Prodrugs of biologically active hydroxyaromatic compounds

• US 5,001,115 A
• Filed: 05/17/1989
• Issued: 03/19/1991
• Est. Priority Date: 05/17/1989
• Status: Expired due to Fees

• Current Assignee: University of Florida (State University System of Florida)
• Original Assignee: University of Florida (State University System of Florida)
• Inventors: Sloan, Kenneth B.
• Primary Examiner(s): Shah, Mukund J.
• Assistant Examiner(s): WARD, EDWARD C
• Application Number:
  US07/352,919
• Time in Patent Office: 671 Days
• Field of Search: 514/169, 514/289, 514/373, 514/417, 514/425, 514/222.8, 514/328, 514/360, 514/518, 514/603, 514/34, 536/6.4, 564/82, 564/155, 552/626, 546/44, 546/176, 546/75, 544/2, 548/123, 548/209, 548/256, 548/477, 548/595
• US Class Current: 514/34
• CPC Class Codes: A61K 47/555 pre-targeting systems involving an organic compound, other than a peptide, protein or antibody, for targeting specific cells
• CPC Class Codes: C07D 207/404 with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms, e.g. succinimide
• CPC Class Codes: C07D 207/416 with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to other ring carbon atoms
• CPC Class Codes: C07D 207/42 Nitro radicals
• CPC Class Codes: C07D 209/48 with oxygen atoms in positions 1 and 3, e.g. phthalimide
• CPC Class Codes: C07D 275/06 with hetero atoms directly attached to the ring sulfur atom
• CPC Class Codes: C07D 417/12 linked by a chain containing hetero atoms as chain links

Abstract

Prodrugs of bio-active hydroxyaromatic drugs having the structural formula:

A pharmaceutically acceptable prodrug of a biologically active, therapeutically effective hydroxyaromatic drug, said prodrug being selected from the group consisting of, (A) compounds having the structural formula:

DRUG--O--CR'"'"'R"--Z].sub.n

wherein:

DRUG --O-- is the hydroxyaromatic O-dehydro residue of said drug;

R'"'"' and R'"'"' may be the same or different and may be H, alkyl, aryl or electron withdrawing groups;

Z is a displaceable leaving group; and

n is an integer in the range of from 1 to 3, and (B) pharmaceutically acceptable salts thereof.

Claims

1. A pharmaceutically acceptable prodrug of a biologically active, therapeutically effective hydroxyaromatic compound (HAC) drug, said prodrug being selected from the group consisting of (A) compounds having the structural formula:

space="preserve" listing-type="equation">DRUG--O--CR'"'"'R"--].sub.n

wherein;

DRUG--O--is the HAC O-dehydro residue of the drug;

R'"'"' and R" may be the same or different and are selected from the group consisting of H, cycloalkyl groups having up to 10 carbon atoms, straight or branched chain alkyl, alkenyl or alkynyl groups of 1 to 10 carbon atoms, wherein the chains thereof (1) may be interrupted by at least one N, S or O atom, or (2) may be substituted by at least one group selected from the group consisting of COR'"'"'", COOR'"'"'" and CON(R'"'"'")₂, hydrocarbyl aryl groups, aryl groups substituted by at least one group seelcted from teh goup consisting of COR'"'"'", COOR'"'"'", CON(R'"'"'")₂, N(R'"'"'")₂, OR'"'"'", halogen, SR'"'"'", NO₂ and R'"'"'", mono- and bi-cyclic saturated or unsaturated heterocyclic rings, each ring consisting of 3 to 7 members selected from the group consisting of carbon, nitrogen, oxygen and sulfur, CN, COR'"'"'", COOR'"'"'", CON(R'"'"'")₂ and C(halogen)₃ ;

R'"'"'" is selected from the group consisting of cycloalkyl groups having up to 10 carbon atoms, straight or branched chain alkyl, alkenyl and alkynyl groups having 1 to 10 carbon atoms, straight or branched chain alkyl, alkenyl and alkynyl groups of 1 to 10 carbon atoms wherein the chains thereof may be interupted by at least one N, S or O atom, hydrocarbyl aryl groups, and in the case of --N(R'"'"'")₂ taken with the other R'"'"'" group an N is a mono- or bi-cyclic saturated or unsaturated hetereocyclic ring, wherein each ring consists of 3 to 7 members selected from the group consisting of carbon, nitrogen,oxygen and sulfur;

Z is a displaceable leaving group and is the dehydro residue of the compound Z--H wherein the pKa of Z--H→

Z^- +H⁺ is the range of from 1.0 to 12.0; and

n is an integer in the range of from 1 to 3, and

(B) pharmaceutically acceptable salts thereof;

said prodrug having enhanced stability against premature metabolism upon oral administration and being chemically hydrolyzable to the HAC drug.

2. A pharmaceutical composition in unit dosage form adapted for oral or topical administration to a human or non-human animal in need thereof comprising a therapeutically effective amount of a prodrug of claim 1 and a pharmaceutically acceptable carrier therefor.

3. A method of treatment comprising orally or topically administering to a human or non-human animal in need thereof a therapeutically effective amount of a prodrug of claim 1.