR100268654B1 (en) |
| AT (1) | ATE172450T1 (en) |
| AU (1) | AU681349B2 (en) |
| CA (1) | CA2101104C (en) |
| CZ (1) | CZ287028B6 (en) |
| DE (1) | DE69321729T2 (en) |
| DK (1) | DK0651740T3 (en) |
| ES (1) | ES2123662T3 (en) |
| FI (1) | FI115048B (en) |
| GB (1) | GB9314960D0 (en) |
| HK (1) | HK1002683A1 (en) |
| HU (1) | HUT69288A (en) |
| IL (1) | IL106459A (en) |
| MY (1) | MY111635A (en) |
| NZ (1) | NZ254864A (en) |
| PH (1) | PH30004A (en) |
| PL (1) | PL174617B1 (en) |
| RU (1) | RU2129542C1 (en) |
| SK (1) | SK281338B6 (en) |
| TW (1) | TW272971B (en) |
| WO (1) | WO1994002450A1 (en) |
| ZW (1) | ZW9293A1 (en) |
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| US6451995B1 (en) | 1996-03-20 | 2002-09-17 | Sloan-Kettering Institute For Cancer Research | Single chain FV polynucleotide or peptide constructs of anti-ganglioside GD2 antibodies, cells expressing same and related methods |
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| US6765019B1 (en) | 1999-05-06 | 2004-07-20 | University Of Kentucky Research Foundation | Permeable, water soluble, non-irritating prodrugs of chemotherapeutic agents with oxaalkanoic acids |
| GB0001653D0 (en) * | 2000-01-26 | 2000-03-15 | Astrazeneca Uk Ltd | Chemical compound |
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| EP1303481A1 (en) * | 2000-07-26 | 2003-04-23 | Patrick Anthony Riley | Phenylethylamine derivatives and their use in the treatment of melanoma |
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| US20040175378A1 (en) | 2002-07-15 | 2004-09-09 | Board Of Regents, The University Of Texas System | Selected antibody compositions and methods for binding to aminophospholipids |
| US20040092735A1 (en) * | 2002-11-08 | 2004-05-13 | Orchid Chemicals & Pharmaceuticals Limited | Process for the preparation of cefuroxime sodium |
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| GB8809616D0 (en) * | 1988-04-22 | 1988-05-25 | Cancer Res Campaign Tech | Further improvements relating to drug delivery systems |
| GB8820850D0 (en) * | 1988-09-05 | 1988-10-05 | Cancer Res Campaign Tech | Improvements relating to pro-drugs |
| GB8920011D0 (en) * | 1989-09-05 | 1989-10-18 | Mann J | New route of synthesis for tertiary butyl esters |
| CA2122036C (en) * | 1991-10-23 | 2002-09-17 | Gillian Anlezark | Bacterial nitroreductase for the reduction of cb 1954 and analogues thereof to a cytotoxic form |
| GB9314960D0 (en) * | 1992-07-23 | 1993-09-01 | Zeneca Ltd | Chemical compounds |
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1993
- 1993-07-21 GB GB939314960A patent/GB9314960D0/en active Pending
- 1993-07-22 US US08/094,952 patent/US5405990A/en not_active Expired - Lifetime
- 1993-07-22 CA CA002101104A patent/CA2101104C/en not_active Expired - Fee Related
- 1993-07-22 IL IL106459A patent/IL106459A/en not_active IP Right Cessation
- 1993-07-23 KR KR1019950700225A patent/KR100268654B1/en not_active IP Right Cessation
- 1993-07-23 PL PL93307226A patent/PL174617B1/en not_active IP Right Cessation
- 1993-07-23 HU HU9500145A patent/HUT69288A/en unknown
- 1993-07-23 DE DE69321729T patent/DE69321729T2/en not_active Expired - Fee Related
- 1993-07-23 AU AU47156/93A patent/AU681349B2/en not_active Ceased
- 1993-07-23 PH PH6570A patent/PH30004A/en unknown
- 1993-07-23 ZW ZW9293A patent/ZW9293A1/en unknown
- 1993-07-23 NZ NZ254864A patent/NZ254864A/en unknown
- 1993-07-23 WO PCT/GB1993/001560 patent/WO1994002450A1/en active IP Right Grant
- 1993-07-23 JP JP50430994A patent/JP3541037B2/en not_active Expired - Lifetime
- 1993-07-23 RU RU95105246A patent/RU2129542C1/en not_active IP Right Cessation
- 1993-07-23 AT AT93917904T patent/ATE172450T1/en not_active IP Right Cessation
- 1993-07-23 ES ES93917904T patent/ES2123662T3/en not_active Expired - Lifetime
- 1993-07-23 MY MYPI93001454A patent/MY111635A/en unknown
- 1993-07-23 DK DK93917904T patent/DK0651740T3/en active
- 1993-07-23 EP EP93917904A patent/EP0651740B1/en not_active Expired - Lifetime
- 1993-07-23 CZ CZ1995151A patent/CZ287028B6/en not_active IP Right Cessation
- 1993-07-23 SK SK69-95A patent/SK281338B6/en unknown
- 1993-07-27 TW TW082106015A patent/TW272971B/zh active
-
1994
- 1994-12-21 US US08/361,424 patent/US5587161A/en not_active Expired - Lifetime
-
1995
- 1995-01-19 FI FI950230A patent/FI115048B/en not_active IP Right Cessation
- 1995-05-16 US US08/442,348 patent/US5660829A/en not_active Expired - Lifetime
-
1996
- 1996-09-30 US US08/722,669 patent/US5714148A/en not_active Expired - Lifetime
-
1997
- 1997-10-22 US US08/956,008 patent/US5958971A/en not_active Expired - Lifetime
-
1998
- 1998-02-27 HK HK98101571A patent/HK1002683A1/en not_active IP Right Cessation
-
1999
- 1999-05-19 US US09/314,894 patent/US6277880B1/en not_active Expired - Lifetime
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