WO2000008033A1 - 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
WO2000008033A1
WO2000008033A1 PCT/US1999/017779 US9917779W WO0008033A1 WO 2000008033 A1 WO2000008033 A1 WO 2000008033A1 US 9917779 W US9917779 W US 9917779W WO 0008033 A1 WO0008033 A1 WO 0008033A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
group
compound according
formula
camptothecin
Prior art date
Application number
PCT/US1999/017779
Other languages
English (en)
French (fr)
Inventor
Valentino J. Stella
Jan J. Zygmunt
Ingrid Gunda Georg
Muhammed S. Safadi
Original Assignee
The University Of Kansas
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Priority to UA2001031520A priority Critical patent/UA73479C2/uk
Priority to CA2339834A priority patent/CA2339834C/en
Priority to SI9930903T priority patent/SI1102776T1/sl
Priority to EP99939030A priority patent/EP1102776B1/en
Priority to NZ509795A priority patent/NZ509795A/en
Priority to HU0200317A priority patent/HU229401B1/hu
Priority to PL347211A priority patent/PL198141B1/pl
Priority to CZ20010479A priority patent/CZ304020B6/cs
Application filed by The University Of Kansas filed Critical The University Of Kansas
Priority to BR9912853-5A priority patent/BR9912853A/pt
Priority to JP2000563666A priority patent/JP4554081B2/ja
Priority to DE69930269T priority patent/DE69930269T2/de
Priority to MXPA01001431A priority patent/MXPA01001431A/es
Priority to AU53394/99A priority patent/AU769755B2/en
Priority to IL14131699A priority patent/IL141316A/en
Publication of WO2000008033A1 publication Critical patent/WO2000008033A1/en
Priority to NO20010659A priority patent/NO330357B1/no
Priority to HK03100006.9A priority patent/HK1047939B/zh
Priority to CY20061100710T priority patent/CY1105043T1/el

Links

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

Definitions

  • An example of a sterically hindered, poorly water soluble phenol is propofol, an anesthetic.
  • the invention described herein involves new compositions of matter.
  • the invention relates to the water soluble phosphonooxymethyl derivatives of alcohol and phenol containing pharmaceuticals represented by the general formula I :
  • Figure 1 illustrates an in vi tro enzymatic conversion of propofol prodrug to propofol.
  • phosphonooxymethoxy or "phosphonooxymethyl ether” means generically the group -OCH 2 OP (0) (OH) 2 .
  • Metalthiomethyl refers to the group -CH 2 SCH 3 .
  • compounds of formula II of the present invention may be used in a manner similar to that of camptothecin.
  • the structure of the camptothecin prodrug is shown above. Therefore, an oncologist skilled in the art of cancer treatment will be able to ascertain, without undue experimentation, an appropriate treatment protocol for administering a compound of the present invention.
  • the dosage, mode and schedule of administration of compounds of this invention are not particularly restricted, and will vary with the particular compound employed.
  • a compound of the formula II may be administrated via any suitable route of administration, preferable parenterally; the dosage may be, for example, in the range of about 0.1 to about 100 mg/kg of body weight, or about 5 to 500 mg/m2.
  • the present invention also provides pharmaceutical compositions containing a pharmaceutically effective amount of compound of formula I in combination with one or more pharmaceutically acceptable carriers, excipients, diluents or adjuvants.
  • compounds of the present invention may be formulated in the form of tablets, pills, powder mixtures, capsules, injectables, solutions, suppositories, emulsions, dispersions, food premix, and in other suitable forms. They may also be manufactured in the form of sterile solid compositions, for example, freeze- dried and, if desired, combined with other pharmaceutically acceptable excipients.
  • the solution is filtered, concentrated at reduced pressure to -10 mL volume. After standing at room temperature for one hour, the solution is placed in a refrigerator overnight. The crystalline precipitate that forms overnight is filtered off and dried in vacuo to give the title compound as a solid. The filtrate is concentrated to ⁇ 1 mL volume and kept in the refrigerator for one hour to give additional product.
PCT/US1999/017779 1998-08-07 1999-08-06 Water soluble prodrugs of hindered alcohols or phenols WO2000008033A1 (en)

Priority Applications (17)

Application Number Priority Date Filing Date Title
UA2001031520A UA73479C2 (uk) 1998-08-07 1999-06-08 Водорозчинні проліки блокованих спиртів чи фенолів, фармацевтична композиція на їх основі, спосіб їх одержання, проміжна сполука (варіанти) та спосіб її одержання (варіанти)
JP2000563666A JP4554081B2 (ja) 1998-08-07 1999-08-06 ヒンダードアルコールまたはフェノールの水溶性プロドラッグ
SI9930903T SI1102776T1 (sl) 1998-08-07 1999-08-06 V vodi topna predzdravila oviranih fenolov
DE69930269T DE69930269T2 (de) 1998-08-07 1999-08-06 Wasserlösslische prodrugs von gehinderten phenolen
HU0200317A HU229401B1 (en) 1998-08-07 1999-08-06 Water soluble prodrugs of hindered phenols
PL347211A PL198141B1 (pl) 1998-08-07 1999-08-06 Prolek propofolu, zawierające go kompozycje farmaceutyczne, jego zastosowanie, sposób jego wytwarzania i związki pośrednie oraz sposób ich wytwarzania
CZ20010479A CZ304020B6 (cs) 1998-08-07 1999-08-06 Vodorozpustná léciva bránených fenolu
CA2339834A CA2339834C (en) 1998-08-07 1999-08-06 Water soluble prodrugs of hindered alcohols or phenols
BR9912853-5A BR9912853A (pt) 1998-08-07 1999-08-06 Pró-drogas solúveis em água de álcoois ou defenóis impedidos
EP99939030A EP1102776B1 (en) 1998-08-07 1999-08-06 Water soluble prodrugs of hindered phenols
NZ509795A NZ509795A (en) 1998-08-07 1999-08-06 Water soluble prodrugs of hindered alcohols or phenols
MXPA01001431A MXPA01001431A (es) 1998-08-07 1999-08-06 Profarmacos solubles en agua de alcoholes o fenoles impedidos.
AU53394/99A AU769755B2 (en) 1998-08-07 1999-08-06 Water soluble prodrugs of hindered alcohols or phenols
IL14131699A IL141316A (en) 1998-08-07 1999-08-06 Water-soluble pro-drugs of disturbed alcohols or phenols
NO20010659A NO330357B1 (no) 1998-08-07 2001-02-07 Vannloselige, fenolinneholdende forbindelser og fremstilling derav, farmasoytisk sammensetning inneholdende disse, og anvendelse av forbindelsene i fremstilling av medikamenter
HK03100006.9A HK1047939B (zh) 1998-08-07 2003-01-02 位阻醇或酚的水溶性前藥
CY20061100710T CY1105043T1 (el) 1998-08-07 2006-06-02 Υδατοδιαλυτa προφaρμακα παρεμποδισμeνων φαινολων

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US09/131,385 US6204257B1 (en) 1998-08-07 1998-08-07 Water soluble prodrugs of hindered alcohols
US09/131,385 1998-08-07

Publications (1)

Publication Number Publication Date
WO2000008033A1 true WO2000008033A1 (en) 2000-02-17

Family

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Family Applications (1)

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

Country Status (27)

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US (4) US6204257B1 (US20010025035A1-20010927-C00001.png)
EP (2) EP1102776B1 (US20010025035A1-20010927-C00001.png)
JP (1) JP4554081B2 (US20010025035A1-20010927-C00001.png)
KR (1) KR100662799B1 (US20010025035A1-20010927-C00001.png)
CN (2) CN1680402A (US20010025035A1-20010927-C00001.png)
AT (1) ATE319723T1 (US20010025035A1-20010927-C00001.png)
AU (1) AU769755B2 (US20010025035A1-20010927-C00001.png)
BR (1) BR9912853A (US20010025035A1-20010927-C00001.png)
CA (1) CA2339834C (US20010025035A1-20010927-C00001.png)
CY (1) CY1105043T1 (US20010025035A1-20010927-C00001.png)
CZ (1) CZ304020B6 (US20010025035A1-20010927-C00001.png)
DE (1) DE69930269T2 (US20010025035A1-20010927-C00001.png)
DK (1) DK1102776T3 (US20010025035A1-20010927-C00001.png)
ES (1) ES2268876T3 (US20010025035A1-20010927-C00001.png)
HK (1) HK1047939B (US20010025035A1-20010927-C00001.png)
HU (1) HU229401B1 (US20010025035A1-20010927-C00001.png)
IL (1) IL141316A (US20010025035A1-20010927-C00001.png)
MX (1) MXPA01001431A (US20010025035A1-20010927-C00001.png)
NO (1) NO330357B1 (US20010025035A1-20010927-C00001.png)
NZ (1) NZ509795A (US20010025035A1-20010927-C00001.png)
PL (1) PL198141B1 (US20010025035A1-20010927-C00001.png)
PT (1) PT1102776E (US20010025035A1-20010927-C00001.png)
RU (1) RU2235727C2 (US20010025035A1-20010927-C00001.png)
TR (1) TR200100772T2 (US20010025035A1-20010927-C00001.png)
UA (1) UA73479C2 (US20010025035A1-20010927-C00001.png)
WO (1) WO2000008033A1 (US20010025035A1-20010927-C00001.png)
ZA (1) ZA200101039B (US20010025035A1-20010927-C00001.png)

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