Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1997-02-28
1998-06-09
Rotman, Alan L.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
546126, 546128, 546130, C07D45106, C07D45108, C07D45112, A61K 3146
Patent
active
057634564
DESCRIPTION:
BRIEF SUMMARY
CROSS-REFERENCE
This application is a 371 of PCT/US95/07268 filed Jun. 14, 1995.
TECHNICAL FIELD OF THE INVENTION
The present invention relates to a novel class of covalently coupled benzoylecgonine, ecgonine and ecgonidine derivatives that are useful for alleviating the symptoms of immunoregulatory disorders, neuromuscular disorders, joint disorders, connective tissue disorders,. circulatory disorders and pain. Accordingly, this invention also relates to pharmaceutical compositions and methods for their use.
BACKGROUND OF THE INVENTION
Benzoylecgonine, ecgonine and ecgonidine are known metabolites of cocaine (see, for example, S. M. Roberts et al., "An Assay for Cocaethylene and Other Cocaine Metabolites in Liver Using High-Performance Liquid Chromatography", Anal. Biochem., 202, pp. 256-61 (1992); D. T. Chia and J. A. Gere, "Rapid Drug Screening Using Toxi-Lab Extraction Followed by Capillary Gas Chromatography/Mass Spectroscopy", Clin. Biochem., 20, pp. 303-06 (1987)). Routes for their preparation have been established (see, for example, A. H Lewin et al., "2.beta.-Substituted Analogues of Cocaine. Synthesis and Binding to the Cocaine Receptor", J. Med. Chem., 35, pp. 135-40 (1992); M. R. Bell and S. Archer, "L(+)-2-Tropinone", J. Amer. Chem. Soc.. 82, pp. 4642-44 (1960)).
We have demonstrated the pharmaceutical efficacy of benzoylecgonine and ecgonine in the treatment of rheumatoid arthritis, osteoarthritis and related inflammatory disorders (see, for example, U.S. Pat. Nos. 4,469,700, 4,512,996 and 4,556,663). We have also demonstrated the pharmaceutical efficacy of certain 2-.beta.-derivatized analogues of benzoylecgonine, ecgonine and ecgonidine (see, for example, co-pending U.S. patent application Ser. No. 07/999,307). We have now discovered a new class of easily synthesized, covalently coupled benzoylecgonine, ecgonine and ecgonidine derivatives that have novel therapeutic features and improve certain therapeutic properties of underivatized benzoylecgonine, ecgonine and ecgonidine.
SUMMARY OF THE INVENTION
It is a principal object of this invention to provide easily synthesized, covalently linked benzoylecgonine, ecgonine and ecgonidine derivatives which are useful for alleviating the symptoms of immunoregulatory disorders, neuromuscular disorders, joint disorders, connective tissue disorders, circulatory disorders and pain.
The benzoylecgonine, ecgonine and ecgonidine derivatives of this invention are represented by formulas I and II, respectively: ##STR1## wherein:
each R.sup.1 is independently selected from the group consisting of H; COR.sup.2 ; COBn; alkyl; alkenyl; and alkynyl, said alkyl, alkenyl and alkynyl being optionally substituted with OH, SH, NH.sub.2, CN, CF.sub.3 or halogen;
A is --L--(M).sub.p ;
B is --L--(M').sub.p ';
each p and p' is independently selected from the group consisting of 1 or 2;
each L is independently a linker which, consisting of --(CR.sup.2 R.sup.2).sub.n --CO--Q--; --(CR.sup.2 R.sup.2).sub.n --Q--CO--; --(CR.sup.2 R.sup.2).sub.n --O--C(OH)--; and --(CR.sup.2 R.sup.2).sub.n --Q--; or ##STR2## (c) if lining two ring systems chosen from compounds of formulas I and II, the same or different, to M or M' is ##STR3##
each n is independently selected from the group consisting of 0, 1, 2 and 3;
each Q is independently selected from the group consisting of --NH--, --O-- and --S--;
each M and M' is independently a moiety that, either alone or in combination with other M or M' moieties, enhance the distribution characteristics, intrinsic activity or efficacy of said compound, provided that M is not a moiety having the formula --CH.sub.2 --CHX--R.sup.3 when B is --O--CO--M', --O--M' or when B is not present (i.e., in compounds of formula II);
each R.sup.2 is independently selected from the group consisting of H; alkyl; alkenyl; alkynyl; alkoxy; aminoalkyl; haloalkyl; aryl; heterocyclyl; aralkyl; cycloalkyl; cycloalkylalkyl; halogen; aroyl, acyl; and aralkyl; any of said R.sup.2 being optionally substituted with OH, SH, NH.sub.2, oxo and halogen;
X is selected from
REFERENCES:
patent: 2893996 (1959-07-01), Rudner et al.
patent: 2948730 (1960-08-01), Rudner et al.
patent: 4469700 (1984-09-01), Somers
patent: 4512996 (1985-04-01), Somers
patent: 4556663 (1985-12-01), Somers
patent: 5376667 (1994-12-01), Somers et al.
patent: 5525613 (1996-06-01), Wynn et al.
patent: 5559123 (1996-09-01), Somers et al.
W.H. Anderson and D.T. Stafford, "Applications of Capillary Gas Chromatography in Routine Toxicological Analyses", High Resolut. Chromatogr., Commun., 6(5), pp. 247-254 (1983).
E.J. Ariens and A.M. Simonis, "A Molecular Basis for Drug Action. The Interaction of One or More Drugs with Different Receptors", J. Pharm. Pharmacol., 16, pp. 289-313.
M.R. Bell and S. Archer, "L(+)-2-Tropinone", J. Amer. Chem. Soc., 82, pp. 4642-4644 (1960).
R. Bingham, "Esterene in the Treatment of Rheumatoid Arthritis", Arthritis News Today, 2(7), pp. 1-4 (1980).
C.S. Boyer and D.R. Peterson, "Enymatic Basis for the Transesterification of Cocaine in the Presence of Ethanol: Evidence for the Participation of Microsomal Carboxylesterases", J. Pharmacol. Exp. Ther., 260 (3), pp. 939-946 (1992).
M.R. Brzezinski et al., "Convenient Synthesis of Benzoylecgonine Ethyl Ester, a Homolog of Cocaine", Synth. Commun., 22(7), pp. 1027-1032 (1992).
R.D. Budd, "Cocaine Radioimmunoassay--Structure Versus Reactivity", Clin. Toxicol., 18(7), pp. 773-782 (1981).
D.T. Chia and J.A. Gere, "Rapid Drug Screening Using Toxi-Lab Extraction Followed by Capillary Gas Chromatography/Mass Spectroscopy", Clin. Biochem., 20(5), pp. 303-306 (1987).
A.J. Clark, "The Antagonism of Acetyl Choline by Atropine", J. Physiol., 61, pp. 547-556 (1926).
E.J. Cone et al., "Testing Human Hair for Drug Abuse. II. Identification of Unique Cocaine Metabolites in Hair of Drug Abusers and Evaluation of Decontamination Procedures", J. Anal. Toxicol., 15(5), pp. 250-255 (1991).
R.A. Dean et al., "Human Liver Cocaine Esterases: Ethanol-Mediated Formation of Ethylococaine", FASEB J., 5(12), pp. 2735-2739 (1991).
F. Fish and W.D.C. Wilson, "Excretion of Cocaine and its Metabolites in Man", J. Pharm. Pharmac., 21 suppl., pp. 135s-138s (1969).
J.R. Fozard et al., "Structure--Activity Relationship of Compounds Which Block Receptors for 5-Hydroxytryptamine on the Sympathetic Nerves of the Rabbit Heart", Br. J. Pharmacol., 61(3), pp. 499P-500P (1977).
J.R. Fozard et al., "Blockade of Serotonin Receptors on Autonomic Neurones by (-)-31 Cocaine and Some Related Compounds", Eur. J. Pharmacol., 59(3-4), pp. 195-210 (1979).
J.H. Gaddum, "The Action of Adrenalin and Ergotamine on the Uterus of the Rabbit", J. Physiol., 61, pp. 141-150 (1926).
J.H. Gaddum, "The Quantitative Effects of Antagonistic Drugs", J. Physiol., 89, pp. 7-9 (1937).
J.M.G. Galvez and A.P. de Abram, "Cocaina: Avances en su Investigacion", Bol. Soc. Quim. Peru, 56(1), pp. 12-20 (Galvez).
C. Hansch and W.J. Dunn, "Linear Relationships Between Lipophilic Activity and Biological Activity of Drugs", J. Pharm. Sci., 61, pp. 1-19 (1972).
W.L. Hearn et al., "Cocaethylene is More Potent than Cocaine in Mediating Lethality", Pharmacol. Biochem. Behav., 39(2), pp. 531-533 (1991).
W.L. Hearn et al., "Cocaethylene: A Unique Cocaine Metabolite Displays High Affinity for the Dopamine Transporter", J. Neurochem., 56(2), pp. 698-701 (1991).
G.W. Hime et al., "Analysis of Cocaine and Cocaethylene in Blood and Tissues by GC-NPD and GC-ion Trap Mass Spectrometry", J. Anal. Toxicol., 15(5), pp. 241-245 (1991).
P. Jatlow et al., "Cocaethylene: A Neuropharmacologically Active Metabolite Associated with Concurrent Cocaine-Ethanol Ingestion", Life Sci., 48(18), pp. 1787-1794 (1991).
J.L. Katz et al., "Comparative Behavioral Pharmacology and Toxicology of Cocaine and its Ethanol-Derived Metabolite, Cocaine Ethyl-Ester (Cocaethylene)", Life Sci., 50(18), pp. 1351-1361 (1992).
A. Leo et al., "Partition Coefficients and Their Uses", Chemical Reviews, 71, pp. 525-616 (1971).
A.H. Lewin, "2.beta.Substituted Analogs of Cocaine. Synthesis and Inhibition of Binding to the
Somers Lowell M.
Wynn James E.
Entropin, Inc.
Loring Denise L.
Rotman Alan L.
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