MXPA06007565A - Piperazines useful for treating pain - Google Patents

Piperazines useful for treating pain

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Publication number
MXPA06007565A
MXPA06007565A MXPA/A/2006/007565A MXPA06007565A MXPA06007565A MX PA06007565 A MXPA06007565 A MX PA06007565A MX PA06007565 A MXPA06007565 A MX PA06007565A MX PA06007565 A MXPA06007565 A MX PA06007565A
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Mexico
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group
halo
another embodiment
alkyl
compound
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MXPA/A/2006/007565A
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Spanish (es)
Inventor
Tafesse Laykea
Sun Qun
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Euroceltique Sa
Sun Qun
Tafesse Laykea
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Publication of MXPA06007565A publication Critical patent/MXPA06007565A/en

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Abstract

Compounds of formulae (I) and (II) where Ar1, Ar2, R3, R4, and m, are disclosed herein, or a pharmaceutically acceptable salt thereof (a"Nitro(cyano)vinylpiperazine Compound");compositions comprising an effective amount of a Nitro(cyano)vinylpiperazine Compound;and methods for treating or preventing pain and other conditions in an animal comprising administering to an animal in need thereof an effective amount of a Nitro(cyano)vinylpiperazine Compound are disclosed.

Description

USEFUL PGPERAZINES FOR THE TREATMENT OF PAIN 1. FIELD OF THE INVENTION The present invention relates to Nitro (cyano) vinylpiperazine Compounds, compositions comprising an effective amount of a Compound Nitro (cyano) vinylpiperazine and methods for treating or preventing a Condition such as pain comprising administering to an animal in need thereof an effective amount Q of a Nitro (cyano) vinyl piperazine Compound. 2. BACKGROUND OF THE INVENTION Pain is the most common symptom for which patients seek medical advice and treatment. The pain can be acute or chronic. While acute pain is usually self-limited, chronic pain persists for 3 months or longer and can produce significant changes in the patient's personality, lifestyle, functioning ability, and overall lifestyle (KM Foley, Pain, in Cecil Textbook of Q Medicine 100-107 (JC Bennett and F. Plu eds., 20th ed., 1996)).
In addition, chronic pain can be classified as either nociceptive or neuropathic. Nociceptive pain includes pain from tissue damage and inflammatory pain such as that associated with arthritis. Neuropathic pain is caused by damage to the peripheral or central nervous system and is maintained by injurious somato sensory processes. There is a wide range of evidence related to activity in both Group I mGluRs (mGluRl and mGluR5) (ME Fundytus, CNSD gs 15: 29-58 (2001)) and vanilloid receptors (VRl) (V. Di Marzo et al, Current Opinion in Neurobiology 12: 372-379 (2002)) for the pain process. Inhibiting mGluRl or mGluR5 reduces pain, as demonstrated by in vivo treatment with selective anticuefos for either mGluRl or mGluR5, where the neuropathic pain in rats was attenuated (ME Fundytus et al, NeuroReport 9: 731-735 (1998)) . It has also been demonstrated that the collapse of mGluRl antisense oligonucleotides alleviates both neuropathic pain and inflammatory pain (ME Fundytus et al, British Journal of Pharmacology 132: 354-367 (2001); ME Fundytus et al, Pharmacology, Biochemsitry.; Behavior 73: 401-410 (2002)). Small antagonistic molecules. for attenuated pain mGluR5 in animal models in vivo are described in, for example, K. Walker et al, Neuropharmacology 40: 1-9 (2000) and A. Dogrul et al, Neuroscience Letters 2S2L-115-118 (2000)) . Traditionally, nociceptive pain has been managed by administration of non-opioid analgesics, such as acetylsalicylic acid, magnesium choline trisalicylate, acetaminophen, ibuprofen, fenoprofen, diflusinal, and naproxen; or opioid analgesics, including morphine, hydromorphone, methadone, levorphanol, fentanyl, oxycodone, and oxymorphone. Id. In addition to the treatments indicated above, neuropathic pain, which may be difficult to treat, has also been treated with anti-epileptics (eg, gabapentin, carbamazapine, valproic acid, topiramate, phenytoin), NMDA antagonists (eg, ketamine, dextromethorphan), topical lidocaine (for post-herpetic neuralgia), and tricyclic anti-depressants (eg, fluoxetine, sertraline, and amitriptyline).
Urinary incontinence ("Ul") is uncontrollable urination, usually caused by instability of the detrusor muscle of the bladder. Ul affects people of all ages and levels of physical health, both in the health area and in the community as a whole. Physiological contractions of the bladder are produced in large part by the acetylcholine-induced stimulation of post-ganglionic muscarinic receptors in the soft muscles of the bladder. Treatments for Ul include the administration of drugs with relaxing bladder properties, which help to control the over activity of the detrusor muscle of the bladder. For example, anticholinergics such as propantheline bromide and glycopyrrolate, and combinations of mild muscle relaxants such as a combination of racemic oxybutynin and dicyclomine or an anticholinergic, have been used to treat Ul (See, eg, A. Wein, Urol Clin. N. Am. 22: 557-577 (1995); Levin et al., J. Urol. 128: 396-398 (1982); Cooke et al, S. Afr. Med. J. 63: 3 (1983); R.K. Mirakhur et al, Anesthesia 38: 1195-1204 (1983)). However, these drugs are not effective in patients with non-inhibited bladder contractions. The administration of anticholinergic drugs represents the main basis in this type of treatment. However, none of the commercially available drug treatments for Ul has achieved total success in all Ul patient classes, nor has treatment been achieved without significant adverse side effects. For example, drowsiness, dry mouth, constipation, blurred vision, headache, tachycardia, and cardiac arrhythmia, related to the anticholinergic activity of traditional anti-UI drugs, can occur frequently and adversely affect patient compliance. However, despite the prevalence of anticholinergic effects in many patients, anticholinergic drugs are currently prescribed to patients with Ul. The Merck Manual of Medical Information 631-634 (R. Berkow ed., 1997). About 1 to 10 people develop an ulcer. Ulcers occur 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 bicarbonate, mucosal secretion and prostaglandins The treatment of ulcers typically involves reducing or inhibiting aggressive factors. For example, antacids such as aluminum hydroxide, magnesium hydroxide, sodium bicarbonate and calcium bicarbonate can be used to neutralize stomach acids. However, antacids can cause alkalosis, producing nausea, headache and weakness. Antacids can also interfere with the absorption of other drugs into the bloodstream and cause diarrhea. H2 antagonists, such as cimetidine, ranitidine, famotidine and nizatidine, are also used to treat ulcers. H2 Antagonists promote the healing of ulcers by reducing gastric acid and the secretion of digestive enzymes produced by histarnins and other H2 antagonists in the stomach and duodenum. However, H2 antagonists can cause breast enlargement and impotence in men, mental changes (especially in elderly people), headache, dizziness, nausea, myalgia, diarrhea, rash and fever. Inhibitors H "1", K + - ATPase such as omeprazole and lansoprazole are also used to treat ulcers. Inhibitors H +, K + - ATPase inhibit the production of enzymes used by the stomach to secrete acids. Side effects associated with H +, K + - ATPase inhibitors include nausea, diarrhea, abdominal colic, headache, dizziness, drowsiness, skin rash and transient elevation of plasma aminotransferase activity.
Sucralfate is also used to treat ulcers. Sucralfate adheres to epithelial cells and is thought to form a protective layer at the base of an ulcer to promote its healing. However, sucralfate can cause constipation, dry mouth and interfere with the absorption of other drugs. Antibiotics are used when Helicobacter pylori is the main cause of the ulcer. Frequently, antibiotic therapy is coupled with the administration of bismuth compounds such as bismuth subsalicylate and colloid bismuth citrate. It is believed that bismuth compounds increase mucosal secretion and HCO3", inhibit peptic activity and act as an antibacterial against H. pylori, however, ingestion of bismuth compounds can produce high concentrations of Bi + plasma and can interfere With the absorption of other drugs, prostaglandin analogs, such as misoprostatic, inhibit acid secretion and stimulate mucous and bicarbonate secretion and are also used to treat ulcers, especially ulcers in patients requiring non-steroidal anti-inflammatory drugs. , effective oral doses of prostaglandin analogs can produce diarrhea and abdominal pains.Also, some prostaglandin analogs are abortive.Carhexolone, a mineral corticoid, can also be used to treat ulcers.Carhexoxone seems to alter the composition and amount of mucosa, thus increasing the mucosal barrier, however, carbenoxolone, it can produce 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. Side effects of muscarinic cholinergic antagonists may include oral dryness, blurred vision and constipation. The Merck Manual of Medical Information 496-500 (R. Berkow ed., 1997) and Goodman and Gilman's The Pharmacological Basis of Therapeutics 901-915 (J. Hardman and L. Limbird eds., 9th ed.1996).
Inflammatory bowel disease (IBD) is a chronic disorder in which the intestine becomes inflamed, often producing abdominal pain and diarrhea. The two classes of IBD are Crohn's disease and ulcerative colitis. Crohn's disease, which may include regional enteritis, granulomatous ileitis, and ileocolitis, is a chronic inflammation of the intestinal wall. Crohn's disease occurs equally in both sexes and is more common in Jews with Western European ancestry. Most cases of Crohn's disease begin before the age of 30 and most begin between 14 and 24 years of age. The disease usually affects the total thickness of the intestinal wall. Usually, the disease affects the lower portion of the small intestine (ileum) and the large intestine, but it can occur anywhere in the digestive tract. The first symptoms of Crohn's disease are chronic diarrhea, pain from abdominal cramping, fever, loss of appetite and weight loss. Complications associated with Crohn's disease include the development of intestinal obstructions, abnormal connection channels (fistulas) and abscesses. The risk of cancer in the large intestine increases in people with Crohn's disease. Frequently, Crohn's disease is associated with other disorders such as gallstone, inadequate absorption of nutrients, amyloidosis, arthritis, episcleritis, aged stomatitis, erythema nodosa, pyoderma gangrenosum, ankylosing spondylitis, sacroiliitis, uveitis, and primary sclerose cholangitis. There is no known treatment for Crohn's disease.
Cramps and diarrhea, side effects associated with Crohn's disease, can be relieved with anticholinergic drugs, diphenoxylate, loperamide, deodorized opium dye or codeine. Generally, the drug is administered orally before the meals. A wide range of antibiotics are usually administered to treat the symptoms of Crohn's disease. The antibiotic metranidazole is frequently administered when the disease affects the large intestine or causes abscesses and fistulas, "around the anus. However, prolonged use of metranidazole can damage the nerves,. resulting in a tingling sensation in the arms and legs. Sulfasalazine and chemically related drugs can suppress mild inflammation, especially in the large intestine. However, these drugs are less effective in severe sudden inflammations. Corticosteroids, such as prednisone, reduce fever and diarrhea as well as abdominal pain and sensitivity. However, a prolonged corticosteroid therapy inevitably results in serious side effects such as high blood sugar, increased risk of infection, osteoporosis, fluid retention, and skin fragility. Drugs such as azathioprine and mercaptopurine can either compromise the immune system and are frequently effective in patients with Crohn's disease who do not respond to other drugs. However, these drugs generally need between 3 to 6 months before producing benefits and can cause serious side effects such as allergy, pancreatitis and low white cell counts. When Crohn's disease causes the bowel to become clogged or when 5 abscesses or fistulas do not heal, surgery may be necessary to remove diseased sections of the intestine. However, surgery does not cure the disease, and inflammation usually returns when the bowel is reattached. In almost half of the cases, a second surgery is necessary. The Merck Manual of Medical Information 528-530 (R. Berkow ed., 1997).
Ulcerative colitis is a chronic disease in which the large intestine becomes inflamed and ulcerated, producing episodes of diarrhea with bleeding, abdominal pain and fever. Ulcerative colitis usually starts between 15 and 30 years; However, a small group of people have their first attack between 50 and 70 years. Unlike Crohn's disease, ulcerative colitis never affects the small intestine and does not affect the total thickness of the intestine. The disease usually begins in the rectum and sigmoid colon and eventually extends partially or completely through the large intestine.
The cause of ulcerative colitis is not known. The treatment of ulcerative colitis is aimed at controlling inflammation, reducing symptoms and replacing lost fluids and nutrients. Irritable bowel syndrome ("IBS") is a mobility disorder of the entire gastrointestinal tract, which causes abdominal pain, constipation, and / or diarrhea. IBS affects three times more women than men. There are two main types of IBS. The first type, spastic colon type, is commonly triggered by eating and usually produces constipation and diarrhea with pain. Mucus usually appears in the stool. Pain may occur in attacks of constant weak pain, usually in the lower abdomen. The person suffering from spastic colon IBS may experience swelling, gas, nausea, headache, fatigue, depression, anxiety and difficulty concentrating. The second type of IBS usually produces diarrhea without pain or constipation. Diarrhea can begin "suddenly and with extreme urgency." Diarrhea often occurs after a meal and sometimes immediately after awakening.The treatment of IBS generally involves modifications in the diet of the patient with IBS. patient with IBS avoid beans, cabbage, sorbitol and fructose. A diet low in fat and high in fiber can also help some patients with IBS. Physical activity on a regular basis can also help keep the gastrointestinal tract working correctly. Drugs such as? n Propanthelin that decrease the function of the gastrointestinal tract are not generally effective in 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 to treat addictions. US Patent No. 5,556,838 to Mayer et al. describes the use of non-toxic blocking agents NMDA co-administered with an addictive substance to prevent the development of tolerance or withdrawal symptoms. U.S. Patent No.
. No. 574,052 to Rose et al. describes the co-administration of an addictive substance with an antagonist to partially block the pharmacological effects of the substance. The U.S. Patent No. 5,075,341 to Mendelson et al. describes the use of an opiate agonist / antagonist mixture to treat addictions to cocaine and opiates. U.S. Patent No. 5,232,934 to Downs describes the administration of 3-phenoxypyridine to treat addiction. U.S. Patent No. 5,039,680 and 5,198,459 to Imperato et al. describes the use of a serotonin antagonist to treat a chemical addiction. U.S. Patent No. 5,556,837 to Nestler et. 'al. describes how BDNF or NT-4 growth factors are infused to inhibit or reverse adaptive neurological changes that correlate with behavioral changes in an addict. U.S. Patent No. 5,762,925 to Sagan discloses implanting adrenal medullary cells encapsulated in the central nervous system of the animal to inhibit the development of opioid intolerance. U.S. Patent No. 6,204,284 to Beer et al. describes (±) -l- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] racemic hexane for use in the prevention or alleviation of a withdrawal syndrome resulting from drug addiction and for -. "The treatment of chemical dependencies. Without treatment, Parkinson's disease evolves into a rigid akinetic state where patients are unable to take care of themselves. Death occurs frequently as a result of complications resulting from 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. However, the need for drugs useful for the treatment of Parkinson's disease and with an improved therapeutic profile persists. 0 Anxiety is a fear, apprehension or panic of imminent danger commonly accompanied by restlessness, tension, tachycardia and dyspnea. Currently, benzodiazepines are the most used anti-anxiety agents for generalized anxiety disorders. However, benzodiazepines carry the risk of producing cognitive impairments and specialized motor functions, particularly in the elderly, which can cause confusion, delirium and falls with fractures. Sedatives are also commonly prescribed to treat anxiety. Azapirones, such as buspirone, are also used to treat moderate anxiety, however, azapirones are less useful in treating severe anxiety accompanied by panic attacks.
Epilepsy is a disorder characterized by the tendency to have recurrent attacks. Examples of drugs used to treat seizures and epilepsy include .carbamazepine, ethosuximide, gabapentin, lamotrigine, phenobarbital, phenytoin, primidone, volproic acid, trimethadione, benzodiazepines, gabapentin, lamotrigine,? -vinyl GABA, acetazolamide, and felbamate. However, 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 disturbance 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. The Merck Manual of Medical Information 345-350 (R. Berkow ed., 1997). The symptoms of heart attacks vary depending on the part of the affected brain.
Symptoms include loss or abnormal feeling in an arm or leg or side of the body, weakness or paralysis of an arm or leg or side of the body, partial loss of vision or hearing, double vision, dizziness, slurred speech, difficulty thinking about the correct word or saying it, inability to recognize parts of the body, unusual movement, loss of bladder control, imbalance, falls and fainting. Symptoms may be permanent and may be associated with coma or stupor. Examples of drugs for treating heart attacks include anticoagulants such as heparin, drugs that dissolve clots such as streptokinase or tissue plasminogen activator, and drugs that reduce swelling such as mannitol or corticosteroids. The Merck Manual of Medical Information 352-355 (R. Berkow ed., 1997). Itching in an unpleasant sensation that induces scratching. Usually, pruritus is treated by ultraviolet B or PUVA phototherapy or by therapeutic agents such as naltrexone, nalmefene, danazol, tricyclics and antidepressants. Selective antagonists of the metabotropic glutamate receptor 5 ("mGluR5") have been shown to exert an analgesic activity in the animal model in vivo (K. Walker et al, Neuropharmacology 40: 1-9 (2000) and A. Dogrul et al, Neuroscience Letters, 292 (2): 115-118 (2000)). Selective antagonists of the mGluR5 receptor have also been shown to exert anxiolytic and anti-depressant activity in the animal model in vivo (E. Tatarczynska et al, Br. J. Pharmacol. 132 (7): 1423-1430 (2001) and PJ.M. Will et al, Trends in Pharmacological Sciences 22 (7): 331-37 (2001)). Selective antagonists of the mGluR5 receptor have also been shown to exert anti-Parkinson activity in vivo (KJ Ossowska et al, Neuropharmacology 41 (4): 413-20 (2001) and PJ.M. Will et al, Trends in Pharmacological Sciences 22 (7 ): 331-37 (2001)). There is, however, a clear need in the art for compounds that are useful for treating or preventing pain, Ul, an ulcer, IBD, IBS, an addictive disorder, Parkinson's disease, parkinsonism, anxiety, epilepsy, infarction, attack, a pruritic condition, psychosis, cognitive disorder, memory deficit, restricted brain function, Huntington's disease, amyotrophic lateral sclerosis ("ALS"), dementia, retinopathy, muscle spasm, migraine, vomiting, dyskinesia, or depression.
The mention of any reference in Section 2 of the present application should not be considered as an admission that such reference is prior art to the present application. 3. SUMMARY OF THE INVENTION The present invention comprises compounds of the formula (1): (r > (I) and pharmaceutically acceptable salts thereof, wherein: Ari is Ar2 is RI is -H, -halo, -CH3, -CN, -NO2, -OH, -OCH3, -HG2, -C (halo) 3, -CH (halo) 2, or -CH2 (halo); each R2 is independently: (a) -halo, -OH, -NH2, -CN, or -NO2; (b) - (C? -C? o) alkyl, - (C2-C10) alkenyl, - (C2-C1o) alkynyl, - (C3-C! o) cycloalkyl, - (C8-C1) bicycloalkyl, - ( C8-C14) tricycloalkyl, - (C5-C8) cycloalkenyl, - (C8-C14) bicycloalkenyl, - (C8-C14) tricycloalkenyl, - (3- to 7-bodies) heterocycle, or - (7- to 10-) ? s) bicycloheterocycle, each of which is substituted or not with one or more groups 5; or (c) -phenyl, -naphthyl, - (C14) aryl or - (5- to 10-cells) heteroaryl, each of which is substituted or unsubstituted with one or more R6 groups; each R3 is independently: (a) -halo, -OH, -NH2; -CN, or -NO2; (b) - (C? -C? o) alkyl, - (C2-C10) alkenyl, - (C2-C10) alkynyl, - (C3-C10) cycloalkyl, - (Cg-C1) bicycloalkyl, - (C8-) C14) xriccycloalkyl, - (C5-C10) cycloalkenyl, - (C8-C? 4) bicycloalkenyl, (C8-C? 4) tricycloalkenyl, - (3- to 7-well) heterocycle, or - (7- to 10- cuef? s) bicycloheterocycle, each of which is substituted or not with one or more R5 groups; or (c) -phenyl, -nanel, - (C14) aryl or - (5- to 10 -acids) heteroaryl, each of which is substituted or not with one or more Re groups; each R4 is -H, -CN, - € (O) O (C? -CL) a] quiL, or -C (O) NH ((C1-C4) alkyl; each R5 is independently -CN, -OH, - (C? -C6) alkyl, - (C2-C6) alkenyl, - (C2-C6) alkynyl, -halo, -N3, -NO2, -N (R7) 2, -CH = NR7, -NR7OH, - OR7, -COR7, -C (O) OR7, -OC (O) R7, -OC (O) OR7, -SR7, -S (O) R7, or -S (O) 2R7; each Rd is independently - (-C ^ alkyl, - (C2-C6) alkenyl, - (C2-C6) alkynyl, - (C3C8) cycloalkyl, - (C5-C8) cycloalkenyl, -phenyl, - (3- to 5) -trues) heterocycle, -C (halo) 3, ~ CH (halo) 2, -CH2 (halo), -CN, -OH, -halo, -N3, -NO2, N (R7) 2, -CH = NR7 , -NR7OH, -OR7, -COR7, -C (O) OR7, -OC (O) R7, -OC (O) OR7, -SR7, -S (O) R7, or -S (0) 2R7; each R7 is independently -H, - (C2-C6) alkenyl, - (C2-C6) alkynyl, - (C3-C8) cycloalkyl, - (C5-C8) cycloalkenyl, -phenyl, - (3- to 5-cos ) heterocycle, -C (halo) 3, -CH (halo) 2, or CH 2 (halo); each Rs is independently - (-C ^ alkyl, - (C2-C6) alkenyl, - (C2-C6) alkynyl, - (C3-C8) cycloalkyl, - (C5-C8) cycloalkenyl, -phenyl, - (3- at 5-ca) s, heterocycle, -C (halo) 3, -CH (halo) 2, -CH2 (halo), -CN, -OH, -halo, -N3, -NO2, -N (R7) 2 , -CH = NR7, -NR7OH, -OR7, -COR7, -C (O) OR7, -OC (O) R7, -OC (O) OR7, -SR7, -S (O) R7, or -S ( O) 2R7, each halo is independently -F, -Cl, -Br, or -I; m is an integer in a range from 0 to 2; n is an integer in a range from 0 to 3; p is an integer in a range from 0 to 2; q is an integer in a range from 0 to 6; r is an integer in a range from 0 to 5; Y s is an integer in a range from 0 to 4.
The invention further comprises compounds of the formula (11): (II) and pharmaceutically acceptable salts thereof, wherein Arts Ar2 is Ri is -H, -halo, -CH3, -CN, -NO2, -OH, OCH3, NH2, -C (halo) 3, -CH (halo) 2, or -CH2 (halo); each R2 is independently: (a) -halo, -OH, -NH2, -CN, or -NO2; (b) - (C? -C? o) alkyl, - (C2-C] .o) alkenyl, - (C2-C1o) alkynyl, - (C3-C? o) cycloalkyl, - (C8-C14) bicycloalkyl , - (C8-C14) tricycloalkyl, - (C5-C8) cycloalkenyl, - (Cg-C14) bicycloalkenyl, - (C8-C14) tricycloalkenyl, - (3- to 7-well) heterocycle, or - (7- a 10-cells) bicycloheterocycle, each of which is substituted or not with one or more R5 groups; or (c) -phenyl, -naphthyl, - (C? 4) aryl or - (5- to 10 -copes) heteroaryl, each of which is substituted or not with one or more Re groups; each R3 is independently: (a) -halo, -OH, -NH2, -CN, or -NO2; (b) - (C] -C10) alkyl, - (C2-C1o) alkenyl, - (C2-C10) alkynyl, - (C3-C1o) cycloalkyl, - (C8-C14) bicycloalkyl, - (Cs-C14) tricycloalkyl, - (C5-C1o) cycloalkenyl, - (C8- C14) bicycloalkenyl, - (C8-C14) tricycloalkenyl, - (3- to 7-chain) heterocycle, or - (7- to 10-line) bicycloheterocycle, each one of which is substituted or not with one or more groups R5; or (c) -phenyl, -naphthyl, - (C? 4) aryl or - (5- to 10-well) heteroaryl, each of which is substituted or unsubstituted with one or more R6 groups; each R4 -H, -CN, -C (O) O (C? -C4) alky or -C (O) NH ((C? -C4) alkyl); each R5 is independently -CN, -OH, - (C? -C6) alkyl, - (C2-C6) alkenyl, - (C2-C6) alkynyl, -halo, -N3, -NO2, -N (R7) 2 , -CH = NR7, -NR7OH, -OR7, -COR7, -C (O) OR7, -OC (O) R7, -OC (O) OR7, -SR7, -S (O) R7, or -S ( O) 2R7; each Re is independently - (C? -C6) alkyl, - (C2-C6) alkenyl, - (C2-C6) alkynyl, - (C3-C8) cycloalkyl, - (C5-C8) cycloalkenyl, -phenyl, - ( 3- to 5-cells) heterocycle, -C (halo) 3, -CH (halo) 2, -CH 2 (halo), -CN, -OH, -halo, -N 3, -NO 2, N (R 7) 2, -CH = NR7, -NR7OH, -OR7, -COR7, -C (O) OR7, -OC (O) R7, -OC (O) OR7, -SR7, -S (O) R7, or -S (O 2R7; each R7 is independently -H, - (Ci-Cß-alkyl, - (C2-C6) alkenyl, - (C2-C6) alkynyl, - (C3-C8) cycloalkyl, - (C5-C8) cycloalkenu, -phenyl, - ( 3- to 5-cells) heterocycle, -C (halo) 3, -CH (halo) 2, or CH2 (halo), each R8 is independently - (-Cejalquü, - (C2-C6) alkenyl, - (C2- C6) alkynyl, ~ (C3-C8) cycloalkyl, - (C5-C8) cycloalkenyl, -phenyl, - (3- to 5-cells) heterocycle, C (halo) 3, -CH (halo) 2, -CH2 ( halo), -CN, -OH, -halo, -N3, -NO2, -N (R7) 2, -CH = NR7, -NR7OH, -OR7, -COR7, -C (O) OR7, -OC (O ) R7, -OC (O) OR7, -SR7, -S (O) R7, or -S (O) 2R7; each halo is independently -F, -Cl, -Br, or -I; m is a whole number in a range from 0 to 2, n is an integer in a range from 0 to 4, p is an integer in a range from 0 to 2, q is an integer in a range from 0 to 6, r is a whole number in a range from 0 to 5, and s is an integer in a range from 0 to 4. A compound of formula (I) or (H) or a pharmaceutically acceptable salt thereof (a "Nitro Compound (cyano ) vin ilpiperazine ") is useful to treat or prevent pain, Ul, ulcer ulcer, IBD, IBS, an addictive disorder, Parkinson's disease, parkinsonism, anxiety, epilepsy, infarction, an attack, a pruritus condition, psychosis, a cognitive disorder, a memory deficit, restricted brain function, Korea of Huntington, ALS, dementia, retinopathy, a muscle spasm, a migraine, vomiting, dyskinesia, or depression (each being a "Condition") in an animal.
The invention also relates to. compositions containing an effective amount of a Nitro (cyano) vinyl piperazine Compound and a pharmaceutically acceptable carrier. The compositions are useful for treating or preventing a Condition in an animal.
The invention also relates to methods for treating a Condition, comprising administering to an animal, in need thereof, an effective amount of a Nitro (cyano) vinylpiperazine compound.
The invention further relates to methods for preventing a Condition, which comprises administering to an animal in need thereof an effective amount of a Nitro (cyano) vinyl piperazine Compound.
The invention further relates to methods for inhibiting the function of the Vanilloid Receptor 1 ("VR1") in a cell, which comprises contacting a cell capable of expressing VR1 with an effective amount of a Nitro (cyano) vinyl piperazine Compound.
The invention further relates to methods for inhibiting mGluR5 function in a cell, which comprises contacting a cell capable of expressing mGluR5 with an effective amount of a Nitro (cyano) vinylpiperazine Compound.
The invention further relates to methods for inhibiting the function of the metabotropic glutamate receptor 1 ("mGluRl") in a cell, which comprises contacting a cell capable of expressing mGluRl with an effective amount of a Kitro (cyano) vinylpiperazine Compound. The invention further relates to methods for preparing a composition comprising the step of mixing a Nitro (cyano) vinyl piperazine Compound and a pharmaceutically acceptable carrier or excipient.
The invention further relates to a kit comprising a container containing an effective amount of Nitro (cyano) vinyl piperazine Compound. The present invention can be understood in greater depth through the following detailed description and illustrative examples, which are intended to exemplify non-limiting embodiments of the invention. 4. DETAILED DESCRIPTION OF THE INVENTION 4. 1 Nitro (cyano) vinyl piperazine Compound of Formula (I) As indicated above, the present invention comprises Nitro (cyano) vinyl piperazine Compounds of Formula (I) (I) wherein Arl3 Ar2, R3, X, and m are defined above for Nitro (cyano) vinylpiperazine compounds of the formula (I).
In one modality, Ar! it is a pyridyl group. In another embodiment, Ari is xm pyrimidinyl group.
In another embodiment, Aii is xm pyrazinyl group. In another embodiment, Arj is xm pyridazinyl group.
In another modality, A? It is a thiadiazolyl group.
In another embodiment, At2 is a benzoimidazolyl group.
In another embodiment, At2 is a benzothiazolyl group.
In another embodiment, At2 is a benzooxazolyl group.
In another modality, X is O. In another modality, Ar2 is In another modality, Ar2 is jj hw.
In another modality, t2 is In another modality, Ar2 is In another modality, Ar2 is In another modality, Ar2 is In another modality, Ar2 is In another modality, m is 0.
In another modality, m is 1. In another modality, m is 2. In another modality, m is 3. In another modality, n is 0. In another modality, n is 1. In another modality, n is 2. In another modality, n is modality, n is 3. In another modality, p is 0. In another modality, p is 1. In another modality, p is 2. In another modality, or is 0. In another modality, r is 0. In another modality, r is 1. In another mode, r is 2. In another mode, r is 3.
In another modality, r is 4. In another modality, r is 5. In another modality, q is 0. In another modality, q is 1.
In another modality, q is 2. In another modality, q is 3. In another modality, q is 4. In another modality, q is 5. In another modality, q is 6. In another modality, s is 0. In another modality, s is 0. modality, s is 1. In another modality, s is 2. In another modality, s is 3. In another modality, s is 4. In another modality, Ri is - H. In another modality, Ri is -halo. In another modality, RÍ is -Cl. In another modality, R i is -Br. In another modality, R.}. is -I.
In another modality, R \ is -F. In another modality, R! is -CH3. In another embodiment, R \ is - CN. In another modality, it is -NO2.
In another embodiment, Rt is -OH.
In another embodiment, Rt is -OCH3.
In another modality, RÍ is -NH2.
In another embodiment, RÍ is -C (halo) 3.
In another embodiment, Rt is -CH (halo) 2.
In another embodiment, Ri is -CH2 (halo).
In another embodiment, Rt is -CF3.
In another embodiment, n or p is 1 and R2 is -halo, -OH, -NH2, -CN, or -NO2.
In another embodiment, nop is 1 and R2 is - (CrC10) alkyl, - (C2-C10) alkenyl, - (C2-C10) alkynyl, - (C3-C1o) cycloalkyl, - (C8-C1) bicycloalkyl, - ( C5-C8) cycloalkenyl, - (C8-C? 4) bicycloalkenyl, - (C8-C14) tricycloalkenyl, - (3- to 7-well) heterocycle, or - (7- to 10-well) bicycloheterocycle, each of which is substituted or not with one or more R5 groups.
In another embodiment, n or p is 1 and R 2 is -phenyl, -naphthyl, - (C 14) aryl or - (5- to 10 -acids) heteroaryl, each of which is substituted or not with one or more Re groups.
In another embodiment, m is 1 and R3 is -halo, -OH, -NH2, -CN, or -NO2. In another embodiment, m is 1 and R3 is - (C1-C10) alkyl, - (C2-C10) alkenyl, - (C2-C10) alkynyl, - (C3-C1o) cycloalkyl, - (C8-C14) bicycloalkyl, - (C8-C14) 1-cycloalkyl, - (C5-C10) cycloalkenyl, - (C8-C1) bicycloalkenyl, - (C8-C14) tricycloalkenyl, - (3- to 7-well) heterocycle, or - (7- to 10) (c) bicycloheterocycle, each of which is substituted or not with one or more groups R5, In another embodiment, m is 1 and R3 is -phenyl, -naphthyl, - (C? 4) aryl or - (5- a 10-) heteroaril, each imo of which is substituted or not with one or more RÓ groups.
In another embodiment, m is 1 and R3 is - (C1-C10) alkyl.
In another embodiment, m is 1, R3 is (- (C1-C1o) alkyl, and the carbon atom to which the R3 group is attached is in the (R) configuration.
In another embodiment, m is 1, R3 is (- (C? -C?) Alkyl, and the carbon atom to which the group R3 is attached is in the (S) configuration.
In another embodiment, m is 1 and R3 is -CH3. In another embodiment, m is 1, R3 is -CH3, and the carbon atom to which the group R3 is attached is in the (R) configuration.
In another embodiment, m is 1, R3 is -CH3, and the carbon atom to which group 3 is find attached is in the configuration (S).
In another modality, m is 1 and R3 is -halo.
In another mode, m is 1 and R3 is -Cl.
In another mode, m is 1 and R3 is -Br.
In another mode, m is 1 and R3 is -I.
In another mode, m is 1 and R3 is -F.
In another modality, R4 is -H.
In another modality, t is -CN.
In another embodiment, R 4 is -C (O) O ((C 1 -C 4) alkyl.
In another embodiment, ^ is - (C (O) NH ((C? -C4) alkyl). In another embodiment, Ar2 is a benzothiazolyl group and s is 1. In another embodiment, Ar2 is a benzoimidazolyl group and s is 1.
In another embodiment, Ar2 is a benzooxazolyl group and s is 1.
In another modality, Ar2 is ys is 1. In another mode, Ar2 is and s is 1. In another mode, Ar2 is and r is 1. In another modality, At2 is yqes 1.
In another modality, Ar2 is and res 1. In another modality, Ar2, is and res 1. In another modality, Ar2 is and res 1.
In another embodiment, A ^ is a pyridyl group, m is 0, and At2 is a benzothiazolyl group. In another embodiment, Ari is a pyridyl group, m is 0, and Ar 2 is a benzooxazolyl group. In another modality, Ar! is xm pyridyl group, m is 0, and At 2 is a benzoimidazolyl group. In another modality, Ar! is a pyridyl group, m is 0, and Ar2 is In another embodiment, Aii is a pyridyl group, m is 0, and Ar2 is In another modaliadd, Ari is a pyridyl group, m is 0, and Ar2 is In another embodiment, it is a pyridyl group, m is 0, and Ar2 is In another embodiment, Ai \ is a pyridyl group, m is 0, and Ar2 is In another modality, Ar! is a pyridyl group, m is 0, and Ar2 is In another modality, Ar! is xm pyridyl group, m is 0, and Ar2 is In another embodiment, Ar1 is a group, pyridyl, r is 1, m is 0, Ar 2 is and R8 is a - (dC ^ alkyl) In another embodiment, the - (CrC ^ alkyl is substituted on the para-position of the phenyl group.) In another embodiment, the - (C1-C6) alkyl is a tert-butyl group. another embodiment, the - (C.! - Ce) alkyl is a tert-butyl group and is substituted in the phenyl group paraposition In another embodiment, the - (dC ^ alkyl is a? propyl group. another embodiment, the - (C1-C6) alkyl is a wo-propyl group and is substituted in the para-position of the phenyl group.
In another embodiment, Aii is a pyridyl group, r is 1, m is 0, At2 is and R8 ¿s -CF3. In another embodiment, CF3 is substituted in the ara-position of the phenyl group.
In another embodiment, Arl is a pyridyl group, r is 1, m is 0, Ar2 is and Rg is -halo. In another embodiment, the -halo is substituted in the p-group position. In another modality, -halo is -Cl. In another embodiment, -halo is -Cl and is substituted in the para-position of the phenyl group. In another modality, -halo is -Br. In another modality, -halo is -Br and it is substituted in the / > ara-position of the phenyl group. In another modality, -halo is -I. In another modality, -halo is -I and is substituted in the p ara-position of the phenyl group. In another modality, -halo is -F. In another embodiment, -halo is -F and is substituted in the ara-position of the phenyl group.
In another modality, Ar! is xm pyrazinyl group, m is 0, and Ar2 is xm benzothiazolyl group.
In another embodiment, Aii is xm pyrazinyl group, m is 0, and Ar2 is a benzooxazolyl group. In another embodiment, Ax \ is a pyrazinyl group, m is 0, and At2 is a benzoimidazolyl group.
In another embodiment, Aii is a pyrazinyl group, m is 0, and Ar2 is In another modality, Ax? is xm pyrazinyl group, m is 0, and A12 is In another modality, Ar! is xm pyrazinyl group, m is 0, and Ar2 is 11 ^ - (R8) s In another embodiment, An is a pyrazinyl group, m is 0, and Ar2 is In another embodiment, An is xm pyrazinyl group, m is 0, and Ar2 is In another embodiment, A is xm pyrazinyl group , m is 0, and Ar2 is In another embodiment, An is xm pyrazinyl group, m is 0, and Ar2 is In another embodiment, An is a pyrazinyl group, m is 0, and Ar2 is and Rg is xm - (C1-C6) alkyl. In another embodiment, the - (QC ^ alkyl and substituted in the para-position of the phenyl group) In another embodiment, the - (C? -C6) alkyl is a tert-butyl group In another embodiment, the - (C C6) alkyl is a tert-butyl group and is substituted at the p-group position of the phenyl group.In another embodiment, the - (dC ^ alkyl is x m-propyl group. - (C1-Ce) alkyl is a so-propyl group and is substituted on the other-position of the phenyl group.
In another embodiment, An is a pyrazinyl group, r is 1, m is 0, Ar2 is and Rg is -CF3. In another embodiment, -CF3 is substituted in the /? Ara-position of the phenyl group.
In another embodiment, Ar1 is xm pyrazinyl group, r is 1, m is 0, Ar2 is and Rg is -halo. In another modality, the -halo is replaced in the > ara-position of the phenyl group. In another modality, -halo is -Cl. In another embodiment, -halo is -Cl and it is substituted in the ara-position of the phenyl group. In another modality, -halo is -Br. In another modality, -halo is -Br and it is substituted in the j? Ara-position of the phenyl group. In another modality, - halo is -I. In another modality, -halo is -I and is substituted in the ra-position of the phenyl group. In another embodiment, -halo is -F and is substituted in the ara-position of the phenyl group.
In another embodiment, An is a pyrimidinyl group, m is 0, and Ar2 is a benzothiazolyl group. In another embodiment, An is a pyrimidinyl group, m is 0, and Ar2 is a benzooxazolyl group. In another embodiment, An is a pyrimidinyl group, m is 0, and Ar2 is a benzoimidazolyl group. In another embodiment, An is a pyrimidinyl group, m is 0, and Ar2 is In another embodiment, An is a pyrimidinyl group, m is 0, and Ar2 is In another embodiment, A is a pyrimidinyl group, m is 0, and Ar2 is In another embodiment, An is a pyrimidinyl group, m is 0, and Ar2 is In another embodiment, An is xm pyrimidinyl group, m is 0, Ar2 is In another embodiment, An is a pyrimidimyl group, m is 0, Ar2 is In another embodiment, An is xm pyrimidinyl group, m is 0, Ar2 is In another embodiment, An is a pyrimidinyl group, m is 0, Ar2 is and Rs is a - (d-C6) alkyl. In another embodiment, the - (dC 6) alkyl is substituted on the other-position of the phenyl group. In another embodiment, the - (d-C6) alkyl is a tert-butyl group. In another embodiment, the - (dC ^ alkyl is a tert-butyl group and is substituted in the paraposition of the phenyl group In another embodiment, the - (d-C6) alkyl is xm wo-propyl group. - (C? -C6) alkyl is x? Propyl group and is substituted on the ara-position of the phenyl group.
In another modality, Ar! is a pyrimidinyl group, r is 1, m is 0, Ar2 is and R-8 is -CF3. In another embodiment, -CF3 is substituted on the other-position of the phenyl group.
In another embodiment, An is a pyrimidinyl group, r is 1, m is 0, Ar2 is and Rs is -halo. In another embodiment, the -halo is substituted in the p-position of the phenyl group. In another modality, -halo is -Cl. In another embodiment, -halo is -Cl and is substituted in the para-position of the phenyl group. In another modality, -halo is -Br. In another embodiment, -halo is -Br and is substituted in the s ^ ra-position of the phenyl group. In another modality, -halo is -I. In another modality, -halo is -I and is substituted in the para-position of the phenyl group. In another modality, -halo is -F. In another modality, -halo is -F and it is substituted in the para-position of the phenyl group.
In another embodiment, An is a pyridazinyl group, m is 0, and Ar 2 is a benzothiazolyl group.
In another embodiment, An is a pyridazinyl group, m is 0, and Ar2 is a benzoolyl group.
In another embodiment, An is a pyridazinyl group, m is 0, and Ar2 is a benzoimidazolyl group.
In another embodiment, Ar1 is a pyridazinyl group, m is 0, and Ar2 is In another embodiment, An is a pyridazinyl group, m is 0, and Ar2 is In another embodiment, An is x pyridazinyl group, m is 0, and Ar2 is In another embodiment, Ar! is a pyridazinyl group, m is 0, and Ar2 is In another embodiment, An is xm pyridazinyl group, m is 0, Ax2 is In another embodiment, An is xm pyridazinyl group, m is 0, At2 is In another embodiment, An is xm pyridazinyl group, m is 0, Ar2 is In another embodiment, An is a pyridazinyl group, r is 1, m is 0, Ar2 is and R8 is a - (dC6) alkyl. In another embodiment, he - (C! -C6) alkyl is substituted at the p-group position. In another embodiment, the - (-Ce ^ alkyl is a tert-butyl group In another embodiment, the - (dC6) alkyl is a tert-butyl group and is substituted at the para-position of the phenyl group. In another embodiment, the - (dC6) alkyl is an iso-propyl group and is substituted in the para-position of the phenyl group.
In another embodiment, An is xm piradizinyl group, r is 1, m is 0, Ar2 is and Rg is -CF3. In another embodiment, -CF3 is substituted in the para-position of the phenyl group.
In another modality, Ar! is a piradizinyl group, r is 1, m is 0, Ar2 is and Rs is -halo. In another embodiment, the -halo is substituted in the sara-position of the phenyl group. In another modality, -halo is -Cl. In another embodiment, -halo is -Cl and is substituted in the para-position of the phenyl group. In another modality, -halo is -Br. In another modality, -halo is -Br and is substituted in the s < zra-position of the phenyl group. In another modality, -halo is -I. In another modality, -halo is -I and is substituted in the s < zra-position of the phenyl group. In another modality, -halo is -F. In another embodiment, -halo is -F and it is substituted in the para-position of the phenyl group. In another embodiment, An is a thiadiazolyl group, m is 0, and Ar2 is xm benzothiazolyl group.
In another embodiment, An is xm thiadiazolyl group, m is 0, and At 2 is a benzoolyl group.
In another embodiment, An is xm thiadiazolyl group, m is 0, and Ar2 is a benzoimidazolyl group. In another embodiment, An is xm thiadiazolyl group, m is 0, and Ar2 is In another embodiment, A is a thiadiazolyl group, m is 0, and Ar2 is In another embodiment, An is a tiazolyl group, m is 0, and Ar2 is In another embodiment, An is a thiadiazolyl group, m is 0, and Ar2 is In another embodiment, An is a thiadiazolyl group, m is 0, and At2 is In another modality, Ar! is a thiadiazolyl group, m is 0, and Ar2 is In another embodiment, An is xm thiadiazolyl group, m is 0, and Ar2 is In another embodiment, An is a thiadiazolyl group, r is 1, m is 0, Ar2 is and Rs is a - (d-C6) alkyl. In another embodiment, the - (C1-C6) alkyl is substituted at the position of the phenyl group. In another embodiment, the - (d-C6) alkyl is a tert-butyl group. In another embodiment, the - (d-C6) alkyl is a tert-butyl group and is substituted at the para-position of the phenyl group. In another embodiment, the - (d-C6) alkyl is a wo-propyl group. In another embodiment, the - (d-C6) alkyl is a so-propyl group and is substituted in the para-position of the phenyl group.
In another embodiment, A is a thiadiazolyl group, r is 1, m is 0, At2 is and Rg is -CF3. In another embodiment, -CF3 is substituted in the para-position of the phenyl group.
In another embodiment, An is a thiadiazolyl group, r is 1, m is 0, A12 is and R8 is -halo. In another embodiment, the -halo is substituted in the para-position of the phenyl group. In another modality, -halo is -Cl. In another embodiment, -halo is -Cl and is substituted in the para-position of the phenyl group. In another modality, -halo is -Br. In another embodiment, -halo is -Br and is substituted in the s-ra-position of the phenyl group. In another modality, -halo is -I. In another embodiment, -halo is -I and it is substituted in the phenyl group. In another modality, -halo is -F. In another embodiment, -halo is -F and it is substituted in the para-position of the phenyl group. In another embodiment, An is a pyridyl group, m is 1, R3 is -CH3, and Ar2 is a benzothiazolyl group. In another embodiment, An is a pyridyl group, m is 1, R3 is -CH3, and Ar2 is a benzooxazolyl group. In another embodiment, An is a pyridyl group, m is 1, R3 is -CH3 and Ar2 is a benzoimidazolyl group.
In another embodiment, An is a pyridyl group, m is 1, 3 is -CH3, and Ar2 is In another embodiment, An is xm pyridyl group, m is 1, R3 is -CH3, and At2 is In another embodiment, An is a pyridyl group, m is 1, R3 is -CH3, and At is * your? vn N - (R8).
In another embodiment, An is xm pyridyl group, m is 1, R3 is -CH3, and Ar2 is In another embodiment, An is a pyridyl group, m is 1, R3 is -CH3, and Ar2 is In another embodiment, An is a pyridyl group, m is 1, R3 is -CH3, and Ar2 is In another embodiment, An is a pyridyl group, m is 1, R3 is -CH3, and At2 is In another embodiment, An is a pyridyl group, r is 1, m is 1, R3 is -CH3, Ar2 is and Rg is a - (dC ^ alkyl) In another embodiment, the - (d-C6) alkyl is substituted at the p-aryl group position In another embodiment, the - (d-C6) alkyl is a tert-butyl group In another embodiment, the - (d-C6) alkyl is a tert-butyl group and is substituted in the para-position of the phenyl group In another embodiment, the - (C1-C6) alkyl is a ws-propyl group. In another embodiment, the - (d-C6) alkyl is an SO-propyl group and is substituted at the para-position of the phenyl group.
In another embodiment, An is a pyridyl group, r is 1, m is 1, R3 is -CH3, Ar2 is and Rs is -CF3. In another embodiment, -CF3 is substituted at the sixth position of the phenyl group.
In another embodiment, An is a pyridyl group, r is 1, m is 1, R3 is -CH3, Ar2 is and Rs is -halo. In other. modality, the -halo is substituted in the para-position of the phenyl group. In another modality, -halo is -Cl. In another embodiment, -halo is -Cl and is substituted in the para-position of the phenyl group. In another modality, -halo is -Br. In another embodiment, -halo is -Br and is substituted in the s ^ ra-position of the phenyl group. In another modality, -halo is -I. In another modality, -halo is -I and is substituted in the para-position of! phenyl group. In another modality, -halo is -F. In another embodiment, -halo is -F and is substituted in the ara-position of the phenyl group. In another embodiment, An is a pyrazinyl group, m is 1, R3 is -CH3, and Ar2 is xm benzothiazolyl group. In another embodiment, An is a pyrazinyl group, m is 1, R3 is -CH3, and Ar2 is a benzooxazolyl group. In another embodiment, An is a pyrazinyl group, m is 1, R3 is -CH3 and Ar2 is a benzoimidazolyl group.
In another embodiment, An is a pyrazinyl group, m is 1, R3 is -CH3, and Ar2 is In another embodiment, An is xm pyrazinyl group, m is 1, R3 is -CH3, and Ar2 is In another embodiment, An is xm pyrazinyl group, m is 1, R3 is -CH3, and Ar2 is In another embodiment, An is a pyrazinyl group, m is 1, R3 is -CH3, and Ar2 is In another modality, Ar! is xm pyrazinyl group, m is 1, R3 is -CH3, and Ar2 is In another embodiment, A is xm pyrazinyl group, m is 1, R3 is -CH3, and Ar2 is In another embodiment, An is a pyrazinyl group, m is 1, R3 is -CH3, and Ar2 is In another modality, Ar! is xm pyrazinyl group, r is 1, m is 1, 3 is -CH3, Ar2 is and Rs is a - (d-C6) alkyl. In another embodiment, the - (C1-Ce) alkyl is substituted at the position of the phenyl group. In another embodiment, the - (d-C6) alkyl is a tert-butyl group. In another embodiment, the - (d-C6) alkyl is a tert-butyl group and is substituted at the para-position of the phenyl group. In another embodiment, the - (C1-C6) alkyl is a so-propyl group. In another embodiment, the - (C! -C6) alkyl is a z'50-propyl group and is substituted at the para-position of the phenyl group.
In another embodiment, An is a pyrazinyl group, r is 1, m is 1, R3 is -CH3, Ar2 is and Rs is -CF3. In another embodiment, -CF3 is substituted in the s < zra-position of the phenyl group.
In another embodiment, An is a pyrazinyl group, r is 1, m is 1, R3 is -CH3, Ar2 is and R8 is -halo. In another embodiment, the -halo is substituted in the s ^ ra-position of the phenyl group. In another modality, -halo is -Cl. In another embodiment, -halo is -Cl and is substituted in the para-position of the phenyl group. In another modality, -halo is -Br. In another embodiment, -halo is -Br and is substituted in the s-ra-position of the phenyl group. In another modality, - halo is -I. In another embodiment, -halo is -I and is substituted in the s ^ ra-position of the phenyl group. In another modality, -halo is -F. In another embodiment, -halo is -F and it is substituted in the para-position of the phenyl group. In another embodiment, An is a pyrimidinyl group, m is 1, R3 is -CH3, and Ar2 is a benzothiazolyl group.
In another embodiment, An is a pyrimidinyl group, m is 1, R3 is -CH3, and Ar2 is a benzooxazolyl group.
In another modality, Ar! is a pyrimidinyl group, m is 1, R3 is -CH3 and Ar2 is a benzoimidazolyl group.
In another embodiment, An is a pyrimidinyl group, m is 1, R3 is -CH3, and Ar2 is • In another embodiment, An is a pyrimidinyl group, m is 1, R3 is -CH3, and Ar2 is In another embodiment, An is xm pyrimidinyl group, m is 1, R3 is -CH3, and Ar2 is In another embodiment, An is xm pyrimidmyl group, m is 1, R3 is -CH3, and Ar2 is In another embodiment, An is a pyrimidinyl group, m is 1, R3 is -CH3, and At2 is In another embodiment, An is a pyrimidinyl group, m is 1, R3 is -CH3, and Ar2 is In another embodiment, An is a pyrimidinyl group, m is 1, R3 is -CH3, and Ar2 is In another modality, Ar! is xm pyrimidinyl group, r is 1, m is 1, R3 is -CH3, Ar2 is and R8 is a - (dC6) alkyl. In another embodiment, the - (C1-C6) alkyl is substituted at the "position of the phenyl group. In another embodiment, the - (C? -C6) alkyl is a tert-butyl group. In another embodiment, the - (C1-C6) alkyl is a tert-butyl group and is substituted at the para-position of the phenyl group. In another embodiment, the - (d-C6) alkyl is a z '? O-propyl group. In another embodiment, the - (dC6) alkyl is a zosopropyl group and is substituted at the para-position of the phenyl group.
In another modality, Ar! is a pyrimidinyl group, r is 1, m is 1, R3 is -CH3, Ar2 is and R8 is -CF3. In another embodiment, -CF3 is substituted in the parent-position of the phenyl group.
In another embodiment, An is a pyrimidinyl group, r is 1, m is 1, 3 is -CH3, Ar2 is and Rs is -halo. In another embodiment, the -halo is substituted in the sara-position of the phenyl group. In another modality, -halo is -Cl. In another embodiment, -halo is -Cl and is substituted in the para-position of the phenyl group. In another modality, -halo is -Br. In another modality, -halo is -Br and is substituted in the sara-position of the phenyl group. In another modality, -halo is -I. In another modality, -halo is -I and is substituted in the ara-position of the phenyl group. In another modality, -halo is -F. In another embodiment,.-Halo is -F and is substituted in the laa7-a-position of the phenyl group. In another modality, Ar! is xm pyridazinyl group, m is 1, R3 is -CH3, and Ar2 is a benzothiazolyl group.
In another embodiment, An is xm pyridazinyl group, m is 1, R3 is -CH3, and Ar2 is a benzooxazolyl group.
In another embodiment, An is xm pyridazinyl group, m is 1, R3 is -CH3 and Ar2 is a benzoimidazolyl group. In another embodiment, Ar1 is a pyridazinyl group, m is 1, R3 is -CH3, and Ar2 is In another embodiment, An is a pyridazinyl group, m is 1, R3 is -CH3, and Ar2 is wyuv In another embodiment, An is a pyridazinyl group, m is 1, R3 is -CH3, and Ar2 is In another embodiment, An is xm pyridazinyl group, m is 1, R3 is -CH3, and Ar2 is In another embodiment, Ar1 is xm pyridazinyl group, m is 1, R3 is -CH3, and Ar2 is In another embodiment, An is a pyridazinyl group, m is 1, R3 is -CH3, and Ar2 is In another embodiment, An is xm pyridazinyl group, m is 1, R3 is -CH3, and Ar2 is In another embodiment, An is a pyridazinyl group, r is 1, m is 1, R3 is -CH3, Ar2 is and Rs is a - (C1-C6) alkyl. In another embodiment, the - (C1-C6) alkyl is substituted at the position of the phenyl group. In another embodiment, it is a tert-butyl group. In another embodiment, the - (d-C6) alkyl is a tert-butyl group and is substituted in the phenyl group. In another embodiment, the - (C? -C6) alkyl is a z '? O-propyl group. In another embodiment, the - (d-C ^ alkyl) is a zsO-propyl group and is substituted in the parent-position of the phenyl group.
In another embodiment, An is a pyridazinyl group, r is 1, m is 1, R3 is -CH3, Ar2 is and Rg is -CF3. In another embodiment, -CF3 is substituted in the parent-position of the phenyl group.
In another embodiment, An is a pyrazinyl group, r is 1, m is 1, R3 is -CH3, Ar2 is and Rg is -halo. In another embodiment, the -halo is substituted in the sara-position of the phenyl group. In another modality, -halo is -Cl. In another embodiment, -halo is -Cl and is substituted in the para-position of the phenyl group. In another modality, -halo is -Br. In another modality, -halo is -Br and is substituted in the sara-position of the phenyl group. In another modality, -halo is -I. In another modality, -halo is -I and is substituted in the ara-position of the phenyl group. In another modality, -halo is -F. In another embodiment, -halo is -F and it is substituted in the para-position of the phenyl group.
In another embodiment, An is a thiadiazolyl group, m is 1, R3 is -CH3, and Ar2 is a benzothiazolyl group. In another embodiment, An is a thiadiazolyl group, m is 1, R3 is -CH3, and Ar2 is a benzooxazolyl group. In another embodiment, An is a thiadiazolyl group, m is 1, R3 is -CH3 and Ar2 is a benzoimidazolyl group. In another embodiment, An is xm thiadiazolyl group, m is 1, R3 is -CH3, and Ar2 is In another embodiment, An is xm thiadiazolyl group, m is 1, R3 is -CH3, and Ar2 is In another embodiment, An is a thiadiazolyl group, m is 1, R3 is -CH3, and Ar2 is In another embodiment, An is a thiadiazolyl group, m is 1, R3 is -CH3, and Ar2 is jjl hRA In another embodiment, Ar1 is a thiadiazolyl group, m is 1, R3 is -CH3, and Ar2 is In another embodiment, An is xm thiadiazolyl group, m is 1, R3 is -CH3, and Ar is In another embodiment, An is xm thiadiazolyl group, m is 1, R3 is -CH3, and Ar2 is In another embodiment, An is a thiadiazolyl group, r is 1, m is 1, R3 is -CH3, Ar is and R8 is a - (d-C6) alkyl. In another embodiment, the - (dC ^ alkyl is substituted in the paraposition of the phenyl group In another embodiment, the - (C? -C6) alkyl is a tert-butyl group. -C6) alkyl is xm tez-butyl group and is substituted at the p-group position sara.In another embodiment, the - (d-C6) alkyl is a zss-propyl group.In another embodiment, the - (d- C6) alkyl is a wo-propyl group and is substituted in the para-position of the phenyl group.
In another embodiment, An is a thiadiazolyl group, r is 1, m is 1, R3 is -CH3, Ar2 is and R8 is -CF3. In another embodiment, -CF3 is substituted in the parent-position of the phenyl group.
. In another modality, Ar! is a thiadiazolyl group, r is 1, m is 1, R3 is -CH3, Ar2 is and R8 is -halo. In another embodiment, the -halo is substituted in the sara-position of the phenyl group. In another modality, -halo is -Cl. In another embodiment, -halo is -Cl and is substituted in the para-position of the phenyl group. In another modality, -halo is -Br. In another modality, -halo is -Br and is substituted in the sara-position of the phenyl group. In another modality, -halo is -I. In another embodiment, -halo is -I and is substituted in the para-position of the phenyl group. In another modality, -halo is -F. In another embodiment, -halo is -F and it is substituted in the para-position of the phenyl group. 4. 2 COMPOUNDS MTRO (CIANOWI LPIPERAZINA DE LA FORMULA (Yes ' The present invention also comprises Nitio (cyano) vmylpiperazine Compounds of the formula (11) (LD j5 where An, At2, R3, R4 and m are defined above for the Compounds Nitro (cyano) vinylpiperazine of the formula (H). In one embodiment, An is a pyridyl group. In another embodiment, An is a pyrimidinyl group. In another embodiment, An is a pyrazinyl group. 0 In another modality, Ar! It is a pyridazinyl group. In another embodiment, An is a thiadiazolyl group. In another embodiment, Ar2 is a bezoimidazolyl group. In another embodiment, Ar2 is a benzothiazolyl group. In another embodiment, Ar2 is a benzooxazolyl group.
In one modality, A12 is In another modality, Ar2 is In another modality, Ar2 is In another modality, At is In another modality, At2 is In another modality, Ar2 is In another modality, Ar2 is In another modality, m is 0. In another modality, m is 1. In another modality, m is 2. In another modality, n is 1. In another modality, n is 2. In another modality, n is 3. In otia modality, p is 0. In another modality, p is 1. In another modality, p is 2. In another modality, r is 0. In another modality, r is 1. In another modality, r is 2. In another modality, r is 3.
In another modality, r is 4. In another modality, r is 5. In another modality, q is 0. In another modality, q is 1. In another modality, q is 2. In another modality, q is 3. In another modality, modality, q is 4. In another modality, q is 5. In another modality, q is 6. In another modality, s is 0. In another modality, s is 1. In another modality, s is 2. In another modality, s is 3. In another mode, s is 4. In another mode, R \ is -halo. In another modality, R? is -Cl. In another modality, Rt is -Br. In another modality, R \ is -I.
In another mode, Ri is -F. In another modality, Ri is -CH3. In another embodiment, R i is -CN. In another mode, Ri is -NO2. In another mode, Ri is -OH. In another mode, Ri is -OCH3.
In another modality, R! is -C (halo) 3.
In another embodiment, Ri is -CH (halo) 2. In another embodiment, Rt is -CH (halo).
In another embodiment, R i is -CF3. In another embodiment, n or p is 1 and R2 is -halo, -OH, -NH2, -CN, or -NO2. In another embodiment, nop is 1 and R2 is - (d-C10) alkyl, - (C2-C10) alkenyl, - (C2-C10) alkynyl, - (C3-C0) cycloalkyl, - (C8-C14) bicycloalkyl, - (C8-C? 4) tricycloalkyl, - (C5-C8) cycloalkenyl, - (Cg-C? 4) bicycloalkenyl, - (Cg-C? 4) tricycloalkenyl, - (3- to 7- cuef? s ) heterocycle, or - (7- to 10-cells) bicycloheterocycle, each of which is substituted or not with one or more R5 groups.
In another embodiment, n or p is 1 and R2 is -phenyl, -naphthyl, - (C14) aryl or - (5- to 10-cells) heteroaryl, each of which is substituted or unsubstituted with one or more radical groups.
-, - In another mode, m is 1 and R3 is -halo, -OH, -NH2j -CN, or -NO2.
In another embodiment, m is 1 and R3 is - (C1-C10) alkyl, - (C2-C? O) alkenyl, - (C2-C10) alkynyl, - (C3-C? O) cycloalkyl, - (Cg-) C? 4) bicycloalkyl, - (Cg-C14) tricycloalkyl, - (C5-C10) cycloalkenyl, - (C8-C14) bicycloalkereryl, - (C8-C14) tricycloalkenyl, - (3- to 7- cuef? S) heterocycle, or - (7- to 10-cells) bicycloheterocycle, each of which is substituted or not with one or more R5 groups.
In another embodiment, m is 1 and -R3 is -phenyl, -naphthyl, - (C14) aryl or - (5- to 10-ca) heteroaryl, each of which is substituted or not with one or more groups Re.
~ - In another embodiment, m is 1 and R3 is - (d-C10) alkyl.
In another embodiment, m is 1, R3 is (- (d-d0) alkyl, and the carbon atom to which the group R3 is attached is in the (R) configuration.
In another embodiment, m is 1, R3 is - (C? -C?) Alkyl, and the carbon atom to which the group R3 is attached is in the (S) configuration. 5 In another embodiment, m is 1 and R3 is -CH3.
In another embodiment, m is 1, R3 is -CH3, and the carbon atom to which the group R3 is attached is in the (R) configuration.
In another embodiment, m is 1, R3 is -CH3, and the carbon atom to which the group R3 is attached is in the (S) configuration.
In another modality, m is 1 and R3 is -halo.
In another mode, m is 1 and R3 is -Cl.
In another mode, m is 1 and R3 is -Br.
In another mode, m is 1 and R3 is -I.
In another mode, m is 1 and R3 is -F.
In another modality, R4 is -H. In another embodiment, R4 is -CN.
In another embodiment, R 4 is -C (O) O (C 1 -C 4) alkyl.
In another embodiment, R4 is -C (O) NH ((d-C4) alkyl).
In another embodiment, Ar2 is xm benzothiazolyl group and s is 1.
In another embodiment, Ar2 is a benzoimidazolyl group and s is 1.
In another embodiment, Ar2 is a benzooxazolyl group and s is 1.
In another modality, At2 is and s is 1. In another modality, Ar2 is and s is 1. In another mode, Ar2 is yr is 1. In another mode, Ar? is and q is 1.
In another modality, At2 is and r is 1. In another mode, Ar2, is and r is 1. In another mode, Ar2 is and r is 1. In another embodiment, An is a pyridyl group, m is 0, and Ar2 is a benzothiazolyl group. In another modality, Ar! is a pyridyl group, m is 0, and Ar2 is a benzooxazolyl group.
In another embodiment, A is a pyridyl group, m is 0, and Ar2 is a benzoimidazolyl group. In another modality, An is a pyridyl group, m is 0, and Ar2 is In another modality, An is a pyridyl group, m is 0, and Ar2 is In another modaliadd, An is a pyridyl group, m is 0, and Ar2 is In another embodiment, An is a pyridyl group, m is 0, and Ar2 is In another modality, An is a pyridyl group, m is 0, and Ai2 is In another modality, Ar! is a pyridyl group, m is 0, and Ar2 is In another embodiment, An is a pyridyl group, m is 0, and At2 is In another embodiment, An is a pyridyl group, r is 1, m is 0, Ar 2 is and R8 is a - (dC6) alkyl. In another embodiment, the - (dC 6) alkyl is substituted at the position of the phenyl group. In another embodiment, the - (C1-C6) alkyl is a tert-butyl group. In another embodiment, the - (d-C6) alkyl is xm tert-butyl group and is substituted at the parent-position of the phenyl group. In another embodiment, the - (C1-Ce) alkyl is a zso-propyl group. In another embodiment, the - (C? -C6) alkyl is xm? Ss-propyl group and is substituted in the parent-position of the phenyl group.
In another mode, An is a pyridyl group, r is 1, m is 0, Ar2 is and R8 is -CF3. In another embodiment, -CF3 is substituted in the ara-position of the phenyl group.
In another embodiment, An is a pyridyl group, r is 1, m is 0, At2 is and R8 is -halo. In another modality, the -halo is substituted in the sara-position of the phenyl group. In another modality, -halo is -Cl. In another embodiment, -halo is -Cl and is substituted in the para-position of the phenyl group. In another modality, -halo is -Br. In another modality, -halo is -Br and is substituted in the sara-position of the phenyl group. In another modality, -halo is -I. In another modality, -halo is -I and is substituted in the sara-position of the phenyl group. In another modality, -halo is -F. In another embodiment, -halo is -F and it is substituted in the para-position of the phenyl group. .
In another modality, Ar! is a pyrazinyl group, m is 0, and Ar2 is xm benzothiazolyl group.
In another embodiment, Aii is a pyrazinyl group, m is 0, and Ar2 is a benzooxazolyl group. In another embodiment, Axi is a pyrazinyl group, m is 0, and Ax2 is a benzoimidazolyl group. In another embodiment, An is a pyrazinyl group, m is 0, and Ar2 is In another embodiment, An is a pyrazinyl group, m is 0, and Ar2 is In another embodiment, An is xm pyrazinyl group, m is 0, and Ar2 is In another modality, Ar! is xm pyrazinyl group, m is 0, and Ar2 is In other modality, An is a pyrazinyl group, m is 0, and Ar2 is In another embodiment, An is a pyrazinyl group, m is 0, and Ar2 is In another embodiment, An is a pyrazinyl group, m is 0, and Ar2 is In another embodiment, Ar1 is a pyrazinyl group, r is 1, m is 0, Ar2 is and Rs is a - (d-C6) alkyl. In another embodiment, the - (dC 6) alkyl is substituted at the position of the phenyl group. In another embodiment, the - (d-C6) alkyl is a tert-butyl group. In another embodiment, the - (C? -C6) alkyl is a tert-butyl group and is substituted in the sara-position of the phenyl group. In another embodiment, the - (C! -C6) alkyl is a z'jo-propyl group. In another embodiment, the - (d-C6) alkyl is an iso-p-p-tyl group and is substituted at the p-p-group position.
In another modality, An is a pyrazinyl group, r is 1, m is 0, At2 is and Rs is -CF3. In another embodiment, -CF3 is substituted in the parent-position of the phenyl group.
In another embodiment, An is a thiadiazolyl gxupo, r is 1, m is 0, A 2 is and R8 is -halo. In another embodiment, the -halo is substituted in the sara-position of the phenyl group. In another modality, -halo is -Cl. In another modality, -halo is -Cl and is substituted in the ara-position of the phenyl group. In another modality, -halo is -Br. In another modality, -halo is -Br and is substituted in the sara-position of the phenyl group. In another modality, -halo is -I. In another embodiment, -halo is -I and is substituted in the para-position of the phenyl group. In another modality, -halo is -F. In another modality, -halo is -F and is substituted in lasa? * -position of the phenyl group. In another modality, Ar! is a pyrimidinyl group, m is 0, and Ar2 is a benzothiazolyl group.
In another embodiment, An is a pyrimidinyl group, m is 0, and Ar2 is a benzooxazolyl group.
In another embodiment, An is a pyrimidinyl group, m is 0, and Ar2 is a benzoimidazolyl group. In another embodiment, An is xm pyrimidinyl group, m is 0, and Ar2 is In another embodiment, An is xm pyrimidinyl group, m is 0, and Ar2 is In another modality, An is a pyrimidinyl group, m is 0, and Ar2 is ¡L ^ - (8) e In another modality, An is a pyrimidinyl group, m is 0, and Ar2 is In another embodiment, An is a pyrimidinyl group, m is 0, and Ar2 is In another embodiment, Ai \ is xm pyrimidinyl group, m is 0, and Ar2 is In another embodiment, An is a pyrimidinyl group, m is 0, and Ar2 is In another embodiment, An is a pyrimidinyl group, r is 1, m is 0, Ar2 is and RB is a - (d-C6) alkyl. In another embodiment, the - (d-C6) alkyl is substituted in the para-position of the phenyl group. In another embodiment, the - (d-C6) alkyl is a tert-butyl group. In another embodiment, the - (d-C6) alkyl, is a tert-butyl group and is substituted in the para-position of the phenyl group. In another embodiment, the - (d-Ce) alkyl is a z'so-propyl group. In another embodiment, the - (dC6) alkyl is a z'ss-propyl group and is substituted in the paraposition of the phenyl group.
In another embodiment, An is a pyrimidinyl group, r is 1, m is 0, Ar2 is and Rg is -CF3. In another embodiment, -CF3 is substituted in the parent-position of the phenyl group.
In another modality, An is a pyrimidinyl group, r is 1, m is 0, Ax2 is and Rs is -halo. In another embodiment, the -halo is substituted in the para-position of the phenyl group. In another modality, -halo is -Cl. In another modality, -halo is -Cl and is substituted in the para-position of the phenyl group. In another modality, -halo is -Br. In another embodiment, halo is -Br and is substituted in the parent-position of the phenyl group. In another mode, - 5 halo is -I. In another modality, -halo is -I and is substituted in the ara-position of the phenyl group. In another modality, -halo is -F. In another modality, -halo is -F and it is substituted in the para-position of the phenyl group. In another embodiment, An is a pyridazinyl group, m is 0, and Ar2 is a group? n benzothiazolyl. In another embodiment, An is xm pyridazinyl group, m is 0, and Ar 2 is a benzooxazolyl group. In another embodiment, An is a pyridazinyl group, m is 0, and Ar2 is a benzoimidazolyl group.
In another modality, An is a pyridazinyl group, m is 0, and Ar2 is In another modality, An is a pyridazinyl group, m is 0, and Ax2 is In another embodiment, A is a pyridazinyl group, m is 0, and Ar2 is In another embodiment, An is a pyridazinyl group, m is 0, and Ar2 is In another modality, A is a gxupo pyridazinyl, m is 0, and Ar2 is In another modality, An is a pyridazinyl group, m is 0, and Ax2 is In another modality, An is a pyridazinyl group, m is 0, and Ax2 is In another embodiment, An is a pyridazinyl group, r is 1, m is 0, Ax2 is and Rg is a - (d-C6) alkyl. In another embodiment, the - (C! -C6) alkyl is substituted at the position of the phenyl group. In another embodiment, the - (d-Ce) alkyl is a tert-butyl group. In another embodiment, the - (d-C6) alkyl is a tert-butyl group and is substituted in the parent-position of the phenyl group. In another embodiment, the - (C? -C6) alkyl is a so-propyl group. In another embodiment, the - (C? -C6) alkyl is an iso-propyl group and is substituted in the parent group of the phenyl group.
In another embodiment, An is a pyridazinyl group, r is 1, m is 0, Ax2 is and Rg is -CF3. In another embodiment, -CF3 is substituted in the parent-position of the phenyl group.
In another embodiment, An is a pyridazinyl group, r is 1, m is 0, Ar2 is and R8 is -halo. In another modality, the -halo is substituted in the para-position of the phenyl group. In another modality, -halo is -Cl. In another embodiment, -halo is -Cl and is substituted in the para-position of the phenyl group. In another modality, -halo is -Br. In another modality, -halo is -Br and is substituted in the sara-position of the phenyl group. In another modality, -halo is -I. In another modality, -halo is -I and is substituted in the para-position of the phenyl group. In another modality, -halo is -F. In another modality, -halo is -F and it is substituted in the la / 'a-position of the phenyl group. In another embodiment, An is a thiadiazolyl group, m is 0, and Ar 2 is a benzothiazolyl group. In another embodiment, An is a thiadiazolyl group, m is 0, and Ar 2 is a benzooxazolyl group. In another embodiment, An is xm thiadiazolyl group, m is 0 and Ar2 is a benzoimidazolyl group.
In another embodiment, An is a thiadiazolyl group, m is 0, and Ar2 is In another embodiment, it is a thiadiazolyl group, m is 0, and Ar 2 is another form, An is a thiadiazolyl group, m is 0, and Ar 2 is another form, An is a thiadiazolyl group, m is 0, and Ar 2 is In another embodiment, An is a thiadiazolyl group, m is 0, and Ar2 is In another modality, Ar! is a thiadiazolyl group, m is 0, and Ar2 is In another embodiment, Art is a thiadiazolyl gxupo, m is 0, and Ar2 is In another embodiment, An is a thiadiazolyl group, r is 1, m is 0, Ar2 is and Rs is a - (d-C6) alkyl. In another embodiment, the - (dC6) alkyl is substituted in the para-position of the phenyl group. In another embodiment, the - (C? -C6) alkyl is a tert-butyl group. In another embodiment, the - (C? -Ce) alkyl is xm tert-butyl group and is substituted in the parent group of the phenyl group. In another embodiment, the - (d-C-Jak alkyl is a z-so-propyl group.) In another embodiment, the - (C? -C6) alkyl is an iso-propyl group and is substituted in the sara-position of the phenyl group.
In another embodiment, An is a thiadiazolyl group, r is 1, m is 0, Ar2 is and Rg is -CF3. In another embodiment, -CF3 is substituted in the parent-position of the phenyl group.
In another embodiment, An is a thiadiazolyl group, r is 1, m is 0, Ar2 is and Rg is -halo. In another modality, the -halo is substituted in the sara-position of the phenyl group. In another modality, -halo is -Cl. In another embodiment, -halo is -Cl and is substituted in the para-position of the phenyl group. In another modality, -halo.es -Br. In another modality, -halo is -Br and is substituted in the sara-position of the phenyl group. In another modality, -halo is -I. In another modality, -halo is -I and is substituted in the sara-position of the phenyl group. In another modality, -halo is -F. In another modality, -halo is -F and it is substituted in the para-position of the phenyl group. In another modality, Ar! is a pyridyl group, m is 1, R3 is -CH3, and Ar2 is a benzothiazolyl group.
In another embodiment, An is a pyridyl group, m is 1, R3 is -CH3, and AX2 is a benzooxazolyl group.
In another modality, Ax! is a pyridyl group, m is 1, R3 is -CH3 and Ar2 is a benzoimidazolyl group. In another embodiment, An is a pyridyl group, m is 1, R3 is -CH3, and Ar2 is In another modality, An is a pyridyl group, m is 1, R3 is -CH3, and Ar2 is In another embodiment, An is a pyridyl group, m is 1, R3 is -CH3, and Ar2 is • jv wi In another modality, Ax is a pyridyl group, m is 1, R3 is -CH3, and Ar2 is In another embodiment, An is a pyridyl group, m is 1, R3 is -CH3, and Ar2 is In another modality, Ax! is a pyridyl group, m is 1, R3 is -CH3, and Ar2 is In another embodiment, An is xm pyridyl group, m is 1, R3 is -CH3, and Ar2 is In another embodiment, An is a pyridyl group, r is 1, m is 1, R3 is -CH3, Ax2 is and Rg is a - (C1-C6) alkyl. In another embodiment, the - (dC 6) alkyl is substituted at the para-position of the phenyl group. In another embodiment, the - (d-C6) alkyl is a tert-butyl group. In another embodiment, the - (dC6) alkyl is a tert-butyl group and is substituted in the phenyl group. In another embodiment, the - (C! -C6) alkyl is a zosopropyl group. In another modality, the - (d-C6) alkyl is a so-propyl group and is substituted in the sara-position of the phenyl group.
In another modality, Ar! is a pyridyl group, r is 1, m is 1, R3 is -CH3, Ar2 is and R8 is -CF3. In another embodiment, -CF3 is substituted in the parent-position of the phenyl group.
In another modality, An is a pyridyl group, r is 1, m is 1, R3 is -CH3, Ar2 is and Rs is -halo. In another embodiment, the -halo is substituted in the sara-position of the phenyl group. In another modality, -halo is -Cl. In another embodiment, -halo is -Cl and is substituted in the para-position of the phenyl group. In another modality, -halo is -Br. In another modality, -halo is -Bx and is substituted in the sara-position of the phenyl group. In another modality, -halo is -I. In another modality, -halo is -I and is substituted in the sara-position of the phenyl group. In another modality, -halo is -F. In another modality, -halo is -F and it is substituted in the para-position of the phenyl group.
In another embodiment, An is a pyrazinyl group, m is 1, R3 is -CH3, and Ar2 is a benzothiazolyl group. In another embodiment, An is a pyrazinyl group, m is 1, R3 is -CH3, and Ar2 is a benzooxazolyl group. In another embodiment, An is a pyrazinyl group, m is 1, R3 is -CH3 and Ar2 is a benzoimidazolyl group. In another embodiment, An is a pyrazinyl group, m is 1, R3 is -CH3, and Ar2 is In another embodiment, An is a pyrazinyl group, m is 1, R3 is -CH3, and Ar2 is In another embodiment, An is a pyrazinyl group, m is 1, R3 is -CH3, and Ar2 is In another embodiment, An is a pyrazinyl group, m is 1, R3 is -CH3, and Ar2 is In another embodiment, Axt is xm gxupo pyrazinyl, m is 1, R3 is -CH3, and Ar2 is In another embodiment, An is a pyrazinyl group, m is 1, R3 is -CH3, and Ar2 is In another embodiment, An is a pyrazinyl group, m is 1, R3 is -CH3, and Ar2 is In another embodiment, An is xm pyrazinyl group, r is 1, m is 1, R3 is -CH3, Ar2 is and Rg is a - (d-Ce quil.) In another embodiment, the - (C1-C6) alkyl is substituted at the para-position of the Phenyl group In another embodiment, the - (C! -C6) alkyl is a tert-butyl group.In another embodiment, the - (d-C6) alkyl is a tert-butyl group and is substituted at the phenyl group In another embodiment, the - (C1-C6) alkyl is a z.so-propyl group.In another embodiment, the - (d-C6) alkyl is a z.so-propyl group and is substituted in the -position of the phenyl group.
In another modality, An is a pyrazinyl group, r is 1, m is 1, R3 is -CH3, Ax2 is and Rg is -CF3. In another embodiment, -CF3 is substituted at the p-group position.
In another modality, An is a pyrazinyl group, r is 1, m is 1, R3 is -CH3, Ax2 is and Rg is -halo. In another modality, the -halo is substituted in the ara-position of the phenyl group. In another modality, -halo is -Cl. In another modality, -halo is -Cl and is substituted in the para-position of the phenyl group. In another modality, -halo is -Br. In another modality, -halo is -Br and it is substituted in the sara-position of the phenyl group. In another modality, -halo is -I. In another modality, -halo is -I and is substituted in the ara-position of the phenyl group. In another modality, -halo is -F. In another embodiment, -halo is -F and it is substituted in the para-position of the phenyl group. In another embodiment, An is a pyrimidinyl group, m is 1, R3 is -CH3, and Ax2 is a benzothiazolyl group. In another embodiment, An is a pyrimidinyl group, m is 1, R3 is -CH3, and Ar2 is xm gxupo benzooxazoliol. In another modality, Ax! is a pyrimidinyl group, m is 1, R3 is -CH3 and Ar2 is a benzoimidazolyl group. In another embodiment, An is a pyrimidinyl gxupo, m is 1, R3 is -CH3, and Ax2 is In another embodiment, An is a pyrimidinyl gxupo, m is 1, R3 is -CH3, and Ax2 is In another modality, it is a gxupo piximidinyl, m is 1, R3 is -CH3, and Ar2 is '• suyin. ll ~ (R8) s In another embodiment, An is a pyrimidinyl group, m is 1, R3 is -CH3, and Ar2 is In another embodiment, An is a pyrimidinyl group, m is 1, R3 is -CH3, and At2 is In another embodiment, An is xm pyrimidinyl group, m is 1, R3 is -CH3, and Ax2 is In another embodiment, An is a pyrimidinyl group, m is 1, R3 is -CH3, and Ar2 is In another embodiment, Ax! is a gxupo piximidinyl, r is 1, m is 1, R3 is -CH3, Ar2 is and Rg is a - (d-C6) alkyl. In another embodiment, the - (dC6) alkyl is substituted in the para-position of the phenyl group. In another embodiment, the - (d-C6) alkyl is a tert-butyl group. In another embodiment, the - (C1-C6) alkyl is a tert-butyl group and is substituted in the second position of the phenyl group. In another embodiment, the - (d-C6) alkyl is a z'sO-pxopyl group. In another embodiment, the - (d-C6) alkyl is a so-propyl group and is substituted in the para-phenyl group.
In another embodiment, An is a pyrimidinyl group, r is 1, m is 1, R is -CH 3, Ar 2 is and Rg is -CF3. In another embodiment, -CF3 is substituted in the parent-position of the phenyl group.
In another embodiment, An is a pyrimidinyl group, r is 1, m is 1, R3 is -CH3, Ax2 is and Rs is -halo. In another embodiment, the -halo is substituted in the sara-position of the phenyl group. In otia modahdad, -halo is -Cl. In another modality, -halo is -Cl and is substituted in the para-position of the phenyl group. In another modality, -halo is -Br. In another embodiment, halo is -Br and is substituted in the parent-position of the phenyl group. In another modality, -halo is -I. In another modality, -halo is -I and it is substituted in the sara-position of the phenyl group. In another modality, -halo is -F. In another modality, -halo is -F and it is substituted in the para-position of the phenyl group. In another modality, Ar! is a pyridazinyl group, m is 1, R3 is -CH3, and Ar2 is a benzothiazolyl group. & In another modality, Ar! is a pyridazinyl group, m is 1, R3 is -CH3, and Ax2 is a benzooxazolyl group.
In another embodiment, An is a pyridazinyl group, m is 1, R3 is -CH3 and Ar2 is a benzoimidazolyl group.
In another embodiment, An is a pyridazinyl group, m is 1, R3 is -CH3, and Ar2 is In another modality, An is a pyridazinyl group, m is 1, R3 is -CH3, and Ar2 is In another mode, An is my pyridazinyl group, m is 1, R3 is -CH3, and Ar2 is In another embodiment, Axi is a pyridazinyl group, m is 1, R3 is -CH3, and Ar2 is In another embodiment, An is a pyridazinyl group, m is 1, R3 is -CH3, and Ar2 is In another modality, Ar! is a pyridazinyl group, m is 1, R3 is -CH3, and Ar2 is In other mode, An is a pyridazinyl group, m is 1, R3 is -CH3, and Ar2 is In another modality, AXI is a pyridazinyl group, r is 1, m is 1, 3 is -CH3, Ar2 is and Rg is a - (C? -C6) alkyl. In another embodiment, the - (C! -C6) alkyl is substituted at the position of the phenyl group. In another embodiment, the - (d-C6) alkyl is a tert-butyl group. In another embodiment, the - (d-C6) alkyl is a tert-butyl group and is substituted in the sara-position of the phenyl group. In another embodiment, the - (C! -C6) alkyl is a so-propyl group. In another embodiment, the - (d-Ce) alkyl is a zosopropyl group and is substituted in the ara-position of the phenyl group.
In another modality, An is a pyridazinyl group, r is 1, m is 1, R3 is -CH3, Ar2 is and Rg is -CF3. In another embodiment, -CF3 is substituted in the sara-position of the phenyl group.
In another embodiment, An is a pyridazinyl group, r is 1, m is 1, R3 is -CH3, Ar2 is and Rg is -halo. In another modality, the -halo is substituted in the sara-position of the phenyl group. In another modality, -halo is -Cl. In another embodiment, -halo is -Cl and is substituted in the para-position of the phenyl group. In another modality, -halo is -Br. In another modality, -halo is -Br and it is substituted in the sara-position of the phenyl group. In another modality, -halo is -I. In another modality, -halo is -I and is substituted in the para-position of the phenyl group. In another modality, -halo is -F. In another embodiment, -halo is -F and it is substituted in the para-position of the phenyl group. In another embodiment, An is xm thiadiazolyl group, m is 1, R3 is -CH3, and Ar2 is a benzothiazolyl group. In another embodiment, An is xm thiadiazolyl group, m is 1, R3 is -CH3, and Ar2 is a benzooxazolyl group. In another embodiment, An is xm thiadiazolyl group; m is 1, R3 is -CH3 and Ax2 is a benzoimidazolyl group.
In another embodiment, An is a thiadiazolyl group, m is 1, R3 is -CH3, and Ar2 is In another embodiment, it is a thiadiazolyl group, m is 1, R3 is -CH3, and Ax2 is In another embodiment, An is a thiadiazolyl group, m is 1, R3 is -CH3, and Ax2 is In another embodiment, An is a thiadiazolyl group, m is 1, R3 is -CH3, and Ax2 is In another embodiment, An is a thiadiazolyl group, m is 1, R3 is -CH3, and Ax2 is In another embodiment, An is a thiadiazolyl group, m is 1, R3 is -CH3, and Ax2 is In another embodiment, Axi is a thiadiazolyl group, m is 1, R3 is -CH3, and Ar2 is In another modality, An is a thiadiazolyl group, r is 1, m is 1, R3 is -CH3, Ar2 is and Rg is a - (d-C6) alkyl. In another embodiment, the - (dC 6) alkyl is substituted at the position of the phenyl group. In another embodiment, the - (d-C6) alkyl is a tert-butyl group. In another embodiment, the - (C1-C6) alkyl is a tert-butyl group and is substituted in the parent-position of the phenyl group. In another embodiment, the - (d-C6) alkyl is a z '^ o-propyl group. In another embodiment, the - (d-Ce) alkyl is a z'so-propyl group and is substituted in the sara-position of the phenyl group.
In another modality, An is a thiadiazolyl group, r is 1, m is 1, R3 is -CH3, Ar2 is and Rg is -CF3. In another modality, -CF3 is substituted in the parent-position of the phenyl group.
In another modality, An is a thiadiazolyl group, r is 1, m is 1, R3 is -CH3, Ar2 is and Rg is -halo. In another embodiment, the -halo is substituted in the sara-position of the phenyl group. In another modality, -halo is -Cl. In another modality, -halo is -Cl and is substituted in the para-position of the phenyl group. In another modality, -halo is -Br. In another modality, -halo is -Br and is substituted in the sara-position of the phenyl group. In another modality, -halo is -I. In another modality, -halo is -I and it is substituted in the sara-position of the phenyl group. In another modality, -halo is -F. In another embodiment, -halo is -F and it is substituted in the p-group position. 4. 3 Certain compounds Niteo (cyano) vinylpiperazine can have asymmetric centers and therefore exist in different enantiomeric and diastereomeric forms. This invention relates to the use of all optical isomers and stereoisomers of the Nitio (cyano) vinylpiperazine Compounds, and mixtures thereof, and to all pharmaceutical compositions and methods of treatment which may employ or contain them.
The Nitro (cyano) vinylpiperazine Compounds have a double bond to which a group R4 and a group Ar2-NH- are linked, each of which can be cis or trans sex relative to one otio. Accordingly, the present invention comprises Nitio (cyano) vinylpipexazine Compounds wherein the R4 group and the Ar2-NH- group are trans relative to each other, and all mixtures thereof. Formula (I) and (H) are intended to comprise: (i) Nitro (cyano) vinyl piperazine compounds wherein the group _t and group 10 Ar2-NH- are trans relative to each other, (ii) Nitro compounds (cyano) ) vinylpiperazine in where the group R and the group Ar2-NH- are cis xelative with each other, and (iii) all mixtures thereof.
In the Nitio (cyano) vinylpiperazine Compounds, each R3 group can be attached to a , - carbon atom of the piperazino ring. In a fashion, the Compounds Niteo (cyano) vinylpiperazine have only one group R3j sto es, m = l, and that group R3 is attached to the nitrogen atom adjacent to the carbon atom attached to the pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or thiadiazolyl group. In another embodiment, the Compound Nitro (cyano) vinylpiperazine has only one group R3 and that group R3 is attached to a carbon atom 0 adjacent to the nitrogen atom attached to the group -C (NHAx2) = C (CN) (R4) or to group -C (NHAx2) = C (NO2) (R4).
In another embodiment, two R3 groups are attached to a single carbon atom of the piperazine ring. In another embodiment, a group R3 is attached to a carbon atom adjacent to the nitrogen atom attached to the pyridyl group, pyrimidinyl, pyrrazinyl, pyridazinyl, or thiadiazolyl and other group R3 is attached to a carbon atom adjacent to the nitrogen atom. adjunct of the gupo -C (NHAr2) = C (CN) (R4) or to the group -C (NHAr2) = C (NO2) (R). In another modality, the Niteo Compound (cyano) vinyl piperazine has two R3 groups, that is, m = 2, each attached to a different carbon atom adjacent to the nitrogen atom attached to the pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or thiadiazolyl group. In another embodiment, the Compound Nitium (cyano) vinyl piperazine has two R3 groups, each attached to a different carbon atom adjacent to the carbon atom attached to the group-C (NHAr2) = C (CN) (R4) or to the group - C (NHAr2) = C (NO2) (R4).
In one embodiment, wherein the Nitro (cyano) vinyl piperazine Compound has one or two R3 groups, a carbon atom to which the R3 group is attached has the (R) configuration. In another embodiment, wherein the Nitro Compound (cyano) vinyl piperazine has one or two R3 groups, a carbon atom to which the group R3 is attached has the configuration (S). In another embodiment, the Nitro (cyano) vinylpiperazine Compound has x or two R3 groups and at least one of the carbon atoms to which the R3 group is attached has the (R) configuration. In another modaliadd, the Compound Nitro (cyano) vinylpiperazine has one or two R3 groups, and at least one of the carbon atoms to which a group R3 is attached has the configuration (S).
In another embodiment, the Niteo (cyano) vinylpiperazine Compound has one or two R3 groups, a R3 group is attached to a carbon atom adjacent to the nitrogen atom attached to the pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or thiadiazolyl group, and carbon to which the group R3 is attached is in the Configuration (R). In another embodiment, the Compound Nitium (cyano) vinyl piperazine has one or two R3 groups, a group R3 is attached to a carbon atom adjacent to the nitrogen attached to the pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or thiadiazolyl group, the carbon to which the Group R3 is attached is in the Configuration (RL), and.R3 is - (d-C4) alkyl, substituted or not with one or more halo groups. In another embodiment, the Nitro (cyano) vinylpiperazine Compound has one or two R3 groups, a R3 group is attached to a carbon atom adjacent to the nitrogen atom attached to the pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or thiadiazolyl group, the carbon at which group R3 is attached was in Configuration (R) and 3 is -CH3. In another embodiment, the Nitro (cyano) vinylpiperazine Compound has one or two R3 groups, a R3 group is attached to a carbon atom adjacent to the nitrogen atom attached to the pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or thiadiazolyl group, the carbon at which group R3 is attached was in the Configuration (R) and R3 is -CF3. In another embodiment, the Nitro Compound (cyano) vinyl piperazine has one or two R3 groups, a group R3 is attached to a carbon atom adjacent to the nitrogen attached to the pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or thiadiazolyl group, the carbon to which the Group R3 is attached is in the Configuration (R), and R3 is -CH2CH3.
In another embodiment, the Compound Nitium (cyano) vinyl piperazine has one or two R3 groups, a group R3 is attached to a carbon atom adjacent to the nitrogen atom attached to the group -C (NHAr2) = C (CN) (R4) or to the group -C (NHAr2) = C (NO2) (R4), and the carbon to which the group R3 is attached is found in the Configuration (R). In another embodiment, the Compound Niteo (cyano) vinylpiperazine has one or two R3 groups, a group R3 is attached to a carbon atom adjacent to the nitrogen atom attached to group-C (NHAr2) or to the group -C (NHAr2) = C (NO2) (R4), and the carbon to which the group R3 is attached was in the Configuration (R) and R3 is - (d-C4) alkyl, substituted or not with one or more halo groups. In another embodiment, the Nitro Compound (cyano) vinyl piperazine has one or two R3 groups, a group R3 is attached to a carbon atom adjacent to the nitrogen atom attached to the gxupo -C (NHAr2) = C (CN) (R4) or to the group -C (NHAx2) = C (NO2) (R4), the carbon to which the group R3 is attached is found in the Configuration (R) and R3 -CH3. In another embodiment, the Compound Niteo (cyano) vinylpiperazine has one or two R3 groups, a group R3 is attached to a carbon atom adjacent to the nitrogen attached to the group -C (NHAr2) = C (CN) (R4) or to the group -C (NHAr2) = C (NO2) (R4), the carbon to which the group R3 is attached was in the Configuration (R) and R3 is -CF3. In another embodiment, the Nitro Compound (cyano) vinyl piperazine has one or two R3 groups, a group 3 is attached to a carbon atom adjacent to the nitrogen atom attached to the group -C (NHAr2) = C (CN) (R?) or to the group -C (NHAr2) = C (NO2) (R4), and the carbon to which the group R3 is attached is found in the Configuration (R) and R3 - CH2CH3.
In another embodiment, the Compound Nitium (cyano) vinylpiperazine has one or two R3 groups, a group R3 is attached to a carbon atom adjacent to the nitrogen atom attached to the pyridyl, pyrimidinyl, pixazinyl, pyridazinyl, or thiadiazolyl group, and carbon to which the group R3 is attached was in the Configuration (S). In another modality, the Compound Nitro (cyano) vinylpiperazine has one or two R3 groups, a group R3 is attached to a carbon atom adjacent to the nitrogen atom attached to the pyridyl, pyrimidinyl, pixazinyl, pyridazinyl, or thiadiazolyl group, the carbon to which the R3 group is attached is found in the Configuration (S), and R3 is - ( C? -C4) alkyl, substituted or unsubstituted with one or more halo groups. In another embodiment, the Nitro Compound (cyano) vinyl piperazine has one or two R3 groups, a R3 group is attached to a carbon atom adjacent to the nitrogen atom attached to the pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or thiadiazolyl group, the carbon at which group R3 is attached was in the Configuration (S) and R3 is -CH3. In another embodiment, the Compound Nitium (cyano) vinyl piperazine has one or two R3 groups, a group R3 is attached to a carbon atom adjacent to the nytogen atom attached to the pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or thiadiazolyl group, the carbon at which group R3 is attached is in the Configuration (S) and R3 is -CF3. In another embodiment, the Compound Niteo (cyano) vinylpiperazine has one or two R3 groups, a group R3 is attached to a carbon atom adjacent to the nitrogen attached to the pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or thiadiazolyl group, the carbon to which the Group R3 is attached was in the Configuration (S), and R3 is -CH2CH3.
In another embodiment, the Compound Nitium (cyano) vinyl piperazine has one or two R3 groups, xm group R3 is attached to a carbon atom adjacent to the nytogen atom attached to the group -C (NHAr2) = C (CN) (R) or to the group -C (NHAr2) = C (NO2) (R4), and the carbon to which the group R3 is attached was in the Configuration (S). In another embodiment, the Nitro Compound (cyano) vinyl piperazine has one or two R3 groups, a group R3 is attached to a carbon atom adjacent to the nitrogen atom attached to the group -C (NHAx2) = C (CN) (R or gxupo -C (NHAr2) = C (NO2) (R4), and the carbon to which the group R3 is attached was in the Configuration (S) and R3 is - (d-C4) alkyl, substituted or not with one or more halo groups In another embodiment, the Compound Nitium (cyano) vinylpipexazine has one or two R3 groups, one group R3 is attached to a carbon atom adjacent to the nitrogen atom attached to the group -C (NHAr2) = C (CN) (R4) or to the group -C (NHAr2) = C (NO2) (R4), the carbon to which the group R3 is attached was in the Configuration (S) and R3 -CH3 In another modality, the Nitium Compound ( cyano) vinylpiperazine has one or two g3P3 R3, a group R3 is attached to a carbon atom adjacent to the nitrogen attached to the group -C (NHAr2) = C (CN) (R4) or the group -C (NHAr2) = C ( NO2) (R4), the carbon to which the R3 group is ad together it is in the Configuration (S) and R3 is -CF3. In another embodiment, the Compound Nitium (cyano) vinyl piperazine has one or two groups R3, xm group R3 is attached to a carbon atom adjacent to the nitrogen atom attached to the group -C (NHAr2) = C (CN) (E) or to the group -C (NHAr2) = C (NO2) (R4), and the carbon to which the group R3 is attached was in the Configuration (S) and R3 -CH2CH3.
In another embodiment, the Compound Nitium (cyano) vinylpiperazine has only one group R3, the group R3 is attached to a carbon atom adjacent to the nitrogen atom attached to the pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or thiadiazolyl group, and the carbon to which the R3 group is attached is found in the Configuration (R). In another modality, the Compound Nitium (cyano) vinylpiperazine has only one R3 group, the R3 group is attached to a carbon atom adjacent to the nytogen atom attached to the pyridyl, pyrimidinyl, pyrazinyl group, pyridazinyl, or thiadiazolyl, the carbon to which the group R3 is attached is found in the Configuration (R), and R3 is - (C? -C4) alkyl, substituted or unsubstituted with one or more halo groups. In another embodiment, the Nitro Compound (cyano) vinylpiperazine has only one R3 group, the R3 group is attached to a carbon atom adjacent to the nitrogen atom attached to the pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or thiadiazolyl group, the carbon to which group R3 is attached was in Configuration (R) and R3 is -CH3.
In another embodiment, the Compound Nitium (cyano) vinyl piperazine has only one group R3, the group R3 is attached to a carbon atom adjacent to the nitrogen atom attached to the pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or thiadiazolyl group, the carbon to which group R3 is attached was in Configuration (R) and R3 is -CF3. In another embodiment, the Compound Nitium (cyano) vinyl piperazine has only one group R3, the group R3 is attached to a carbon atom adjacent to the nitrogen attached to the pyridyl group, p rimidinyl, pixazinyl, pixidazinyl, or thiadiazolyl, the carbon to which the Group R3 is attached was in the Configuration (R), and R3 is -CH2CH3.
In another embodiment, the Nitro Compound (cyano) vinylpiperazine has only one group R3, the group R3 is attached to a carbon atom adjacent to the nucleotide atom attached to the group -C (NHAr2) = C (CN) (R4) or to the group -C (NHAr2) = C (NO2) (R4), and the carbon to which the R3 group is attached is found in the Configuration (R). In another embodiment, the Compound Nitium (cyano) vinyl piperazine has only one R3 group, the group R3 is attached to a carbon atom adjacent to the nitrogen atom attached to the group -C (NHAr2) = C (CN) (R4) or group -C (NHAr2) = C (NO2) (R4), and the carbon to which the group R3 is attached is in the Configuration (R) and R3 is - (d-C) alkyl, substituted or not with one or more halo groups. In another embodiment, the Nitro Compound (cyano) vinyl piperazine has only one R3 group, the R3 group is attached to a carbon atom adjacent to the nytogen atom attached to the group -C (NHAr2) = C (CN) (R4) or group -C (NHAr2) = 0 1 ^ 0 ^ (1 ^), the carbon to which the group R3 is attached is in the Configuration (R) and R3 --CH3. In another embodiment, the Nitro Compound (cyano) vinyl piperazine has only one R3 group, the R3 group is attached to a carbon atom adjacent to the nitrogen attached to the group -C (NHAr2) = C (CN) (R) or the group - C (NHAr2) ^ (NO ^ ÍR ^, the carbon to which gxupo R3 is attached is in the Configuration (R) and R3 is -CF3. In another embodiment, the Compound TSfitio (cyano) vinylpiperazine has only one R3 group , the group R3 is attached to a carbon atom adjacent to the nitrogen atom attached to the group-C (NHAx2) = C (CN) (R4) or to the gxupo -C (NHAx2) = C (NO2) (R4), and the carbon to which the group R3 is attached is found in the Configuration (R) and R3 -CH2CH3.
In another embodiment, the Compound Nitium (cyano) vinyl piperazine has only one group R3, the group R3 is attached to a carbon atom adjacent to the nitrogen atom attached to the pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or thiadiazolyl group, and the carbon at which group R3 is attached was in the Configuration (S). In another embodiment, the Compound Nitium (cyano) vinyl piperazine has only one group R3, the group R3 is attached to a carbon atom adjacent to the nitrogen atom attached to the pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or thiadiazolyl group, the carbon to which the group R3 is attached is in the Configuration (S), and R3 is - (d-C4) alkyl, substituted or not with one or more halo groups. In another embodiment, the Niteo (cyano) vinylpiperazine Compound has only one R3 group, the R3 group is attached to a carbon atom adjacent to the nytogen atom attached to the pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or thiadiazolyl group, the carbon to which the group R3 is attached is in the Configuration (S) and R3 is -CH3.
In another embodiment, the Niteo (cyano) vinylpiperazine Compound has only one R3 group, the R3 group is attached to a carbon atom adjacent to the nitrogen atom attached to the pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or thiadiazolyl group, the carbon to which The R3 GXupo is attached in the Configuration (S) and R3 is -CF3. In another embodiment, the Nitro (cyano) vinyl piperazine Compound has only one R3 group, the R3 group is attached to a carbon atom adjacent to the nitrogen attached to the pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or thiadiazolyl group, the carbon to which the group R3 is attached was in the Configuration (S), and R3 is -CH2CH3.
In another embodiment, the Compound Nitium (cyano) vinylpiperazine has only one group R3, the group R3 is attached to a carbon atom adjacent to the nitrogen atom attached to the group -C (NHAr2) = C (CN) (R4) or group -C (NHAr2) ^ (NO ^^), and the carbon to which the group R3 is attached is listed in the Configuration (S). In another embodiment, the Compound Nitium (cyano) vinyl piperazine has only one group R3, the group R3 is attached to a carbon atom adjacent to the nytogen atom attached to the group-C (NHAr2) = C (CN) (R4) or group -C (NHAr2) = C (NO2) (R4), and the carbon to which the group R3 is attached was in the Configuration (S) and R3 is - (dC) alkyl, substituted or not with one or more groups halo. In another modality, the Compound Nitio (cyano) vinylpiperazine has only one group R3, the group R3 is attached to a carbon atom adjacent to the nitrogen atom attached to the group -C (NHAr2) = C (CN) (R4) or to the group -C (NHAr2) = C (N? 2) (Rt), the carbon to which the group R3 is attached is found in the Configuration (S) and R3 -CH3. In another embodiment, the Compound Nitium (cyano) vinylpiperazine has only one group R3, the group R3 is attached to a carbon atom adjacent to the nitrogen attached to the group -C (NHAr2) = C (CN) (R) or the group -C (NHAr2) = C (NO2) (R4), the carbon to which the group R3 is attached was in the Configuration (S) and R3 is -CF3. In another embodiment, the Compound Nitium (cyano) vinyl piperazine has only one group R3, the group R3 is attached to a carbon atom adjacent to the nytogen atom attached to the group - C (NHAr2) = C (CN) (R4) or to gxupo -C (NHAx2) = C (NO2) (R4), and the carbon to which the group R3 is attached in the Configuration (S) and R3 -CH2CH3. i The links represented by a line *? / w | in the Compounds Nitro (cyano) vinylpiperazine of the Formula (I) and Formula (II) mean that the group t and the group Ar2 can be cz ', s relative one with ote, trans relative one with otio, or a mixture of the cis and trans isomers. 4. 4 NITROÍCIAN COMPOUNDS INILOPYTAZINE ILLUSTRATIVES Nitro (cyano) vinylpiperazine compounds are listed below in Tables 1-7.
For the chemical structure represented, for example, at the beginning of each of Tables 1-7, a is independently 0 or 1. When a = 0, the group in position "a" is -H. When a = 1, the group in the "a" (Rsa) position is other than -H, that is, it is Rg. Table 1 (? D and pharmaceutically acceptable salts thereof, wherein: "a" means that R3 is -H3 .. "b" means that R3 is -CH3 and the Compound Nitio (cyano) vinylpiperazine is racemic. "c" means that R3 is -CH3 and the carbon atom to which R3 is attached was in the (R) configuration. "d" means that R3 is -CH3 and the carbon atom to which R3 is attached is in the (S) configuration.
Table 2 and pharmaceutically acceptable salts thereof, wherein: "a" means that R3 is -H3. "b" means that R3 is -CH3 and the Compound Niteo (cyano) vinylpiperazine is racemic. "c" means that R3 is -CH3 and the carbon atom to which R3 is attached is in the (R) configuration. "d" means that R3 is -CH3 and the carbon atom to which R3 is attached is in the (S) configuration. "Table 3 and pharmaceutically acceptable salts thereof, wherein: '15 20 25 "a" means that R3 is -H3. "b" means that R3 is -CH3 and the Compound Niteo (cyano) vinylpiperazine is racemic. . "c" means that R3 is -CH3 and the carbon atom to which R3 is attached is in the (R) configuration. - n "d" means that R3 is -CH3 and the carbon atom to which R3 is attached was in the configuration (S).
Table 4 (YOU And pharmaceutically acceptable salts thereof, wherein: "a" means that R3 is -H3. "b" means that R3 is -CH3 and the Compound Niteo (cyano) vinylpiperazine is racemic. "c" means that R3 is -CH3 and the carbon atom to which R3 is attached was in the (R) configuration. "d" means that R3 is -CH3 and the carbon atom to which R3 is attached is listed in the (S) configuration.
Table 5 (vp) and pharmaceutically acceptable salts thereof, wherein: : 'a' means that R3 is -H3. "b" means that R3 is -CH3 and the Compound Niteo (cyano) vinylpiperazine is racemic. "c" means that R3 is -CH3 and the carbon atom to which R3 is attached was in the (R) configuration. "d" means that R3 is -CH3 and the carbon atom to which R3 is attached is listed in the (S) configuration.
Table 6 (HIV) and pharmaceutically acceptable salts thereof, wherein: "a" means that R3 is -H3. "b" means that R3 is -CH3 and the Compound Nitio (cyano) vinylpiperazine is racemic. "c" means that R3 is -CH3 and the carbon atom to which R3 is attached is in the (R) configuration. "d" means that R3 is -CH3 and the carbon atom to which R3 is attached is listed in the (S) configuration.
Table 7 (DO and pharmaceutically acceptable salts thereof, wherein: "a" means that R3 is -H3. "b" means that R3 is -CH3 and the Compound Nitio (cyano) vinylpiperazine is racemic. "c" means that R3 is -CH3 and the carbon atom to which R3 is attached was in the configuration (R). "d" means that R3 is -CH3 and the carbon atom to which R3 is attached is in n the configuration (S). 4. 4 Definitions According to the use granted in this document, the terms used above have the meaning: 5"- (C1-C1o) alkyl" means a straight or branched chain of non-cyclic hydrocarbon having from 1 to 10 carbon atoms. Representative linear chain - (d-do) alkyl includes -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl, -n-hexyl, -n-heptyl, -n-octyl, -n- nonyl, and -n-decyl. Representative branching - (C1-C1o) alkyl includes -z'so-propyl, -sec-butyl, -z'-butyl, -tert-butyl, -z'so-pentyl, -neo-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1-ethylbutyl, 2-ethylbutyl, 3-ethylbutyl, 1, 1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-methylhexyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 1,2-dimethylpentyl, 1,3-dimethylpentyl, 1,2-dimethylhexyl, 1,3-dimethylhexyl, 3,3-dimethylhexyl, 1,2-dimethyl-heptyl, 1,3-dimethylheptyl, and 3,3-dimethylheptyl. "- (d-C6) alkyl" means a straight or branched chain of non-cyclic hydrocarbon having from 1 to 6 carbon atoms. Representative linear chain - (d-C6) alkyls includes -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl, and -n-hexyl. Representative branched - (d-C6) alkyls includes -z'so-propyl, -sec-butyl, -z'-butyl, -tert-butyl, -z'so-pentyl, -neo-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1-ethylbutyl, 2-ethylbutyl, 3-ethylbutyl, 1, 1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, and 3,3-dimethylbutyl.
"- (C2-C10) alkeny" means a straight or branched chain of non-cyclic hydrocarbon having from 2 to 10 carbon atoms including at least one carbon-carbon double bond. Linear and branched chain representative (C2-C10) alkenyl includes -vinyl, -allyl, -1-butenyl, -2-butenyl, -z'-butynyl, -1-pentynyl, -2-pentenyl, -3-methyl- l-butenyl, -2-methyl-2-butenyl, -2,3-dimethyl-2-butenyl, -1-hexenyl, -2-hexenyl, -3-hexenyl, -1-heptenyl, -2-heptenyl, - 3-heptenyl, -1-octenyl, -2-octenyl, -3-octenyl, -1-nonenyl, -2-nonenyl, -3-nonenyl, -1-decenyl, -2-decenyl, -3-decenyl and the like .
"- (C2-C6) alkenyl" means a straight or branched chain of non-cyclic hydrocarbon having from 2 to 6 carbon atoms and including at least one carbon-carbon double bond. Representative linear and branched chain (C2-Ce) alkenyl includes -vinyl, -allyl, -1-butenyl, -2-butenyl, -z'-butynyl, -1-pentenyl, -2-pentenyl, -3-methyl- 1 -butenyl, -2-methyl-2-butenyl, -2,3-dimethyl-2-butenyl, -1-hexenyl, 2-hexenyl, 3-hexenyl and the like.
"- (C2-do) alkynyl" means a straight or branched chain of non-cyclic hydrocarbon having from 2 to 10 carbon atoms and including at least one carbon-carbon triple bond. Representative linear or branched chain - (C2-do) alk mTs includes -. acetylenyl, -propynyl, -1-butynyl, -2-butynyl, -1 -pentinyl, -2-pentynyl, -3-methyl-1-butynyl, -4-pentynyl, -1-hexyl, -2-hexynyl, - 5-Hexynyl-1-heptynyl-2-heptynyl -6-heptynyl-1-octynyl, -2-octynyl, -7-octynyl, -1-nonynyl-2-noninyl, -8-noninyl, -1- 5 decolor, -2-decinyl, -9-decinyl and the like.
"- (C2-C6) alkynyl" means a straight or branched chain of non-cyclic hydrocarbon having from 2 to 6 carbon atoms and including at least one carbon-carbon triple bond. Linear and branched chain (C2-Ce) alkynyl includes -acetylenyl, 10 -propynyl, -1-butynyl, -2-butynyl, -1-pentynyl, -2-pentynyl, -3-methyl-1-butynyl, -4- pentinyl, -1-hexyl, -2-hexinyl, -5-hexinyl and the like. "- (C3-C10) cycloalkyl" means a saturated cyclic hydrocarbon having from 3 to 10 carbon atoms. (C3-C10) Representative cycloalkyls are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, and cyclodecyl. "- (C3-Cg) cycloalkyl" means a saturated cyclic hydrocarbon having from 3 to 8 carbon atoms. (C3-Cg) Representative cycloalkyls include -cyclopropyl, -cyclobutyl, -cyclopentyl, -cydohexyl, -cycotheptyl, and -cyclooctyl.
"- (Cg-C14) bicycloalkyl" means a bicyclic hydrocarbon ring system having from 8 to 14 carbon atoms and at least one saturated cyclic alkyl ring. - (C 8 -C 14) Representative bicycloalkyl include -indanyl, -1,2,3,4-tetiahydronaphthyl, -5,6,7,8-tetiahydronaphthyl, -perhydronaphthyl and the like. je "- (Cg-C14) tricycloalkyl" means a tri-cyclic hydrocarbon ring system having from 8 to 14 carbon atoms and at least one saturated cyclic alkyl ring. - (Cg-C14) representative tricycloalkyl include -pyrenyl, -1,2,3,4-tetrahydxoantiacenyl, -perhydroanthracenyl -aceantienyl, -1,2,3,4-tetranidropenanthrenyl, -5,6,7,8-tetrahydrophenantienyl, -perhydrofenantrenyl and the like.
"- (C5-C10) cycloalkenyl" means a non-axomatic cyclic hydrocarbon with al minus a carbon-carbon double bond in the cyclic system and from 5 to 10 carbon atoms. (C5-C1o) representative cicloalquenils include -cyclopentenyl, cyclopentadienyl, -cycloheptenyl, -cycloheptadienyl, -cycloheptatrienyl, -cyclooctenyl, - cycloheptatrienyl, -ciclooctenilo, -cyclooctadienyl, -cyclooctatrienyl, -ciclooctatetiaenilo, -10 cyclononenyl, -cyclononadienyl, -cyclodecenyl, -cyclodecadienyl and the like.
"- (C5-C8) cycloalkenu" means a non-aromatic cyclic hydrocarbon having at least one carbon-carbon double bond in the cyclic system and from 5 to 8 carbon atoms.
(C5-Cg) Representative cycloalkenyl include -cyclopentenyl, -cyclopentadienyl, , r-cyclohexenyl, -cyclohexadienyl, -cycloheptenyl, -cycloheptadienyl, -cycloheptatrienyl, Cyclooctenyl, cyclooctadienyl, cyclooctatrienyl, cyclooctatetraenyl and the like.
"- (Cg-C14) bicycloalkenü" means a bi-cyclic hydrocarbon ring system having at least xm double carbon-carbon bond in each ring and from 8 to 14 carbon atoms. . - (C8-C14) Representative bicycloalkenyls include -indenyl, -pentalenyl, -0-naphthalenyl, -azenyl, -heptalenyl, -1,2,7,8-teteahidronaphthalenyl and the like.
"- (C8-C14) tricycloalkenu" means a tri-cyclic hydxocaxbono ring system having at least one carbon-carbon double bond in each ring and from 8 to 14 carbon atoms. - (C8-C14) representative tricycloalkenyl include -anthracenyl, -phenanthrenyl, 5-phenylenyl, -cenaphthalenyl, as-indacenyl, s-indacenyl and the like. "- (3- to 7-cells) heterocycle" or "- (3- to 7-cells) heterocycle" means xm 3- to 7-chain monocyclic heterocyclic ring which is either saturated, unsaturated, non-aromatic, or aromatic. A 3- or 4-stranded heterocycle can contain up to 3 heteroatoms, a 5-stranded heterocycle can contain up to 4 heteroatoms, a 6-stranded heterocycle can contain up to 6 heteroatoms, and a 7-stranded 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-well) heterocycle can be attached by means of a nitrogen or carbon atom. - (3- to 7-cations) representative heterocycles include pyridyl, furyl, thiophenyl, pyrrolyl, oxazolyl, imidazolyl, thiazolyl, thiadiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, morpholinyl, pyrrolidinonyl, pixrolidinyl, piperidinyl, piperazinyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydroxypyranyl, teteratedipixindinyl, tetrahydropyrimidinyl, tetiahydrothiophenyl, tetiahydrothiopyranyl and the like. "- (3- to 5-caffeine) heterocycle" or "- (3- to 5-chain) heterocycle" means a 3- to 5-chain monocyclic heterocyclic ring which is either saturated, unsaturated, non-aromatic, or aromatic. A 3- or 4-chain heterocycle can contain up to 3 heteroatoms, and a 5-chain heterocycle can contain up to 4 heteroatoms. Each heteroatom is independently selected from nitrogen, which can be quaternized; oxygen; and sulfur, including sulfoxide and sulfone. The - (3- to 5-cells) heterocycle can be attached by means of a nitrogen or carbon atom. - (3- to 5-cells) representative heterocycles include furyl, thiophenyl, pyrrolyl, oxazolyl, imidazolyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, triazinyl, pyrrolidinonyl, pyrrolidinyl, hydantoinyl, oxyranyl, oxetanyl, tetrahydrofuranyl, tetiahydrothiophenyl, and the like. "- (7- to 10-words) bicycloheterocycle" or "- (7- to 10-words) bicycloheterocycle" means a 7- to 10-bicyclic heterocyclic ring which is either saturated, unsaturated non-aromatic, or aromatic. A - (7- to 10-cells) bicycloheterocycle contains from 1 to 4 heteroatoms independently selected from nitrogen, which may be quaternized; oxygen; and sulfur, including sulfoxide and sulfone. The bicycloheterocycle - (7- to 10-caffeine) can be attached by means of a nitrogen or caxone atom. - (7- to 10-cells) Representative bicycloheterocycles include -quinolinyl, -isoquinolinyl, -chromonyl, -coumarinyl, -indolyl, -indolizinyl, -benzo [b] furanyl, -benzo [b] thiophenyl, -indazolyl, -purinyl, -4H-quinolizinyl, -isoquinolyl, -quinolyl, -phthalazinyl, -naphthyridinyl, -carbazolyl, -β-carbolinyl and the like.
, - "- (C14) aryl" means a 14-carbon aromatic carbocyclic moiety such as -antrile or -phenanthryl. "- (5- to 10-cells) heteroaryl" means xm aromatic heterocyclic ring of 5 to 10 cores, including both mono- and bicyclic ring systems, wherein at least one carbon atom of one or both rings is substituted with a heteroatom 0 independently selected from nitrogen, oxygen and sulfur. In one embodiment, one of the - (5- to 10-story) heteroaryl rings contains at least one carbon atom. In another embodiment, both rings of the 5- (5- to 10-chain) heteroaryl contain at least one carbon atom. - (5- to 10-cells) Representative heteroarils include pi idyl, fxaryl, 5-benzofuranyl, thiophenyl, benzothiophenyl, quinolinyl, pyrrolyl, indolyl, oxazolyl, benzoxazolyl, imidazolyl, benzimidazolyl, thiazolyl, benzothiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidyl, pyrimidinyl, thiadiazolyl, triazinyl, cinnolinyl, phthalazinyl and quinazolinyl.
"-CH2 (halo)" means a methyl group in which one of the hydrogens of the methyl group has been replaced with a halogen. Representative -CH2 (halo) groups include -CH2F, -CH2C1, -CH2Br, and -CH2L "-CH (halo) 2" means a methyl group in which two of the hydrogens of the methyl group have been replaced with a halogen. Representative -CH (halo) 2 groups include -CHF2, -CHC12, -CHBr2, -CHBrCl, -CHC1I, and -CHI2.
"-C (halo) 3" means a methyl group in which each xmo of the hydrogens has been replaced with xm halogen. Representative -C (halo) 3 groups include -CF3, -CCI3, -CBr3, and -CI3. "-Halogen" or "-halo" means -F, -Cl, -Br, or -I.
The phrase "pyridyl group" means where R1; R2, and n are defined above for the Nitro (cyano) vinylpiperazine Compounds of the formulas (I) and (II).
The phrase "pyrazinyl group" means, wherein Rls R2, and p are defined above for the Nitio (cyano) vinylpiperazine Compounds of formulas (I) and (H).
The phrase "pyrimidinyl group" means wherein Rl5 R2, and p are defined above for the itio (cyano) vinyl piperazine Compounds of the formulas (I) and (U).
The phrase "pyridazinyl group" means wherein Rl5 R2, and p are defined above for the itio (cyano) vinyl piperazine Compounds of formulas (I) and (II).
The phrase "thiadiazolyl group" means wherein Ri is defined above for the Nitro (cyano) vinyl piperazine Compounds of formulas (I) and (TI). The phrase "2- (3-chloropyridyl)" means The phrase "2- (3-fluoropyridyl)" means The phrase "2- (3-methylpyridyl)" means The phrase "2- (3-CF3-pyridyl)" means The phrase "2- (3-CHF2-pyridyl)" means The phrase "2- (3-hydroxypyridyl)" means The phrase "2- (3-nitropyridyl)" means The phrase "2- (3-cyanopyridyl)" means The phrase "2- (3-bromopyridyl)" means The phrase "2- (3-odopyridyl)" means The phrase "4- (5-chloropyrimidinyl)" means The phrase "4- (5-methylpyrimidinyl)" means The phrase "4- (5-fluoropyrimidinyl)" means The phrase "2- (3-chloropyrazinyl)" means The phrase "2- (3-mitilpyrazinyl)" means The phrase "2- (3-fluoropyrazinyl)" means The phrase "3- (4-chloropyridazinyl)" means The phrase "3- (4-methypyridazinyl)" means The phrase "3- (4-fluoropyridazinyl)" means The phrase "5- (4-chlorothiadiazolyl)" means The phrase "5- (4-methylthiadiazolyl)" means The phrase "5- (4-fluorothiadiazolyl)" means The phrase "benzoimidiazolyl group" means wherein Rs and s are defined above for the Nitio (cyano) vinylpiperazine Compounds of the formulas (I) and (H). The phrase "benzothiazolyl group" means wherein R8 and s are defined above for the compounds Nitio (cyano) vinylpiperazine or of the formulas (I) and (D). The phrase "benzooxazolyl group" means wherein Rs and s are defined above for the Nitro (cyano) vinyl piperazine Compounds of formulas (I) and (? L). The phrase "piperazine ring" means The term "animal," includes, but is not limited to, a cow,. monkey, chimpanzee, baboon, horse, sheep, pig, chicken, turkey, quail, cat, dog, rat, mouse, guinea pig and human. The phrase "pharmaceutically acceptable salt," according to the use herein given, is any pharmaceutically acceptable salt that can be prepared from a Nitium (cyano) vinyl piperazine Compound, including a salt formed from an acid and a basic functional group, such as a group of nytogen, from one of the Niteo (cyanp) vinylpiperazine Compounds. Exemplary salts include, but are not limited to, sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, phosphonic acid, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, s-toluenesulfonate and gt; and pamoate (that is, salts 1, -methylene-bis- (2-hydroxy-3-naphthoate)). The term "pharmaceutically acceptable salt" also includes a salt prepared from xm Nitro (cyano) vinyl piperazine compound having an acidic functional group, such as a functional carboxylic acid group, and a pharmaceutically acceptable inorganic or organic base. Suitable bases include, but are not limited to, alkali metal hydroxides such as sodium, potassium and lithium; alkali metal hydroxides such as calcium and magnesium; hydroxides of other metals such as aluminum and zinc; ammonia and organic amines, such as mono-, di-, hydroxy-substituted or unsubstituted, or trialkylamines; dicyclohexyl amine; tributyl arnine; pyridine; N-methyl, N-ethyl amine; diethyl amine; triethyloamine; lower mono-, bis-, or tris- (2-hydroxy-amines), such as mono-, bis-, or tris- (2-hydroxyethyl) amine, 2-hydroxy-tert-butylamino, or tris- (hydroxymethyl) methyloamine, N, N-di-lower alkyl-N- (lower hydroxy-lower alkyl) -amines, such as N, N-dimethyl-N- (2- hydroxyethyl) amine, or tri- (2-hydroxyethyl) amine; N-methyl-D-glucamine; and amino acids such as arginine, lysine and the like.
The phrase "effective amount," used in connection with a Nitro (cyano) vinylpiperazine Compound means an amount effective to: (a) treat or prevent a Condition; or (b) inhibit the VR1, mGluR1, or mGluR5 function in a cell. The phrase "effective amount," used in connection with another therapeutic agent means an amount to provide the therapeutic effect of the therapeutic agent. When a first group is "substituted with one or more" second groups, one or more hydrogen atoms of the first group is replaced with a corresponding number of second groups. In one embodiment, each carbon atom of a first group is independently substituted with one or two second groups. In another mode, each carbon atom is independently substituted with only a second group. The term "Ul" means urinary incontinence.
The term "IBD" means inflammatory bowel disease.
The term "IBS" means irritable bowel syndrome.
The term "ALS" means lateral amyotrophic sclerosis.
The term "DMF" means dimethylformamide.
The term "DIEA" means di-zso-propylethyl amine.
The term "DIC" means di-z'so-propylcarbodimide.
The phrases "treatment of", "tiatar" and the like include the alleviation or amelioration of a Condition or symptom thereof.
In one embodiment, treating includes inhibiting, for example, decreasing the overall frequency of episodes of a Condition or symptoms thereof. The phrases, "prevention of," "preventing" and the like include avoiding the onset of a Condition or symptom thereof. 4. 6 Methods for Preparing Nitiof Ciano) Vinylpiperazine Compounds The Nitro (cyano) vinylpiperazine Compounds can be prepared using conventional oxigenic synthesis or by means of the following illustrative methods shown in the following schemes. 4. 6.1 Methods for Preparing the Niteo (cyano) vinylpiperazine Compounds of Formula I.
The Niteo (cyano) vinylpiperazine Compounds of Formula (I) can be obtained by the following illustrative method illustrated below in Scheme 1.
Scheme 1 Cyano (niteo) vinylpiperazine compounds of the formula (I) wherein Arl, Ar2, R3, R4, and m are defined above for the Nitio (cyano) vinylpiperazine Compounds of the formula (I). For example, a DMF solution of isothiocyanate A (2.5 mmol) and nitrile B is allowed to react in the presence of DIEA (2.5 mmol) at a temperature of about 25 ° C for about 16 h to provide a DMF solution. of a compound of formula C. A compound of formula D (3 mmol) and DIC (4.5 mmol) is then added to the DMF solution of the compound of formula C and the resulting solution is allowed to stir at a temperature of about 25. ° C for about 16 h. The solvent is then removed under reduced pressure to provide a residue. The residue is then purified using flash column matography (silica gel eluted with a gradient of 5:95 ethyl acetate: hexane at 20:80 ethyl acetate: hexane) to provide the Compound Cyano (nitro) vinylpiperazine of the Formula (I). Typically, the Compound Cyano (nitio) vinylpiperazine of the formula (I) is obtained as a mixture of the isomer wherein the group R4 and the group Ar2-NH- are cis relative to one another and the isomer wherein the group R4 and the group Ax2-NH they are trans xelative one with otio. The individual czs and trans isomers can be separated using methods known to those skilled in the art. Representative methods for separating the cis and trans isomers include, but are not limited, to recrystallization and column chromatography. If the group An of the compound of formula D is substituted with a hydroxyl or amine group or -R3 is a hydroxyl group or amine, the hydroxyl group or amine can be protected using a suitable protecting group, using methods known to those skilled in the art. art, before the compound of formula D is reacted with a compound of formula C. Suitable protecting groups include, but are not limited to, methyl ether, methoxymethyl ether, methoxythiomethyl ether, 2-methoxyethoxymethyl ether, bis (2-chloroethoxy) ethyl ether, tetrahydropyranyl ether, tetiahydrothiophenyl ether, 4-methoxytetehydropyranium ether, methoxytetrahydrothiopyranyl ether, tetiathermofofuranyl ether, tetiathermothrifophilyl ether, 1-ethoxyethyl ether , 1-methyl-1-methoxyethyl ether, 2- (phenylenyl ether), tert-butyl ether, allyl ether, benzyl ether, o-nitrobenzyl ether, triphenylmethyl ether, o-naphthyldiphenylmethyl ether, s-methoxydifsnilmethyl ether, 9- (9) phenyl-10-oxo) -xenxyl ether (tritylone), trimethylsilyl ether, so-propyldimethylusyl ether, tert-butyldimethylsilyl ether, tert-butyldiphenylsilyl ether, thiibenzilyl ether, tris-propyl silyl ether, formate ester, acetate ester, thioloroacetate ester , phenoxyacetate ester, ester-so-butyrate, ester pivaloate, adamanttoate ester, benzoate ester, 2,4,6-trimethyl ester (mesitoate), methyl carbonate, 2,2,2-trichlorocarbonate, allil carbonate, s- Nitiphenyl carbonate, benzyl carbonate, S-nitrobenzyl carbonate, S-benzylthiocarbonate, N-phenylcarbamate, nitrate ester, and ester. 2,4-dinitrophenylsulfenate (See, for example, T. W. Greene et al, Protective Groups in Organic Synthesis, 17-200 (3d ed, 1999)). Suitable protecting groups for an amine include, but are not limited to, 1, l-dimethyl-2,2,2-trichloroethyl carbamate, 1-methyl-1- (4-biphenyloyl) ethyl carbamate, 2-thiimethylsilyl ethyl carbamate, 9- fluorenylmethyl carbamate and tert-butyl carbamate (TW Greene et al, Protective Groups in Organic Synthesis, 494-653 (2d ed.1991)).
Isothiocyanates, Ax2NCS (A), are commercially available or can be prepared by methods known to those skilled in the art (See, eg, J. March, Advanced Organic Chemistry Reactions, Mechanisms, and Structure All, 429, 670 , 904, and 930 (4th ed., 1992)).
The nitriles (B) are commercially available or can be prepared by methods known to those skilled in the art. The nitrile (B) wherein Rt is -CN was commercially available from Sigma-Aldrich, St. Louis, MO (www.sigma-aldrich.com). The nitriles (B) wherein Rt is -C (O) O (C1-C4) alkyl or -C (O) NH ((d-C4) alkyl) can be obtained by reacting an alcohol of formula R9OH or an amine of Formula R9NH2, wherein R9 is a C? -C4 alkyl group with a cyanoacetyl halide. In one embodiment, the cyanoacetyl halide is cyanoacetyl chloride (Cl-C (O) CH2CN). Cyanoacetyl halides can be obtained from cyanoacetic acid (commercially available from Sigma-Aldrich.) Methods for dissolving acid halides from carboxylic acids are known to those skilled in the art and are described in J. March, Advanced Organic Chemistry, Reactions Mechanisms, and Structure 437-8 (4th ed., 1992) For example, halide acids can be prepared by reacting the carboxylic acid with thionyl chloride, bromide, or iodide.An acid chloride can also be prepared by reacting a carboxylic acid with phosphorous trichloride or tribromide. Acid chloride can also be prepared by reacting the carboxylic acid with PI13P in carbon tetrachloride An acid fluoride can be obtained by reacting a carboxylic acid with cyanuric fluoride.
The Compound of formula D can be obtained according to what is illustrated in Scheme 2: Scheme 2 wherein Rls R2, R3, m, n, and p are defined above for the thio (cyano) vinylpiperazine compounds of the formula (I) and X is a halogen. In one embodiment, X is bromide, chloride, or iodide.
For example, a compound of formula E1-E5 (of about 20 xmol) is activated with a compound of formula F (about 27.5 mmol) in 15 ml of dimethyl sulfoxide in the presence of triethylamine (about 30 xmol). , optionally with heat, for about 24 hours to provide a compound of formula D1-D5. The compound of formula D1-D5 can be isolated from the reaction mixture and purified. In one embodiment, the compound of formula D1-D5 is purified using column chromatography or recrystallization. If the compound of formula F is substituted with a hydroxyl or amine group, the hydroxyl group or amine can be protected using a suitable protecting group, using methods known to those skilled in the art, before being reacted with a compound of formula E1 -E5.
Suitable protecting groups include, but are not limited to, those described above.
Compounds of formula E and F are commercially available or can be prepared by methods known to those skilled in the art. The compound of formula F wherein m is 0 was commercially available from Sigma-Aldrich. 4. 6.2 Methods for Preparing Nitro (cyano) vinyl piperazine Compounds of the Formula (ID The Nitio (cyano) vinylpiperazine Compounds of the formula (II) wherein R 4 is -H can be obtained by the following illustrative method illustrated in Scheme 3: Cyan (nitrio) vinyl piperazine compound of the Formula (H) wherein An, Ar2, R3, Rt, and m are defined above for the Nitio (cyano) vinylpiperazine Compounds of the formula (H).
For example, xma amine ethanol solution Ar NH 2 (G) (1 mmol) and a compound of formula H are allowed to react at a temperature of about 70 ° C for up to 15 h to provide an ethanol solution of a compound of formula J. A compound of formula D (1.2 mmol) is then added to the ethanol solution of a compound of formula J and the resulting solution is allowed to recirculate for a period of 15 h. The solvent is then removed under reduced pressure to provide a residue. The residue is then purified using column chromatography (silica gel eluted with a gradient of 20:80 ethyl acetate: hexane at 50:50 ethyl acetate: hexane) to give the Compound Cyan (nitio) vinyl piperazine of the Formula (JL). Typically, the cyano (nitrio) vinylpiperazine Compound of the formula (II) is obtained as a mixture of the isomer wherein the group R4 and in group Ar2-NH are cis relative to one with otio and the isomer wherein the group R4 and the group Ar2-NH are relative trans xmo with otio. The individual cis and trans isomers can be separated using methods known to those skilled in the art. Representative methods for separating the cz's and trans isomers include, but are not limited to, recrystallization and chromatography on colurhna. The Nitio (cyano) vinylpiperazine Compounds of the formula (II) wherein 4 is -CN can be obtained using a procedure analogous to that used to prepare Nitio (cyano) vinylpiperazine Compounds of the formula (I) wherein 4 is -CN, as is described above in Schemes 1 and 2, except that a compound of the formula O 2 N -CH 2 -CN is used instead of the compound of the formula B. The compound of the formula O 2 N -CH 2 -CN can be obtained by reacting sodium cyanide with bromonitromethane O 2 N- CH2-Br, (commercially available from Sigma-Aldrich), in DMF at 70 ° C. The Nitro (cyano) vinylpiperazine Compounds of the formula (p) wherein R 4 is -C (O) O (d-C 4) alkyl or -C (O) NH ((C 1 -C 4) alkyl) can be obtained using an analogous procedure to that used to prepare Nitio (cyano) vinylpiperazine Compounds of the formula (I) wherein R4 is C (O) O (d-C4) alkyl or -C (O) NH ((d-C4) alkyl), respectively, as described above in Schemes 1 and 2, except that a compound of formula O2N-CH2-C (O) O (dC) alkyl or -C (O) NH ((dC) alkyl), respectively, is used instead of the compound of the formula B. The compound of the formula O2N-CH2-C (O) O (dC) alkyl can be obtained by reacting a niteoacetyl halide with an alcohol of R9OH wherein R9 is a dC alkyl group. The compound of formula 2N-CH2-C (O) (NHd-C) alkyl can be obtained by reacting a nitroacetyl halide with an amine of formula R9NH2 wherein R9 is a d-C4 alkyl group. Nitioacetyl halides can be obtained from nitroacetic acid using methods known to those skilled in the art include, but not limited to, the methods described above for prepaxax acid halide. Nitroacetic acid can be obtained by hydrolyzing methyl nitroacetate (commercially available from Sigma-Aldrich) using methods known to those skilled in the art. Certain Nitro (cyano) vinylpiperazine compounds may have one or more asymmetric centers and therefore exist in different enantiomeric and diastereomeric forms. A Nitio (cyano) vinylpiperazine Compound may be in the form of an isomer or an optical diastereomer. Therefore, the invention comprises Nitro (cyano) vinylpiperazin compounds and their uses as described herein in the form of their optical isomers, diastereomers, and mixtures thereof, including a racemic mixture. Optical isomers of the Nitro (cyano) vinylpiperazine Compounds can be obtained by known techniques such as chiral chromatography or diastereomeric salt formation from an optimally active acid or base. In addition, one or more hydrogen, carbon or other atoms of a Compound Nitium (cyano) vinylpiperazine can be replaced with an isotope of hydrogen, carbon or other atoms. Such compounds, encompassed by the present invention, are useful as a research and diagnostic tool in studies of pharmacokinetic metabolism and in assays. 4. 7 THERAPEUTIC USES OF THE NITRO COMPOUND (VINYLPIPERAZINE CELL) According to the invention, the Nitio (cyano) vinylpiperazine Compounds are administered to an animal in need of treatment or prevention of a Condition.
In one embodiment, an effective amount of a Nitium (cyano) vinyl piperazine Compound can be used to thiatar or prevent a tiatable or preventable condition by means of inhibiting VR1. Examples of treatable or preventable conditions by inhibiting VR1 include, but are not limited to, pain, Ul, ulcer, IBD, and IBS.
In another embodiment, an effective amount of a Nitio (cyano) vinylpiperazine Compound can be used to treat or prevent a condition treatable or preventable by means of the inhibition of mGluR5. Examples of conditions treatable or preventable by the inhibition of mGluR5 include, but are not limited to, pain, addictive disorders, Parkinson's disease, parkinsonism, anxiety, pruritic condition, and psychosis. In another embodiment, an effective amount of a Nitro (cyano) vinyl piperazine Compound can be used to thiatar or prevent any tiatable or preventable condition by inhibiting mGluRl. Examples of conditions that are treatable or preventable by inhibiting mGluRl include, but are not limited to, pain, Ul, an addictive disorder, Parkinson's disease, parkinsonism, anxiety, epilepsy, infarction, an attack, a pruritus condition , psychosis, a cognitive disorder, a memory deficit, restricted brain function, Huntington's disease, ALS, dementia, retinopathy, a muscle spasm, a migraine, vomiting, dyskinesia, and depression.
The Nitio (cyano) vinylpiperazine Compounds can be used to treat or prevent acute or chronic pain. Examples of pain treatable or preventable using the Compound Nitro (cyano) vinyl piperazine include, but are not limited to, cancer product dolox, labor pain, pain from myocardial infarction, pancreatic pain, pain from colic, post-operative pain, pain headache, muscle pain, arthritic pain, and pain associated with periodontal disease, including gingivitis and periodontitis. The Nitro (cyano) vinylpiperazine Compounds can also be used to treat or prevent pain associated with inflammation or with an inflammatory disease in an animal. Said pain may occur where there is an inflammation of the tissue of the body, which may be a local inflammatory response and / or a systemic inflammation. For example, the Nitro (cyano) vinylpiperazine 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. Mol Cell Cardiol 31: 297-303 (1999)) including, but not limited to, heart, lung, liver or kidney transplantation; chronic inflammatory diseases of the joints, including arthritis, rheumatic arthritis, osteoariritis and bone diseases associated with increased bone resorption; Inflammatory bowel diseases, such as ileitis, ulcerative colitis, Barret and Crohn's disease; inflammatory diseases of the lungs, such as asthma, respiratory distress syndrome in adults, and chronic airway obstruction disease; inflammatory diseases of the eye, including corneal dystrophy, trachoma, onchocerciasis, uveitis, sympathetic ophthalmitis and endophthalmitis; chronic gum diseases, including gingivitis and periodontitis; tuberculosis; leprosy; inflammatory diseases of the kidney, including uraemic complications, glomerulonephritis and nephrosis; inflammatory diseases of the skin, including sclerodermatitis, psoriasis and eczema; inflammatory diseases of the central nervous system, including chronic demyelinating diseases of the central nervous system, multiple sclerosis, neurodegeneration related to AIDS and Alzheimer's disease, infectious meningitis, encephalomyelitis, Parkinson's disease, Huntington's disease, lateral amyotrophic sclerosis and viral or auto encephalitis immune; autoimmune diseases, including Type I and Type II diabetes mellitus; diabetic complications, including, but not limited to, diabetic cataract, glaucoma, retinopathy, nephropathy (such as microaluminuria and progressive diabetic nephropathy), polyneuropathy, mononeuropathies, autonomic nauropathy, gangrene of the feet, atherosclerotic arterial coronary disease, peripheral arterial disease, hyperglycemic coma -non-ketosal hyperosmolar, foot ulcer, joint problems, and skin or mucosal involvement (such as an infection, an area with pimples, a pure diabetic infection or lipid necrosis); immunocomplex vasculitis and systemic lupus erythematosus (SLE); inflammatory diseases of the heart, such as cardiomyopathy, ischemic heart disease, hypercholesterolemia, and atherosclerosis; as well as other diseases that may have significant inflammatory components, including preclaimsia, chronic liver failure, brain and spinal cord trauma, and cancer. The Compounds Nitro (cyano) vinylpiperazine can also be used to tiatar or prevent pain associated with an inflammatory disease that can, for example, sex a systemic inflammation of the body, exemplified by gram-positive or gram-negative shock, hemorrhagic or anaphylactic shock, or shock product of chemotherapy for cancer in response to pro-inflammatory cytokines, for example, shock associated with pro-inflammatory cytokines. Such a shock can be induced, for example, a chemotherapeutic agent administered as a treatment for cancer. The Niteo (cyano) vinylpiperazine Compounds can be used to treat or prevent UT. Examples of Ul treatable or preventable using Compounds Nitium (cyano) vinylpiperazine include, but are not limited to, impulsive incontinence, stress incontinence, overflow incontinence, neurogenic incontinence, and total incontinence. The Nitro (cyano) vinylpiperazine Compounds can be used to treat or prevent an ulcer. Examples of treatable or preventable ulcers using Nitio (cyano) vinyl piperazine compounds include, but are not limited to, duodenal ulcer, gastric ulcex, marginal ulcer, ulcer to the esophagus or ulcer produced by stress.
The Niteo (cyano) vinylpiperazine Compounds can be used to treat or prevent IBD, including Crohn's disease and ulcerative colitis.
The Niteo (cyano) vinylpiperazine Compounds can be used to treat or prevent IBS. Examples of treatable or elusive IBS using Compounds Nitium (cyano) vinylpipexazine include, but are not limited to, spastic colon type IBS and predominant constipation IBS.
The Nitro (cyano) vinylpiperazine 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, a disorder related to amphetamines, cannabis-related disorder, a cocaine-related disorder, a hallucinogen-related disorder, inhalant-related disorders and an opioid-related disorder, all of which are sub-classified below. Eating disorders include, but are not limited to Bulimia Nervosa, Non-Purgative Type; Nervous Bulimia, Purgative Type; Anorexy; and Eating Disorders of another form not specified (NOS). Impulse control disorders include, but are not limited to Intermittent Explosive Disorder, Kleptomania, Pyromania, Impulsive Gambler, Trichotillomania, and Impulse Control Disorders other than specified (NOS). Alcohol-related disorders include, but are not limited to, Alcohol-Induced Psychotic Disorder with Delusions, Alcohol Abuse, Alcohol Poisoning, Alcohol Abstinence, Delirium from Alcohol Poisoning, Alcohol Abstinence Delirium, Persistent Dementia Induced by Alcohol Alcohol, Alcohol-induced persistent amnestic disorder, Alcohol dependence, Alcohol-induced mood disorders, Psychotic disorders with alcohol-induced hallucinations, Alcohol-induced Anxiety disorders, Alcohol-induced sexual dysfunction, Sleeping disorders induced by alcohol Alcohol and Other Alcohol-Induced Disorders Not Otherwise Specified (NOS). Disorders related to Nicotine include, but are not limited to, Nicotine Dependence, Nicotine Withdrawal, and Nicotine-Related Disorders Not Otherwise Specified (NOS). Disorders related to Amphetamines include, but are not limited to Amphetamine Dependence, Amphetamine Abuse, Amphetamine Intoxication, Amphetamine Withdrawal, Amphetamine Intoxication Delirium, Psychotic Disorder with Pox Induced Amphetamine Disorder, Psychotic Disorder with Amphetamine Induced Hallucinations, Mood Disorder Amphetamine-Induced, Amphetamine-Induced Anxiety Disorder, Amphetamine-Induced Sexual Dysfunction, Amphetamine-Induced Sleeping Disorder, and Other Unspecified Amphetamine Related Disorders (NOS). Disorders related to Canabis include, but are not limited to, Cannabis Dependence, Cannabis Abuse, Cannabis Intoxication, Cannabis Delirium Intoxication, Pysicotic Disorder with Cannabis Delusions, Psychotic Disorders with Cannabis-Induced Hallucinations, Cannabis-Induced Anxiety Disorder, and Cannabis-Related Disorders of Other Form Not Otherwise Specified ( US). Cocaine-related disorders include, but are not limited to, cocaine Dependence, Cocaine abuse, Cocaine poisoning, Cocaine abstinence, Cocaine poisoning rant, Psychotic disorder with cocaine-induced delusions, Psychotic disorders with hallucinations Cocaine-induced, disorders Psychic Cocaine-Induced, Cocaine-Induced Anxiety Disorder, Sexual Dysfunction Cocaine-Induced, Cocaine Induced Sleeping Disorder, and Other Unspecified Cocaine-Related Disorders (NOS). Disorders related to hallucinogens include, but are not limited to, Hallucinogenic Dependence, Hallucinogenic Abuse, Hallucinogenic Intoxication, Hallucinogenic Abstinence, Hallucinogenic Intoxication Delirium, Persistent Perception by Hallucinogen (Flashbacks), Psychotic disorder with delusions Induced by hallucinogen, Psychotic disorder with hallucinations Induced by Hallucinogen, hallucinogen-induced mood disorder, Anxiety disorder Induced by Hallucinogen, Hallucinogen-Induced Sexual Dysfunction, Hallucinogen-Induced Sleep Disorder, and other hallucinogen-related disorders of other than unspecified form (NOS). Disorders related to Inhalants include, but are not limited to, Inhalant Dependence, Inhalant Abuse, Inhalant Poisoning, Inhalant Poisoning Delirium, Inhalant Induced Psychotic Disorder, Psychotic Disorder with Inhalant Induced Alucinations, Induced Anxiety Disorder by Inhalants, and disorders related to Inhalants other than unspecified (NOS). Opioid-related disorders include, but are not limited to, Opioid Dependence, Opioid Abuse, Opioid Withdrawal, Opioid Intoxication, Opioid Intoxication Delirium, Psychotic Disorder with Opioid Induced Delusions, Psychotic Disorder with Opioid Induced Alloys, Disorder from Anxiety Induced by Opioids, and other disorders of other form not specified (NOS).
The Nitio (cyano) vinylpiperazine Compounds can be used to treat or prevent Parkinson's disease, parkinsonism and the symptoms associated with Parkinson's disease.
Parkinson's and parkinsonism, including but not limited to, bradykinesia, muscle rigidity, resting tremors and impaired postural balance. The Nitio (cyano) vinylpiperazine Compounds can be used to treat or prevent generalized or severe anxiety and symptoms associated with anxiety, including, but not limited to, agitation, tension, tachycardia, dyspnea; depression, including depression "neurotic" chronic; panic disorder; agoraphobia and other specific phobias; eating disorders; and personality disorders. Theo (cyano) vinylpiperazine Compounds can be used to treat or prevent epilepsy, including but not limited to partial epilepsy, generalized epilepsy, and symptoms associated with epilepsy, including, but not limited to, simple partial attacks, jacksonian attacks, complex partial seizures (psychomotor), seizures (grand mal or tonic-clonic seizure) ), petit mal attacks (absence), and status epilepticus. The Nitro (cyano) vinylpiperazine Compounds can be used to treat or prevent infarcts, including, but not limited to, ischemic infarcts and hemorrhagic infarcts. The Nitro (cyano) vinylpiperazine Compounds can be used to treat or prevent an attack, including, but not limited to, infantile spasms, febrile seizures and epileptic seizures. The Nitro (cyano) vinylpiperazine Compounds can be used to treat or prevent a pruritic condition, including, but not limited to, itching product of dry skin, scabs, dermatitis, hepathema, atopic dermatitis, pruritus vulvae et ani, milaria, insect bite, pediculosis, contact dermatitis, drug reactions, urticaria, urticarial pregnancy, psoriasis, lichen planus, lichen simplex chronicus, exfoliating dermatitis, folliculitis, pemphigoid hullosa, or dermatitis caused by contact with fiberglass. The Nitro (cyano) vinylpiperazine 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, schizophrenia of the negative subtype or deficit, and non-deficit schizophrenia; a delirium disorder, including illusory erotomatic subtype disorder, delusional illusory subtype disorder, illusory jealous subtype disorder, persecution delusional subtype disorder, and somatic delirium subtype disorder; and brief psychosis.
The Nitro (cyano) vinylpiperazine Compounds can be used to treat or prevent a cognitive disorder, including but not limited to delirium and dementia such as multi-infarct dementia, pugilistic dementia, dementia caused by AIDS, and dementia caused by Alzheimer's. The Nitro (cyano) vinyl piperazine Compounds can be used to treat or prevent a memory deficit, including but not limited to dissociated amnesia and fleeting dissociation. The Niteo (cyano) vinylpiperazine Compounds can be used to treat or prevent restricted brain functions, including, but not limited to, that caused by surgery or organ transplant, restricted supply of blood to the brain, injury to the spinal cord, injury to the head , hypoxia, cardiac arrest or hypoglycemia. The Nitro (cyano) vinylpiperazine Compounds can be used to treat or prevent Huntington's disease. The Nitro (cyano) vinylpiperazine Compounds can be used to treat or prevent ALS. The Nitro (cyano) vinylpiperazine Compounds can be used to treat or prevent retinopathy, including but not limited to atherosclerotic retinopathy, atherosclerotic diabetic retinopathy, hypertensive retinopathy, non-proliferating retinopathy and proliferating retinopathy. The Nitro (cyano) vinylpiperazine Compounds can be used to treat or prevent a muscle spasm.
The Nitro (cyano) vinylpiperazine Compounds can be used to treat or prevent a migraine including, but not limited to, migraine without aura ("common migraine"), migraine with aura ("classic migraine"), migraine without headache, basilar migraine , migraine familial hemiplegic, migraine infarction, and migraine with prolonged aura.
The Nitio (cyano) vinylpiperazine Compounds can be used to treat or prevent vomiting, including but not limited to, vomiting product of nausea, dry vomiting (retching) . . , and regurgitation. The Nitio (cyano) vinylpiperazine Compounds can be used to treat or prevent dyskinesia, including but not limited to, tardive dyskinesia and biliary dyskinesia. The Nitro (cyano) vinylpiperazine Compounds can be used to treat or prevent or depression, including but not limited to severe depression and bi-polar disorder. Without wishing to be bound by theory, the Requesters believe that the Compounds Niteo (cyano) vinylpiperazine are antagonists for VR1. The invention also relates to methods for inhibiting VR1 function in a cell which comprises contacting a cell capable of expressing VR1 with an effective amount of a Niteo (cyano) vinyl piperazine Compound to inhibit VR1 function in the cell. East The method can be used in vitro, for example, as an assay to select cells capable of expressing VR1 and, therefore, useful as part of an assay to select compounds useful for thiazing or preventing pain, UL.a ulcer, IBD, or IBS. The method is also useful for inhibiting VR1 function in a cell in vivo, in animal xm (eg, human xm), by contacting a cell in an animal with an effective amount of a Nitro (cyano) vinylpiperazine compound. In one embodiment, the method is useful to treat or prevent pain in an animal that needs it. In another modality, the method is useful to tiatar or prevent Ul in an animal that needs it. In another embodiment, the method is useful to treat or prevent an ulcer in an animal in need thereof. In another modality, the method is useful to treat or prevent IBD in an animal that needs it. In another modality, the method is useful to tiatar or prevent IBS in an animal that needs it.
Examples of cells capable of expressing VR1 include, but are not limited to, neuronal, cerebral, kidney, urothelial cells, and bladder tissue. Methods for studying VR1 expressing cells are known in the art.
Without-} wishing to be limited by theory, the Applicants believe that the Nitio (cyano) vinylpiperazine Compounds are antagonists for mGluR5.
The invention further relates to methods for inhibiting mGluR5 function in a cell which comprises contacting a cell capable of expressing mGluR5 with an effective amount of a Nitro (cyano) vinyl piperazine Compound to inhibit mGluR5 function in the cell. This method can be used in vitro, for example, as an assay to select cells capable of expressing mGluR5 and, therefore, they are useful as part of an assay for selecting compounds useful for tiatar or preventing pain, an addictive disorder, Parkinson's disease, parkinsonism, anxiety, a pruritus condition, or psychosis. The method is also useful for inhibiting mGluR5 function in a cell in vivo, in an animal (eg, a human), by contacting a cell in an animal with an effective amount of a Nixro Compound (cyano) vinyl piperazine to inhibit mGluR5 function in the cell. In one embodiment, the method is useful to tiatar or prevent pain in an animal that needs it. In another embodiment, the method is useful for treating an addictive disorder in an animal in need thereof. In another embodiment, the method is useful for tiatar or preventing Parkinson's disease in an animal that needs it.
In another modality, the method is useful to treat or prevent parkinsonism in an animal that needs it. In another modality, the method is useful to treat or prevent anxiety in an animal that needs it. In another embodiment, the method is useful for treating or preventing an itching condition in an animal in need of it. In another modality, the method is useful to tiatar or prevent psychosis in an animal that needs it.
Examples of cells capable of expressing mGluR5 are the neuronal and glial cells of the central nervous system, particularly the brain, especially in the nucleus accumbens. Methods for studying cells expressing mGluR5 are known in the art.
Without wishing to be bound by theory, Applicants believe that the Nitio (cyano) vinyl piperazine Compounds are antagonists for mGluRl.
The invention also relates to methods for inhibiting mGluRl function in a cell, which comprises contacting a cell capable of expressing mGluRl with an effective amount of a Nitio (cyano) vinylpiperazine Compound in order to inhibit mGluRl function in the cell. This method can be used in vitro, for example, as an assay to select cells capable of expressing mGluRl and, therefore, they are useful as part of an assay for selecting compounds to tiatar or prevent pain, Ul, an addictive disorder, Parkinson's disease , parkinsonism, anxiety, epilepsy, stroke, an attack, a pruritus condition, psychosis, a cognitive disorder, a memory deficit, restricted brain function, Huntington's disease, ALS, dementia, retinopathy, muscle spasm, migraine, vomiting , dyskinesia, or depression. The method is also useful for inhibiting mGluRl function in a cell in vivo, in an animal (eg, a human), by contacting a cell in an animal with an effective amount of a Compound.
Niteo (cyano) vinylpiperazine. In one embodiment, the method is useful to tiatar or prevent pain in an animal that needs it. In another embodiment, the method is useful to treat or prevent Ul in an animal in need thereof. In another mode, the method is useful to tiatar or prevent an addictive disorder in an animal that needs it. In another modality, the method is useful to treat or prevent Parkinson's disease in an animal that needs it. In another modality, the method is useful to treat or prevent parkinsonism in an animal that needs it. In another modality, the method is useful to tiatar or prevent anxiety in an animal that needs it. In another modality, the method is useful to tiatar or prevent epilepsy in an animal that needs it. In another modality, the method is useful for treating or preventing a heart attack in an animal that needs it. In another modality, the method is useful to treat or prevent an attack on an animal that needs it. In another modality, the method is useful to tiatar or prevent a pruritus condition in an animal that needs it. In another modality, the method is useful to tiatar or prevent psychosis in an animal that needs it. In another embodiment, the method is useful to treat or prevent a cognitive disorder in an animal that needs it. In another modality, the method is useful to tiatar or prevent a memory deficit in an animal that needs it. In another modality, the method is useful to tiatar or prevent restricted brain function in an animal that needs it. In another modality, the method is useful to tiatar or prevent Hxmtington's Korea in an animal that needs it. In another embodiment, the method is useful for treating or preventing ALS in an animal, which needs it. In another embodiment, the method is useful for treating or preventing dementia in an animal in need thereof. In another modality, the method is useful to treat or prevent retinopathy in an animal that needs it. In another embodiment, the method is useful to treat or prevent a muscle spasm in an animal in need thereof. In another embodiment, the method is useful to treat or prevent a migraine in an animal that needs it. In another modality, the method is useful to tiatar or prevent vomiting in an animal that needs it. In another embodiment, the method is useful to treat or prevent dyskinesia in an animal in need thereof. In another embodiment, the method is useful for tiatar or preventing depression in an animal that needs it.
Examples of cells capable of expressing mGluR1 include, but are not limited to, neurons from the Purkinje cerebellum, Purkinje cell (punctate) cells, spinal cord (s) cells of the cerebellum; neurons and neurophil cells of the olfactory bulb glomerulus; cells of the superficial layer of the cerebral cortex; hippocampal cells; thalamic cells; superior coliculus cells; and cells of the core of the spinal cord, triglyminal spinal cord. Methods for studying cells expressing mGluRl are known in the art. 4. 8 THERAPEUTIC / PROPHYLACTIC ADMINISTRATION AND COMPOSITIONS OF THE INVENTION i Due to their activity, the Nitro (cyano) vinyl? Iperazine Compounds are advantageously useful in veterinary and human medicine. As described above, the Niteo (cyano) vinyl piperazine Compounds are useful for treating or preventing a Condition in an animal in need thereof.
When administered to an animal, the Nitro (cyano) vinylpiperazine Compounds can be administered as a component of a composition comprising a pharmaceutically acceptable carrier. The present compositions, which comprise a Nitro (cyano) vinylpiperazine Compound, can be administered orally. The Nitio (cyano) vinyl piperazine 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 coatings (e.g., oral, rectal, mucosa). and intestinal mucosa, etc.) and can be administered in conjunction with another activated therapeutic agent. The administration can be systemic or local. Several delivery systems are known, for example, encapsulation in liposomes, microparticles, microcapsules, capsules, etc., and can be used to administer the Compound Nitium (cyano) vinylpiperazine.
Methods of administration include, but are not limited to intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, oral, sublingual, intiacerebral, inteavaginal, teansdermal, rectal, inhalation, or topical, particularly to the ears, nose, eyes or skin. The mode of administration is left to the discretion of the physician. In most instances, the administration xesultaxá in the release of Compound Nitio (cyano) vinylpiperazine to the blood system.
In specific modalities, it may be desirable to administer the Compounds Nitium (cyano) vinylpiperazine locally. This can be achieved, for example, and not by limitation, by local infusion during surgery, topical application, for example, together with a bandage disposed in the wound 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 silastic membranes, or fibers. In certain modalities, it may be desirable to introduce the Compounds Nitium (cyano) vinylpiperazine to the central nervous system or gastrointestinal tract through any suitable route, including intiaventiicular, intrathecal, and epidural injection, and enema. Intraventricular injection can be facilitated through an intiaventricular catheter, for example, attached to a reservoir, such as an Ommaya reservoir.
Pulmonary administration may also be employed, for example, by the use of an inhaler or nebulizer, and formulation with an aerosolizing agent, or via perfusion in a fluorocarbon or synthetic pulmonary surfactant. In certain modalities, the Nitio (cyano) vinylpiperazine compounds can be formulated as suppositories, with traditional binders and excipients such as triglycerides. In another embodiment, the Nitio (cyano) vinylpiperazine 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 Influent Disease and Cancer 317-327 and 353-365 (1989)). In yet another mode, the Niteo (cyano) vinylpiperazine Compounds can be delivered under a controlled delivery system or sustained delivery system (see, for example, Goodson, in Medical Applications of Contiolled Relay, supra, vol.2, pp. 115- 138 (1984)). Other systems of controlled and sustained delivery discussed in the publication of Langer, Science 249: 1527-1533 (1990) can be used. In one embodiment, a bowler can be used (Langer, Science 249: 1527-1533 (1990), Sefton, CRC Crit Ref Biomed, Eng. 14: 201 (1987), Buchwaid et al., Surgery 88: 507 ( 1980), and Saudek et al, N. Engl.
Med. 321. "574 (1989).) In another embodiment, polymeric materials can be used (see Medical Applications of Controlled Relays (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)). In yet another modality, a controlled or sustained system may be placed near a target of the Nitio (cyano) vinyl piperazine Compounds, for example, the spinal column, brain or gastrointestinal tract, such that only a fraction of the dose is required. systemic In one embodiment, the pharmaceutically acceptable carrier is an excipient. Such a pharmaceutical excipient may be a liquid such as water or an oil, including those of petroleum, animal, vegetable or synthetic origin, such as peanut / peanut oil, soybean oil, mineral oil, sesame oil and the like. The pharmaceutical excipient may be saline, acacia gum, gelatin, starch paste, talcum, keratin, colloidal silica, urea and the like. In addition, auxiliary agents, stabilizers, thickeners, lubricants and colorants can be used. In one embodiment, the pharmaceutically acceptable excipient is listed as sterile when administered to an animal. Water is a particularly useful excipient when the Compound Niteo (cyano) vinyl piperazine is administered intravenously. Salt solutions and aqueous dextiosa and glycerol solutions can also be used 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, glycexol monostearate, talc, sodium chloride, skim milk powder, glycerol, propylene, glycol , water, ethanol and the like. The present composition, if desired, may also contain minor amounts of moisturizing or emulsifying agents, or pH buffers. The present compositions may take the form of solutions, suspensions, emulsions, tablets, pills, pellets, capsules, capsules containing liquids, powders, sustained release formulations, suppositories, emulsions, aerosols, sprays, suspensions, or any other form of use. suitable. In one embodiment, the composition was in the form of a capsule (see for example, U.S. Patent No. 5,698,155). Other examples of pharmaceutically suitable excipients are disclosed in Remington's Pharmaceutical Sciences 1447-1676 (Alfonso R. Gennaro ed., 19th ed., 1995), untitled by reference to this document. In one embodiment, the Nitro (cyano) vinylpiperazine Compounds are formulated according to ratin methods as a composition adapted for oral administration in humans. Compositions for oral delivery can be presented, for example, in the form of tablets, lozenges, aqueous or oily suspensions, granules, powders, emulsions, capsules, syrups or elixirs. Oxally-administered compositions may contain one or more agents, for example, sweetening agents such as fructose, aspartame or saccharin; savoring agents such as peppermint, oil of wintergreen or cherry; coloring agents; and preservative agents, to provide a pharmaceutically palatable preparation. Moreover, when in the form of a tablet or a pill, the composition can be coated to delay disintegration and absorption in the gastrointestinal tract thereby providing a sustained action over a prolonged period of time. Selective permeable membranes enveloping the osmotic release active compound are also suitable for compositions administered orally. In these last platforms, fluid from the environment enveloping the capsule is impregnated by the release compound, which swells to displace the agent or agents through an opening. These platforms can provide an essentially zero order release profile as opposed to instant profiles of immediate release formulations. A delayed release material such as glycerol monostearate or glycerol stearate may also be used. Oral compositions may also include standard excipients such as mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, and magnesium carbonate. In one embodiment, the excipients are pharmaceutical grade. In another embodiment, the Nitio (cyano) vinylpiperazine Compounds can be formulated for intravenous administration. Typically, compositions for oral administration comprise an aqueous isotonic buffer. Of necessary sex, the compositions may also include a solubilizing agent. Compositions for intravenous administration may optionally include a local anesthetic such as lignocaine to reduce pain at the site of injection. Generally, the ingredients are provided either separately or mixed in unit doses, for example, as a freeze-dried dry powder or water-free concentrate in a hermetically sealed container such as a blister or sachette indicating the amount of active agent. Where the Nitro (cyano) vinyl piperazine Compounds should be administered by infusion, these can be dispensed, for example, with an infusion bottle containing water or a pharmaceutically sterile pharmaceutical grade saline solution. Where the Nitro (cyano) vinyl piperazine Compounds should be administered by injection, an ampoule of sterilized water for injection or saline may be provided so that the ingredients can be mixed before being administered. The Nitio (cyano) vinyl piperazine Compounds can be administered by means of controlled release or sustained release or by delivery mechanisms known to those skilled 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 included in this document by reference. Such dosage forms can be used to provide sustained or sustained release of one or more active agents using, for example, hydroxopromopomethyl cellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, microspheres, or a combination of them to provide the desired release in varying proportions. Suitable contiolated or sustained release formulations known to those skilled in the art, including those described herein, can be readily selected for use with the active ingredients of the invention. Accordingly, the invention encompasses suitable unit doses for oral administration, such as, but not limited to, tablets, capsules and soft capsules, adapted for sustained or sustained release. Controlled or sustained release pharmaceutical compositions may have a common goal of improving drug therapy over that achieved by non-controlled or non-sustained counterparts. In one embodiment, a sustained or sustained delivery composition comprises a minimum amount of a Nitro (cyano) vinyl piperazine Compound to thiart or prevent the Condition or symptom thereof in the minimum of time. The advantages of controlled or sustained release compositions include prolonged activity of the drug, decrease in the frequency of the dose, and greater compliance of the patient. Also, controlled or sustained release compositions can favorably affect the action starting time or other characteristics, such as blood levels of the Nitro (cyano) vinyl piperazine Compound, and thereby reduce the occurrence of adverse side effects. . Controlled or sustained release compositions can, in principle, release an amount of Nitro (cyano) vinylpiperazine Compound that will immediately produce the desired therapeutic or prophylactic effect, and gradually and continuously release other amounts of Nitium Compound (cyano) vinyl piperazine in order to maintain this level of therapeutic or prophylactic effectiveness during a prolonged period of time. To maintain a constant level of Compound N ith (cyano) vinyl piperazm in the cell, the Compound Nitium (cyano) vinyl piperazine can be released from its dosage form at a rate that replaces the amount of Compound Niteo (cyano) vinyl piperazine being metabolized and excreted of the cuefo. Sustained 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 or compound conditions . The amount of Compound Nitium (cyano) vinyl piperazine effective for the treatment or prevention of a condition can be determined by standard clinical techniques. Likewise, in vitro or in vivo assays can be optionally employed in order to help identify the optimal dose ranges. The precise dose to be used will also depend on the route of administration, and the seriousness of the condition and can be decided according to the criteria of a doctor and / or the circumstance of each animal. However, effective amounts of effective doses vary from about 0.01 mg / kg of coforal weight to about 2500 mg / kg of coforal weight, although typically they are 100 mg / kg of coforal weight or less. In one embodiment, the effective dose amount varies from about 0.01 mg / kg of coforal weight to about 100 mg / kg of coforal weight of a Compound Nitium (cyano) vinyl piperazine, in another embodiment, of about 0.02. mg / kg of coforal weight at about 50 mg / kg of coforal weight, and in another embodiment, about 0.025 mg / kg of coforal weight at about 20 mg / kg of coforal weight. In one embodiment, an effective dose amount is administered every 24 hours until the Condition is contiolada. In another modality, an effective dose amount is administered every 12 hours until the condition is controlled. In another modality, an effective dose amount is administered every 8 hours until the Condition is discontinued. In another modality, an effective dose amount is administered every 6 hours until the Condition is discontinued. In another modality, the amount of effective dose is administered every 4 hours until Condition is controlled. The amount of effective dose described in this document refers to the total amount achnitized; that is, if more than one Nitium (cyano) vinyl piperazine Compound is administered, the effective dose amounts correspond to the total amount administered. Where a cell capable of expressing VR1, mGluR5 or mGluR1 is contacted with a Nitio (cyano) vinylpiperazine Compound in vitro, the amount effective to inhibit the receptor function VR1, mGluR5 or mGluR1 in a cell will typically vary between 0.01 μg or less. / L to about 5 mg / L, in one embodiment, from about 0.01 μg / L to about 2.5 mg / L, in another embodiment, from about 0.01 μg L to about 0, 5 mg / L, and in another embodiment, from about 0.01 μg / L to about 0.25 mg / L of a solution or suspension of a pharmaceutically acceptable carrier or excipient. In one embodiment, the volume of solution or suspension comprising the Compound Niteo (cyano) vinylpiperazine is about 0.01 μL to about 1 mL. In another embodiment, the volume of solution or suspension is around 200 μL. Where a cell capable of expressing VR1, mGluR5, or mGhiR1 is contacted with a Nitium (cyano) vinylpiperazine Compound in vivo, the amount effective to inhibit the receptor function in a cell will typically vary between about 0.01 mg / kg of body weight. coforal at about 2500 mg / kg of coforal weight, although typically it varies from about 100 mg kg of coforal weight or less. In one embodiment, the effective dose amount ranges from about 0.01 mg / kg of coforal weight to about 100 mg / kg of coforal weight of a Niteo (cyano) vinyl piperazine Compound, in another embodiment, about 0.02. mg / kg of coforal weight at about 50 mg / kg of coforal weight, and in another modality, about 0.025 mg / kg of coforal weight at about 20 mg / kg of coforal weight. In one embodiment, an effective dose amount is administered every 24 hours. In another embodiment, an effective dose amount is administered every 12 hours. In another modality, an effective dose amount is administered every 8 hours. In another modality, an effective dose amount is administered every 6 hours. In another embodiment, an effective dose amount is administered every 4 hours. The Nitro (cyano) vinylpiperazine Compounds can be analyzed in vitro or in vivo for the desired therapeutic or prophylactic activity before being used in humans. Animal model systems can be used to demonstrate safety and efficacy.
The methods present for treating or preventing a Condition in an animal in need thereof may further comprise administration to the animal being treated a Nitium Compound (cyano) vinyl piperazine, or other therapeutic agent. In one embodiment, the other therapeutic agent is administered in an effective amount.
The methods present for inhibiting VR1 function in a cell capable of expressing VR1 may also comprise contacting the cell with an effective amount of another therapeutic agent.
The methods present for inhibiting mGluR5 function in a cell capable of expressing mGluR5 may further comprise contacting the cell with an effective amount of another therapeutic agent.
The methods present for inhibiting mGluRl function in a cell capable of expressing mGluRl may also comprise contacting the cell with an effective amount of another therapeutic agent. Effective amounts of other therapeutic agents are known to those skilled in the art. Nevertheless, it is within the scope of the skilled person, to determine the variation of the optimal effective amount of the other therapeutic agent. In one embodiment of the invention, when another therapeutic agent is administered to an animal, the minimum effective amount of the compound teo (cyano) vinylpiperazine is less than would be the minimum effective amount of not having administered the other therapeutic agent. In this modality, without being limited to theory, it is believed that the Nitio (cyano) vinylpiperazine Compounds and the other therapeutic agent act synergistically to tiate or prevent a Condition. The other therapeutic agent may be, but is not limited to, an opioid agonist, a non-opioid analgesic, a non-steroidal anti-inflammatory agent, an anti-migraine agent, a Cox-II inhibitor, an antiemetic, a β-blocker. -adrenergic, an anticonvulsant, an antidepressant, a Ca2 + channel blocker, an anticancer agent, an agent to tiatar or prevent Ul, an agent to teach or prevent an ulcer, an agent to tiatar or prevent IBD, an agent to treat or prevent IBS, an agent for tiatax addictive disorders, an agent for tiatar Parkinson's disease and parkinsonism, an agent to tiatar anxiety, an agent to tiatar epilepsy, an agent to treat a heart attack, an agent to thiatar an attack, an agent for treat xm pruritic condition an agent to treat psychosis, an agent to tittle Korea of Huntington, an agent to tiatar ALS, an agent to teach a cognitive disorder, an agent to teach a migraine, an agent for trafficking V vomiting, xm agent for teatar dyskinesia or an agent to treat depression and mixtures thereof. Examples of useful opioid agonists include, but are not limited to, alfentanil, allylprodin, alphaprodin, anileridin, benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, desomorphine, dextiomoramide, dezocin, diampromide, diamorphone, dihydrocodeine, dihydromorphine, dimenoxadol, dimefeptanol , dimethyl thiambutane, dioxafethyl butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene, fentanyl, heroin, hydrocodone, hydromorphone, hydroxypetidine, isomethadone, ketobemidone, levorphanol, levofenacillinfuran, lofentanil, meperidine, meptazinol, metazocine, methadone, metopona, morphine, mirofin , nalbuphine, narcein, nicomorphine, norlevorphanol, normetadone, nalorphine, normorphine, nofipanone, opium, oxycodone, oxymorphone, papaveretum, pentazocine, fenadoxone, fenomorphan, phenazocine, phenoperidine, piminodine, piritramide, proheptazine, promedol, properidin, propiram, prophoxydiphen, sufentanil Tilidine, tramadol, salts fa rmeaceutically acceptable thereof and mixtures thereof. In certain embodiments, the opioid agonist is selected from codeine, hydromorphone, hydrocodone, oxycodone, dihydrocodeine, dihydromorph, morphine, tramadol, oxymorphone, pharmaceutically acceptable salts thereof, and mixtures thereof. Examples of useful non-opioid analgesics include non-steroidal anti-inflammatory agents, such as aspirin, ibuprofen, diclofenac, naproxen, benoxaprofen, flurbiprofen, fenprofen, flubufen, ketoprofen, indoprofen, piroprofen, carprofen, oxaprozin, pramoprofen, muroprofen, trioxaprofen, suprofen, aminoprofen, thiaprofenic acid, fluprofen, bucilloxic acid, indomethacin, sulindac, tolmetin, zomepirac, tiopinac, zidometacin, acemetacin, fentiazac, clidanac, oxpinac, mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid, tolfenamic acid, diflurisal, flufenisal , piroxicam, sudoxicam, isoxicam, and pharmaceutically acceptable salts thereof and mixtures thereof. Other suitable non-opioid analgesics include the following chemical classes, non-limiting analgesics, antipyretics, and non-steroidal anti-inflammatory drugs: derivatives of salicylic acids, including aspirin, sodium salicylate, magnesium choline trisalicylate, salsalate, diflunisal, salicylsalicylic acid, sulfasalazine, and olsalazine; para-aminophenol derivatives including acetaminophen and phenacetin; type and indene acetic acids, including indomethacin, sulindac, and etodolac; heteroaryl acetic acids, including tolmetin, diclofenac, and ketorolac; antianilic acids (fenamates), including mefenamic acid and meclofenamic acid; enolic acids, including oxicams (piroxicam, tenoxicam), and pyrazolidinediones (phenylbutazone, oxifentartazone); and alkanones, including nabumetone. For a more detailed description of the NSAIDs, see Paul A. Insel, Analgesic-Antipyretic and Anti-inflammatory Agents and Drugs Employed in the Treatment of Gout, in Goodman & Gilman's The Pharmacological Basis of Therapeutics 617-57 (Perry B. Molinhoff and Raymond W. Ruddon eds., 9th ed.1996) and Glen R. Hanson, Analgesic, Antipyretic and Anti-Inflammatory Drugs in Remington: The Science and Practice of Pharmacy Vol II 1196-1221 (AR Gennaro ed., 19th ed., 1995) which are listed in full in this document by reference. Examples of useful Cox-II inhibitors and 5-lipoxygenase inhibitors, as well as combinations thereof, are described in U.S. Patent No. 6,136,839, which is incorporated herein by reference in its entirety. Examples of Cox-II inhibitors include, but are not limited to, rofecoxib and celecoxib.
Examples of useful anti-migraine agents include, but are not limited to, alpiropride, bromocriptine, dihydroergotamine, dolaseteone, ergocomin, ergocorninin, exgocriptine, ergonovine, ergot, ergotamine, flumedroxone acetate, fonazine, ketanserin, lisuride, lomerizine, methylergonovine, methysergide , metoprolol, naratriptan, oxetorone, pizotiline, propranolol, risperidone, rizatriptan, sumatriptan, timolol, teazodone, zolmitriptan, and mixtures thereof. The other therapeutic agent may be an antiemetic agent. Examples of useful antiemetic agents include, but are not limited to, metoclopromide, domperidone, procloferazine, promethazine, clofromazine, trimethobenzamide, ondansetiona, granisectone, hydroxyzine, acetylleucine monoethanolamine, alizapride, azasethione, benzquinamide, bietanautin, bromopride, buclizine, clebopride, cyclizine, dimeritachinate, diphenidol, dolasetiona, meclizine, metallatal, metopimazine, nabilone, oxyperendil, pipamizine, scopolamine, sulpiride, tetiahydrocannabinol, thiethylperazine, thioproperazine, tropisetron, and mixtures thereof. Examples of useful β-adrenergic blockers include, but are not limited to, acebutolol, alprenolol, amosulabol, arotinolol, atenolol, befunolol, betaxolol, bevantolol, bisoprolol, bopindolol, bucumolol, bufetolol, bufxxralol, buniteolol, bupranolol, butidrine hydrochloride, butofilolol. , carazolol, carteolol, carvedilol, celiprolol, cetamolol, cloranolol, dilevalol, epanolol, esmolol, indenolol, labetalol, levobunolol, epindolol, metipranolol, metoprolol, moprolol, nadolol, nadoxolol, nebivalol, nifenalol, nipradilol, oxprenolol, penbutolol, pindolol, practolol , pronetalol, propranolol, sotalol, sulfinalol, talinolol, tertatolol, tilisolol, timolol, toliprolol, yxibenolol. Examples of useful anticonvulsants include, but are not limited to acetylpheneturide, albutoin, alloxidone, aminoglutethimide, 4-amine-3-hydroxybutyric acid, ateolactamide, beclamide, buramate, calcium bromide, carbamazepine, cinromide, clomethiazole, clonazepam, decimemide, dietdione, dimethadione, doxenithioin, eterobarb, etadione, ethosuximide, ethotoin, felbamate, fluoresone, gabapentin, 5-hydroxytryptophan, lamotrigine, magnesium bromide, magnesium sulfate, mephenytoin, mephobarbital, metarbital, metetoin, methsuximide, 5-methyl-5- (3 -phenyantiyl) -hydantoin, 3-methyl-5-phenylhydantoin, naxcobarbital, nimetazepam, nitrazepam, oxcarbazepine, parametadione, phenacemide, phenetarbital, pheneturide, phenobarbital, phensuximide, phenylmethylbarbituric acid, phenytoin, sodium fetenilate, potassium bromide, pregabalin, primidone, progabide, sodium bromide , solanum, strontium bromide, suclofenide, sultiam, tetiantoin, tiagabine, topiramate, trimethadione, valproic acid, valpromide, vigabatrin, and zonisamide. Examples of useful antidepressants include, but are not limited to, binedaline, caroxazone, citalopram, (S) -citalopram, dimethazan, fencamine, indalpine, indeloxazine cloxhydrate, ñofopam, nomifensm, oxytriptan, oxypertin, paroxetine, sertraline, thiazidem, teazodone, benmoxin. , iproclozide, iproniazid, isocarboxazid, nialamide, octamoxin, phenelzine, cotinine, rolicyprine, rolipram, maprotiline, metralindole, mianserin, mirtazepine, adinazolam, amitriptyline, amitriptilinoxida, amoxapine, butriptyline, clomipramine, demexiptiline, desipramine, dibenzepin, dimetacrine, dothiepin, doxepin , fluacizine, imipramine, imipramine N-oxide, iprindole, lofepramine, melitiaceno, metapramine, nortriptyline, noxiptilin, opipramol, pizotyline, propizepine, protriptyline, quinupramine, tianeptine, trimipramine, adrafinil, benactyzina, bupropion, butacetin, dioxadrol, duloxetine, etoperidone, febarbamate, femoxetine, fenpentadiol, fluoxetine, fluvoxamine, hematoporphyrin, hypericin, vofacetoperano, medifoxamina, milnacipran, minaprine, moclobemide, nefazodone, oxaflozane, piberalina, prolintano, pirisuccideanol, ritanserina, roxindole, chlorinated xubidium, sulpiride, tandospirone, tozalinone, tofenacin, toloxatone, thianylcypromine, L-tryptophan, venlafaxine, viloxazine, and zimeldine. Examples of Ca2 + channel blockers include, but are not limited to, bepridil, clentiazem, diltiazem, fendiline, gallopamil, mibefradil, prenylamine, semothiadil, terodiline, verapamil, amlodipine, aranidipine, barnidipine, benidipine, cilnidipine, efonidipine, eldipipine, felodipine, isradipine, lacidipine, lercanidipine, manidipine, nicardipine, nifedipine, nilvadipine, nimodipine, nisoldipine, nitiendipine, cinnarizine, flunarizine, lidoflazine, lomerizine, benciclane, etafenone, phanopharone, and perhexilin. Examples of useful anticancer agents include, but are not limited to, acivicin, aclarubicin, acodazole hydrochloride, acronine, adozelesin, aldesleukin, altretamine, ambomycin, ametantrone acetate, aminoglutethimide, amsacrine, anastrozole, anteamycin, asparaginase, asperlin, azacitidine, azetepa, azotomycin, batystatate, benzodepa, bicalutamide, bisantene hydrochloride, bisnafide dimesylate, bizelesin, bleomycin sulfate, brequinar sodium, biririmine, busulfan, cactinomycin, calusterone, caracemide, carbetimer, carboplatin, carmustine, carubicin hydrochloride, carzelesin, cedefingol, chlorambucil, cirolemycin , cisplatin, cladribine, chrysanthine mesylate, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin hydrochloride, decitabine, dexormaplatin, dezaguanine, dezaguanine mesylate, diazicuone, docetaxel, doxorubicin, doxorubicin hydrochloride, droloxifene, droloxifene cytite, dromostanolone propionate, duazomycin, edateexate , hydrochloride of eflomitin, elsamitiucina, enloplatina, empromato, epipropidina, epirubicin hydrochloride, erbulozole, esorabicin hydrochloride, estramustine, estramustine sodium phosphate, etanidazole, etoposide, etoposide phosphate, etoprine, fadrozole hydrochloride, fazarabine, fenretinide, floxuridine, fludarabine phosphate, fluorouracil, flurocitabine, fosquidone, fostriecin sodium, gemcitabine, gemcitabine hydrochloride, hydroxyurea, idarubicin hydrochloride, ifosfamide, ilmofosin, interleukin II (including recombinant intexleukin II or rLL2), interferon alfa-2a, interferon alfa-2b, interferon alfa-nl , interferon alfa-n3, interferon beta-I a, interferon gamma-I b, iproplatin, irinotecan hydrochloride, lanreotide acetate, letrozole, leuprolide acetate, liarozole hydrochloride, lomethexol sodium, lomustine, losoxantrone hydrochloride, masoprocol, maytansine, hydrochloride of mechlorethamine, megestiol acetate, melengestrol acetate, melphalan, menogaril, mercaptopurine, methotie xato, methotrexate sodium, metoprine, meturedepa, mitindomide, mitocarcin, mitochromin, mitogilin, mitomalcin, mitomycin, mitosper, mitotane, mitoxanthion hydrochloride, myophenolic acid, nocodazole, nogalamycin, ormaplatin, oxisurane, paclitaxel, pegaspargase, peliptmycin, pentamustine, peplomycin sulfate , perfosfamide, pipobroman, piposulfane, piroxantone hydrochloride, plicamycin, plomestan, porfimero sodium, porfiromycin, prednimustine, procarbazine hydrochloride, puromycin, puromycin hydrochloride, phazofurin, riboprine, rogletimide, safingol, safingol hydrochloride, semustine, simtiazene, sodium propafosate , sparsomycin, spirogermanium hydrochloride, spiromustine, spixoplatin, esteeptonigrin, esteeptozocin, sulphenurin, talisomycin, tecogalan sodium, tegafur, teloxantrone hydrochloride, temoporfin, teniposide, teroxirone, testolactone, thiamiprine, thioguanine, thiotepa, thiazofurine, tirapazamine, toremifene citrate, tiestolone acetate, triciri's phosphate bina, trimetrexate, trimetrexate glucuronate, triptorelin, tubulozole hydrochloride, uracil mustard, uredepa, vapreotide, verteporfin, vinblastine sulfate, vincristine sulfate, vindesine, vindesine sulfate, vinepidine sulfate, vinglicinato sulfato, vinleurosina sulfato, vinorelbine tartiato, vinrosidina sulfato, vinzolidina sulfato , vorozol, zeniplatina, zinostatin, zorubicin hydrochloride.
Examples of other anticancer drugs include, but are not limited to, 20-epi-l, 25 dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; aclarubicin; acrylic fulvene; adecipenol; adozelesina; aldesleukin; ALL-TK antagonists; altretamine; ambamustine; amidox; amifostine; aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole; andrografol; angiogenesis inhibitors; antagonist D; antagonist G; antarelix; morphogenetic protein-1 anti-splitting; antiandrogen, prostatic carcinoma; antiestrogen; antineoplaston; antisense oligonucleotides; afidicolin glycinate; modulators of the apoptosis gene; regulators apoptosis; Apurinic acid; ara-CDP-DL-PTBA; arginine deaminase; asulacrine; atamestane; atrimustine; axinastatin 1; axinastatin 2; axinastatin 3; azasetron; azatoxin; azathirosine; Bacatin DI derivatives; balanol Batimastat; BCR / ABL antagonists; benzoclorins; benzoylstaurosporin; beta lactam derivatives; beta-aletine; betaclamycin B; betulinic acid; bFGF inhibitor; bicalutamide; bisantiene; bisaziridinyl espermine; bisnafide; bistiaten A; bizelesin; breflate; biririmine; budotitan; butionine sulfoximine; calcipotriol; calfostin C; camptothecin derivatives; canaripox B0-2; capecitabine; carboxamide-amine-triazole; carboxyamidotriazole; CaRest M3; CARN 700; inhidor derived from cartilage; carzelesin; inhibitors casein kinase (ICOS); castanospermine; cecropin B; cetrorelix; clorlns; chloroquinoxaline sulfonamide; cicaprost; cis-porphyrin; cladribine; clomiphene analogues; clotrimazole; colismicin A; colismicin B; combretastatin A4; analogous combretastatin; conagenina; crambescidin 816; crisnatol; cryptophycin 8; Cryptophycin A derivatives; Cure A; cyclopentantiaquinones; Cycloplatam; cipemycin; citaxabine ocphosphate; cytolytic factor; cytostatin; dacliximab; decitabine; deMdrodidemnin B; deslorelin; dexamethasone; dexiphosphamide; dexrazoxane; dexverapamil; diazicuone; didemnin B; didox; diethylonorspermine; dihydro-5-azacytidine; 9-dihydrotaxol; dioxamycin; diphenyl spiromustine; docetaxel; docosanol; dolasetiona; doxifluridine; dxoloxifene; dronabinol; duocarmicin SA; ebselen; ecomustine; edelfosin; Edrecolomab; eflomitin; elemene; emitefur; epirubicin; epristerida; estiamustine analogue; Estiogeho antagonists; Stiogen antagonists; etanidazole; etoposide phosphate; exemestane; fadrozole; fazarabine; fenretinide; filgrastima; Finasteride; flavopiridol; flezelastine; fluasterone; fludarabine; fluorodaunorunicin hydrochloride; forfenimex; formestane; fostriecin; fotemustine; gadolinium texaphylline; gallium nitrate; galocitabine; ganirelix; gelatinase inhibitors; gemcitabine; glutathione inhibitors; hepsulfam; heregulina; hexamethylene bisacetamide; hypericin; ibandronic acid; idarubicin; idoxifene; idramantone; ilmofosin; ilomastat; imidazoacridones; imiquimod; immunostimulatory peptides; insulin-like factor-1 growth receptor inhibitor; interferon agonists; interferonase; interleukins; iobenguane; iododoxorubicin; 4-ipomeanol; iroplact; irsogladine; isobengazole; isohomohalicondrine B; itasetion; jasplakinolide; kahalalide F; lamelarine-N triacetate; lanreotide; Ieinamycin; lenograstima; lentinan sulfate; leptolstatin; letrozole; leukemia inhibitory factors; alpha leukocyte interferon; -leuprolide + estiogen + progesterone; leuprorelin; levamisole; liarozola; linear analogous polyamine; lipophilic disaccharide peptide; lipophilic platinum compounds; lissoclinamide 7; lobaplatin; lombricin; lometrexol; lonidamine; losoxantrone; lovastatin; loxoribine; lurtotecan; luteciu texafixin; lyophilin; lytic peptides; Maytansine; Handstatin A; marimastat; masoprocol; maspina; matrilysin inhibitors; inhibitors of metalloproteinase matrix; menogaril; merbarone; meterelin; methioninase; metoclopramide; MIF inhibitor; mifepristone; miltefosine; mirimostim; Uneven RNA of double slob; mitoguazone; mitolactol; mitomycin analogues; mitonafide; growth factor fibroblast mycotoxin; mitoxanthione; mofarotene; molgramostim; anticoclonal monoclonal, coronary human gonadotrophin; lipid monophosphoryl cell wall A + myobacterium sk; mopidamol; gene inhibitor for multiple drug resistance; therapy 1 -based suppressor of multiple tumors; anticancer agent of mustard; micaperoxida B; mycobacterial cell wall extract; myriaporone; N-acetyldinaline; N-substituted benzamides; nafarelin; nagrestip; naloxone + pentazocinea; napavina; naphthefin; nartograstim; nedaplatin; nemombicin; neridronic acid; neutral endopeptidase; nilutamide; nisamycin; Nitric oxide modulators; nitroxide antioxidants; niteulin; O6-benzylguanine; octeeotide; okicenone; oligonucleotides; onapristone; ondanseteona; ondansetrone; oracine; oral cytokine inducer; ormaplatin; osaterone; Oxaliplatin; oxaunomycin; paclitaxel; analogous paclitaxel; paclitaxel derivatives; palauamine; palmitoihhizoxin; pamidronic acid; panaxitriol; panomiphene; parabactin; pazeliptina; pegaspargasa; peldesina; sodium pentosan polysulfate; pentostatin; pentrozole; perflubron; perfosfamide; perilyl alcohol; phenazinomycin; phenylacetate; phosphatase inhibitors; picibanil; pilocafine hydrochloride; pirarabicin; piritiexim; placetina A; placetina B; inhibidox of activadox plasminogen; platinum complexes; platinum compounds; platinum-triamine complexes; porfimer sodium; porphyromycin; prednisone; propyl bis-acridone; prostaglandin J2; proteasome inhibitors; A-based immune protein modulator; inhibitor of protein kinase C, microalgal; inhibitors of tyrosine phosphate protein; inhibitors of nucleoside purine phosphorylase; pufurinsa; pyrazoloacridine; conjugate of pyridoxylated hemoglobin plioxyethylene; raf antagonists; raltitiexed; ramosetron; inhibitors of ras famesil tiansferasa protein; ras inhibitors; ras-GAP inhibitor; demethylated reteliptina; rhenium Re 186 etidxonate; rhizoxin; ribozymes; RH retinamide; rogletimide; rohitukina; romurtida; roquinimex; Rubiginone Bl; ruboxil; safingol; saintopine; SarCNU; sarcophitol A; sargramostima; Sdi 1 mimetics; semustine; inhibitor 1 derived from senescence; oligonucleotides sense; inhibitors of the translation signal; modulators of the translation signal; simple protein binding agent of the antigenic chain; sizofirana; Sobuzoxane; sodium borocaptate; sodium phenylacetate; solverol; somatomedin binding protein; sonermin; Esparfosic acid; Spicamycin D; spiromustine; splenopentin; spongistatin 1; squalamine; cell root inhibitor; inhibitors of root-cell division; stihadid; inhibitors of esteomelisin; Sulfinosine; vasoactive superactive antagonist of the intestinal peptide; suradista suramin; Swainsonin; synthetic glycosaminoglycans; talimustine; tamoxifen methiodide; tauromustine; tazarotene; tecogalan sodium; tegafur; Telurapyrilium; telomerase inhibitors; temoporfin; temozolomide; teniposide; tetiaclorodecaoxide; tetiazomina; Taliblastine; thiocoraline; thrombopoietin; mimetic theombopoietin; timalfasin; timopoietin antagonist receptor; thymotrinan; Hormone thyroid stimulant; ethyl ethyl etiopufurine; tirapazamine; bicyclic titanocene; topsentin; toremifene; totipotent factor of cellular root; Translation inhibitors; teetinoin; triacetyluridine; triciribine; trimethexate; triptorelin; tiopisetiona; turosteride; tyrosine kinase inhibitors; Tyrphostins; inhibitors UBC; ubenimex; sine-derived urogenital growth inhibitory factor; urokinase antagonist receptor; vapxeotide; variolin B; vector system, erythrocyte gene therapy; velaresol; veramina; verdins; verteporfin; vinorelbine; vinxaltine; vitaxin; vorozole; zanoterone; zipiplatine; zilascorb; and zimatatin stimalamer. Examples of therapeutic agents useful for thiazing or preventing Ul include, but are not limited to, propantheline, imipramine, hyoscyamine, oxybutynin, and dicyclomin. Examples of therapeutic agents useful in treating or preventing an ulcer include antacids such as aluminum hydroxide, magnesium hydroxide, sodium bicarbonate, and calcium bicarbonate; sucralfate; bismuth compounds such as bismuth subsalicylate and bismuth subcytheate; H2 antagonists such as cimetidine, ranitidine, famotidine, and nizatidine; H +, K + - ATPase inhibitors such as omeprazole iansoprazole, and lansoprazole; carbenoxolone; misprostol; and antibiotics such as teteacicline, meteonidazole, thymidazole, clarithromycin, and amoxicillin. Examples of therapeutic agents useful for thiatar or preventing D3D include, but are not limited to, anticholinergic drugs; diphenoxylate; loperamide; deodorized opium dye; codeine; wide range of antibiotics such as methionidazole; sulfasalazine; olsalazine; mesalamine; prednisone; azathioprine; mercaptopurine; and methotrexate. Examples of therapeutic agents useful for thiazing or preventing IBS include, but are not limited to, propantheline; muscarin antagonist receptors such as pirenzapine, methoctiamine, ipratiopium, thioteopium, scopolamine, metscopolamine, homatiopine, homathiopine methyl bromide, and metanyl; and antidiarrheal drugs such as diphenoxylate and loperamide. Examples of therapeutic agents useful to thiatar or prevent 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. Examples of therapeutic agents useful for treating or preventing the disease of Parkinson's and parkinsonism include, but are not limited to, carbidopa / levodopa, pergolide, bromocriptine, ropinirola, pxamipexole, entacapone, tolcapone, selegiline, amantadine, and trihexyphenidyl hydrochloride. Examples of useful therapeutic agents for treating or preventing anxiety, include, but are not limited to, benzodiazepines, such as alprazolam, brotizolam, clordiazepoxide, clobazam, clonazepam, clorazepate, demoxepam, diazepam, estazolam, flumazenil, flurazepam, halazepam, lorazepam, midazolam , nitiazepam, nordazepam, oxazepam, prazepam, quazepam, temazepam, and triazolam; non-benzodiazepine agents, such as buspirone, gepirone, ipsaprione, thiospirone, zolpicone, zolpidem, and zaleplone; tranquilizers, such as barbiturates, for example, amobarbital, aprobarbital, butabarbital, butalbital, mephobarbital, methohexital, pentobarbital, phenobarbital, secobarbital, and thiopental; and propanediol carbomatos, such as meprobamate and tibamate. Examples of therapeutic agents useful for thiazing or preventing epilepsy include, but are not limited to carbamazepine, ethosuximide, gabapentin, lamotrignin, phenobarbital, phenytoin, primidone, valproic acid, trimethadione, bemzodiaepines, gabapentin, lamotrigine,? -vinyl GABA, acetazolamide, and felbamate Examples of therapeutics useful for teaching or preventing infarcts include, but are not limited to, anticoagulants such as heparin, clot dissolving agents such as streptokinase or tissue plasminogen activator, swelling reducing agents such as mannitol or corticosteroids, and acetylsalicylic acid. Examples of therapeutic agents useful for thiazing or preventing an attack include, but are not limited to, carbamazepine, ethosuximide, gabapentin, lamotrignin, phenobarbital, phenytoin, primidone, valproic acid, trimethadione, bemzodiaepines, gabapentin, lamotrigine,? -vinyl GABA, acetazolamide. , and felbamate. Examples of therapeutic agents useful for thiazing or preventing a pruritic condition include, but are not limited to, naltiexono; nalmefene; Danazol; tricyclics such as amitriptyline, imipramine, and doxepin; antidepressants such as those indicated below, menthol; camphor, phenol, pramoxin, capsaicin, tar; steroids; and antihistamines.
Examples of therapeutic agents useful for thiatar or preventing psychosis include, but are not limited to, phenothiazines such as clofromazine cloxhydrate, mesylazine besylate, and toridazine hydrochloride; thioxanthenes such as chloroprothixene and thiothixene hydrochloride; clozapine; risperidone; olanzapine; quetiapine; quetiapine fumarate; haloperidol; haloperidol decanoate; loxapine succinate; molindone hydrochloride; pimozide; and ziprasidone. Examples of therapeutics useful for thiatar or preventing Huntington's disease include, but are not limited to, haloperidol and pimozide. Examples of therapeutic agents useful for thiazing or preventing ALS include, but are not limited to, baclofen, neuroteopic factors, riluzole, tizanidine, benzodiazepines such as clonazepam and dantrolene. Examples of therapeutic agents useful for thiazing or preventing cognitive disorders include, but are not limited to, agents for thiazing or preventing demensia such as tacrine; donepezil; ibuprofen; antisychotic dxogas such as thioridazine and haloperidol; and anti-depressant drugs such as those indicated below. Examples of therapeutic agents useful for treating or preventing a migraine include, but are not limited to, sumatriptan; methysergide; ergotamine; caffeine; and beta-blockers such as propranolol, verapamil, and divalproex. Examples of therapeutic agents useful for thiazing or preventing vomiting include, but are not limited to, 5-HT 3 antagonist receptors such as ondansetiona, dolasetron, graniseteone, and tropisethione; dopamine antagonist receptors such as procloferazine, tiethylperazine, clofromazine, metoclopramide, and domperidone; glucocorticoids such as dexamethasone; and benzodiazepines such as lorazepam and alprazolam.
Examples of therapeutic agents useful for thiazing or preventing dyskinesia include, but are not limited to, resephine and tetiabenazine. Examples of therapeutic agents useful for treating or preventing depression include, but are not limited to, tricyclic antidepressants such as amitriptyline, amoxapine, bupropion, clomipramine, desipramine, doxepin, imipramine, maprotiline, nefazadone, nortriptyline, protriptyline, thiazodone, thiipipramine, and venlaflaxin.; selective serotonin reukptake inhibitors, such as citalopram, (S) -citalopram, fluoxetine, fluvoxamine paroxetine, and setealine; monoamine oxidase inhibitors such as isocarboxazide, parguin, phenelzine, and thianylcypromine; and psychostimulants such as dextroamphetamine and methylphenidate. A Nitro (cyano) vinyl piperazine Compound and the other therapeutic agent may act together or, in one embodiment, synergistically. In one embodiment a Niteo (cyano) vinyl piperazine Compound is administered concurrently with another therapeutic agent, for example a composition comprising an effective amount of a Nitium Compound (cyano) vinyl piperazine and an effective amount of other therapeutic agent can be administered. Alternatively, a composition comprising an effective amount of a Nitium Compound (cyano) vinyl piperazine and a different composition comprising an effective amount of another therapeutic agent may be administered concurrently. In another embodiment, an effective amount of a Nitium Compound (cyano) vinyl piperazine may be administered before or after administration of an effective amount of another therapeutic agent. In this modality, the Compound Nitio (cyano) vinyl? Iperazine is administered while the other therapeutic agent exerts its therapeutic effect, or the other therapeutic agent is administered while the Compound Nitro (cyano) vinyl piperazine exerts its therapeutic effect to tiatar or prevent a Condition. . A composition of the invention is prepared according to a method comprising mixing a Compound Nitio (cyano) vinylpiperazine and a pharmaceutically acceptable carrier or excipient. The mixture can be achieved using known methods for mixing a compound (or salt) and a pharmaceutically acceptable carrier. In one embodiment the Nitro (cyano) vinyl piperazine Compound is present in the composition in an effective amount. 4. 9 KITS The invention comprises kits that can simplify the administration of a Nitium (cyano) vinyl piperazine Compound to an animal. A typical kit of the invention comprises unit dose formulation of a Nitium (cyano) vinyl piperazine Compound. In one embodiment, the unit dose is a container, which can be sterile, containing an effective amount of a Niteo (cyano) vinyl piperazine Compound and a pharmaceutically acceptable carrier. The kit may additionally comprise a label or printed instructions instructing on the use of the Compound Nitro (cyano) vinyl piperazine to treat a Condition. The kit may further comprise a unit dose 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. In another embodiment, the kit comprises a container containing an effective amount of a Nitium Compound (cyano) vinyl piperazine, an effective amount of another therapeutic agent, a pharmaceutically acceptable carrier or excipient. Examples of other therapeutic agents include, but are not limited to, those indicated above. Kits of the invention may further comprise a device useful for administering unit dosage forms. Examples of such devices include, but are not limited to, a syringe, a drip bag, a patch, an inhaler and an enema bag. The following examples are set forth to assist in the understanding of the invention and should not be construed as limiting the invention described and claimed herein. Such variations of the invention, including the substitution of all equivalents currently known or developed in the future, which would be within the scope of those skilled in the art, and changes in formulations or changes in experimental design, should be considered of the field of the invention herein uncovered.
. Examples Examples 1-8 refer to the synthesis of illiterative Niteo (cyano) vinylpiperazine compounds. - . 1 Example 1: Synthesis of Compound E14 (a) 2,3-dichloropyridine (5) (5g) and piperazine (6) (8 g, 04.5 mmol) (each of which was commercially available from Sigma-Aldrich) was dissolved in 70 mL of DMF. To the resulting solution was added DIEA (12.21 g, 94.5 mmol) and the resulting reaction mixture was allowed to stir at a temperature of about 150 ° C for up to 15 h. Water (100 mL) and ethyl acetate (150 mL) were added to the reaction mixture and the organic phase and the separated aqueous phases. The aqueous phase was extracted with ethyl acetate (about 100 mL / ext.) And the combined ethyl acetate layers. The combined ethyl acetate layers were then washed with water (50 mL), washed with brine (50 mL) and dried (Na2SO). The solvent was removed under reduced pressure to provide a residue that was purified using column chromatography (silica gel eluted with 20% methanol in ethyl acetate) to provide the compound of formula 4 (5.2 g, 81% yield) 4-Zso-β-aniline aniline (1) (0.5 g, 3.6 mmol) and 1,1-bis (methylthio) -2-nitroethylene (H) (0.61 g, 3.6 mmol) (commercially available from Sigma) -Aldrich) were dissolved in ethanol and the resulting solution heated to recirculating temperature for about 2 h. The solvent was removed under reduced pressure to provide a residue which was purified using column chromatography (silica gel with gradient elution of 10% ethyl acetate in hexane to 20% ethyl acetate in hexane) to provide xm compound of formula 3 as a yellow solid (85 mg, 93% delivery).
The compound of formula 3 and a compound of formula 4 were dissolved in 50 ml of ethanol and the resulting solution heated to recirculating temperature for about 2 h. Then, the solvent was removed under reduced pressure to provide a residue.
The residue was purified using column chromatography (silica gel with elution gradient of 20% atyl acetate in hexane to 50% ethyl acetate in hexane) to give Compound E14 (a) as a yellow solid (55 mg, 68% yield) . The identity of Compound E14 (a) was confirmed using 1H NMR and mass spectroscopy (MS).
Compound E14 (a): 1 H NMR (400 MHz CD3OD): d 1.3 (bs, 6H), 2.72 (m, HH), 3.33 (bd, 4H), 3.45 (bd, 4H) 6.72 (s, ÍH), 6.91 (m, ÍH), 7.15 (d, 2H), 7.26 (t, 2H), 7.75 (t, ÍH), 8.22 (t , lH), 11.09 (s, ÍH) ppm. . 2 Example 2: Synthesis of the Compound The (a) Compound El (a) was prepared by an analogous procedure to that used to prepare Compound E14 (a) except that 4-tert-butyl aniline (commercially available from Sigma-Aldrich) was used instead of 4-zso-propyl aniline. The identity of Compound E 1 (a) was confirmed using 1 H NMR and MS.
Compound El (a): * H NMR (400 MHz CD3OD): d 1.3 (s, 9H), 3.33-3.75 (bd, 4H), 3.40-3.45 (bd, 4H) 6.72 (s, ÍH), 6.91 (m, ÍH), 7.35 (d, 2H), 7.45 (t, 2H), 7, 65 (t, ÍH), 8.22 (t, 1H), 11.09 (s, lH) ppm.
MS (E?): M / z = 415 (m + l). . 3 Example 3: Synthesis of Compound 4 Ka) Compound 41 (a) was prepared by a procedure analogous to that used to prepare Compound El except that 4,5-dichloropyrimidino was used in place of 2,3-dichloropyridino. The identity of Compound E141 (a) was confixed using 1H NMR and MS.
Compound E141 (a): * H NMR (400 MHz CD3OD): d 1.3 (s, 9H), 3.32-3.34 (bd, 4H), 3.35-3.36 (bd, 4H) 6.72 (s, ÍH), 7.25 (d, 2H), 7.45 (t, 2H), 7.99 (s, ÍH), 8.22 (s, ÍH), 11.19 (s) , ÍH) ppm.
MS (EI): m / z = 416 (m + l). . 4 Example 4: Synthesis of Compound E7 (a Compound E7 (a) was prepared by a procedure analogous to that used to prepare Compound E14 (a) except that 4-trifluoromethyl aniline was used in place of 4-z'so-propyl aniline. The identity of Compound E7 (a) was confirmed using 1H NMR and MS.
Compound E7 (a): ^ NMR ^ OO MHz CD3OD): d 3.25-4.25 (bm, 8H), 5.68 (s, ÍH), 7.23 (m, 1H), 7.35 ( m, 2H), 7.88 (t, 2H), 7.91 (m, HH), 7.22 (t, HH), 10.01 (s, ÍH) ppm.
MS (EI): m / z = 427 (m + l). . 5 Example 5: Synthesis of Compound E267fa Compound E267 (a) was prepared by a procedure analogous to that used to make Compound El except that 4,5-dichloro-2-thia-1,3-diazole was used in place of 2,3-dichloropyridino. The identity of Compound E267 (a) was confirmed using 1H NMR and MS.
Compound E267 (a): H NMR (400 MHz CD3OD): d 1.3 (s, 9H), 3.12-3.14 (bd, 4H), 3.25-3.26 (bd, 4H), 6.25 (s, ÍH), 7.15 (d, 2H), 7.45 (d, 2H), 11.20 (s, ÍH) ppm.
MS (EI): m / z = 422 (m + l). . 6 Example 6: Synthesis of Elic Compound Compound El (c) was prepared by a procedure analogous to that used to make Compound El except that (R) -2-methylpiperazine (commercially available from Sigma-Aldrich) was used in. place of piperazine. The identity of Compound El (c) was confirmed using 1H NMR and MS.
Compound El (c): * H NMR (400 MHz CD3OD): d 1.3 (s, 9H), 1.52 (t, 3H), 2.85-2.87 (bm, 2H), 3.25 -3.27 (bm, 3H), 3.68 (s, ÍH), 3.72 (s, ÍH), 6.58 (s, ÍH), 6.75 (m, ÍH), 7.12 ( m, 2H), 7.55 (t, 2H), 7.79 (t, ÍH), 8.25 (s, ÍH), 11.35 (s, ÍH) ppm.
MS (El): m / z = 429 (m + 1). . 7 Example 7: Synthesis of Compound E43 (a) Compound E43 (a) was prepared by a procedure analogous to that used to make Compound El except that 2-chloro-3-trifluoromethylpyridino was used in place of 2,3-dichloro-iridino. The identity of Compound E43 (a) was confirmed using 1H NMR and MS.
Compound E267 (a): H NMR (400 MHz CD3OD): d 1.35 (s, 9H), 3.54 (t, 4H), 3.60 (t, 4H), 6.55 (s, ÍH) , 7.12 (m, ÍH), 7.21 (t, 2H), 7.49 (t, 2H), 7.78 (d, ÍH), 8.45 (s, ÍH), 11.05 (s, ÍH) ppm.
MS (EI): m / z = 449 (m + l). . 8 Example 8: Synthesis of Compound DI (a) l l < a) tert-Butyl isocyanate, 5, (0.353 g, 2.5 mmol) (commercially available from Lancaster Chemicals of Windham, NH (www.lancastersvnthesis.com)): 4-tert-butyl isothiocyanate, 6, (commercially available from Transworld Chemicals, Inc., of Rockville, MD), and DIEA (0.87 mL, 5 mmol) were dissolved in DMF and the resulting solution stirred for a further 16 h at 25 ° C to provide the compound 7. The reaction was monitored using high pressure liquid chromatography until the reaction was complete. When the reaction was complete, piperazine 4 (0.593 g, 3 mmol) and DIC (0.568 g, 4.5 mmol) were added to the reaction mixture and the reaction mixture was allowed to stir for a temperature of about 18 h around of 25 ° C. The solvent was then removed under reduced pressure to provide a residue. The resulting residue was purified using column chromatography on silica gel eluted with a gradient of 5:95 ethyl acetate: hexane at 20:80 ethyl acetate: hexane to provide Compound Dl (a) as a solid (110 mg, 9% delivery). The identity of Compound Dl (a) was confirmed using 1H NMR and MS.
Compound Dl (a):? NMR (400 MHz CD3OD): d 1.3 (s, 9H), 1.51 and 1.58 (s, 9H), 3.35-3.40 (m, 4H), 3.43-3.48 (m, 4H), 6.85 (dd, lH), 6.95 (2, dH), 7.37 (d, 2H), 7.58 (dd, ÍH), 8.14 (dd, ÍH), 9 , 85 (s, ÍH) ppm.
MS (EI): m / z = 496 (m + l). . 9 Example 9: Bonding or Bonding of Nifro Compounds (cyanovinylpiperazine to mGluR5 The following test can be used to demonstrate that Nitium (cyano) vinyl piperazine compounds bind or bind to mGluR5 and, therefore, are useful for thiatal or prevente, eg pain.
Cell Culture: Primary glial cell cultures are prepared from 18 day Sprague-Dawley embryo cortices. The cortices are dissected and then dissociated by means of grinding. The resulting homogeneous cell is disposed on the plate on TI 75 flasks pre-coated with poly-D-lysine ((BIOCOAT, commercially available from Becton Dickinson and Company Inc. in Franklin Lakes, NJ) in the Modified Eagle Dulbecco Medium ("DMEM," pH 7.4), buffered with 25 mM HEPES, and supplemented with 15% fetal calf serum ("FCS," commercially available from Hyclone Laboratories Inc. in Omaha, NE), and incubated at 37 ° C and 5% CO2.Following 24 hours, the FCS supplement is reduced to 10%. 'On the sixth day, oligodendrocytes and microglia are removed by strongly striking the contour of the vials One day after this purification step, secondary astiocyte cultures are established by replacing 96 TI-75 coated poly-D-lysine pxe flasks (BIOCOAT) at a density of 65,000 cells / originals in DMEM and 10% FCS. of 24 hours, the astrocytes are washed s with a serum free medium and then cultured in DMEM, without glutamate, supplemented with 0.5% FCS, 20 mM HEPES, 10 ng / mL of epidemial growth factor ("EGF"), 1 mM sodium pyrata, and IX penicillin steeptomycin at pH 7.5 for 3 to 5 days at 37 ° C and 5% CO2. The method allows the expression of mGluR5 receptor by astrocytes, as demonstrated by S. Miller et al., J. Neuroscience 15 (9): 6103-6109 (1995).
Test Protocol: After a 3 to 5 day incubation with EGF, the asteocytes are washed with 127 mM NaCl, 5 mM KCl, 2 mM MgCl2, 700 mM NaH2PO4, 2 mM CaCl2, 5 mM NaHCO3, 8 mM HEPES, 10 mM Glucose at pH 7.4 ("Assay Buffer") and loaded with Fluo-4 dye (commercially available from Molecular Probes Inc. of Eugene, OR) using 0.1 mL of Assay Buffer containing Fh? o-4 ( 3 mM final). After 90 minutes of caxga dyeing, the cells are washed twice with 0.2 mL of Assay Buffer and xesuspended in 0.1 mL of Test Buff. The plates containing the asteocytes are then transferred to a Fluorometric Image Plate Reader ("FLIPR," commercially available from Molecular Devices Coforation of Sunnyvale, CA) for calculation of calcium mobilization flux in the presence of glutamate and in the presence or absence of antagonist. After monitoring the fluorescence for 15 seconds in order to establish a baseline, DMSO solutions containing various concentrations of a Nitium Compound (cyano) vinylpiperazine diluted in Assay Buffer (0.05 mL of 4X solutions for competitive 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 original to provide a final concentration of glutamate in each original of 10 mM. The fluorescence of the plate is then monitored for an additional 60 seconds after the addition of the agonist. The final concentration of DMSO in the assay is 1.0%. In each experiment, the fluorescence is monitored as a function of time and the data analyzed using Microsoft Excel and GraphPad Prism. The dose-response curves are adjusted using a non-linear regression to determine the IC50 value. In each experiment, each data point is determined twice. . 10 Example 10: In Vivo Tests for the Prevention or Treatment of Pain Test animals: Each experiment uses rats weighing 200-260 g at the beginning of the experiment. Rats are grouped and have free access to food and water at any time, except before oral administration of a Compound Nitro (cyano) vinyl piperazine when the food is removed 16 hours before the dose. A control group acts as a comparison for rats treated with a Compound Nitro (cyano) vinylpiperazine. The carrier of the Compound is administered to the control group Ñitio (cyano) vinylpiperazine. The volume of carrier administered to the control group is equal to the volume of carrier and Compound Nitium (cyano) vinylpiperazine administered to the test group. Acute Pain: In order to evaluate the actions of the Niteo (cyano) vinylpiperazine Compounds for the treatment or prevention of acute pain, the rapid tail movement test of the rat can be used. The rats are carefully restrained with the hand and tail exposed to a focused beam of radiant heat light at a point 5 cm from the tip using a fast tail movement unit (Model 7360, commercially available from Ugo Basile of Italy). The latencies of the fast tail movements are defined as the interval between the beginning of the thermal stimulus and the rapid movement of the tail. Animals that do not respond within 20 seconds are removed from the fast tail movement unit and assigned a latency delay of 20 seconds. The latencies of fast tail movements are measured immediately before (pre-treatment) and 1, 3, and 5 hours after the administration of a Nitro (cyano) vinylpiperazine Compound. The data are expressed as fast tail movement latency (s) and the maximum possible effect percentage (% MPE), that is, 20 seconds, is calculated as follows: [(post-administration latency) - (pre-administration latency)]% MPE = "x 100 (20 s pre-management latency) The rapid tail movement test in rats is described in F.E. D'Amoux et al, "A Method for Determining Loss of Pain Sensation," J. Pharmacol Exp. Ther. 72: 74-79 (1941). Acute pain can also be assessed by measuring the response of the animal to noxious mechanical stimulus by determining the leg withdrawal threshold ("PWT"), as described below.
Inflammatory Pain: In order to evaluate the actions of the Niteo (cyano) vinylpiperazine Compounds for the treatment or prevention of inflammatory pain, Freund's complete adjuvant inflammatory pain model ("FCA") is used. The FCA-induced inflammation of the hind paw of the rat is associated with the development of persistent inflammatory mechanical hyperalgesia and provides reliable predictions of the anti-hyperalgesic action of clinically useful analgesic drugs. (L. Bartho et al, "frrvolvement of Capsaicin-sensitive Neurons in Hyperalgesia and Enhanced, Opioid Antinociception in Inflammation," Naunyn-Schmiedeberg's Archives of Pharmacol 342: 666-670 (1990)). An intiaplanax injection of 50 μL of 50% ACF is administered to the left hind paw of each animal. 24 hours after the injection, the animal is evaluated on its response to noxious mechanical stimulus, determining the PWT, as described below. The rats are then administered a single injection of 1, 3, 10 or mg / Kg of either a Nitium (cyano) vinylpiperazine Compound; 30 mg / Kg of a control selected from Celebrex, indomethacin or naproxen; or carrier The noxious mechanical stimulus responses are then determined 1, 3, 5 and 24 hours after their administration. The percentage of inversion of hyperalgesia for each animal is defined as: [(PWT post administration) - (PWT pre-administiación)]% Investment = x 100 [(baseline PWT) - (PWT pre-adnninistiación)] Neuropathic Dolox: To evaluate the actions of Compounds Nitro (cyano) vinylpiperazine for the treatment of neuropathic pain, you can use either the Seltzer or Chung model. In the Seltzer model, the neuropathic pain model of partial ligation of the sciatic nerve 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 Nexve Injury, "Pain 43: 205-218 (1990).) The partial ligation of the left sciatic nerve is performed under the inhalation of enflurane / O2 anesthesia After the induction of anesthesia, the left thigh of the rat is shaved and the sciatic nerve exposed at the level of the thigh height through a small incision and is carefully isolated from the surrounding connective tissue, in a location near the teoncater just distal to the point where the semitendenous nerves of the posterior biceps branch out from the nerve common sciatic A 7-0 silk suture is inserted into the nerve with a reversible mini-needle with a 3/8 curve firmly attached so that the dorsal 1/3 to Vz of the nerve is dentin-bound. The wound is closed with a single muscle suture (4-0 nylon (Vicryl)) and vetbond tissue glue.After surgery, the wound area is dusted with antibiotic powder.The substitute-treated rats are subjected to a identical surgical procedure except that the sciatic nerve is not manipulated.
After the cirage, the animals are weighed and placed on a warm pad until they recover from anesthesia. The animals are then returned to their cages until the behavior tests begin. The animal is evaluated for its response to noxious mechanical stimulus, determining PWT, as described below, before surgery (baseline), then immediately before and 1, 3, and 5 hours after the administration of drugs to the hind leg of the animal. The hyperalgesia inversion percentage is defined as: [(PWT post-administration) - (PWT pre-adnninistiación)] % Investment = '- X 100 [(baseline PWT) - (PWT pre-administering)] In the Chung model, the neuropathic pain model of spinal nerve ligation is used to produce mechanical hyperalgesia, thermal hyperalgesia and tactile allodynia in rats.
The surgery is carried out under inhalation of isoflurane / O2 anesthesia. After the induction of anesthesia, a 3 cm incision is made and the left paraspinal muscles are separated from their vertebral process at the L4 - S2 levels. The tiansversal L6 process is carefully removed with a pair of small forceps to visually identify the vertebral nerves L4 - L6. The left nerve (s) L5 (or L5 and L¿) is isolated and firmly linked with silk thread. A complete hemostasis is confirmed and the wound sutured using non-absorbent sutures, such as nylon sutures or stainless steel staples. Substituted-teared rats are subjected to an identical surgical procedure, except that the vertebral nerve (s) is not manipulated. After the cirage, the animals are weighed, given a subcutaneous (s.c.) injection of saline or lactose, the area of the wound dusted with antibiotic powder kept on a warm pad until they recover from anesthesia. The animals are then returned to their cages until the behavior test begins. The animals are evaluated for their response to noxious mechanical stimulus, determining PWT, as described below, before the cirage (baseline), then immediately prior to and 1, 3, and 5 hours after they are administered a Compound Nitium (cyano) vinylpiperazine for the animal's left rear leg. The animal can also be evaluated for its response to noxious thermal stimulus or 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 Stimulation as Evaluation of Mechanical Hyperalgesia: The leg pressure test can be used to evaluate mechanical hyperalgesia. For this test, hind leg hindrance thresholds (PWT) to a noxious mechanical stimulus are determined using an analgesimeter (Model 7200, commercially available at Ugo Basile in Italy) as described in C. Stein, "Unilateral Inflation of the Hindpaw in Rats as a Model of Pxolonged 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 rear leg is set at 250 g and the end point is taken as the complete withdrawal of the leg. PWT is determined once for each rat at each time point and only the affected paw (ipsilateral) is tested.
Response to Thermal Stimulation as Evaluation of Thermal Hyperalgesia: The plantar test can be used to evaluate thermal hyperalgesia. For this test, withdrawal latencies of the hind paw to a noxious thermal stimulus are determined using a plantar test apparatus (commercially available at Ugo Basile of Italy) following the technique described by K. Hargreaves et al, "A New and Semantic Method for Measuring Thermal Nociception in Cutaneous Hyperalgesia, "Pain 32 (l): 77-88 (1988) .The maximum exposure time is set at 32 seconds in order to avoid tissue damage and any - Direct withdrawal of the leg of the heat source is taken at this final point. Three «latencies are determined in each period of time and averaged. Only the affected leg (ipsilateral) is tested. Tactile Allodynia Evaluation: To assess tactile allodynia, the rats are placed in transparent plexiglass compartments with a mesh floor where they are allowed to become habituated for a period of at least 15 minutes. After habituation, a series of von Frey monofilaments are placed on the plantar surface of the left paw (operated) of each rat. The von Frey monofilament series consist of six monofilaments of increasing diameter, with the smaller diameter fiber presented first.
Five tests are conducted with each strand, each test with approximately 2 minutes of separation. Each presentation lasts a period of 4-8 seconds or until nociceptive withdrawal behavior is observed. Retraction, paw withdrawal or licking of the leg are responses considered as nociceptive behavior. . 11 Example 11: In Vivo Tests for the Prevention or Treatment of Anxiety The elevated plus maze praeba or the probe-shock concealment test can be used to evaluate the anxiolytic activity of Nitium (cyano) vinyl piperazine compounds in rats and mice.
Praeba de laberinto Elevado Plus: The praeba of elevated plus labyrinth consists of a platform with four sleeves, two open and two closed (50x10x50 cm capped with an open roof). Rats (or mice) are placed in the center of the platform, at the intersection of the four sleeves, facing one of the closed sleeves. The time of stay in the open sleeves vs. Closed sleeves and number of open sleeves entries is recorded. This praeba is conducted before drug administration and again, after drug administration. The results of the test are expressed as the average time spent in open sleeves and the average number of open sleeves. Known anxiolytics increase both the open sleeves time and the open sleeves entry number. The elevated plus maze praeba is described in D. Treit, "Animal Models for the Study of Anti-anxiety Agents: A Reyiew," Neuroscience & Biobehavioral Reviews 9 (2): 203-222 (1985). Praeba for concealment probe-shock: For the probe-shock concealment test, the praeba apparatus consists of a plexiglass box measuring 40x30x40 cm, uniformly covered with approximately 5 cm of bedding material (cat litter absorbing odors) with a small hole at one end through which a shock probe is inserted (6.5 cm long and with a diameter of 0.5 cm). The Plexiglas discharge probe is spirally wrapped with two copper cables through which electrical current is administered. The current is set to 2 mA. Rats are habituated to the praeba apparatus for 30 minutes for 4 consecutive days without the shock probe in the box.
On the day of the test, the rats are placed in a corner of the test chamber after drug administration. The probe was not electrified until the rat touches it with its nose or front legs, at which point the rat receives a brief 2 mA discharge. The praeba period of 15 min begins once the rat receives its first discharge and the probe remains electrified for the remainder of the praeba period. The discharge induces a burial or concealment behavior on the part of the rat. After the first discharge, the length of time the rat spends spraying bed material to or above the probe with its front nose or legs (burial or concealment behavior) is measured as well as the number of discharges that the rat receives from the probe induced by contact. Known anxiolytic drugs reduce the amount of burial or concealment behavior. Also, the rate of rat reactivity to each discharge is recorded on a scale of 4 points. The total immobility time during the praeba period of 15 minutes is used as an index of general activity. The praeba of probe-shock concealment is described in D. Treit, 1985, supra. . 12 Example 12: In Vivo Tests for the Prevention or Treatment of an Addictive Disorder The praeba of preference of conditioned place or drug self-administration test can be used to evaluate the ability of Nitro (cyano) vinylpiperazine compounds to attenuate the gratifying properties of known drug abuse. The praeba preferably of conditioned place: The apparatus for praeba preferably of conditioned place consists of two large compartments (45 x 45 x 30 cm) made of wood with a front wall of plexiglass. These two large compartments are clearly different. Doors in the back of each compartment lead to a smaller box (36 x 18 'x 20 cm) made of wood, painted gray, with a mesh roof. The two large compartments differ in terms of shade (white vs. black), level of illumination (the plexiglass door of the white compartment is covered with aluminum foil except for a 7 x 7 cm window), texture (the white compartment has a table 3 cm thick (40 x 40 cm) with nine holes of a diameter of 5 cm equally spaced and black has a mesh floor), and controls of smell (saline in the white compartment and 1 mL of a 10 % acetic acid in the black compartment). In the days of habituation and praeba, the doors to the small box remain open, granting the free rat access to both large compartments. The first session in which a rat is placed in the apparatus is a habituation session and the entrances to the smaller gray compartment remain open giving the rat free access to both large compartments. During habituation, rats generally show no preference for either compartment.
After habituation, the rats are given 6 conditioning sessions. The rats are divided into 4 groups: carrier pre-treatment + carrier (control group), Compound Nitium (cyano) vinylpiperazine pre-treatment + carrier, pre-treatment carrier + Morphine, Compound Niteo (cyano) vinylpiperazine pre-treatment + morphine. During each session, the rat is injected with one of the drug combinations and confined to a compartment for 30 minutes. The next day, the rat receives a portadox training + carrier and is confined to the other large compartment. Each rat receives three conditioning sessions consisting of 3 combinations-drug compartments and three compartment-carrier pairs. The order of the injections and the compartment / drug pairs are counterbalanced within the groups. On the day of the test, the rats are injected, before the praeba (30 min to 1 hour), with either morphine or a carrier and the rat is placed in the apparatus, the doors to the gray compartment remain open and the rat can explore the entire apparatus for 20 min. The time that remains in each compartment is recorded. Abuse of known drugs increase the time spent in the par-dxoga compartment during the test session. If the Compound Nitium (cyano) vinylpiperazine blocks the range of preference of the place conditioned with morphine (prize), there will be no difference in the residence time on each side in rats pretreated with a Compound Nitro (cyano) vinylpiperazine and the group does not it will be different from the group of rats that were given carrier + carrier in both compartments. The information will be analyzed as the time of permanence in each compartment (pair-combination dxoga vs. pax-carrier). In general, the experiment is repeated with a minimum of 3 doses of a Niteo (cyano) vinylpiperazine Compound. Self-Administered Drug Praeba: The apparatus for self-administered drug praeba is a standard chamber commercially available as an operational conditioning chamber. Before the drug tests begin, the rats are trained to press a lever for a reward in food. Once a stable lever pressure behavior is acquired, the rats are tested to exert pressure on the lever for a drug reward. The rats are implanted with chronic residence jugular catheters for intea venous administration of compounds and allowed to recover for 7 days before the start of training. Experimental sessions are conducted daily for 5 days in 3-hour sessions. Rats are trained to self-administer a known abuse disorder, such as morphine. The rats are then presented with two levers, an "active" lever and an "inactive" lever. Pressing the active lever results in a drug infusion in a fixed ratio program of 1 (FR1) (that is, a lever pressure gives an infusion) followed by a recess period of 20 seconds (indicated by the illumination of a light above the levers). Pressing the inactive lever results in the infusion of excipients. The interpretation continues until the total number of morphine infusions stabilizes within ± 10% per session. Rats are trained to evaluate the effect of pretreatment with Niteo (cyano) vinyl piperazine compounds in the self-administration of drugs. On the day of the test, the rats are pretreated with a Compound Nitio (cyano) vinylpiperazine or excipient and then allowed to self-administer drugs, as usual. If the Nitro (cyano) vinylpiperazine Compound blocks the reward effect of morphine, the rats pretreated with the Compound Nitium (cyano) vinylpiperazine will demonstrate a lower response rate compared to the previous response rate and compared to pre-thiatal rats. with excipients. The information is analyzed according to the change in the number of drug infusions per test session (number of infusions during the test session - number of infusions during the training session). . 13 Example 13: Functional Assay for Characterizing mGluRl Antagonist Properties Functional assays for the characterization of mGluR 1 antagonist properties are known in the art. For example, the following procedure can be used. A CHO-rat mGluRl cell line is generated using cDNA encoding the rat mGluRl receptor (M. Masu and S. Nakanishi, Nature 349: 760-765 (1991)). The cDNA encoding the mGluRl receptor can be obtained from, for example, Prof. S. Nakanishi (Kyoto, Japan). 40,000 cells / original CHO-rat mGluRl are plated on a tissue plate treated with culture tissue, 96 deposits, light background, black, COSTAR 3409 (commercially available from Fisher Scientific of Chicago, IL) and incubated in an Eagle Medium Modified Dulbecco (DMEM, pH 7.4) supplemented with glutamine, 10% FBS, 1% Pen / Stiep, and 500 μg / mL Geneticin for about 12 hours. The CHO-rat mGluRl cells are then washed and treated with an Optimem medium (commercially available from hrvitrogen, Carisbad, CA) and incubated for 1 to 4 hours before loading the cells with FLUO-4 dye. After incubation, the cell plates are washed with a loading buffer (127 mM NaCl, 5 mM KCl, 2 mM MgCl2, 700 μM, NaH2PO4, 2 mM CaCl2, 5 mM NaHCO3, 8 mM HEPES, and 10 mM glucose, pH 7.4) and incubated with 3 μM FLUO-4 in 0.1 mL of loading buffer for 90 minutes. The cells are then washed twice with 0.2 mL of loading buffer, resuspended in 0.1 mL of loading buffer, and transferred to a FLIPR for flow measurement of calcium mobilization in the presence of glutamate and in the presence or absence of a Compound Niteo (cyano) vinylpiperazine. To measure the flow of calcium mobilization, the fluorescence is monitored for a period of 15 seconds to establish a baseline and DMSO solutions containing a variety of concentrations of a Nitro (cyano) vinylpiperazine Compound ranging from 50 μM to 0.8 nM. diluted in a bulking agent (0.05 mL of a 4X dilution) are added to cell plates and the fluorescence monitored for about 2 minutes. Then, 0.05 mL of a 4X glutamate solution (agonist) is added to each original to provide a final concentration of glutamate in each original of 10 μM and the fluorescence is monitored for about an additional 1 minute. The final concentration of DMSO in the assay is 1%. In each experiment, the fluorescence is monitored as a function of time and the data are analyzed using a non-linear regression to determine the IC50 value. In each experiment, each data point is determined twice. . 14? Example 14: Bonding or Compounding of Nitro (cyano) vinylpiperazine Compound to VRl Methods for demonstrating the ability of a compound to inhibit VR1 are known to those skilled in the art, for example, those methods described in U.S. Patent No. 6,239,267 to Duckworth et al .; U.S. Patent No. 6,406,908 to Mclntyre et al .; or United States Patent No. 6. 335,180 to Julius et al.
Ligación or Union of the Compound El (a) to VRl: Test Protocol Cloning of Human VRl: Human spinal cord RNA was used (commercially available in Clontech, Palo Alto, CA). Reverse transcription was performed on 1.0 μg of total RNA, using Reverse Transcriptase Termoscript (commercially available from Invitrogen) and oligo dT primers as detailed in the product description. Reverse transcription reactions are incubated to 55 ° C for 1 hour, inactivated by heat at 85 ° C for 5 min, and treated with RNase H- a 37 ° C for 20 minutes. The human VR1 cDNA sequence is obtained by comparison of the human genomic sequence, prior to annotation, with the published sequence of the rat. The sequences of the intion are removed and the flanking exonic sequences are joined to generate the hypothetical human cDNA. Primers flanking the human VR1 coding region were designed as follows: primer (primer) forward, AAGATCTTCGCTGGTTGCACACTGGGCCACA; and primer (first) back, GAAGATCTTCGGGGACAGTGACGGTTGGATGT. VR1 PCR was carried out in a tenth of the reverse transcription reaction mixture, using Expand Long Tissue Polymers and Expand Buffer 2 in a final volume of 50 μL according to the manufacturer's instructions (Roche Applied Sciences, Indianapolis, IN). After denaturation at 94 ° C for 2 minutes, the PCR amplification was carried out for 25 cycles at 94 ° C for 15 'seconds, 58 ° C for seconds, and 68 ° C for 3 minutes, followed by a final incubation at 72 ° C for 7 minutes to complete the amplification. A PCR product of -2.8 kb was isolated gel using 1.0% agarose, Tris-Acetao gel containing 1.6 μg / mL crystal violet and purified with an S.N.A.P. UV-free gel purification kit (commercially available from Invitiogen). The VR1 PCR product was cloned into the pIND / V5-His-TOPO vector (commercially available from Invitiogen) according to the manufacturer's instructions. DNA preparations, restricted digestion of enzymes, and preliminary DNA sequencing were carried out according to standard protocols.
Full-length sequencing confirms the identity of human VR1. Generation of Inducible Cell Lines: Unless otherwise indicated, cell culture reagents were purchased from Life Technologies of Rockville, MD.
HEK293-EcR cells expressing the ecdysone receptor (commercially available from Invitiogen) are cultured in a Growth Medium (Dulbecco's Eagle Medium) Modified with 10% fetal bovine serum (commercially available from HYCLONE, Logan, UT), lx penicillin streptomycin, lx glutamine, 1 mM sodium pyravate and 400 μg / mL Zeocin (commercially available from Invitiogen)). The VR1-pIND constructs are synthesized from the HEK293-EcR cell line using Fugene teasing reagent (commercially available from Roche Applied Sciences, Basel, Switzerland). After 48 hours, the cells are teased to a Selection Medium (Growth Medium containing 300 μg / mL G418 (commercially available from Invitrogen)). Approximately 3 weeks later, Zeocin / G418 resistant individual colonies are isolated and expanded. In order to identify functional clones, multiple colonies are arranged in 96-well dentio plates and expression is induced for 48 hours using a Selection Medium supplemented with 5 μM ponasterone A ("PonA") (commercially available from Invitiogen). On the day of the assay, the cells are loaded with Fluo-4 (xm calcium-sensitive dye commercially available in Molecular Probes) and the influx of CAP-mediated calcium is measured using a FLIPR, as described below. Functional clones are re-analyzed, expanded and cryopreserved. PH-Based assay: Two days prior to carrying out this assay, the cells were seeded in 96 transparent bottom black plates coated with poly-D-lysine- (commercially available in Becton-Dickinson) at 75,000 cells / originals in a medium of growth containing 5 μM PonA to induce expression. On the day of the assay, plates were washed with 0.2 mL lx Hank's Balanced Salt Solution (commercially available from Life Technologies) containing 1.6 mM CaCl2 and 20 mM HEPES, pH 7.4 ("wash buffer"), and loaded using 0.1 mL of wash buffer containing Fluo-4 (3 μM final concentration, commercially available in Molecular Probes). After 1 hour, the cells were washed twice with 0.2 mL of wash buffer and resuspended in 0.05 mL lx of Hank's Balanced Salt Solution containing 3.5 mM CaCl2 and 10 mM Citrate, pH 7.4 ("test buffer"). The plates were then transferred to a FLIPR for testing. Compound El (a) was diluted in the assay buffer, and 50 mL of the resulting solution was added to the cell plates and the solution monitored for 2 minutes. The final concentration of Compound El (a) ranges from about 50 pM to about 3 μM. An agonist buffer (wash buffer flushed with IN HCl to provide a solution with a pH of 5, 5 when mixed 1: 1 with assay buffer) (0.1 mL) is then added to each original, and the plates incubated for an additional 1 minute. The data is collected on the total time course and using Excel and Graph Pad Prism. When tested according to this protocol, Compound El (a) had an IC50 of 290.7 + 67.4 nM (n = 4). Capsaicin-based assay: Two days before carrying out this assay, the cells were seeded in 96 black transparent bottom plates coated with poly-D-lysine- (50,000 cells / originals) in a growth medium containing 5 μM PonA for induce expression. On the day of the assay, the plates were washed with 0.2 mL lx of Hank's Balanced Salt solution containing 1 mM CaCl2 and 20 mM HEPES, pH 7.4, and the loaded cells using 0.1 mL of wash buffer containing Fluo-4 (final 3 μM).
After one hour, the cells are washed twice with 0.2 mL of wash buffer and resuspended in 0.1 mL of wash buffer. The plates are transferred to a FLIPR for testing. 50 μL of Compound (a), diluted with assay buffer was added to the cell plates and incubated for 2 minutes. The final concentration of Compound El (a) ranges from about 50 pM to about 3 μM. Human VR1 was activated by the addition of 50 μL of capsaicin (400 nM), and the plates were incubated for an additional 3 minutes. The data was collected during the whole period and analyzed using Excel and GraphPad Prism. When tested according to this protocol, Compound El (a) had an IC50 of 92.2 ± 28 nM (n = 3). The results of the pH-based and capsaicin-based assay showed that Compound El (a), an illicitiative Nitro (cyano) vinylpiperazine Compound, binds or binds to and modulates human VR1 activity and, consequently, is useful for tiatar or preventing pain, Ul, an ulcer, D3D or IBS in an animal. The present invention should not be limited in scope by the specific embodiments described in the examples which are intended to illustrate some aspects of the invention and any modalities that are functionally equivalent are within the scope of this invention. Indeed, various modifications of the invention, in addition to those indicated and described in this document, will be apparent to those persons skilled in the art and are intended to be within the scope of the Claims requested. A number of references have been cited, the descriptions of which are completely unaffected to this document by reference. 2 and a pharmaceutically acceptable vehicle.

Claims (12)

    CLAIMS A compound of the formula (I): or xma pharmaceutically acceptable salt thereof, CHARACTERIZED because:
  1. An is Ar2 is R! is -H, -halo, -CH3, -CN, -NO2, -OCH3, -NH2, -C (halo) 3, -CH (halo) 2, or - 'CH2 (halo); each R2 is independently: (a) -halo, -OH, -NH2, -CN, or -NO2; 5 (b) - (C? -do) alkyl, - (C2-C10) alkenyl, - (C2-C10) alkynyl, - (C3-C10) cycloalkyl, - (C8-C14) bicycloalkyl, - (C8-C14) ) tricycloalkyl, - (C5-C8) cycloalkenyl, - (C8-C1) bicycloalkenyl, - (Cs-C14) tricycloalkenyl, - (3- to 7-chain) heterocycle, or - (7- to 10-chain) bicycloheterocycle, each of which is substituted or not with one or more R5 groups; or (c) -phenyl, -naphthyl, - (C14) aryl or - (5- to 10-cells) heteroaryl, each of which 0 is substituted or not with one or more Re graphers; each R3 is independently: (a) -halo, -OH, -NH2) -CN, or -NO2; (b) - (d-C10) alkyl, - (C2-C10) alkenyl, - (C2-C10) alkynyl, - (C3-C1o) cycloalkyl, - (C8- C14) bicycloalkyl, - (C8-C14) tricycloalkyl , - (C5-C10) cycloalkenyl, - (C8-C! 4) bicycloalkenyl, - (C8-C14) tricycloalkenyl, - (3- to 7-well) heterocycle, or - (7- to 10-5-well) bicycloheterocycle , each of which is substituted or not with one or more R5 staples; or (c) -phenyl, -naphthyl, - (C14) aryl or - (5- to 10-cells) heteroaryl, each of which is substituted or not with one or more Re graphers; RA is -H, -CN, -C (O) O (d-C4) alkyl, O -C (O) NH ((d-C4) alkyl); each R5 is independently -CN, -OH, - (C? -Ce) alkyl, - (C2-C6) alkenyl, - (C -0? C6) alkynyl, -halo, -N3, -NO2, -N (R7 ) 2, -CH = NR7, -NR7OH, -OR7, -COR7, -C (O) OR7, -OC (O) R7, -OC (O) OR7, -SR7, -S (O) R7, or -S (O) 2R7; each Re is independently - (d-Ce) alkyl, - (C2-Ce) alkenyl, - (C2-C6) alkynyl, - (C3-C8) cycloalkyl, - (C5-C8) cycloalkenyl, -phenyl, - (3- to 5-carbon) heterocycle, -C (halo) 3, - CH (halo) 2, -CH 2 (halo), -CN, -OH, -halo, -N 3, -NO 2, N (R 7) 2, -CH = NR 7, -NR 7 OH, -OR 7, -COR7, -C (O) OR7, -OC (O) R7, -OC (O) OR7, -SR7, -S (O) R7, or -S (O) 2R7; each R is independently -H, - (d-C6) alkyl, - (C2-C6) alkenyl, - (C2-C6) alkynyl, - (C3-C8) cycloalkyl, - (C5-Cs) cycloalkenyl, -phenyl, - (3- to 5-capes) hetexocycle, -C (halo) 3, -CH (halo) 2, or CH 2 (halo); each Rs is independently - (d-C6) alkyl, - (C2-C6) alkenyl, - (C2-C6) alkynyl, - (C3-Cs) cycloalkyl, - (C5-Cs) cycloalkenyl, -phenyl, - (3 to 5 characters) heterocycle, -C (halo) 3, -CH (halo) 2, -CH2 (halo), -CN, -OH, -halo, -N3, -NO2, -N (R7) 2, -CH = NR7, -NR7OH, -OR7, -COR7, -C (O) OR7, -OC (O) R7, -OC (O) OR7, -SR7, -S (O) R7, or -S (O) 2R7; each halo is independently -F, -Cl, -Br, or -I; m is an integer in a range from 0 to 2; n is an integer in a range from 0 to 3; p is an integer in a range from 0 to 2; q is an integer in a range from 0 to 6; r is an integer in a range from 0 to 5; and s is an integer in a range from 0 to 4.
  2. 2. Compound of formula (11) (U) or a pharmaceutically acceptable salt thereof, CHARACTERIZED because: An is Ax2 is Ri is -H, -halo, -CH3, -CN, -NO2, -OCH3, -NH2, -C (halo) 3, -CH (halo) 2, or CH2 (halo); each R2 is independently: (a) -halo, -OH, -NH2, -CN, or -NO2; (b) - (C? -do) alkyl, - (C2-C10) alkenyl, - (C2-C10) alkynyl, - (C3-C10) cycloalkyl, - (C8-C14) bicycloalkyl, - (C8-C14) tricycloalkyl, - (C5-C8) cycloalkenyl, - (C8-C14) bicycloalkenyl, - (C8-C1) tricycloalkenyl, - (3- to 7-well) heterocycle, or - (7- to 10-well) bicycloheterocycle, each one of which is substituted or not with one or more R5 staples; or (c) -phenyl, -naphthyl, - (C14) aryl or - (5- to 10-cells) heteroaryl, each of which is substituted or unsubstituted with one or more Re groups; each R3 is independently: (a) -halo, -OH, -NH2, -CN, or -NO2; (b) - (C? -do) alkyl, - (C2-C? 0) alkenyl, - (C2-C! 0) alkynyl, - (C3-C10) cycloalkyl, - (C8-C14) bicycloalkyl, - ( C8-C14) tricycloalkyl, - (C5-C? O) cycloalkenyl, - (C8-C14) bicycloalkenyl, - (C8-C14) tricycloalkenyl, - (3- to 7-well) heterocycle, or - (7- to 10) -colds) bicycloheterocycle, each of which is substituted or not with one or more R5 graphers; or (c) -phenyl, -naphthyl, - (C14) aryl or - (5- to 10-well) heteroaryl, each of which is substituted or not with one or more R groups; R 4 is -H, -CN, -C (O) O (CrC 4) alkyl, O -C (O) NH ((d-C 4) alkyl); each R5 is independently -CN, -OH, - (d-Ce) alkyl, - (C2-Ce) alkenyl, - (C2-C6) alkynyl-halo, -N3, -NO2, -N (R7) 2, - CH = NR7, -NR7OH, -OR7, -COR7, -C (O) OR7, -OC (O) R7, -OC (O) OR7, -SR7, -S (O) R7, or -S (O) 2R7; each Re is independently - (d-Ce) alkyl, - (C2-Ce) alkenyl, - (C2-C6) alkynyl, - (C3-C8) cycloalkyl, - (C5-Cs) cycloalkenyl, -phenyl, - (3 - to 5-cells) heterocycle, -C (halo) 3, - CH (halo) 2, -CH2 (halo), -CN, -OH, -halo, -N3, -NO2, N (R7) 2, - CH = NR7, -NR7OH, -OR7, -COR7, -C (O) OR7, -OC (O) R7, -OC (O) OR7, -SR7, -S (O) R7, or -S (O) 2R7; each R7 is independently -H, - (d-Ce) alkyl, - (C2-C6) alkenyl, - (C2-C6) alkynyl, - (C3-C8) cycloalkyl, - (C5-C8) cycloalkenyl, -phenyl, - (3- to 5-carbon) heterocycle, -C (halo) 3, -CH (halo) 2, or CH 2 (halo); each R8 is independently - (C1-Ce) alkyl, - (C2-C6) alkenyl, - (C2-Ce) alkynyl, - (C3-C8) cycloalkyl, - (C5-C8) cycloalkenyl, -phenyl, - (3 to 7 cells) heterocycle, -C (halo) 3, -CH (halo) 2, -CH 2 (halo), -CN, -OH, -halo, -N 3, -NO 2, -N (R 7) 2, -CH = NR7, -NR7OH, -OR7, -COR7, -C (O) OR7, -OC (O) R7, -OC (O) OR7, -SR7, -S (O) R7, or -S (O 2R7; each halo is independently -F, -Cl, -Br, or -I; m is an integer in a range from 0 to 2; n is an integer in a range from 0 to 3; p is an integer in a range from 0 to 2; q is an integer in a range from 0 to 6; r is an integer in a range from 0 to 5; and s is an integer in a range from 0 to 4.
  3. 3. Compound according to Claim 1 or 2, CHARACTERIZED 'because it is - H; Ax! is p or n is 0; month; R! is -halo, -CF3, or -CH3; and Ar2es
  4. 4. Compound according to Claim 1 or 2, CHARACTERIZED because R 4 is -H; Ax! is p or n is 0; month 1; R i is -halo, -CF3, or -CH3; R3 is methyl; and Ar2es
  5. 5. Compound according to any of Claims 3-4, CHARACTERIZED because r is 0 or r is 1 and Ar2 is substituted in its SAP.
  6. 6. Compound according to Claim 5, CHARACTERIZED in that Rs is a group -CF3 or R8 is a group - (C6C6) alkyl, preferably a tert-butyl group. or a zso-propyl group.
  7. 7. CHARACTERIZED composition because it comprises an effective amount of the compound or a pharmaceutically acceptable salt of the compound according to Claim 1 or 2 and a pharmaceutically acceptable carrier.
  8. 8. CHARACTERIZED kit because it comprises a container containing an effective amount of the compound or pharmaceutically acceptable salt of the compound according to Claim 1 or 2.
  9. 9. Method for preparing a composition, CHARACTERIZED because it comprises the step of mixing a compound or a pharmaceutically acceptable salt of the compound according to Claim 1 or 2 and a pharmaceutically acceptable carrier.
  10. 10. Use of a compound or a pharmaceutically acceptable salt thereof according to claim 1 or 2, characterized in that it serves to prepare xm medicament for the treatment of pain, urinary incontinence, ulcer, irritable bowel syndrome or inflammatory bowel disease.
  11. 11. Use of a compound or a pharmaceutically acceptable salt thereof according to claim 1 or 2 characterized in that it serves to prepare xm drug to inhibit VR1 function in a cell.
  12. 12. Use of a compound substantially as demonstrated and illustrated in this document, CHARACTERIZED because it serves for the production of a medicament for the treatment of a condition or disease.
MXPA/A/2006/007565A 2003-12-30 2006-06-29 Piperazines useful for treating pain MXPA06007565A (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
US60/533,037 2003-12-30

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MXPA06007565A true MXPA06007565A (en) 2006-12-13

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