WO2005012287A1 - Therapeutic agents useful for treating pain - Google Patents

Therapeutic agents useful for treating pain Download PDF

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Publication number
WO2005012287A1
WO2005012287A1 PCT/US2004/024753 US2004024753W WO2005012287A1 WO 2005012287 A1 WO2005012287 A1 WO 2005012287A1 US 2004024753 W US2004024753 W US 2004024753W WO 2005012287 A1 WO2005012287 A1 WO 2005012287A1
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WO
WIPO (PCT)
Prior art keywords
compound
substituted
phenyl
halo
animal
Prior art date
Application number
PCT/US2004/024753
Other languages
English (en)
French (fr)
Inventor
Donald J. Kyle
Qun Sun
Original Assignee
Euro-Celtique S.A.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to EP04779721A priority Critical patent/EP1648880B1/en
Priority to DK04779721.2T priority patent/DK1648880T3/da
Priority to DE602004025244T priority patent/DE602004025244D1/de
Priority to JP2006522640A priority patent/JP5148110B2/ja
Application filed by Euro-Celtique S.A. filed Critical Euro-Celtique S.A.
Priority to CA2534088A priority patent/CA2534088C/en
Priority to MXPA06001331A priority patent/MXPA06001331A/es
Priority to AU2004261666A priority patent/AU2004261666B2/en
Priority to SI200431383T priority patent/SI1648880T1/sl
Priority to PL04779721T priority patent/PL1648880T3/pl
Priority to AT04779721T priority patent/ATE455773T1/de
Publication of WO2005012287A1 publication Critical patent/WO2005012287A1/en
Priority to US11/344,937 priority patent/US7696208B2/en
Priority to HK06111025.0A priority patent/HK1093489A1/xx
Priority to US12/715,825 priority patent/US8030310B2/en
Priority to HR20100229T priority patent/HRP20100229T1/hr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/84—Nitriles
    • C07D213/85—Nitriles in position 3

Definitions

  • the present invention relates to 3-substituted Pyridyl Compounds, compositions comprising an effective amount of a 3-substituted Pyridyl Compound and methods for treating or preventing a condition such as pain comprising administering to an animal in need thereof an effective amount of a 3-substituted Pyridyl Compound.
  • Pain is the most common symptom for which patients seek medical advice and treatment. Pain can be acute or chronic.
  • Nociceptive pain includes tissue injury-induced pain and inflammatory pain such as that associated with arthritis. Neuropathic pain is caused by damage to the peripheral or cental nervous system and is maintained by aberrant somatosensory processing.
  • Nociceptive pain has been traditionally managed by administering non-opioid analgesics, such as acetylsalicylic acid, choline magnesium trisalicylate, acetaminophen, ibuprofen, fenoprofen, diflusinab and naproxen; or opioid analgesics, including morphine, hydromorphone, methadone, levorphanob fentanyb oxycodone, and oxymorphone.
  • opioid analgesics including morphine, hydromorphone, methadone, levorphanob fentanyb oxycodone, and oxymorphone.
  • neuropathic pain which can be difficult to treat, has also been treated with anti-epileptics (e.g., gabapentin, carbamazepine, valproic acid, topiramate, phenytoin), NMDA antagonists (e.g., ketamine, dextromethorphan), topical lidocaine (for post-herpetic neuralgia), and tricyclic antidepressants (e.g., fluoxetine, sertraline and amitriptyline).
  • anti-epileptics e.g., gabapentin, carbamazepine, valproic acid, topiramate, phenytoin
  • NMDA antagonists e.g., ketamine, dextromethorphan
  • topical lidocaine for post-herpetic neuralgia
  • tricyclic antidepressants e.g., fluoxetine, sertraline and amitriptyline
  • Urinary incontinence is uncontrollable urination, generally caused by bladder-detrusor-muscle instability. UI affects people of all ages and levels of physical health, both in health care settings and in the community at large.
  • Physiologic bladder contraction results in large part from acetylcholine-induced stimulation of post- ganglionic muscarinic-receptor sites on bladder smooth muscle.
  • Treatments for UI include the administration of drugs having bladder-relaxant properties, which help to control bladder-detrusor-muscle overactivity.
  • anticholinergics such as propantheline bromide and glycopyrrolate
  • smooth-muscle relaxants such as a combination of racemic oxybutynin and dicyclomine or an anticholinergic
  • Ulcers develop as a result of an imbalance between acid-secretory factors, also known as "aggressive factors," such as stomach acid, pepsin, and Helicobacter pylori infection, and local mucosal-protective factors, such as secretion of bicarbonate, mucus, and prostaglandins.
  • Treatment of ulcers typically involves reducing or inhibiting the aggressive factors.
  • antacids such as aluminum hydroxide, magnesium hydroxide, sodium bicarbonate, and calcium bicarbonate can be used to neutralize stomach acids. Antacids, however, can cause alkalosis, leading to nausea, headache, and weakness. Antacids can also interfere with the absorption of other drugs into the blood stream and cause diarrhea.
  • H 2 antagonists such as cimetidine, ranitidine, famotidine, and nizatidine are also used to treat ulcers.
  • H 2 antagonists promote ulcer healing by reducing gastric acid and digestive-enzyme secretion elicited by histamine and other H 2 agonists in the stomach and duodenum.
  • H 2 antagonists can cause breast enlargement and impotence in men, mental changes (especially in the elderly), headache, dizziness, nausea, myalgia, diarrhea, rash, and fever.
  • U ⁇ K + - ATPase inhibitors such as omeprazole and lansoprazole are also used to treat ulcers.
  • Y , K + - ATPase inhibitors inhibit the production of enzymes used by the stomach to secrete acid.
  • Side effects associated with H*, K + - ATPase inhibitors include nausea, diarrhea, abdominal colic, headache, dizziness, somnolence, skin rashes, and transient elevations of plasma activities of aminotransferases.
  • Sucraflate is also used to treat ulcers. Sucraflate adheres to epithelial cells and is believed to form a protective coating at the base of an ulcer to promote healing. Sucraflate, however, can cause constipation, dry mouth, and interfere with the absorption of other drugs. Antibiotics are used when Helicobacter pylori is the underlying cause of the ulcer.
  • bismuth compounds such as bismuth subsalicylate and colloidal bismuth citrate.
  • the bismuth compounds are believed to enhance secretion of mucous and HCO 3 " , inhibit pepsin activity, and act as an antibacterial against H. pylori.
  • Ingestion of bismuth compounds can lead to elevated plasma concentrations of Bi +3 and can interfere with the absorption of other drugs.
  • Prostaglandin analogues such as misoprostab inhibit secretion of acid and stimulate the secretion of mucous and bicarbonate and are also used to treat ulcers, especially ulcers in patients who require nonsteroidal anti-inflammatory drugs.
  • prostaglandin analogues can cause diarrhea and abdominal cramping.
  • some prostaglandin analogues are abortifacients.
  • Carbenoxolone a mineral corticoid, can also be used to treat ulcers.
  • Carbenoxolone appears to alter the composition and quantity of mucous, thereby enhancing the mucosal barrier.
  • Carbenoxolone can lead to Na + and fluid retention, hypertension, hypokalemia, and impaired glucose tolerance.
  • Muscarinic cholinergic antagonists such as pirenzapine and telenzapine can also be used to reduce acid secretion and treat ulcers.
  • IBD Inflammatory-bowel disease
  • Crohn's disease occurs equally in both sexes and is more common in Jews of eastern-European ancestry. Most cases of Crohn's disease begin before age 30 and the majority start between the ages of 14 and 24. The disease typically affects the full thickness of the intestinal wall. Generally the disease affects the lowest portion of the small intestine (ileum) and the large intestine, but can occur in any part of the digestive tract. Early symptoms of Crohn's disease are chronic diarrhea, crampy abdominal pain, fever, loss of appetite, and weight loss. Complications associated with Crohn's disease include the development of intestinal obstructions, abnormal connecting channels (fistulas), and abscesses. The risk of cancer of the large intestine is increased in people who have Crohn's disease.
  • Crohn's disease is associated with other disorders such as gallstones, inadequate absorption of nutrients, amyloidosis, arthritis, episcleritis, aphthous stomatitis, erythema nodosum, pyoderma gangrenosum, ankylosing spondylitis, sacroilitis, uveitis, and primary sclerosing cholangitis.
  • Cramps and diarrhea side effects associated with Crohn's disease, can be relieved by anticholinergic drugs, diphenoxylate, loperamide, deodorized opium tincture, or codeine. Generally, the drug is taken orally before a meal.
  • antibiotics are often administered to treat the symptoms of Crohn's disease.
  • the antibiotic metronidazole is often administered when the disease affects the large intestine or causes abscesses and fistulas around the anus.
  • Long-term use of metronidazole can damage nerves, resulting in pins-and-needles sensations in the arms and legs.
  • Sulfasalazine and chemically related drugs can suppress mild inflammation, especially in the large intestine. These drugs, however, are less effective in sudden, severe flare-ups.
  • Corticosteroids such as prednisone, reduce fever and diarrhea and relieve abdominal pain and tenderness.
  • Ulcerative colitis is a chronic disease in which the large intestine becomes inflamed and ulcerated, leading to episodes of bloody diarrhea, abdominal cramps, and fever. Ulcerative colitis usually begins between ages 15 and 30; however, a small group of people have their first attack between ages 50 and 70. Unlike Crohn's disease, ulcerative colitis never affects the small intestine and does not affect the full thickness of the intestine.
  • ulcerative colitis The disease usually begins in the rectum and the sigmoid colon and eventually spreads partially or completely throughout the large intestine.
  • the cause of ulcerative colitis is unknown.
  • Treatment of ulcerative colitis is directed to controlling inflammation, reducing symptoms, and replacing lost fluids and nutrients.
  • Anticholinergic drugs and low doses of diphenoxylate or loperamide are administered for treating mild diarrhea. For more intense diarrhea higher doses of diphenoxylate or loperamide, or deodorized opium tincture or codeine are administered.
  • Sulfasalazine, olsalazine, prednisone, or mesalamine can be used to reduce inflammation.
  • Azathioprine and mercaptopurine have been used to maintain remissions in ulcerative-colitis patients who would otherwise need long-term corticosteroid treatment.
  • ulcerative colitis the patient is hospitalized and given corticosteroids intravenously. People with severe rectal bleeding can require transfusions and intravenous fluids. If toxic colitis develops and treatments fail, surgery to remove the large intestine can be necessary. Non-emergency surgery can be performed if cancer is diagnosed, precancerous lesions are detected, or unremitting chronic disease would otherwise make the person an invalid or dependent on high doses of corticosteroids. Complete removal of the large intestine and rectum permanently cures ulcerative colitis.
  • IBS Irritable-bowel syndrome
  • IBS intracranial pressure
  • spastic-colon type is commonly triggered by eating, and usually produces periodic constipation and diarrhea with pain. Mucous often appears in the stool. The pain can come in bouts of continuous dull aching pain or cramps, usually in the lower abdomen.
  • the person suffering from spastic-colon type IBS can also experience bloating, gas, nausea, headache, fatigue, depression, anxiety, and difficulty concentrating.
  • the second type of IBS usually produces painless diarrhea or constipation.
  • the diarrhea can begin suddenly and with extreme urgency. Often the diarrhea occurs soon after a meal and can sometimes occur immediately upon awakening.
  • Treatment of IBS typically involves modification of an IBS-patient's diet. Often it is recommended that an IBS patient avoid beans, cabbage, sorbitob and fructose. A low-fat, high-fiber diet can also help some IBS patients. Regular physical activity can also help keep the gastrointestinal tract functioning properly. Drugs such as propantheline that slow the function of the gastrointestinal tract are generally not effective for treating IBS. Antidiarrheal drugs, such as diphenoxylate and loperamide, help with diarrhea. The Merck Manual of Medical Information 525-526 (R. Berkow ed., 1997). Certain pharmaceutical agents have been administered for treating addiction.
  • U.S. Patent No. 5,556,838 to Mayer et al. discloses the use of nontoxic NMDA-blocking agents co- administered with an addictive substance to prevent the development of tolerance or withdrawal symptoms.
  • U.S. Patent No. 5,574,052 to Rose et al. discloses co-administration of an addictive substance with an antagonist to partially block the pharmacological effects of the addictive substance.
  • Mendelson et al. discloses the use of a mixed opiate agonist/antagonist to treat cocaine and opiate addiction.
  • U.S. Patent No. 5,232,934 to Downs discloses administration of 3-phenoxypyridine to treat addiction.
  • U.S. Patents No. 5,039,680 and 5,198,459 to Imperato et al. disclose using a serotonin antagonist to treat chemical addiction.
  • U.S. Patent No. 5,556,837 to Nestler et. al. discloses infusing BDNF or NT-4 growth factors to inhibit or reverse neurological adaptive changes that correlate with behavioral changes in an addicted individual.
  • U.S. Patent No. 6,204,284 to Beer et al. discloses racemic ( ⁇ )-l-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane for use in the prevention or relief of a withdrawal syndrome resulting from addiction to drugs and for the treatment of chemical dependencies. Without treatment, Parkinson's disease progresses to a rigid akinetic state in which patients are incapable of caring for themselves. Death frequently results from complications of immobility, including aspiration pneumonia or pulmonary embolism.
  • Drugs commonly used for the treatment of Parkinson's disease include carbidopa/levodopa, pergolide, bromocriptine, selegiline, amantadine, and trihexyphenidyl hydrochloride.
  • drugs useful for the treatment of Parkinson's disease and having an improved therapeutic profile.
  • benzodiazepines are the most commonly used anti-anxiety agents for generalized anxiety disorder. Benzodiazepines, however, carry the risk of producing impairment of cognition and skilled motor functions, particularly in the elderly, which can result in confusion, delerium, and falls with fractures. Sedatives are also commonly prescribed for treating anxiety.
  • the azapirones, such as buspirone are also used to treat moderate anxiety.
  • azapirones are less useful for treating severe anxiety accompanied with panic attacks.
  • drugs for treating a seizure and epilepsy include carbamazepine, ethosuximide, gabapentin, lamotrigine, phenobarbital, phenytoin, primidone, valproic acid, trimethadione, benzodiazepines, ⁇ - vinyl GABA, acetazolamide, and felbamate.
  • Anti-seizure drugs can have side effects such as drowsiness; hyperactivity; hallucinations; inability to concentrate; central and peripheral nervous system toxicity, such as nystagmus, ataxia, diplopia, and vertigo; gingival hyperplasia; gastrointestinal disturbances such as nausea, vomiting, epigastric pain, and anorexia; endocrine effects such as inhibition of antidiuretic hormone, hyperglycemia, glycosuria, osteomalacia; and hypersensitivity such as scarlatiniform rash, morbilliform rash, Stevens-Johnson syndrome, systemic lupus erythematosus, and hepatic necrosis; and hematological reactions such as red-cell aplasia, agranulocytosis, thrombocytopenia, aplastic anemia, and megaloblastic anemia.
  • Symptoms of strokes vary depending on what part of the brain is affected. Symptoms include loss or abnormal sensations in an arm or leg or one side of the body, weakness or paralysis of an arm or leg or one side of the body, partial loss of vison or hearing, double vision, dizziness, slurred speech, difficulty in thinking of the appropriate word or saying it, inability to recognize parts of the body, unusual movements, loss of bladder control, imbalance, and falling, and fainting. The symptoms can be permanent and can be associated with coma or stupor.
  • drugs for treating strokes include anticoagulants such as heparin, drugs that break up clots such as streptokinase or tissue plasminogen activator, and drugs that reduce swelling such as mannitol or corticosteroids.
  • anticoagulants such as heparin
  • drugs that break up clots such as streptokinase or tissue plasminogen activator
  • drugs that reduce swelling such as mannitol or corticosteroids.
  • Pruritus is an unpleasant sensation that prompts scratching.
  • pruritus is treated by phototherapy with ultraviolet B or PUVA or with therapeutic agents such as naltrexone, nalmefene, danazob tricyclics, and antidepressants.
  • mGluR5 metabotropic glutamate receptor 5
  • 2001-328938 discloses cyanophenyl derivatives that allegedly have anti-androgen activity and are useful for the treatment of prostrate cancer and prostrate hypertrophy.
  • Japanese patent application no. 2001-261657 discloses cyanophenyl derivatives that allegedly have anti-androgen activity.
  • R] is -CF 3 , -NO 2 , or -CN; each R 2 is independently: (a) -halo,-CN, -OH, -NO 2 , or -NH 2 ; (b) -(C ⁇ -C ⁇ o)alkyl, -(C 2 -C 10 )alkenyb -(C 2 -C 10 )alkynyb -(C 3 - Ci 0 )cycloalkyb -(C 8 -C ⁇ )bicycloalkyb -(C 8 -C 14 )tricycloalkyb -(C 5 -C ⁇ o)cycloalkenyb -(C 8 -C ⁇ 4 )bicycloalkenyb -(C 8 -C ⁇ 4 )tricycloalkenyb -(3- to 7-membered)heterocycle, or -(7- to 10-membered)bicycloheterocycle, each of which is unsubstitute
  • each R 8 is independently -(C ⁇ - )alkyb -(C 2 -C 6 )alkenyb -(C 2 -C 6 )alkynyb -(C 3 - C 8 )cycloalkyb -(C 5 -C 8 )cycloalkenyb -phenyb -(3- to 5-membered)heterocycle, -C(halo) 3 , -CH(halo) 2 , or -CH 2 (halo); each R 9 is independently -(Cj-C 6 )alky ⁇ , -(C 2 -C 6 )alkenyb -(C 2 -C
  • compositions comprising an effective amount of a 3-substituted Pyridyl Compound and a pharmaceutically acceptable carrier or excipient.
  • compositions are useful for treating or preventing a Condition in an animal.
  • the invention further relates to methods for treating a Condition, comprising administering to an animal in need thereof an effective amount of a 3-substituted Pyridyl Compound.
  • the invention further relates to methods for preventing a Condition, comprising administering to an animal in need thereof an effective amount of a 3-substituted Pyridyl Compound.
  • the invention still further relates to methods for inhibiting Vanilloid Receptor 1 ("VR1") function in a cell, comprising contacting a cell capable of expressing VR1 with an effective amount of a 3-substituted Pyridyl Compound.
  • VR1 Vanilloid Receptor 1
  • the invention still further relates to methods for inhibiting mGluR5 function in a cell, comprising contacting a cell capable of expressing mGluR5 with an effective amount of a 3-substituted Pyridyl Compound.
  • the invention still further relates to methods for inhibiting metabotropic glutamate receptor 1 ("mGluRl") function in a cell, comprising contacting a cell capable of expressing mGluRl with an effective amount of a 3-substituted Pyridyl Compound.
  • mGluRl metabotropic glutamate receptor 1
  • the invention still further relates to methods for preparing a composition, comprising the step of admixing a 3-substituted Pyridyl Compound and a pharmaceutically acceptable carrier or excipient.
  • the invention still further relates to a kit comprising a container containing an effective amount of a 3-substituted Pyridyl Compound.
  • Ri is -CF 3 .
  • Ri is -NO 2 .
  • Ri is -CN.
  • n is 0.
  • n is 1 and R 2 is -halo,-OH, or -NH 2 .
  • n is 1 and R 2 is -(C ⁇ -C ⁇ o)alkyb -(C 2 -C ⁇ o)alkenyb -(C 2 -
  • n is 1 and R 2 is -phenyb -naphthyl, -(C ⁇ )aryl or -(5- to 10-membered)heteroaryb each of which is unsubstituted or substituted with one or more R 6 groups.
  • m is 1 and R 3 is -halo, -CN, -OH, -NO 2 , or -NH 2 .
  • m is 1 and R 3 is -(C ⁇ -C ⁇ o)alkyb -(C 2 -C ⁇ o)alkenyb -(C 2 - C ⁇ o)alkynyb -(C 3 -C ⁇ o)cycloalkyb -(C 8 -C ⁇ 4 )bicycloalkyb -(C 8 -C 14 )tricycloalkyb -(C 5 - C 1 o)cycloalkenyb -(C 8 -Cj 4 )bicycloalkenyb -(C 8 -C ⁇ 4 )tricycloalkenyb -(3- to 7- membered)heterocycle, or -(7- to 10-membered)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R 5 groups.
  • m is 1 and R 3 is -phenyb -naphthyl, -(C ⁇ )aryl or -(5- to 10-membered)heteroaryb each of which is unsubstituted or substituted with one or more R 6 groups.
  • m is 1 and R 3 is -CH 3 .
  • R 3 is -CH 3 , and the carbon atom to which the R 3 is attached is in the (R)-configuration.
  • m is 1, R 3 is -CH 3 , and the carbon atom to which the R 3 is attached is in the (S)-configuration.
  • Rn and q are defined above for the 3-substituted Pyridyl Compounds of formula (II).
  • Rj is -CF 3 .
  • Rj is -NO 2 .
  • Rj is -CN.
  • n is 0.
  • n is 1 and R 2 is -halo,-OH, or -NH .
  • n is 1 and R 2 is -(C ⁇ -C ⁇ o)alkyb -(C 2 -C ⁇ 0 )alkenyb -(C 2 - Ci 0 )alkynyb -(C 3 -C ⁇ 0 )cycloalkyb -(C 8 -C ⁇ 4 )bicycloalkyb -(C 8 -C ⁇ 4 )tricycloalkyb -(C 5 - C ⁇ o)cycloalkenyb -(C 8 -C) )bicycloalkenyb -(C 8 -C ⁇ 4 )tricycloalkenyb -(3- to 7- membered)heterocycle, or -(7- to 10-membered)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R 5 groups.
  • n is 1 and R 2 is -phenyb -naphthyl, -(Cj 4 )aryl or -(5- to 10-membered)heteroaryb each of which is unsubstituted or substituted with one or more R 6 groups.
  • m is 1 and R 3 is -halo, -CN, -OH, -NO 2 , or -NH 2 .
  • m is 1 and R 3 is -(C ⁇ -C]o)alkyb -(C 2 -C ⁇ alkenyb -(C - c alkynyb -(C 3 -C ⁇ o)cycloalkyb -(C 8 -C ⁇ 4 )bicycloalkyb -(C 8 -C ⁇ 4 )tricycloalkyb -(C5- C ⁇ o)cycloalkenyb -(C 8 -C ⁇ 4 )bicycloalkenyb -(C 8 -C ⁇ 4 )tricycloalkenyb -(3- to 7- membered)heterocycle, or -(7- to 10-membered)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R 5 groups.
  • m is 1 and R 3 is -phenyb -naphthyl, -(C ⁇ 4 )aryl or -(5- to 10-membered)heteroaryb each of which is unsubstituted or substituted with one or more R 6 groups.
  • m is 1 and R 3 is -CH 3 .
  • m is 1, R 3 is -CH 3 , and the carbon atom to which the R 3 is attached is in the (R)-configuration.
  • m is 1, R 3 is -CH 3 , and the carbon atom to which the R 3 is attached is in the (S)-configuration.
  • Pyridyl Compound can be in the form of an optical isomer or a diastereomer.
  • the invention encompasses 3-substituted Pyridyl Compounds and their uses as described herein in the form of their optical isomers, diasteriomers, and mixtures thereof, including a racemic mixture.
  • each R 3 can be on any carbon of the piperazine ring.
  • the 3-substituted Pyridyl Compounds have only one R 3 group, and that R 3 group is attached to a carbon atom adjacent to the nitrogen atom attached to the pyridyl group.
  • the 3-substituted Pyridyl Compound has only one R 3 group, and that R 3 group is attached to a carbon atom adjacent to the nitrogen atom attached to the phenethyl or phenpropyl group.
  • two R 3 groups are on a single atom of the piperazine ring.
  • an R 3 group is attached to a carbon atom adjacent to the nitrogen atom attached to the pyridyl group and another R 3 group is attached to a carbon atom adjacent to the nitrogen atom attached to the phenethyl or phenpropyl group.
  • the 3-substituted Pyridyl Compound has two R 3 groups, each being attached to a different carbon atom adjacent to a nitrogen atom attached to the pyridyl group.
  • the 3-substituted Pyridyl Compound has two R 3 groups, each being attached to a different carbon atom adjacent to a nitrogen atom attached to the phenethyl or phenpropyl group.
  • the carbon atom to which an R 3 group is attached has the (R) configuration.
  • the carbon atom to which the R 3 group is attached has the (S) configuration.
  • the 3-substituted Pyridyl Compound has one or two R 3 groups, and at least one of the carbon atoms to which an R 3 group is attached has the (R) configuration.
  • the 3-substituted Pyridyl Compound has one or two R 3 groups, and at least one of the carbon atoms to which an R 3 group is attached has the (S) configuration.
  • the 3-substituted Pyridyl Compound has one or two R 3 groups, and an R 3 group is attached to a carbon atom adjacent to a nitrogen atom attached to the pyridyl group, and the carbon to which the R 3 group is attached is in the (R) configuration.
  • the 3-substituted Pyridyl Compound has one or two R 3 groups, an R 3 group is attached to a carbon atom adjacent to a nitrogen attached to the pyridyl group, the carbon to which the R 3 group is attached is in the (R) configuration, and R 3 is -(C ⁇ -C )alkyl unsubstituted or substituted with one or more halo groups.
  • the 3-substituted Pyridyl Compound has one or two R 3 groups, an R 3 group is attached to a carbon atom adjacent to a nitrogen attached to the pyridyl group, the carbon to which the R 3 group is attached is in the (R) configuration, and R 3 is -CH 3 .
  • the 3-substituted Pyridyl Compound has one or two R 3 groups, an R 3 group is attached to a carbon atom adjacent to a nitrogen attached to the pyridyl group, the carbon to which the R 3 group is attached is in the (R) configuration, and R 3 is -CF 3 .
  • the 3-substituted Pyridyl Compound has one or two R 3 groups, an R 3 group is attached to a carbon atom adjacent to a nitrogen attached to the pyridyl group, the carbon to which the R 3 group is attached is in the (R) configuration, and R 3 is -CH 2 CH 3 .
  • the 3-substituted Pyridyl Compound has one or two R 3 groups, an R 3 group is attached to a carbon atom adjacent to a nitrogen atom attached to the phenethyl or phenpropyl group, and the carbon to which the R 3 group is attached is in the (R) configuration.
  • the 3-substituted Pyridyl Compound has one or two R 3 groups, an R 3 group is attached to a carbon atom adjacent to a nitrogen attached to the phenethyl or phenpropyl group, the carbon to which the R 3 group is attached is in the (R) configuration, and R 3 is -(C ⁇ -C 4 )alkyl unsubstituted or substituted with one or more halo groups.
  • the 3-substituted Pyridyl Compound has one or two R 3 groups, an R 3 group is attached to a carbon atom adjacent to a nitrogen attached to the phenethyl or phenpropyl group, the carbon to which the R 3 group is attached is in the (R) configuration, and R 3 is -CH 3 .
  • the 3-substituted Pyridyl Compound has one or two R 3 groups, an R 3 group is attached to a carbon atom adjacent to a nitrogen attached to the phenethyl or phenpropyl group, the carbon to which the R 3 group is attached is in the (R) configuration, and R 3 is -CF 3 .
  • the 3-substituted Pyridyl Compound has one or two R 3 groups, an R 3 group is attached to a carbon atom adjacent to a nitrogen attached to the phenethyl or phenpropyl group, the carbon to which the R 3 group is attached is in the (R) configuration, and R 3 is -CH 2 CH 3 .
  • the 3-substituted Pyridyl Compound has one or two R 3 groups, an R 3 group is attached to a carbon atom adjacent to a nitrogen atom attached to the pyridyl group, and the carbon to which the R 3 group is attached is in the (S) configuration.
  • the 3-substituted Pyridyl Compound has one or two R 3 groups, an R 3 group is attached to a carbon atom adjacent to a nitrogen attached to the pyridyl group, the carbon to which the R 3 group is attached is in the (S) configuration, and R3 is -(C ⁇ -C 4 )alkyl unsubstituted or substituted with one or more halo groups.
  • the 3-substituted Pyridyl Compound has one or two R 3 groups, an R 3 group is attached to a carbon atom adjacent to a nitrogen attached to the pyridyl group, the carbon to which the R 3 group is attached is in the (S) configuration, and R 3 is -CH 3 .
  • the 3-substituted Pyridyl Compound has one or two R 3 groups, an R 3 group is attached to a carbon atom adjacent to a nitrogen attached to the pyridyl group, the carbon to which the R 3 group is attached is in the (S) configuration, and R 3 is -CF3.
  • the 3-substituted Pyridyl Compound has one or two R 3 groups, an R 3 group is attached to a carbon atom adjacent to a nitrogen attached to the pyridyl group, the carbon to which the R3 group is attached is in the (S) configuration, and R 3 is -CH 2 CH 3 .
  • the 3-substituted Pyridyl Compound has one or two R3 groups, an R 3 group is attached to a carbon atom adjacent to a nitrogen atom attached to the phenethyl or phenpropyl group, and the carbon to which the R3 group is attached is in the (S) configuration.
  • the 3-substituted Pyridyl Compound has one or two R 3 groups, an R 3 group is attached to a carbon atom adjacent to a nitrogen attached to the phenethyl or phenpropyl group, the carbon to which the R3 group is attached is in the (S) configuration, and R 3 is -(Cj-C 4 )alkyl unsubstituted or substituted with one or more halo groups.
  • the 3-substituted Pyridyl Compound has one or two R 3 groups, an R 3 group is attached to a carbon atom adjacent to a nitrogen attached to the phenethyl or phenpropyl group, the carbon to which the R 3 group is attached is in the (S) configuration, and R 3 is -CH 3 .
  • the 3-substituted Pyridyl Compound has one or two R 3 groups, an R 3 group is attached to a carbon atom adjacent to a nitrogen attached to the phenethyl or phenpropyl group, the carbon to which the R 3 group is attached is in the (S) configuration, and R 3 is -CF 3 .
  • the 3-substituted Pyridyl Compound has one or two R 3 groups, an R 3 group is attached to a carbon atom adjacent to a nitrogen attached to the phenethyl or phenpropyl group, the carbon to which the R 3 group is attached is in the (S) configuration, and R 3 is -CH 2 CH 3 .
  • the 3-substituted Pyridyl Compound has only one R 3 group, the R 3 group is attached to a carbon atom adjacent to a nitrogen atom attached to the pyridyl group, and the carbon to which the R 3 group is attached is in the (R) configuration.
  • the 3-substituted Pyridyl Compound has only one R 3 group, the R 3 group is attached to a carbon atom adjacent to a nitrogen attached to the pyridyl group, the carbon to which the R 3 group is attached is in the (R) configuration, and R 3 is -(C ⁇ -C 4 )alkyl unsubstituted or substituted with one or more halo groups.
  • the 3-substituted Pyridyl Compound has only one R 3 group, the R 3 group is attached to a carbon atom adjacent to a nitrogen attached to the pyridyl group, the carbon to which the R 3 group is attached is in the (R) configuration, and R 3 is -CH 3 .
  • the 3-substituted Pyridyl Compound has only one R 3 group, the R 3 group is attached to a carbon atom adjacent to a nitrogen attached to the pyridyl group, the carbon to which the R 3 group is attached is in the (R) configuration, and R 3 is -CF 3 .
  • the 3-substituted Pyridyl Compound has only one R 3 group, the R 3 group is attached to a carbon atom adjacent to a nitrogen attached to the pyridyl group, the carbon to which the R 3 group is attached is in the (R) configuration, In another embodiment, the 3-substituted Pyridyl Compound has only one R 3 group, the R 3 group is attached to a carbon atom adjacent to a nitrogen atom attached to the phenethyl or phenpropyl group, and the carbon to which the R 3 group is attached is in the (R) configuration.
  • the 3-substituted Pyridyl Compound has only one R 3 group, the R 3 group is attached to a carbon atom adjacent to a nitrogen attached to the - phenethyl or phenpropyl group, the carbon to which the R 3 group is attached is in the (R) configuration, and R 3 is -(C]-C 4 )alkyl unsubstituted or substituted with one or more halo groups.
  • the 3-substituted Pyridyl Compound has only one R 3 group, the R 3 group is attached to a carbon atom adjacent to a nitrogen attached to the phenethyl or phenpropyl group, the carbon to which the R 3 group is attached is in the (R) configuration, and R 3 is -CH 3 .
  • the 3-substituted Pyridyl Compound has only one R3 group, the R 3 group is attached to a carbon atom adjacent to a nitrogen attached to the phenethyl or phenpropyl group, the carbon to which the R 3 group is attached is in the (R) configuration, and R 3 is -CF 3 .
  • the 3-substituted Pyridyl Compound has only one R 3 group, the R 3 group is attached to a carbon atom adjacent to a nitrogen attached to the phenethyl or phenpropyl group, the carbon to which the R 3 group is attached is in the (R) configuration, and R 3 is -CH 2 CH 3 .
  • the 3-substituted Pyridyl Compound has only one R 3 group, the R 3 group is attached to a carbon atom adjacent to a nitrogen atom attached to the pyridyl group, and the carbon to which the R 3 group is attached is in the (S) configuration.
  • the 3-substituted Pyridyl Compound has only one R3 group, the R 3 group is attached to a carbon atom adjacent to a nitrogen attached to the pyridyl group, the carbon to which the R 3 group is attached is in the (S) configuration, and R 3 is -(Cj-C 4 )alkyl unsubstituted or substituted with one or more halo groups.
  • the 3-substituted Pyridyl Compound has only one R3 group, the R 3 group is attached to a carbon atom adjacent to a nitrogen attached to the pyridyl group, the carbon to which the R 3 group is attached is in the (S) configuration, and R 3 is -CH 3 .
  • the 3-substituted Pyridyl Compound has only one R 3 group, the R 3 group is attached to a carbon atom adjacent to a nitrogen attached to the pyridyl group, the carbon to which the R 3 group is attached is in the (S) configuration, and R 3 is -CF 3 .
  • the 3-substituted Pyridyl Compound has only one R 3 group, the R 3 group is attached to a carbon atom adjacent to a nitrogen attached to the pyridyl group, the carbon to which the R 3 group is attached is in the (S) configuration, and R 3 is -CH 2 CH 3 .
  • the 3-substituted Pyridyl Compound has only one R 3 group, the R 3 group is attached to a carbon atom adjacent to a nitrogen atom attached to the phenethyl or phenpropyl group, and the carbon to which the R 3 group is attached is in the (S) configuration.
  • the 3-substituted Pyridyl Compound has only one R 3 group, the R 3 group is attached to a carbon atom adjacent to a nitrogen attached to the phenethyl or phenpropyl group, the carbon to which the R 3 group is attached is in the (S) configuration, and R 3 is -(C ⁇ -C 4 )alkyl unsubstituted or substituted with one or more halo groups.
  • the 3-substituted Pyridyl Compound has only one R 3 group, the R 3 group is attached to a carbon atom adjacent to a nitrogen attached to the phenethyl or phenpropyl group, the carbon to which the R 3 group is attached is in the (S) configuration, and R 3 is -CH 3 .
  • the 3-substituted Pyridyl Compound has only one R 3 group, the R 3 group is attached to a carbon atom adjacent to a nitrogen attached to the phenethyl or phenpropyl group, the carbon to which the R 3 group is attached is in the (S) configuration, and R 3 is -CF 3 .
  • the 3-substituted Pyridyl Compound has only one R 3 group, the R 3 group is attached to a carbon atom adjacent to a nitrogen attached to the phenethyl or phenpropyl group, the carbon to which the R 5 group is attached is in the (S) configuration, and R3 is -CH 2 CH 3 .
  • Optical isomers of the 3-substituted Pyridyl Compounds can be obtained by known techniques such as chiral chromatography or formation of diastereomeric salts from an optically active acid or base.
  • one or more hydrogen, carbon or other atoms of a 3-substituted Pyridyl Compound can be replaced by an isotope of the hydrogen, carbon or other atoms.
  • Such compounds, which are encompassed by the present invention are useful as research and diagnostic tools in metabolism pharmacokinetic studies and in binding assays.
  • Illustrative 3-substituted Pyridyl Compounds are listed below in Tables 1-12.
  • Representative straight chain -(C ⁇ -C ⁇ o)alkyls include -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyb -n-hexyb -n-heptyb -n-octyb
  • branched -(C ⁇ -C ⁇ o)alkyls include -iso-propyl, -sec-butyl, -iso-butyl, -tert-butyl, -iso-pentyb -neo-pentyl, 1-methylbutyl, 2-methylbutyb 3-methylbutyb 1,1-dimethylpropyb 1,2-dimethylpropyb 1-methylpentyb 2-methylpentyb 3-methylpentyb 4-methylpentyb 1-ethylbutyb 2-ethylbutyb 3-ethylbutyb 1,1-dimethylbutyb 1,2-dimethylbutyb 1,3-dimethylbutyb 2,2-dimethylbutyb
  • Representative straight chain -(C ⁇ -C 6 )alkyls include -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl and -n-hexyb
  • Representative branched -(C ⁇ -C 6 )alkyls include -iso-propyl, -sec-butyl, -iso-butyl, -tert-butyl, -iso-pentyb -rceo-pentyb 1-methylbutyb 2-methylbutyb 3-methylbutyb 1,1-dimethylpropyb 1,2-dimethylpropyb 1-methylpentyb 2-methylpentyb 3-methylpentyb 4-methylpentyb 1-ethylbutyb 2-ethylbutyb 3-ethylbutyb 1,1-dimethtylbutyb 1,2-dimethylbutyb 1,3-dimethylbutyb 2,2-dimethylbutyb
  • Representative straight chain and branched (C 2 -C ⁇ o)alkenyls include -vinyl, -allyl, -1-butenyl, -2-butenyb - iso-butyl enyb -1-pentenyb -2-pentenyb -3-methyl-l-butenyb -2-methyl-2-butenyb -2,3-dimethyl-2-butenyb -1-hexenyb -2-hexenyb -3-hexenyb -1-heptenyb -2-heptenyb -3-heptenyb -1-octenyb -2-octenyb -3-octenyb -1-nonenyb -2-nonenyb -3-nonenyb -1-decenyb -2-decenyb -3-decenyl and the like.
  • -(C 2 -C 6 )alkenyl means a straight chain or branched non-cyclic hydrocarbon having from 2 to 6 carbon atoms and including at least one carbon-carbon double bond.
  • Representative straight chain and branched (C 2 -C 6 )alkenyls include -vinyl, -allyl, -1-butenyb -2-butenyb -iso-butylenyb -1-pentenyb -2-pentenyb -3 -methyl -1-butenyb -2-methyl-2-butenyb -2,3-dimethyl-2-butenyb -1-hexenyb 2-hexenyb 3-hexenyl and the like.
  • -(C 2 -C ⁇ o)alkynyl means a straight chain or branched non-cyclic hydrocarbon having from 2 to 10 carbon atoms and including at lease one carbon-carbon triple bond.
  • Representative straight chain and branched -(C 2 -C ⁇ o)alkynyls include -acetylenyb -propynyb -1-butynyb -2-butynyb -1-pentynyb -2-pentynyb -3 -methyl- 1-butynyb -4-pentynyb -1-hexynyb -2-hexynyb -5-hexynyb -1-heptynyb -2-heptynyb -6-heptynyb -1-octynyb -2-octynyb -7-octynyb -1-nonynyb -2-nonynyb -8-
  • -(C 2 -C 6 )alkynyl means a straight chain or branched non-cyclic hydrocarbon having from 2 to 6 carbon atoms and including at lease one carbon-carbon triple bond.
  • Representative straight chain and branched (C 2 -C 6 )alkynyls include -acetylenyb -propynyb -1-butynyb -2-butynyb -1-pentynyb -2-pentynyb -3-methyl- 1-butynyb -4-pentynyb -1-hexynyb -2-hexynyb -5-hexynyl and the like.
  • “-(C 3 -C ⁇ o)cycloalkyl” means a saturated cyclic hydrocarbon having from 3 to 10 carbon atoms.
  • Representative (C 3 -C 1 o)cycloalkyls are -cyclopropyl, -cyclobutyl, -cyclopentyl, -cyclohexyl, -cycloheptyl, -cyclooctyl, -cyclononyl and -cyclodecyl.
  • “-(C 3 -C 8 )cycloalkyl” means a saturated cyclic hydrocarbon having from 3 to 8 carbon atoms.
  • Representative (C 3 - )cycloalkyls include -cyclopropyl, -cyclobutyl, -cyclopentyl, -cyclohexyl, -cycloheptyl and -cyclooctyl.
  • "-(C 8 -C ⁇ 4 )bicycloalkyl” means a bi-cyclic hydrocarbon ring system having from 8 to 14 carbon atoms and at least one saturated cyclic alkyl ring.
  • Representative -(C 8 - C ⁇ 4 )bicycloalkyls include -indanyl, -1,2,3,4-tetrahydronaphthyb -5,6,7,8-tetrahydronaphthyb -perhydronaphthyl and the like.
  • "-(C 8 -C ⁇ )tricycloalkyl” means a tri-cyclic hydrocarbon ring system having from 8 to 14 carbon atoms and at least one saturated ring.
  • Representative -(C 8 - C] 4 )tricycloalkyls include -pyrenyb -1,2,3,4-tetrahydroanthracenyb -perhydroanthracenyl -aceanthreneyb - 1 ,2,3,4-tetrahydropenanthrenyb -5,6,7,8-tetrahydrophenanthrenyb -perhydrophenanthrenyl and the like.
  • "-(C 5 -C ⁇ o)cycloalkenyl” means a cyclic non-aromatic hydrocarbon having at least one carbon-carbon double bond in the cyclic system and from 5 to 10 carbon atoms.
  • Representative (C5-C ⁇ o)cycloalkenyls include -cyclopentenyb -cyclopentadienyb -cyclohexenyb -cyclohexadienyb-cycloheptenyb -cycloheptadienyb -cycloheptatrienyb -cyclooctenyb -cyclooctadienyb -cyclooctatrienyb -cyclooctatetraenyb -cyclononenyl -cyclononadienyb -cyclodecenyb -cyclodecadienyl and the like.
  • -(C 5 -C 8 )cycloalkenyl means a cyclic non-aromatic hydrocarbon having at least one carbon-carbon double bond in the cyclic system and from 5 to 8 carbon atoms.
  • Representative (C 5 -C 8 )cycloalkenyls include -cyclopentenyb -cyclopentadienyb -cyclohexenyb -cyclohexadienyb -cycloheptenyb -cycloheptadienyb -cycloheptatrienyb -cyclooctenyb -cyclooctadienyb -cyclooctatrienyb -cyclooctatetraenyl and the like.
  • -(C 8 -C 1 )bicycloalkenyl means a bi-cyclic hydrocarbon ring system having at least one carbon-carbon double bond in each ring and from 8 to 14 carbon atoms.
  • Representative -(C 8 -C ⁇ )bicycloalkenyls include -indenyb -pentalenyb -naphthalenyb -azulenyb -heptalenyb -1,2,7,8-tetrahydronaphthalenyl and the like.
  • "-(C 8 -C ⁇ 4 )tricycloalkenyl” means a tri-cyclic hydrocarbon ring system having at least one carbon-carbon double bond in each ring and from 8 to 14 carbon atoms.
  • Representative -(C 8 -Cj )tricycloalkenyls include -anthracenyl, -phenanthrenyb -phenalenyb -acenaphthalenyb ⁇ s-indacenyl, s-indacenyl and the like.
  • "-(3- to 7-membered)heterocycle” or "-(3- to 7-membered)heterocyclo” means a 3- to 7-membered monocyclic heterocyclic ring which is either saturated, unsaturated non-aromatic, or aromatic.
  • a 3- or a 4-membered heterocycle can contain up to 3 heteroatoms, a 5-membered heterocycle can contain up to 4 heteroatoms, a 6-membered heterocycle can contain up to 6 heteroatoms, and a 7-membered heterocycle can contain up to 7 heteroatoms.
  • Each heteroatom is independently selected from nitrogen, which can be quaternized; oxygen; and sulfur, including sulfoxide and sulfone.
  • the -(3- to 7- membered)heterocycle can be attached via a nitrogen, sulfur, or carbon atom.
  • Representative -(3- to 7-membered)heterocycles include pyridyb furyb thiophenyl, pyrrolyb oxazolyb imidazolyb thiazolyb thiadiazolyb isoxazolyb pyrazolyl, isothiazolyb pyridazinyb pyrimidinyb pyrazinyb triazinyb morpholinyb pyrrolidinonyb pyrrolidinyb piperidinyb piperazinyb hydantoinyb valerolactamyb oxiranyb oxetanyb tetrahydrofuranyb tetrahydropyranyb tetrahydropyrindinyb tetrahydropyrimidinyb tetrahydrothiophenyb tetrahydrothiopyranyl and the like.
  • “-(3- to 5-membered)heterocycle” or “-(3- to 5-membered)heterocyclo” means a 3- to 5-membered monocyclic heterocyclic ring which is either saturated, unsaturated non- aromatic, or aromatic.
  • a 3- or a 4-membered heterocycle can contain up to 3 heteroatoms, and a 5-membered heterocycle can contain up to 4 heteroatoms.
  • Each heteroatom is independently selected from nitrogen, which can be quatemized; oxygen; and sulfur, including sulfoxide and sulfone.
  • the -(3- to 5-membered)heterocycle can be attached via a nitrogen, sulfur, or carbon atom.
  • Representative -(3- to 5- membered)heterocycles include furyl, thiophenyl, pyrrolyb oxazolyb imidazolyb thiazolyb isoxazolyb pyrazolyl, isothiazolyb triazinyb pyrrolidinonyb pyrrolidinyb hydantoinyb oxiranyb oxetanyb tetrahydrofuranyb tetrahydrothiophenyl and the like.
  • -(7- to 10-membered)bicycloheterocycle or "-(7- to 10- membered)bicycloheterocyclo” means a 7- to 10-membered bicyclic, heterocyclic ring which is either saturated, unsaturated non- aromatic, or aromatic.
  • a -(7- to 10- membered)bicycloheterocycle contains from 1 to 4 heteroatoms independently selected from nitrogen, which can be quatemized; oxygen; and sulfur, including sulfoxide and sulfone.
  • the -(7- to 10-membered)bicycloheterocycle can be attached via a nitrogen, sulfur, or carbon atom.
  • Representative -(7- to 10-membered)bicycloheterocycles include -quinolinyl, -isoquinolinyl, -chromonyl, -coumarinyb -indolyb -indolizinyb -benzo[b]furanyb -benzo[b]thiophenyb -indazolyb -purinyb -4H-quinolizinyb -isoquinolyb -quinolyb -phthalazinyb -naphthyridinyb -carbazolyl, - ?-carbolinyl and the like.
  • -(C ⁇ 4 )aryl means a 14-membered aromatic carbocyclic moiety such as -anthryl or -phenanthryl.
  • "-(5- to 10-membered)heteroaryl” means an aromatic heterocycle ring of 5 to 10 members, including both mono- and bicyclic ring systems, where at least one carbon atom of one or both of the rings is replaced with a heteroatom independently selected from nitrogen, oxygen and sulfur.
  • one of the -(5- to 10- membered)heteroaryl's rings contain at least one carbon atom.
  • both of the -(5- to 10-membered)heteroaryl's rings contain at least one carbon atom.
  • Representative -(5- to 10-membered)heteroaryls include pyridyb furyb benzofuranyb thiophenyl, benzothiophenyb quinolinyl, pyrrolyb indolyb oxazolyb benzoxazolyb imidazolyb benzimidazolyb thiazolyb benzothiazolyb isoxazolyb pyrazolyl, isothiazolyb pyridazinyb pyrimidinyb pyrazinyb thiadiazolyb triazinyb cinnolinyb phthalazinyb and quinazolinyb "-Halogen" or "-halo" means -F, -CI, -Br or -I.
  • pyridyl group means
  • phenethyl group means an ethylene group attached to a terminal Ax- group, where one or each of two hydrogens of the ethylene group can optionally be substituted with an R 8 group.
  • a phenethyl group is depicted below:
  • R 8 Ar 2 , and t are defined above for the 3-substituted Pyridyl Compounds of formulas (I).
  • a phenpropyl group is depicted below
  • R 8 , Ar 2 , and t are defined above for the 3-substituted Pyridyl Compounds of formulas (II).
  • the phrase "effective amount,” when used in connection with a 3-substituted Pyridyl Compound means an amount effective for: (a) treating or preventing a Condition; or (b) inhibiting VR1, mGluRl, or mGluR5 function in a cell.
  • the phrase "effective amount,” when used in connection with the another therapeutic agent means an amount for providing the therapeutic effect of the therapeutic agent.
  • the term "animal,” includes, but is not limited to, a cow, monkey, chimpanzee, baboon, horse, sheep, pig, chicken, turkey, quail, cat, dog, mouse, rat, rabbit, guinea pig and human.
  • pharmaceutically acceptable salt is any pharmaceutically acceptable salt that can be prepared from a 3-substituted Pyridyl Compound, including a salt formed from an acid and a basic functional group, such as a nitrogen group, of one of the 3-substituted Pyridyl Compounds.
  • Illustrative salts include, but are not limited, to sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, /?-toluenesulfonate, and pamoate (i.e., l,l'-methylene-bis-(2-hydroxy-3-naphthoate)) salts.
  • pamoate i.e., l,l'-m
  • pharmaceutically acceptable salt also refers to a salt prepared from a 3-substituted Pyridyl Compound having an acidic functional group, such as a carboxylic acid functional group, and a pharmaceutically acceptable inorganic or organic base.
  • Suitable bases include, but are not limited to, hydroxides of alkali metals such as sodium, potassium, and lithium; hydroxides of alkaline earth metal such as calcium and magnesium; hydroxides of other metals, such as aluminum and zinc; ammonia, and organic amines, such as unsubstituted or hydroxy-substituted mono-, di-, or trialkylamines; dicyclohexylamine; tributyl amine; pyridine; N-methybN-ethylamine; diethylamine; triethylamine; mono-, bis-, or tris-(2-hydroxy-lower alkyl amines), such as mono-, bis-, or tris-(2-hydroxyethyl)amine, 2-hydroxy-tert-butylamine, or tris-(hydroxymethyl)methylamine, N,N-di-lower alkyl-N-(hydroxy lower alkyl)- amines, such as N,N-dimethyl-N-(2-
  • each of one or more of the first group's hydrogen atoms is replaced with a second group.
  • each carbon atom of a first group is independently substituted with one or two second groups.
  • each carbon atom of a first group is independently substituted with only one second group.
  • UI urinary incontinence.
  • IBD means inflammatory-bowel disease.
  • IBS means irritable-bowel syndrome.
  • ALS means amyotrophic lateral sclerosis.
  • DMSO means dimethyl sulfoxide.
  • DMF means dimethyl formamide.
  • DCM means dichloromethane.
  • the term "DIEA” means diisopropylethylamine.
  • treatment of includes the amelioration or cessation of a Condition or a symptom thereof.
  • treating includes inhibiting, for example, decreasing the overall frequency of episodes of a Condition or a symptom thereof.
  • prevention of includes the avoidance of the onset of a Condition or a symptom thereof.
  • 4.5 METHODS FOR MAKING THE 3-SUBSTITUTED PYRIDYL COMPOUNDS The 3-substituted Pyridyl Compounds can be made using conventional organic synthesis or by the following illustrative methods shown in the schemes below.
  • the 3-substituted Pyridyl Compounds of Formula (I) and (II) can be obtained using conventional organic syntheses or by the following illustrative methods shown in below in Scheme 1.
  • Suitable protecting groups for hydroxyl group include, but are not limited to, methyl ether, methoxymethyl ether, methoxythiomethyl ether, 2-methoxyethoxymethyl ether, bis(2-chloroethoxy)ethyl ether, tetrahydropyranyl ether, tetrahydrothiopyranyl ether, 4-methoxytetrahydropyranyl ether, methoxytetrahydrothiopyranyl ether, tetrahydrofuranyl ether, tetrahydrothiofuranyl ether, 1-ethoxyethyl ether, 1-methyl- 1-methoxyethyl ether, 2-(phenylselenyl ether), tert-butyl ether, allyl ether, benzyl ether, o-nitrobenzyl ether, triphenylmethyl ether, o-napthyldiphenylmethyl ether, /?-methoxydipheny
  • the compound of formula A can be prepared by reacting a 3-halo-substituted pyridine of formula D with a piperazine E in chloroform, in the presence of triethylamine at a temperature of about 50°C as shown below in Scheme 2.
  • Isothiocyanates B and C are commercially available or preparable by reacting an amine of formula F or G with thiophosgene (See, e.g., Tetrahedron Lett, 41(37):7207- 7209 (2000); Synlett 11: 1784-1786 (1999); Heterocycles 32:2343-2355 (1991); Org. Prep., Proced., Int. 23(6):729-734 (1991); J.
  • isothiocyanates B and C can be prepared by reacting an amine of formula F or G with carbon disulfide in the presence of triethylamine in tetrahydrofuran, followed by reaction with hydrogen peroxide and hydrochloric acid in water (See, e.g., J. Org. Chem., 62 (13), 4539-4540 (1997)).
  • the 3-substituted Pyridyl Compounds of Formula (I) and (II) where X is O can also be prepared by reacting an amine of formula F or G with 4- nitrophenylchloroformate (commercially available from Sigma-Aldrich, St. Louis, MO (www.sigma-aldrich.com)) to provide a carbamate, Compound H or I, and then reacting Compound H or I with Compound A as shown below in Schemes 3 and 4 (See, e.g., J. Org. Chem. 63(23):8515-8521 (1998) and European Patent Publication No. 549 039).
  • 4- nitrophenylchloroformate commercially available from Sigma-Aldrich, St. Louis, MO (www.sigma-aldrich.com)
  • the 3-substituted Pyridyl Compounds are administered to an animal in need of treatment or prevention of a Condition.
  • an effective amount of a 3-substituted Pyridyl Compound can be used to treat or prevent any condition treatable or preventable by inhibiting VRl .
  • conditions that are treatable or preventable by inhibiting VRl include, but are not limited to, pain, UI, an ulcer, IBD, and IBS.
  • an effective amount of a 3-substituted Pyridyl Compound can be used to treat or prevent any condition treatable or preventable by inhibiting mGluR5.
  • Examples of conditions that are treatable or preventable by inhibiting mGluR5 include, but are not limited to, pain, an addictive disorder, Parkinson's disease, parkinsonism, anxiety, a pruritic condition, and psychosis.
  • an effective amount of a 3-substituted Pyridyl Compound can be used to treat or prevent any condition treatable or preventable by inhibiting mGluRl .
  • Examples of conditions that are treatable or preventable by inhibiting mGluRl include, but are not limited to, pain, UI, an addictive disorder, Parkinson's disease, parkinsonism, anxiety, epilepsy, stroke, a seizure, a pruritic condition, psychosis, a cognitive disorder, a memory deficit, restricted brain function, Huntington's chorea, ALS, dementia, retinopathy, a muscle spasm, a migraine, vomiting, dyskinesia, and depression.
  • the 3-substituted Pyridyl Compounds can be used to treat or prevent acute or chronic pain.
  • Examples of pain treatable or preventable using the 3-substituted Pyridyl Compounds include, but are not limited to, cancer pain, labor pain, myocardial infarction pain, pancreatic pain, colic pain, post-operative pain, headache pain, muscle pain, arthritic pain, and pain associated with a periodontal disease, including gingivitis and periodontitis.
  • the 3-substituted Pyridyl Compounds can also be used for treating or preventing pain associated with inflammation or with an inflammatory disease in an animal. Such pain can arise where there is an inflammation of the body tissue which can be a local inflammatory response and/or a systemic inflammation.
  • the 3-substituted Pyridyl Compounds can be used to treat or prevent pain associated with inflammatory diseases including, but not limited to: organ transplant rejection; reoxygenation injury resulting from organ transplantation (see Grupp et al, J.
  • the 3-substituted Pyridyl Compounds can also be used for inhibiting, treating, or preventing pain associated with inflammatory disease that can, for example, be a systemic inflammation of the body, exemplified by gram-positive or gram negative shock, hemorrhagic or anaphylactic shock, or shock induced by cancer chemotherapy in response to pro-inflammatory cytokines, e.g., shock associated with pro-inflammatory cytokines. Such shock can be induced, e.g., by a chemotherapeutic agent that is administered as a treatment for cancer.
  • the 3-substituted Pyridyl Compounds can be used to treat or prevent UI.
  • Examples of UI treatable or preventable using the 3-substituted Pyridyl Compounds include, but are not limited to, urge incontinence, stress incontinence, overflow incontinence, neurogenic incontinence, and total incontinence.
  • the 3-substituted Pyridyl Compounds can be used to treat or prevent an ulcer.
  • Examples of ulcers treatable or preventable using the 3-substituted Pyridyl Compounds include, but are not limited to, a duodenal ulcer, a gastric ulcer, a marginal ulcer, an esophageal ulcer, or a stress ulcer.
  • the 3-substituted Pyridyl Compounds can be used to treat or prevent IBD, including Crohn's disease and ulcerative colitis.
  • the 3-substituted Pyridyl Compounds can be used to treat or prevent IBS.
  • IBS treatable or preventable using the 3-substituted Pyridyl Compounds include, but are not limited to, spastic-colon-type IBS and constipation-predominant IBS.
  • the 3-substituted Pyridyl Compounds can be used to treat or prevent an addictive disorder, including but not limited to, an eating disorder, an impulse-control disorder, an alcohol-related disorder, a nicotine-related disorder, an amphetamine-related disorder, a cannabis-related disorder, a cocaine-related disorder, an hallucinogen-related disorder, an inhalant-related disorders, and an opioid-related disorder, all of which are further sub- classified as listed below.
  • Eating disorders include, but are not limited to, Bulimia Nervosa, Nonpurging Type; Bulimia Nervosa, Purging Type; Anorexia; and Eating Disorder not otherwise specified (NOS).
  • Impulse control disorders include, but are not limited to, Intermittent Explosive Disorder, Kleptomania, Pyromania, Pathological Gambling, Trichotillomania, and Impulse Control Disorder not otherwise specified (NOS).
  • Alcohol-related disorders include, but are not limited to, Alcohol Induced Psychotic Disorder with delusions, Alcohol Abuse, Alcohol Intoxication, Alcohol Withdrawal, Alcohol Intoxication Delirium, Alcohol Withdrawal Delirium, Alcohol Induced Persisting Dementia, Alcohol Induced Persisting Amnestic Disorder, Alcohol Dependence, Alcohol Induced Psychotic Disorder with hallucinations, Alcohol Induced Mood Disorder, Alcohol Induced Anxiety Disorder, Alcohol Induced sexual Dysfunction, Alcohol Induced Sleep Disorder, and Alcohol Related Disorder not otherwise specified (NOS).
  • Nicotine-related disorders include, but are not limited to, Nicotine Dependence,
  • Amphetamine-related disorders include, but are not limited to, Amphetamine Dependence, Amphetamine Abuse, Amphetamine Intoxication, Amphetamine Withdrawal, Amphetamine Intoxication Delirium, Amphetamine Induced Psychotic Disorder with delusions, Amphetamine Induced Psychotic Disorders with hallucinations, Amphetamine Induced Mood Disorder, Amphetamine Induced Anxiety Disorder, Amphetamine Induced sexual Dysfunction, Amphetamine Induced Sleep Disorder, and Amphetamine Related Disorder not otherwise specified (NOS).
  • Cannabis-related disorders include, but are not limited to, Cannabis Dependence, Cannabis Abuse, Cannabis Intoxication, Cannabis Intoxication Delirium, Cannabis
  • Cocaine-related disorders include, but are not limited to, Cocaine Dependence, Cocaine Abuse, Cocaine Intoxication, Cocaine Withdrawal, Cocaine Intoxication Delirium, Cocaine Induced Psychotic Disorder with delusions, Cocaine Induced Psychotic Disorders with hallucinations, Cocaine Induced Mood Disorder, Cocaine Induced Anxiety Disorder, Cocaine Induced Sexual Dysfunction, Cocaine Induced Sleep Disorder, and Cocaine Related Disorder not otherwise specified (NOS).
  • Hallucinogen-related disorders include, but are not limited to, Hallucinogen Dependence, Hallucinogen Abuse, Hallucinogen Intoxication, Hallucinogen Withdrawal, Hallucinogen Intoxication Delirium, Hallucinogen Persisting Perception Disorder (Flashbacks), Hallucinogen Induced Psychotic Disorder with delusions, Hallucinogen Induced Psychotic Disorders with hallucinations, Hallucinogen Induced Mood Disorder, Hallucinogen Induced Anxiety Disorder, Hallucinogen Induced sexual Dysfunction, Hallucinogen Induced Sleep Disorder, and Hallucinogen Related Disorder not otherwise specified (NOS).
  • Inhalant-related disorders include, but are not limited to, Inhalant Dependence, Inhalant Abuse, Inhalant Intoxication, Inhalant Intoxication Delirium, Inhalant Induced Psychotic Disorder with delusions, Inhalant Induced Psychotic Disorder with hallucinations, Inhalant Induced Anxiety Disorder, and Inhalant Related Disorder not otherwise specified (NOS).
  • Opioid-related disorders include, but are not limited to, Opioid Dependence, Opioid Abuse, Opioid Withdrawal, Opioid Intoxication, Opioid Intoxication Delirium, Opioid Induced Psychotic Disorder with delusions, Opioid Induced Psychotic Disorder with hallucinations, Opioid Induced Anxiety Disorder, and Opioid Related Disorder not otherwise specified (NOS).
  • the 3-substituted Pyridyl Compounds can be used to treat or prevent Parkinson's disease and parkinsonism and the symptoms associated with Parkinson's disease and parkinsonism, including but not limited to, bradykinesia, muscular rigidity, resting tremor, and impairment of postural balance.
  • the 3-substituted Pyridyl Compounds can be used to treat or prevent generalized anxiety or severe anxiety and the symptoms associated with anxiety, including but not limited to, restlessness; tension; tachycardia; dyspnea; depression, including chronic "neurotic" depression; panic disorder; agoraphobia and other specific phobias; eating disorders; and personality disorders.
  • the 3-substituted Pyridyl Compounds can be used to treat or prevent epilepsy, including but not limited to, partial epilepsy, generalized epilepsy, and the symptoms associated with epilepsy, including but not limited to, simple partial seizures, jacksonian seizures, complex partial (psychomotor) seizures, convulsive seizures (grand mal or tonic-clonic seizures), petit mal (absence) seizures, and status epilepticus.
  • the 3-substituted Pyridyl Compounds can be used to treat or prevent a stroke, including but not limited to, an ischemic stroke and a hemorrhagic stroke.
  • the 3-substituted Pyridyl Compounds can be used to treat or prevent a seizure, including but not limited to, infantile spasms, febrile seizures, and epileptic seizures.
  • the 3-substituted Pyridyl Compounds can be used to treat or prevent a pruritic condition, including but not limited to, pruritus caused by dry skin, scabies, dermatitis, herpetiformis, atopic dermatitis, pruritus vulvae et am, miliaria, insect bites, pediculosis, contact dermatitis, drug reactions, urticaria, urticarial eruptions of pregnancy, psoriasis, lichen planus, lichen simplex chronicus, exfoliative dermatitis, folliculitis, bullous pemphigoid, or fiberglass dermatitis.
  • the 3-substituted Pyridyl Compounds can be used to treat or prevent psychosis, including but not limited to, schizophrenia, including paranoid schizophrenia, hebephrenic or disorganized schizophrenia, catatonic schizophrenia, undifferentiated schizophrenia, negative or deficit subtype schizophrenia, and non-deficit schizophrenia; a delusional disorder, including erotomanic subtype delusional disorder, grandiose subtype delusional disorder, ashamed subtype delusional disorder, persecutory subtype delusional disorder, and somatic subtype delusional disorder; and brief psychosis.
  • schizophrenia including paranoid schizophrenia, hebephrenic or disorganized schizophrenia, catatonic schizophrenia, undifferentiated schizophrenia, negative or deficit subtype schizophrenia, and non-deficit schizophrenia
  • a delusional disorder including erotomanic subtype delusional disorder, grandiose subtype delusional disorder, ashamed subtype delusional disorder, persecutory subtype delusional disorder, and somatic subtype delusional disorder
  • the 3-substituted Pyridyl Compounds can be used to treat or prevent a cognitive disorder, including but not limited to, delirium and dementia such as multi-infarct dementia, dementia pugilistica, dementia caused by AIDS, and dementia caused by Alzheimer's disease.
  • the 3-substituted Pyridyl Compounds can be used to treat or prevent a memory deficiency, including but not limited to, dissociative amnesia and dissociative fugue.
  • the 3-substituted Pyridyl Compounds can be used to treat or prevent restricted brain function, including but not limited to, that caused by surgery or an organ transplant, restricted blood supply to the brain, a spinal cord injury, a head injury, hypoxia, cardiac arrest, or hypoglycemia.
  • the 3-substituted Pyridyl Compounds can be used to treat or prevent
  • the 3-substituted Pyridyl Compounds can be used to treat or prevent ALS.
  • the 3-substituted Pyridyl Compounds can be used to treat or prevent retinopathy, including but not limited to, arteriosclerotic retinopathy, diabetic arteriosclerotic retinopathy, hypertensive retinopathy, non-proliferative retinopathy, and proliferative retinopathy.
  • the 3-substituted Pyridyl Compounds can be used to treat or prevent a muscle spasm.
  • the 3-substituted Pyridyl Compounds can be used to treat or prevent a migraine.
  • the 3-substituted Pyridyl Compounds can be used to treat, inhibit, or prevent vomiting, including but not limited to, nausea vomiting, dry vomiting (retching), and regurgitation.
  • the 3-substituted Pyridyl Compounds can be used to treat or prevent dyskinesia, including but not limited to, tardive dyskinesia and biliary dyskinesia.
  • the 3-substituted Pyridyl Compounds can be used to treat or prevent depression, including but not limited to, major depression and bipolar disorder. Applicants believe that the 3-substituted Pyridyl Compounds are antagonists for VRl.
  • the invention also relates to methods for inhibiting VRl function in a cell, comprising contacting a cell capable of expressing VRl with an effective amount of a 3- substituted Pyridyl Compound.
  • This method can be used in vitro, for example, as an assay to select cells that express VRl and, accordingly, are useful as part of an assay to select compounds useful for treating or preventing pain, UI, an ulcer, IBD, or IBS.
  • the method is also useful for inhibiting VRl function in a cell in vivo, in an animal, a human in one embodiment, by contacting a cell, in an animal, with an effective amount of a 3-substituted Pyridyl Compound. In one embodiment, the method is useful for treating or preventing pain in an animal.
  • the method is useful for treating or preventing UI in an animal. In another embodiment, the method is useful for treating or preventing an ulcer in an animal. In another embodiment, the method is useful for treating or preventing IBD in an animal. In another embodiment, the method is useful for treating or preventine IBS in an animal.
  • tissue comprising cells capable of expressing VRl include, but are not limited to, neuronab brain, kidney, urothelium, and bladder tissue. Methods for assaying cells that express VRl are known in the art. Applicants believe that the 3-substituted Pyridyl Compounds are antagonists for mGluR5.
  • the invention also relates to methods for inhibiting mGluR5 function in a cell, comprising contacting a cell capable of expressing mGluR5 with an amount of a 3-substituted Pyridyl Compound effective to inhibit mGluR5 function in the cell.
  • This method can be used in vitro, for example, as an assay to select cells that express mGluR5 and, accordingly, are useful as part of an assay to select compounds useful for treating or preventing pain, an addictive disorder, Parkinson's disease, parkinsonism, anxiety, a pruritic condition, or psychosis.
  • the method is also useful for inhibiting mGluR5 function in a cell in vivo, in an animal, a human in one embodiment, by contacting a cell, in an animal, with an amount of a 3-substituted Pyridyl Compound effective to inhibit mGluR5 function in the cell.
  • the method is useful for treating or preventing pain in an animal in need thereof.
  • the method is useful for treating or preventing an addictive disorder in an animal in need thereof.
  • the method is useful for treating or preventing Parkinson's disease in an animal in need thereof.
  • the method is useful for treating or preventing parkinsonism in an animal in need thereof.
  • the method is useful for treating or preventing anxiety in an animal in need thereof.
  • the method is useful for treating or preventing a pruritic condition in an animal in need thereof.
  • the method is useful for treating or preventing psychosis in an animal in need thereof.
  • Examples of cells capable of expressing mGluR5 are neuronal and glial cells of the central nervous system, particularly the brain, especially in the nucleus accumbens. Methods for assaying cells that express mGluR5 are known in the art. Applicants believe that the 3-substituted Pyridyl Compounds are antagonists for mGluRl.
  • the invention also relates to methods for inhibiting mGluRl function in a cell, comprising contacting a cell capable of expressing mGluRl with an amount of a 3-substituted Pyridyl Compound effective to inhibit mGluRl function in the cell.
  • This method can be used in vitro, for example, as an assay to select cells that express mGluRl and, accordingly, are useful as part of an assay to select compounds useful for treating or preventing pain, UI, an addictive disorder, Parkinson's disease, parkinsonism, anxiety, epilepsy, stroke, a seizure, a pruritic condition, psychosis, a cognitive disorder, a memory deficit, restricted brain function, Huntington's chorea, ALS, dementia, retinopathy, a muscle spasm, a migraine, vomiting, dyskinesia, or depression.
  • the method is also useful for inhibiting mGluRl function in a cell in vivo, in an animal, a human in one embodiment, by contacting a cell, in an animal, with an amount of a 3-substituted Pyridyl Compound effective to inhibit mGluRl function in the cell.
  • the method is useful for treating or preventing pain in an animal in need thereof.
  • the method is useful for treating or preventing UI in an animal in need thereof.
  • the method is useful for treating or preventing an addictive disorder in an animal in need thereof.
  • the method is useful for treating or preventing Parkinson's disease in an animal in need thereof.
  • the method is useful for treating or preventing parkinsonism in an animal in need thereof.
  • the method is useful for treating or preventing anxiety in an animal in need thereof. In another embodiment, the method is useful for treating or preventing epilepsy in an animal in need thereof. In another embodiment, the method is useful for treating or preventing stroke in an animal in need thereof. In another embodiment, the method is useful for treating or preventing a seizure in an animal in need thereof. In another embodiment, the method is useful for treating or preventing a pruritic condition in an animal in need thereof. In another embodiment, the method is useful for treating or preventing psychosis in an animal in need thereof. In another embodiment, the method is useful for treating or preventing a cognitive disorder in an animal in need thereof. In another embodiment, the method is useful for treating or preventing a memory deficit in an animal in need thereof.
  • the method is useful for treating or preventing restricted brain function in an animal in need thereof. In another embodiment, the method is useful for treating or preventing Huntington's chorea in an animal in need thereof. In another embodiment, the method is useful for treating or preventing ALS in an animal in need thereof. In another embodiment, the method is useful for treating or preventing dementia in an animal in need thereof. In another embodiment, the method is useful for treating or preventing retinopathy in an animal in need thereof. In another embodiment, the method is useful for treating or preventing a muscle spasm in an animal in need thereof. In another embodiment, the method is useful for treating or preventing a migraine in an animal in need thereof. In another embodiment, the method is useful for treating, preventing, or inhibiting vomiting in an animal in need thereof.
  • the method is useful for treating or preventing dyskinesia in an animal in need thereof.
  • the method is useful for treating or preventing depression in an animal in need thereof.
  • Examples of cells capable of expressing mGluRl include, but are not limited to, cerebellar Purkinje neuron cells, Purkinje cell bodies (punctate), cells of spine(s) of the cerebellum; neurons and neurophil cells of olfactory-bulb glomeruli; cells of the superficial layer of the cerebral cortex; hippocampus cells; thalamus cells; superior colliculus cells; and spinal trigeminal nucleus cells. Methods for assaying cells that express mGluRl are known in the art.
  • the 3-substituted Pyridyl Compounds are useful for treating or preventing a Condition in an animal in need thereof.
  • the 3-substituted Pyridyl Compounds are administered as a component of a composition that comprises a pharmaceutically acceptable carrier or excipient.
  • the present compositions, which comprise a 3-substituted Pyridyl Compound can be administered orally.
  • the 3-substituted Pyridyl Compounds of the invention can also be administered by any other convenient route, for example, by infusion or bolus injection, by absorption through epithelial or mucocutaneous linings (e.g., oral, rectal, and intestinal mucosa, etc.) and can be administered together with another therapeutically active agent. Administration can be systemic or local.
  • Various delivery systems are known, e.g., encapsulation in liposomes, microparticles, microcapsules, or capsules and can be used to administer the 3-substituted Pyridyl Compound.
  • Methods of administration include, but are not limited to, intradermal, intramuscular, intraperitoneab intravenous, subcutaneous, intranasab epidurab oral, sublinguab intracerebrab intravaginab transdermal, rectal, by inhalation, or topical, particularly to the ears, nose, eyes, or skin.
  • the mode of administration is left to the discretion of the practitioner. In most instances, administration will result in the release of the 3-substituted Pyridyl Compounds into the bloodstream.
  • This can be achieved, for example, and not by way of limitation, by local infusion during surgery, topical application, e.g., in conjunction with a wound dressing after surgery, by injection, by means of a catheter, by means of a suppository or enema, or by means of an implant, said implant being of a porous, non-porous, or gelatinous material, including membranes, such as sialastic membranes, or fibers.
  • Intraventricular injection can be facilitated by an intraventricular catheter, for example, attached to a reservoir, such as an Ommaya reservoir.
  • Pulmonary administration can also be employed, e.g., by use of an inhaler or nebulizer, and formulation with an aerosolizing agent, or via perfusion in a fluorocarbon or synthetic pulmonary surfactant.
  • the 3-substituted Pyridyl Compounds can be formulated as a suppository, with traditional binders and excipients such as triglycerides.
  • the 3-substituted Pyridyl Compounds can be delivered in a vesicle, in particular a liposome (see Langer, Science 249:1527-1533 (1990) and Treat et al, Liposomes in the Therapy of Infectious Disease and Cancer 311-321 and 353-365 (1989)).
  • the 3-substituted Pyridyl Compounds can be delivered in a controlled-release system or sustained-release system (see, e.g., Goodson, in Medical Applications of Controlled Release, supra, vol. 2, pp. 115-138 (1984)).
  • Other controlled- or sustained-release systems discussed in the review by Langer, Science 249:1527-1533 (1990) can be used.
  • a pump can be used (Langer, Science 249:1527-1533 (1990); Sefton, CRC Crit. Ref. Biomed. Eng. 14:201 (1987); Buchwald et al, Surgery 88:507 (1980); and Saudek ei al, N. Eng J. Med. 321:574 (1989)).
  • polymeric materials can be used (see Medical Applications of Controlled Release (Langer and Wise eds., 1974); Controlled Drug Bioavailability, Drug Product Design and Performance (Smolen and Ball eds., 1984); Ranger and Peppas, J. Macromol Sci. Rev. Macromol Chem. 23:61 (1983); Levy et al, Science 228:190 (1985); During et al., Ann. Neurol 25:351 (1989); and Howard et al, J. Neurosurg. 71:105 (1989)).
  • a controlled- or sustained- release system can be placed in proximity of a target of the 3-substituted Pyridyl Compounds, e.g., the spinal column, brain, or gastrointestinal tract, thus requiring only a fraction of the systemic dose.
  • the present compositions can optionally comprise a suitable amount of a pharmaceutically acceptable excipient so as to provide the form for proper administration to the animal.
  • a pharmaceutically acceptable excipients can be liquids, such as water and oils, including those of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like.
  • the pharmaceutical excipients can be saline, gum acacia, gelatin, starch paste, talc, keratin, colloidal silica, urea and the like.
  • auxiliary, stabilizing, thickening, lubricating, and coloring agents can be used.
  • the pharmaceutically acceptable excipients are sterile when administered to an animal. Water is a particularly useful excipient when the 3- substituted Pyridyl Compound is administered intravenously. Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid excipients, particularly for injectable solutions.
  • Suitable pharmaceutical excipients also include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycob water, ethanol and the like.
  • the present compositions can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents.
  • compositions can take the form of solutions, suspensions, emulsion, tablets, pills, pellets, capsules, capsules containing liquids, powders, sustained-release formulations, suppositories, emulsions, aerosols, sprays, suspensions, or any other form suitable for use.
  • the composition is in the form of a capsule (see e.g., U.S. Patent No. 5,698,155).
  • suitable pharmaceutical excipients are described in Remington's Pharmaceutical Sciences 1447-1676 (Alfonso R. Gennaro ed., 19th ed. 1995), incorporated herein by reference.
  • compositions for oral delivery can be in the form of tablets, lozenges, aqueous or oily suspensions, granules, powders, emulsions, capsules, syrups, or elixirs, for example.
  • Orally administered compositions can contain one or more agents, for example, sweetening agents such as fructose, aspartame or saccharin; flavoring agents such as peppermint, oil of wintergreen, or cherry; coloring agents; and preserving agents, to provide a pharmaceutically palatable preparation.
  • compositions can be coated to delay disintegration and absorption in the gastrointestinal tract thereby providing a sustained action over an extended period of time.
  • Selectively permeable membranes surrounding an osmotically active driving compound are also suitable for orally administered compositions. In these latter platforms, fluid from the environment surrounding the capsule is imbibed by the driving compound, which swells to displace the agent or agent composition through an aperture.
  • These delivery platforms can provide an essentially zero order delivery profile as opposed to the spiked profiles of immediate release formulations.
  • a time-delay material such as glycerol monostearate or glycerol stearate can also be used.
  • compositions can include standard excipients such as mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, and magnesium carbonate.
  • the excipients are of pharmaceutical grade.
  • the 3-substituted Pyridyl Compounds can be formulated for intravenous administration.
  • compositions for intravenous administration comprise sterile isotonic aqueous buffer.
  • the compositions can also include a solubilizing agent.
  • Compositions for intravenous administration can optionally include a local anesthetic such as lidocaine to lessen pain at the site of the injection.
  • the ingredients are supplied either separately or mixed together in unit dosage form, for example, as a dry lyophilized powder or water free concentrate in a hermetically sealed container such as an ampule or sachette indicating the quantity of active agent.
  • a hermetically sealed container such as an ampule or sachette indicating the quantity of active agent.
  • the 3-substituted Pyridyl Compounds are to be administered by infusion, they can be dispensed, for example, with an infusion bottle containing sterile pharmaceutical grade water or saline.
  • an ampule of sterile water for injection or saline can be provided so that the ingredients can be mixed prior to administration.
  • the 3-substituted Pyridyl Compounds can be administered by controlled-release or sustained-release means or by delivery devices that are known to those of ordinary skill in the art. Examples include, but are not limited to, those described in U.S. Patent Nos.: 3,845,770; 3,916,899; 3,536,809; 3,598,123; 4,008,719; 5,674,533; 5,059,595; 5,591,767; 5,120,548; 5,073,543; 5,639,476; 5,354,556; and 5,733,566, each of which is incorporated herein by reference.
  • Such dosage forms can be used to provide controlled- or sustained-release of one or more active ingredients using, for example, hydropropylmethyl cellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, microspheres, or a combination thereof to provide the desired release profile in varying proportions.
  • active ingredients for example, hydropropylmethyl cellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, microspheres, or a combination thereof to provide the desired release profile in varying proportions.
  • Suitable controlled- or sustained-release formulations known to those of ordinary skill in the art, including those described herein, can be readily selected for use with the active ingredients of the invention.
  • the invention thus encompasses single unit dosage forms suitable for oral administration such as, but not limited to, tablets, capsules, gelcaps, and caplets that are adapted for controlled- or sustained-release.
  • Controlled- or sustained-release pharmaceutical compositions can have a common goal of improving drug therapy over that achieved by their non-controlled or non-sustained counterparts.
  • a controlled- or sustained-release composition comprises a minimal amount of a 3-substituted Pyridyl Compound to cure or control the condition in a minimum amount of time.
  • controlled- or sustained-release compositions include extended activity of the drug, reduced dosage frequency, and increased patient compliance.
  • controlled- or sustained- release compositions can favorably affect the time of onset of action or other characteristics, such as blood levels of the 3-substituted Pyridyl Compound, and can thus reduce the occurrence of adverse side effects.
  • Controlled- or sustained-release compositions can initially release an amount of a 3-substituted Pyridyl Compound that promptly produces the desired therapeutic or prophylactic effect, and gradually and continually release other amounts of the 3-substituted Pyridyl Compound to maintain this level of therapeutic or prophylactic effect over an extended period of time.
  • the 3-substituted Pyridyl Compound can be released from the dosage form at a rate that will replace the amount of 3-substituted Pyridyl Compound being metabolized and excreted from the body.
  • Controlled- or sustained- release of an active ingredient can be stimulated by various conditions, including but not limited to, changes in pH, changes in temperature, concentration or availability of enzymes, concentration or availability of water, or other physiological conditions or compounds.
  • the amount of the 3-substituted Pyridyl Compound that is effective in the treatment or prevention of a condition can be determined by standard clinical techniques.
  • in vitro or in vivo assays can optionally be employed to help identify optimal dosage ranges.
  • the precise dose to be employed will also depend on the route of administration, and the seriousness of the Condition and can be decided according to the judgment of a practitioner and and/or each animal's circumstances. Suitable effective dosage amounts, however, range from about 0.01 mg kg of body weight to about 2500 mg kg of body weight, although they are typically about 100 mg/kg of body weight or less.
  • the effective dosage amount ranges from about 0.01 mg/kg of body weight to about 100 mg kg of body weight of a 3-substituted Pyridyl Compound, in another embodiment, about 0.02 mg kg of body weight to about 50 mg/kg of body weight, and in another embodiment, about 0.025 mg/kg of body weight to about 20 mg/kg of body weight.
  • an effective dosage amount is administered about every 24 h until the Condition is abated.
  • an effective dosage amount is administered about every 12 h until the Condition is abated.
  • an effective dosage amount is administered about every 8 h until the
  • an effective dosage amount is administered about every 6 h until the Condition is abated. In another embodiment, an effective dosage amount is administered about every 4 h until the Condition is abated.
  • the effective dosage amounts described herein refer to total amounts administered; that is, if more than one 3-substituted Pyridyl Compound is administered, the effective dosage amounts correspond to the total amount administered.
  • the amount effective for inhibiting the VRl, mGluR5 or mGluRl receptor function in a cell will typically range from about 0.01 ⁇ g/L to about 5 mg/L, in one embodiment, from about 0.01 ⁇ g/L to about 2.5 mg/L, in another embodiment, from about 0.01 ⁇ g/L to about 0.5 mg/L, and in another embodiment, from about 0.0 ⁇ ⁇ g/L to about 0.25 mg L of a solution or suspension of a pharmaceutically acceptable carrier or excipient.
  • the volume of solution or suspension comprising the 3-substituted Pyridyl Compound is from about 0.01 ⁇ L to about 1 mL. In another embodiment, the volume of solution or suspension is about 200 ⁇ L.
  • the amount effective for inhibiting the receptor function in a cell will typically range from about 0.01 mg/kg of body weight to about 2500 mg/kg of body weight, although it typically ranges from about 100 mg/kg of body weight or less.
  • the effective dosage amount ranges from about 0.01 mg/kg of body weight to about 100 mg/kg of body weight of a 3-substituted Pyridyl Compound, in another embodiment, about 0.020 mg/kg of body weight to about 50 mg/kg of body weight, and in another embodiment, about 0.025 mg/kg of body weight to about 20 mg/kg of body weight.
  • an effective dosage amount is administered about every 24 h.
  • an effective dosage amount is administered about every 12 h.
  • an effective dosage amount is administered about every 8 h.
  • an effective dosage amount is administered about every 6 h.
  • an effective dosage amount is administered about every 4 h.
  • the 3-substituted Pyridyl Compounds can be assayed in vitro or in vivo for the desired therapeutic or prophylactic activity prior to use in humans.
  • Animal model systems can be used to demonstrate safety and efficacy.
  • the present methods for treating or preventing a Condition in an animal in need thereof can further comprise administering to the animal being administered a 3-substituted Pyridyl Compound another therapeutic agent.
  • the other therapeutic agent is administered in an effective amount.
  • VRl can further comprise contacting the cell with an effective amount of another therapeutic agent.
  • the present methods for inhibiting mGluR5 function in a cell capable of expressing mGluR5 can further comprise contacting the cell with an effective amount of another therapeutic agent.
  • the present methods for inhibiting mGluRl function in a cell capable of expressing mGluRl can further comprise contacting the cell with an effective amount of another therapeutic agent.
  • Effective amounts of the other therapeutic agents are known to those skilled in the art. However, it is within the skilled artisan's purview to determine the other therapeutic agent's optimal effective- amount range.
  • the effective amount of the 3-substituted Pyridyl Compound is less than its effective amount would be where the other therapeutic agent is not administered.
  • the 3-substituted Pyridyl Compound s and the other therapeutic agent act synergistically to treat or prevent a Condition.
  • the other therapeutic agent can be, but is not limited to, an opioid agonist, a non- opioid analgesic, a non-steroidal anti-inflammatory agent, an antimigraine agent, a Cox- II inhibitor, an antiemetic, a ⁇ -adrenergic blocker, an anticonvulsant, an antidepressant, a Ca2+-channel blocker, an anticancer agent, an agent for treating or preventing UI, an agent for treating or preventing an ulcer, an agent for treating or preventing IBD, an agent for treating or preventing IBS, an agent for treating addictive disorder, an agent for treating Parkinson's disease and parkinsonism, an agent for treating anxiety, an agent for treating epilepsy, an agent for treating a stroke, an agent for treating a seizure, an agent for treating a pruritic condition, an agent for treating psychosis, an agent for treating Huntington's chorea, an agent for treating ALS, an agent for treating a cognitive disorder, an agent for treating a migraine, an agent for treating vomiting
  • Examples of useful opioid agonists include, but are not limited to, alfentanib allylprodine, alphaprodine, anileridine, benzylmorphine, bezitramide, buprenorphine, butorphanob clonitazene, codeine, desomorphine, dextromoramide, dezocine, diampromide, diamorphone, dihydrocodeine, dihydromorphine, dimenoxadob dimepheptanob dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene fentanyb heroin, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levorphanob levophenacylmorphan, lofentanib meperidine, m
  • the opioid agonist is selected from codeine, hydromorphone, hydrocodone, oxycodone, dihydrocodeine, dihydromorphine, morphine, tramadob oxymorphone, pharmaceutically acceptable salts thereof, and mixtures thereof.
  • non-steroidal anti-inflammatory agents such as aspirin, ibuprofen, diclofenac, naproxen, benoxaprofen, flurbiprofen, fenoprofen, flubufen, ketoprofen, indoprofen, piroprofen, carprofen, oxaprozin, pramoprofen, muroprofen, trioxaprofen, suprofen, aminoprofen, tiaprofenic acid, fluprofen, bucloxic acid, indomethacin, sulindac, tolmetin, zomepirac, tiopinac, zidometacin, acemetacin, fentiazac, clidanac, oxpinac, mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid, tolfenamic acid
  • non-opioid analgesics include the following, non-limiting, chemical classes of analgesic, antipyretic, nonsteroidal anti-inflammatory drugs: salicylic acid derivatives, including aspirin, sodium salicylate, choline magnesium trisalicylate, salsalate, diflunisal, salicylsalicylic acid, sulfasalazine, and olsalazin; para-aminophenol derivatives including acetaminophen and phenacetin; indole and indene acetic acids, including indomethacin, sulindac, and etodolac; heteroaryl acetic acids, including tolmetin, diclofenac, and ketorolac; anthranilic acids (fenamates), including mefenamic acid and meclofenamic acid; enolic acids, including oxicams (piroxicam, tenoxicam), and pyrazolidinediones (phenylbutazone
  • useful antimigraine agents include, but are not limited to, alpiropride, bromocriptine, dihydroergotamine, dolasetron, ergocomine, ergocominine, ergocryptine, ergonovine, ergot, ergotamine, flumedroxone acetate, fonazine, ketanserin, lisuride, lomerizine, methylergonovine, methysergide, metoprolob naratriptan, oxetorone, pizotyline, propranolob risperidone, rizatriptan, sumatriptan, timolob trazodone, zolmitriptan, and mixtures thereof.
  • the other therapeutic agent can also be an agent useful for reducing any potential side effect of a 3-substituted Pyridyl Compounds.
  • the other therapeutic agent can be an antiemetic agent.
  • useful antiemetic agents include, but are not limited to, metoclopromide, domperidone, prochlorperazine, promethazine, chlorpromazine, trimethobenzamide, odansteron, granisetron, hydroxyzine, acetylleucine monoethanol amine, alizapride, azasetron, benzquinamide, bietanautine, bromopride, buclizine, clebopride, cyclizine, dimenhydrinate, diphenidol, dolasetron, meclizine, methallatal, metopimazine, nabilone, oxyperndyb pipamazine, scopolamine, sulpiride, tetrahydrocannabinob thieth
  • ⁇ -adrenergic blockers include, but are not limited to, acebutolol, alprenolol, amosulabol, arotinolol, atenolol, befunolob betaxolob bevantolob bisoprolob bopindolob bucumolob bufetolob bufuralob bunitrolob bupranolob butidrine hydrochloride, butofilolol, carazolol, carteolol, carvedilol, celiprolol, cetamolol, cloranolob dilevalob epanolob esmolob indenolob labetalob levobunolob mepindolol, metipranolob metoprolob moprolob nadolob nadoxolob nebivalob nifenalob nipradilob oxprenolob penbutolob pindolob practolob pronethalob
  • Examples of useful antidepressants include, but are not limited to, binedaline, caroxazone, citalopram, (S)-citalopram, dimethazan, fencamine, indalpine, indeloxazine hydrocholoride, nefopam, nomifensine, oxitriptan, oxypertine, paroxetine, sertraline, thiazesim, trazodone, benmoxine, iproclozide, iproniazid, isocarboxazid, nialamide, octamoxin, phenelzine, cotinine, rolicyprine, rolipram, maprotiline, metralindole, mianserin, mirtazepine, adinazolam, amitriptyline, amitriptylinoxide, amoxapine, butriptyline, clomipramine, demexiptiline
  • Ca2+-channel blockers examples include, but are not limited to, bepridil, clentiazem, diltiazem, fendiline, gallopam ⁇ , mibefradib prenylamine, semotiadib terodiline, verapamib amlodipine, aranidipine, barnidipine, benidipine, cilnidipine, efonidipine, elgodipine, felodipine, isradipine, lacidipine, lercanidipine, manidipine, nicardipine, nifedipine, nilvadipine, nimodipine, nisoldipine, nitrendipine, cinnarizine, flunarizine, lidoflazine, lomerizine, bencyclane, etafenone, fantofarone, and perhexiiine.
  • useful anticancer agents include, but are not limited to, acivicin, aclarubicin, acodazole hydrochloride, acronine, adozelesin, aldesleukin, altretamine, ambomycin, ametantrone acetate, aminoglutethimide, amsacrine, anastrozole, anthramycin, asparaginase, asperlin, azacitidine, azetepa, azotomycin, batimastat, benzodepa, bicalutamide, bisantrene hydrochloride, bisnafide dimesylate, bizelesin, bleomycin sulfate, brequinar sodium, bropirimine, busulfan, cactinomycin, calusterone, caracemide, carbetimer, carboplatin, carmustine, carubicin hydrochloride, carzelesin, cedefingol, chlorambuc ⁇ ,
  • anti-cancer drugs include, but are not limited to, 20-epi-l,25 dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; aclarubicin; acylfulvene; adecypenol; adozelesin; aldesleukin; ALL-TK antagonists; altretamine; ambamustine; amidox; amifostine; aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole; andrographolide; angiogenesis inhibitors; antagonist D; antagonist G; antarelix; anti-dorsalizing morphogenetic protein- 1; antiandrogen, prostatic carcinoma; antiestrogen; antineoplaston; antisense oligonucleotides; aphidicolin glycinate; apoptosis gene modulators; apoptosis regulators; apurinic acid; ara-CDP-DL
  • BCR/ABL antagonists benzochlorins; benzoylstaurosporine; beta lactam derivatives; beta-alethine; betaclamycin B; betulinic acid; bFGF inhibitor; bicalutamide; bisantrene; bisaziridinylspermine; bisnafide; bistratene A; bizelesin; breflate; bropirimine; budotitane; buthionine sulfoximine; calcipotriol; calphostin C; camptothecin derivatives; canarypox 1L-2; capecitabine; carboxamide-amino-triazole; carboxyamidotriazole;
  • ICOS castanospermine
  • cecropin B cetrorelix
  • chlorlns chloroquinoxaline sulfonamide
  • cicaprost cis-porphyrin
  • cladribine clomifene analogues
  • clotrimazole collismycin A; collismycin B; combretastatin A4; combretastatin analogue; conagenin; crambescidin 816; crisnatol; cryptophycin 8; cryptophycin A derivatives; curacin A; cyclopentanthraquinones; cycloplatam; cypemycin; cytarabine ocfosfate; cytolytic factor; cytostatin; dacliximab; decitabine; dehydrodidemnin B; deslorelin; dexamethasone; dexifosfamide; dexrazoxane; dexverap
  • useful therapeutic agents for treating or preventing UI include, but are not limited to, propantheline, imipramine, hyoscyamine, oxybutynin, and dicyclomine.
  • useful therapeutic agents for treating or preventing an ulcer include, antacids such as aluminum hydroxide, magnesium hydroxide, sodium bicarbonate, and calcium bicarbonate; sucraflate; bismuth compounds such as bismuth subsalicylate and bismuth subcitrate; H 2 antagonists such as cimetidine, ranitidine, famotidine, and nizatidine; H 1" , K + - ATPase inhibitors such as omeprazole, iansoprazole, and lansoprazole; carbenoxolone; misprostol; and antibiotics such as tetracycline, metronidazole, timidazole, clarithromycin, and amoxicillin.
  • useful therapeutic agents for treating or preventing IBD include, but are not limited to, anticholinergic drugs; diphenoxylate; loperamide; deodorized opium tincture; codeine; broad-spectrum antibiotics such as metronidazole; sulfasalazine; olsalazine; mesalamine; prednisone; azathioprine; mercaptopurine; and methotrexate.
  • useful therapeutic agents for treating or preventing IBS include, but are not limited to, propantheline; muscarine receptor antagonists such as pirenzapine, methoctramine, ipratropium, tiotropium, scopolamine, methscopolamine, homatropine, homatropine methylbromide, and methantheline; and antidiarrheal drugs such as diphenoxylate and loperamide.
  • muscarine receptor antagonists such as pirenzapine, methoctramine, ipratropium, tiotropium, scopolamine, methscopolamine, homatropine, homatropine methylbromide, and methantheline
  • antidiarrheal drugs such as diphenoxylate and loperamide.
  • useful therapeutic agents for treating or preventing an addictive disorder include, but are not limited to, methadone, desipramine, amantadine, fluoxetine, buprenorphine, an opiate agonist, 3-phenoxypyridine, levomethadyl acetate hydrochloride, and serotonin antagonists.
  • useful therapeutic agents for treating or preventing Parkinson's disease and parkinsonism include, but are not limited to, carbidopa/levodopa, pergolide, bromocriptine, ropinirole, pramipexole, entacapone, tolcapone, selegiline, amantadine, and trihexyphenidyl hydrochloride.
  • useful therapeutic agents for treating or preventing anxiety include, but are not limited to, benzodiazepines, such as alprazolam, brotizolam, chlordiazepoxide, clobazam, clonazepam, clorazepate, demoxepam, diazepam, estazolam, flumazenil, flurazepam, halazepam, lorazepam, midazolam, nitrazepam, nordazepam, oxazepam, prazepam, quazepam, temazepam, and triazolam; non- benzodiazepine agents, such as buspirone, gepirone, ipsapirone, tiospirone, zolpicone, zolpidem, and zaleplon; tranquiiizers, such as barbituates, e.g., amobarbitab aprobarbitab butabarbitab butalbit
  • useful therapeutic agents for treating or preventing epilepsy include, but are not limited to, carbamazepine, ethosuximide, gabapentin, lamotrigine, phenobarbitab phenytoin, primidone, valproic acid, trimethadione, benzodiazepines, ⁇ -vinyl GABA, acetazolamide, and felbamate.
  • useful therapeutic agents for treating or preventing stroke include, but are not limited to, anticoagulants such as heparin, agents that break up clots such as streptokinase or tissue plasminogen activator, agents that reduce swelling such as mannitol or corticosteroids, and acetylsalicylic acid.
  • useful therapeutic agents for treating or preventing a seizure include, but are not limited to, carbamazepine, ethosuximide, gabapentin, lamotrigine, phenobarbitab phenytoin, primidone, valproic acid, trimethadione, benzodiazepines, gabapentin, lamotrigine, ⁇ -vinyl GABA, acetazolamide, and felbamate.
  • useful therapeutic agents for treating or preventing a pruritic condition include, but are not limited to, naltrexone; nalmefene; danazol; tricyclics such as amitriptyline, imipramine, and doxepin; antidepressants such as those given below, menthol; camphor; phenol; pramoxine; capsaicin; tar; steroids; and antihistamines.
  • useful therapeutic agents for treating or preventing psychosis include, but are not limited to, phenothiazines such as chlorpromazine hydrochloride, mesoridazine besylate, and thoridazine hydrochloride; thioxanthenes such as chloroprothixene and thiothixene hydrochloride; clozapine; risperidone; olanzapine; quetiapine; quetiapine fumarate; haloperidol; haloperidol decanoate; loxapine succinate; molindone hydrochloride; pimozide; and ziprasidone.
  • phenothiazines such as chlorpromazine hydrochloride, mesoridazine besylate, and thoridazine hydrochloride
  • thioxanthenes such as chloroprothixene and thiothixene hydrochloride
  • clozapine
  • Examples of useful therapeutic agents for treating or preventing Huntington's chorea include, but are not limited to, haloperidol and pimozide.
  • Examples of useful therapeutic agents for treating or preventing ALS include, but are not limited to, baclofen, neurotrophic factors, riluzole, tizanidine, benzodiazepines such as clonazepan and dantrolene.
  • Examples of useful therapeutic agents for treating or preventing cognitive disorders include, but are not limited to, agents for treating or preventing dementia such as tacrine; donepezil; ibuprofen; antipsychotic drugs such as thioridazine and haloperidol; and antidepressant drugs such as those given below.
  • useful therapeutic agents for treating or preventing a migraine include, but are not limited to, sumatriptan; methysergide; ergotamine; caffeine; and beta-blockers such as propranolob verapamib and divalproex.
  • useful therapeutic agents for treating, inhibiting, or preventing vomiting include, but are not limited to, 5-HT 3 receptor antagonists such as odansteron, dolasetron, granisetron, and tropisetron; dopamine receptor antagonists such as prochlorperazine, thiethylperazine, chlorpromazin, metoclopramide, and domperidone; glucocorticoids such as dexamethasone; and benzodiazepines such as lorazepam and alprazolam.
  • useful therapeutic agents for treating or preventing dyskinesia include, but are not limited to, reserpine and tetrabenazine.
  • useful therapeutic agents for treating or preventing depression include, but are not limited to, tricyclic anti depressants such as amitryptyline, amoxapine, bupropion, clomipramine, desipramine, doxepin, imipramine, maprotiline, nefazadone, nortriptyline, protriptyline, trazodone, trimipramine, and venlafaxine; selective serotonin reuptake inhibitors such as citalopram, (S)-citalopram, fluoxetine, fluvoxamine, paroxetine, and setraline; monoamine oxidase inhibitors such as isocarboxazid, pargyline, phenelzine, and tranylcypromine; and psychostimulants such as dextroamphetamine and methylphenidate.
  • tricyclic anti depressants such as amitryptyline, amoxapine, bupropion, clomipramine,
  • a 3-substituted Pyridyl Compound and the other therapeutic agent can act additively or, in one embodiment, synergistically.
  • a 3-substituted Pyridyl Compound is administered concurrently with another therapeutic agent; for example, a composition comprising an effective amount of a 3-substituted Pyridyl
  • Compound and an effective amount of another therapeutic agent can be administered.
  • a composition comprising an effective amount of a 3-substituted Pyridyl Compound and a different composition comprising an effective amount of another therapeutic agent can be concurrently administered.
  • an effective amount of a 3-substituted Pyridyl Compound is administered prior or subsequent to administration of an effective amount of another therapeutic agent.
  • the 3-substituted Pyridyl Compound is administered while the other therapeutic agent exerts its therapeutic effect, or the other therapeutic agent is administered while the 3-substituted Pyridyl Compound exerts its therapeutic effect for treating or preventing a Condition.
  • a composition of the invention is prepared by a method comprising admixing a 3-substituted Pyridyl Compound or a pharmaceutically acceptable salt and a pharmaceutically acceptable carrier or excipient. Admixing can be accomplished using methods known for admixing a compound (or salt) and a pharmaceutically acceptable carrier or excipient. In one embodiment the 3-substituted Pyridyl Compound is present in the composition in an effective amount. 4.6.2 KITS The invention encompasses kits that can simplify the administration of a 3-substituted Pyridyl Compound to an animal.
  • a typical kit of the invention comprises a unit dosage form of a 3-substituted Pyridyl Compound.
  • the unit dosage form is a container, which can be sterile, containing an effective amount of a 3-substituted Pyridyl Compound and a pharmaceutically acceptable carrier or excipient.
  • the kit can further comprise a label or printed instructions instructing the use of the 3-substituted Pyridyl Compound to treat a Condition.
  • the kit can also further comprise a unit dosage form of another therapeutic agent, for example, a second container containing an effective amount of the other therapeutic agent and a pharmaceutically acceptable carrier or excipient.
  • the kit comprises a container containing an effective amount of a 3-substituted Pyridyl Compound, an effective amount of another therapeutic agent and a pharmaceutically acceptable carrier or excipient.
  • Kits of the invention can further comprise a device that is useful for administering the unit dosage forms.
  • a device include, but are not limited to, a syringe, a drip bag, a patch, an inhaler, and an enema bag.
  • Compound 3 was obtained by dissolving 5 g of 2-chloro-3-cyano-pyridine (commercially available from Sigma- Aldrich, St. Louis, MO (www.sigma-aldrich.com)), 6.21 g of piperazine (72.16 mmol) (commercially available from Sigma-Aldrich, St. Louis, MO (www.sigma-aldrich.com)), and 1.25 mL (72.16 mmol) of DIEA in DMF and allowing the resulting reaction mixture to stir for about 15 h. Water and ethyl acetate were then added to the reaction mixture, the aqueous and organic phases separated, and the aqueous phase was extracted twice with ethyl acetate.
  • Compound E19 was confirmed using ⁇ H-NMR spectroscopy and mass spectrometry.
  • Compound E19 iH-NMR (400 MHz, CD 3 OD): ⁇ 8.48-8.43 (m, IH), 7.92-7.87
  • Compound 119 was confirmed using ⁇ H-NMR spectroscopy and mass spectrometry.
  • EXAMPLE 6 BINDING OF 3-SUBSTITUTED PYRIDYL COMPOUNDS TO MGLUR5 The following assay can be used to demonstrate that 3-substituted Pyridyl Compounds bind to mGluR5 and, accordingly, are useful for treating or preventing, e.g., pain.
  • Cell cultures Primary glial cultures are prepared from cortices of Sprague- Dawley 18 days old embryos. The cortices are dissected and then dissociated by trituration. The resulting cell homogenate is plated onto poly-D-lysine precoated T175 flasks (BIOCOAT, commercially available from Becton Dickinson and Company Inc.
  • FCS fetal calf serum
  • astrocyte cultures are established by subplating onto 96 poly-D-lysine precoated T175 flasks (BIOCOAT) at a density of 65,000 cells/well in DMEM and 10% FCS. After 24 hours, the astrocytes are washed with serum free medium and then cultured in DMEM, without glutamate, supplemented with 0.5% FCS, 20 mM HEPES, 10 ng/mL epidermal growth factor ("EGF”), 1 mM sodium pyruvate, and IX penicillin/streptomycin at pH 7.5 for 3 to 5 days at 37°C and 5% CO 2 .
  • BIOCOAT poly-D-lysine precoated T175 flasks
  • DMSO solutions containing various concentrations of a 3-substituted Pyridyl Compound diluted in Assay Buffer (0.05 mL of 4X dilutions for competition curves) are added to the cell plate and fluorescence is monitored for 2 minutes.
  • 0.05 mL of a 4X glutamate solution (agonist) is then added to each well to provide a final glutamate concentration in each well of 10 mM. Plate fluorescence is then monitored for an additional 60 seconds after agonist addition.
  • the final DMSO concentration in the assay is 1.0%.
  • fluorescence is monitored as a function of time and the data analyzed using Microsoft Excel and GraphPad Prism.
  • EXAMPLE 7 IN VIVO ASSAYS FOR PREVENTION OR TREATMENT OF PAIN Test Animals: Each experiment uses rats weighing between 200-260 g at the start of the experiment. The rats are group-housed and have free access to food and water at all times, except prior to oral administration of a 3-substituted Pyridyl Compound when food is removed for 16 hours before dosing. A control group acts as a comparison to rats treated with a 3-substituted Pyridyl Compound. The control group is administered the carrier for the 3-substituted Pyridyl Compound.
  • the volume of carrier administered to the control group is the same as the volume of carrier and 3-substituted Pyridyl Compound administered to the test group.
  • Acute Pain To assess the actions of the 3-substituted Pyridyl Compounds for the treatment or prevention of acute pain the rat tail flick test can be used. Rats are gently restrained by hand and the tail exposed to a focused beam of radiant heat at a point 5 cm from the tip using a tail flick unit (Model 7360, commercially available from Ugo Basile of Italy). Tail flick latencies are defined as the interval between the onset of the thermal stimulus and the flick of the tail. Animals not responding within 20 seconds are removed from the tail flick unit and assigned a withdrawal latency of 20 seconds.
  • FCA Freund's complete adjuvant
  • FCA-induced inflammation of the rat hind paw is associated with the development of persistent inflammatory mechanical hyperalgesia and provides reliable prediction of the anti-hyperalgesic action of clinically useful analgesic drugs (L. Bartho et al, "Involvement of Capsaicin-sensitive Neurones in Hyperalgesia and Enhanced Opioid Antinociception in Inflammation," Naunyn-Schmiedeberg's Archives of Pharmacol 342:666-670 (1990)).
  • the left hind paw of each animal is administered a 50 ⁇ L intraplantar injection of 50% FCA. 24 hour post injection, the animal is assessed for response to noxious mechanical stimuli by determining the PWT, as described below.
  • Rats are then administered a single injection of 1, 3, 10 or 30 mg Kg of either a 3-substituted Pyridyl Compound; 30 mg/Kg of a control selected from Celebrex, indomethacin or naproxen; or carrier. Responses to noxious mechanical stimuli are then determined 1, 3, 5 and 24 hours post administration. Percentage reversal of hyperalgesia for each animal is defined as:
  • the Seltzer model To assess the actions of the 3-substituted Pyridyl Compounds for the treatment or prevention of neuropathic pain either the Seltzer model or the Chung model can be used.
  • the Seltzer model the partial sciatic nerve ligation model of neuropathic pain is used to produce neuropathic hyperalgesia in rats (Z. Seltzer et al, "A Novel Behavioral Model of Neuropathic Pain Disorders Produced in Rats by Partial Sciatic Nerve Injury," Pain 43:205-218 (1990)). Partial ligation of the left sciatic nerve is performed under isoflurane/O 2 inhalation anaesthesia.
  • the left thigh of the rat is shaved and the sciatic nerve exposed at high thigh level through a small incision and is carefully cleared of surrounding connective tissues at a site near the trocanther just distal to the point at which the posterior biceps semitendinosus nerve branches off of the common sciatic nerve.
  • a 7-0 silk suture is inserted into the nerve with a 3/8 curved, reversed-cutting mini-needle and tightly ligated so that the dorsal 1/3 to l ⁇ of the nerve thickness is held within the ligature.
  • the wound is closed with a single muscle suture (4-0 nylon (Vicryl)) and vetbond tissue glue. Following surgery, the wound area is dusted with antibiotic powder.
  • the spinal nerve ligation model of neuropathic pain is used to produce mechanical hyperalgesia, thermal hyperalgesia and tactile allodynia in rats.
  • Surgery is performed under isoflurane/O 2 inhalation anaesthesia. Following induction of anaesthesia a 3 cm incision is made and the left paraspinal muscles are separated from the spinous process at the L 4 - S 2 levels. The L ⁇ transverse process is carefully removed with a pair of small rongeurs to identify visually the L 4 - L 6 spinal nerves.
  • the left L 5 (or L 5 and L ⁇ ) spinal nerve(s) is isolated and tightly ligated with silk thread.
  • non-absorbab ⁇ e sutures such as nylon sutures or stainless steel staples.
  • Sham-treated rats undergo an identical surgical procedure except that the spinal nerve(s) is not manipulated. Following surgery animals are weighed, administered a subcutaneous (s.c.) injection of saline or ringers lactate, the wound area is dusted with antibiotic powder and they are kept on a warm pad until they recover from the anesthesia. Animals are then be returned to their home cages until behavioral testing begins.
  • the animals are assessed for response to noxious mechanical stimuli by determining PWT, as described below, prior to surgery (baseline), then immediately prior to and 1, 3, and 5 hours after being administered a 3-substituted Pyridyl Compound for the left rear paw of the animal.
  • the animal can also be assessed for response to noxious thermal stimuli or for tactile allodynia, as described below.
  • the Chung model for neuropathic pain is described in S.H. Kim, "An Experimental Model for Peripheral Neuropathy Produced by Segmental Spinal Nerve Ligation in the Rat," Pain 50(3):355-363 (1992).
  • Response to Mechanical Stimuli as an Assessment of Mechanical Hyperalgesia The paw pressure assay can be used to assess mechanical hyperalgesia.
  • hind paw withdrawal thresholds (PWT) to a noxious mechanical stimulus are determined using an analgesymeter (Model 7200, commercially available from Ugo Basile of Italy) as described in C. Stein, "Unilateral Inflammation of the Hindpaw in Rats as a Model of Prolonged Noxious Stimulation: Alterations in Behavior and Nociceptive Thresholds," Pharmacol. Biochem. and Behavior 31 :451 -455 (1988).
  • the maximum weight that can be applied to the hind paw is set at 250 g and the end point is taken as complete withdrawal of the paw.
  • PWT is determined once for each rat at each time point and only the affected (ipsilateral) paw is tested.
  • the plantar test can be used to assess thermal hyperalgesia.
  • hind paw withdrawal latencies to a noxious thermal stimulus are determined using a plantar test apparatus (commercially available from Ugo Basile of Italy) following the technique described by K. Hargreaves et al, "A New and Sensitive Method for Measuring Thermal Nociception in Cutaneous Hyperalgesia," Pain 32(l):77-88 (1988).
  • the maximum exposure time is set at 32 seconds to avoid tissue damage and any directed paw withdrawal from the heat source is taken as the end point. Three latencies are determined at each time point and averaged. Only the affected (ipsilateral) paw is tested.
  • Tactile Allodynia To assess tactile allodynia, rats are placed in clear, plexiglass compartments with a wire mesh floor and allowed to habituate for a period of at least 15 minutes. After habituation, a series of von Frey monofilaments are presented to the plantar surface of the left (operated) foot of each rat. The series of von Frey monofilaments consists of six monofilaments of increasing diameter, with the smallest diameter fiber presented first. Five trials are conducted with each filament with each trial separated by approximately 2 minutes. Each presentation lasts for a period of 4-8 seconds or until a nociceptive withdrawal behavior is observed. Flinching, paw withdrawal or licking of the paw are considered nociceptive behavioral responses.
  • EXAMPLE 8 IN V ⁇ VO ASSAYS FOR PREVENTION OR TREATMENT OF ANXIETY
  • the elevated plus maze test or the shock-probe burying test can be used to assess the anxiolytic activity of 3-substituted Pyridyl Compounds in rats or mice.
  • the Elevated Plus Maze Test The elevated plus maze consists of a platform with 4 arms, two open and two closed (50x10x50 cm enclosed with an open roof). Rats (or mice) are placed in the center of the platform, at the crossroad of the 4 arms, facing one of the closed arms. Time spent in the open arms vs the closed arms and number of open arm entries during the testing period are recorded. This test is conducted prior to drug administration and again after drug administration.
  • Test results are expressed as the mean time spent in open arms and the mean number of entries into open arms. Known anxiolytic drugs increase both the time spent in open arms and number of open arm entries.
  • the elevated plus maze test is described in D. Treit, "Animal Models for the Study of Anti-anxiety Agents: A Review,” Neuroscience & Biobehavioral Reviews 9(2):203-222 (1985).
  • the Shock-Probe Burying Test For the shock-probe burying test the testing apparatus consists of a plexiglass box measuring 40x30x40 cm, evenly covered with approximately 5 cm of bedding material (odor absorbent kitty litter) with a small hole in one end through which a shock probe (6.5 cm long and 0.5 cm in diameter) is inserted.
  • the plexiglass shock probe is helically wrapped with two copper wires through which an electric current is administered.
  • the current is set at 2 mA.
  • Rats are habituated to the testing apparatus for 30 min on 4 consecutive days without the shock probe in the box. On test day, rats are placed in one comer of the test chamber following drug administration. The probe is not electrified until the rat touches it with its snout or fore paws, at which point the rat receives a brief 2 mA shock. The 15 min testing period begins once the rat receives its first shock and the probe remains electrified for the remainder of the testing period. The shock elicits burying behavior by the rat.
  • the duration of time the rat spends spraying bedding material toward or over the probe with its snout or fore paws is measured as well as the number of contact- induced shocks the rat receives from the probe.
  • Known anxiolytic drugs reduce the amount of burying behavior.
  • an index of the rat's reactivity to each shock is scored on a 4 point scale. The total time spent immobile during the 15 min testing period is used as an index of general activity. The shock-probe burying test is described in D. Treit, 1985, supra.
  • the conditioned place preference test or drug self-administration test can be used to assess the ability of 3-substituted Pyridyl Compounds to attenuate the rewarding properties of known drugs of abuse.
  • the Conditioned Place Preference Test The apparatus for the conditioned place preference test consists of two large compartments (45 x 45 x 30 cm) made of wood with a plexiglass front wall. These two large compartments are distinctly different. Doors at the back of each large compartment lead to a smaller box (36 x 18 x 20 cm) box made of wood, painted grey, with a ceiling of wire mesh.
  • the two large compartments differ in terms of shading (white vs black), level of illumination (the plexiglass door of the white compartment is covered with aluminum foil except for a window of 7 x 7 cm), texture (the white compartment has a 3 cm thick floor board (40 x 40 cm) with nine equally spaced 5 cm diameter holes and the black has a wire mesh floor), and olfactory cues (saline in the white compartment and 1 mL of 10% acetic acid in the black compartment).
  • the doors to the small box remain open, giving the rat free access to both large compartments.
  • the first session that a rat is placed in the apparatus is a habituation session and entrances to the smaller grey compartment remain open giving the rat free access to both large compartments.
  • Rats During habituation, rats generally show no preference for either compartment. Following habituation, rats are given 6 conditioning sessions. Rats are divided into 4 groups: carrier pre-treat ent ⁇ + carrier (control group), 3-substituted Pyridyl Compound pre-treatment + carrier, carrier pre-treatment + morphine, 3-substituted Pyridyl Compound pre-treatment + morphine.
  • carrier pre-treat ent ⁇ + carrier control group
  • 3-substituted Pyridyl Compound pre-treatment + carrier carrier pre-treatment + morphine
  • 3-substituted Pyridyl Compound pre-treatment + morphine 3-substituted Pyridyl Compound pre-treatment + morphine.
  • the order of injections and the drag/compartment pairings are counterbalanced within groups.
  • rats are injected prior to testing (30 min to 1 hour) with either morphine or carrier and the rat is placed in the apparatus, the doors to the grey compartment remain open and the rat is allowed to explore the entire apparatus for 20 min.
  • the time spent in each compartment is recorded.
  • Known drugs of abuse increase the time spent in the dmg-paired compartment during the testing session.
  • the Drug Self-Administration Test The apparatus for the drug self- administration test is a standard commercially available operant conditioning chamber. Before drug trials begin rats are trained to press a lever for a food reward.
  • Rats are tested for acquisition of lever pressing for drug reward. Rats are implanted with chronically indwelling jugular catheters for i.v. administration of compounds and are allowed to recover for 7 days before training begins. Experimental sessions are conducted daily for 5 days in 3 hour sessions. Rats are trained to self-administer a known drug of abuse, such as morphine. Rats are then presented with two levers, an "active" lever and an “inactive” lever. Pressing of the active lever results in drug infusion on a fixed ratio 1 (FRl) schedule (i.e., one lever press gives an infusion) followed by a 20 second time out period (signaled by illumination of a light above the levers).
  • FRl ratio 1
  • CHO-rat mGluRl cells/well are plated into a COSTAR 3409, black, clear bottom, 96 well, tissue culture treated plate (commercially available from Fisher Scientific of Chicago, IL) and are incubated in Dulbecco's Modified Eagle's Medium (DMEM, pH 7.4) supplemented with glutamine, 10% FBS, 1% Pen/Strep, and 500 ⁇ g/mL Geneticin for about 12 h.
  • DMEM Dulbecco's Modified Eagle's Medium
  • the CHO-rat mGluRl cells are then washed and treated with OPTIMEM medium (commercially available from Invitrogen, Carlsbad, CA) and incubated for a time period ranging from 1 to 4 hours prior to loading the cells with the dye FLUO-4 (commercially available from Molecular Probes Inc., Eugene, OR).
  • OPTIMEM medium commercially available from Invitrogen, Carlsbad, CA
  • FLUO-4 commercially available from Molecular Probes Inc., Eugene, OR
  • the cell plates are washed with loading buffer (127 mM NaCl, 5 mM KC1, 2 mM MgCl 2 , 700 ⁇ M, NaH 2 PO 4 , 2 mM CaCl 2 , 5 mMNaHCO 3 , 8 mM HEPES, and 10 mM glucose, pH 7.4) and incubated with 3 ⁇ M FLUO-4 in 0.1 mL loading buffer for 90 min.
  • loading buffer 127 mM NaCl, 5 mM KC1, 2 mM MgCl 2 , 700 ⁇ M, NaH 2 PO 4 , 2 mM CaCl 2 , 5 mMNaHCO 3 , 8 mM HEPES, and 10 mM glucose, pH 7.4
  • the cells are then washed twice with 0.2 mL loading buffer, resuspended in 0.1 mL of loading buffer, and transferred to a FLEPR for measurement of calcium mobilization flux in the presence of glutamate and in the presence or absence of a 3-substituted Pyridyl Compound.
  • fluoresence is monitored for about 15 s to establish a baseline and DMSO solutions containing various concentrations of a 3-substituted Pyridyl Compound ranging from about 50 ⁇ M to about 0.8 nM diluted in loading buffer (0.05 mL of a 4X dilution) are added to the cell plate and fluoresence is monitored for about 2 min.
  • Primers flanking the coding region of human VRl were designed as follows: forward primer, GAAGATCTTCGCTGGTTGCACACTGGGCCACA; and reverse primer, GAAGATCTTCGGGGACAGTGACGGTTGGATGT.
  • PCR of VRl was performed on one tenth of the Reverse transcription reaction mixture using Expand Long Template Polymerase and Expand Buffer 2 in a final volume of 50 ⁇ L according to the manufacturer's instructions (Roche Applied Sciences, Indianapolis, IN). After denaturation at 94°C for 2 min PCR amplification was performed for 25 cycles at 94°C for 15 sec, 58°C for 30 sec, and 68°C for 3 min followed by a final incubation at 72°C for 7 min to complete the amplification.
  • a PCR product of -2.8 kb was gel-isolated using a 1.0% agarose, Tris- Acetate gel containing 1.6 ⁇ g/mL of crystal violet and purified with a S.N.A.P. UV-Free Gel Purification Kit (commercially available from Invitrogen).
  • the VRl PCR product was cloned into the pIND/V5-His-TOPO vector (commercially available from Invitrogen) according to the manufacturer's instructions. DNA preparations, restriction enzyme digestions, and preliminary DNA sequencing were performed according to standard protocols. Full- length sequencing confirmed the identity of the human VRl. Generation of Inducible Cell Lines: Unless noted otherwise, cell culture reagents were purchased from Life Technologies of Rockville, MD.
  • HEK293-EcR cells expressing the ecdysone receptor were cultured in Growth Medium (Dulbecco's Modified Eagles Medium containing 10% fetal bovine serum (commercially available from HYCLONE, Logan, UT), lx penicillin/streptomycin, lx glutamine, 1 mM sodium pyruvate and 400 ⁇ g/mL Zeocin (commercially available from Invitrogen)).
  • the VRl-pIND constructs were transfected into the HEK293-EcR cell line using Fugene transfection reagent (commercially available from Roche Applied Sciences, Basel, Switzerland).
  • pH-Based Assay Two days prior to performing this assay, cells were seeded on poly-D-lysine-coated 96-well clear-bottom black plates (commercially available from Becton-Dickinson) at 75,000 cells/well in growth media containing 5 ⁇ M PonA (commercially available from invitrogen) to induce expression.
  • the plates were washed with 0.2 mL lx Hank's Balanced Salt Solution (commercially available from Life Technologies) containing 1.6 mM CaCl 2 and 20 mM HEPES, pH 7.4 ("wash buffer”), and loaded using 0.1 mL of wash buffer containing Fiuo-4 (3 ⁇ M final concentration, commercially available from Molecular Probes). After 1 h, the cells were washed twice with 0.2 mL wash buffer and resuspended in 0.05 mL lx Hank's Balanced Salt Solution (commercially available from Life Technologies) containing 3.5 mM CaCl 2 and 10 mM Citrate, pH 7.4 ("assay buffer”).
  • Compound A19 when assayed according to this protocol had an IC 50 of 808.2 ⁇ 253.7 nM (n 5).
  • Capsaicin-based Assay Two days prior to performing this assay, cells were seeded in poly-D-lysine-coated 96-well clear-bottom black plates (50,000 cells/well) in growth media containing 5 ⁇ M PonA (commercially available from Invitrogen) to induce expression.
  • the plates were washed with 0.2 mL lx Hank's Balanced Salt Solution (commercially available from Life Technologies) containing 1 mM CaCl 2 and 20 mM HEPES, pH 7.4, and cells were loaded using 0.1 mL of wash buffer containing Fluo-4 (3 ⁇ M final). After one hour, the cells were washed twice with 0.2 mL of wash buffer and resuspended in 0.1 mL of wash buffer. The plates were transferred to a FLEPR (commercially available from Molecular Devices) for assay. 50 ⁇ L of Compound A19 diluted with assay buffer were added to the cell plates and incubated for 2 min.
  • FLEPR commercially available from Molecular Devices
  • Compound A19 ranged from about 50 pM to about 3 ⁇ M.
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MXPA06001331A MXPA06001331A (es) 2003-08-01 2004-07-30 Agentes terapeuticos utiles para el tratamiento del dolor.
DE602004025244T DE602004025244D1 (de) 2003-08-01 2004-07-30 Zur behandlung von schmerzen geeignete therapeutische mittel
JP2006522640A JP5148110B2 (ja) 2003-08-01 2004-07-30 疼痛の治療に有用な治療薬
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PL04779721T PL1648880T3 (pl) 2003-08-01 2004-07-30 Środki lecznicze użyteczne do leczenia bólu
AT04779721T ATE455773T1 (de) 2003-08-01 2004-07-30 Zur behandlung von schmerzen geeignete therapeutische mittel
US11/344,937 US7696208B2 (en) 2003-08-01 2006-01-31 Therapeutic agents useful for treating pain
HK06111025.0A HK1093489A1 (en) 2003-08-01 2006-10-05 Therapeutic agents useful for treating pain
US12/715,825 US8030310B2 (en) 2003-08-01 2010-03-02 Therapeutic agents useful for treating pain
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