Lee, David A. H. (Chadds Ford, PA, US)
35. A method for the treatment of neuropathic pain in a patient, comprising administering an effective amount of a compound of the formula:
36. A method for the treatment of neuropathic pain in a patient, comprising administering an effective amount of a compound of the formula:
37. A method for the treatment of neuropathic pain in a patient, comprising administering an effective amount of a compound of the formula:
38. A method for the treatment of neuropathic pain in a patient, comprising administering an effective amount of a compound of the formula:
39. A method for the treatment of neuropathic pain in a patient, comprising administering an effective amount of a compound of the formula:
40. A method for the treatment of neuropathic pain in a patient, comprising administering an effective amount of a compound of the formula:
41. A method for the treatment of neuropathic pain in a patient, comprising administering an effective amount of a compound of the formula:
42. The method of claim 35, wherein the compound is selected from the group consisting of: (a) 4-(3′-Thienyl)-α,α, 1-trimethyl-4-piperidinemethanol; (b) 4-(3′-Chlorophenyl)-α, 1-dimethylpiperidinemethanol; (c) 4-(3′-Chlorophenyl)-α,α, 1-trimethyl-4-piperidinemethanol; (d) 4-(3′-Bromophenyl)-α, 1-dimethylpiperidinemethanol; (e) 4-(3′-Bromophenyl)-α,α, 1-trimethyl-4-piperidinemethanol; (f) 4-(2-Thienyl)-α, 1-dimethylpiperidinemethanol; (g) 4-(3-Thienyl)-α, 1-dimethylpiperidinemethanol; (h) 4-(3′-Chlorophenyl)-α, 1-dimethyl-2,3,4,5,6,7-hexahydro-1H-azepine-1-methanol; (i) 3-(3′-Chlorophenyl)-α,α,1-trimethyl-3-pyrrolidinemethanol; (j) 4(4′-Trifluoromethylphenyl)-α-1-dimethylpiperidinemethanol; or a pharmaceutically suitable salt thereof.
43. A method for the treatment of neuropathic pain in a patient, comprising administering an effective amount of a compound of the formula:
44. -67. (Cancelled)
68. The method according to claim 43, wherein the lower alkyl is C1-C6 optionally substituted, branched or straight-chained alkyl.
69. The method of claim 35, wherein the compound is in the form of a dosage unit.
70. The method of claim 69, wherein the patient is a human.
71. The method of claim 69, wherein the dosage is 50-1000 mg.
72. The method of claim 69, wherein the dosage unit is an immediate release tablet, controlled release tablet, capsule, oral solution, oral suspension, pill, gel, or cream.
73. The method of claim 35, wherein the compound is suitable for oral delivery.
74. The method of claim 35, wherein the compound is suitable for parental delivery.
75. The method of claim 35, wherein the compound is suitable for intravenous delivery or intranasal delivery.
76. The method of claim 35, wherein the compound is suitable for transdermal delivery.
77. The method of claim 35, wherein the compound is suitable for rectal suppository delivery or transmucosal delivery.
78. The method of claim 35, wherein the neuropathic pain is caused by a disorder selected from carpal tunnel syndrome, cervical or lumbar radiculopathy, complex regional pain syndrome, spinal cord injury, or stump pain.
79. The method of claim 35, wherein the neuropathic pain is caused by a disorder selected from metabolic or toxic diseases.
80. The method of claim 35, wherein the neuropathic pain is caused by endocrinologic disorders.
81. The method as in claim 80, wherein the endocrinologic disorder is selected from diabetes mellitus, diabetic neuropathy, amyloidosis, or amyloid polyneuropathy.
82. The method as in claim 35, wherein the neuropathic pain is caused by a malignant tumor, Eosinophilia-myalgia syndrome, monoclonal gammopathy, mulitiple sclerosis, stroke, postherpetic neuralgia, neuropathy with monoclonal protein, vasculitic neuropathy, neuropathy associated with Guillain-Barré syndrome, neuropathy associated with Fabry's disease, entrapment due to anatomic abnormality, trigeminal, CNS neuralgia, malignancy, inflammatory condition, autoimmune disorder, idiopathic distal small-fiber neuropathy, toxin, drug, dietary or absorption abnormality, immuno-globulinemia, hereditary abnormality, mastectomy, or amputation.
83. The method of claim 35, wherein the neuropathic pain is caused by a viral infection.
84. The method of claim 83, wherein the viral infection is HIV infection or herpes.
85. The method as in claim 82, wherein said autoimmune disorder is selected from the group consisting of demyelinating inflammatory disorders, rheumatoid arthritis, systemic lupus erythematosus, or Sjögren's syndrome.
86. The method as in claim 82, wherein toxin or drug is selected from the group consisting of arsenic, lead, mercury, thallium, alcohol, vincrisitne, cisplatinum, or dideoxynucleo-side.
87. The method of claim 35, wherein the compound inhibits uptake of serotonin, norepinephrine, or dopamine.
88. The method of claim 35, wherein the compound inhibits ectopic activity.
89. The method of claim 35, wherein the compound inhibits ectopic discharge in the peripheral nervous system pathways.
90. The method of claim 35, wherein the compound inhibits ectopic discharge in the dorsal-root-ganglion cells of damaged afferent axons.
91. The method of claim 35, wherein the treatment is a maintenance treatment to prevent the reoccurrence of neuropathic pain.
92. The method of claim 35, wherein the other agents are at least one selected from the group consisting of gabapentin, lamotrigine, baclofen, topiramate, pregabalin, phenytoin, carbamazepine, valproic acid, venlafaxine, paroxetine, amitriptyline HCl, nortriptyline HCl, dothiepin, imipramine, maprotiline, desipramine HCl, mexiletine HCl, tocainide, lidocaine, clomipramine, clonazepam, dexamethasone, morphine, methadone HCl, fentanyl, oxycodone, tramadol HCl and capsaicin.
93. The method of claim 36, wherein the other agents are at least one selected from the group consisting of gabapentin, lamotrigine, baclofen, topiramate, pregabalin, phenyloin, carbamazepine, valproic acid, venlafaxine, paroxetine, amitriptyline HCl, nortriptyline HCl, dothiepin, imipramine, maprotiline, desipramine HCl, mexiletine HCl, tocainide, lidocaine, clomipramine, clonazepam, dexamethasone, morphine, methadone HCl, fentanyl, oxycodone, tramadol HCl and capsaicin.
94. The method of claim 37, wherein the other agents are at least one selected from the group consisting of gabapentin, lamotrigine, baclofen, topiramate, pregabalin, phenyloin, carbamazepine, valproic acid, venlafaxine, paroxetine, amitriptyline HCl, nortriptyline HCl, dothiepin, imipramine, maprotiline, desipramine HCl, mexiletine HCl, tocainide, lidocaine, clomipramine, clonazepam, dexamethasone, morphine, methadone HCl, fentanyl, oxycodone, tramadol HCl and capsaicin.
95. The method of claim 38, wherein the other agents are at least one selected from the group consisting of gabapentin, lamotrigine, baclofen, topiramate, pregabalin, phenyloin, carbamazepine, valproic acid, venlafaxine, paroxetine, amitriptyline HCl, nortriptyline HCl, dothiepin, imipramine, maprotiline, desipramine HCl, mexiletine HCl, tocainide, lidocaine, clomipramine, clonazepam, dexamethasone, morphine, methadone HCl, fentanyl, oxycodone, tramadol HCl and capsaicin.
96. The method of claim 39, wherein the other agents are at least one selected from the group consisting of gabapentin, lamotrigine, baclofen, topiramate, pregabalin, phenyloin, carbamazepine, valproic acid, venlafaxine, paroxetine, amitriptyline HCl, nortriptyline HCl, dothiepin, imipramine, maprotiline, desipramine HCl, mexiletine HCl, tocainide, lidocaine, clomipramine, clonazepam, dexamethasone, morphine, methadone HCl, fentanyl, oxycodone, tramadol HCl and capsaicin.
97. The method of claim 40, wherein the other agents are at least one selected from the group consisting of gabapentin, lamotrigine, baclofen, topiramate, pregabalin, phenyloin, carbamazepine, valproic acid, venlafaxine, paroxetine, amitriptyline HCl, nortriptyline HCl, dothiepin, imipramine, maprotiline, desipramine HCl, mexiletine HCl, tocainide, lidocaine, clomipramine, clonazepam, dexamethasone, morphine, methadone HCl, fentanyl, oxycodone, tramadol HCl and capsaicin.
98. The method of claim 41, wherein the other agents are at least one selected from the group consisting of gabapentin, lamotrigine, baclofen, topiramate, pregabalin, phenyloin, carbamazepine, valproic acid, venlafaxine, paroxetine, amitriptyline HCl, nortriptyline HCl, dothiepin, imipramine, maprotiline, desipramine HCl, mexiletine HCl, tocainide, lidocaine, clomipramine, clonazepam, dexamethasone, morphine, methadone HCl, fentanyl, oxycodone, tramadol HCl and capsaicin.
This application claims priority to U.S. Ser. No. 60/329,869, filed on Oct. 16, 2001.
FIELD OF THE INVENTION
This invention describes the use of 4-aryl-4-piperidinecarbinols in the treatment of neuropathic dysfunction and neuropathic pain.
BACKGROUND OF THE INVENTION
Many people, including over three million in the United States alone, experience neuropathic dysfunction. Neuropathic pain associated with neuropathic dysfunction is defined as pain associated with damage or dysfunction of peripheral or central nervous system.
Neuropathic pain is considered a malfunction in the response to a pathologic process occurring along and within the nervous system nociceptive pathways and is a much more complex phenomenon than simple pain. Pain has been defined as “an unpleasant sensory and emotional experience associated with tissue damage or described in terms of such damage.”
The most common types of conventional pain are associated with a response to a pathophysiologic process occurring within the tissues, such as inflammation, due to an ongoing injury or damage. The pain signal generates from intact primary afferent nerves that signal noxious events, or nociceptors. Nociceptors can be sensitized by release of algogenic agents (eg, protons, prostaglandins, bradykinin, serotonin, adenosine, cytokines, etc).
In contrast, neuropathic pain is associated with signals generated ectopically and often in the absence of ongoing noxious events by pathologic processes in the peripheral or central nervous system. This dysfunction is associated with common symptoms such as allodynia (pain evoked by normally nonpainful touch), hyperalgesia (abnormally intensive and long-lasting pain from a painful stimuli), intermittent abnormal sensations, and spontaneous, burning, shooting, stabbing, paroxysmal or electrical-sensations.
Neuropathic pain has been associated with sensory changes such as paresthesias (abnormal, intermittent but nonpainful sensations, perceived spontaneously or evoked by a stimulus) or dysesthesias (abnormal painful sensations that are spontaneous or evoked). Allodynia, hyperalgesia and hyperpathia are positive sensory phenomena as opposed to the negative sensory phenomena defined by anesthesia and hypoesthesia. Allodynia, which may be mechanical or thermal, is the painful response to an ordinarily non-noxious stimulus, such as one's clothing, the mere movement of air, touch, or the nonpainful application of a cold or warm stimulus. Hyperalgesias are exaggerated pain responses to a mildly noxious mechanical or thermal stimulus. Hyperpathia may be characterized as a delayed and explosive pain response to a noxious, or at times, non-noxious stimulus.
Neuropathic pain may result from peripheral or central nervous system pathologic events (eg, trauma, ischemia, infections) or from ongoing metabolic or toxic diseases, infections or endocrinologic disorders (eg, diabetes, mellitus, diabetic neurophathy, amyloidosis, amyloid polyneuropathy (primary and familial), neuropathies with monoclonal proteins, vasculitic neuropathy, HIV infection, herpes zoster—shingles and postherpetic neuralgia, etc), neuropathy associated with Guillain-Barré syndrome, neuropathy associated with Fabry's disease, entrapment due to anatomic abnormalities, trigeminal and other CNS neuralgias, malignancies, inflammatory conditions or autoimmune disorders (including demyelinating inflammatory disorders, rheumatoid arthritis, systemic lupus erythematosus, Sjögren's syndrome), and cryptogenic causes (idiopathic distal small-fiber neuropathy). Other causes of neuropathic pain include exposure to toxins or drugs (such as aresnic, thallium, alcohol, vincristine, cisplatinum and dideoxynucleosides), dietary or absorption abnormalities, immuno-globulinemias, hereditary abnormalities and amputations (including mastectomy). Neuropathic pain may also result from compression of nerve fibers, such as radiculopathies and carpal tunnel syndrome.
During neuropathic pain, ectopic activity causes a spontaneous discharge in the peripheral nervous system (PNS) pathways, or depending on the location and type of nerve injury, ectopic discharge also may originate in the dorsal-root-ganglion (DRG) cells of damaged afferent axons. Within the same DRG, cell bodies of uninjured axons may exhibit ectopic activity too. Within the central nervous system (CNS), hyperexcitability of the signaling neurons may arise, and other mechanisms that facilitate or distort afferent input are likely. Central mechanisms underlying chronic neuropathic pain are poorly understood. Neuroanatomic, neurophysiologic, and neurochemical changes all occur as a response to PNS or CNS injury. Central sensitization at a dorsal horn level, which is mediated in part via the N-methyl-D-aspartate (NMDA) receptor, is the best characterized change involved in the generation of this dysfunction.
Table 4 below sets out common causes of neuropathic dysfunction. Se generally: www.uspharmacist.com/NewLook/DisplayArticle.cfm?item_num=536 ).
| Common Etiologies of Neuropathic pain | ||
| Alcohol | ||
| Diabetes mellitus | ||
| type 1 and 2 | ||
| Eosinophilia-myalgia | ||
| syndrome | ||
| Guillain-Barre | ||
| syndrome | ||
| Heavy metals | ||
| Arsenic | ||
| Lead | ||
| Mercury | ||
| Thallium | ||
| HIV/AIDS | ||
| Malignant tumor-related | ||
| Medications | ||
| amiodarone | ||
| aurothioglucose | ||
| cisplatinum | ||
| dapsone | ||
| d4T (stavudine) | ||
| ddC (zalcitabine) | ||
| ddI (didanosine) | ||
| disulfiram | ||
| FK 506 | ||
| hydralazine | ||
| isoniazid | ||
| metronidazole | ||
| nitrofurantoin | ||
| paclitaxel | ||
| phenytoin | ||
| vincristine | ||
| Monoclonal gammopathies | ||
| Multiple sclerosis | ||
| Post-stroke central pain | ||
| Postherpetic neuralgia | ||
| Traumatic/Compression | ||
| Carpal tunnel syndrome | ||
| Radiculopathy(sciatica, etc) | ||
| Cervical or lumbar radiculopathy | ||
| Complex regional pain syndrome | ||
| Spinal cord injury | ||
| Stump pain | ||
| Trigeminal neuralgia | ||
| Vasculitis | ||
| Vitamin B 6 megadosing | ||
| Vitamin deficiencies | ||
| (B 12 , B 1 , B 6 and E) | ||
The treatment of neuropathic pain continues to be a difficult and often unsuccessful medical challenge. For years neuropathic pain has confounded scientists. Drugs for the treatment of standard pain are typically ineffective against neuropathic pain, the drugs for the treatment of neuropathic pain often have no effect on normal pain sensation. Traditional pain treatments, including powerful medications of last resort such as morphine and other opioid analgesics, useful in the treatment of severe pain, rarely alleviate neuropathic pain. The development of tolerance, psychic and physical dependence and potentially serious opioid side effects also limit the usefulness of opioids in treating dysfunction. Anti-inflammatory analgesics, including the Cox-2 inhibitors, lack the efficacy of opioid analgesics and produce other serious side effects including gastrointestinal bleeding and gastric erosion that limits their usefulness in treating neuropathic pain.
Starting in 1988, researchers began to identify animal models that mimic the clinical signs of neuropathic pain. For example, a rat with nerve injuries has been found to exhibit a super-sensitive reaction to a hair tapped on its hindpaw. The rat will quickly jerk away. Some humans with neuropathic pain experience a similarly severe reaction. For them, the tickle of a hair can translate into a long lasting, burning sensation. The animal models of the ailment are helping scientists understand the underlying mechanism of neuropathic pain.
Drugs that have been investigated for the use to treat neuropathic pain include sodium channel antagonists, calcium channel supressors, N-methyl-D-aspartate (NMDA) receptor blockers, anticonvulsant medications, and oral tricyclic antidepressants.
Neurons have many calcium channels, including the high-conductance channel found in the NMDA receptor. Some participate in triggering the release of neurotransmitter from presynaptic vesicles. In chronic constriction injury (CCI) rats, calcium channels are known to affect the spontaneous discharge of injured nociceptive afferents (FIG. 2). However, the drug also exerts its well-known effects on calcium channels in cardiovascular muscle, and the dosages that relieve pain are at or above those causing unacceptable heart-rate and blood-pressure changes.
However, among the many varieties of calcium channels, at least one, the N-type, a voltage-gated channel, occurs only on neurons, not on cardiovascular muscle. In the Philippines, and subsequently at the University of Utah, B. M. Olivera and colleagues studied the venom of poisonous marine snails of the genus Conus. Among hundreds of snail species throughout the Indian and Pacific Oceans, a few survive by hunting fish. Waving a long proboscis, they evidently create the impression of a worm. When a fish investigates, the snail employs the proboscis to sting the fish in the gills. In this way, it introduces a poison directly into the fish's cardiopulmonary circulation. The fish drops dead on the spot. Fractionating this powerful venom, the researchers found it to be a collection of small peptides, each consisting of 13 to 29 amino acids.
Among these substances (classified as omega-conopeptides), the researchers found one that affects the N-type calcium channel. A synthetic replica of a compound from the fish-paralyzing snail venom is one agent that offers relief in these animal models and now also appears to benefit humans. New human studies indicate that low doses of the agent cause minimal side effects and offer relief for patients with neuropathic pain. Under the name SNX-111, it has been synthesized by a biotechnology firm. When applied to the site of sciatic-nerve injury in CCI rats, the treatment reduced heat hyperalgesia and mechanical allodynia for at least three hours, but had no effect on mechanical hyperalgesia. Application to normal nerve had no effect on the animals' responses to any sensory stimuli, thermal or mechanical. Hence, the relief did not represent any anesthetic-like nerve block. Since the boluses were too small for any significant quantities to have diffused to the spinal cord, presynaptic blockade of neurotransmitter release within the dorsal horn was not a tenable explanation, either. Most probably, the SNX compound had reduced spontaneous discharge in primary afferent fibers at and near the site of nerve damage. However, patients cannot take the drug orally, because the stomach digests these agents before they are able to reach the calcium entryways. Instead, physicians administer the agent directly into the spinal cord during a hospital visit. SNX-111 is administered by an implanted pump and catheter that delivers it directly to the lumbar spinal cord.
Other promising agents that can be consumed in pill form incapacitate areas on cells called N-methyl-D-aspartate (NMDA) receptors. Animal models have helped researchers uncover evidence that these receptors share a special relationship with neuropathic pain. It appears that continuous activation of NMDA receptors reorganizes pain-sensing circuits and leads to the super-sensitive quality of neuropathic pain. In a range of animal models studied in numerous laboratories, several different NMDA receptor blockers have significantly reduced neuropathic pain. Limited data amassed from human volunteers suggest a similar effect. Among the drugs is dextrorphan, known pharmacologically as the primary metabolite of the over-the-counter cough suppressant dextromethorphan. When dextrorphan was tested in CCI rats, an intraperitoneal dosage of 25 mg/kg was beneficial against heat hyperalgesia, where it normalized the latency of the withdrawal reflex on the nerve-injured side, but had no effect against mechanical allodynia and caused no changes on the animals' control side.
However, unlike a neurotransmitter receptor that binds acetylcholine or serotonin, the NMDA receptor has binding sites not only for neurotransmitter (glutamate) but also for many other ligands, which modifies the receptor's responsiveness. Indeed, glutamate has no effect unless other conditions are met. The first of these conditions involves a glycine binding site. If the site is unoccupied, the receptor remains inactive. Throughout the CNS, however, the extracellular concentration of glycine seems perennially sufficient to saturate the site. A further hurdle involves magnesium ions. The receptor incorporates a high-conductance ion channel, which in turn can bind Mg 2+ . The binding is voltage-sensitive. If the cell membrane is at its resting bioelectric potential, the ion stays in place, preventing other ions from passing. If, however, the cell has been excited by other inputs, so that the membrane is partially depolarized, the Mg 2+ is released and ionic currents can flow. The partial depolarization can be accomplished by the cell's excitatory inputs, which, for a dorsal-horn neuron, may include glutamate (received at non-NMDA receptors), acetylcholine, and, among peptide neurotransmitters, substance P and calcitonin gene-related peptide. Inhibitory influences are a similarly long list, including GABA (from local inhibitory neurons), norepinephrine and serotonin (from the brain), and, among neuropeptides, dynorphin and enkephalin; Presumably, exogenous Mg 2+ keeps NMDA receptors unresponsive to glutamate. Only with glycine present and the membrane partially depolarized, the binding of glutamate to the NMDA receptor can have an effect. The opened ion channel conducts not only Na + , which enters the cell, and K + , which leaves, but also Ca 2+ , which enters.
Because the receptors are important components of a variety of circuits in the brain and spinal cord that carry out different mental functions, blocking their activity also has side effects, such as clouded thinking. The NMDA receptor occurs at a high density in the cerebral cortex and hippocampus. In consequence, drugs that block the receptor can have psychological effects. One strategy has been to identify a relatively ineffective blocker, such that normal mental activity involving NMDA receptors may represent low-frequency discharge at the brain's NMDA synapses and hence may not be affected by a weak receptor blockade. In contrast, neuropathic pain may represent high-frequency discharge, which might be blunted even by a blocker with low affinity for the receptor. Another strategy has been to identify usable differences among NMDA receptor subtypes. So far, at least five have been identified, among which one appears to show a high concentration only in the spinal cord. A drug specific for this spinal subtype might avoid side effects arising from engagement of the brain's NMDA receptors.
In certain respects, epilepsy resembles neuropathic pain. Injured sensory fibers may discharge spontaneously, though with a clocklike regularity unlike the irregular pattern of an epileptiform burst in cortical neurons. In both cases, the discharge is probably due in part to abnormal distribution or activation of voltage-gated sodium channels at the neuronal cell-surface membrane. Therefore, the standard anticonvulsant carbamazepine has been used against neuropathic pain, in particular, tic douloureux, which is one of the rarest of neuropathic syndromes. Against neuropathic pain, as against epilepsy, the drug is thought to have dual modes of action: blockade of sodium channels (in the manner of lidocaine) along with potentiation of GABAergic neurotransmission (in the manner of a barbiturate). Cells utilizing GABA as their inhibitory neurotransmitter are known to affect the dorsal-horn neurons that receive primary sensory afferents and emit ascending fibers. In both neuropathic pain and epilepsy, use of the drug has been impeded by the need to monitor liver function.
New generations of anticonvulsant medications, in particular felbamate, were found to be effective against abnormalities involved in neuropathic pain, at least as modeled in CCI rats. Felbamate is implicated in a voltage-gated sodium-channel blockade, a slight potentiation of GABAergic neurotransmission, and NMDA receptor blockade (owing to its capacity to bind not only glutamate but also NMDA). Nociceptive C fibers are known to use glutamate to signal dorsal-horn neurons, which express NMDA receptors (along with other known types of glutamate receptor). At intraperitoneal doses of up to 600 mg/kg (the drug's antiepileptic range in rats), the high doses completely abolished abnormal sensations in the four measurable ways: heat hyperalgesia, mechanical hyperalgesia, mechanical allodynia and hindpaw guarding. Heat hyperalgesia was tested by noxious heat to the hindpaw. Mechanical hyperalgesia was tested by the tip of a safety pin, pushed slowly until it dimpled the hindpaw skin. Mechanical allodynia was tested by von Frey hairs. All effects lasted two to 12 hours. In the control hindpaw, all responses were unaffected, indicating that the drug acted specifically against neuropathic pain, rather than being broadly analgesic. With only limited solubility in intrathecal media, felbamate could not be tested directly for a spinal site of action. However, the U.S. Food and Drug Administration found that felbamate had been found to cause liver failure and aplastic anemia, sometimes fatally, in humans.
Anticonvulsants, gabapentin and lamotrigine, have been widely used for several years. In CCI rats, gabapentin was tested both intraperitoneally (at 10 to 75 mg/kg) and intrathecally (to the lumbar spinal cord, at 37.5 to 150 mg/kg). At two and four hours, the intraperitoneal injections suppressed heat hyperalgesia and mechanical allodynia. In some instances, the suppression of heat hyperalgesia was complete. Against mechanical hyperalgesia, the drug lacked effect. At 24 hours, abnormal responses had returned. For the intrathecal injections, the pattern was similar, implying a spinal site of drug action. On the control side, gabapentin, like felbamate, caused no significant change in any responses. Chemically, gabapentin is a small, cyclic GABA analogue. Curiously, it has no direct effect on GABA receptors. Indirect effects have been proposed, for example, an upregulation of intracellular GABA storage. Gabapentin binds with high affinity to a subunit of a voltage-gated calcium channel distributed unevenly throughout the nervous system. It remains uncertain precisely which types of calcium channel have the subunit.
It is widely accepted that oral tricyclic antidepressants (TCAs) are useful adjuncts in treating neuropathic pain. In addition, tricyclic antidepressants may be better tolerated than anticonvulsants. While tricyclic antidepressants are not recognized as primary agents to treat neuropathic pain, TCAs have an effect of serotonin (5-HT) release, the noradrenergic pathways and a sodium channel blocking effect (S. Butler, Adv. Pain Res. Ther. 7:173-197, 1984), with evidence of efficacy existing for amitriptylin, imipramine, desimipramine and clomipramine. This effect is independent of their antidepressant effect and may be dose related. In fact, there is a lack of evidence for efficacy of selective serotonin reuptake inhibitors (SSRI) antidepressants for treating neuropathic pain. Recent work has highlighted a potential effect of topical doxepin, a TCA, in neuropathic pain. The topical application of doxepin is associated with few side effects, and particularly central side-effects.
Venlafaxine has been clinically evaluated for painful diabetic neuropathy (See for example, Pernia, A.; Mico, J. A.; Calderon, E.; Torres, L. M. “Venlafaxine for the treatment of neuropathic pain” J Pain Symptom Manage, 2000, 19(6):408-10; Kiayias, J. A.; Vlachou E. D.; Lakka-Papadodima, E. “Venlafaxine HCl in the treatment of painful peripheral diabetic neuropathy” Diabetes Care, 2000, 23(5):699; Ansari, A. “The efficacy of newer antidepressants in the treatment of chronic pain: a review of current literature” Harv Rev Psychiatry 2000; 7(5):257-77; and Davis, J. L.; Smith, R. L. “Painful peripheral diabetic neuropathy treated with venlafaxine HCl extended release capsules” Diabetes Care 1999, 22(11):1909-10).
Despite the research on, neuropathic pain to date, very few therapies have been identified that are not associated with significant negative side effects. The research has been made more difficult by the inability to extrapolate success in conventional pain therapy to successful treatment of neuropathic dysfunction and associated pain. Because of neuropathic pains' distinct pathophysiology and response to pharmacotherapy, the FDA considers “neuropathic pain”, a unique and stand-alone indication, separate from “chronic pain,” “arthritis pain,” “migraine pain,” and “acute pain.” Certain 4-arylpiperidinecarbinols are known to have antidepressant activity. These compounds and methods for preparing them are disclosed in Ciganek, U.S. Pat. No. 4,485,109, issued Nov. 27, 1984 (E. I. DuPont de Nemours and Company).
4-Aryl4-piperdine (or pyrrolidine or hexahydroazepine)carbinols and heterocyclic analogs, including 4-(3-thienyl)-α,α,1-trimethyl-4-piperidinemethanol, are disclosed in U.S. Pat. Nos. 5,019,650 and 5,086,063 as compounds useful in the treatment of depression and conventional pain.
U.S. Pat. No. 3,108,111 to Stern et al., Nov. 22, 1963, discloses piperidine compounds useful as cough suppressants and analgesics.
U.S. Pat. No. 3,080,372 to Janssen, Mar. 5, 1963, discloses pharmaceutically useful piperidines.
JP 5,9106-460-A discloses antifungal and analgesic nitrogen containing heterocycles, including piperidines.
BE 775,611 discloses 1-(3,3-diphenyl-1-propyl)-4-arylpiperidines as analgesics, spasmolytics and antitussive agents.
Several secondary piperidinecarbinols have been reported in the literature. Representative of these are M. A. lorio et al., Tetrahedron, 4983 (1971); F. Bergel et al., J. Chem. Soc., 26, (1944); A. D. MacDonald et al., Brit J. Pharmacol., 1,4 (1946); A. L. Morrison et al., J. Chem. Soc., 1467, (1950); H. Kagi et al., Helv. Chim. Acta, 7,2489 (1949); U. Bondesson et al., Drug Metab. Dispos., 9, 376 (1981); U. Bondesson et al., Acta Pharm. Suec., 11, 1 (1980).
Given that neuropathic disorders are chronic, extremely disabling and refractory to currently available analgesics, it would be of great benefit to provide new compositions and methods for its treatment.
Therefore, it is one object of the present invention to provide pharmaceutical compositions for the treatment of neuropathic disorders and associated dysfunction and pain.
It is another embodiment of the present invention to provide methods and uses of compounds and compositions for the treatment of neuropathic pain.
SUMMARY OF THE INVENTION
It has been discovered that 4-(3-thienyl)-α,α,1,1-trimethyl-4-piperidinemethanol (the compound of formula III, also referred to herein as compound A or EN 3215) or its pharmaceutically acceptable salt or prodrug is a superior compound for the treatment of neuropathic pain, and thus can be used to treat a patient suffering from any symptom arising from this dysfunction. Unlike opioid analgesics, it does not show significant activity at mu, kappa, delta or sigma receptor sites in the brain. Studies in animals show that it lacks the addictive and respiratory depressant properties of narcotic-related analgesics. Unlike anti-inflammatory analgesics, it does not inhibit prostaglandin synthesase activity or show anti-inflammatory effects in vivo. Like the tricyclic antidepressants, it inhibits uptake of serotonin, norepinephrine and/or dopamine in rat brain preparations. Effective doses of the compound of the invention for the treatment of neuropathic pain are not accompanied by significant anticholinergic side effects, sedation or other signs of motor impairment observed with tricyclic antidepressants.
In another embodiment, a compound of the formula (I) is provided for the treatment of neuropathic pain:
or its pharmaceutically acceptable salt or prodrug thereof, wherein:
- m is 1, 2 or 3;
- R 1 is CH 3 , C 2 H 5 , n-C 3 H 7 or allyl;
- R 2 and R 3 independently are H or alkyl of 1-4 carbon atoms; or R 1 and R 2 taken together is a branched or unbranched alkylene bridge wherein the bridge is of 3 or 4 carbon atoms; or R 2 and R 3 taken together is a branched or unbranched alkylene bridge wherein the bridge is of 3 to 6 carbon atoms;
- R 4 is:
- (a) phenyl or
- wherein X is one or two substituents, the same or different, selected from F, Cl, Br, perfluoroalkyl, alkyl, alkyl- or dialkylamino, alkylthio, alkoxy or phenoxy, said alkyl in the alkyl-containing groups being of 1 to 12 carbon atoms;
- (b) 2-, 3-, or 4-biphenyl or 2-, 3-, or 4-biphenyl where either or both aromatic groups are substituted with 1 or 2 substituents, the same or different, selected from F, Cl, alkyl, perfluoroalkyl, alkoxy, aryloxy, alkylthio, perfluoroalkoxy, arylthio, perfluoroalkyl-thio and dialkylamino, said alkyl and alkoxy groups being of 1-12 carbon atoms and said aryl groups being of 6-12 carbon atoms;
- (c) 1- or 2-naphthyl optionally having one or two X substituents as defined in (a) above;
- (d) 2-, 3-, or 4-pyridyl, or 2-, or 3-pyrrolyl optionally substituted with one to three alkyl groups of 1-4 carbon atoms;
- (e) 2- or 3-thienyl optionally substituted with one substituent selected from Cl, Br, or alkyl of 1-4 carbon atoms; or
- (f) 2- or 3-benzothienyl or benzofuryl optionally substituted on the aromatic ring with Cl, Br, or CF 3 ;
- (a) phenyl or
- R 5 is alkyl of 1-4 carbon atoms, or is taken together with R 6 to form a branched or unbranched alkylene bridge of 3-11 carbon atoms;
- R 6 is H, alkyl of 1-4 carbon atoms, or is taken together with R 5 to form a branched or unbranched alkylene bridge of 3-11 carbon atoms; and
- R 7 is H, alkyl of 1-4 carbon atoms, alkanoyl of 14 carbon atoms, or —CH 2 phenyl; or a pharmaceutically salt or N-oxide thereof, provided that when
- 1) R 1 , R 5 and R 6 are methyl, and R 2 and R 3 are H, then R 4 is not 3,4-F 2 C 6 H 3 , 3,4-C 12 C 6 H 3 , p-t-butylphenyl, 2,3-(MeO) 2 C 6 H 3 , 2,5-(MeO) 2 C 6 H 3 , or 3-pyridyl;
- 2) R 1 , R 5 and R 6 are methyl or R 5 and R 6 are taken together as —(CH 2 ) 6 — and —(CH 2 ) 7 —, then R 4 is not 3-(MeO)C 6 H 4 .
Also provided is a novel class of carbinols useful for the treatment of neuropathic pain, having the formula (II):
wherein
- when m is 2 and R 6 is other than H, R 1 , R 2 and R 3 are as defined above;
- R 4 is:
- (a)
- (b) 1-naphthyl optionally substituted with one or two substituents, the same or different, selected from F, Cl, Br; perfluoroalkyl, alkylthio, alkoxy, phenoxy, alkyl, alkyl- or dialkylamino, said alkyl in the alkyl-containing groups being 1-12 carbon atoms.
- (c) 3-pyrrolyl optionally substituted with one to three alkyl groups of 1-4 carbon atoms,
- (d) 2-, or 3-thienyl optionally substituted with Cl, Br, or alkyl of 1-4 carbon atoms, provided when 2-thienyl is substituted with alkyl it is other than the 5-position, or
- (e) 2-, or 3-benzothienyl or benzofuryl optionally substituted on the aromatic ring with Cl, Br or CF 3 ;
- (a)
- R 5 independently is alkyl of 1-4 carbon atoms or when taken together with R 6 is a branched or unbranched alkylene bridge of 3-11 carbon atoms;
- R 6 independently is alkyl of 1-4 carbon atoms, or when taken together with R 5 is a branched or unbranched alkylene bridge of 3-11 carbon atoms;
- R 7 is H, alkyl of 14 carbon atoms, alkanoyl, or —CH 2 phenyl; and
- R 4 is:
- when m is 1 or 3, or when R 6 is H and m is 2; then R 1 independently is CH 3 , C 2 H 5 , n-C 3 H 7 , or allyl;
- R 2 and R 3 independently are H or alkyl of 1-4 carbon atoms; or R 1 and R 2 taken together is a branched or unbranched alkylene bridge wherein the bridge is of 3 or 4 carbon atoms;
- or R 2 and R 3 taken together is a branched or unbranched alkylene bridge where the bridge is of 3 to 6 carbon atoms;
- R 4 is:
- (a) phenyl or
- where X is one or two substituents the same or different selected from F, Cl, Br, perfluoroalkyl, alkyl, alkyl- or dialkylamino, alkylthio, alkoxy or phenoxy, said alkyl in the alkyl-containing groups being of 1 to 12 carbon atoms;
- (b) 2-, 3-, or 4-biphenyl where either or both aromatic groups are substituted with 1 or 2 substituents, the same or different selected from F, Cl, alkyl, perfluoroalkyl, alkoxy, aryloxy, alkylthio, arylthio, perfluoroalkoxy, perfluoroalkylthio and dialkylamine, amino, said alkyl and alkoxy groups being of 1-12 carbon atoms and said aryl groups being of 6-12 carbon atoms;
- (c) 1- or 2-naphthyl optionally having one or two X substituents as defined in (a) above;
- (d) 2-, 3-, or 4-pyridyl, or 2-, or 3-pyrrolyl optionally substituted with one to three alkyl groups of 1-4 carbon atoms;
- (e) 2- or 3-thienyl optionally substituted with one substituent selected from Cl, Br, or alkyl of 1-4 carbon atoms; or
- (f) 2- or 3-benzothienyl or benzofuryl optionally substituted on the aromatic ring with Cl, Br, or CF 3 ;
- (a) phenyl or
- R 5 independently is alkyl of 1-4 carbon atoms, or when taken together with R 6 is a branched or unbranched alkylene bridge of 3-11 carbon atoms;
- R 6 independently is H, alkyl of 1-4 carbon atoms, or when taken together with R 5 is a branched or unbranched alkylene bridge of 3-11 carbon atoms;
- R 7 is H, alkyl of 1-4 carbon atoms, alkanoyl, or —CH 2 ° phenyl; or
- a pharmaceutically suitable salt or N-oxide thereof,
- provided that when R 6 is H, R 1 is methyl and m is 2, then R 4 is other than C 6 H 5 , 2-(MeO)C 6 H 4 , 2,3-(MeO) 2 C 6 H 3 and pharmaceutically suitable salts or N-oxides thereof.
Preferred compounds are those of Formula (I) where when m is 2:
- (a) R 1 is CH 3 ; or
- (b) R 2 and R 3 are H; or
- (c) R 4 is 2- or 3-thienyl, or
- where X is Cl, Br, F, CF 3 ; or
- (d) R 5 is CH 3 ; or
- (e) R 6 is H or CH 3 ; or
- (f) R 7 is H.
Preferred compounds are those of Formula (I) where when m is 1 or 3;
- (a) R 1 is CH 3 ; or
- (b) R 2 , R 3 and R 7 are H; or
- (c) R 4 is
- where X is Cl, Br, F or CF 3 ; or
- (d) R 5 is CH 3 ; or
- (e) R 6 is H or CH 3 .
Specifically preferred compounds are the following:
- (a) 4-(3′-Thienyl)-α,α,1-trimethyl-4-piperidinemethanol;
- (b) 4-(3′-Chlorophenyl)-α, 1-dimethylpiperidinemethanol;
- (c) 4-(3′-Chlorophenyl)-α,α,1-trimethyl-4-piperidinemethanol ;
- (d) 4-(3′-Bromophenyl)-α,1-dimethylpiperidinemethanol;
- (e) 4-(3′-Bromophenyl)-α,α,1-trimethyl-4-piperidinemethanol;
- (f) 4-(2-Thienyl)-α,1-dimethylpiperidinemethanol;
- (g) 4-(3-Thienyl)-α,1-dimethylpiperidinemethanol;
- (h) 4-(3′-Chlorophenyl)-α,1-dimethyl-2,3,4,5,6,7-hexahydro-1H -azepine-1-methanol;
- (i) 3-(3′-Chlorophenyl)-α,α,1-trimethyl-3-pyrrolidinemethano l; and
- (j) 4(4′-Trifluoromethylphenyl)-α-1-dimethylpiperidinemethano
l
or a pharmaceutically suitable salt thereof.
Also provided is a compound having the formula (III):
or its pharmaceutically acceptable salt or prodrug thereof, for the treatment or prophylaxis of neuropathic pain.
Alternatively, provided is a compound having the formula (IV):
or its pharmaceutically acceptable salt or prodrug thereof, wherein:
- X 1 and X 2 are independently O or NR 2 ; and
- R 1 is H, alkyl, lower alkyl (such as a C 1 to C 6 optionally substituted branched or straight-chained alkyl); alkenyl, alkynyl, acyl, —C(O)R 5 , —C(O)NR 5 R 6 , —C(O)OR 5 , —C(O)SR 5 , —C(S)R 5 , —C(S)NR 5 R 6 , —C(S)OR 5 , —C(S)SR 5 , —C(NR 7 )R 5 , —C(NR 7 )NR 5 R 6 , —C(NR 7 )OR 5 , —C(NR 7 )SR 5 or phosphate; and
- R 2 , R 5 , R 6 and R 7 are independently H, alkyl or lower alkyl (such as a C 1 to C 4 optionally substituted branched or straight-chained alkyl).
In one embodiment of the present invention, a compound of formula (I)-(IV), optionally in a pharmaceutically acceptable carrier, are used for the treatment or prophylaxis of neuropathic disorders and associated dysfunction and neuropathic pain.
In another embodiment of the invention, compositions comprising compounds of the formula (I)-(IV), optionally in a pharmaceutically acceptable carrier, in combination with one or more other agents are useful for the treatment of neuropathic pain.
In another embodiment of the invention, a method is provided for the treatment or prophylaxis of neuropathic disorder, dysfunction or pain comprising administering to a host, preferably a human, an effective amount of a compound of formula (I)-(IV).
In yet another embodiment of the invention, a method is provided for the treatment or prophylaxis of neuropathic disorder, dysfunction or pain comprising administering to a host, preferably a human, an effective amount of a compound of formula (I)-(IV) in combination or alternation with one or more other active agents.
In yet another embodiment, a use of compounds of the formula (I)-(IV), optionally in a pharmaceutically acceptable carrier, and optionally in combination or alternation with one or more other agents for the treatment or prophylaxis of neuropathic disorder, dysfunction or pain is provided.
In yet another embodiment, a use of compounds of the formula (I)-(IV), optionally in a pharmaceutically acceptable carrier, optionally in combination or alternation with one or more other agents in the manufacture of a medicament for the treatment or prophylaxis of neuropathic pain is provided.
BRIEF DESCRIPTION OF THE FIGURES
FIG. 1 is an illustration of the anatomic and biochemical rewiring seen in the CNS after nerve injury, indicating that neuropathic pain represents the activity of a sensory processing system at least partly new. In the normal circuitry (top), sensory axons with cell bodies in dorsal root ganglia convey sensation to the spinal cord's dorsal horn, which in turn emits signals via ascending sensory pathways. A representative large-diameter touch fiber has its own ascending branch, while a thinner pain fiber is shown making local spinal connections. After nerve injury, the pain fiber appears to use an altered set of peptides. Meanwhile, substance P begins to appear in touch fibers, which now arborize in dorsal-horn laminae, where their ramifications would not normally occur. See Table below:
| Site | Biochemical Change | Anatomic Change | |
| 1. | Sensory periphery | De novo expression of functional | |
| receptors (e.g., opioid, alpha- | |||
| adrenergic) at nociceptive terminals | |||
| 2. | Primary afferent | Decreased synthesis (e.g., of | Sprouting of sympathetic |
| neuron with small- | substance P, calcitonin gene-related | fibers from normal targets | |
| diameter, presumably | peptide) | (blood vessels) to primary | |
| nociceptive, fiber | Increased synthesis (e.g., of neuro- | afferent cell bodies | |
| peptide Y, vasoactive intestinal | |||
| polypeptide, somatostatin, galanin) | |||
| 3. | Primary afferent | Increased synthesis (e.g., of | Sprouting of presynaptic |
| neuron with large- | substance P, neuropeptide Y) | ramifications into | |
| diameter touch fiber | superficial dorsal horn, | ||
| where normally only | |||
| nociceptors terminate | |||
| 4. | Dorsal-horn neuron | Increased synthesis (e.g., of opioid | |
| peptides) | |||
| Time-varying changes in opioid | |||
| receptor classes (micro, delta, | |||
| kappa) | |||
| 5. | Brainstem neuron | Responsiveness to substance P | |
| (dorsal column nuclei) | released from touch fibers | ||
This rewiring helps explain why drugs useful against normal pain are largely ineffective against neuropathic pain, whereas drugs against neuropathic pain are not analgesic (see www.hosppract.com/issues/1998/10/bennett.htm).
FIG. 2 is an illustration of the receptor implicated in the treatment of neuropathic pain.
FIG. 3 is a non-limiting example of the synthesis of compounds of the present invention.
FIG. 4 is a non-limiting example of a preferred embodiment for the synthesis of a compound of the present invention, 4-(3-thienyl)-α,α,1-trimethyl-4-piperidinemethanol.
FIG. 5 is an illustration of the efficacy of the compound of the present invention, and in particular of 4-(3-thienyl)-α,α,1-trimethyl-4-piperidinemethanol, in the treatment of neuropathic pain using the formalin model with respect to venlafaxine and a saline control. FIGS. 5A and 5C are line graphs showing the measured flinches per minute over sixty minutes of observation of animals dosed with EN3512 or venlafaxine, respectively. EN3512 and venlafaxine were given at 200 mg/100 mg/50 mg per kg orally and saline was administered as a control. FIGS. 5B and 5D are bar graphs depicting the cumulative measured flinches during the two main phases of the formalin test: phase I—an acute nociceptive component; and phase II—a chronic nociceptive component characterized by hyperalgesia.
FIG. 6 is an illustration of the efficacy of the compound of the present invention, and in particular of 4-(3-thienyl)-α,α,1-trimethyl-4-piperidinemethanol, in the treatment of neuropathic pain using the Chung model with respect to venlafaxine and a saline control. FIGS. 6A and 6C are line graphs showing the increased tactile threshold of the animals at different doses of compound A (200 mg/kg; 100 mg/kg, 50 mg/kg, and saline PO control) and venlafaxine (200 mg/kg; 100 mg/kg; 50 mg/kg; and saline PO control), respectively, over a 24 hour period. FIGS. 6B and 6D are bar graphs depicting the percent maximum effect of drug relative to rats that did not undergo the surgical procedure.
DETAILED DESCRIPTION OF THE INVENTION
It has been discovered that the compound of formulas I-IV, and in particular, 4-(3-thienyl)-α,α,1-trimethyl-4-piperidinemethanol (the compound of formula III, also referred to herein as compound A or EN3215) or its pharmaceutically acceptable salt or prodrug is a superior compound for the treatment of neuropathic dysfunction and associated pain, and thus can be used to treat a patient suffering from any symptom arising from this dysfunction.
Unlike opioid analgesics, EN3215 does not show significant activity at mu, kappa, delta or sigma receptor sites in the brain. Studies in animals show that it lacks the addictive and respiratory depressant properties of narcotic-related analgesics. Unlike anti-inflammatory analgesics, it does not inhibit prostaglandin synthesase activity or show anti-inflammatory effects in vivo. Like the tricyclic antidepressants, it inhibits uptake of serotonin, norepinephrine and/or dopamine in rat brain preparations. However, effective doses of the compound of the invention for the treatment of neuropathic pain are not accompanied by anticholinergic side effects, sedation or other signs of motor impairment observed with tricyclic antidepressants.
In one embodiment, compounds of the present invention, optionally in a pharmaceutically acceptable carrier, are used for the treatment or prophylaxis of neuropathic dysfunction or pain.
In another embodiment of the invention, compositions comprising compounds of the present invention, optionally in a pharmaceutically acceptable carrier, in combination with one or more other agents are useful for the treatment of neuropathic dysfunction or pain.
In another embodiment of the invention, a method is provided for the treatment or prophylaxis of neuropathic dysfunction or pain comprising administering to a host, preferably a human, an effective amount of a compounds of the present invention.
In yet another embodiment of the invention, a method is provided for the treatment or prophylaxis of neuropathic dysfunction or pain comprising administering to a host, preferably a human, an effective amount of a compounds of the present invention in combination or alternation with one or more other agents are useful for the treatment of neuropathic pain.
In yet another embodiment, use of the compound of the present invention, optionally in a pharmaceutically acceptable carrier, and optionally in combination or alternation with one or more other agents for the treatment or prophylaxis of neuropathic dysfunction or pain is provided.
In yet another embodiment, use of the compound of the present invention, optionally in a pharmaceutically acceptable carrier, and optionally in combination or alternation with one or more other agents in the manufacture of a medicament for the treatment or prophylaxis of neuropathic dysfunction or pain is provided.
I. Active Compounds of the Invention
The invention includes a compound of the formula:
or its pharmaceutically acceptable salt or prodrug thereof, wherein:
- m is 1, 2 or 3;
- R 1 is CH 3 , C 2 H 5 , n-C 3 H 7 or allyl;
- R 2 and R 3 independently are H or alkyl of 1-4 carbon atoms; or R 1 and R 2 taken together is a branched or unbranched alkylene bridge wherein the bridge is of 3 or 4 carbon atoms; or R 2 and R 3 taken together is a branched or unbranched alkylene bridge wherein the bridge is of 3 to 6 carbon atoms;
- R 4 is:
- (g) phenyl or
- wherein X is one or two substituents, the same or different, selected from F, Cl, Br, perfluoroalkyl, alkyl, alkyl- or dialkylamino, alkylthio, alkoxy or phenoxy, said alkyl in the alkyl-containing groups being of 1 to 12 carbon atoms;
- (h) 2-, 3-, or 4-biphenyl or 2-, 3-, or 4-biphenyl where either or both aromatic groups are substituted with 1 or 2 substituents, the same or different, selected from F, Cl, alkyl, perfluoroalkyl, alkoxy, aryloxy, alkylthio, perfluoroalkoxy, arylthio, perfluoroalkyl-thio and dialkylamino, said alkyl and alkoxy groups being of 1-12 carbon atoms and said aryl groups being of 6-12 carbon atoms;
- (i) 1- or 2-naphthyl optionally having one or two X substituents as defined in (a) above;
- (1) 2-, 3-, or 4-pyridyl, or 2-, or 3-pyrrolyl optionally substituted with one to three alkyl groups of 1-4 carbon atoms;
- (k) 2- or 3-thienyl optionally substituted with one substituent selected from Cl, Br, or alkyl of 1-4 carbon atoms; or
- (l) 2- or 3-benzothienyl or benzofuryl optionally substituted on the aromatic ring with Cl, Br, or CF 3 ;
- (g) phenyl or
- R 5 is alkyl of 1-4 carbon atoms, or is taken together with R 6 to form a branched or unbranched alkylene bridge of 3-11 carbon atoms;
- R 6 is H, alkyl of 1-4 carbon atoms, or is taken together with R 5 to form a branched or unbranched alkylene bridge of 3-11 carbon atoms; and
R 7 is H, alkyl of 1-4 carbon atoms, alkanoyl of 1-4 carbon atoms, or —CH 2 phenyl; or a pharmaceutically salt or N-oxide thereof, provided that when
- 3) R 1 , R 5 and R 6 are methyl, and R 2 and R 3 are H, then R 4 is not 3,4-F 2 C 6 H 3 , 3,4-Cl 2 C 6 H 3 , p-t-butylphenyl, 2,3-(MeO) 2 C 6 H 3 , 2,5-(MeO) 2 C 6 H 3 , or 3-pyridyl;
- 4) R 1 , R 5 and R 6 are methyl or R 5 and R 6 are taken together as —(CH 2 ) 6 — and —(CH 2 ) 7 —, then R 4 is not 3-(MeO)C 6 H 4 .
Also provided is a novel class of carbinols useful for the treatment of neuropathic pain, having the formula (II):
wherein
- when m is 2 and R 6 is other than H, R 1 , R 2 and R 3 are as defined above;
- R 4 is:
- (f)
- (g) 1-naphthyl optionally substituted with one or two substituents, the same or different, selected from F, Cl, Br; perfluoroalkyl, alkylthio, alkoxy, phenoxy, alkyl, alkyl- or dialkylamino, said alkyl in the alkyl-containing groups being 1-12 carbon atoms.
- (h) 3-pyrrolyl optionally substituted with one to three alkyl groups of 1-4 carbon atoms,
- (i) 2-, or 3-thienyl optionally substituted with Cl, Br, or alkyl of 14 carbon atoms, provided when 2-thienyl is substituted with alkyl it is other than the 5-position, or
- (j) 2-, or 3-benzothienyl or benzofuryl optionally substituted on the aromatic ring with Cl, Br or CF 3 ;
- (f)
- R 5 independently is alkyl of 1-4 carbon atoms or when taken together with R 6 is a branched or unbranched alkylene bridge of 3-11 carbon atoms;
- R 6 independently is alkyl of 1-4 carbon atoms, or when taken together with R 5 is a branched or unbranched alkylene bridge of 3-11 carbon atoms;
- R 7 is H, alkyl of 1-4 carbon atoms, alkanoyl, or —CH 2 phenyl; and
- R 4 is:
- when m is 1 or 3, or when R 6 is H and m is 2; then R 1 independently is CH 3 , C 2 H 5 , n-C 3 H 7 , or allyl;
- R 2 and R 3 independently are H or alkyl of 1-4 carbon atoms; or R 1 and R 2 taken together is a branched or unbranched alkylene bridge wherein the bridge is of 3 or 4 carbon atoms; or R 2 and R 3 taken together is a branched or unbranched alkylene bridge where the bridge is of 3 to 6 carbon atoms;
- R 4 is:
- (g) phenyl or
- where X is one or two substituents the same or different selected from F, Cl, Br, perfluoroalkyl, alkyl, alkyl- or dialkylamino, alkylthio, alkoxy or phenoxy, said alkyl in the alkyl-containing groups being of 1 to 12 carbon atoms;
- (h) 2-, 3-, or 4-biphenyl where either or both aromatic groups are substituted with 1 or 2 substituents, the same or different selected from F, Cl, alkyl, perfluoroalkyl, alkoxy, aryloxy, alkylthio, arylthio, perfluoroalkoxy, perfluoroalkylthio and dialkylamine, amino, said alkyl and alkoxy groups being of 1-12 carbon atoms and said aryl groups being of 6-12 carbon atoms;
- (i) 1- or 2-naphthyl optionally having one or two X substituents as defined in (a) above;
- (1) 2-, 3-, or 4-pyridyl, or 2-, or 3-pyrrolyl optionally substituted with one to three alkyl groups of 1-4 carbon atoms;
- (k) 2- or 3-thienyl optionally substituted with one substituent selected from Cl, Br, or alkyl of 1-4 carbon atoms; or
- (1) 2- or 3-benzothienyl or benzofuryl optionally substituted on the aromatic ring with Cl, Br, or CF 3 ;
- (g) phenyl or
- R 5 independently is alkyl of 1-4 carbon atoms, or when taken together with R 6 is a branched or unbranched alkylene bridge of 3-11 carbon atoms;
- R 6 independently is H, alkyl of 1-4 carbon atoms, or when taken together with R 5 is a branched or unbranched alkylene bridge of 3-11 carbon atoms;
- R 7 is H, alkyl of 1-4 carbon atoms, alkanoyl, or —CH 2 phenyl; or
- a pharmaceutically suitable salt or N-oxide thereof,
- provided that when R 6 is H, R 1 is methyl and m is 2, then R 4 is other than C 6 H 5 , 2-(MeO)C 6 H 4 , 2,3-(MeO) 2 C 6 H 3 and pharmaceutically suitable salts or N-oxides thereof.
Preferred compounds are those of Formula (I) where when m is 2: - (g) R 1 is CH 3 ; or
- (h) R 2 and R 3 are H; or
- (i) R 4 is 2- or 3-thienyl, or
- where X is Cl, Br, F, CF 3 ; or
- (j) R 5 is CH 3 ; or
- (k) R 6 is H or CH 3 ; or
- (l) R 7 is H.
Preferred compounds are those of Formula (I) where when m is 1 or 3; - (f) R 1 is CH 3 ; or
- (g) R 2 , R 3 and R 7 are H; or
- (h) R 4 is
- where X is Cl, Br, F or CF 3 ; or
- (i) R 5 is CH 3 ; or
- (j) R 6 is H or CH 3 .
Specifically preferred compounds are the following: - (a) 4-(3′-Thienyl)-α,α,1-trimethyl-4-piperidinemethanol;
- (b) 4-(3′-Chlorophenyl)-α, 1-dimethylpiperidinemethanol;
- (c) 4-(3′-Chlorophenyl)-α,α,1-trimethyl-4-piperidinemethanol ;
- (d) 4-(3′-Bromophenyl)-α,1-dimethylpiperidinemethanol;
- (e) 4-(3′-Bromophenyl)-α,α,1-trimethyl-4-piperidinemethanol;
- (f) 4-(2-Thienyl)-α,1-dimethylpiperidinemethanol;
- (g) 4-(3-Thienyl)-α,1-dimethylpiperidinemethanol;
- (h) 4-(3′-Chlorophenyl)-α, 1-dimethyl-2,3,4,5,6,7-hexahydro-1H-azepine-1-methanol;
- (i) 3-(3′-Chlorophenyl)-α,α,1-trimethyl-3-pyrrolidinemethano l; and
- (j) 4(4′-Trifluoromethylphenyl)-α,1-dimethylpiperidinemethano
l
or a pharmaceutically suitable salt thereof.
Also provided is a compound having the formula (III):
or its pharmaceutically acceptable salt or prodrug thereof, for the treatment or prophylaxis of neuropathic pain.
Alternatively, provided is a compound having the formula (IV):
or its pharmaceutically acceptable salt or prodrug thereof, wherein:
- X 1 and X 2 are independently O or NR 2 ; and
- R 1 is H, alkyl, lower alkyl (such as a C 1 to C 6 optionally substituted branched or straight-chained alkyl); alkenyl, alkynyl, acyl, —C(O)R 5 , —C(O)NR 5 R 6 , —C(O)OR 5 , —C(O)SR 5 , —C(S)R 5 , —C(S)NR 5 R 6 , —C(S)OR 5 , —C(S)SR 5 , —C(NR 7 )R 5 , —C(NR 7 )NR 5 R 6 , —C(NR 7 )OR 5 , —C(NR 7 )SR 5 or phosphate; and
- R 2 , R 5 , R 6 and R 7 are independently H, alkyl or lower alkyl (such as a C 1 to C 4 optionally substituted branched or straight-chained alkyl).
II. Definitions
The term “alkyl,” as used herein, unless otherwise specified, refers to a saturated straight, branched, or cyclic, primary, secondary, or tertiary hydrocarbon, including but not limited to those of C 1 to C 16 , and specifically includes methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl, t-butyl, pentyl, cyclopentyl, isopentyl, neopentyl, hexyl, isohexyl, cyclohexyl, cyclohexylmethyl, 3-methylpentyl, 2,2-dimethylbutyl, and 2,3-dimethylbutyl. The alkyl group can be optionally substituted with one or more moieties selected from the group consisting of alkyl, halo, haloalkyl, hydroxyl, carboxyl, acyl, acyloxy, amino, amido, carboxyl derivatives, alkylamino, dialkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, thiol, imine, sulfonic acid, sulfate, sulfonyl, sulfanyl, sulfinyl, sulfamonyl, ester, carboxylic acid, amide, phosphonyl, phosphinyl, phosphoryl, phosphine, thioester, thioether, acid halide, anhydride, oxime, hydrozine, carbamate, phosphonic acid, phosphate, phosphonate, or any other viable functional group that does not inhibit the pharmacological activity of this compound, either unprotected, or protected as necessary, as known to those skilled in the art, for example, as taught in Greene, et al., Protective Groups in Organic Synthesis , John Wiley and Sons, Second Edition, 1991, hereby incorporated by reference.
The term lower alkyl, as used herein, and unless otherwise specified, refers to a C 1 to C 6 saturated straight, branched, or if appropriate, a cyclic (for example, cyclopropyl) alkyl group, including both substituted and unsubstituted forms. Some non-limiting examples include methyl, (cyclopropyl)methyl, (cyclobutyl)methyl, (cyclopentyl)methyl, ethyl, 1-cyclopropyl-ethyl, 2-cyclopropylethyl, 1-cyclobutylethyl, 2-cyclobutylethyl, propyl, isopropyl, 1-(cyclo-propyl)propyl, 2-(cyclopropyl)propyl, 3-(cyclopropyl)propyl, cyclopropyl, methylcyclopropyl, 2,2-dimethylcyclopropyl, 1,2-dimethylcyclopropyl, ethylcyclopropyl, propylcyclopropyl, 1-ethyl-1-methylcyclopropyl, 1-ethyl-2-methylcyclopropyl, 1,1,2-trimethylcyclopropyl, 1,2,3-trimethylcyclopropyl, butyl, isobutyl, t-butyl, sec-butyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, cyclobutyl, methylcyclobutyl, 1,1-dimethylcyclobutyl, 1,2-dimethylcyclobutyl, 1,3-dimethylcyclobutyl, ethylcyclobutyl, pentyl, isopentyl, neopentyl, 2-methylpentyl, 3-methylpentyl, cyclopentyl, methylcyclopentyl, spiropentyl, methylspiropentyl, hexyl, isohexyl and cyclohexyl.
The term alkylene refers to a saturated hydrocarbyldiyl radical of straight or branched configuration, including but not limited to those that have from one to ten carbon atoms. Included within the scope of this term are methylene, 1,2-ethane-diyl, 1,1-ethane-diyl, 1,3-propane-diyl, 1,2-propane-diyl, 1,3-butane-diyl, 1,4-butane-diyl and the like.
The term “protected” as used herein and unless otherwise defined refers to a group that is added to an oxygen, nitrogen, or phosphorus atom to prevent its further reaction or for other purposes. A wide variety of oxygen and nitrogen protecting groups are known to those skilled in the art of organic synthesis.
The term acyl refers to a carboxylic acid ester in which the non-carbonyl moiety of the ester group is selected from straight, branched, or cyclic alkyl or lower alkyl, alkoxyalkyl including methoxymethyl, aralkyl including benzyl, aryloxyalkyl such as phenoxymethyl, aryl including phenyl optionally substituted with halogen, C 1 to C 4 alkyl or C 1 to C 4 alkoxy, sulfonate esters such as alkyl or aralkyl sulphonyl including methanesulfonyl, the mono, di or triphosphate ester, trityl or monomethoxytrityl, substituted benzyl, trialkylsilyl (e.g. dimethyl-t-butylsilyl) or diphenylmethylsilyl. Aryl groups in the esters optimally comprise a phenyl group. The term “lower acyl” refers to an acyl group in which the non-carbonyl moiety is lower alkyl.
The term “neuropathic dysfunction” refers to any malfunction in the response to a pathologic process occurring along and within the nervous system nociceptive pathways. As nonlimiting examples, neuropathic pain refers to the dysfunction associated with the following conditions (see www.postgradmed.com/issues/1999/11 — 99/neuropathic.htm).
| Type or distribution of | ||
| Condition | dysfunction | |
| Diabetes | Peripheral neuropathy | |
| Mononeuropathy | ||
| Radiculopathy | ||
| HIV infection or AIDS | Peripheral neuropathy | |
| Mononeuropathy | ||
| Radiculopathy | ||
| Myelopathy | ||
| Multiple sclerosis | Myelopathy | |
| Trigeminal neuralgia | ||
| Scattered nerve pain | ||
| Cancer chemotherapy | Peripheral neuropathy | |
| Spine surgery | Radiculopathy | |
| Alcoholism with neuropathy | Peripheral neuropathy | |
| Mononeuropathy | ||
| Herpes zoster | Radiculopathy (dermatome) | |
| Amputation | Neuroma | |
| Phantom limb | ||
The term host refers to animals, in particular, mammals, primates and humans. In most animal applications of the present invention, the host is a human patient. Veterinary applications, in certain indications, however, are included by the present invention.
The term “pharmaceutically acceptable salt or prodrug” is used throughout the specification to describe any pharmaceutically acceptable form (such as an ester, phosphate ester, salt of an ester or a related group) of an active compound which, upon administration to a patient, provides the active compound. Pharmaceutically acceptable salts include those derived from pharmaceutically acceptable inorganic or organic bases and acids. Suitable salts include those derived from alkali metals such as potassium and sodium, alkaline earth metals such as calcium and magnesium, among numerous other acids well known in the pharmaceutical art. Pharmaceutically acceptable prodrugs refer to a compound that is metabolized, for example hydrolyzed or oxidized, in the host to form the compound of the present invention. Typical examples of prodrugs include compounds that have biologically labile protecting groups on a functional moiety of the active compound. Prodrugs include, but are not limited to, compounds that can be oxidized, reduced, aminated, deaminated, hydroxylated, dehydroxylated, hydrolyzed, dehydrolyzed, alkylated, dealkylated, acylated, deacylated, phosphorylated, or dephosphorylated to produce the active compound. The compounds of this invention are effective for the treatment or prophylaxis of neuropathic pain, or are metabolized to a compound that exhibits such activity.
III. Combination and Alternation Therapies
Therapy for the treatment of neuropathic pain can be augmented with or with without increasing dosage, via combination and/or alternation therapy with another active agent that treats the same or a different indication. In general, in combination therapy, effective dosages of two or more agents are administered together, whereas during alternation therapy, an effective dosage of each agent is administered serially. The dosage will depend on absorption, inactivation and excretion rates of the drug as well as other factors known to those of skill in the art. It is to be noted that dosage values will also vary with the severity of the condition to be alleviated. It is to be further understood that for any particular subject, specific dosage regimens and schedules should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions.
Nonlimiting examples of agents that can be used in combination or alternation with the compounds of the present invention include the following.
| Drug | Class | |
| Gabapentin (Neurontin ®) | Antiepileptic | |
| Lamotrigine | Antiepileptic | |
| Baclofen | Antiepileptic | |
| Topiramate | Antiepileptic | |
| Pregabalin | Antiepileptic | |
| Phenytoin (Dilatin ®) | Antiepileptic | |
| Carbamazepine (Tegratol ®) | Antiepileptic | |
| Valproic acid (Depakote) | Antiepileptic | |
| Venlafaxine | Antidepressant | |
| Paroxetine | Antidepressant | |
| Amitriptyline HCl (Elavil) | Tricyclic antidepressant | |
| Nortriptyline HCl (Aventyl | Tricyclic antidepressant | |
| HCl Pulvules, Pamelor) | ||
| Dothiepin (Dolsulepine, | Tricyclic antidepressant | |
| Prothiaden) | ||
| Imipramine | Tricyclic antidepressant | |
| Maprotiline | Tricyclic antidepressant | |
| Desipramine HCl (Norpramin) | Tricyclic antidepressant | |
| Mexiletine HCl (Mexitil ®) | Antiarrhythmic | |
| Tocainide (Tonocard ®) | Antiarrhythmic | |
| Lidocaine HCl (Lidoderm ®) | Antiarrhythmic | |
| Clomipramine | Benzodiazepine | |
| Clonazepam (Klonopin) | Benzodiazepine | |
| Dexamethasone (Decadron) | Corticosteroid | |
| Morphine | Opioid | |
| Methadone HCl (Dolophine | Opioid | |
| HCl, Methadose) | ||
| Fentanyl | Opioid | |
| Oxycodone | Opioid | |
| Tramadol HCl (Ultram) | Mixed weak opioid and | |
| serotonin reuptake blocker | ||
| Zostrix ® and Zostrix-HP ® | Capsaicinoid | |
IV. Pharmaceutical Compositions
A host, including a human, exhibiting symptoms of a neuropathic disorder or neuropathic pain, can be treated by administering to the patient an effective amount of the active compound or a pharmaceutically acceptable prodrug or salt thereof optionally in the presence of a pharmaceutically acceptable carrier or diluent. The active materials can be administered by any appropriate route, for example, orally, parenterally, intravenously, intradermally, subcutaneously, or topically, in liquid or solid form. Nonlimiting examples include oral dosage forms, in both immediate release and extended-release or controlled release formulations, transdermal drug delivery as either a patch, gel, or cream, injection for intravenous, intraarterial, subcutaneous, epidural, intrathecal, or peripheral nerve, rectal suppository, and intranasal or inhalation therapy. The drug can be in the form of IR or ER liquid, oral solution or suspension, immediate release or controlled release tablets, pills or capsules.
A preferred dose of the compound for a neuropathic disorder will be in the range from about 1 to 50 mg/kg, preferably 1 to 20 mg/kg, of body weight per day, more generally 0.1 to about 100 mg per kilogram body weight of the recipient per day. The effective dosage range of the pharmaceutically acceptable salts and prodrugs can be calculated based on the weight of the parent compound to be delivered. If the salt or prodrug exhibits activity in itself, the effective dosage can be estimated as above using the weight of the salt or prodrug, or by other means known to those skilled in the art.
The compound is conveniently administered in any suitable dosage form, including, but not limited to one containing 7 to 3000 mg, preferably 70 to 1400 mg of active ingredient per unit dosage form. An oral dosage of 50-1000 mg is usually convenient.
The concentration of active compound in the drug composition will depend on absorption, inactivation and excretion rates of the drug as well as other factors known to those of skill in the art. It is to be noted that dosage values will also vary with the severity of the condition to be alleviated. It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions, and that the concentration ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed composition. The active ingredient may be administered at once, or may be divided into a number of smaller doses to be administered at varying intervals of time.
A preferred mode of administration of the active compound is oral. Oral compositions will generally include an inert diluent or an edible carrier. They may be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound can be incorporated with excipients and used in the form of tablets, troches or capsules. Pharmaceutically compatible binding agents, and/or adjuvant materials can be included as part of the composition. Oral dosage forms include IR and ER liquids.
The tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring. When the dosage unit form is a capsule, it can contain, in addition to material of the above type, a liquid carrier such as a fatty oil. In addition, dosage unit forms can contain various other materials which modify the physical form of the dosage unit, for example, coatings of sugar, shellac, or other enteric agents.
The compound can be administered as a component of an elixir, solution, suspension, syrup, wafer, chewing gum or the like. A syrup may contain, in addition to the active compounds, sucrose as a sweetening agent and certain preservatives, dyes and colorings and flavors. Oral dosage forms include IR and ER liquids.
The compound or a pharmaceutically acceptable prodrug or salts thereof can also be mixed with other active materials that do not impair the desired action, or with materials that supplement the desired action, such as antibiotics, antifungals, anti-inflammatories, antivirals, antiepileptics, antidepressants, including tricyclic antidepressants, antiarrhythmics, benzodiazepines, corticosteroids, opioids, serotonin reuptake blockers/inhibitors, and/or capsaicinoids. Solutions or suspensions used for parenteral, intradermal, subcutaneous, or topical application can include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose. The parental preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.
If administered intravenously, preferred carriers are physiological saline or phosphate buffered saline (PBS).
In a preferred embodiment, the active compounds are prepared with carriers that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters and polylactic acid. Methods for preparation of such formulations will be apparent to those skilled in the art. The materials can also be obtained commercially from Alza Corporation.
Liposomal suspensions (including liposomes targeted to particular cells, for example with monoclonal antibodies) are also preferred as pharmaceutically acceptable carriers. These may be prepared according to methods known to those skilled in the art, for example, as described in U.S. Pat. No. 4,522,811 (which is incorporated herein by reference in its entirety). For example, liposome formulations may be prepared by dissolving appropriate lipid(s) (such as stearoyl phosphatidyl ethanolamine, stearoyl phosphatidyl choline, arachadoyl phosphatidyl choline, and cholesterol) in an inorganic solvent that is then evaporated, leaving behind a thin film of dried lipid on the surface of the container. An aqueous solution of the active compound or its monophosphate, diphosphate, and/or triphosphate derivatives is then introduced into the container. The container is then swirled by hand to free lipid material from the sides of the container and to disperse lipid aggregates, thereby forming the liposomal suspension.
The dosage administered will, of course, vary depending upon known factors, such as the pharmacodynamic characteristics of the particular agent and its mode and route of administration; the age, health and weight of the recipient; the nature and extent of the symptoms; the kind of concurrent treatment; the frequency of treatment; and the effect desired. Usually, a daily dosage of active ing