Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Reexamination Certificate
2001-08-20
2002-11-05
Shah, Mukund J. (Department: 1623)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
C514S588000, C514S599000, C514S613000, C514S718000, C560S008000, C560S142000
Reexamination Certificate
active
06476076
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Technical Field of the Invention
The present invention relates to vanilloid analogues containing resiniferatoxin pharmacophores, pharmaceutical compositions comprising such analogues, and methods of using such analogues as vanilloid receptor agonists and potent analgesics.
2. Related Arts of the Invention
Capsaicin (CAP), which has the structure shown hereinafter, stimulates and then desensitizes sensory afferent C-fibers. The induced desensitization may have an application in arthritis, asthma, allergic responses including rhinitis, fever, pain, bladder hypersensitivity and the like.
Besides, the vanilloid receptor(VR)(or capsaicin receptor) is a specific neuronal membrane recognition site for CAP and related irritant compounds. It is expressed almost exclusively by primary sensory neurons involved in nociception and neurogenic inflammation. The receptor functions as a cation-selective ion channel with a preference for calcium, and its functional subtype, VR1, activated by both CAP and noxious heat has recently been cloned. Its desensitization caused by specific ligands has been recognized as a promising therapeutic approach to mitigate neuropathic pain and other pathological conditions in which neuropeptides released from primary sensory neurons play a crucial role.
Most exogenous VR agonists which are being developed or used as analgesics are structually related to CAP(i.e., Zostrix™, Olvanil™, SDZ-249482™, and DA-5018™) and resiniferatoxin. Their structures include a common vanilloid ring which appears to be important for agonist activity. However, in a recent report, it was demonstrated that compounds lacking the vanilloid moiety, such as sesquiterpenoid unsaturated dialdehydes or triprenyl phenol, may also activate the receptor. Although receptor antagonists are fewer, several compounds such a capsazepine, which acts competitively at the CAP binding site, the channel blocker ruthenium red and capsazocaine have been reported.
Resiniferatoxin (RTX), a tricyclic diterpene isolated from
Euphorbia resinifera
, has been regarded as an ultrapotent CAP analogue. Indeed, the specific binding of RTX to the CAP binding site in dorsal root ganglia has been demonstrated with labeled [
3
H]RTX. RTX is being developed as an ultrapotent sensory neuron desensitizing agent for the treatment of urinary urge incontinence and the pain assoaciated with diabetic neuropathy. Recently, a totally enantiocontrolled synthesis and a conformational analysis of RTX have been reported. However, the pharmacophoric groups of RTX have not yet been clearly defined, although structure-activity studies suggest that the C
20
-homovanillic moiety, the C
3
-keto group, and the ortho-ester phenyl group on ring C are crucial structural elements responsible for the extremely high potency of RTX. The lower potency of CAP relative to RTX, on the other hand, may be rationalized by the lack of some of these critical pharmacophoric groups, especially C
3
-keto group.
U.S. Pat. No. 4,939,149 discloses a method for desensitizing a subject animal by administering a therapeutically effective desensitizing amount of RTX for desensitizing the animal to neurogenic inflammation, to chemically and thermally induced pain and to responses involving sensory afferent pathways sensitive to CAP.
Although a number of vanilloid agonist based on the structures of CAP and RTX have been reported as potential analgesics (e.g., U.S. Pat. No. 5,021,450 discloses homovanillyl diterpene derivatives such as 12-deoxyphorbol 13-phenylacetate 20-homovanillate and mezerein 20-homovanillate as mimics of RTX), these CAP-like analogues are limited by their intrinsic lower potency and narrow therapeutic index. RTX, on the other hand, is of limited availability from natural sources and is difficult to obtain synthetically due to its structural complexity.
The present inventors have made extensive researches to discover novel analgesic agents based on the vanilloid receptor, which has simpler structure than RTX or known RTX- or CAP-like analogues. As results thereof, we found that the new compounds having modifications on C
20
-homovanillic moiety, the C
3
-carbonyl, and the ortho-ester phenyl moiety as essential groups for recognition and binding showed potent vanilloid agonist activity in terms of the receptor binding assay and the CAP-activated single channel assay.
SUMMARY OF THE INVENTION
Thus, the present invention provides novel compounds represented by the following formula (I):
wherein,
X is an oxygen or sulfuir atom;
A is —NHCH
2
— or —CH
2
—;
R
1
is a substituted or unsubstituted C
1-4
alkylaryl group, or the group of formula: R
4
CO— wherein R
4
is an alkyl group having 1 to 18 carbon atoms, an alkenyl group having 2 to 18 carbon atoms, or substituted or unsubstituted aryl group having 6 to 10 carbon atoms;
R
2
is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, a haloalkyl group having 1 to 6 carbon atoms or a halogen atom;
R
3
is a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, an aminoalkyl, a diacid monoester or &agr;-alkyl acid; and
the asteric mark * indicates a chiral carbon atom, and their pharmaceutically acceptable salts.
The present invention also provides pharmaceutical compositions comprising the compound (I) as an active ingredient in an amount effective to alleviate pain, together with a pharmaceutically acceptable carrier.
The present invention also provides a use of the compounds as an active ingredient in medicines for treating pain or urinary incontinence.
The present invention still provides processes for preparing the compound (I).
DETAILED DESCRIPTION OF THE INVENTION
The compounds of the present invention is represented by the following formula (I):
wherein,
X is an oxygen or sulfur atom;
A is —NH—CH
2
— or —CH
2
—;
R
1
is a substituted or unsubstituted C
1-4
alkylaryl group, or the group of formula R
4
CO— wherein R
4
is an alkyl group having 1 to 18 carbon atoms, an alkenyl group having 2 to 18 carbon atoms, or substituted or unsubstituted aryl group having 6 to 10 carbon atoms;
R
2
is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, a haloalkyl group having 1 to 6 carbon atoms or a halogen atom;
R
3
is an aminoalkyl, a diacid monoester or &agr;-alkyl acid; and
the asteric mark * indicates a chiral carbon atom, and their pharmaceutically acceptable salts.
The preferred compounds may be represented by the following formula (I-a) and (I-b):
wherein, R
1
, R
2
and R
3
have the same meanings as defined above.
In a preferred embodiment, the compounds have the general formula (I-a) or (I-b) wherein R
1
is the group of formula R
4
CO— wherein R
4
is an alkyl group having 1 to 18 carbon atoms; R
2
is an alkyl group having 1 to 6 carbon atoms; and R
3
is —(CH
2
)
n
NH
2
, —CO(—CH
2
)
n
COOH or —(CH
2
)
n
COOH, wherein n is an integer of 1 to 4. When R
1
or R
4
is a substituted aryl group, the substituents may be one or more lower alkyls having 1 to 4 carbon atoms or halogen atoms.
In a more preferred embodiment, the compounds have the general formula (I-a) or (I-b) wherein R
1
is the group of formula R
4
CO— wherein R
4
is an alkyl group having 1 to 6 carbon atoms; R
2
is an alkyl group having 1 to 6 carbon atoms; and R
3
is —CH
2
CH
2
NH
2
, —COCH
2
CH
2
COOH or —CH
2
COOH,
In all cases, the compound (I) may be in racemic mixture, or in R or S stereoisomer. And, the present invention encompasses the compound (I) in the form of their pharmaceutically acceptable salts.
The compounds of the invention may be chemically synthesized by the methods in the reaction schemes hereinafter, which are merely exemplary and in no way limit the invention. The reaction schemes show the steps for preparing the representative compounds of the present invention, and other compounds also may be produced by following the steps with appropriate modifications of reagents and starting materials, which are envisaged by those skilled in the art.
GENERAL SYNTHETIC PROCED
Kim Hee-Doo
Lee Jeewoo
Oh Uhtaek
Park Hyeung-Geun
Park Young-Ho
Anderson Kill & Olick PC
Pacific Corporation
Shah Mukund J.
Tucker Zachary
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