Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-08-25
2003-05-13
Killos, Paul J. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S276400, C546S268100, C546S194000, C546S278400
Reexamination Certificate
active
06562847
ABSTRACT:
FIELD OF THE INVENTION
Briefly, according to the present invention, there are provided selective modulators of nicotinic acetylcholine receptors. More particularly, the present invention provides pyridyl ethers and thioethers as selective nicotinic acetylcholine receptor agonists, partial agonists, antagonists or allosteric binding molecules useful in the treatment of pain, Alzheimer's disease, memory loss or dementia or loss of motor function.
BACKGROUND OF THE INVENTION
Holladay, et. al., in “Identification and Initial Structure-Activity Relationship of (R)-5-(2-Azetidinylmethoxy)-2-chloropyridine (ABT594), a Potent, Orally Active, Non-Opiate Analgesic Agent Acting via Neuronal Nicotinic Acetylcholine Receptors”, 1998,
J. Med. Chem.,
41, 407, describe the preparation of ABT594 and its therapeutic utility. A similar disclosure is made by Donnelly-Roberts, et. al., 1998,
J. Pharmacol. Exp. Ther.,
285, 777 & 787; Decker, et. al., 1998,
Eur. J. Pharmacol.,
346, 23 and in WO 98/25920; wherein ABT594 is contained within the general structure:
Abreo, et. al., in “Heterocyclic Ether Compounds that enhance Cognitive Function”, 1994, W.O. Patent 94/08992, describes the preparation of heterocyclic ether compounds and itstherapeutic utility. A similar disclosure is made in Abreo, et. al., 1996,
J. Med. Chem.
39, 817. Generally, the heterocyclic ether compounds have the structure:
where A is saturated heterocycle, B is unsaturated heterocycle and R is H or C
1-6
alkyl.
Lin, et. al., in “3-Pyridyloxymethyl Heterocyclic ether Compounds useful in Controlling Chemical Synaptic Transmission”, 1997, U.S. Pat. No. 5,629,325, describe the preparation of pyridyl ether compound and its therapeutic utility. A similar disclosure is made by Lin, et. al., 1997,
J. Med. Chem.
40, 385. Generally, the 3-Pyridyloxymethyl heterocyclic ether compounds have the structure:
wherein R
1
is H or C
1-6
alkyl; R
2
is H, F, Cl, vinyl or phenyl; L is a C
1-6
linking group and R
3
is H or C
1-6
alkyl.
Shanklin, et. al., in “Aryloxy and Aryloxyalklazetidines as Antiarrhythmic and Anticonvulsant Agents”, 1992, U.S. Pat. No. 5,130,309, describe the preparation of Aryloxy and aryloxyalkyllazetidines and their therapeutic utilities. Generally, the described azetidines have the formula:
wherein n is 0 to 3, R is H, C
1-4
alkyl or arylalkyl and Ar is phenyl or substituted phenyl.
Cosford, et. al., in “Substituted Pyridine Derivatives, Their Preparation and Their Use as Modulators of Acetylcholine Receptors”, 1996, W.O. Patent 96/31475, describe the preparation of substituted pyridine derivatives and its therapeutic utility. Generally, the pyridine derivative have the formula:
wherein A is 1-6 atoms bridging species linking pyridine and N, B is 1-4 atoms bridging species linking N and Z, Z is H, C
1-6
alkyl, alkynyl or aryl; R
3
is H or lower alkyl; and R
2
, R
4
, R
5
, and R
6
are H, C
1-6
alkyl, alkynyl, aryl or S-containing groups.
McDonald, et. al., in “Modulators of Acetylcholine Receptors”. 1998, U.S. Pat. No. 5,723,477, describe the preparation of C-3 substituted pyridyl compounds and its therapeutic utility. A similar disclosure is made in McDonald, et. al., 1997, U.S. Pat. No. 5,703,100; McDonald, et. al., 1997, U.S. Pat. No. 5,677,459; Menzaghi, et. al., 1997,
J. Pharmacol Exp. Ther.
280, 373, 384, and 393; and Lloyd, et. al., 1998,
Life Sci.,
62, 1601. Generally, the C-3 substituted pyridyl compounds have the formula:
wherein A is 1-3 atom bridging moiety, forming a 5-7 membered ring; B is —O—, —S—, —NR
10
—, —CHR
10
—, ═CR
10
— or ═N—; R
2
, R
4
, R
5
and R
6
are H, C
1-6
alkyl, aryl, alkynyl, or O-, S-, or N(R)-containing group; and R
7
and R
9
are H, C
1-6
alkyl, aryl, or alkynyl.
Caldwell, et. al., in “Method for Treatment of Neurodegenerative Diseases” 1993, U.S. Pat. No. 5,212,188, describe the preparation of alkenyl pyridyl compounds and its therapeutic utility. A similar disclosure is made in Bencherif, et. al., 1996
J. Pharmacol. Exp. Ther.,
279, 1413 and 1422. Generally, the alkenyl pyridyl compounds have the general formula:
wherein n is 1-5, R is H or C
1-5
alkyl and X is halogen.
Crooks, et. al., in “Nicotinic Receptor Antagonists in the Treatment of Neuropharmacological Disorders” 1997, U.S. Pat. No. 5,691,365, describe the preparation of nicotine analogs and its therapeutic utility. Generally, the nicotinic analogues have the structure:
wherein R is alkyl or branched alkyl with 2-19 carbon atoms, cycloalkyl, aralkyl or alkenyl.
Shen, et. al., in “7-Azabicyclo[2.2.2]-Heptane and -Heptene Derivatives as Cholinergic Receptor Ligands” 1996, W.O. Patent 96/06093, describe the preparation of 7-azabicyclo[2.2.2]-heptane and -heptene derivatives and their therapeutic utilities. A similar disclosure is made by Shen, et. al., 1994, W.O. Patent 94/22868. Generally, the heptane and heptene derivatives have the formula:
wherein R
1
, R
2
, R
3
, R
4
, R
5
, R
6
, and R
7
are H, alkyl or an alkyl-heteroatom containing group.
Dybes, et. al., in “Anticoccidal Cyclicaminoethanols and Esters Thereof” 1978, U.S. Pat. No. 4,094,976, describe the preparation of cyclicaminoethanols and esters and their therapeutic utilities. Generally, the cyclicaminoethanols have the formula:
wherein n is 3-5 and R is H or acyl radical.
Caldwell, et. al., in “Method for Treatment of Neurodegenerative Disease” 1993, U.S. Pat. No. 5,214,060 describes the preparation of 3-aminoalkylpyridines and its therapeutic utilities. Generally, the 3-aminoalkylpyrimidines have the formula:
wherein R is C
1-7
alkyl, X is substituent other than H, p is 1-5, m is 0-4 and n is 0-8.
There are two recent reviews on the topic of the nicotinic acetylcholine receptor: Holladay, et. al., in “Neuronal Nicotinic Acetylcholine Receptors as Targets for Drug Discovery” 1997,
J. Med. Chem.,
40, 4169; and Holladay, et. al., in “Structure-Activity Relationships of Nicotinic Acetylcholine Receptor Agonists as Potential Treatments for Dementia” 1995,
Drug Dev. Res.,
35, 191.
SUMMARY OF THE INVENTION
There are provided by the present invention selective modulators of the nicotinic acetylcholine receptor of the general formula:
wherein
m is selected from 0, 1 or 2;
p is selected from 0 or 1;
Y is selected from the group consisting of O, S, S(O) and S(O)
2
;
R
1
is independently selected from the group consisting of H—, HO—, O—, C
1-6
alkyl-, C
2-6
alkenyl-, C
2-6
alkynyl-, C
3-6
cycloalkylC
1-3
alkyl-, phenylC
1-3
alkyl-, —C(O)C
1-6
alkyl, —C(O)phenyl, —C(O)C
1-6
alkylphenyl, —C(O)OC
1-6
alkyl, —C(O)Ophenyl, —C(O)NHC
1-6
alkyl, —C(O)N(C
1-6
alkyl)
2
and —C(O)NHphenyl; wherein R
1
is optionally substituted on a carbon atom with one to three R
a
substituents; wherein R
a
is independently selected from the group consisting of C
1-4
alkyl, C
1-4
alkoxy, hydroxyC
1-4
alkyl, carbomethoxy, acetoxy, nitro, Cl, Br and F;
R
2
is independently selected from the group consisting of H, C
1-6
alkyl, phenyl and heteroaryl; wherein heteroaryl is as defined below;
R
3
is selected from the group consisting of H, C
1-6
alkyl, Cl, Br and F; with the proviso that if m is 0, then R
3
is not Cl, Br or F; and
R
4
, R
5
, R
6
and R
7
are independently selected from the group consisting of hydrogen and selected radicals; wherein the radicals are selected from the group consisting of:
a) a trifluoromethyl group: —CF
3
;
b) a halogen atom: —Br, —Cl, —F or —I;
c) a C
1-4
alkoxy radical: —OC
1-4
alkyl; wherein the alkyl is optionally mono- or di-substituted by R
q
; wherein
R
q
is selected from the group consisting of —OH, —OCH
3
, —CN, —C(O)NH
2
, —OC—(O)NH
2
, CHO, —OC(O)N(CH
3
)
2
, —SO
2
NH
2
, SO
2
N(CH
3
)
2
, —SOCH
3
, SO
2
CH
3
, —F, —CF
3
, —COOM
a
(wherein M
a
is selected from the group consisting of hydrogen, alkali metal, methyl and phenyl), tetrazolyl (wherein the point of attachment is the carbon atom of the tetrazole ring and one of the nitrogen atoms is mono-substituted by M
a
, as defined previously) and —SO
3
M
b
(wherein M
b
is selected from the group consisting of hydrogen and an alkali me
Killos Paul J.
Ortho-McNeil Pharmaceutical , Inc.
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