Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-04-26
2002-11-19
Rotman, Alan L. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S128000, C546S130000
Reexamination Certificate
active
06482831
ABSTRACT:
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&bgr;-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-&bgr;-derivatized analogues of benzoylecgonine, ecgonine and ecgonidine (see, for example, co-pending U.S. Pat. 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:
wherein:
each R
1
is independently selected from the group consisting of H; COR
2
; COBn; alkyl; alkenyl; and alkynyl, said alkyl, alkenyl and alynyl being optionally substituted with OH, SH, NH
2
, CN, CF
3
or halogen;
A is —L—(Kp;
B is —L—(M′)
p′
;
each p and p′ is independently selected from the group consisting of 1 or 2;
each L is independently a linker which,
(a) if linking one M or M′ to the ring system, is selected from the group consisting of —(CR
2
R
2
)
n
—CO—Q—; —(CR
2
R
2
)
n
—Q—CO—; —(CR
2
R
2
)
n
—O—C(OH)—; and —(CR
2
R
2
)
n
—Q—; or
(b) if linking two M or M′, the same or different, to the ring system is
(c) if linking two ring systems chosen from compounds of formulas I and II, the same or different, to M or M′ is
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
2
—CHX—R
3
when B is —O—CO—M′, —O—M′ or when B is not present (i.e., in compounds of formula II);
each R
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
2
being optionally substituted with OH, SH, NH
2
, oxo and halogen;
X is selected from the group consisting of OH; SH; NH
2
; and halogen; and
R
3
is selected from the group consisting of alkyl, alkenyl and alkynyl, optionally substituted with OH, SH, NH
2
or halogen; COCH
3
; COPh; and COBn.
It is a further object of this invention to provide pharmaceutical compositions comprising compounds of formulas I and II, and mixtures thereof.
It is also an object of this invention to provide methods for alleviating the symptoms of immunoregulatory disorders, neuromuscular disorders, joint disorders, connective tissue disorders, circulatory disorders and pain using the compounds and pharmaceutical compositions described herein.
DETAILED DESCRIPTION OF THE INVENTION
In accordance with this invention, the following definitions apply:
The following abbreviations are used herein:
Bn=benzyl radical; and Ph=phenyl radical.
The term “alkyl”, alone or in combination, refers to a straight chain or branched chain alkyl radical having from one to ten, preferably from one to six, carbon atoms. Examples of such alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, neopentyl, hexyl and isohexyl.
The terms “alkenyl” and “alkynyl”, alone or in combination, refer to a straight chain or branched chain alkenyl or alkynyl radical, respectively, having from two to ten, preferably from two to six, carbon atoms. The alkenyl radicals can be in the cis, ans, E— or Z— form. Examples of such alkenyl radicals are vinyl, ethenyl, propenyl and 1,4-butadienyl. Examples of alkynyl radicals are ethynyl and propynyl.
The term “alkoxy”, alone or in combination, refers to an alkyl ether radical, wherein alkyl is defined as above. Examples of such alkoxy radicals are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy and tert-butoxy.
The terms “aralkyl”, “aminoalkyl” and “haloalkyl”, alone or in combination, refer to an alkyl radical as defined above wherein one hydrogen atom is replaced by an aryl radical, an amino radical or a halogen radical, respectively. The aryl, amino or halogen radical may be located on the terminal carbon or an internal carbon of the alkyl radical.
The term “aryl”, alone or in combination, refers to a phenyl or naphthyl radical optionally substituted with one or more substituents selected from the group consisting of alkyl, alkoxy, halogen, hydroxy, amino, nitro, cyano and haloalkyl. The aryl radical may be attached through any member of the ring that results in the creation of a stable structure. Examples of such aryl radicals include tolyl, xylyl, cymyl, mesityl and phenyl. The most preferred aryls are phenyl and phenyl substituted with alkyl having from one to five carbon atoms.
The term “aroyl” refers to an acyl radical derived from an aromatic carboxylic acid. Examples of such aroyl radicals include optionally substituted benzoic acid and naphthoic acid, such as benzoyl, 4-chlorobenzoyl, 4-carboxybenzoyl, 4-(benyloxycarbonyl)benzoyl, 1-naphthoyl, 2-naphthoyl, 6-carboxy-2-naphthoyl, 6-(benzyloxycarbonyl)-2-naphthoyl and 3-hydroxy-2-naphthoyl.
The terms “benzoylecgonine compound”, “ecgonine compound” and “ecgonidine compound” refer not only to those compounds, but also to the corresponding 2-&bgr; derivatized analogs (such as the corresponding 2-&bgr; acids and 2-&bgr; alcohols) of benzoylecgonine, ecgonine, ecgonidine and the compounds of formulas I and II. For example, the 2-&bgr; acid of a compound of formula II will be referred to herein as an ecgonidine compound.
The term “acyl” refers to an alcyl radical as defined above linked via a carbonyl.
The term “cycloalkyl”, alone or in combination, refers to a monocyclic, bicyclic or tricyclic alkyl radical, wherein each cyclic moiety contains from about three to about eight carbon atoms. Examples of such cycloalkyl radicals are cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
The term “cycloalkylalkyl” refers to an alkyl radical as defined above which is substituted with a cycloalkyl radical containing from about three to about eight carbon atoms.
The term “distribution characteristics” refers to the abilit
Somers Lowell M.
Wynn James E.
Coppins Janet L.
Entropin, Inc.
Fish & Neave
Horan Nina R.
Loring Denise L.
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