Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-04-20
2001-07-17
Goldberg, Jerome D. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S331000
Reexamination Certificate
active
06262078
ABSTRACT:
DESCRIPTION OF THE FIELD
The present invention relates to phenoxymethyl piperidine derivatives, and pharmaceutically acceptable salts and N-oxides thereof, which are sodium channel blockers, and thus exhibit useful pharmacological properties, including utility for the treatment of neuropathic pain conditions. The invention is also directed to formulations and methods for treatment.
BACKGROUND OF THE INVENTION
Neuropathic pain can be described as pain associated with damage or permanent alteration of the peripheral or central nervous system. Clinical manifestations of neuropathic pain include a sensation of burning or electric shock, feelings of bodily distortion, allodynia and hyperalgesia.
Sodium channel-blocking agents have been reported to be effective in the treatment of various disease states, and have found particular use as local anesthetics and in the treatment of cardiac arrhythmias. It has also been reported for many years that sodium channel-blocking agents may also be useful in the treatment of pain, including neuropathic pain; see for example, Tanelian et al.
Pain Forum.
1995, 4(2), 75-80. Preclinical evidence demonstrates that sodium channel-blocking agents selectively suppress abnormal ectopic neural firing in injured peripheral and central neurons, and it is via this mechanism that they are believed to be useful for relieving pain. Consistent with this hypothesis, it has been shown that sodium channels accumulate in the peripheral nerve at sites of axonal injury (Devor et al.
J. Neurosci.
1993, 132, 1976-1992). Alterations in either the level of expression or distribution of sodium channels within an injured nerve, therefore, have a major influence on the pathophysiology of pain associated with this type of trauma. This concept is supported by the relative success of employing sodium channel modulating agents (e.g., anticonvulsants, local anesthetics) for the treatment of neuropathic pain. However, pain relief has often been obtained concomitantly with numerous adverse events and/or limitations in efficacy which have restricted tolerability of these drugs. It can be seen that a need still exists for an orally active agent that is effective for the treatment of neuropathic pain, but having fewer side effects.
Various phenoxymethyl piperidine derivatives have been described in the patent and non-patent literature. For example, PCT Published Application Nos. WO 92/02501 (Smithkline & French) and WO 93/15052 (Smithkline Beecham) generically discloses various optionally substituted 3-phenoxymethyl piperidine and 3-phenoxyethyl piperidine derivatives, respectively, useful as calcium channel blocking agents.
U.S. Pat. No. 3,634,437 (Todd) discloses optionally substituted 3-phenoxymethyl piperidine compounds, which may be used in the treatment of depressive illness, anxiety, neurotic states and epilepsy. U.S. Pat. No. 3,709,892 (Leeming et al.) discloses substituted 3-phenoxyalkylamines, for example, 3-[(2-cyclohexylethyl)phenoxymethyl]-1-methylpiperidine, which possess gastric antisecretory activity. U.S. Pat. Nos. 4,877,799; 4,985,446; and 5,019,582 (Drejer et al.); and U.S. Pat. Nos. 5,158,961 and 5,227,379 (Jakobsen et al.) disclose 4-phenyl-3-phenoxymethyl piperidine derivatives as calcium overload inhibitors useful in the treatment of anoxia, ischemia, migraine and epilepsy.
U.S. Pat. No. 4,508,724 (Taylor et al.) discloses 3-phenoxymethyl-3-piperidinol derivatives having antiarrhythmic, antidepressant and antihypertensive activity. U.S. Pat. No. 4,822,778 (Aberg et al) discloses optionally substituted 2-phenoxymethyl piperidine derivatives, particularly N-methyl-2-[(2,6-xyloxy)methyl]-piperidine, having anesthetic and antiarrhythmic activity.
Arya et al.
Indian J. Chem.
1977, 15B, 1125-1128 describes the synthesis and pharmacological activity of piperidyl ethers, particularly 3-(4-fluorophenoxymethyl)-1-methylpiperidine, as central nervous system depressants. Balsamo et al.
J. Med. Chem.
1987, 30, 222-225, describes the synthesis and antidepressant activity of 3-[(2-ethoxyphenoxy)methyl]-piperidine derivatives.
The disclosures of these and other documents referred to throughout this application are incorporated herein by reference.
SUMMARY OF THE INVENTION
One aspect of the invention relates to compounds represented by Formula I:
where:
R
1
is hydrogen, (C1-4)alkyl, −(CH
2
)
m
cyclolkyl, −(CH
2
)
m
NR
7
R
8
, or −(CH
2
)
m
NR
7
SO
2
R
9
;
where:
m is 1 to 3;
R
2
, R
3
, R
5
, and R
6
are independently hydrogen, (C1-4)alkyl, or halogen;
R
4
is hydrogen, (C1-4)alkyl, hydroxy, alkyloxy, fluoroalkyloxy, halogen, or phenyl or mono- or di-substituted phenyl, the substituents selected from alkyloxy, amino, nitro, or acetylamino;
R
7
and R
8
are independently hydrogen or (C1-4)alkyl; and
R
9
is (C1-4)alkyl;
provided that when R
1
is hydrogen at least two of R
2,
R
3
, R
4
, R
5
, and R
6
are other than hydrogen; and further provided that when R
1
is methyl and R
2
, R
3,
R
5
and R
6
are hydrogen, R
4
is other than fluoro;
or a pharmaceutically acceptable salt or N-oxide thereof, as an individual isomer or as a racemic or non-racemic mixture of isomers.
A second aspect of this invention relates to pharmaceutical compositions containing a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt or N-oxide thereof, in admixture with one or more pharmaceutically acceptable, non-toxic excipients.
A third aspect of this invention relates to a method for treating a mammal having a disease state which is treatable by administration of a sodium channel-blocker, comprising administering to a mammal in need of a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt or N-oxide thereof.
REFERENCES:
patent: 3634437 (1972-01-01), Todd
patent: 3709892 (1973-01-01), Leeming et al.
patent: 4508724 (1985-04-01), Taylor, Jr. et al.
patent: 4822778 (1989-04-01), Aberg et al.
patent: 4877799 (1989-10-01), Drejer et al.
patent: 4985446 (1991-01-01), Drejer et al.
patent: 5019582 (1991-05-01), Drejer et al.
patent: 5158961 (1992-10-01), Jakobsen et al.
patent: 5210086 (1993-05-01), George et al.
patent: 5227379 (1993-07-01), Jakobsen et al.
patent: 1203149 (1970-08-01), None
patent: WO 92/02501 (1992-02-01), None
patent: WO 93/15052 (1993-08-01), None
patent: WO 94/13291 (1994-06-01), None
Ayra et al.,Indian J. Chem(1977), vol. 15B, pp. 1125-1128, “Synthesis & CNS Depressant Activity of Some Pyridyl & Piperidyl Ethers” .
Balsamo et al.,J. Med. Chem. (1987), vol. 30, pp. 222-225, “3-[(2-Ethoxyphenoxy)methyl]piperidine Derivatives. Synthesis and Antidepressant Activity”.
Catterall, W.A., “Common Modes of Drug Action on Na+ Channels: Local Anesthetics, Antiarrhythmics and Anticonvulsants”,Trends in Pharmacological Science, 1997, 8(2), pp. 57-65.
Ragsdale et al, “Frequency and Voltage-Dependent Inhibition of Type IIA Na+ Channels, Expressed in a Mammalian Cell Line, by Local Anesthetic, Antiarrhythmic, and Anticonvulsant Drugs”,Molecular Pharmacology, 1991, 40(5), pp. 756-765.
Colatsky et al, “K+ Channel Blockers and Activators in Cardiac Arrhythmias”,Cardiovascular Drug Review, 1989, 7(3), pp. 199-209.
Hondeghem et al, “Antiarrhythmic Agents: The Modulated Receptor Mechanism of Action of Sodium and Calcium Channel-Blocking Drugs”,Annual. Review. Pharmacol. Toxicol, 1984, 24, pp. 387-423.
Roufos et al, “A Structure-Activity Relationship Study of Novel Phenylacetamides Which are Sodium Channel Blockers”,Journal of Medical Chemistry, 1996, 39(7), pp. 1514-1520.
Roufos et al, “Synthesis and Pharmacological Evaluation of Phenylacetamides as Sodium-Channel Blockers”,J. Medical Chemistry, 1997, 37(2), pp. 268-274.
Flippin Lee Allen
Lin Xiao-Fa
Loughhead David Garrett
Weikert Robert James
Goldberg Jerome D.
Kaku Janet
Pfister Gloria
Syntex (U.S.A.) LLC
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