Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Reexamination Certificate
2002-01-08
2004-12-28
Hui, San-Ming (Department: 1617)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
C514S642000, C514S720000
Reexamination Certificate
active
06835754
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to the use of aryl nitrone compounds as therapeutic agents for the treatment of neuropathic pain in mammals.
2. State of the Art
Neuropathic pain is a category of chronic pain that has been widely studied. Neuropathic pain occurs when the peripheral and/or central nervous systems are sensitized following an injury to the peripheral system. This initial injury can occur from a wide variety of causes including traumatic physical injury, as well as systematic diseases such as diabetes, herpes zoster, AIDS/HIV, syphilis and various other autoimmune diseases.
Examples of pain syndromes of this class include post hepatic neuralgia, neuritis, temporomandibular disorder, myofascial pain, back pain, pain induced by inflammatory conditions. Neuropathic pain may occur in all body regions. Thus, neuropathic pain may e.g., originate from the dental region. Burn injury also often leads to neuropathic hyperalgesia in the affected body area. Neuralgia is characterized, in its acute phase, by intraneural inflammation which can cause damage to primary afferent axons, this inducing neuropathic pain. Neuropathic pain may also be induced by diabetic conditions (diabetic neuropathy). Neuropathy of primary afferent axons in long nerves is found in diabetic patients. Nociceptor sensitization may ensue.
The following more complete listing of pain conditions included within the definition of neuropathic pain may be found in PAIN MANAGEMENT, Rochelle Wagner and Robert R. Myers.
Examples and Causes of Neuropathic Pain
Peripheral nerve trauma
Spinal cord
Entrapment neuropathy
Trauma, transaction, hemisection,
Nerve transection, including surgery
Lissauer tract section
Causalgia
Syrinx
Amputation and stump pain
Mutiple sclerosis
Neuroma
Tumor compression
Post-choracotomy pain
Arteriovenous malformation
Other mononeuropathies
Dyscraphism
Diabetic
Vitamin B12 deficiency
Malignant nerve/plexus invasion
Hematomyelia
Plexus irradiation
Syphilitic myelitis
Ischemic irradiation
Commissural myelotomy
Connective tissue disease
Brain stem
(rheumatoid arthritis, systemic
Wallenberg's syndrome
lupus erythematosus,
Multiple sclerosis
polyarteritis nodosa)
Tuberculoma
Polyneuropathies
Tumor
Diabetic
Syrinx
Alcoholic
Thalamus
Nutritional
Infarction
Amyloid
Tumor
Fabry disease
Surgical lesions in main
Chemical (e.g., anticancer therapies)
sensory necleus
Idiopathic
Hemorrahage
AIDS neuropathy
Corrical/subcorrical
Root and dorsal root ganglion
Infarction
Prolapsed disk/compression
Trauma
Postherpetic or trigeminal neuralgia
Tumor
Arachnoiditis
Arteriovenous malformation
Root avulsion
Tumor compression
Surgical rhizotomy
Neuropathic pain conditions are characterized by hyperesthesia (enhanced sensitivity to a natural stimuli), hyperalgesia (abnormal sensitivity to pain), allodynia (widespread tenderness, characterized by hypersensitivity to tactile stimuli) and/or spontaneous burning pain. In humans, neuropathic pains tend to be chronic. Neuropathic pain is generally considered to be nonresponsive or only partially responsive to conventional opioid analgesic regimens. Treatment which work with neuropathic pain are often non-helpful in other pain conditions. Consequently, alternate therapies for the management of neuropathic pain are widely sought.
The present invention provides compositions and methods for treating these forms of neuropathic pain. These compositions and methods employ 3,4,5-trisubstituted arylnitrone compounds as their active agents. Many of the compounds themselves have already been disclosed in commonly-owned U.S. Patent Application Ser. No. 60/110,541 (filed 2 Dec. 1998) and PCT Application WO 0032567 (published 8 Jun. 2000). Other compounds were disclosed in U.S. Pat. No. 5,455,272.
SUMMARY OF THE INVENTION
In accord with this invention, pain, particularly neuropathic pain as described above, is treated by administering to a patient suffering from such pain an effective, pain-treating amount of one or more 3,4,5-trisubstituted aryl nitrone compounds.
Accordingly, in one aspect, this invention is directed to administering to a neuropathic pain sufferer one or more compounds of formula I:
wherein R
1
is selected from the group consisting of hydrogen, alkyl
each R
2
is independently selected from a group of the formula:
R
3
is selected from the group consisting of hydrogen, alkyl, cycloalkyl and aryl;
R
4
is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl and substituted cycloalkenyl;
R
5
is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl and substituted cycloalkenyl;
R
6
and R
7
are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl and substituted cycloalkenyl; or R
6
and R
7
can be joined to form an alkylene or substituted alkylene group having from 2 to 10 carbon atoms;
R
8
is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl and substituted cycloalkenyl;
R
9
is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl and substituted cycloalkenyl; or R
8
and R
9
can be joined to form an alkylene or substituted alkylene group having from 2 to 10 carbon atoms;
R
10
is selected from the group consisting of hydrogen, lower alkyl and lower cycloalkyl; or R
1
and R
10
can be joined to form an alkylene, substituted alkylene, —C(O)— —S(O)— or —S(O)
2
— group;
R
11
and R
12
are independently selected from the group consisting of lower alkyl and lower cycloalkyl; or R
11
and R
12
can be joined to form an alkylene group having from 2 to 10 carbon atoms;
X is oxygen, sulfur, —S(O)— or —S(O)
2
—; and
W is oxygen or sulfur; and pharmaceutically-acceptable salts thereof.
Preferably, R
3
is hydrogen or lower alkyl. More preferably, R
3
is hydrogen or alkyl having 1 to 4 carbon atoms, more preferably 1 or 2 carbon atoms. Still more preferably, R
3
is hydrogen.
R
4
is preferably selected from the group consisting of alkyl, substituted alkyl and cycloalkyl. More preferably, R
4
is alkyl having 3 to 6 carbon atoms or cycloalkyl having 5 to 6 carbon atoms. Particularly preferred R
4
groups include methyl, n-propyl, isopropyl, 1-hydroxy-2-methylprop-2-yl, n-butyl, tert-butyl, 3-thiomethylpropyl, 3-(thiomethoxy)but-1-yl, cyclohexyl, 4-trifluoromethybenzyl and 3,4,5-trimethoxybenzyl.
R
5
is preferably selected from the group consisting of alkyl and cycloalkyl. More preferably, R
5
is lower alkyl. Particularly preferred R
5
groups include methyl, ethyl, n-propyl, isopropyl and n-butyl.
R
6
is preferably selected from the group consisting of alkyl and alkoxycarbonylalkyl (i.e., ROC(O)-alkyl-, where R is alkyl or cycloalkyl). Particularly preferred R
6
groups include ethyl, n-propyl, isopropyl, n-butyl, ethoxycarbonylmethyl and 2-(ethoxycarbonyl)ethyl. R
7
is preferably hydrogen.
Preferably, R
8
is alkyl or alkoxyalkyl (i.e., RO-alkyl-, where R is alkyl). Particularly preferred R
8
groups include methyl and methoxyethyl. R
9
is preferably hydrogen.
Preferably, X is oxygen.
Preferably, R
10
, R
11
and R
12
are independently lower alkyl. More preferably, R
10
, R
11
and R
12
are methyl.
W is preferably oxygen.
In one preferred embodiment, this method employs a compound of formula IA:
wherein R
14
is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl and substituted cycloalkyl; and pharmaceutically-acceptable salts thereof and R
14
is preferably selected from the group consisting of alkyl, substituted alkyl and cycloalkyl. More preferably, R
14
is a
Khan M. Amin
Upasani Ravindra B.
Waterbury L. David
Wood Paul L.
Burns Doane Swecker & Mathis L.L.P.
Hui San-Ming
Renovis, Inc.
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