HK1088220A - Methods of using and compositions comprising selective cytokine inhibitory drugs for treatment, modification and management of pain - Google Patents

Description

Compositions comprising selective cytokine inhibitory drugs for the treatment, alleviation and management of pain and methods of use

1. Field of the invention

The present invention relates to methods of treating, preventing, alleviating and managing pain using selective cytokine inhibitory drugs alone or in combination with known drugs. The invention also relates to pharmaceutical compositions and administration regimens. In particular, the invention includes uses for the combined use of selective cytokine inhibitory drugs with nerve blocking agents and/or other standard therapies for pain symptoms.

2. Background of the invention

Pain is an important symptom of many different diseases and is defined as an unpleasant sensory and emotional experience with actual or potential tissue damage or is described in the terminology of such damage. Merskey H, Bogduk N, editors (Classification of ChronicDain), Classification of chronic pain, Classification made by the international association for pain research (IASP) taxonomy task group, IASP Press: seattle, 209 Across 214, 1994. The perception of pain is highly subjective, making it one of the most difficult diseases to diagnose and effectively treat. Pain can cause serious damage to the patient's functions such as work, social interaction, and family life. About five percent of adults are disabled due to severe pain. ChojnowskA E, Standard C.epidemic of Chronic Pain, Chapter 2, pages 15-26: t.s.jensen, p.r.wilson, a.s.c.Editing, Clinical Pain Management Chronic Pain，Arnold，London，2003。

In most pain conditions, with enhanced nerve input from the periphery, sensory nerve impulses pass through the axons of primary afferent neurons to the dorsal horn of the spinal cord, transmitting nerve impulses to neurons in the dorsal horn by releasing excitatory amino acids and neuropeptides at the synapses. Dorsal horn projection neurons process stimulation of peripheral nerves and transmit to the brain through ascending spinal pathways. Mannion, r.j. and Woolf, c.j., clin.j.of Pain 16: S144-S156 (2000).

Firing of dorsal horn projection neurons is not only determined by excitatory inputs they receive, but also relies on inhibitory inputs from the spinal cord or higher order nerve centers. Some areas of the brain participate in the descending inhibitory pathway. Nerve fibers in these pathways release endogenous opioids, gamma-aminobutyric acid ("GABA"), and 5-hydroxytryptamine, for example, at synaptic sites associated with the dorsal horn or primary afferent neurons and inhibit pain propagation. Peripheral nerve injury can produce changes in dorsal horn excitability by lowering the amount of dorsal horn inhibitory control through a variety of mechanisms.

Repetitive or prolonged stimulation of dorsal horn neurons due to activation of C-nociceptors or damage to nerves can cause increased excitability, prolonged responsiveness of dorsal horn neurons, which can last for hours longer than stimulation. Sensitization of dorsal horn neurons can increase their excitability, causing them to appear exaggerated and prolonged for normal input. It is known that this persistent excitation of primary afferent C-fibers results in morphologically and biochemically difficult changes in the dorsal horn. In the dorsal horn, several changes have been noted to occur simultaneously with central sensitization, including: (i) the expanded acceptance range of the dorsal horn allows spinal neurons to respond to noxious stimuli in areas to which they are not normally responsive; (ii) increased intensity, prolonged time of response to a given noxious stimulus (hyperalgesia); (iii) producing a pain response to a generally innocuous stimulus, such as primary afferent a β -fibers to the sensation of a mechanical stimulus (allodynia); (iv) pain spreads to undamaged tissues (referred pain). Koltzenburg, M.Clin.J.of pain.16: S131-S138 (2000); mannion, r.j. and Woolf, c.j., clin.j.of Pain 16: S144-S156 (2000).

Central sensitization may explain to some extent the persistent pain and pain hypersensitivity after injury and may play a role in the healing phase by enhancing the protection of the injured site. However, central sensitization can continue for a long time after the wound has healed, resulting in chronic pain. Sensitization plays a key role in chronic pain, which may help us explain why chronic pain often outperforms intolerable stimuli in part and time, and may help us explain why existing pain is more difficult to suppress than acute pain. Koltzenburg, M.Clin.J.of Pain 16: S131-S138(2000).

2.1 type of pain

2.1.1 nociceptive pain

Nociceptive pain is caused by noxious stimuli such as inflammatory chemical mediators released by tissue injury, disease, or inflammation, and can be detected at the site of injury by a general functional sensory receptor (nociceptor). Koltzenburg, M.Clin.J.of Pain 16: S131-S138(2000) nociceptive pain clinical examples include, but are not limited to, pain associated with chemical or thermal burns, cuts and abrasions of the skin, osteoarthritis, rheumatoid arthritis, tendonitis, and myofascial pain.

Nociceptors (sensory receptors) are distributed around the periphery of the tissue. They are sensitive to noxious stimuli (e.g., thermal, mechanical, chemical) that, if prolonged, would destroy the tissue. Activation of peripheral pain receptors by such stimulation stimulates the production of output in two different classes of primary afferent neurons: slow-conducting unmyelinated C-fibers and fast-conducting thinly myelinated a δ fibers. C-fibers are associated with burning pain and a δ fibers are associated with stabbing pain. Koltzenburg, m.clin.j.of Pain 16: S131-S138 (2000); besson, j.m.lancet 353: 1610-15 (1999); and Johnson, b.w. paiinmechaniszzas: anatozy, Physiology and Neurochemistry, inPractical Management of Pain11 th of (1)Chapter p.prithvi raj. editor (3 rd edition, Mosby, inc. st Louis, 2000). Most nociceptive pain involves signals emitted by primary afferent nerve fibers of the a δ and C-types.

Peripheral nociceptors are sensitized by inflammatory mediators such as prostaglandins, substance P, bradykinin, histamine, 5-hydroxytryptamine and stressful repetitive or prolonged noxious stimuli. In addition, cytokines and growth factors (e.g., nerve growth factor) can affect neuronal phenotype and function. Besson, j.m.lancet 353: 1610-15(1999). After sensitization of nociceptors, a decrease in activation threshold is observed, with an increase in the frequency of triggers, which means that they are more likely to produce nerve impulses more frequently. Peripheral sensitization of pain receptors plays an important role in spinal cord dorsal horn central sensitization and clinical pain states such as hyperalgesia and allodynia.

Inflammation also plays an important role in peripheral pain receptors. Some C-nociceptors generally do not respond to any level of mechanical and thermal stimulation and are only activated in the presence of inflammation or tissue damage. These nociceptors are called "silent" nociceptors, and have been shown to be present in visceral and cutaneous tissues. Besson, j.m.lancet 353: 1610-15 (1999); koltzenburg, M.Clin.J.of Pain 16: S131-S138 (200).

The different control patterns of noxious stimulation in different tissues contribute to the different characteristics of nociceptive pain. For example, cutaneous pain is often described as a localized sharp prick or burn, while pain in the deep layers of the body is often described as a diffuse dull or sore pain. In general, there is a variable link between pain perception and stimulus intensity, as the central nervous system and general experience influence the perception of pain.

2.1.2 Neuropathy of neuropathic pain

Neuropathic pain reflects damage to the nervous system and is defined by IASP as "pain caused or caused by primary damage or dysfunction of the nervous system. ' Merskey H, Bogduk N, eds, Classification of Chronic Pain, International Association for the student of Pain (IASP) Task Forceon Taxomy, IASP Press: seattle, 209 Aconition 214, 1994 some neuropathic pain is caused by damage or dysfunction of the peripheral nervous system. Due to the damage, the expression of key sensor molecule media and ion channels changes, which changes the excitability of peripheral neurons. Johnson, b.w.painmechanisms: anatanmy, Physiology and Neurochemistry, inPractical Management of PainChapter 11 p.prithvi raj. editor (3 rd edition, Mosby, inc. Louis, 2000). Clinical examples of neuropathic pain include, but are not limited to, trigeminal neuralgia after herpes infections accompanied by diabetic neuropathy and pain after stroke.

Neuropathic pain is often associated with several prominent features, such as persistent pain or occasional pain, and can be described using a variety of means, such as burning, tingling, stinging, feeling in impact, shocking, poking, squeezing, deep pain, or cramping. Patients with neuropathic pain have a reduced sensation of thermal and mechanical stimuli, often resulting in paradoxical partial or total sexual sensory shortages. The patient may also feel an unusual unfamiliar discomfort (feeling badly), which in turn causes pain. Other features are the perception of innocuous stimuli (allodynia) that do not normally cause pain or inappropriate pain (hyperalgesia) in response to suprathreshold stimulation. Johnson, b.w.painmechanisms: anatomy, Physiology and Neurochemistry, inPractical Management of PainChapter 11 p.prithvi raj. editor (3 rd edition, Mosby, inc. st Louis, 2000); and Attal, n.clin.j.ofpain 16: S118-S130 (2000).

Complex Regional Pain Syndrome (CRPS) is a neuropathic pain that usually affects the extremities in the absence (CRPS type I) or presence (CRPS type II) of nerve damage. Type I CRPS includes a symptom called reflex sympathetic atrophy (RSD), type II CRPS includes a symptom called causalgia, and both types contain a subtype of sympathetically persistent pain syndrome. In 1993, a conference specialization of IASP established a diagnosis and terminology for the disease, and the term CRPS was used for both subtypes. Subsequent studies and meetings make this definition more accurate, with current guidelines having high sensitivity (0.70) and specificity (0.95). Bruehl, et al, Pain 81: 147-154(1999). However, there is currently no widespread consensus on the cause and optimal treatment of this disease. Paice, E., British Medical Journal 310: 1645-1648(1995).

CRPS is a multi-symptomatic, multi-systemic syndrome affecting a variety of nerves, bones, and soft tissues, including one or more extremities, characterized by intense pain. Although it was first described 130 years ago, the understanding of CRPS is rather poor. For example, changes in the control of the sensory system, autonomic nervous system, motor nervous system, peripheral and central, pathological roles between sympathetic and afferent systems are all considered possible mechanisms. Wasner et al demonstrated a complete loss of function of cutaneous sympathetic vasoconstrictive neural activity in the early stages of CRPS recovery. Wasner g., Heckmann k., Maier c., Arch Neurol 56 (5): 613-20(1999), Kurvers et al believe that the spinal column component during the CRPSI phase is a microcirculatory disturbance, and this statement appears to hope to demonstrate itself with a neurogenic inflammatory mechanism. Kurvers h.a., Jacobs m.j., Beuk r.j., Pain 60 (3): 333-40(1995). The cause of vascular abnormalities is not clear, and the debate is also whether the Sympathetic Nervous System (SNS) is involved in the development of such changes.

The actual incidence of CRPS in the united states is unclear and epidemiological information about the disease is quite limited. Both sexes can develop, but women have a higher incidence of the syndrome. The symptoms may occur in people of any age, including children. Schwartzman r.j., Curr OpinNeurol neurourg 6 (4): 531-6(1993). Reasons that may lead to CRPS include, but are not limited to, poliomyelitis tumor from head injury, traumatic Amyloidosis Lateral Sclerosis (ALS), myocardial infarction, polymyalgia rheumatica, surgery, arm plexus disease, model/splint immobilization, minimal limb injury, and malignancy.

Symptoms of CRPS include, but are not limited to, pain, autonomic dysfunction, edema, movement disorders, malnutrition, and atrophy. Schwartzman r.j., N Engl J Med 343 (9): 654-6(2000). Pain is described as extremely severe and persistent, often accompanied by a burning sensation. Ninety percent of CRPS patients have spontaneous burning pain and allodynia, i.e., pain from mild contact. Most of the difficulties encountered by clinicians are that this pain is far more severe than what is expected based on physiological findings. As described above. Pain is often accompanied by swelling, joint tenderness, increased sweating, sensitivity to temperature and light contact, and changes in skin tone. Indeed, the diagnosis of CRPS cannot be based on pain alone. The patient must have signs and symptoms of sensory abnormalities and vascular dysfunction with profuse sweating, edema, and nutritional changes in the skin.

As described above, IASP classifies CRPS into two types, i.e., CRPS type I (also called RSD) and CRPS type II (also called causalgia). The distinction between these two types is based primarily on whether there is exact nerve damage in each case. Type I CRPS occurs after an adverse event occurs, not after nerve injury. Type II CRPS occurs after nerve damage. CRPS is further divided into three distinct stages in its development and performance. However, the course of disease between different patients appears to be unpredictable, so that staging of the disease in treatment is not always clear or helpful. Schwartzman r.j., NEngl JMed 343 (9): 654(2000).

In phase I, or "early RSD", the pain is much more severe than would be expected from injury, with burning pain characteristics. Pain can be exacerbated by limb affiliation, physical contact, and emotional distress. The painful area often becomes edematous, possibly hot or cold, and may also have a tendency to increase hair and nail growth. Radiographs may show early skeletal changes. As in (Id).

In stage II, or "mid-RSD", edematous tissue becomes hard. The skin usually becomes cold and sweaty, with the symptoms of reticular macula or cyanosis. May be hair loss, nail wrinkling, fissures, and brittle. The hands were clearly dry and skin and subcutaneous tissues were significantly atrophied. The primary symptom is still pain. Pain is generally persistent and any stimulation of the affected area may cause an increase in pain sensation. The hardness increases during this period and radiographs can show diffuse osteoporosis. As described above.

In stage III, or "late RSD," pain spreads to adjacent areas. Although pain intensity may decrease, it is still a major feature. The disease may occur spontaneously. Irreversible tissue damage occurs and the skin becomes thinner and brighter. Edema disappears but contractures may appear. Radiographs can show significant bone softening. As described above.

Patients suffer severe chronic pain during all phases of CRPS, and most patients have insomnia. CRPS has a high incidence and therefore it is important to improve vigilance for the disease. Early and effective treatment may alleviate CRPS effects in some people. William D.Dzwierzynski et al, Hand Clinics Vol 10 (1): 29-44(1994).

2.1.3 other types of pain

Visceral pain is generally considered a variant of somatic pain, but there are many differences in the neurological mechanisms. Visceral pain is generally thought to involve resting pain receptors, which are visceral afferent fibers that are activated only upon inflammation. Cervero, f. and Laird j.m.a., Lancet 353: 2145-48(1999).

Visceral pain has several rare features in the clinic: (I) it is not entirely caused by viscera and is not always associated with visceral damage; (ii) due to the organization of visceral pain sensory pathways in the central nervous system, and in particular due to the lack of separate visceral sensory pathways and a low proportion of visceral afferent nerve fibers, visceral pain often spreads and is inaccurately localized; (iii) it sometimes involves some other non-visceral tissue; (iv) motor and autonomic reflexes, such as nausea, are often associated. Johnson, b.w., Pain mechanics: antomo, Physiologyand Neurochemistry, inPractical Management of PainChapter 11 p.prithvila j. editions (3 rd edition, Mosby, inc. Louis, 2000); and Cervero, f.and Laird j.m.a., Lancet 353: 2145-48(1999).

Headache is classified into primary headache and secondary headache. The two most common primary headaches are migraine and tension-type headaches, both of which are very complex in pathophysiology and are not yet fully understood. Recent studies have shown that pain input to the central nervous system may be amplified by activation and hyperactivation of peripheral pain receptors, or by secondary and tertiary neuron activation and sensitization of the central nervous system due to blockade of hyperalgesia. Thus, central sensitization appears to play a role in the development and persistence of migraine and tension-type headaches. Johnson, b.w.pain mechanics: anatomy, Physiology and Neurochemistry, inPractical Management of PainChapter 11 p.prithvi raj. editor (3 rd edition, Mosby, inc. Louis, 2000).

Post-operative pain, such as tissue trauma from surgery, can create a barrier to pain afferent. After surgery, there is an inflammatory response at the wound site that includes cytokines, neuropeptides, and other inflammatory mediators. These chemicals cause over-sensitization and amplification of the response to external stimuli, resulting in, for example, a decrease in threshold or an increase in the response to stimuli above the threshold. Overall, these processes result in peripheral and central over-sensitization. Johnson, B.W.Painmechanisms.Anatomy, Physiology and Neurochemistry, inPractical Management of PainEdited in chapter 11 p.prithvi Raj (3 rd edition, Mosby, inc. Louis, 2000).

Mixed pain is a chronic pain that includes nociceptive pain and neuropathic pain. For example, pain may arise from one pain pathway and persist by another pain pathway. Symptoms of mixed pain include, but are not limited to, cancer pain and low back pain.

2.2 treatment of pain

Current treatments for CRPS-associated pain include pain management and extended physical therapy, which can help prevent edema and joint contractures and can minimize pain. Pain is usually treated with medication and nerve block. At present, the regional nerve block is carried out by a Bier block method, and different medicaments are adopted, including local anesthetics, brombenzyl ethylamine, steroids, calcitonin, reserpine, guanethidine and the like. Perez r.s., et al, JPain Symptom Manage2001, 6 months; 21(6): 511-26. The implementation of specific, selective sympathetic central blockade is used for both diagnostic and therapeutic purposes. The principle of selective blockade of the sympathetic nerve center is to disturb the sympathetic nervous system, reducing activation of sensory nerves. Patients who do not have better control over sympathetic blockade therapy may have sympathetic-independent CRPS. Once difficult to control by nerve blockade, pain is often lifelong and very difficult to relieve. As described above.

Current drugs for the treatment of chronic pain generally include narcotic-free analgesics, opioid analgesics, calcium channel blockers, muscle relaxants and systemic corticosteroids. However, it does not allow the patient to completely eliminate the pain. In addition, treatment is entirely empirical, as pain and autonomic dysfunction are not fully understood. Five to ten percent of CRPS patients develop chronic pain, often with severe disability and high use of analgesics. Thus, there remains a need for safe and effective methods of treating and managing pain.

2.3 Selective cytokine inhibitory drugs

Known as SelCIDs^TM(Celgene Corporation) or selective cytokine inhibitory drugs have been synthesized and tested. These compounds effectively inhibit TNF-alpha production and have mild inhibitory effects on LPS-induced IL1 beta and IL 12. L.g.corral, et al, ann.rheum.dis.58: (supplement I) 1107-.

A further feature of selective cytokine inhibitory drugs is that they are both potent inhibitors of PDE 4. PDE4 is a major isoenzyme of the phosphodiesterase enzymes found in human bone marrow and lymphocyte cell lines. This enzyme plays an important role in regulating cellular activities by degrading the ubiquitous second messenger cAMP and keeping it at low intracellular concentrations. As described above. Inhibition of PDE4 results in increased cAMP levels that modulate LPS-induced cytokines, including inhibition of TNF- α production in mononuclear nuclear lymphocytes.

3. Summary of the invention

The invention encompasses methods of treating, preventing, modifying or managing (e.g., prolonging the time of remission) pain, which comprise administering to a patient in need thereof a prophylactically or therapeutically effective amount of a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof.

Another embodiment of the invention includes the use of one or more selective cytokine inhibitory drugs in combination with other therapeutic agents currently in use for the prevention and treatment of pain such as (but not limited to): antidepressants, antihypertensives, anxiolytics, calcium channel blockers, muscle relaxants, non-narcotic analgesics, opioid analgesics, alpha-adrenoceptor agonists or antagonists, anti-inflammatory agents, COX-2 inhibitors, immunomodulatory agents, immunosuppressive agents, hyperbaric oxygen, JNK inhibitors, and corticosteroids.

Yet another embodiment of the invention encompasses the use of one or more selective cytokine inhibitory drugs in combination with other therapies currently used to treat, prevent or manage pain, including (but not limited to): surgery, interventional methods (e.g., nerve block), physical therapy, and psychotherapy.

The invention also includes pharmaceutical compositions, unit dosage forms and kits suitable for treating, preventing, alleviating and or managing pain. Including selective cytokine inhibitory drugs, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof.

4. Detailed description of the invention

The present invention is based, in part, on the belief that the compounds disclosed herein can be used alone or in combination with other drugs to effectively treat, prevent, alleviate and/or manage various types and degrees of pain. The medicament of the present invention is not limited by theory and can, but need not, act as an analgesic. In more detail, since some compounds can significantly affect the production of cytokines (e.g., TNF- α, IL1 β, IL12, and IL4), they are believed to act as anti-hyperalgesics and/or neuromodulators by restoring the baseline or normal pain threshold of the animal or human to which they are administered. Thus, rather than reducing the response to stimulation as with analgesics, the compounds of the present invention can alter the patient's tolerance by inhibiting pain from being painful or by directly reducing the response to pain receptors. For this reason, it is believed that the compounds disclosed herein may be useful not only in the treatment, prevention, alleviation and control of nociceptive pain, but also in pain caused by other etiologies (e.g., neuropathic pain). In addition, since the mechanism of action of some of the compounds of the present invention is believed to be unique, they are believed to not cause the typical side effects (e.g., hallucinogenic effects) of some analgesics (e.g., opioids) even when used systemically.

A first embodiment of the invention encompasses methods for treating, preventing, modifying or managing pain, which comprise administering to a patient in need thereof a therapeutically or prophylactically effective amount of a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof. The present invention further relates to the treatment, prevention, alleviation or control of certain types of pain, including but not limited to: nociceptive pain, neuropathic pain, mixed pain of nociceptive and neuropathic pain, visceral pain, migraine, headache, and post-operative pain.

Unless otherwise indicated, the term "nociceptive pain" includes, but is not limited to, pain associated with chemical or thermal burns, skin incisions, skin abrasions, osteoarthritis, rheumatoid arthritis, tenosynovitis, and myofascitis.

Unless otherwise indicated, the term "neuropathic pain" includes, but is not limited to, CRPS type I, CRPS type II, Reflex Sympathetic Dystrophy (RSD), reflex neurovascular dystrophy, reflex dystrophy, sympathetically sustained pain symptoms, causalgia, grandke (Sudeck) bone atrophy, painful neurotrophia, shoulder-hand syndrome, post traumatic dystrophy, trigeminal neuralgia, post herpetic neuralgia, cancer-related pain, phantom limb pain, fibromyalgia, chronic fatigue symptoms, spinal cord injury pain, central post-stroke pain, radiculopathy, diabetic neuralgia, post-stroke pain, syphilitic neuralgia, and other neuralgia induced by vincristine, Velcade, thalidomide, and the like.

As used herein, the terms "complex regional pain syndrome", "CRPS" and "CRPS-associated symptoms" mean a chronic pain characterized by one or more of the following characteristics: pain, whether spontaneous or triggered, includes allodynia (the sensation of pain arising from a stimulus that normally does not produce pain) and hyperalgesia (an exaggerated response to a stimulus that normally causes only mild pain); pain that is inconsistent with the stimulus experienced (e.g., painful sensations years after ankle sprain); regional pain not limited to a single peripheral nerve distribution; autonomic dysregulation (e.g., edema, altered blood flow, and hyperhidrosis) associated with skin nutritional changes (abnormal nail growth and skin ulceration).

Another embodiment of the invention encompasses methods of alleviating or modulating thresholds, the development of pain, and/or the duration of pain tolerance comprising administering to a patient in need thereof a therapeutically or prophylactically effective dose of a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof.

Another embodiment of the invention encompasses pharmaceutical compositions comprising a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof, and an optional carrier.

The invention also encompasses unit dosage forms comprising a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof, and an optional carrier.

Another embodiment of the invention encompasses kits comprising a pharmaceutical composition of a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof. The invention further encompasses kits comprising a single unit dosage form. The kits of the invention further comprise additional active agents or combinations thereof.

Without being limited by theory, it is believed that certain selective cytokine inhibitory drugs and other drugs that may be used to treat pain symptoms may exert a complementary and synergistic effect in the treatment, alleviation or control of pain. Accordingly, one embodiment of the present invention is directed to methods of treating, preventing, modifying and managing pain, which comprises administering to a patient in need thereof a therapeutically or prophylactically effective amount of a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof, and a therapeutically or prophylactically effective amount of a second active agent.

Examples of second active agents include, but are not limited to, conventional agents used in the prevention and treatment of pain such as antidepressants, anticonvulsants, antihypertensives, anxiolytics, calcium channel blockers, muscle relaxants, non-narcotic analgesics, opioid analgesics, anti-inflammatory agents, COX-2 inhibitors, immunomodulators, alpha-adrenoceptor agonists and antagonists, immunosuppressants, corticosteroids, hyperbaric oxygen, ketamine, other anesthetics, NMDA antagonists and other agents found, for example, in Physician's Desk Reference 2003.

The invention also includes pharmaceutical compositions, single unit dosage forms, and kits comprising one or more selective cytokine inhibitory drugs, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof, and a second active drug. For example, a kit may include one or more compounds of the invention and an antidepressant, calcium channel blocker, non-narcotic analgesic, opioid analgesic, anti-inflammatory agent, COX-2 inhibitor, alpha-adrenoceptor agonist or antagonist, immunomodulator, immunosuppressant, anticonvulsant or other drug which treats or alleviates a symptom of pain.

It is further believed that certain selective cytokine inhibitory drugs may reduce or eliminate the side effects associated with administration of drugs for treating pain, thereby allowing for administration of greater amounts of drugs to patients or improving patient compliance. Next, another embodiment encompassed by the present invention encompasses reversing, reducing or avoiding the side effects associated with the administration of a second active agent to a patient afflicted with pain, comprising administering to a patient in need thereof a therapeutically or prophylactically effective amount of a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof, and the like. Examples of side effects include, but are not limited to, nausea, epigastric discomfort, vomiting, prolonged bleeding time, respiratory depression, metabolic acidosis, hyperpyrexia, Urticaria, bronchoconstriction, angioneurotic edema, and Riyee's syndrome.

As described elsewhere herein, pain symptoms may be blocked with physical therapy, psychotherapy, a particular type of surgery, such as (but not limited to) selective somatic or sympathetic trunk nerves. Without being limited by theory, it is believed that the combination of such conventional therapies with selective cytokine inhibitors may produce unique and unexpected effects to alleviate complications associated with conventional therapies. Accordingly, the invention includes methods for treating, preventing, alleviating and/or managing pain, which comprise administering to a patient (e.g., a human) a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof, prior to, during, or after surgery (e.g., nerve block surgery), physical therapy, psychiatric therapy or other conventional, non-drug therapy.

4.1 Selective cytokine inhibitory drugs

The compounds used in the present invention include racemic, optically pure and optically enriched selectionsA sex cytokine inhibitory drug, a stereoisomerically or enantiomerically pure compound having selective cytokine inhibitory activity, and pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, clathrates, or prodrugs thereof. The present invention is more intended to use the known selective cytokine inhibitory drugs (SelCIDs) of Celgene corporation^TM)。

As used herein, unless otherwise indicated, "selective cytokine inhibitory drugs" and "SelCIDs^TM"includes small molecule drugs such as non-peptides, proteins, nucleic acids, oligosaccharides or other large organic molecules. Preferred are compounds that inhibit TNF- α production. These compounds may also have a mild inhibitory effect on LPS-induced IL1 β and IL 12. More preferred compounds of the invention inhibit angiogenesis and PDE, especially PDE 4. PDE4 is a major isozyme of phosphodiesterase found in human bone marrow and lymphocyte lineages. This enzyme plays an important role in regulating cellular activities by degrading the ubiquitous second messenger cAMP and keeping it at low intracellular concentrations. Without being limited by theory, inhibition of PDE4 activity results in increased cAMP levels, enabling modulation of LPS-induced cytokines, including inhibition of TNF- α production in monocytes and lymphocytes.

Specific examples of selective cytokine inhibitory drugs include, but are not limited to: cyclic imides disclosed in U.S. Pat. Nos. 5,605,914 and 5,463,063, cycloalkyl amides and cycloalkyl nitriles disclosed in U.S. Pat. Nos. 5,728,844, 5,728845, 5,968,945, 6,180,644 and 6,518,281, aryl amides disclosed in U.S. Pat. Nos. 5,801,195, 5,736,570, 6,046,221 and 6,284,780 (e.g., N-benzoyl-3-amino-3- (3 ', 4' -dimethoxyphenyl) -propionamide), imide amide ethers and alcohols disclosed in U.S. Pat. No. 5,703,098 (e.g., 3-phthalimido-3- (3 ', 4' -dimethoxyphenyl) -1-propanol, succinimides and maleimides disclosed in U.S. Pat. application No. 5,658,940 (e.g., methyl 3- (3 ', 4', 5 ', 6' -tetrahydrophthalimido) -3- (3 ", 4" -dimethoxyphenyl) propane), imide and amide substituted alkyl hydroxamic acids disclosed in U.S. patent 6,214,857 and international patent WO 99/06041, substituted phenethylsulfones disclosed in U.S. patent 6,011,050 and 6,020,358, substituted imides disclosed in U.S. patent 6,429,221 (e.g., 2-phthalimido-3- (3 ', 4' -dimethoxyphenyl) propane), substituted 1, 3, 4-oxadiazoles disclosed in U.S. patent 6,326,388 (e.g., 2- [1- (3-cyclopentyloxy-4-methoxyphenyl) -2- (1, 3, 4-oxadiazol-2-yl) ethyl ] -5-methylisoindoline-1, 3-dione), U.S. patent 5,929,117; 6,130,226, respectively; 6,262,101 and 6,479,554 (e.g., 3-bis- (3, 4-dimethoxyphenyl) -acrylonitrile), isoindolin-1-one and indoline-1, 3-dione substituted with an alpha- (3, 4-disubstituted phenyl) group at the 2-position and with a nitrogen-containing group at the 4-and/or 5-position as disclosed in WO 01/34606, and imide-and amide-substituted acylhydroxamic acid (e.g., 3- (1, 3-dioxoisoindolin-2-yl) -3- (3-ethoxy-4-methoxyphenyl) propionylamino) propionate as disclosed in WO 01/45702. All documents are incorporated herein by reference in their entirety.

Other selective cytokine inhibitory drugs belong to a class of synthetic compounds, typical examples being 3- (1, 3-dioxobenzo- [9] isoindol-2-yl) -3- (3-cyclopentyloxy-4-methoxyphenyl) propionamide and 3- (1, 3-dioxo-4-azaisoindol-2-yl) -3- (3, 4-dimethoxyphenyl) -propionamide.

Other selective cytokine inhibitory drugs are described in U.S. Pat. Nos. 5,698,579; 5,877,200; 6,075,041 and 6,200,987. Representative cyclic amides include compounds having the structure:

wherein n is 1,2 or 3;

R⁵is ortho-phenylene, unsubstituted or substituted with 1 to 4 substituents independently selected from: nitro, cyano, trifluoromethyl, ethoxyformyl, methoxycarbonyl, propoxycarbonyl, acetyl, carbamoylAcyl, acetoxy, carboxyhydroxy, amino, alkylamino, dialkylamino, acylamino, alkyl of 1 to 10 carbon atoms and halogen;

R⁷is (i) phenyl or phenyl substituted with one or more substituents independently selected from: nitro, cyano, trifluoromethyl, ethoxyformyl, methoxycarbonyl, propoxycarbonyl, acetyl, carbamoyl, acetoxy, carboxyl, hydroxyl, amino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms and halogen (ii) unsubstituted benzyl or benzyl substituted with 1 to 3 substituents independently selected from the group consisting of: nitro, cyano, trifluoromethyl, ethoxyformyl, methoxycarbonyl, propoxycarbonyl, acetyl, carbamoyl, acetoxy, carboxyl, hydroxyl, amino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms and halogen (iii) naphthyl and (iv) benzyloxy;

R¹²is hydroxy, alkoxy of 1 to 12 carbon atoms or

R⁸Is hydrogen or alkyl having 1 to 10 carbon atoms; and

R⁹is hydrogen, alkyl having 1 to 10 carbon atoms, -COR¹⁰Or SO₂R¹⁰Wherein R is¹⁰Is hydrogen, alkyl having 1 to 10 carbon atoms or phenyl.

Specific compounds within this class include, but are not limited to:

3-phenyl-2- (1-oxoisoindolin-2-yl) propionic acid;

3-phenyl-2- (1-oxoisoindolin-2-yl) propionamide;

3-phenyl-3- (1-oxoisoindolin-2-yl) propionic acid;

3-phenyl-3- (1-oxoisoindolin-2-yl) propionamide;

3- (4-methoxyphenyl) -3- (1-oxoisoindolinyl) propionic acid;

3- (4-methoxyphenyl) -3- (1-oxoisoindolinyl) propionamide;

3- (3, 4-dimethoxyphenyl) -3- (1-oxoisoindolin-2-yl) propionic acid;

3- (3, 4-dimethoxyphenyl) -3- (1-oxo-1, 3-dihydroisoindol-2-yl) propionamide;

3- (3, 4-dimethoxyphenyl) -3- (1-oxoisoindolin-2-yl) propionamide;

3- (3, 4-diethoxyphenyl) -3- (1-oxoisoindolinyl) propionic acid;

3- (1-oxoisoindolin-2-yl) -3- (3-ethoxy-4-methoxyphenyl) propionic acid methyl ester;

3- (1-oxoisoindolin-2-yl) -3- (3-ethoxy-4-methoxyphenyl) propionic acid;

3- (1-oxoisoindolin-2-yl) -3- (3-propoxy-4-methoxyphenyl) propionic acid;

3- (1-oxoisoindolin-2-yl) -3- (3-butoxy-4-methoxyphenyl) propionic acid;

3- (1-oxoisoindolin-2-yl) -3- (3-propoxy-4-methoxyphenyl) propionamide;

3- (1-oxoisoindolin-2-yl) -3- (3-butoxy-4-methoxyphenyl) propionamide;

3- (1-oxoisoindolin-2-yl) -3- (3-butoxy-4-methoxyphenyl) propionic acid methyl ester;

3- (1-oxoisoindolin-2-yl) -3- (3-propoxy-4-methoxyphenyl) propionic acid methyl ester.

Other specific selective cytokine inhibitory drugs include imide and amide substituted alkyl hydroxamic acids as disclosed in WO 99/06041, which is incorporated herein by reference. Examples of such compounds include, but are not limited to:

wherein when R is¹And R²Each is independently hydrogen, lower alkyl; when both are attached to the carbon atom, they are each ortho-phenylene, ortho-naphthylene, cyclohexene-1, 2-diyl, unsubstituted or substituted with 1 to 4 substituents independently selected from nitro, cyano, trifluoromethyl, ethoxyformyl, methoxycarbonyl, propoxycarbonyl, acetyl, carbamoyl, acetoxy, carboxyl, hydroxyl, amino, alkylamino, dialkylamino, acylamino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms and halogen;

R³is phenyl substituted by 1 to 4 substituents selected from nitro, cyano, trifluoromethyl, ethoxyformyl, methoxycarbonyl, propoxycarbonyl, acetyl, carbamoyl, acetoxy, carboxyl, hydroxyl, amino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, alkylthio of 1 to 10 carbon atoms, benzyloxy, cycloalkoxy of 3 to 6 carbon atoms, C₄-C₆Cycloalkylidenemethyl, C₃-C₁₀Cycloalkylidenemethyl, indanyloxy and halogen;

R⁴is hydrogen, alkyl of 1 to 6 carbon atoms, phenyl or benzyl;

R^4′is hydrogen or alkyl of 1 to 6 carbon atoms;

R⁵is-CH₂-、-CH₂-CO-、-SO₂-, -S-or-NHCO-;

n is 0, 1 or 2;

and acid addition salts of said compounds containing a protonatable nitrogen atom.

Additional specific selective cytokine inhibitory drugs for use in the present invention include, but are not limited to:

3- (3-ethoxy-4-methoxyphenyl) -N-hydroxy-3- (1-oxoisoindolinyl) propionamide;

3- (3-ethoxy-4-methoxyphenyl) -N-methoxy-3- (1-oxoisoindolinyl) propionamide;

n-benzyloxy-3- (3-ethoxy-4-methoxyphenyl) -3-phthalimidopropionamide;

n-benzyloxy-3- (3-ethoxy-4-methoxyphenyl) -3- (3-nitrophthalimido) propanamide;

n-benzyloxy-3- (3-ethoxy-4-methoxyphenyl) -3- (1-oxoisoindolinyl) propionamide;

3- (3-ethoxy-4-methoxyphenyl) -N-hydroxy-3-phthalimidopropionamide;

n-hydroxy-3- (3, 4-dimethoxyphenyl) -3-phthalimidopropionamide;

3- (3-ethoxy-4-methoxyphenyl) -N-hydroxy-3- (3-nitrophthalimido) propionamide;

3- (3, 4-dimethoxyphenyl) -3- (1-oxoisoindolinyl) propionamide;

3- (3-ethoxy-4-methoxyphenyl) -N-hydroxy-3- (4-methyl-phthalimido) propionamide;

3- (3-cyclopentyloxy-4-methoxyphenyl) -N-hydroxy-3-phthalimidopropionamide;

3- (3-ethoxy-4-methoxyphenyl) -N-hydroxy-3- (1, 3-dioxo-2, 3-dihydro-1H-benzo [ f ] isoindol-2-yl) propionamide;

n-hydroxy-3- {3- (2-propoxy) -4-methoxyphenyl } -3-phthalimidopropionamide;

3- (3-ethoxy-4-methoxyphenyl) -3- (3, 6-difluorophthalimido) -N-hydroxypropionamide;

3- (4-aminophthalimido) -3- (3-ethoxy-4-methoxyphenyl) -N-hydroxypropionamide;

3- (3-aminophthalimido) -3- (3-ethoxy-4-methoxyphenyl) -N-hydroxypropionamide;

3- (3, 4-dimethoxyphenyl) -3- (1-oxoisoindolinyl) propionamide;

3- (3-cyclopentyloxy-4-methoxyphenyl) -N-hydroxy-3- (1-oxoisoindolinyl) propionamide;

n-benzyloxy-3- (3-ethoxy-4-methoxyphenyl) -3- (3-nitrophthalimidoyl) propanamide.

Additional selective cytokine inhibitory drugs useful in the present invention include substituted phenethylsulfones, substituted on the phenyl with an oxoisoindolyl group. Examples of such compounds include, but are not limited to, those disclosed in U.S. Pat. No. 6,020,358, which is incorporated herein, including the following:

the carbon atoms in this band are chiral centers;

y is C ═ O, CH₂，SO₂Or CH₂C＝O；R¹，R²，R³，R⁴Each independently of the others being hydrogen, halogen, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, nitro, cyano, hydroxy or-NR⁸R⁹(ii) a Or R¹，R²，R³，R⁴Any two adjacent of (a) together with said phenylene ring form a naphthylene group;

R⁵and R⁶Independently of one another, are hydrogen, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, cycloalkoxy having a cyano group of up to 18 carbon atoms;

R⁷is hydroxy, alkyl having 1 to 8 carbon atoms, phenyl, benzyl or N R^8′R^9′；

R⁸And R⁹Each independently of the others being hydrogen, alkyl having 1 to 8 carbon atoms, phenyl, or benzyl, or R⁸And R⁹One is hydrogen and the other is-COR¹⁰or-SO₂R¹⁰Or R is⁸And R⁹Both of which together are tetramethylene, pentamethylene, hexamethylene, or-CH₂CH₂X¹CH₂CH₂-, wherein X¹is-O-, -S-or-NH-; and

R^8′and R^9′Independently of one another, is hydrogen, alkyl having 1 to 8 carbon atoms, phenyl or benzyl, or R^8′And R^9′One of which is hydrogen and the other is-COR^10′or-SO₂R^10′Or R is^8′And R^9′Both of which together are tetramethylene, pentamethylene, hexamethylene, or CH₂CH₂X²CH₂CH₂Wherein X is²is-O-, -S-or-NH-;

it will be appreciated that for convenience the above compounds are characterized as phenethylsulfone when R is⁷Is NR^8′R^9′And include sulfonamides.

The limiting group of the compound is that Y is C ═ O or CH₂；

Another limitation of this class of compounds is that R¹，R²，R³，R⁴Each independently of the others being hydrogen, halogen, methyl, ethyl, methoxy, ethoxy, nitro, cyano, hydroxy or NR⁸R⁹Wherein each R⁸And R⁹Independently of one another is hydrogen or methyl; or R⁸And R⁹One being hydrogen and the other being-COCH₃；

Particular compounds are those wherein R¹，R²，R³，R⁴One of them is-NH₂And others are hydrogen;

particular compounds are those wherein R¹，R²，R³，R⁴One of them is-NHCOCH₃And others are hydrogen;

particular compounds are those wherein R¹，R²，R³，R⁴One of them is-N (CH)₃)₂And others are hydrogen;

further preferred radicals of such compounds are R¹，R²，R³，R⁴One of them is methyl and the others are hydrogen;

particular compounds are those wherein R¹，R²，R³，R⁴One of them is fluorine and the others are hydrogen;

particular compounds are those wherein each R⁵And R⁶Independently of one another, hydrogen, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, cyclopentyloxy or cyclohexyloxy.

Specific compound is R⁵Is methoxy, R⁶Those which are monocyclic alkoxy, polycyclic alkoxy or benzocycloalkoxy;

specific compound is R⁵Is methoxy, R⁶Is ethoxy;

specific compound is R⁷Is hydroxy, methyl, ethyl, phenyl, benzyl or NR^8′R^9′Wherein R is^8′And R^9′Independently of one another, hydrogen or methyl.

Specific compound is R⁷Is methyl, ethyl, phenyl, benzyl or NR^8′R^9′Wherein R is^8′And R^9′Independently of one another, hydrogen or methyl.

Specific compound is R⁷Is methyl.

Specific compound is R⁷Is NR^8′R^9′Wherein R is^8′And R^9′Independently of one another, is hydrogen or methyl.

Other selective cytokine inhibitory drugs include fluoroalkoxy-substituted 1, 3-dihydro-isoindolyl compounds in U.S. patent application 60/436,975, filed on provisional application, g.muller et al, 2002, 12, 30, which is incorporated herein by reference in its entirety. Representative fluoroalkoxy-substituted 1, 3-dihydro-isoindolyl compounds include those of the formula:

wherein

Y is-C (O) -, -CH₂、-CH₂C(O)-、-C(O)CH₂-or SO₂；

Z is-H, -C (O) R³、-(C_0-1-alkyl) -SO₂-(C_1-4-alkyl), -C_1-8-alkyl, -CH₂OH、CH₂(O)(C_1-8Alkyl) or-CN;

R₁and R₂Independently of one another is-CHF₂、-C_1-8-alkyl, -C_3-18-cycloalkyl or- (C)_1-10-alkyl) (C_3-18-cycloalkyl), and R¹And R²At least one of which is CHF₂；

R³is-NR⁴R⁵Alkyl, hydroxy, -O-alkyl, phenyl, benzyl, substituted phenyl or substituted benzyl;

R⁴and R⁵Independently of one another are-H, -C_1-8-alkyl, -OH, -OC (O) R⁶；

R⁶is-C_1-8Alkyl, amino (C)_1-8-alkyl), phenyl, benzyl orAn aryl group;

X₁、X₂、X₃、X₄independently of one another are-H, -halogen, -nitro, -NH₂、-CF₃、-C_1-6Alkyl, - (C)_0-4-alkyl) - (C_3-6-cycloalkyl), (C)_0-4-alkyl) -NR⁷R⁸、(C_0-4-alkyl) -N (H) C (O) - (R)⁸)、(C_0-4Alkyl) -N (H) C (O) N (R)⁷R⁸)、(C_0-4Alkyl) -N (H) C (O) O (R)⁷R⁸)、(C_0-4-alkyl) -OR⁸、(C_0-4-alkyl) -imidazolyl, (C)_0-4-alkyl) -pyrrolyl, (C)_0-4-alkyl) -oxadiazolyl, or (C)_0-4-alkyl) -triazolyl, or X₁、X₂、X₃And X₄May be joined to form a cycloalkyl or heterocycloalkyl ring, (e.g., X₁And X₂，X₂And X₃，X₃And X₄，X₁And X₃，X₂And X₄Or X₁And X₄May form a 3, 4,5, 6 or 7 membered ring, which may also be aromatic, thus forming a bicyclic system with the isoindolyl ring); and

R⁷and R⁸Each independently is H, C_1-9Alkyl radical, C_3-6-cycloalkyl, (C)_1-6-alkyl) - (C_3-6Cycloalkyl group), (C)_1-6-alkyl) -N (R)⁷R⁸)、(C_1-6-alkyl) -OR⁸Phenyl, benzyl or aryl;

or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof, and the like.

Preferred compounds include, but are not limited to:

3- (4-acetylamino-1, 3-dioxo-1, 3-dihydro-isoindol-2-yl) -3- (3-cyclopropylmethoxy-4-difluoromethoxy-phenyl) -propionic acid;

3- (4-acetylamino-1, 3-dioxo-1, 3-dihydro-isoindol-2-yl) -3- (3-cyclopropylmethoxy-4-difluoromethoxy-phenyl) -N, N-dimethylpropionamide;

3- (4-acetylamino-1, 3-dioxo-1, 3-dihydro-isoindol-2-yl) -3- (3-cyclopropylmethoxy-4-difluoromethoxy-phenyl) -propionamide;

3- (3-cyclopropylmethoxy-4-difluoromethoxy-phenyl) -3- (1, 3-dioxo-1, 3-dihydro-isoindol-2-yl) -propionic acid;

3- (3-cyclopropylmethoxy-4-difluoromethoxy-phenyl) -3- (1, 3-dioxo-1, 3-dihydro-isoindol-2-yl) -N-hydroxy-propionamide;

3- (3-cyclopropylmethoxy-4-difluoromethoxy-phenyl) -3- (7-nitro-1-oxo-1, 3-dihydro-isoindol-2-yl) -propionic acid methyl ester;

3- (3-cyclopropylmethoxy-4-difluoromethoxy-phenyl) -3- (7-nitro-1-oxo-1, 3-dihydro-isoindol-2-yl) -propionic acid;

3- (3-cyclopropylmethoxy-4-difluoromethoxy-phenyl) -3- (7-nitro-1-oxo-1, 3-dihydro-isoindol-2-yl) -N, N-dimethyl-propionamide;

3- (7-amino-1-oxo-1, 3-dihydro-isoindol-2-yl) -3- (3-cyclopropylmethoxy-4-difluoromethoxy-phenyl) -N, N-dimethyl-propionamide;

3- (4-difluoromethoxy-3-ethoxy-phenyl) -3- (7-nitro-1-oxo-1, 3-dihydro-isoindol-2-yl) -propionic acid methyl ester;

3- (7-amino-1-oxo-1, 3-dihydro-isoindol-2-yl) -3- (4-difluoromethoxy-3-ethoxy-phenyl) -propionic acid methyl ester;

3- [7- (cyclopropylcarbonyl-amino) -1-oxo-1, 3-dihydro-isoindol-2-yl ] -3- (4-difluoromethoxy-3-ethoxy-phenyl) -propionic acid methyl ester;

3- (7-acetamido-1-oxo-1, 3-dihydro-isoindol-2-yl) -3- (4-difluoromethoxy-3-ethoxy-phenyl) -propionic acid methyl ester;

3- (7-acetamido-1-oxo-1, 3-dihydro-isoindol-2-yl) -3- (4-difluoromethoxy-3-ethoxy-phenyl) -propionic acid;

3- [7- (cyclopropylcarbonyl-amino) -1-oxo-1, 3-dihydro-isoindol-2-yl ] -3- (4-difluoromethoxy-3-ethoxy-phenyl) -propionic acid;

{2- [ 2-carbamoyl-1- (4-difluoromethoxy-3-ethoxy-phenyl) -ethyl ] -3-oxo-2, 3-dihydro-1H-isoindol-4-yl } -cyclopropylcarboxamide;

{2- [1- (4-difluoromethoxy-3-ethoxy-phenyl) -2-dimethylcarbamoyl-ethyl ] -3-oxo-2, 3-dihydro-1H-indol-4-yl } -cyclopropanecarboxylic acid;

{2- [1- (4-difluoromethoxy-3-ethoxy-phenyl) -2-hydroxycarbamoyl-ethyl ] -3-oxo-2, 3-dihydro-1H-indol-4-yl } -cyclopropylcarboxamide;

3- (7-acetylamino-1-oxo-1, 3-dihydro-isoindol-2-yl) -3- (4-difluoromethoxy-3-ethoxy-phenyl) -propionamide;

3- (7-acetylamino-1-oxo-1, 3-dihydro-isoindol-2-yl) -3- (4-difluoromethoxy-3-ethoxy-phenyl) -N, N-dimethyl-propionamide;

3- (7-acetylamino-1-oxo-1, 3-dihydro-isoindol-2-yl) -3- (4-difluoromethoxy-3-ethoxy-phenyl) -N-hydroxy-propionamide;

3- (4-acetylamino-1, 3-dioxo-1, 3-dihydro-isoindol-2-yl) -3- (4-difluoromethoxy-3-ethoxy-phenyl) -propionic acid;

3- (4-acetylamino-1, 3-dioxo-1, 3-dihydro-isoindol-2-yl) -3- (4-difluoromethoxy-3-ethoxy-phenyl) -propionamide;

3- (4-acetylamino-1, 3-dioxo-1, 3-dihydro-isoindol-2-yl) -3- (4-difluoromethoxy-3-ethoxy-phenyl) -N, N-dimethylpropionamide;

3- (4-acetylamino-1, 3-dioxo-1, 3-dihydro-isoindol-2-yl) -3- (4-difluoromethoxy-3-ethoxy-phenyl) -N-hydroxy-propionamide;

{2- [1- (4-difluoromethoxy-3-ethoxy-phenyl) -2-methanesulfonyl-ethyl ] -3-oxo-2, 3-dihydro-1H-isoindol-4-yl) -cyclopropylcarboxamide;

n- (2- [1- (4-difluoromethoxy-3-ethoxy-phenyl) -2-methanesulfonyl-ethyl ] -1, 3-dioxo-2, 3-dihydro-1H-isoindol-4-yl } -acetamide;

{2- [ 2-carbamoyl-1- (4-difluoromethoxy-3-ethoxy-phenyl) -ethyl ] -7-chloro-3-oxo-2, 3-dihydro-1H-isoindol-4-yl } -cyclopropylcarboxamide.

Other selective cytokine inhibitory drugs include 7-amido substituted isoindolyl compounds of U.S. patent provisional application 60/454,155 to g.muller et al, filed 5/12/2003, which is incorporated herein by reference in its entirety. Representative 7-amino substituted isoindolyl compounds include those comprising the following structural formula:

wherein:

y is-C (O) -, -CH₂、-CH₂C (O) -or SO₂；

X is hydrogen;

z is (C)_0-4-alkyl) -C (O) R³、C_1-4Alkyl radicals, (C)_0-4-alkyl) -OH, (C)_1-4-alkyl) -O (C)_1-4Alkyl group), (C)_1-4-alkyl) -SO₂(C_1-4Alkyl group), (C)_0-4-alkyl) -SO (C)_1-4Alkyl group), (C)_0-4-alkyl) -NH₂、(C_0-4-alkyl) -N (C)_1-8-alkyl groups)₂、(C_0-4Alkyl) -N (H) (OH), CH₂NSO₂(C_1-4-an alkyl group);

R₁and R₂Independently of each other areC_1-8-alkyl, cycloalkyl or (C)_1-4-alkyl) cycloalkyl;

R³is NR⁴R⁵OH or O- (C)_1-8-an alkyl group);

R⁴is hydrogen;

R⁵is-OH or-OC (O) R⁶；

R⁶Is C_1-8Alkyl, amino- (C)_1-8Alkyl group), (C)_1-8-alkyl) - (C_3-6-cycloalkyl), C_3-6Cycloalkyl, phenyl, benzyl or aryl;

or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof, or the like, or of the formula:

wherein the content of the first and second substances,

y is-C (O) -, -CH₂、-CH₂C (O) -or SO₂；

X is halogen, -CN, -NR₇R₈、-NO₂or-CF₃，

W is

Or

Z is (C)_0-4-alkyl) -SO₂(C_1-4-alkyl), -C_0-4-alkyl) -CN, - (C)_0-4-alkyl) -C (O) R³、C_1-4Alkyl radicals, (C)_0-4-alkyl) OH, (C)_0-4Alkyl) O (C)_1-4Alkyl group), (C)_0-4Alkyl) SO (C)_1-4Alkyl group), (C)_0-4-alkyl) NH₂、(C_0-4Alkyl) N (C)_1-8-alkyl groups)₂、(C_0-4Alkyl group N (H), (OH) or (C)_0-4-alkyl) NSO₂(C_1-4-an alkyl group);

w is C_3-6-cycloalkyl, - (C)_1-8-alkyl) - (C_3-6-cycloalkyl), -C_0-8-alkyl) - (C_3-6-cycloalkyl) -NR₇R₈、(C_0-8-alkyl) -NR₇R₈、(C_0-4-alkyl) -CHR₉-(C_0-4-alkyl) -NR₇R₈；

R₁And R₂Independently of one another are C_1-8-alkyl, cycloalkyl or (C)_1-4-alkyl) cycloalkyl;

R³is C_1-8Alkyl, NR⁴R⁵OH or O- (C)_1-8-an alkyl group);

R⁴and R⁵Independently of one another is H, C_1-8Alkyl radicals, (C)_0-8-alkyl) - (C_3-6-cycloalkyl), OH or-OC (O) R⁶；

R⁶Is C_1-8Alkyl radicals, (C)_0-8-alkyl) - (C_3-6-cycloalkyl), amino- (C)_1-8-alkyl), phenyl, benzyl or aryl;

R₇and R₈Independently of one another is H, C_1-8Alkyl radicals, (C)_0-8-alkyl) - (C_3-6-cycloalkyl), phenyl, benzyl, aryl or, together with the atoms to which they are attached, a heterocycloalkyl or heteroaryl ring group with 3-7 members;

R₉is C_1-4Alkyl radicals, (C)_0-4-alkyl) aryl, (C)_0-4-alkyl) - (C_3-6-cycloalkyl), (C)_0-4-alkyl) -heterocycle;

or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof, and the like.

Still other selective cytokine inhibitory drugs include the N-alkyl-hydroxamic acid-isoindolyl compounds of U.S. patent provisional application 60/454,149 to g.muller et al, filed 3/12/2003, including compounds having the following structural formula:

wherein:

y is-C (O) -, -CH₂、-CH₂C (O) -or SO₂；

R₁And R₂Independently of one another are C_1-8-alkyl, CF₂H、CF₃、CH₂CHF₂Cycloalkyl or (C)_1-8-alkyl) cycloalkyl;

Z₁is H, C_1-6-alkyl, -NH₂、-NR₃R₄OR OR₅；

Z₂Is H or C (O) R₅；

X₁、X₂、X₃And X₄Independently of one another are H, halogen, NO₂、OR₃、CF₃、C_1-6Alkyl radicals, (C)_0-4-alkyl) - (C_3-6-cycloalkyl), (C)_0-4-alkyl) -N- (R)₈R₉)、(C_0-4-alkyl) -NHC (O) - (R)₈)、(C_0-4-alkyl) -NHC (O) CH (R)₈)(R₉)、(C_0-4-alkyl) -NHC (O) N (R)₈R₉)、(C_0-4-alkyl) -NHC (O) O (R)₈)、(C_0-4-alkyl) -O-R₈、(C_0-4-alkyl) -imidazolyl, (C)_0-4-alkyl) -pyrrolyl, (C)_0-4-alkyl) -oxadiazolyl, (C)_0-4-alkyl) -triazolyl or(C_0-4-alkyl) -heterocycle;

R₃，R₄and R₅Independently of one another is H, C_1-6Alkyl, O-C_1-6-alkyl, phenyl, benzyl or aryl;

R₆and R₇Independently of one another are H or C_1-6-an alkyl group;

R₈and R₉Independently of one another is H, C_1-9Alkyl radical, C_3-6-cycloalkyl, (C)_1-6-alkyl) - (C_3-6-cycloalkyl), (C)_0-6-alkyl) -N (R)₄R₅)、(C_1-6-alkyl) -OR₅Phenyl, benzyl, aryl, piperidinyl, piperazinyl, pyrrolidinyl, morpholino or C_3-7-a heterocycloalkyl group;

or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof, and the like.

Such selective cytokine inhibitory drugs include, but are not limited to:

2- [1- (3-ethoxy-4-methoxyphenyl) -2-methyl-sulfonylethyl ] isoindolin-1-one;

2- [1- (3-ethoxy-4-methoxyphenyl) -2- (N, N-dimethyl-aminosulfonyl) ethyl ] isoindolin-1-one;

2- [1- (3-ethoxy-4-methoxyphenyl) -2-methyl-sulfonylethyl ] isoindoline-1, 3-dione;

2- [1- (3-ethoxy-4-methoxyphenyl) -2-methyl-sulfonylethyl ] -5-nitro-isoindoline-1, 3-dione;

2- [1- (3-ethoxy-4-methoxyphenyl) -2-methyl-sulfonylethyl ] -4-nitroisoindoline-1, 3-dione;

2- [1- (3-ethoxy-4-methoxyphenyl) -2-methanesulfonylethyl ] -4-aminoisoindoline-1, 3-dione;

2- [1- (3-ethoxy-4-methoxyphenyl) -2-methanesulfonylethyl ] -5-methylisoindoline-1, 3-dione;

2- [1- (3-ethoxy-4-methoxyphenyl) -2-methanesulfonylethyl ] -5-acetylaminoisoindoline-1, 3-dione;

2- [1- (3-ethoxy-4-methoxyphenyl) -2-methanesulfonylethyl ] -4-dimethylaminoisoindoline-1, 3-dione;

2- [1- (3-ethoxy-4-methoxyphenyl) -2-methanesulfonylethyl ] -5-dimethylaminoisoindoline-1, 3-dione;

2- [1- (3-ethoxy-4-methoxyphenyl) -2-methanesulfonylethyl ] benzo [ e ] isoindoline-1, 3-dione;

2- [1- (3-ethoxy-4-methoxyphenyl) -2-methanesulfonylethyl ] -4-methoxyisoindoline-1, 3-dione;

1- (3-cyclopentyloxy-4-methoxyphenyl) -2-methanesulfonylethyl-amine;

2- [1- (3-cyclopentyloxy-4-methoxyphenyl) -2-methanesulfonylethyl ] -isoindoline-1, 3-dione;

2- [1- (3-cyclopentyloxy-4-methoxyphenyl) -2-methanesulfonylethyl ] -dimethylaminoisoindoline-1, 3-dione; and

other selective cytokine inhibitory drugs include enantiomerically pure compounds from U.S. patent application 10/392,195, filed 3/19/2003 in g.muller et al, international patent application PCT/US03/08737, filed 3/20/2003 in g.muller et al, U.S. provisional patent applications 60/438,450 and 60/438,448, filed 1/7/2003 in g.muller et al, and U.S. provisional patent application 60/452,460, filed 3/5/2003 in g.muller et al, all of which are incorporated herein by reference. Preferred compounds include one pair of enantiomers of 2- [1- (3-ethoxy-4-methoxyphenyl) -2-methanesulfonylethyl ] -4-acetylaminoisoindoline-1, 3-dione and one pair of enantiomers of 3- (3, 4-dimethoxy-phenyl) -3- (1-oxo-1, 3-dihydro-isoindol-2-yl) -propionamide.

Preferred selective cytokine inhibitory drugs in this application are 3- (3, 4-dimethoxy-phenyl) -3- (1-oxo-1, 3-dihydro-isoindol-2-yl) -propionamide and {2- [1- (3-ethoxy-4-methoxy-phenyl) -2-methanesulfonylethyl ] -3-oxo-2, 3-dihydro-1H-isoindol-4-yl } cyclopropylcarboxamide, all of which are available from Celgene Corp. 3- (3, 4-dimethoxy-phenyl) -3- (1-oxo-1, 3-dihydro-isoindol-2-yl) -propionamide has the following chemical structure:

{2- [1- (3-ethoxy-4-methoxy-phenyl) -2-methanesulfonylethyl- ] -3-oxo-2, 3-dihydro-1H-isoindol-4-yl } cyclopropylcarboxamide has the following chemical structure:

the compounds of the present invention are commercially available or may be prepared by the methods described in this application or the methods of the patents disclosed herein. Alternatively, the optically pure components can be resolved by asymmetric synthesis or by known resolving agents or chiral columns, as well as other standard organic chemical synthesis techniques.

The term "pharmaceutically acceptable salts" as used herein, unless otherwise indicated, includes salts of the compounds with non-toxic acids and bases. Acceptable salts of non-toxic acids include those derived from organic and inorganic acids and compounds known herein, including, for example, hydrochloric, hydrobromic, phosphoric, sulfuric, methanesulfonic, acetic, tartaric, lactic, succinic, citric, malic, maleic, sorbic, aconitic, salicylic, phthalic, embonic, heptanoic, and the like.

The compounds which are acidic in nature can form salts with a variety of pharmaceutically acceptable bases. Non-toxic bases used to form pharmaceutically acceptable salts with such acidic materials are bases capable of forming non-toxic salts, such as salts containing pharmaceutically acceptable cations such as, but not limited to, alkali metals and alkaline earth metals, and specifically calcium, magnesium, sodium, potassium salts. Suitable organic bases include, but are not limited to, N-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-meglumine (N-methylglucamine), lysine, and procaine.

The term "prodrug" as used herein, unless otherwise indicated, refers to a substance that can hydrolyze, oxidize, or otherwise react under biological conditions (in vivo or in vitro) to provide a prodrug. Examples of prodrugs include, but are not limited to, derivatives of selective cytokine inhibitory drugs that contain hydrolyzable moieties such as biohydrolyzable amides, esters, carbamates, carbonates, ureides, and phosphate analogs. Other types of prodrugs include selective cytokine inhibitory drugs containing-NO, -NO₂、-ONO、-ONO₂Derivatives of moieties. Prodrugs can be prepared by well known methods, such as those described in Burger's Medicinal Chemistry and Drug Discovery, 172-178, 949-982 (manufactured E.Wolffused. 5 th edition 1995) and Design of Prodrugs (H.Bundgaard eds., Elselvier, New York 1985).

Herein, unless otherwise indicated, the terms "biohydrolyzable amide", "biohydrolyzable ester", "biohydrolyzable carbamate", "biohydrolyzable carbonate", "biohydrolyzable ureide", "biohydrolyzable phosphate" refer to an amide, ester, carbamate, carbonate, ureide, and phosphate of a compound that 1) does not affect the biological activity of the compound but retains the advantages of the compound in vivo, such as uptake, persistence or onset of action, or; 2) biologically inactive but converted in vivo to biologically active compounds. Biohydrolyzable esters include, but are not limited to, lower alkyl acyloxyalkyl esters (e.g., acetoxymethyl, acetoxyethyl, carbamoyloxymethyl, trimethylacetoxymethyl, and trimethylacetoxyethyl esters), lactones (esters of 2-benzofuranone and thio-2-benzofuranone), lower alkoxyacyloxyalkyl esters (e.g., methoxyacyloxymethyl, ethoxyacyloxyethyl, and isopropoxyacyloxyethyl esters), alkoxyalkyl esters, choline esters, and acylaminoalkyl esters (e.g., acetamidomethyl esters). Biohydrolyzable amides include, but are not limited to, lower alkyl amides, alpha-amino acid amides, alkoxyacyl amides, and alkylaminoalkyl carboxamides. Biohydrolyzable carbamates include, but are not limited to, lower alkylamines, substituted ethylenediamines, amino acids, hydroxyalkylamines, heterocyclic and heteroaromatic amines, and polyether amines.

Many selective cytokine inhibitory drugs have one or more chiral centers and may exist as racemic mixtures of enantiomers or mixtures of diastereomers. The invention includes the use of these compounds in pure stereoisomer or mixture form. For example, enantiomers containing equal or unequal amounts of selective cytokine inhibitory drugs are used in the methods and pharmaceutical compositions of the present invention. The pure (R) or (S) isomer of a particular compound disclosed herein can be used substantially free of the other isomer.

The term "stereomerically pure" as used herein, unless otherwise indicated, means that a component contains one stereoisomer of a compound and that the component is substantially free of another stereoisomer of the compound. For example, a stereomerically pure component of a compound having one chiral center is substantially free of another stereoisomer of the compound, and a stereomerically pure component of a compound having two chiral centers is substantially free of the other stereoisomer of the compound. A stereomerically pure component comprises greater than about 80% by mass of one stereoisomer of the compound, less than about 20% by mass of the other stereoisomers of the compound, preferably a component comprising greater than about 90% by mass of one stereoisomer of the compound, less than about 10% by mass of the other stereoisomers of the compound, more preferably a component comprising greater than about 95% by mass of one stereoisomer of the compound, less than about 5% by mass of the other stereoisomers of the compound, most preferably a component comprising greater than about 97% by mass of one stereoisomer of the compound, and less than about 3% by mass of the other stereoisomers of the compound. Herein, unless otherwise indicated, the term "stereomerically enriched" means that a stereomerically pure component contains greater than about 60% by mass of one stereoisomer of the compound, more preferably a component contains greater than about 70% by mass of one stereoisomer of the compound, and most preferably a component contains greater than about 80% by mass of one stereoisomer of the compound.

The term "enantiomerically pure" as used herein, unless otherwise indicated, means that a compound contains a chiral center in a stereomerically pure component. Likewise, "enantiomerically enriched" means that a compound contains a chiral center in a stereoisomeric excess of the component.

It should be noted that if a depicted structure is not consistent with a given name for that structure, it should be more heavily referred to as depicted. In addition, a structure or portion of a structure should be considered to include all isomers thereof if the stereochemistry of the structure or portion is not indicated by the use of lines such as dashes or dashes.

4.2 A second active agent

A second active ingredient or drug may be used in the methods and compositions of the present invention along with a selective cytokine inhibitory drug. In preferred embodiments, the second active agent may relieve pain, inhibit inflammatory response, have a sedative or anti-neuropathic effect, or ensure patient comfort.

Examples of second active agents include, but are not limited to, opioid analgesics, non-narcotic analgesics, anti-inflammatory agents, COX-2 inhibitors, alpha-adrenoreceptor agonists and antagonists, ketamine, anesthetics, NMDA antagonists, immunomodulatory agents, immunosuppressive agents, antidepressants, anticonvulsants, antihypertensive agents, anxiolytic agents, calcium channel blockers, muscle relaxants, corticosteroids, hyperbaric oxygen, JNK inhibitors, other therapies known to alleviate pain, and pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, clathrate prodrugs, and pharmacologically active metabolites.

Opioids can be used to treat pain. Examples of opioid analgesics include, but are not limited to, oxycodone (OxyContin)^*) Morphine sulfate (MS Contin)^*，Duramorph^*，Astramorph^*) Piperidine (Demerol)^*) Fentanyl transdermal patch (Duragesic)^*) And other known conventional drugs; see, for example, Physicians' Desk Reference, 594-595, 2851 and 2991 (57 th edition, 2003). Oxycodone (OxyContin)^*(ii) a ) Is a long-acting form of opiates and is used in early and late CRPS. Morphine sulfate can be used as an analgesic due to its reliable, predictable potency, safety, and ease of withdrawal from naloxone. Morphine sulfate is used in MS Continu in the United states^*、Duramorph^*Or Astramorph^*Trade names are sold. See, for example, the Physicians' Desk Reference, 594-. Fentanyl patch (Duragesic)^*) Is an effective non-narcotic analgesic with a much shorter half-life than morphine. Pethidine (Demerol)^*) And hydromorphone (dilaudi)^*) Can also be used for pain control. See, for example, Physicians' Desk Reference, 2991 (57 th edition, 2003).

Pain treatment during pregnancy and lactation is preferably non-narcotic analgesics and anti-inflammatory agents. Anti-inflammatory agents such as non-steroidal anti-inflammatory drugs (NSAIDs) and COX-2 inhibitors inhibit inflammatory responses and pain by decreasing the activity of cyclooxygenase enzymes that act on prostaglandin synthesis. NSAIDs may act to relieve pain in the early stages of pain symptoms. Examples of anti-inflammatory agents are, but are not limited to, acetylsalicylic acid (Aspirin)^*) Ibuprofen (Motrino)^*，Advil^*) Ketoprofen (Oruvail)^*) Rofecoxib (Vioxx)^*) Naproxen sodium (Anaproxext)^*、Naprelan^*、Naprosyn^*) Ketorolac (Acular)^*) And other known conventional drugs. Celecoxib (Celebrex)^*) Is a specific COX-2 inhibitor. See, e.g., Physicians' Desk Reference, 1990, 1910- & 1914 & 2891 (57 th edition, 2003); physicians' Desk referThe nc for nonpressure Drugs and digital Supplements, 511, 667 and 773 (23 rd edition, 2002).

Antidepressants increase the concentration of serotonin and/or norepinephrine at synapses in the central nervous system by inhibiting their reuptake by presynaptic neural membranes. Some antidepressants also have sodium channel blockers to reduce the activity of injured peripheral nerve afferent fibers. Examples of antidepressants include, but are not limited to, nortriptyline (Pamelor)^*) Amitriptyline (Elavil)^*) Imipramine (tofraneil)^*) Sinequan (Sinequan)^*) Clomipramine (Anafranil)^*) Fluoxetine (Prozac)^*) Sertraline (Zoloft)^*) Nefazodone (Serzone)^*) Venlafaxine (Effexor)^*) Triazolones (Desyrel)^*) Bupropion (Wellbutrin)^*) And other known conventional drugs. See, for example, Physicians' Desk Reference, 329, 1417, 1831 and 3270 (57 th edition, 2003).

Anticonvulsants may also be used in embodiments of the invention. Examples of anticonvulsants include, but are not limited to, carbamazepine, oxcarbazepine, gabapentin (Neurontin)^*) Phenytoin, sodium valproate, clonostane, topiramate, lamotrigine, zonisamide, and tiagabine. See, for example, Physicians' Desk Reference, 2563 (57 th edition, 2003).

Cortisols (e.g., prednisone, dexamethasone, hydrocortisone), orally active group Ib antiarrhythmics (e.g., mexiletine), calcium channel blockers (e.g., nifedipine), beta-blockers (e.g., propranolol), alpha blockers (e.g., phenoxybenzamine), and alpha 2-adrenergic agonists (e.g., clonidine) may also be used in combination with the selective cytokine inhibitory drugs. See, for example, Physicians' Desk Reference, 1979, 2006 and 2190 (57 th edition, 2003).

The second active agent used in the present application includes, but is not limited to, acetylsalicylic acid (Aspirin)^*) Celecoxib (Celebrex)^*)、Enbrel^*Ketamine, gabapentin (Neurontin)^*) Dilantin (Dilantin)^*) Carbamazepine (Tegretol)^*) Oxcarbazepine (Trileptal)^*) Valproic acid (Depakene)^*) Morphine sulfate, hydromorphone, prednisone, griseofulvin, penthonium, alendronate, diphenhydramide, guanethidine, ketoprofen (Acula)^*) Calcitonin, dimethyl sulfoxide (DMSO), clonidine (Cataprress)^*) Benzalkonium bromide, ketanserin, reserpine, droperidol, atropine, phentolamine, bupivacaine, lidocaine, acetaminophen, nortriptyline (Pamelor)^*) Amitriptyline (Elavil)^*) Imipramine (Tofranil) and Sinequan (Sinequan)^*) Clomipramine (Anafranil)^*) Fluoxetine (Prozac)^*) Sertraline (Zoloft)^*) Nefazodone (Serzone)^*) Venlafaxine (Effexor)^*) Triazolones (Desyrel)^*) Bupropion (wellbutrin)^*) Mexiletine, nifedipine, propranolol, tramadol, lamotrigine, ziconotide (zipontile), ketamine, dextromethorphan, benzo (o) diaza * types, baclofen, tizanidine and phenoxybenzamine.

4.3 methods of treatment and control

The present invention includes methods for the prevention, treatment, amelioration, and management of various types of pain. The term "preventing pain" as used herein includes, but is not limited to, inhibiting and reducing the severity of one or more symptoms associated with pain, unless otherwise indicated. Symptoms associated with pain include, but are not limited to, autonomic dysfunction, loss of motor power, weakness, tremor, muscle spasm, dytonia, malnutrition, atrophy, edema, stiffness, joint weakness, increased sweating, sensitivity to temperature and light contact (hyperalgesia), changes in skin color, high or low temperature, increased nail growth, early bone changes, hyperhidrosis with plaques or cyanosis, hair loss, nail embrittlement and stiffening, hand dryness, diffuse osteoporosis, irreversible tissue damage, thin and bright skin, joint contracture, and significant bone demineralization.

As used herein, unless otherwise indicated, the term "treating pain" means administering a compound of the invention or other second active agent after the onset of the symptoms of pain, and "preventing" means administering the compound or other second active agent to a patient, particularly one who may be experiencing pain, before the onset of the symptoms of pain. Patients at risk of pain include, but are not limited to, trauma, neurological disorders, myocardial injury, musculoskeletal disorders, and malignancies. Patients with a family history of pain symptoms are also a priority for preventive regimens.

As used herein, unless otherwise indicated, the term "alleviating pain" includes modulating the threshold, development and tolerance of pain, or altering the way a patient responds to pain. Without being limited by theory, it is believed that selective cytokine inhibitory drugs may be useful as anti-hyperalgesic and/or neuromodulatory agents. In one embodiment, "alleviating pain" includes removing an excessive response to pain from a patient (e.g., a patient's pain is more painful than normal pain from a particular stimulus) and returning a person or animal to a general pain threshold. In another embodiment, "alleviating pain" includes reducing pain in a patient from a stimulus of a particular intensity. In another embodiment, "alleviating pain" comprises increasing the pain threshold in the patient relative to the threshold prior to administration of the effective amount of the selective cytokine inhibitory drug.

As used herein, unless otherwise indicated, the term "managing pain" includes preventing the recurrence of pain in a patient suffering from pain, and/or extending the time period over which pain is relieved in a patient suffering from pain.

The present invention includes methods for the treatment, prevention, alleviation and management of pain syndromes in patients with various stages and specific types of disease, including but not limited to those referred to as nociceptive pain, neuropathic pain, mixed nociceptive and neuropathic pain, visceral pain, migraine and post-operative pain. Specific types of pain include, but are not limited to, chemical or thermal burns, skin cuts, skin abrasions, osteoarthritis, rheumatoid arthritis, or tenosynovitis, myofascitis-associated pain; CRPS type I, CRPS type II, Reflex Sympathetic Dystrophy (RSD), reflex neurovascular dystrophy, reflex dystrophy, sympathetically sustained pain symptoms, causalgia, grandke's bone atrophy, painful dystrophy, shoulder and hand syndrome, post traumatic dystrophy, trigeminal neuralgia, post herpetic neuralgia, cancer-related pain, phantom limb pain, fibromyalgia, chronic fatigue symptoms, spinal cord injury pain, central post-stroke pain, radiculopathy, diabetic neuralgia, syphilitic neuralgia and other neuralgia induced by vincristine, velcade and thalidomide drugs.

The invention also includes methods of treating, alleviating and controlling pain in patients who have previously been treated for pain but who have not responded adequately or not to standard therapy, as well as those patients who have not previously been treated for pain. Because patients with pain have different clinical manifestations and different clinical outcomes, the treatment, remission and control of a patient may vary depending on the prognosis of his/her condition. An experienced clinician can readily determine the particular second medicament, the type of procedure, and the type of therapy that is effective for treating an individual patient without undue experimentation.

The methods encompassed by the present invention comprise administering one or more selective cytokine inhibitory drugs, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer clathrate, or prodrug thereof, to a patient (e.g., a human) suffering from, or at risk of, pain.

In one embodiment of the invention, the selective cytokine inhibitory drug is administered in an oral dose of about 1mg to about 10,000mg once or more times a day. More particularly, the daily dose is administered in divided doses twice. Typically, the daily dosage range should be from about 1mg to about 5,000mg per day, more specifically, from about 10mg to about 2,500mg per day, from about 100mg to about 800mg per day, from about 100mg to about 1,200mg per day, or from about 25mg to about 2,500mg per day. In the control of patients, treatment should be initiated at small doses, perhaps from about 1mg to about 2,500mg, and then, if necessary, increased to about 200mg to about 5,000mg per day, administered in single or multiple doses depending on the patient's systemic response. In particular embodiments, about 400, 800, 1,200, 2,500, 5,000 or 10,000mg of 3- (3, 4-dimethoxy-phenyl) -3- (1-oxo-1, 3-dihydro-isoindol-2-yl) propionamide may be administered orally (in two divided doses) daily. In a particular embodiment, a dose of about 400mg to about 1,200mg of 3- (3, 4-dimethoxy-phenyl) -3- (1-oxo-1, 3-dihydro-isoindol-2-yl) propionamide may be administered orally daily, every other day, or other distribution.

In one embodiment, the invention relates to a method of treating, preventing, managing and/or alleviating pain, comprising administering to a patient in need thereof an effective amount of a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer clathrate, or prodrug thereof. In certain embodiments, nociceptive pain is pain resulting from physical trauma (e.g., skin cuts or bruises; or chemical or thermal burns), osteoarthritis, rheumatoid arthritis, or tenosynovitis. In another embodiment, the nociceptive pain is myofascial pain.

In another embodiment, the invention is directed to a method of treating, preventing, managing and/or alleviating neuropathic pain, comprising administering to a patient in need thereof an effective amount of a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer clathrate, or prodrug thereof. In certain embodiments, neuropathic pain is associated with stroke, diabetic neuropathy, syphilitic neuropathy, postherpetic neuralgia, trigeminal neuralgia, or painful neuropathy caused by therapeutic agents such as vincristine, Velcade, or thalidomide.

In another embodiment, the invention is directed to a method of treating, preventing, managing and/or alleviating multiple-modality pain (i.e., pain that is both nociceptive and neuropathic), comprising administering to a patient in need thereof an effective amount of a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof.

Another embodiment comprises administering to a patient one or more selective cytokine inhibitory drugs, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof, for treating, preventing, managing, and/or alleviating visceral pain, headache pain (e.g., migraine), CRPS type I, CRPS type II, RSD, reflex neurovascular dystrophy, reflex dystrophy, sympathetic persistent pain, causalgia, grandke's atrophy of bone, painful neurotrophies, shoulder and hand syndrome, post-traumatic dystrophy, autonomic dysfunction, cancer-related pain, phantom limb pain, fibromyalgia, chronic fatigue syndrome, post-operative pain, spinal cord injury pain, post-stroke central pain, radiculopathy.

In another embodiment, the invention relates to a method of treating, preventing, managing and/or ameliorating pain associated with a cytokine, comprising administering to a patient in need thereof an effective amount of a selective cytokine inhibitory drag, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, inclusion or prodrug thereof. In one embodiment, inhibiting the activity of a cytokine or its production results in the treatment, prevention, control and/or alleviation of pain. In another embodiment, the cytokine is TNF- α factor. In another embodiment, the cytokine-related pain is neuropathic pain.

In another embodiment, the invention is directed to a method of treating, preventing, managing and/or ameliorating pain associated with inflammation, comprising administering to a patient in need thereof an effective amount of a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof.

In another embodiment, the invention relates to a method of treating, preventing, managing and/or ameliorating pain associated with Mitogenic Activated Protein Kinase (MAPK), comprising administering to a patient in need thereof an effective amount of a selective cytokine inhibitory drug. In another specific embodiment, the MAPK is JNK (e.g., JNK1, JNK2, or JNK 3). In another embodiment, the MAPK is an extracellular signal-regulated kinase (ERK) (e.g., ERK1 or ERK 2).

In another embodiment, the invention relates to a method of treating, preventing, managing and/or alleviating pain associated with surgery, in a planned surgery (e.g., planned trauma) embodiment, comprising administering to a patient in need thereof an effective amount of a selective cytokine inhibitory drug. In this embodiment, the selective cytokine inhibitory drug may be administered before, during and/or after the planned surgery. In a particular embodiment, the patient is administered from about 5 to about 25mg of the selective cytokine inhibitory drug per day 1-21 days prior to the planned surgery and/or from about 5 to about 25mg of the selective cytokine inhibitory drug per day 1-21 days after the planned surgery. In another embodiment, the patient is administered about 10mg of the selective cytokine inhibitory drug daily from 1 to 21 days prior to the planned surgery and/or about 10mg of the selective cytokine inhibitory drug daily from 1 to 21 days after the planned surgery.

4.3.1 Combination therapy with a second active agent

Particular methods of the invention comprise administering an effective amount of a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof, in combination with a second active agent or ingredient. Examples of selective cytokine inhibitory drugs are disclosed herein (see, e.g., section 4.1), as are examples of second active drugs (see, e.g., section 4.2).

The selective cytokine inhibitory drug and the second active agent may be administered to the patient simultaneously or sequentially by the same or different routes of administration. Whether a particular route of administration is appropriate for a particular active agent depends on the active agent itself (e.g., whether it can be administered orally without degradation prior to plasma entry) and the disease being treated. The preferred route of administration of the selective cytokine inhibitory drug is oral. Preferred routes of administration for the second active agents or ingredients of the invention are those commonly used in the art, see, e.g., Physicians' Desk Reference 594-.

In one embodiment, the second active agent can be administered orally, intravenously, intramuscularly, subcutaneously, intraperitoneally, or transdermally, once or twice daily, in an amount of from about 1 to about 3,500mg, from about 5 to about 2,500mg, from about 10 to about 500mg, or from about 25 to about 250 mg.

The particular amount of the second active agent administered will depend upon the particular agent used, the type of pain being treated and controlled, the severity and stage of the pain, as well as the amount of the selective cytokine inhibitory drug and any other active agents reasonably co-administered to the patient. In a particular embodiment, the second active agent is acetylsalicylic acid (Aspirin)^*) Celecoxib (Celebrex)^*)、Enbrel^*，Remicade^*，Humira^*，Kineret^*Ketamine, gabapentin (Neurontin)^*) Dilantin (Dilantin)^*) Carbamazepine (Tegretol)^*) Oxcarbazepine (Trileptal)^*) Valproic acid (Depakene)^*) Morphine sulfate, hydromorphone, prednisone, griseofulvin, penthonium, alendronate, diphenhydramide, guanethidine, ketoprofen (Acula)^*) Calcitonin, dimethyl sulfoxide (DMSO), clonidine (Cataprress)^*) Benzalkonium bromide, ketanserin, reserpine, droperidol, atropine, phentolamine, bupivacaine, lidocaine, acetaminophen, nortriptyline (Pamelor)^*) Amitriptyline (Elavil)^*) Imipramine (tofraneil)^*) Multiple filtering (Sinequant)^*) Clomipramine (Anafranil)^*) Fluoxetine (Prozac)^*) Sertraline (Zoloft)^*) Nefazodone (Serzone)^*) Venlafaxine (Effexor)^*) Triazolones (Desyrel)^*) Bupropion (wellbutrin)^*) Mexiletine, nifedipine, propranolol, tramadol, lamotrigineOxazines, ziconotides, ketamine, dextromethorphan, benzodiazepines *, baclofen, tizanidine and phenoxybenzamine or combinations thereof, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer clathrate, prodrug or pharmacologically active metabolite thereof.

Hydromorphone (dilaudi)^*) Preferably, the first dose is about 2mg orally, or about 1mg intravenously, for moderate or severe pain. See, for example, Physicians' Desk Reference, 2991 (57 th edition, 2003). Morphine sulfate (Duramorph)^*，Astramorph^*，MS Contin^*) Preferably, the first dose is about 2mg IV/SC/IM orally, depending on whether the patient has been administered a narcotic analgesic. See, for example, Physicians' Desk Reference2991 (57 th edition, 2003). There is no essential limitation of the amount administered, provided that adverse side-effects, in particular respiratory depression, are observed. Different IV doses can be used, usually titrated until the desired effect is produced. For patients who do not use long-term drugs, as little as 2mgIV/SC is sufficient. Patients who use narcotic analgesics for long periods of time are particularly required to have large doses. Morphine sulfate is also available as an oral immediate release or sustained release formulation. The long-acting oral dosage form may be administered twice a day. Immediate release formulations may need to be administered during the pain outbreak, the dose administered also being dependent on the original dose. Oxycodone (OxyContin)^*) Is a long-acting form of opiates and is used in early and late pain syndromes. Oxycodone (OxyContin)^*) Preferably, a dose of about 10 to 160mg is administered twice a day. See, for example, Physicians' Desk Reference, 2991 (57 th edition, 2003). Pethidine (Demerol)^*) Preferably, the dosage is about 50 to 150mg PO/IV/IM/SC administered every 3-4 hours. Pethidine (Demerol)^*) Typical pediatric doses are 1-1.8mg/kg PO/IV/IM/SC administered every 3-4 hours. See, for example, Physicians' desk reference, 2991 (57 th edition, 2003). Fentanyl patch (Duragesico)^*) Are available as dosage forms for epidermal application. Most patients are administered 72 hours dose intervals. However, some patients require 48 hour intervals. A typical adult dose is 25mcg/h (10 cm)²)，50mcg/h(20cm²)，75mcg/h(75cm²) Or 100mcg/h (100 cm)²) See, e.g., Physicians' Desk reference, 1775 (57 th edition, 2003).

Non-narcotic analgesics and anti-inflammatory agents such as non-steroidal anti-inflammatory agents and cyclooxygenase-2 inhibitors are useful in treating patients suffering from mild or moderate pain. Ibuprofen (Motrin)^*，Advil^*) The dose is 400-800mg three times a day orally. See, e.g., Physicians' desk reference, 1900-; physicians' desk reference for NPRescription Drugs and diameter supplements, 511, 667 and 773 (23 rd edition, 2002)^*、Naprelan^*、Naprosyn^*) Preferably for the relief of mild to moderate pain, the dosage is about 275mg three times a day, or about 550mg twice a day. See, for example, Physicians' Desk Reference, 1417, 2193, and 2891 (57 th edition, 2003).

Antidepressants such as nortriptyline (Pamelor)^*) May also be used in embodiments of the invention to treat patients suffering from chronic and/or neuropathic pain. The oral dosage for an adult is generally about 25-100mg, preferably not more than 200mg per day. The typical pediatric initial dose is about 0.1mg/kgPO, with the dose increasing to about 0.5-2mg per day as tolerance increases. Amitriptyline (Etrafon)^*) Preferred for use in neuropathic pain, adult doses of about 25-100mg PO. are described, for example, in Physicians' Desk Reference, 1417 and 2193 (57 th edition, 2003).

Anticonvulsants such as gabapentin (Neurontin)^*) Can be used for treating patients suffering from chronic and neuropathic pain. The preferred oral dosage of gabapentin is 100-1,200mg, three times a day. See, for example, Physicians' Desk Reference, 2563 (57 th edition, 2003). Carbamazepine (Tegretol)^*) Can be used for treating pain associated with trigeminal neuralgia. Typically, the first dose is about 100mg orally for an adult twice daily. As tolerability increased, the dose increased to about 2400mg per day. See, for example, Physicians' Desk Reference, 2563 (57 th edition, 2003).

In one embodiment, a selective cytokine inhibitory drug and a second active agent are administered sequentially to a patient (preferably a mammal, more preferably a human) together over a period of time, the selective cytokine inhibitory drug being able to work with the other agent more beneficially than if administered otherwise. For example, another active agent may be administered at a different time point, either simultaneously or in any order; however, if not administered simultaneously, they should be administered close enough in time to achieve the desired therapeutic or prophylactic effect. In one embodiment, the selective cytokine inhibitory drug and the second active drug exert their effects during a time overlap. Each of the second active agents may be administered separately in any suitable manner and route. In another embodiment, the selective cytokine inhibitory drug is administered prior to, concurrently with, or subsequent to the administration of the second active drug. Prevention or relief of pain may also be performed surgically.

In various embodiments, the selective cytokine inhibitory drug and the second active agent are administered sequentially for a time interval of less than about one hour, about one to about two hours, about two to about three hours, about three to about four hours, about four to about five hours, about five to about six hours, about six to about seven hours, about seven to about eight hours, about eight to about nine hours, about nine to about ten hours, about ten to about eleven hours, about eleven to about twelve hours, no more than twenty-four hours, or no more than forty-eight hours. In other embodiments, the selective cytokine inhibitory drug and the second active agent are administered simultaneously.

In other embodiments, the selective cytokine inhibitory drug and the second active drug are administered sequentially at a time interval of about 2 to 4 days, about 4 to 6 days, about one week, about 1 to 2 weeks, or more than 2 weeks.

In certain embodiments, the selective cytokine inhibitory drug and optionally a second active agent are administered to the patient in the circulation. Cycling therapy involves the administration of a first agent for a period of time, followed by the administration of a second and/or third agent for another period of time, and then repeated. Cycling therapy may reduce resistance to one or more therapies, avoid or reduce side effects of a therapy, and/or improve treatment efficacy.

In certain embodiments, the selective cytokine inhibitory drug and optional second active agent are administered less than three weeks for a cycle, about once every two weeks, about once every ten days, or about once a week. One cycle includes infusion of the selective cytokine inhibitory drug and the optional second active drug for about 90 minutes per cycle, about one hour per cycle, and about 45 minutes per cycle. Each cycle includes at least one week of intermittency, at least two weeks of intermittency, and at least three weeks of intermittency. The number of application cycles is about 1 to 12 cycles, with about 2 to 10 cycles and 2 to 8 cycles being more typical.

In other embodiments, the selective cytokine inhibitory drug is administered in a regular dosage regimen with frequent administration of continuous infusions without long rest periods. Such regular administration includes doses with no intermittent constant intervals. Typical selective cytokine inhibitory drugs are used at lower doses. Such dosage planning involves daily administration at relatively low doses over an extended period of time. In a preferred embodiment, lower doses are used to minimize toxic side effects and eliminate the rest period. In one embodiment, the selective cytokine inhibitory drug is delivered or continuously infused in a chronic low dose for a period of time ranging from about 24 hours to about 2 days, to about one week, to about two weeks, to about three weeks to about one month to about two months, to about three months, to about four months, to about five months, to about six months. The skilled person is able to optimize this dosage regimen schedule.

In other embodiments, the route of treatment is simultaneous administration to the patient, i.e., a single dose of the second active agent administered separately over a time interval such that the selective cytokine inhibitory drug is able to act in conjunction with the second active agent. For example, one ingredient administered once per week is administered in combination with the other ingredient administered once every two weeks or once every three weeks. That is, the therapy dosage plans, if not administered simultaneously or on the same days, are administered simultaneously.

The second active agent may exert an additional effect, more preferably a synergistic effect with the selective cytokine inhibitory drug. In one embodiment, the selective cytokine inhibitory drug is administered concurrently with one or more second active agents in the same pharmaceutical composition. In another embodiment, the selective cytokine inhibitory drug is administered concurrently with one or more second active agents in different pharmaceutical compositions. In still other embodiments, the selective cytokine inhibitory drug is administered before or after the one or more second active agents. The mode of administration contemplated by the present invention is the same or different method of administration of the selective cytokine inhibitory drug and the second active agent, e.g., oral or parenteral administration. In certain embodiments, when the selective cytokine inhibitory drug and a second active agent having adverse side effects, including (but not limited to) toxicity, are administered concurrently, it may be advantageous for the second active agent to be administered at a dose below the threshold at which the side effects occur.

4.3.2 Used with interventional techniques for pain management

In another embodiment, the invention encompasses methods of treating, preventing, modifying and managing pain, which comprise administering a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof, in conjunction with (e.g., before, during, or after) an interventional technique for managing pain. Examples of interventional techniques for managing pain include, but are not limited to, the use of sympathetic blockers, intravenous local blockers, spinal stimulus placement, or intrathecal infusion device placement to deliver pain medication. Preferred interventional techniques for managing pain provide selective nerve blocking agents that interfere with local sympathetic nervous system activity affected by pain.

The use of selective cytokine inhibitory drugs in combination with pain management interventional techniques provides a unique treatment regimen that is not intentionally effective in certain patients. Without being bound by theory, it is believed that selective cytokine inhibitory drugs may provide additive or synergistic effects when used in combination with interventional techniques for pain management. One example of an interventional technique for managing pain is intravenous systemic blockers using BIER blockers and various blockers such as (without limitation) local anesthetics such as bupivacaine, lidocaine, guanethidine, ketamine, bromobenzylamine, steroids, ketorolac, and reserpine. Perez r.s., et al, J Pain Symptom Manage2001, 6 months; 21(6): 511-26. for CRPS cases involving the upper extremities, stellate (cervicothoracic) ganglion blockers may be used. The invention also includes the use of body blockers, which involves constant epidermal injection of varying amounts of brachial plexus blockers. Physical blockages of the axillary, supraclavicular or intraclavicular pathways may also be useful.

4.3.3 Used together with physiotherapy or psychotherapy

In another embodiment, the invention encompasses methods of treating, preventing, modifying and managing pain, which comprise administering a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof, in combination with physical therapy or psychiatric therapy.

As described above, pain symptoms include vasoconstrictive dysfunction and movement disorders. It is important that a stable change in mild load is a progressive active load for patients with painful symptoms. Gradual desensitization to sensitive stimuli may also be advantageous. The gradual increase in normal sensation helps to re-modulate the effects of the treatment of CNS changes. Thus, physical therapy plays an important role in functional recovery. The goal of physical therapy is to gradually increase strength and flexibility.

It is believed that the use of selective cytokine inhibitory drugs in combination with physical therapy provides a unique treatment regimen with unexpected effects for certain patients. Without being limited by theory, it is believed that the use of selective cytokine inhibitory drugs in combination with physical therapy may provide an additive or synergistic effect.

Many papers on pain mention the accompanying behavioral and psychiatric conditions such as depression and anxiety. It is believed that the use of selective cytokine inhibitory drugs in combination with physical therapy provides a unique treatment regimen with unexpected effects in certain patients. Without being limited by theory, it is believed that the use of selective cytokine inhibitory drugs in combination with psychotherapy may provide additional or synergistic effects including (without limitation) biofeedback, relaxation training, cognitive-behavioral therapy, and personal or home psychotherapy.

The selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof, is administered prior to, during, or after physical therapy or psychiatric therapy. In particular methods, a second active agent is also administered to the patient.

4.4 Pharmaceutical compositions and single unit dosage forms

The pharmaceutical compositions are useful in the preparation of individual, single unit dosage forms. Pharmaceutical compositions and dosage forms of the invention include a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof. The pharmaceutical compositions and dosage forms of the invention also include one or more excipients.

The pharmaceutical compositions and dosage forms of the invention may also comprise one or more additional active ingredients. Accordingly, the pharmaceutical compositions and dosage forms of the invention include the above-mentioned active ingredients (e.g., selective cytokine inhibitory drugs, or pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, clathrates, prodrugs, and a second active agent thereof). Examples of optional additional active ingredients are disclosed herein (see, e.g., section 4.2).

The single unit dosage forms of the invention are suitable for oral, mucosal (e.g., nasal, sublingual, vaginal, buccal, rectal), parenteral (e.g., subcutaneous, intravenous, bolus injection, intramuscular, or arterial), transdermal or transdermal administration to a patient. Examples of dosage forms include, but are not limited to, tablets; a caplet; capsules, such as soft elastic gelatin capsules; a flat bag; a lozenge; a lozenge; a dispersant; suppositories; powder; aerosols (e.g., nasal mucosal sprays or inhalers); a gel; liquid dosage forms suitable for oral or intramuscular administration to a patient, including suspensions (e.g., aqueous or non-aqueous suspensions, oil-in-water emulsions, or water-in-oil emulsions), solutions, elixirs; liquid dosage forms suitable for parenteral administration to a patient; and sterile solids (e.g., crystalline or amorphous solids) that can be formulated into liquid dosage forms suitable for parenteral administration to a patient.

The types of compositions, shapes, and dosage forms of the invention vary with the application. For example, a dosage form for the acute treatment of a disease may include a relatively larger amount of one or more active ingredients than a dosage form for the chronic treatment of the same disease. Similarly, a parenterally administrable dosage form for treating the same disease may comprise relatively less of one or more active ingredients than an oral dosage form. The particular dosage forms of these and other routes of administration in the present invention are different from one another and will be apparent to those skilled in the art. See, e.g., Remington's Pharmaceutical Sciences, 18 th edition, Mack Publishing, Easton PA (1990).

Typical pharmaceutical compositions and dosage forms include one or more excipients. Suitable excipients will be familiar to those skilled in the art, and non-limiting examples of suitable excipients are provided herein. Whether an excipient is suitable for addition to a pharmaceutical composition or dosage form is well known depending upon various factors, including, but not limited to, the route of administration by which the dosage form is administered to a patient. For example, oral dosage forms, such as tablets, may include excipients not suitable for parenteral administration of the dosage form. The suitability of a particular excipient may also depend on the particular active ingredient in the dosage form. For example, degradation of certain active ingredients may be accelerated by certain excipients (e.g., lactose) or by exposure to water. Active ingredients containing primary or secondary amines are more susceptible to such accelerated degradation. Thus, the pharmaceutical compositions and dosage forms of the present invention (if any) contain small amounts of lactose mono-and disaccharides. The term "lactose-free" as used herein means that the amount of lactose is insufficient to greatly accelerate the degradation of the active ingredient.

The lactose-free compositions of the present invention comprise excipients that are common and well documented in the art, e.g., pharmacopeia (usp)25-NF20(2002). in general, lactose-free compositions consist of an active ingredient, a binder/filler, and a lubricant, in pharmaceutically compatible and tolerable amounts. The preferred lactose-free dosage form consists of the active ingredient, microcrystalline cellulose, pregelatinized starch, and magnesium stearate.

The invention also includes anhydrous pharmaceutical compositions and dosage forms containing the active ingredient, as moisture can predispose certain compounds to degradation. For example, filling water (e.g., 5%) is a well-accepted means in the art to simulate long-term storage to measure properties such as shelf life or long-term formulation stability. See, e.g., Jens t. carstensen, Drug Stability: principles & Practice, 2 nd edition, Marcel Dekker, NY, NY, 1995, pages 379-80. In fact, it is water and heat that accelerate the degradation of certain compounds. Thus, the effect of water in the formulation is significant because steam and/or humidity are often encountered during manufacture, handling, packaging, storage, shipping, and use.

The anhydrous pharmaceutical compositions and dosage forms of the present invention are prepared by using anhydrous or low moisture ingredients and an anhydrous or low moisture environment. Pharmaceutical compositions and dosage forms comprising lactose and at least one active ingredient comprising a primary or secondary amine are preferably anhydrous if expected to be exposed to substantial amounts of steam and moisture during manufacture, packaging, and/or storage.

Anhydrous pharmaceutical compositions are manufactured and stored in order to maintain their anhydrous nature. Therefore, packaging anhydrous pharmaceutical compositions is best accomplished using materials known to be water resistant. Examples of suitable packaging include, but are not limited to, melt-sealed foil, plastic, single-dose containers (e.g., vials), mushroom blister packs, and thin elongated packages of material.

The invention also includes pharmaceutical compositions and dosage forms comprised of one or more compounds that attenuate the rate of degradation of an active ingredient. Such compounds (referred to herein as "stabilizers") include, but are not limited to, antioxidants such as ascorbic acid, PH buffers, or salt buffers.

The amount and specific type of active ingredient in a dosage form, as well as the amount and type of excipient, will vary depending upon factors such as, but not limited to, the route of administration to the patient. However, a typical dosage form of the invention will consist of from about 1 to about 10,000mg of the selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof. Exemplary dosage forms of the invention comprise about 1,2, 5, 10, 25, 50, 100, 200, 400, 800, 1200, 2500, 5000, 10000mg of a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof. In a particular embodiment, a preferred dosage form consists of about 400, 800 or 1200mg of 3- (3, 4-dimethoxy-phenyl) -3- (1-oxo-1, 3-dihydroxy-isoindol-2-yl) -propionamide. Typical dosage forms are comprised of about from 1 to about 3500mg, from about 5 to about 2500mg, from about 10 to about 500mg, or from about 25 to about 250mg of the second active agent. The specific amount of the second active agent will, of course, depend upon the specific agent employed, the type of pain being treated or managed, as well as the amount of selective cytokine inhibitory drug and optional additional active ingredients being concurrently administered to the patient.

4.4.1 Oral dosage form

Pharmaceutical compositions suitable for oral administration in the present invention may be in discrete dosage forms such as, but not limited to, tablets (e.g., chewable tablets), caplets; capsules, and liquids (e.g., flavored syrups). These dosage forms contain a predetermined amount of active agent and can be prepared by methods known in the art. See Remington's Pharmaceutical Sciences, 8 th edition, Mack Publishing, Easton PA (1990).

Typical oral dosage forms are prepared in accordance with the present invention by uniformly mixing the active ingredient with at least one excipient according to conventional pharmaceutical techniques. Excipients may vary depending on the desired method of administration. For example, suitable excipients for oral liquids or aerosols include, but are not limited to, water, glycols, oils, alcohols, flavoring agents, preservatives, and coloring agents. Excipients (e.g., powders, tablets, capsules, caplets) suitable for use in oral solid dosage forms include, but are not limited to, starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders and disintegrating agents.

Tablets and capsules with the addition of solid excipients represent the most advantageous oral dosage form because of their ease of administration. Tablets may be coated with aqueous or non-aqueous techniques if desired. These dosage forms may be prepared by any pharmaceutical method. In general, pharmaceutical compositions and dosage forms are prepared by uniformly mixing the active ingredient with a liquid carrier, a finely divided solid carrier, or both, and then, if necessary, shaping the product into the desired shape.

For example, tablets may be made by compression or injection molding. Tableting is prepared by mixing the active ingredient in a free-flowing form, such as a powder or granules, with excipients and compressing in a suitable machine. The dies are prepared by mixing the moist powdered compound with added diluent and casting in a suitable machine.

Examples of excipients that can be used in the oral dosage form of the present invention include, but are not limited to, binders, fillers, disintegrants, and lubricants. Binders suitable for use in pharmaceutical compositions and dosage forms include, but are not limited to, corn starch, potato starch or other starches, gelatin, natural and synthetic gums such as acacia, sodium alginate, alginic acid, other alginates, powdered tragacanth, guar gum, cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose, polyvinyl pyrrolidone, methyl cellulose, ungelatinized starch, hydroxypropyl methyl cellulose, (e.g., nos.2208, 2906, 2910), microcrystalline cellulose, and mixtures thereof.

Suitable forms of microcrystalline cellulose include, but are not limited to, commercially available AVICEL-PH-101, AVICEL-PH-103 AVICEL RC-581, AVICEL-PH-105 (available from FMC corporation, Viscose Division, Avicel Sales, MarcusHook, Pa.) and mixtures thereof. A particular binder sold as avicel rc-581 is a mixture of microcrystalline cellulose and sodium carboxymethylcellulose. Suitable anhydrous or low moisture excipients or additives include AVICEL-PH-103^TMAnd starch 1500 LM.

Examples of fillers suitable for use in pharmaceutical compositions and dosage forms include, but are not limited to, talc, calcium carbonate, (e.g., granules or powder) microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, ungelatinized starch, and mixtures thereof. The binder or additive in the pharmaceutical composition of the invention generally comprises about 50% to about 99% of the pharmaceutical composition or dosage form.

The disintegrant used in the composition of the invention disintegrates the tablet when it is in water. Tablets containing too much disintegrant may disintegrate in storage, while tablets containing too little may not disintegrate or may not disintegrate at a desired rate in the intended environment. Thus, a suitable amount of disintegrant, which should be used to synthesize the solid dosage form of the invention, facilitates a modified release of the active ingredient. The amount of disintegrating dosage depends on the type of formulation and is readily recognized by one of ordinary skill in the art. Typical pharmaceutical compositions contain about 0.5 to about 15% by weight of disintegrant, preferably about 1 to about 5% by weight of disintegrant.

Disintegrants for use in pharmaceutical compositions and dosage forms in the invention include, but are not limited to, agar-agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polacrilin potassium, sodium starch glycolate, potato and tapioca starch, other starches, ungelatinized starches, other starch clays, other algins, other celluloses, gums, and mixtures of these.

Lubricants useful in pharmaceutical compositions and dosage forms of the present invention include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oils (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, ethyl oleate, ethyl laurate, agar, and mixtures thereof. The lubricating oil to be added includes, for example, silicate silica gel (AEROSIL 200, manufactured by W.R. Grace Co. of Baltimore, MD), a synthetic silica gel solidification aerosol (sold by Degussa Co. of Plano, TX), CAB-O-SIL (a fired silica product sold by Cabot Co. of Boston, MA), and a mixture thereof. Lubricants, if used, are typically used in amounts of less than about 1% by weight of the pharmaceutical composition and dosage form.

Preferred solid oral formulations of the invention include selective cytokine inhibitory drugs, anhydrous lactose, microcrystalline cellulose, polyvinylpyrrolidone, stearic acid, anhydrous colloidal silica gel, gelatin.

4.4.2 Sustained release dosage form

The active agents of the present invention may be administered by means of a controlled release or delivery device, as is well known to those skilled in the art. Examples include, but are not limited to, those described in U.S. Pat. Nos. 3,845,770; 3,916,899; 3,536,809, respectively; 3,598,123, respectively; and 4,008,719; 5,674,533, respectively; 5,059,595, respectively; 5,591,767, respectively; 5,120,548, respectively; 5,073,543, respectively; 5,639,476, respectively; 5,354,556, respectively; and 5,733,566, each of which is incorporated by reference. These dosage forms may be used for sustained or controlled release of one or more active ingredients using, for example, hydroxypropylmethyl cellulose, other polymeric matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, microspheres, and combinations thereof to provide the desired release profile for the various moieties. Suitable controlled release formulations are known to those skilled in the art and include the active ingredients readily selected for use in the invention as described above. The invention thus encompasses single unit dosage forms suitable for oral administration, such as, but not limited to, tablets, capsules, gelcaps, and caplets, which are adapted for controlled release.

The common goal of all controlled release drug products is to improve the therapeutic effect of their non-controlled release counterparts. Ideally, the use of an optimally designed controlled release formulation in drug therapy would appear to minimize the amount of drug used to treat or control the condition in the shortest amount of time. Advantages of controlled release formulations include prolonged drug activity, reduced dosage frequency, and increased patient compliance. In addition, controlled release formulations can also be used to alter the duration of action or other characteristics, such as blood levels, which can also affect the incidence of adverse (e.g., adverse) effects.

Most designed controlled release formulations begin to release a portion of the drug (active ingredient) quickly to produce the desired therapeutic effect and then gradually release additional amounts of the drug over a prolonged period of time to maintain the therapeutic or prophylactic effect. In order to maintain a constant blood concentration in the body, the drug must be released at a rate that replaces the amount of drug metabolized and excreted in the body. The controlled release of the active ingredient may be stimulated by various conditions, such as, but not limited to, pH, temperature, enzymes, water, or other physiological environments or substances.

4.4.3 Parenteral dosage form

Parenteral dosage forms are administered to patients by various routes including, but not limited to, subcutaneous, intravenous (including bolus injection), intramuscular, and intraarterial. Because of the natural barrier to contamination that these administrations are specific to across patients, the injectable dosage forms are preferably sterile or capable of being sterilized prior to administration to a patient. Examples of parenteral dosage forms include, but are not limited to, injectable solutions ready for use, dry powders to be dissolved or suspended in a vehicle acceptable for injection, injectable suspensions ready for use, and emulsions.

Suitable media for use in the parenteral dosage forms of the invention are well known to those skilled in the art. Examples include (but are not limited to): USP water for injection, aqueous media such as (but not limited to) sodium chloride for injection, Ringer's injection, dextrose for injection, dextrose and sodium chloride for injection, and Ringer's lactate for injection; water-miscible media such as, but not limited to, ethanol, polyethylene glycol and polypropylene glycol; and non-aqueous media such as, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.

The compounds mentioned herein which increase the solubility of one or more active ingredients can also be added to the injectable dosage forms of the invention. For example, cyclodextrins and derivatives thereof can be used to increase the solubility of selective cytostatic drugs and derivatives thereof. See, for example, U.S. Pat. No. 5,134,127, which is incorporated herein by reference.

4.4.4 Dosage forms for topical and mucosal use

Dosage forms for topical and mucosal use of the present invention include, but are not limited to, sprays, aerosols, solutions, emulsions, suspensions, or other forms known to those skilled in the art. See, e.g., Remington's Pharmaceutical Sciences, 16 and 18 th edition, mack publishing, Easton PA (1980&1990) and Introduction to Pharmaceutical Dosage Forms, 4 th edition, Lea & Febiger, philiadelphia (1985.) Dosage Forms suitable for treating mucosal tissue in the oral cavity can be prepared as mouthwashes or oral gels.

Excipients (e.g., carriers and diluents) and other materials suitable for topical and mucosal dosage forms of the invention are well known to those skilled in the pharmaceutical arts and depend on the particular tissue upon which the pharmaceutical composition and dosage form is to be administered. Given these facts, the topical excipients include, but are not limited to, non-toxic and pharmaceutically acceptable water, acetone, ethanol, ethylene glycol, propylene glycol, 1, 3-dibutanol, isopropyl myristate, isopropyl palmitate, mineral oil, and solutions, emulsions or gels formed from mixtures thereof. Moisturizers or humectants can be added to the pharmaceutical compositions and dosage forms if desired. Examples of such additional ingredients are common in the art. See, for example, Remington's pharmaceutical sciences, 16 th and 18 th edition, Mack Publishing, Easton PA (1980&1990).

The pH of the pharmaceutical compositions and dosage forms may be adjusted to improve the transport of one or more active ingredients. Similarly, adjusting the polarity, ionic strength or tonicity of the solvent carrier can also improve transport. The addition of compounds such as stearates to pharmaceutical compositions and dosage forms facilitates the modification of the hydrophilicity and lipophilicity of one or more active ingredients to improve transport. In this regard, stearates can act as a lipophilic medium in the formulation, as an emulsifier or surfactant, and as a transport and permeation enhancer. Different salts, hydrates or solvates of the active ingredient may also be used to further modify the properties of the compound of interest.

4.4.4 Reagent kit

Typically, the active ingredients of the present invention are preferably not administered to the patient simultaneously or in the same manner. The invention therefore includes kits for use by medical practitioners that simplify the administration of appropriate amounts of active ingredients to patients.

Exemplary kits of the invention include dosage forms of a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, prodrug, or clathrate. The kits of the invention may also include additional active agents or compositions thereof. Examples of additional active agents include, but are not limited to, antidepressants, anticonvulsants, antihypertensives, anxiolytics, calcium channel blockers, muscle relaxants, non-narcotic analgesics, opioid analgesics, anti-inflammatory agents, cyclooxygenase-2 inhibitors, immunomodulators, immunosuppressants, corticosteroids, hyperbaric oxygen agents, or other therapies discussed herein (see, e.g., section 4.2).

The kit of the invention also comprises a device for administering the active ingredient. Examples of such devices include, but are not limited to, syringes, infusion sets, patches or respirators.

The kits of the invention also include media for administering one or more active ingredients and pharmaceutically acceptable. For example, if the active ingredient is a solid that must be reconstituted for administration by injection, the kit will include a container with a suitable medium in which the active ingredient can be dissolved to form a sterile, particle-free solution for injection. Examples of pharmaceutically acceptable media include (but are not limited to): USP water for injection; aqueous media such as, but not limited to, sodium chloride for injection, Ringer's for injection, dextrose and sodium chloride for injection, and Ringer's lactate for injection; water-miscible media such as, but not limited to, ethanol, polyethylene glycol and polypropylene glycol; and non-aqueous media such as, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.

5 Examples

The following examples illustrate certain aspects of the invention, but do not limit its scope.

5.1 Pharmacological research

Pain is initiated by an inflammatory response and is maintained by inflammatory cytokines such as TNF- α. TNF- α may play a pathological role in nociceptive and neuropathic pain. One of the particular physiological roles played by selective cytokine inhibitory drugs is the reduction of TNF- α synthesis. Specific selective cytokine inhibitory drugs increase the degradation of TNF- α mRNA. Human painful neuropathy showed increased expression in Schwann cells. The increase in soluble TNF- α receptors in plasma of patients with allodynia is comparable to patients with neuropathic pain who do not report allodynia. Cytokines induce ectopic activity of major afferent nociceptors. And is therefore an intrinsic cause of hyperalgesia of mental pain. The possible mechanism is that TNF- α may form active sodium channels in cells. The increased sodium ion flux into the nociceptors causes them to discharge ectopically. Cytokines may play a pathological role if they are active at the site of nerve injury or dysfunction.

Without being limited by theory, the use of selective cytokine inhibitory drugs prior to voiding reduced mechanical pain and thermal hyperalgesia in mice suffering from a model of chronic systolic injury in mental pain. In addition to reducing intraneuronal TNF- α, these compounds can also cause a long-term increase in post-spinal enkephalin, an important anti-pain neurotransmitter. Selective cytokine inhibitory drugs may also inhibit inflammatory hyperalgesia in rats and reduce the writhing pain response in mice. In addition, these compounds also had moderate inhibitory effects on LPS-induced IL1 β and IL 12.

Preferred compounds of the invention are potent inhibitors of PDE 4. PDE4 is one of the important isozymes of phosphodiesterase found in human bone marrow and lymphocyte cell lines. This enzyme plays an important role in regulating cellular activity, degrading the ubiquitous second messenger cAMP and maintaining its intracellular low concentration. Inhibition of PDE4 activity results in elevated CAMP levels, which leads to LPS-induced cytokine modulation, including inhibition of TNF- α production in single cells and lymphocytes.

In a particular embodiment, the in vitro pharmacological properties of 3- (3, 4-dimethoxy-phenyl) -3- (1-oxo-1, 3-dihydro-isoindol-2-yl) -propionamide are studied. The effect of this compound on the production of various cytokines was investigated. This compound was also studied for its in vitro TNF- α inhibitory activity against LPS-stimulated production of human PBMC and whole blood. The IC of this compound for inhibiting TNF-alpha production was measured₅₀The value is obtained. In vitro studies have shown that 3- (3, 4-dimethoxy-phenyl) -3- (1-oxo-1, 3-dihydro-isoindol-2-yl) -propionamide is 5 to 50 times more pharmacologically active than thalidomide. The pharmacological activity of 3- (3, 4-dimethoxy-phenyl) -3- (1-oxo-1, 3-dihydro-isoindol-2-yl) -propionamide may be derived from its inflammatory cytokine inhibitory activity.

5.2 Toxicological study

The effect of 3- (3, 4-dimethoxy-phenyl) -3- (1-oxo-1, 3-dihydro-isoindol-2-yl) -propionamide on the cardiovascular and respiratory function of anesthetized dogs was studied. Two groups of Beagle dogs (2/gender/group) were used. One group was administered three doses of the blank vehicle only and the other group was administered three increasing doses (400, 800, and 1,200 mg/kg/day) of 3- (3, 4-dimethoxy-phenyl) -3- (1-oxo-1, 3-dihydro-isoindol-2-yl) -propionamide. In any case, the dose of 3- (3, 4-dimethoxy-phenyl) -3- (1-oxo-1, 3-dihydro-isoindol-2-yl) -propionamide or vehicle is continuously infused through isolated jugular veins over a period of 30 minutes.

3- (3, 4-dimethoxy-phenyl) -3- (1-oxo-1, 3-dihydro-isoindol-2-yl) -propionamide induced minimal cardiovascular and respiratory function changes at all doses compared to the blank control.

5.3 Study Using animal pain model

The activity of a selective cytokine inhibitory drug in the treatment, prevention, control and/or relief of pain can be measured using any pain model known in the art. Different animal Pain models are described in Hogan, q. regional Anesthesia and Pain Medicine, 27 (4): 385- "401 (2002), which is incorporated herein by reference.

Examples of nociceptive pain models include formalin experiments, hot plate experiments, and tail flick experiments. Illustrative examples of formalin experiments, hot plate experiments, and tail flick experiments are arranged in the fourth panel below.

The most commonly used neuropathic pain models are the Bemiett, Selzer, and Chung models. Siddall, P.J. and Munglani, R., Animal Models of Pain, pp.377-384, Bountra, C., Munglani, R., Schmidt, W.K. edit Pain: current understanding theory and novelapplications to Drug Discovery, Marcel Dekker, inc., New York, 2003. The Bennett and Selzer models are well known and are rapidly implemented. The Chung model is stable to mechanical allodynia in most animals, but is complex but well characterized. These models represent a series of tests and methods to simulate the clinical symptoms of certain injuries and disorders. There are also several animal experiments of pain related diseases, such as diabetic psychosis, novel bone cancer and visceral pain models.

5.3.1 Formalin experiment for measuring persistent pain of mice

Animals were injected with selective cytokine inhibitory drugs or vehicle (blank) after epidermal injection of formalin to the dorsal paw. The number of times the animals retracted the injection paw within 60 minutes was observed. This model can be used to evaluate the effect of analgesic drugs on pain treatment. Abbott, f. et al Pain 60: 91-102(1995).

Animals were placed in shoe box cages during the experiment. The toe above and ankle below were pricked with a needle (28.5G) and formalin (50 μ l; 0.5%) was injected below the epidermis on the dorsal surface of the right hind paw. The timer immediately after injection is marked as phase 1 start. The injection was observed for 10 minutes and the number of times the animals retracted the injection paw was counted. 30 minutes after the first formalin injection, phase 2 began, and the number of 20 minutes after retraction was counted as phase 1.

Before formalin experiment, the selective cytokine inhibitory drug is orally taken for 24 hours at a dose of about 100-1200 mg/day. The experiment was repeated for animals in the order of treatment described above. Immediately after the experiment, the experimental animals were euthanized by carbon dioxide asphyxiation according to the method of IACUC. In this study, any unexpected event that occurred in any animal experiment at any time will be assessed by veterinary intervention. Any animal that failed to recover at standard care was euthanasially sacrificed immediately by a veterinarian using carbon dioxide asphyxiation under IACUC guidelines.

5.3.2 Hot plate experiment for measuring acute pain in mice

Animals injected with selective cytokine inhibitory drugs or vehicle (blank) were placed on a hot plate one at a time. Latency to response to thermal stimuli was measured by observing the time the animals licked their paw. Malmberg, a and aksh, t., Pain, 60: 83-90(1995). The model can be used to evaluate the effect of analgesic drugs on pain treatment. Langerman et al, plzarmacol. 23-27(1995).

Morphine therapy was used to determine the optimal hotplate temperature. Morphine (i.v.) at a dose of 8-10 mg/kg produced a near maximal anti-pain response in acute pain assessments. The device was tempered to observe this type of analgesic response with these doses of morphine (approximately 55 ℃). Prior to the hotplate test, the selective cytokine inhibitory drug is administered orally at a dose of about 100 to about 1,200 mg/day for 24 hours. When the post-treatment period ended, individual animal experiments were initiated. An animal is placed on a hot plate, a stopwatch, or a timer to start timing. Animals are observed until a painful response occurs (e.g., licking of the paw), or until 30 seconds reaches a cut-off time (minimizing tissue damage caused by prolonged contact with the hot plate). Animals were removed from the hotplate and latency to the response was recorded. Animals that did not respond before the cut-off time, the cut-off time was taken as their response time. The experiment was repeated for animal experiments in the order of treatment described above. Immediately after the experiment was completed, the experimental animals were euthanasially sacrificed by carbon dioxide asphyxiation according to the teaching of IACUC. In this study, any unexpected event that occurred in any animal experiment at any time will be assessed by veterinary intervention. Any animal that could not be recovered at standard care was euthanized by immediately carbon dioxide asphyxiation by a veterinarian under IACUC guidelines.

5.3.3 Tail flick experiment measurement of acute pain in mice

Animals injected with selective cytokine inhibitory drugs or vehicle (blank) irradiated the tail with concentrated light. Latency to response to stimuli was measured by observing the time the animals were tailed. This model can be used to evaluate the effect of analgesic drugs on pain treatment. See Langerman et al, plzarmacol. 23-27(1995).

According to the IACUC guidelines, selective cytokine inhibitory drugs are administered orally at a dose of about 100 to 1200 mg/day prior to tail flick experiments. When the post-treatment time is over, individual experiments of the animals are started. Individual animals were mounted on a tail-flicking device and the tail skin was exposed to a concentrated beam of light. The reaction latency is the time from the start of light irradiation to the appearance of the fishtailing reaction.

Animals were observed until they exhibited a painful response (such as tail flicking) or until a 10 second cut-off was reached (to minimize tissue damage over extended exposure to hot surfaces). The experimental animals are removed from the light source, the reaction latency is recorded, and then the experimental animals are killed painlessly by a carbon dioxide asphyxiation method directly according to the IACUC guiding principle. The light intensity was corrected so that the baseline extension reaction time was 2.5 to 4 seconds. If the experimental animal does not respond before the cut-off time, the cut-off time will be taken as its response time. The experiment was repeated for animals following the above treatment sequence.

In this study, any unexpected event that occurred in any animal experiment at any time will be assessed by veterinary intervention. Any animal that could not be recovered at standard care was euthanized by immediately carbon dioxide asphyxiation by a veterinarian under IACUC guidelines.

5.3.4. Topical capsaicin-induced thermal allodynia model

A particularly useful model for thermal allodynia is the topical capsaicin induced thermal allodynia model Butelman, e.r. et al, j.pharmacol. exp.thermp.306: 1106-1114(2003). The model is improved from the warm water tail model by Ko, m.c., et al, j.pharmacol.exp.thermp.289: 378-385(1999). Briefly, in a temperature controlled room (20-22 ℃), monkeys were placed in a specially prepared chair, their tail hairs were shaved off with a specially prepared blade, and baseline was determined at increments of 0.1 seconds with warm water stimulation at 38-42 ℃ with tail withdrawal latency of up to 20 seconds. After baseline determination, the tails of monkeys were degreased with a pad of isopropanol and gently dried. Capsaicin was dissolved in a mixed medium consisting of 70% ethanol and 30% sterile water 15 minutes before use, to a final capsaicin concentration of 0.0013 or 0.004M. 0.3 ml of capsaicin solution was slowly injected into the gauze patch to saturate the patch but avoid spillage. The capsaicin patch was firmly held to the tail with a tape within 30 seconds of the capsaicin injection into the patch. After 15 minutes, the patch was removed and the tail-biting latency experiment was performed as described above under warm water stimulation at 38-42 ℃. Allodynia was determined by a decrease in tail withdrawal latency compared to baseline measurements. To determine the efficacy of a selective cytokine inhibitory drug to reduce allodynia, a single dose of the drug was previously administered orally (e.g., 15 minutes, 30 minutes, 60 minutes, 90 minutes prior to affixing the capsaicin patch). Alternatively, the allodynia reversing properties of the selective cytokine inhibitory drug can be administered orally as a single dose of the drug after affixing the capsaicin patch (e.g., immediately after the patch, after 30 minutes, after 60 minutes, or after 90 minutes).

The capsaicin model can be used to evaluate compounds useful for the treatment of hyperalgesia and allodynia (e.g., vanilloid receptor 1(VR1) antagonists and AMPA antagonists), and in addition, Ultraviolet (UV) skin damage can be evaluated, bradykinin B1 receptor antagonists, cannabis agonists and VR1 antagonists. Clinical use of capsaicin models can be supported by the anti-hyperalgesic effects of some of the clinically used drugs, such as opioids, local anesthetics, ketamine and gabapentin, among others. To date, the potential of visceral models in hyperalgesia is still unknown and needs further validation.

5.4 Clinical study of pain patients

Selective cytokine inhibitory drugs of the invention, such as 3- (3, 4-dimethoxy-phenyl) -3- (1-oxo-1, 3-dihydro-isoindol-2-yl) -propionamide, can be administered to patients with pain syndrome for a prolonged period of 3 to 6 months at a daily dose of 400 mg-. A baseline evaluation examined the effect of drug treatment on pain intensity, the effect of pain in daily life, and consumption of other pain medications.

In a particular embodiment, clinical studies are conducted on patients with very severe CRPS for which traditional physical therapy has no effect and for which the course of the disease is over a year. Early in the disease, patients had significant autonomic dysfunction (quantitative sweat secreting motor axon reflex test (QSART), amount of sweating at rest, and thermography) through routine autonomic nervous system testing and clinical data showed that autonomic dysfunction (changes in moisture, body temperature, skin, nail or hair growth) was accompanied by allodynia and edema if this was not available. The patients received continuous therapy with 3- (3, 4-dimethoxy-phenyl) -3- (1-oxo-1, 3-dihydro-isoindol-2-yl) -propionamide drug at an oral dose of 400-1200mg per day. The therapeutic effect was evaluated by standardized pain ratings. For example, digital pain rating Scale (NumericPain Scale Assessmnet (VAS) is used to rate pain ratings, McGill's index is used to rate quality of life, and in clinical examinations considerable symptoms such as visual relief of edema, sweating, skin pigment degradation, body temperature changes, skin changes, hair and nail growth and fine movement are observed.

The examples described herein are merely illustrative of the scope of the invention. A more complete understanding of the present invention may be derived from the following claims.

Claims (26)

1. A method of treating, preventing, modifying or managing pain, which comprises administering to a patient in need of such treatment, prevention, modification or management a therapeutically or prophylactically effective amount of a selective cytokine inhibitory drag, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

2. The method of claim 1, further comprising administering to the patient a therapeutically or prophylactically effective amount of at least one second active agent.

3. The method of claim 2, wherein the second active agent is capable of relieving or reducing pain.

4. The method of claim 2, wherein the second active agent is an antidepressant, antihypertensive, anxiolytic, calcium channel blocker, alpha-adrenoreceptor agonist, alpha-adrenoreceptor antagonist, ketamine, anesthetic, muscle relaxant, non-narcotic analgesic, opioid analgesic, anti-inflammatory agent, immunomodulatory agent, immunosuppressive agent, corticosteroid, anticonvulsant, cox-2 inhibitor, hyperbaric oxygen, or a combination thereof.

5. The method of claim 2, wherein the second active agent is acetylsalicylic acid, celecoxib, ketamine, gabapentin, carbamazepine, oxcarbazepine, phenytoin, sodium valproate, prednisone, nifedipine, clonidine, oxycodone, meperidine, morphine sulfate, hydromorphone, fentanyl, acetaminophen, ibuprofen, naproxen sodium, griseofulvin, amitriptyline, imipramine, or doxepin.

6. The method of claim 1, wherein the pain is nociceptive pain or neuropathic pain.

7. The method of claim 6, wherein the pain is associated with chemical or thermal burn, skin cut, skin abrasion, osteoarthritis, rheumatoid arthritis, tendonitis, or myofascial pain.

8. The method of claim 6, wherein the pain is diabetic neuropathy, postherpetic neuralgia, trigeminal neuralgia, post-stroke pain, complex regional pain syndrome, sympathetic nervous system persistent pain syndrome, reflex sympathetic dystrophy, reflex neurovascular dystrophy, reflex dystrophy, spinal cord injury pain, grandke's atrophy of bone, algoneurodystrophy, shoulder hand syndrome, post-traumatic dystrophy, cancer-related pain, phantom limb pain, fibromyalgia, chronic fatigue syndrome, radiculopathy, syphilitic neuralgia, or painful neuropathy caused by a drug.

9. The method of claim 8, wherein the complex regional pain syndrome is type I or type II.

10. The method of claim 8, wherein the painful neurological condition is induced by treatment with vincristine, Velcade, or thalidomide.

11. The method of claim 1, wherein the pain is visceral pain, migraine, tension headache, post-operative pain, or a mixture of nociceptive and neuropathic pain.

12. The method of claim 1, wherein the selective cytokine inhibitory drug is enantiomerically pure.

13. The method of claim 1, wherein the selective cytokine inhibitory drug is 3- (3, 4-dimethoxy-phenyl) -3- (1-oxo-1, 3-dihydro-isoindol-2-yl) -propionamide.

14. The method of claim 13, wherein the selective cytokine inhibitory drug is enantiomerically pure.

15. The method of claim 1, wherein the selective cytokine inhibitory drug is {2- [1- (3-ethoxy-4-methoxy-phenyl) -2-methanesulfonyl-ethyl ] -3-oxo-2, 3-dihydro-1-H-isoindol-4-yl } -cyclopropylcarboxamide.

16. The method of claim 15, wherein the selective cytokine inhibitory drug is enantiomerically pure.

17. The method of claim 1, wherein the selective cytokine inhibitory drug is of formula (I):

wherein n is 1,2, or 3

R⁵Is ortho-phenylene, unsubstituted or substituted with 1 to 4 substituents independently selected from: nitro, cyano, trifluoromethyl, ethoxyformyl, methoxycarbonyl, propoxycarbonyl, acetyl, carbamoyl, acetoxy, carboxyl, hydroxyl, amino, alkylamino, dialkylamino, acylamino, alkyl of 1 to 10 carbon atoms, and halogen;

R⁷is (i) phenyl or phenyl substituted with one or more substituents independently selected from: nitro, cyano, trifluoromethyl, ethoxyformyl, methoxycarbonyl, propoxycarbonyl, acetyl, carbamoyl, acetoxy, carboxyl, hydroxyl, amino, alkyl having 1 to 10 carbon atoms, alkoxy having 1 to 10 carbon atoms, and halogen;

(ii) unsubstituted benzyl or benzyl substituted with 1 to 3 substituents selected from: nitro, cyano, trifluoromethyl, ethoxyformyl, methoxycarbonyl, propoxycarbonyl, acetyl, carbamoyl, acetoxy, carboxyl, hydroxyl, amino, alkyl having 1 to 10 carbon atoms, alkoxy having 1 to 10 carbon atoms, and halogen,

(iii) (iii) naphthyl, and (iv) benzyloxy;

R¹²is-OH, alkoxy of 1-12 carbon atoms, or

R⁸Is hydrogen or alkyl of 1 to 10 carbon atoms; and

R⁹is hydrogen, alkyl of 1 to 10 carbon atoms, -COR¹⁰or-SO₂R¹⁰Wherein R is¹⁰Hydrogen, alkyl of 1 to 10 carbon atoms, or phenyl.

18. The method of claim 17, wherein the selective cytokine inhibitory drug is enantiomerically pure.

19. The method of claim 1, wherein the selective cytokine inhibitory drug is of formula (II):

wherein when R is¹And R²When they are independent from each other, they are each hydrogen or lower alkyl; or when R is¹And R²(ii) when attached to said carbon atom, is independently ortho-phenylene, ortho-naphthylene, or cyclohexene-1, 2-diyl, unsubstituted or substituted with 1 to 4 substituents independently selected from: nitro, cyano, trifluoromethyl, ethoxyformyl, methoxycarbonyl, propoxycarbonyl, acetyl, carbamoyl, acetoxy, carboxyl, hydroxyl, amino, alkylamino, dialkylamino, amido, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms and halogen;

R³is phenyl having 1 to 4 substituents selected from the group consisting of nitro, cyano, trifluoromethyl, ethoxyformyl, methoxycarbonyl, propoxycarbonyl, acetyl, carbamoyl, acetoxy, carboxyl, hydroxyl, amino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, alkylthio of 1 to 10 carbon atoms, benzyloxy, cycloalkoxy of 3 to 6 carbon atoms, C₄-C₆Cycloalkylidenemethyl, C₃-C₁₀Cycloalkylidenemethyl, indanyloxy and halogen;

R⁴is hydrogen, alkyl of 1 to 6 carbon atoms, phenyl or benzyl;

R^4′is hydrogen or alkyl of 1 to 6 carbon atoms;

R⁵is-CH₂-、-CH₂-CO-、-SO₂-, -S-or-NHCO-; and

n is 0, 1 or 2.

20. The method of claim 19, wherein the selective cytokine inhibitory drug is enantiomerically pure.

21. The method of claim 1, wherein the selective cytokine inhibitory drug is of formula (III):

wherein, the carbon atom with the star is a chiral center;

y is C-O, CH₂、SO₂Or CH₂C＝O；

R¹、R²、R³、R⁴Each independently of the others hydrogen, halogen, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, nitro, cyano, hydroxy, or-NR⁸R⁹(ii) a Or R¹、R²、R³、R⁴Any two of which are attached to a carbon atom and together with the depicted phenylene ring form a naphthylene group;

R⁵、R⁶each independently of the others, hydrogen, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, cyano, or cycloalkoxy of up to 18 carbon atoms;

R⁷is hydroxy, alkyl of 1 to 8 carbon atoms, phenyl, benzyl, or NR^8’R^9’；

R⁸、R⁹Each independently of the others hydrogen, alkyl of 1 to 8 carbon atoms, phenyl or benzyl, or R⁸And R⁹One of them is hydrogen and the other is-COR¹⁰or-SO₂R¹⁰Or R is⁸And R⁹Linked as tetramethylene, pentamethylene, hexamethylene, or-CH₂CH₂X¹CH₂CH₂-, wherein X¹is-O-, -S-, or-NH-; and

R^8’、R^9’each independently of the others hydrogen, alkyl of 1 to 8 carbon atoms, phenyl, or benzyl, or R^8’，R^9’One of them is hydrogen and the other is-COR^10’or-SO₂R^10’Or R is^8’，R^9’Joined together to form tetramethylene, pentamethylene, hexamethylene, or-CH₂CH₂X²CH₂CH₂-, wherein X²is-O-, -S-, or-NH-;

22. the method of claim 21, wherein the selective cytokine inhibitory drug is enantiomerically pure.

23. A method of treating, preventing, modifying or managing pain, which comprises administering to a patient in need of such treatment, prevention, modification or management a therapeutically or prophylactically effective amount of a selective cytokine inhibitory drag, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, before, during or after surgery, psychiatric or physical therapy for the purpose of reducing or avoiding the symptoms of pain in the patient.

24. A pharmaceutical composition comprising a selective cytokine inhibitory drug, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a second active agent capable of reducing or diminishing pain.

25. The pharmaceutical composition of claim 24, wherein the second active agent is an antidepressant, antihypertensive, anxiolytic, calcium channel blocker, alpha-adrenoreceptor agonist, alpha-adrenoreceptor antagonist, ketamine, anesthetic, muscle relaxant, non-narcotic analgesic, opioid analgesic, anti-inflammatory agent, immunomodulator, immunosuppressant, corticosteroid, anticonvulsant, cox-2 inhibitor, hyperbaric oxygen, or a combination thereof.

26. The pharmaceutical composition of claim 24, wherein the second active agent is acetylsalicylic acid, celecoxib, ketamine, gabapentin, carbamazepine, oxcarbazepine, phenytoin, sodium valproate, prednisone, nifedipine, clonidine, oxycodone, meperidine, morphine sulfate, hydromorphone, fentanyl, acetaminophen, ibuprofen, naproxen sodium, griseofulvin, amitriptyline, imipramine, or doxepin.