CA2339834A1 - Water soluble prodrugs of hindered alcohols or phenols - Google Patents

Water soluble prodrugs of hindered alcohols or phenols Download PDF

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Publication number
CA2339834A1
CA2339834A1 CA002339834A CA2339834A CA2339834A1 CA 2339834 A1 CA2339834 A1 CA 2339834A1 CA 002339834 A CA002339834 A CA 002339834A CA 2339834 A CA2339834 A CA 2339834A CA 2339834 A1 CA2339834 A1 CA 2339834A1
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CA
Canada
Prior art keywords
compound
group
compound according
taxol
formula
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
Application number
CA002339834A
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French (fr)
Other versions
CA2339834C (en
Inventor
Valentino J. Stella
Jan J. Zygmunt
Ingrid Gunda Georg
Muhammad S. Safadi
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
University of Kansas
Original Assignee
The University Of Kansas
Valentino J. Stella
Jan J. Zygmunt
Ingrid Gunda Georg
Muhammad S. Safadi
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Filing date
Publication date
Application filed by The University Of Kansas, Valentino J. Stella, Jan J. Zygmunt, Ingrid Gunda Georg, Muhammad S. Safadi filed Critical The University Of Kansas
Publication of CA2339834A1 publication Critical patent/CA2339834A1/en
Application granted granted Critical
Publication of CA2339834C publication Critical patent/CA2339834C/en
Anticipated expiration legal-status Critical
Expired - Fee Related legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/655—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
    • C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
    • A61K38/13—Cyclosporins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P23/00—Anaesthetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/06—Phosphorus compounds without P—C bonds
    • C07F9/08—Esters of oxyacids of phosphorus
    • C07F9/09—Esters of phosphoric acids
    • C07F9/091—Esters of phosphoric acids with hydroxyalkyl compounds with further substituents on alkyl
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/655—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms
    • C07F9/6552—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms the oxygen atom being part of a six-membered ring
    • C07F9/65522—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms the oxygen atom being part of a six-membered ring condensed with carbocyclic rings or carbocyclic ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/64—Cyclic peptides containing only normal peptide links
    • C07K7/645—Cyclosporins; Related peptides
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

The present invention is directed to novel water-soluble prodrugs of aliphatic or aromatic hindered hydroxyl group containing pharmaceuticals.

Claims (21)

1. A compound according to formula I:

wherein, R-O- is a residue of an alcohol-containing or phenol-containing pharmaceutical compound, excluding taxol and taxol derivatives, R1 is hydrogen or an alkali metal ion or a protonated amine or a protonated amino acid, R2 is hydrogen or an alkali metal ion or a protonated amine or a protonated amino acid, and n is an integer of 1 or 2;
m is an integer of at least 1;
and pharmaceutically acceptable salts thereof.
2. The compound according to claim 1, wherein said alcohol-containing or phenol-containing compound is selected from the group consisting of camptothecin, camptothecin analogues, propofol, etoposide, vitamin E
and cyclosporin A.
3. The compound according to claim 1, wherein the alkali metal ion of R1 and R2 is each independently selected from the group consisting of sodium, potassium and lithium.
4. A compound selected from the group consisting of:

wherein Z is selected from the group consisting of hydrogen, alkali metal ion, and amine;
and pharmaceutical1y acceptable salts thereof.
5. The compound according to c1aim 4, wherein each Z is independently selected from the group consisting of sodium, tromethamine, triethanolamine, triethylamine, arginine, lysine, ethanolamine and N-methylglucamine.
6. A compound according to formula III:
wherein, R-O- is a residue of an alcohol-containing or phenol-containing pharmaceutical compound, excluding taxol and taxol derivatives;
and pharmaceutically acceptable salts, thereof.
7. A compound according to claim 6, wherein said compound is selected from the group consisting of:

8. A compound according to formula IV:

wherein, R-O- is a residue of alcohol-containing or phenol-containing pharmaceutical compound, excluding taxol and taxol derivatives, Y is a phosphono protecting group and n is an integer of 1 or 2;
and pharmaceutically acceptable salt thereof.
9. A compound according to claim 8, wherein said compound is selected from the group consisting of:
wherein Y is a phosphono protecting group.
10. The compound according claim 8, wherein said phosphono protecting group is selected from the group consisting of a benzyl group, a t-butyl group, an allyl group, and other acceptable phosphate protecting groups.
11. A pharmaceutical composition, comprising:
an effective amount a compound according to claim 1: and a pharmaceutically acceptable carrier.
12. A process for preparing a compound of claim 4, comprising:
removing a phosphono protecting group from a compound according to one of the following formula:

wherein Y is the phosphono protecting group; and recovering the product.
13. A process for preparing a compound of claim 6, comprising:
reacting a compound of the formula R-O-H, wherein, R-O- is a residue, of an alcohol-containing or phenol-containing pharmaceutical compound, excluding taxol and taxol derivatives, and pharmaceutically acceptable salts thereof, with dimethylsulfoxide in the presence of acetic anhydride and acetic acid; and recovering the product.
14. A process for preparing a compound of claim 8, comprising:
reacting a compound according to formula IV:
wherein, R-O- is a residue of an alcohol-containing or phenol-containing pharmaceutical compound, excluding taxol and taxol derivatives; and pharmaceutically acceptable salts thereof, with N-iodosuccinamide and a protected phosphoric acid of formula HOP(O)(OY)2, wherein Y is a phosphono protecting group; and recovering the product.
15. The process according to claim 14, wherein the phosphono protecting group is selected from the group consisting of a benzyl group, a t-butyl group and an allyl group.
16. A method of treatment which comprises administering to a patient in need thereof an effective amount of a composition according claim 11.
17. The method according to claim 16, wherein said compound is administered orally.
18. The method according to claim 16, wherein said compound is administered parenterally.
19. Use of a compound according to formula I as a medicament.
20. The use according to claim 19, wherein said compound is a propofol derivative the medicament produces an anesthetic effect.
21. The use according to claim 19, wherein said compound excludes propofol derivatives and the medicament has anti-tumor activity.
CA2339834A 1998-08-07 1999-08-06 Water soluble prodrugs of hindered alcohols or phenols Expired - Fee Related CA2339834C (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US09/131,385 1998-08-07
US09/131,385 US6204257B1 (en) 1998-08-07 1998-08-07 Water soluble prodrugs of hindered alcohols
PCT/US1999/017779 WO2000008033A1 (en) 1998-08-07 1999-08-06 Water soluble prodrugs of hindered alcohols or phenols

Publications (2)

Publication Number Publication Date
CA2339834A1 true CA2339834A1 (en) 2000-02-17
CA2339834C CA2339834C (en) 2011-01-25

Family

ID=22449234

Family Applications (1)

Application Number Title Priority Date Filing Date
CA2339834A Expired - Fee Related CA2339834C (en) 1998-08-07 1999-08-06 Water soluble prodrugs of hindered alcohols or phenols

Country Status (27)

Country Link
US (4) US6204257B1 (en)
EP (2) EP1683803A1 (en)
JP (1) JP4554081B2 (en)
KR (1) KR100662799B1 (en)
CN (2) CN1198834C (en)
AT (1) ATE319723T1 (en)
AU (1) AU769755B2 (en)
BR (1) BR9912853A (en)
CA (1) CA2339834C (en)
CY (1) CY1105043T1 (en)
CZ (1) CZ304020B6 (en)
DE (1) DE69930269T2 (en)
DK (1) DK1102776T3 (en)
ES (1) ES2268876T3 (en)
HK (1) HK1047939B (en)
HU (1) HU229401B1 (en)
IL (1) IL141316A (en)
MX (1) MXPA01001431A (en)
NO (1) NO330357B1 (en)
NZ (1) NZ509795A (en)
PL (1) PL198141B1 (en)
PT (1) PT1102776E (en)
RU (1) RU2235727C2 (en)
TR (1) TR200100772T2 (en)
UA (1) UA73479C2 (en)
WO (1) WO2000008033A1 (en)
ZA (1) ZA200101039B (en)

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