CA2484640A1 - Vitamin-mitomycin conjugates - Google Patents
Vitamin-mitomycin conjugates Download PDFInfo
- Publication number
- CA2484640A1 CA2484640A1 CA002484640A CA2484640A CA2484640A1 CA 2484640 A1 CA2484640 A1 CA 2484640A1 CA 002484640 A CA002484640 A CA 002484640A CA 2484640 A CA2484640 A CA 2484640A CA 2484640 A1 CA2484640 A1 CA 2484640A1
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- CA
- Canada
- Prior art keywords
- mitomycin
- group
- vitamin
- composition
- derivative
- 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.)
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
- C07D487/14—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D475/00—Heterocyclic compounds containing pteridine ring systems
- C07D475/02—Heterocyclic compounds containing pteridine ring systems with an oxygen atom directly attached in position 4
- C07D475/04—Heterocyclic compounds containing pteridine ring systems with an oxygen atom directly attached in position 4 with a nitrogen atom directly attached in position 2
-
- 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
- A61K47/54—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 organic compound
- A61K47/55—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 organic compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds
- A61K47/551—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 organic compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds one of the codrug's components being a vitamin, e.g. niacinamide, vitamin B3, cobalamin, vitamin B12, folate, vitamin A or retinoic acid
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- 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
Abstract
The invention relates to vitamin-mitomycin conjugates, to a method of using the conjugates to selectively eliminate a population of pathogenic cells in a host animal harboring the pathogenic cells, and to a method of preparation o f the conjugates. The conjugate is of general formula B-L-X wherein the group B is a vitamin, or an analog or a derivative thereof, that binds to a surface accessible vitamin receptor that is uniquely expressed, overexpressed, or preferentially expressed by a population of pathogenic cells, wherein the group L comprises a cleavable linker, and wherein the group X comprises a mitomycin compound, or an analog or a derivative thereof. An additional therapeutic agent, such as a chemotherapeutic agent, can be administered in combination with the conjugate.
Claims (23)
1. A conjugate of the general formula B-L-X
wherein the group B is a vitamin, or an analog or a derivative thereof, that binds to a surface accessible vitamin receptor that is uniquely expressed, overexpressed, or preferentially expressed by a population of pathogenic cells;
wherein the group L comprises a cleavable linker and wherein the cleavable linker is a disulfide group; and wherein the group X comprises a mitomycin compound, or an analog or a derivative thereof.
wherein the group B is a vitamin, or an analog or a derivative thereof, that binds to a surface accessible vitamin receptor that is uniquely expressed, overexpressed, or preferentially expressed by a population of pathogenic cells;
wherein the group L comprises a cleavable linker and wherein the cleavable linker is a disulfide group; and wherein the group X comprises a mitomycin compound, or an analog or a derivative thereof.
2. The conjugate of claim 1 wherein the vitamin is selected from the group consisting of folate, riboflavin, thiamine, biotin, vitamin B12, and analogs or derivatives thereof.
3. The conjugate of claim 1 wherein the linker is cleaved under reducing conditions.
4. The conjugate of claim 1 wherein the mitomycin is selected from the group consisting of mitomycin A, mitomycin B, mitomycin C, mitomycin D, mitomycin E, mitomycin F, and porfiromycin.
5. A method of selectively eliminating a population of pathogenic cells in a host animal harboring said population of cells wherein the members of said cell population have a surface accessible binding site for a vitamin, said method comprising the steps of:
administering to said host a conjugate of the general formula B-L-X
wherein the group B is a vitamin, or an analog or a derivative thereof, that binds to a surface accessible vitamin receptor that is uniquely expressed, overexpressed, or preferentially expressed by the population of pathogenic cells;
wherein the group L comprises a cleavable linker and wherein the cleavable linker is a disulfide group; and wherein the group X comprises a mitomycin compound, or an analog or a derivative thereof; and selectively eliminating said population of pathogenic cells.
administering to said host a conjugate of the general formula B-L-X
wherein the group B is a vitamin, or an analog or a derivative thereof, that binds to a surface accessible vitamin receptor that is uniquely expressed, overexpressed, or preferentially expressed by the population of pathogenic cells;
wherein the group L comprises a cleavable linker and wherein the cleavable linker is a disulfide group; and wherein the group X comprises a mitomycin compound, or an analog or a derivative thereof; and selectively eliminating said population of pathogenic cells.
6. The method of claim 6 wherein the vitamin is selected from the group consisting of folate, riboflavin, thiamine, biotin, vitamin B12, and analogs or derivatives thereof.
7. The method of claim 6 wherein the linker is cleaved under reducing conditions.
8. The method of claim 6 wherein the mitomycin is selected from the group consisting of mitomycin A, mitomycin B, mitomycin C, mitomycin D, mitomycin E, mitomycin F, and porfiromycin.
9. The method of claim 6 wherein the population of pathogenic cells is a cancer cell population.
10. The method of claim 6 further comprising the step of administering to said host a therapeutic factor selected from the group consisting of a cell killing agent, a tumor penetration enhancer, a chemotherapeutic agent, a cytotoxic immune cell, and a compound capable of stimulating an endogenous immune response.
11. The method of claim 12 wherein the therapeutic factor is a chemotherapeutic agent.
12. The method of claim 13 wherein the chemotherapeutic agent is paclitaxel.
13. A pharmaceutical composition comprising a conjugate of the general formula B-L-X
wherein the group B is a vitamin, or an analog or a derivative thereof, that binds to a surface accessible vitamin receptor that is uniquely expressed, overexpressed, or preferentially expressed by a population of pathogenic cells;
wherein the group L comprises a cleavable linker and wherein the cleavable linker is a disulfide group; and wherein the group X comprises a mitomycin compound, or an analog or a derivative thereof; and a pharmaceutically acceptable carrier therefor.
wherein the group B is a vitamin, or an analog or a derivative thereof, that binds to a surface accessible vitamin receptor that is uniquely expressed, overexpressed, or preferentially expressed by a population of pathogenic cells;
wherein the group L comprises a cleavable linker and wherein the cleavable linker is a disulfide group; and wherein the group X comprises a mitomycin compound, or an analog or a derivative thereof; and a pharmaceutically acceptable carrier therefor.
14. The composition of claim 15 wherein the vitamin is selected from the group consisting of folate, riboflavin, thiamine, biotin, vitamin B12, and analogs or derivatives thereof.
15. The composition of claim 15 wherein the linker is cleaved under reducing conditions.
16. The composition of claim 15 wherein the mitomycin is selected from the group consisting of mitomycin A, mitomycin B, mitomycin C, mitomycin D, mitomycin E, mitomycin F, and porfiromycin.
17. The composition of claim 15 further comprising a therapeutic factor selected from the group consisting of a cell killing agent, a tumor penetration enhancer, a chemotherapeutic agent, and a compound capable of stimulating an endogenous immune response.
18. The composition of claim 20 wherein the therapeutic factor is a chemotherapeutic agent.
19. The composition of claim 21 wherein the chemotherapeutic agent is paclitaxel.
20. A method of preparing a biologically active conjugate of the formula B-L-X
wherein B is a vitamin or a vitamin-receptor-binding analog or derivative thereof;
X comprises a mitomycin compound or an analog or derivative thereof;
and L is a divalent linker comprising a disulfide bond, said method comprising the steps of forming a thiosulfonate intermediate of the formula B-(L")n SSO2R or an intermediate of the formula X-(L')n SSO2R
and reacting said thiosulfonate intermediate with a compound of the formula X-(L')n'-SH or B-(L")n'-SH, respectively, wherein L' and L" are, independently, divalent linkers through which the thiol group SH is covalently bonded to B and X, respectively;
n and n' are 1 or 0; and R is alkyl, substituted alkyl, aryl, heteroaryl or substituted aryl or heteroaryl.
16. The composition of claim 15 wherein the vitamin is selected from the group consisting of folate, riboflavin, thiamine, biotin, vitamin B12, and analogs or derivatives thereof.
17. The composition of claim 15 wherein the linker is cleaved under reducing conditions.
18. The composition of claim 17 wherein the linker is a disulfide group.
19. The composition of claim 15 wherein the mitomycin is selected from the group consisting of mitomycin A, mitomycin B, mitomycin C, mitomycin D, mitomycin E, mitomycin F, and porfiromycin.
20. The composition of claim 15 further comprising a therapeutic factor selected from the group consisting of a cell killing agent, a tumor penetration enhancer, a chemotherapeutic agent, and a compound capable of stimulating an endogenous immune response.
wherein B is a vitamin or a vitamin-receptor-binding analog or derivative thereof;
X comprises a mitomycin compound or an analog or derivative thereof;
and L is a divalent linker comprising a disulfide bond, said method comprising the steps of forming a thiosulfonate intermediate of the formula B-(L")n SSO2R or an intermediate of the formula X-(L')n SSO2R
and reacting said thiosulfonate intermediate with a compound of the formula X-(L')n'-SH or B-(L")n'-SH, respectively, wherein L' and L" are, independently, divalent linkers through which the thiol group SH is covalently bonded to B and X, respectively;
n and n' are 1 or 0; and R is alkyl, substituted alkyl, aryl, heteroaryl or substituted aryl or heteroaryl.
16. The composition of claim 15 wherein the vitamin is selected from the group consisting of folate, riboflavin, thiamine, biotin, vitamin B12, and analogs or derivatives thereof.
17. The composition of claim 15 wherein the linker is cleaved under reducing conditions.
18. The composition of claim 17 wherein the linker is a disulfide group.
19. The composition of claim 15 wherein the mitomycin is selected from the group consisting of mitomycin A, mitomycin B, mitomycin C, mitomycin D, mitomycin E, mitomycin F, and porfiromycin.
20. The composition of claim 15 further comprising a therapeutic factor selected from the group consisting of a cell killing agent, a tumor penetration enhancer, a chemotherapeutic agent, and a compound capable of stimulating an endogenous immune response.
21. The composition of claim 20 wherein the therapeutic factor is a chemotherapeutic agent.
22. The composition of claim 21 wherein the chemotherapeutic agent is paclitaxel.
23. A method of preparing a biologically active conjugate of the formula B-L-X
wherein B is a vitamin or a vitamin-receptor-binding analog or derivative thereof;
X comprises a mitomycin compound or an analog or derivative thereof;
and L is a divalent linker comprising a disulfide bond, said method comprising the steps of forming a thiosulfonate intermediate of the formula B-(L")n SSO2R or an intermediate of the formula X-(L')n SSO2R
and reacting said thiosulfonate intermediate with a compound of the formula X-(L')n'-SH or B-(L")n'-SH, respectively, wherein L' and L" are, independently, divalent linkers through which the thiol group SH is covalently bonded to B and X, respectively;
n and n' are 1 or 0; and R is alkyl, substituted alkyl, aryl, heteroaryl or substituted aryl or heteroaryl.
wherein B is a vitamin or a vitamin-receptor-binding analog or derivative thereof;
X comprises a mitomycin compound or an analog or derivative thereof;
and L is a divalent linker comprising a disulfide bond, said method comprising the steps of forming a thiosulfonate intermediate of the formula B-(L")n SSO2R or an intermediate of the formula X-(L')n SSO2R
and reacting said thiosulfonate intermediate with a compound of the formula X-(L')n'-SH or B-(L")n'-SH, respectively, wherein L' and L" are, independently, divalent linkers through which the thiol group SH is covalently bonded to B and X, respectively;
n and n' are 1 or 0; and R is alkyl, substituted alkyl, aryl, heteroaryl or substituted aryl or heteroaryl.
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US38057902P | 2002-05-15 | 2002-05-15 | |
| US60/380,579 | 2002-05-15 | ||
| US42591802P | 2002-11-13 | 2002-11-13 | |
| US60/425,918 | 2002-11-13 | ||
| PCT/US2003/014969 WO2003097647A1 (en) | 2002-05-15 | 2003-05-13 | Vitamin-mitomycin conjugates |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2484640A1 true CA2484640A1 (en) | 2003-11-27 |
| CA2484640C CA2484640C (en) | 2012-01-17 |
Family
ID=29553501
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA2484640A Expired - Fee Related CA2484640C (en) | 2002-05-15 | 2003-05-13 | Vitamin-mitomycin conjugates |
Country Status (10)
| Country | Link |
|---|---|
| US (1) | US7910594B2 (en) |
| EP (2) | EP2060272A3 (en) |
| JP (1) | JP4814520B2 (en) |
| KR (1) | KR20040106547A (en) |
| AT (1) | ATE426414T1 (en) |
| AU (1) | AU2003243226A1 (en) |
| CA (1) | CA2484640C (en) |
| DE (1) | DE60326833D1 (en) |
| ES (1) | ES2324708T3 (en) |
| WO (1) | WO2003097647A1 (en) |
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-
2003
- 2003-05-13 AU AU2003243226A patent/AU2003243226A1/en not_active Abandoned
- 2003-05-13 JP JP2004505379A patent/JP4814520B2/en not_active Expired - Fee Related
- 2003-05-13 KR KR10-2004-7018375A patent/KR20040106547A/en not_active Application Discontinuation
- 2003-05-13 EP EP09002632A patent/EP2060272A3/en not_active Withdrawn
- 2003-05-13 DE DE60326833T patent/DE60326833D1/en not_active Expired - Lifetime
- 2003-05-13 CA CA2484640A patent/CA2484640C/en not_active Expired - Fee Related
- 2003-05-13 AT AT03752681T patent/ATE426414T1/en not_active IP Right Cessation
- 2003-05-13 ES ES03752681T patent/ES2324708T3/en not_active Expired - Lifetime
- 2003-05-13 WO PCT/US2003/014969 patent/WO2003097647A1/en active Application Filing
- 2003-05-13 EP EP03752681A patent/EP1504010B1/en not_active Expired - Lifetime
- 2003-05-13 US US10/513,372 patent/US7910594B2/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| US20050165227A1 (en) | 2005-07-28 |
| EP1504010B1 (en) | 2009-03-25 |
| EP2060272A3 (en) | 2009-05-27 |
| EP1504010A1 (en) | 2005-02-09 |
| WO2003097647A1 (en) | 2003-11-27 |
| EP2060272A2 (en) | 2009-05-20 |
| JP4814520B2 (en) | 2011-11-16 |
| CA2484640C (en) | 2012-01-17 |
| AU2003243226A1 (en) | 2003-12-02 |
| US7910594B2 (en) | 2011-03-22 |
| EP1504010A4 (en) | 2007-03-28 |
| JP2005531564A (en) | 2005-10-20 |
| ATE426414T1 (en) | 2009-04-15 |
| KR20040106547A (en) | 2004-12-17 |
| ES2324708T3 (en) | 2009-08-13 |
| DE60326833D1 (en) | 2009-05-07 |
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