TWI387455B - Use of benzo-fused heterocycle sulfamide derivatives for the treatment of pain - Google Patents

Description

Use of a benzo-fused heterocyclic sulfonamide derivative for the treatment of pain Cross-reference to related applications

The present application claims the priority of U.S. Provisional Application No. 60/751,686, filed on Dec. 19, 2005, and U.S. Provisional Application Serial No. 60/773,812, filed on For reference herein.

Field of the invention

The present invention relates to the use of a benzo-fused heterocyclic sulfonamide derivative for the treatment of acute, chronic, inflammatory and/or neuropathic pain.

Background of the invention

Pain is generally defined as an unpleasant sensation and emotional experience that is accompanied by actual or potential tissue damage (L. Wyman, Advanced in Pain Management, Scrip Report, 2000 ).

Acute pain is a physiological response to harmful chemical, thermal or mechanical stimuli that may be associated with surgery, trauma or acute illness. These symptoms include, but are not limited to, post-operative pain, sports medicine injuries, carpal tunnel syndrome, burns, muscle and bone sprains and strains, muscle and tendon strain, neck and arm pain syndrome, indigestion, gastric ulcer, duodenal ulcer, Kidney stone pain, gallbladder pain, gallstone pain, menstrual pain, endometrial tissue ectopic, obstetric pain, rheumatic pain, headache or toothache.

Chronic pain is a result of a painful condition that exceeds the normal cause of injury or disease and can be an inflamed or severe, progressive, painful disease stage. Various types of chronic pain include, but are not limited to, headache, migraine, trigeminal neuralgia, tibia and mandibular joint syndrome, fibromuscular inflammatory syndrome, osteoarthritis, rheumatoid arthritis, bone pain due to osteoarthritis, bone Osteoporosis, bone metastases or unexplained causes, gout, fibrinitis, myofascial pain, thoracic outlet syndromes, upper back pain or lower back pain (where the back pain is due to systemic, regional or primary) Spontaneous spinal disease (radial root disease), pelvic pain, cardiac chest pain, non-cardiac chest pain, pain associated with spinal cord injury, central post-stroke pain, cancer pain, AIDS pain, sputum Cellular pain or geriatric pain.

Neuropathic pain is defined as a diabetic peripheral neuropathy caused by systemic somatosensory sensation in the peripheral or central nervous system and including pain. Post-herpetic neuralgia, trigeminal neuralgia, post-stroke pain, associated with multiple sclerosis Pain, pain associated with neuropathy, for example, primary or post-traumatic neuropathy and mononeuritis, HIV-related neuropathic pain, cancer-related neuropathic pain, neuropathic pain associated with the wrist duct, Pain associated with spinal cord injury, complex regional pain syndrome, neuropathic pain associated with fibromyositis, lumbar and cervical pain, reflex sympathetic dystrophy, hallucinogenic limb syndrome and other chronic and associated symptoms of weakness Pain syndrome.

There is still a need to provide effective treatment for pain.

Summary of the invention

The present invention relates to a compound of formula (I), Wherein R ¹ and R ² are each independently selected from the group consisting of hydrogen and lower alkyl; R ⁴ is selected from the group consisting of hydrogen and lower alkyl; a is an integer from 1 to 2; Is selected from the group consisting of: Wherein b is an integer from 0 to 4; and wherein c is an integer from 0 to 2; each R ⁵ is independently selected from the group consisting of halogen, lower alkyl and nitro; for or In the case where a is 1; or the use of a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of pain.

The invention further relates to a compound of formula (II) Or the use of a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of pain.

The invention is exemplified by the use of any of the above compounds or pharmaceutical compositions for the manufacture of a medicament for the treatment of pain, wherein the pain is selected from the group consisting of acute pain or chronic pain.

Further exemplifying the invention is the use of any of the above compounds or pharmaceutical compositions for the manufacture of a medicament for the treatment of pain, wherein the pain is inflammatory pain.

Further exemplifying the present invention is the use of any of the above compounds or pharmaceutical compositions for the manufacture of a medicament for the treatment of pain, wherein the pain is neuropathic pain.

The invention further relates to the use of at least one analgesic and a compound of formula (I) or formula (II) as described herein for the manufacture of a medicament for the treatment of pain.

Detailed description of the invention

The present invention relates to a compound of formula (I), Or a pharmaceutically acceptable salt thereof, wherein , a, R ¹ , R ² and R ⁴ are as defined herein for the manufacture of a medicament for the treatment of pain. The invention further relates to the use of at least one analgesic and a compound of formula (I) or formula (II) as described herein for the manufacture of a medicament for the treatment of pain.

The term "pain" as used herein shall be defined to include acute, chronic, inflammatory, and neuropathic pain (preferably diabetic neuropathy). In addition, pain can be transmitted through the central, through the terminal, caused by structural tissue damage, caused by soft tissue injury, or caused by progressive disease. Any pain associated with central referral, peripheral referral, structural tissue damage, soft tissue injury, or progressive disease can be acute or chronic.

Unless otherwise indicated, the pain used herein should include inflammatory pain, centrally induced pain, peripheral-induced pain, visceral pain, structural-related pain, cancer pain, pain associated with soft tissue injury, and progressive Disease-related pain, neuropathic pain, acute pain from acute injury, acute pain from trauma, acute pain from surgery, headache, toothache, back pain (preferably lower back pain), chronic pain from neuropathic symptoms and Chronic pain from symptoms after stroke.

In a specific embodiment of the invention, a method of treating pain, wherein the pain is acute pain. In another embodiment of the invention is a method of treating pain wherein the pain is chronic pain. In another embodiment of the present invention, the method is a method for treating pain, wherein the pain is neuropathic pain, preferably diabetic neuropathy. In still another specific embodiment of the invention is a method of treating pain wherein the pain is inflammatory pain.

In one embodiment, the pain is selected from the group consisting of osteoarthritis, rheumatoid arthritis, fibromyositis, headache, toothache, burns, sunburn, animal bites (eg, dog bites, cat bites, snakes) Bites, spider bites, insect stings, etc.), neurogenic bladder, benign prostatic hypertrophy, interstitial cystitis, rhinitis, contact dermatitis/allergic, itchy, eczema, pharyngitis, mucositis, enteritis, cellulite Inflammation, burning pain, sciatica, mandibular joint neuralgia, peripheral neuritis, polyneuritis, residual limb pain, hallucinal limb pain, postoperative intestinal obstruction, cholecystitis, pain syndrome after mastectomy, oral neuropathic pain, Xia Ke Charcot's pain, reflex sympathetic dystrophy, Guillain-Barre syndrome, paresthesia, oral-burning syndrome, post-herpetic neuralgia, trigeminal neuralgia, peripheral neuropathy , bilateral peripheral neuropathy, diabetic neuropathy, postherpetic neuralgia, trigeminal neuralgia, optic neuritis, post-heat neuritis, transitional Neuritis, ganglion neuritis, Gombault's neuritis, neurocytitis, neck and arm neuralgia, cranial neuralgia, flexural neuralgia, glossopharyngeal neuralgia, migraine neuralgia, primary Sexual neuralgia, intercostal neuralgia, breast neuralgia, Morton's neuralgia, nasal and ciliary neuralgia, occipital neuralgia, red neuralgia, Sluder's neuralgia, spleen Neuropathic pain, neuralgia on the eyelids, pterygoid neuralgia, inflammatory bowel disease, irritating colonic syndrome, labor, childbirth, menstrual cramps, cancer, back pain, lower back pain and wrist ducts Group pain.

Acute pain includes pain caused by acute injury, trauma, disease, or surgery (eg, open-thoracic surgery (including open-heart or bypass surgery)). Acute pain also includes, but is not limited to, headache, post-operative pain, kidney stone pain, gallbladder pain, gallstone pain, obstetric pain, rheumatic pain, toothache or pain caused by sports-medical injuries, wrist Pipeline syndrome, burns, muscle and bone sprains and strains, muscle and tendon strain, neck and arm pain syndrome, indigestion, gastric ulcer, duodenal ulcer, menstrual pain or endometrial tissue ectopic.

Chronic pain includes pain caused by inflammation, osteoarthritis, rheumatoid arthritis, or a sequela of disease, acute injury or trauma. Chronic pain also includes, and is not limited to, headache, upper back pain or lower back pain (selected from back pain caused by systemic, regional or primary spinal pain, bone pain (selected from osteoarthritis, bone mass) Loose, bone metastases or bone pain of unknown origin), pelvic pain, pain associated with spinal cord injury, cardiac chest pain, non-cardiac chest pain, central post-stoke pain, Myofascial pain, cancer pain, AIDS pain, sickle cell pain, geriatric pain or headache, migraine, trigeminal neuralgia, tibia and mandibular joint syndrome, fibromuscular inflammatory syndrome, osteoarthritis, rheumatic joint Pain caused by inflammation, gout, fibrositis or thoracic outlet syndromes.

Neuropathic pain includes pain caused by chronic or incompetent symptoms or diseases. Chronic or incompetent symptoms or diseases that can cause neuropathic pain include, but are not limited to, painful diabetic neuropathy, herpes-posterior neuralgia, trigeminal neuralgia, stroke-posterior pain, and multiple sclerosis-related pain, Neuropathy-related pain such as primary or traumatic-posterior neuropathy and mononeuritis, HIV-related neuropathic pain, cancer-related neuropathic pain, and carpal tunnel-related neuropathy Pain, associated with spinal cord injury-related pain, complex regional pain syndrome, fibromyositis-related neuropathic pain, lumbar and cervical pain, reflex sympathetic dystrophy, hallucinogenic limb syndrome and other chronic and Pain syndrome associated with weakness symptoms.

The term "analgesic" as used herein shall mean any pharmaceutical agent that provides pain relief , including, but not limited to, opium and its derivatives, non-steroid anti-inflammatory agents, Tylenol-like Compounds, compounds administered by NO, TRAMADOL and Tema-like compounds and antidepressants such as amitriptyline. The painkiller should be Temado or Telino.

Suitable examples include, but are not limited to, para-epiaminophen (Acetaminophen); Alfentanil hydrochloride; potassium amide benzoate; sodium amide benzoate; amine benzoguanamine; Meperidine; ampicillin hydrochloride; amine benzene hydrogen Hydrochloride; Anirolac; Antipyrine; Aspirin; Benzene Propionate; Benzydamine hydrochloride; tolyl azabicyclohexane hydrochloride; Briventanil hydrochloride; Bromadolin succinimide ; Bromfenac sodium; Buprenorphine hydrochloride; Butyric acid aniline; Buticiorate; Cyclobutane dihydroxylamine; Cyclobutane dihydroxy tartaric acid; Amidoxime Carbaspirin calcium; Carbiphene hydrochloride; Carfentanil citrate; Ciprefadol succinate; Ciramadol; Lamadohydrochloride; Clonixeril; Clonixin; Methylmorphine; Methylmorphine phosphate; Methylmorphine sulfate; Conorphone hydrochloride ;Cyclazocine; dextroamphetamine II Alkane hydrochloride; Dexpemedolac; Dezocine; difluorosalicylic acid; dihydrocodeine ditartrate; Dimefadane; Dipyrone; Doxpicomine Hydrochloride; Drinidene; Enadoline Hydrochloride; Epirizole; Ergotamine Tartrate; Ethoxazene Hydrochloride; Etofenamate; eugenol; phenoxyproline; phenoxyprofen; fentanyl citrate; fluoroquinoline phenyl ester; Salicylic acid; fluamine nicotinic acid; fluamine nicotinic acid meglumine; flupirtine cis methacrylate; fluproquazone; fluradoline hydrochloride; Fluorobiphenylpropionic acid; hydromorphone hydrochloride; Ibufenac; indole benzoic acid; ketozolyl; Ketorfanol; Ketorolac Amino Alcohol; Letimide hydrochloride; Levomethadyl acetate; L-methadone acetate hydrochloride; Levonantradol hydrogen Compound; Levorphanol tartrate; Lofemizole hydrochloride; Lofentanil oxalate; Lorcinadol; Lomoxicam; water Magnesium sulphate; Mefenamic acid; Menabitan hydrochloride; Meperidine hydrochloride; Meptazinol hydrochloride; Methadone Hydrochloride; Methadyl acetate; Methhopoline; methoxyisodine ; Metkephamid acetate; Mimbane hydrochloride; Mirfentanil hydrochloride; Molinazone; Morphine sulfate; Moxazocine ); piperidine hydrochloride; cyclobutanol hydroperoxide hydrochloride; pentene hydromorphone hydrochloride; Namoxyrate; phenofolone hydrochloride; methoxynaphthalene Acid; sodium naproxate; methoxynaphthol; toluene Oxaloxine hydrochloride; ampicillin hydrochloride; desmethylammonium methoxide hydrochloride; Ocfentanil hydrochloride; oxazolidine; Olvanil; Heptylamine trans-butenedioate; hydroxyhydrocodone; hydroxydihydrocodeinone hydrochloride; hydroxyhydrocodone ketone terephthalate; oxymorphone hydrochloride; Pemedolac; Pentamorphone; Pentazocine; analgesic new hydrochloride; analgesic new lactate; Phenazopyridine hydrochloride; Phenyramidol hydrogen Chloride; Picenadol hydrochloride; Pinadoline; Pirfenidone; Piroxicam Olamine; Pravadoline cis-butene Diacid salt; Prodilidine hydrochloride; Propofol hydrochloride; Propiram trans-butenedonate; Propoxyphene hydrochloride Propyl phenyl naphthalene sulfonate Diazole Diazole citrate; Proxorphan tartrate; Pyrrololiphen hydrochloride; Remifentanil hydrochloride; Salicylate sulphate (Salcolex) ;Salethamide succinimide; salicyl decylamine; salicylate meglumine; salsalate; sodium salicylate; spiradoline Methanesulfonate; thiophene benzoate; thiophene citrate; Tammetacin; flufenic acid ester; flufenicol acetoin; Tazadolene succinate Tebufelone; Tetrydamine; Tifurac sodium; Tilidine hydrochloride; Diopinac; Tonalazole (Tonazocine) methylsulfonate; tramadol hydrochloride; Trefentanil hydrochloride; triethanolamine; Verdoline hydrochloride; Verilopa hydrogen Chloride; Volazocine; Xorphanol methanesulfonate; toluene (Xylazine) hydrochloride; Zenazocine methanesulfonate; Zomepirac sodium and Zucapsacin.

In addition, the analgesic may be a combination product, including, but not limited to, Novartis' FIORICET or Forests' ESGIC or General Name (alignment) A combination of acetaminophen and butalbital and caffeine), FIORINAL or a generic term (aspirin, a combination of bupropion and caffeine, Novartis , MIGPRIV or general term (a combination of aspirin and o-anisamine hydrochloride; Shannuo-Synthetic Experimental Company), MIDRIN/MIDRID or generic term (para-acetamidophenol and dichloralphenazone) Combination; Carney Filling Company), PARAMMAX of Synerto-Experimental Research Company or MIGRAENERTON or General Name of Dolorit Company (combination of para-acetamide and metoclopramide), Abbott Special company VICODIN or general name (combination of para-acetamide and hydrocodone), STADOL NS (butorphanol nasal spray; must-have Squibb Pharmaceuticals), Boehringer Ingelheim LON ARID or Pfizer's MIGRALEVE or generic name (para-acetamide and codeine) Combination) and so on.

The term "individual sputum" as used herein refers to an animal, preferably a mammal, preferably a human, which is a subject of treatment, observation or experimentation.

The term "therapeutically effective amount" as used herein refers to a tissue system that is sought by a researcher, volunteer, doctor or other clinician. The animal or human can respond biologically or medically, including alleviating the disease being treated. Or the amount of active compound or pharmaceutical agent for the symptoms of the disorder.

Wherein, the present invention relates to a co-treatment or combination therapy comprising administering one or more compounds of formula (I) or formula (II) and one or more analgesics, and a therapeutically effective amount of sputum is a combination of agents Extract together to bring the combined effect to the desired amount of biological or medicinal response. For example, a therapeutically effective amount comprising co-treatment of a compound of formula (I) or formula (II) and at least one analgesic agent should be taken together with a compound of formula (I) or formula (II) and at least one analgesic The number of effects when combined or immediately combined is therapeutically effective. In addition, those skilled in the art will be aware of the amount of the compound of formula (I) or formula (II) and/or analgesics in the case of a therapeutically effective amount of co-treatment, such as in the preceding examples. The amount may or may not be individually effective for treatment.

As used herein, co-treatment with sputum and sputum therapy refers to the administration of one or more compounds of formula (I) or formula (II) in combination with one or more analgesics, wherein formula (I) Or a compound of formula (II) and an analgesic agent are administered to a patient in need thereof by a suitable method, simultaneously, sequentially, separately or in a single pharmaceutical formulation. When the compound of formula (I) or formula (II) and the analgesic are administered in separate dosage forms, the number of doses administered to each compound per day may be the same or different. The compound of formula (I) or formula (II) and the analgesic can be administered via the same or different routes of administration. Examples of suitable modes of administration include, but are not limited to, oral, intravenous (iv), intramuscular (im), subcutaneous (sc), transdermal, and anal administration. Compounds may also be administered directly to the nervous system including, but not limited to, intracranial, intraventricular, intraventricular, intraspinal, intracisternal, intraspinal and/or spinal-peripheral routes of administration by intracranial or The intervertebral needles and/or catheters are delivered with or without a pump device. The compound of formula (I) or formula (II) and the analgesic may be administered in parallel or in a single format at the same or different times during the treatment according to similar or altered ingestion methods.

In a specific embodiment of the invention, R ¹ is selected from the group consisting of hydrogen and methyl. In another embodiment of the invention, R ² is selected from the group consisting of hydrogen and methyl. In still another embodiment of the present invention, each of R ¹ and R ² is hydrogen or R ¹ and R ² are each a methyl group.

In a specific example of the present invention, -(CH ₂ ) _a - is selected from the group consisting of -CH ₂ - and -CH ₂ -CH ₂ -. In another embodiment of the invention, -(CH ₂ ) _a - is -CH ₂ -.

In a specific embodiment of the invention, R ⁴ is selected from the group consisting of hydrogen and methyl, and R ^{4 is} preferably hydrogen.

In a specific example of the present invention, a is 1.

In a specific example of the present invention, b is an integer from 0 to 2. In another embodiment of the invention, c is an integer from 0 to 2. In another embodiment of the invention, b is an integer from 0 to 1. In another embodiment of the invention, c is an integer from 0 to 1. In still another embodiment of the present invention, the sum of b and c is an integer from 0 to 2, preferably an integer from 0 to 1. In still another specific embodiment of the present invention, b is an integer from 0 to 2 and c is 0.

In a specific example of the present invention, Is selected from the group consisting of:

In another specific embodiment of the present invention, Is selected from the group consisting of:

In a specific example of the present invention, Is selected from the group consisting of 2-(2,3-dihydro-benzo[1,4] Octyl), 2-(benzo[1,3] Methoxy, 3-(3,4-dihydro-benzo[1,4] Mercapto), 2-(6-chloro-2,3-dihydro-benzo[1,4] Octyl), 2-(6-fluoro-2,3-dihydro-benzo[1,4] Octyl), 2-( Base), 2-(5-fluoro-2,3-dihydro-benzo[1,4] Octyl), 2-(7-chloro-2,3-dihydro-benzo[1,4] Octyl), 2-(6-chloro-benzo[1,3] Methoxy), 2-(7-nitro-2,3-dihydro-benzo[1,4] Octyl), 2-(7-methyl-2,3-dihydro-benzo[1,4] Octyl), 2-(5-chloro-2,3-dihydro-benzo[1,4] Octyl), 2-(6-bromo-2,3-dihydro-benzo[1,4] Octyl), 2-(6,7-dichloro-2,3-dihydro-benzo[1,4] Octyl), 2-(8-chloro-2,3-dihydro-benzo[1,4] Octyl), 2-(2,3-dihydro-naphtho[2,3-b][1,4] Octyl) and 2-(4-methyl-benzo[1,3] Maoji).

In another specific example of the present invention, Is selected from the group consisting of 2-(benzo[1,3] Methoxy, 2-(2,3-dihydro-benzo[1,4] Octyl), 2-(6-chloro-2,3-dihydro-benzo[1,4] Octyl), 2-(7-chloro-2,3-dihydro-benzo[1,4] Octyl), 2-(7-methyl-2,3-dihydro-benzo[1,4] Octyl), 2-(6-bromo-2,3-dihydro-benzo[1,4] Octyl) and 2-(6,7-dichloro-2,3-dihydro-benzo[1,4] Xinji). In another specific example of the present invention, Is selected from the group consisting of 2-(2,3-dihydro-benzo[1,4] Octyl), 2-(7-methyl-2,3-dihydro-benzo[1,4] Octyl) and 2-(6-bromo-2,3-dihydro-benzo[1,4] Xinji).

In a specific example of the invention, R ⁵ is selected from the group consisting of halogen and lower alkyl. In another embodiment of the invention, R ⁵ is selected from the group consisting of chlorine, fluorine, bromine and methyl.

In a particular embodiment of the invention, the stereocenter of the compound of formula (I) is in the S-configuration. In another embodiment of the invention, the stereocenter of the compound of formula (I) is in the R-configuration.

In a particular embodiment of the invention, the compound of formula (I) is present as a mixture enriched in enantiomers wherein the enantiomeric enrichment percentage (% ee) is greater than about 75%, preferably greater than about 90%, more preferably Preferably, it is greater than about 95%, and most preferably greater than about 98%.

In other embodiments of the invention, including those substituents selected for one or more of the variations defined herein (i.e., R ¹ , R ² , R ³ , R ⁴ , X-Y, and A) A subgroup that is independently selected to be any individual substituent or any substituent selected from all of the enumerations defined herein.

A representative series of the compounds of the present invention are shown in Table 1 below. Other compounds of the invention are listed in Table 3. In Tables 1 and 2 below, the column plus the title 〝 stereo is defined as the stereo-configuration of the carbon atoms attached to the heterocyclic ring with an asterisk bond. When no nomenclature is recited, the compounds are made in a mixture of stereo-configurations. When the nomenclature of 〝R〞 or 〝S〞 is cited, the stereo-configuration is based on the starting material enriched in enantiomers.

As used herein, 〝 halogen 〞 shall mean chlorine, bromine, fluorine and iodine unless otherwise indicated.

Unless otherwise indicated, the term "indenyl" used herein, whether used alone or as part of a substituent group, includes both straight and branched chains. For example, alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, second-butyl, tert-butyl, pentyl, and the like. Unless otherwise indicated, when lower hydrazine is used with an alkyl group, it refers to a carbon chain composition having from 1 to 4 carbon atoms.

Unless otherwise specified, the decyloxy oxime used herein shall mean the oxygen ether group of the above linear or branched alkyl group. For example, methoxy, ethoxy, n-propoxy, second-butoxy, tert-butoxy, n-hexyloxy and the like.

The 〝 ^* 〞 used in this article should indicate the presence of a stereocenter.

When a particular group is a hydrazine substituted hydrazine (e.g., alkyl, aryl, etc.), the group may have one or more substituents, preferably from one to five substituents, more preferably from one to three. The radical, preferably one to two substituents, is independently selected from the list of substituents.

With respect to substituents, the term "independently" means that when such substituents may exceed one, the substituents may be the same or different from each other.

The standard nomenclature used throughout this disclosure first describes the terminal portion of the designated side chain, followed by the functionality adjacent to the attachment point. Thus, for example, a fluorenylphenyl-alkyl-amino-carbonyl-alkylhydrazine substituent refers to a group of the formula below.

The abbreviations used in the specification, particularly in the drawings and examples, are as follows: DCC = dicyclohexylcarbodiimide DCE = dichloroethane DCM = dichloromethane DIPEA or DIEA = diisopropylethylamine DMF = N,N-dimethylformamide DMSO=dimethyl hydrazine EDC=ethyl carbodiimide Et ₃ N or TEA=triethylamine Et ₂ O=diethyl ether EA or EtOAc=ethyl acetate EtOH=ethanol IPA =2-propanol Hept=heptane HOBT=1-hydroxybenzotriazole HPLC=high pressure liquid chromatography Separation method LAH=lithium aluminum hydride M or MeOH=methanol NMR=nuclear magnetic resonance Pd-C=palladium on carbon catalyst RP HPLC = reverse phase high pressure liquid chromatography method RT or rt = room temperature TEA = triethylamine TFA = trifluoroacetic acid THF = tetrahydrofuran TLC = thin layer chromatography

When the compound according to the invention has at least one center of the palm, it may therefore exist as an enantiomer. When a compound possesses two or more pairs of palm centers, it may additionally exist as diastereomeric stereoisomers. It should be understood that all such isomers and mixtures thereof are within the scope of the invention. Furthermore, certain crystalline forms of the compounds may exist as polymorphs and will therefore be included in the present invention. In addition, certain compounds may form solvates from water (i.e., hydrates) or common organic solvents, and such solvates will also be encompassed within the scope of the invention.

When used in medicine, the salt of the compound of the present invention means a non-toxic pharmaceutically acceptable salt . However, other salts may also be used in the preparation of the compounds according to the invention or their pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts of such compounds include acid addition salts which may be, for example, by solution of the compound with a pharmaceutically acceptable acid, for example, hydrochloric acid, sulfuric acid, fumaric acid, Formed by mixing a solution of maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid. Further, when the compound of the present invention carries an acidic group, suitable pharmaceutically acceptable salts thereof may include alkali metal salts such as sodium or potassium salts; alkaline earth metal salts such as calcium or magnesium salts; Salts formed with suitable organic ligands, for example, quaternary ammonium salts. Thus, representative pharmaceutically acceptable salts include the following: acetate, besylate, benzoate, bicarbonate, hydrogen sulfate, hydrogen tartrate, borate, bromide, calcium edetate, Camphor sulfonate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, 1,2-ethanedisulfonate, estolate, y Esylate, trans-butenedioate, gluceptate, gluconate, glutamate, ethanol thiolated acid, hexyl resorcinol ), hydrazine, hydrobromide, hydrochloride, hydroxynaphthate, iodide, isothiosulfate, lactate, lactobionate, laurate, malate, cis succinate , mandelic acid salt, methanesulfonate, methyl bromide, methyl nitrate, methyl sulfate, mucic acid salt, naphthalene sulfonate, nitrate, N-methyl reduced glucosamine ammonium salt, oil Acid salt, pamoate (bis-naphthyl salicylate), palmitate, pantothenate, phosphate/hydrogen phosphate, polygalacturonate, salicylate Stearate, sulfate, subacetate, succinate, tannate, tartrate, teoclate, tosylate, triethiodide and valerate.

Representative acids and bases useful in the preparation of pharmaceutically acceptable salts include the following: acids including acetic acid, 2,2-difluoroacetic acid, deuterated amino acids, adipic acid, alginic acid, ascorbic acid, L - Aspartic acid, benzenesulfonic acid, benzoic acid, 4-ethylguanidinobenzoic acid, (+)-camphoric acid, camphorsulfonic acid, (+)-(1S)-camphor-10-sulfonic acid, tannic acid , hexanoic acid, caprylic acid, cinnamic acid, citric acid, cyclohexylamine sulfonic acid, dodecyl sulfate, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydrocyclo-ethanesulfonic acid, formic acid, Trans-butenedioic acid, galactosedioic acid, gentisic acid, glucoheptonic acid, D-gluconic acid, D-glucoronic acid, L-glutamic acid, α-keto-penta Aldehyde, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, (+)-L-lactic acid, (±)-DL-lactic acid, lactulic acid, maleic acid, (-)-L- Malic acid, malonic acid, (±)-DL-mandelic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, Nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, phosphorus , L-pyroglutamic acid, salicylic acid, 4-amino-salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, (+)-L-tartaric acid, thiocyanic acid , toluenesulfonic acid and undecylenic acid; and alkalis including, ammonia, L-arginine, phenethylamine, benzylthio , calcium hydroxide, choline, dansyl alcohol, diethanolamine, diethylamine, 2-(diethylamino)-ethanol, ethanolamine, ethylenediamine, N-methyl-reduced glucosamine, hydrated amine, 1H -imidazole, L-isoamine, magnesium hydroxide, 4-(2-hydroxyethyl)-morpholine, hexahydropyridyl , potassium hydroxide, 1-(2-hydroxyethyl)-tetrahydropyrrole, second amine, sodium hydroxide, triethanolamine, tromethamine and zinc hydroxide.

Compounds of formula (I) can be prepared according to the methods outlined in Scheme 1.

Therefore, a suitably substituted compound of the formula (X), a known compound or a compound prepared by a known method, and a known compound sulfonamide are preferably wherein the sulfonamide is from about 2 to about An amount in the range of 5 equivalents is present in an organic solvent such as THF, In the alkane or the like, it is preferred to carry out the reaction at an elevated temperature in the range of from about 50 ° C to about 100 ° C, more preferably at a reflux temperature, to obtain a compound of the formula (Ia).

Alternatively, a suitably substituted compound of the formula (X), a known compound or a compound prepared by a known method, and a suitably substituted compound of the formula (XI), a known compound or by The compound prepared by the method is reacted in the presence of a base such as TEA, DIPEA, pyridine or the like in an organic solvent such as DMF, DMSO or the like to obtain a compound of the formula (I).

a compound of formula (X) wherein for It can be prepared according to the method outlined in Scheme 2.

Thus, a suitably substituted compound of the formula (XII), a known compound or a compound prepared by a known method (for example, as illustrated in the above Scheme 3) and a known compound NH ₄ OH, The reaction is carried out selectively in an organic solvent such as acetonitrile or the like to obtain a compound of the formula (XIII).

The compound of the formula (XIII) is reacted with an appropriately selected reducing agent such as LAH or the like in an organic solvent such as THF, diethyl ether or the like to obtain a compound of the formula (Xa).

a compound of formula (X) wherein Lined up It can be prepared according to the method outlined in Scheme 3.

Thus, a suitably substituted compound of the formula (XIV), a known compound or a compound prepared by a known method and NH ₄ OH, in the presence of a coupling agent such as DCC or the like, optionally in an organic solvent such as acetonitrile The reaction is carried out in the same manner to obtain a compound of the formula (XV).

The compound of the formula (XV) is reacted with an appropriately selected reducing agent such as LAH or the like in an organic solvent such as THF, diethyl ether or the like to give a compound of the formula (Xb).

a compound of formula (X) wherein Lined up And wherein a is 2, it can be prepared according to the method outlined in Scheme 4.

Thus, a suitably substituted compound of formula (XVI) wherein J ¹ is a suitable cleavage group such as Br, Cl, I, toluenesulfonyl, methanesulfonyl, triflyl Or a known compound or a compound prepared by a known method (for example, by activating a related compound, wherein J ¹ is OH) and a cyanide such as potassium cyanide, sodium cyanide or the like, in an organic solvent, for example. The reaction is carried out in DMSO, DMF, THF or the like to obtain a compound of the formula (XVII).

The compound of the formula (XVII) is subjected to a reduction reaction according to a known method, for example, by a reaction with a suitable reducing agent such as LAH, borane or the like to obtain a compound of the formula (Xc).

a compound of formula (X) wherein Lined up And wherein a is one, it can be prepared according to the method outlined in Scheme 5.

Thus, a suitably substituted compound of the formula (XVIII), a known compound or a compound prepared by a known method is activated according to a known method to obtain a compound of the formula (XIX), wherein J ² is a suitable release group such as tosylate, Cl, Br, I, methanesulfonate, trifluoromethanesulfonate or the like.

The compound of the formula (XIX) and a guanamine salt such as potassium guanamine, sodium decylamine or the like are used in an organic solvent such as DMF, DMSO, acetonitrile or the like, preferably in an elevated temperature ranging from 50 ° C to about 200 ° C. More preferably, the reaction is carried out at about reflux temperature to obtain a compound of the formula (XX).

The compound of the formula (XX) and the known compound N ₂ H ₄ in an organic solvent such as ethanol, methanol or the like are preferably in an elevated temperature ranging from about 50 ° C to about 100 ° C, more preferably about reflux. The reaction is carried out at a temperature or the like to obtain a compound of the formula (Xd).

Those skilled in the art should be able to understand the compounds of formula (X), among them, Lined up , , , , or The same may be carried out according to known methods or, for example, according to the methods outlined in the above Figures 2 to 5, by selecting and substituting the relevant naphthyl-fused compounds of the benzo-fused starting material. preparation.

Those skilled in the art should also appreciate that what is desired is a single enantiomer (or a mixture of enantiomers in which one enantiomer is enriched) of the compound of formula (X), which can be applied as in the previous figures. The methods illustrated in 1 to 5 will replace the relevant single enantiomer (or a mixture of enantiomers enriched in one enantiomer) of the appropriate starting material.

Those skilled in the art will appreciate that the reaction steps of the present invention can be carried out in a variety of solvents or solvent systems, which can also be carried out in a mixture of suitable solvents or solvent systems.

When a mixture of stereoisomers is produced according to the process for the preparation of the compounds of the invention, such isomers may be separated by conventional techniques such as preparative chromatography. Compounds can be prepared in the form of racemates, or individual enantiomers can be prepared by enantiospecific synthesis or by analytical methods. The compound can be resolved, for example, into its constituent enantiomers by standard techniques, for example, by virtue of a photoactive acid such as (-)-di-p-tolyl-yl-D-tartaric acid and/or (+)-Di-p-tolyl-yl-L-tartaric acid forms a salt, followed by formation of diastereomeric stereoisomers by fractional crystallization and re-formation of the free base. The compound can also be isolated by formation of diastereomeric stereoisomers or guanamines followed by chromatography and removal of the palm adjuvant. Alternatively, the compound can be isolated using a palmitic HPLC column.

In any method of preparation of a compound of the invention, it is desirable and/or desirable to protect sensitive or reactive groups on any of the molecules of interest. It can be achieved by conventional methods of protecting groups, such as the protecting groups described in organic chemistry , JFW Mark Omi, Pluto, 1973; and TW Green and PGM Woods, protecting groups in organic synthesis. , John Wiley & Sons, 1991. The protecting group can be removed at a convenient subsequent stage using methods known in the art.

The invention further comprises a pharmaceutical composition comprising one or more compounds of formula (I) and a pharmaceutically acceptable carrier. A pharmaceutical composition containing one or more of the compounds of the present invention as described herein as an active ingredient can be prepared by intimately mixing a compound or a compound having a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier can take a variety of different forms depending on the desired route of administration (e.g., oral, parenteral). Therefore, in the case of liquid oral preparations such as suspensions, elixirs and solutions, suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, stabilizers, colorants, etc.; In the case of oral preparations such as powders, capsules and lozenges, suitable carriers and additives include starches, saccharides, diluents, granulating agents, lubricants, binders, disintegrating agents and the like. Solid oral preparations may also be embedded in a substance such as a sugar embedding or casing to adjust the main site of absorption. For parenteral administration, the carrier will usually include sterile water and other ingredients may be added to increase solubility or preservative. The suspension or solution for injection can also be prepared using aqueous carriers and suitable additives.

In order to prepare the pharmaceutical composition of the present invention, one or more of the compounds of the present invention can be intimately blended as a active ingredient with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques, which can be administered as desired (for example, oral or non-administered). Various types of formulations are used for gastrointestinal administration, such as intravenous administration. Any of the usual pharmaceutical media can be used in the preparation of the oral dosage form of the composition. Therefore, in the case of liquid oral preparations such as suspensions, elixirs and solutions, suitable carriers and additives include water, ethylene glycol, oils, alcohols, flavoring agents, preservatives, coloring agents, etc.; solid oral preparations For example, in the case of powders, capsules, lozenges, gel caps and lozenges, suitable carriers and additives include starch, sugars, diluents, granulating agents, lubricants, disintegrating agents and the like. Because of their ease of administration, lozenges and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. If desired, the lozenges can be embedded in sugar or casing by standard techniques. For parenteral administration, the carrier will usually comprise sterile water, although other ingredients may be included, for example, to aid in dissolution or preservation. An injection suspension can also be prepared, and in this case, a suitable liquid carrier, suspending agent or the like can be used. Each dosage unit of the pharmaceutical composition herein, for example, a tablet, a capsule, a powder, an injection, a teaspoon or the like, contains an amount of the active ingredient which is required to deliver an effective amount as described above. The unit dosage unit of the pharmaceutical composition herein, for example, a tablet, a capsule, a powder, an injection, a suppository, a teaspoon, etc., contains from about 0.1 to 1000 mg and the dose may be from about 0.01 to 200.0 mg/kg/day, preferably from about 0.1 to 100 mg/kg/day, more preferably 0.5-50 mg/kg/day, more preferably 1.0-25.0 mg/kg/day or any range thereof. However, the dosage may vary depending on the needs of the patient, the severity of the condition being treated, and the compound employed. Daily administration or cycle-post administration can be used.

Such compositions are preferably in unit dosage form, such as lozenges, tablets, capsules, powders, granules, sterile parenteral solutions or suspensions, metered aerosol or liquid sprays, drops, ampoules, automatic injection devices Or a suppository; for oral parenteral, intranasal, sublingual or anal administration, or for administration by inhalation or insufflation. Alternatively, the composition may be adapted for a weekly or monthly administration; for example, an insoluble salt of the active compound, such as a decanoate, may be suitable for providing a depot preparation for intramuscular injection. In the preparation of a solid composition such as a tablet, the main active ingredient can be combined with a pharmaceutical carrier such as a conventional tableting ingredient such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, Calcium hydrogen phosphate or gum, and other pharmaceutical diluents, for example, water, are combined to form a solid pre-formulated composition comprising a homogeneous mixture of a compound of the invention or a pharmaceutically acceptable salt thereof. When the pre-formulated composition referred to is homogeneous, it means that the active ingredient is uniformly dispersed throughout the composition so that the composition can be easily separated into equivalent dosage forms such as tablets, tablets, capsules. The solid pre-formulation composition is then divided into unit dosage forms of the type described above containing from 0.1 to about 1000 mg of the active ingredient of the invention. The tablets or tablets of the novel compositions can be either embedded or compounded to provide a dosage form that can be administered for a longer period of benefit. For example, a lozenge or tablet may comprise an inner dose and an outer dose component, the latter being overlaid on the former in the form of a shell. The two components can be separated by allowing the inner component to pass through the enteric layer for combating decomposition in the stomach and allowing the inner component to pass through to contact the duodenum or can be delayed in release. There are a number of materials that can be used on such casing layers or coatings, including many polymeric acids and such materials as insect film, cetyl alcohol and cellulose acetate.

The novel composition of the present invention may be incorporated into a liquid form for oral administration or by an aqueous solution, a properly flavored syrup, an aqueous or oily suspension, and an edible oil such as cotton agar, sesame oil, coconut oil Or an aromatizing agent of peanut oil, as well as an elixir and a similar pharmaceutical carrier for administration by injection. Suitable disintegrants or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextrin, sodium carboxymethylcellulose, methylcellulose, polyvinyl Pyrrolidone or gelatin.

The method of treating depression as described in the present invention can also be carried out using a pharmaceutical composition comprising any of the compounds as defined herein and a pharmaceutically acceptable carrier. The pharmaceutical composition may contain between about 0.1 mg and 1000 mg, preferably from about 50 to 500 mg, and may be of any type suitable for the chosen mode of administration. The carrier comprises the required and inert pharmaceutical excipients including, but not limited to, binders, suspending agents, lubricants, flavoring agents, sweetening agents, preservatives, dyes, and embedding agents. Compositions suitable for oral administration include solid forms such as tablets, lozenges, ellipses, capsules (each comprising immediate release, time release and sustained release formulations), granules and powders, and liquid forms, such as solutions, Syrups, preparations, emulsions and suspensions. Formulations for parenteral administration include sterile solutions, emulsions and suspensions.

The compounds of the invention may advantageously be administered in a single daily dose, or the total daily dose may be administered two, three or four times daily in discrete doses. Further, the compounds for use in the present invention can be administered intranasally via topical administration using a suitable intranasal vehicle, or via a skin patch well known to those skilled in the art. When administered in the form of a transdermal delivery system, the dosage of the entire dose uptake is of course better than the discontinuity.

For example, in the case of oral administration in a lozenge or capsule form, the active pharmaceutical ingredient may be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, ethylene glycol, water, and the like. In addition, suitable binders; lubricants, disintegrants, and colorants may also be incorporated into the mixture when desired or desired. Suitable binders include, but are not limited to, starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium oleate, hard Sodium lactate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like. Disintegrators include, but are not limited to, starch, methyl cellulose, agar, bentonite, xanthan gum, and the like.

The liquid system is formed in a suitably flavored suspending or dispersing agent such as synthetic and natural gums such as tragacanth, acacia, methyl-cellulose and the like. For parenteral administration, sterile suspensions and solutions are desired. When intravenous administration is desired, an isotonic preparation which generally contains a suitable preservative can be used.

Whenever depression is desired, the compounds of the invention can be administered at any time in any of the foregoing compositions and in accordance with established dosage ingestion techniques.

The daily dose of the product can vary from 0.01 to 200 mg/kg per adult per day. When administered orally, the composition is preferably an ingot containing 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 150, 200, 250, 500 and 1000 mg active ingredients. The dosage form provides a symptomatic adjustment dose for the patient to be treated. An effective amount of the drug is generally provided at a dose concentration of from about 0.01 mg/kg to about 200 mg/kg per day. The range is preferably from about 0.1 to about 100.0 mg/kg per day, preferably from about 0.5 mg/kg to about 50 mg/kg, more preferably from about 1.0 to about 25.0 mg/kg of body weight per day. range. The compound can be administered in an ingestion method from 1 to 4 times per day.

The desired dosage administered can be readily determined by those skilled in the art and will vary depending upon the particular compound employed, mode of administration, strength of preparation, mode of administration, and progression of the disease. In addition, factors associated with the particular patient being treated include the patient's age, weight, diet, and time of administration, which may require adjustment of the dosage.

Those skilled in the art will appreciate that both the in vivo and in vitro tests using appropriate, known and generally accepted cellular and/or animal models predict the ability of a test compound to treat or prevent a given disease. .

Those skilled in the art should also be aware that human clinical trials for the first time, dose range and effect tests in healthy human patients and/or those with a given disease may be based on clinical and A method well known in the art of pharmacy is accomplished.

The following examples are presented to aid the understanding of the present invention and are not intended to be in any way intended to limit the scope of the invention as set forth in the appended claims.

Example 1

((3,4-dihydro-2H-benzo[b][1,4]2 Ind-3-yl)methyl)sulfonamide (Compound #3)

Catechol (5.09 g, 46.2 mmol) and potassium carbonate were combined in acetonitrile and heated to reflux for 1 hour. 2-Chloromethyl-3-chloro-1-propene (5.78 g, 46.2 mmol) was added and the reaction was continued to reflux for 24 hours. The solution was cooled to room temperature and filtered. The filtrate was evaporated and the residue was diluted with water and extracted with diethyl ether (3x). The combined organic solution was dried over MgSO ₄ and concentrated. Chromatography (2% diethyl ether in hexane) gave 3-methylene-3,4-dihydro-2H-benzo[b][1,4] Hey.

MS (ESI): 163.2 (M + H +) 1 H NMR (300 MHz, CDCl 3), δ: 6.94 (m, 4H), 5.07 (s, 2H), 4.76 (s, 4H).

3-Methylene-3,4-dihydro-2H-benzo[b][1,4] 呯 (5.00 g, 30.8 mmol) was dissolved in dry THF (100 mL). Borane-THF (1.0 M in THF, 10.3 mL) was added at 0 °C. The reaction was stirred at room temperature for 5 hours. Aminosulfonic acid (6.97 g, 61.6 mmol) was added. The reaction was heated to reflux overnight. The reaction was cooled to room temperature and aqueous sodium hydroxide (3.0M, 100 mL) was then evaporated. The solution was extracted with ethyl acetate (3 x 100 mL). The combined organic solution was dried over MgSO _4. The solution was concentrated in vacuo and purified by chromatography (2% to EtOAc EtOAc) [1,4] two Ind-3-yl)methyl)amine.

MS (ESI): 180.1 (M+H ⁺ ) ^: NMR (M, MH), NMR (M, MH, MH), δ: 6. s (m, 4H), 4.21. (m, 2H), 4.07 (m, 2H) , 3.16 (d, J = 4 Hz, 1H), 2.72 (d, J = 4 Hz, 1H), 2.30 (m, 1H).

Will ((3,4-dihydro-2H-benzo[b][1,4]) Indole-3-yl)methyl)amine (2.90 g, 16.2 mmol) and sulfonamide (3.11 g, 32.4 mmol) combined in anhydrous Acetone (60 mL) was heated to reflux overnight. Chloroform was added and the precipitate was removed by filtration. The filtrate was concentrated in vacuo and purified by chromatography (2% to EtOAc EtOAc)

258.8(M+H ⁺ ) ¹ H NMR (300 MHz, DMSO), δ: 6.92 (m, 4H), 6.71 (wide, 1H), 6.59 (wide, 2H), 4.19 (m, 2H), 4.04 (m) , 2H), 3.00 (m, 2H), 2.39 (m, 1H).

Example 2

N-(2,3-dihydro-benzo[1,4] Oct-2-ylmethyl)-sulfonamide (Compound #1)

Racemic 2,3-dihydro-1,4-benzoic Oct-2-ylmethylamine (4.4 g, 26 mmol) and sulfonamide (5.1 g, 53 mmol) combined in 1,4 The alkane (100 ml) was refluxed for 2 hours. The reaction was cooled to room temperature and a small amount of solid was filtered and evaporated. The filtrate was evaporated in vacuo and the residue was purified eluting elut elut elut The solid was recrystallized from DCM to give the title compound as a white solid.

Melting point: 97.5-98.5 ° C Elemental analysis: Analysis of calculated value: C, 44.25; H, 4.95; N, 11.47; S, 13.13 Measured value analysis: C, 44.28; H, 4.66; N, 11.21; S, 13.15 ¹ H NMR (DMSO d ₆ ) δ 6.85 (m, 4H), 6.68 (bd s, 3H, NH), 4.28 (m, 2H), 3.97 (dd, J = 6.9, 11.4 Hz, 1H), 3.20 (m, 1H) , 3.10 (m, 1H).

Example 3

(Benzo[1,3] II Methyl-2-ylmethyl)sulfonamide (Compound #2)

Combine catechol (10.26 g, 93.2 mmol), sodium methoxide (25 wt% in methanol, 40.3 g, 186 mmol), and methyl dichloroacetate (13.3 g, 93.2 mmol) In anhydrous methanol (100 ml). The solution was heated to reflux overnight. The reaction was cooled to room temperature, acidified by the addition of concentrated hydrochloric acid and then reduced to a volume of about 50 mL under vacuum. Water was added and the mixture was extracted with diethyl ether (3×100 mL). The combined organic solution was dried with MgSO _4, concentrated to a brown solid, and isolated chromatography (2% ethyl acetate in hexanes) to afford a colorless oil of benzo [1,3] Methyl 2-carboxylate.

MS (ESI): 195.10 (M + H +) 1 H NMR (300 MHz, CDCl 3), δ: 6.89 ( wide, 4H), 6.29 (s, 1H), 4.34 (q, J = 7 Hz, 2H), 1.33 (t, J = 7 Hz, 3H).

Benzo[1,3] Ammonium hydroxide (7.21 g, 40.0 mmol) was added with ammonium hydroxide (29% in water, 10 mL) and sufficient acetonitrile to make the mixture homogeneous (~5 mL). The solution was stirred at room temperature for 2 hours and then distilled water was added. a white solid benzo[1,3] The phthalic acid carboxylic acid decylamine was precipitated and collected by filtration and used without further purification.

MS (ESI): 160.00 (M+H ⁺ ) ¹ H NMR (300 MHz, DMSO), δ: 7.79 (s, wide, 1H), 7.72 (s, wide, 1H), 6.94 (m, 2H), 6.86 (m, 2H), 6.30 (s, 1H).

Benzo[1,3] Methyl-2-carboxylic acid decylamine (5.44 g, 32.9 mmol) was dissolved in tetrahydrofuran (THF, 100 mL). Lithium aluminum hydride (LAH, 1 M in THF, 39.5 mL, 39.5 mmol) was slowly added to the solution at room temperature. The reaction was stirred at room temperature for 24 hours. Distilled water was added to destroy excess LAH. Aqueous sodium hydroxide (3.0 M, 100 mL) was added and the solution was extracted with ethyl acetate (3 x 100 mL). The combined organic solution was washed with water and dried over MgSO _4. Evaporating the solvent to give C-benzo[1,3] as a colorless oil Methyl-2-yl-methylamine.

MS (ESI): 152.1 (M+H ⁺ ) ¹ H NMR (300 MHz, CDCl ₃ ), δ: 6.87 (m, 4H), 6.09 (t, J = 4 Hz, 1H), 3.13 (d, J = 4 Hz , 2H).

C-benzo[1,3] Methyl-2-yl-methylamine (2.94 g, 19.4 mmol) and sulfonamide (3.74 g, 38.9 mmol) combined in anhydrous The solution was heated to reflux in EtOAc (50 mL). The reaction was concentrated and the residue was chromatographed (2% to 10%EtOAc)

MS (ESI): 230.0 (M + H +) 1 H NMR (300 MHz, CDCl 3), δ: 6.87 (m, 4H), 6.25 (t, J = 4 Hz, 1H), 4.79 ( wide, 1H), 4.62 (wide area, 1H), 3.64 (d, J = 4 Hz, 2H).

Example 4

(2S)-(-)-N-(2,3-dihydro-benzo[1,4] Oct-2-ylmethyl)-sulfonamide (Compound #4)

Catechol (13.2 g, 0.12 mol) and potassium carbonate (16.6 g, 0.12 mol) were stirred in DMF (250 mL) and (2R)-toluenesulfonyl glycidyl ester (22.8 g, 0.10 Mo) The ear was added and the reaction was stirred at 60 ° C for 24 hours. The reaction was cooled to rt and diluted with EtOAc (EtOAc) (EtOAc) The combined organic solution was washed three times with 10% aqueous potassium carbonate, washed once with water, washed once with brine and evaporated in vacuo to give a white solid, which was purified by flash column chromatography (DCM:methanol-50: 1) Purification to give a solid ((2S)-2,3-dihydro-benzo[1,4] Oct-2-yl)-methanol.

The solid (13.3 g, 68 mmol) was dissolved in pyridine (85 mL) cooled to 0 ° C, p-toluenesulfonium chloride (13.0 g, 68 mmol) was added and the mixture was stirred at room temperature 20 hours. The reaction was diluted with diethyl ether (1 L) and 1N HCl (1.2 L). The organic layer was separated and washed twice with water (150 mL) with 1N HCl (500 mL), washed 4 times, washed once with brine, dried (MgS04 ₄₎ and evaporated in vacuo to give a white solid, which was by flash Purification by column chromatography (Hept: EA-2:1) to give toluene-4-sulfonic acid (2S)-2,3-dihydro-benzo[1,4] Oct-2-ylmethyl ester.

The white solid was combined with potassium decylamine (14.4 g, 78 mmol) in DMF (250 mL) and heated to reflux for 1 hour, cooled to room temperature and poured into vigorously stirring water (1.5 liters) Stir for 30 minutes. The white solid was filtered off and the solid was washed with water, 2% EtOAc EtOAc EtOAc EtOAc 4] two Oct-2-ylmethyl)-isoindole-1,3-dione.

The powdery white solid was combined with EtOAc (EtOAc (EtOAc) (EtOAc) The white solid was filtered and washed with fresh EtOAc (EtOAc) and evaporated and evaporated. Be the diethyl ether solution was dried (Na ₂ SO ₄₎ and evaporated in vacuo to yield a pale yellow oil. The oil was purified by flash column chromatography (DCM: MeOH-10:1) to afford oil. A portion of the oil (4.82 g, 29 mmol) of 2-propanol (250 mL) was taken from 1N HCl (30 mL) and heated on a steam bath until homogeneous and then cooled to room temperature. After 3 hours, the mixture was ice-cooled for 2 hours. White flake solid ((2S)-C-(2,3-dihydro-benzo[1,4]) The HCl salt of oct-2-yl)-methylamine was filtered off and then recrystallized from 2-propanol to give a white solid.

[α] _D =-69.6 (c=1.06, EtOH)

The white solid was distributed between DCM and dilute NaOH, and the DCM was dried (Na ₂ SO ₄₎ and evaporated to yield an oil of (2S) in vacuo -C- (2,3- dihydro - benzo [1 , 4] two Oct-2-yl)-methylamine.

[α] _D = -57.8 (c = 1.40, CHCl ₃ )

Oil (2.1 g, 12.7 mmol) and sulfonamide (2.44 g, 25.4 mmol) in two The mixture was recrystallized from DCM to give a white solid, which was purified by flash column chromatography (DCM: MeOH 10:1). The target compound of the crystalline solid.

Mp _{102-103 ℃ [α] D = -45.1} ° (c = 1.05, M); 1 H NMR (DMSOd 6) δ 6.86 (m, 4H), 6.81 (bd s, 3H, NH), 4.3 (m, 2H), 3.97 (dd, J = 6.9, 11.4 Hz, 1H), 3.20 (dd, J = 5.5, 13.7 Hz, 1H), 3.10 (dd, J = 6.9, 13.7 Hz, 1H).

Elemental analysis: Analysis of calculated values: C, 44.25; H, 4.95; N, 11.47; S, 13.13 Analysis of measured values: C, 44.20; H, 4.69; N, 11.40; S, 13.22

Example 5

N-(2,3-dihydro-benzo[1,4] Oct-2-ylmethyl)-N',N'dimethylsulfonamide (Compound #6)

Racemic 2,3-dihydro-1,4-benzoic Oct-2-ylmethylamine (8.25 g, 5.0 mmol) and triethylamine (1.52 g, 15 mmol) were combined in DMF (10 mL) and dimethylamine sulfonium chloride (1.44) Gram, 10 millimoles) was cooled in an ice bath. The reaction mixture was then stirred with continuous cooling for 3 hours. The reaction mixture was distributed between ethyl acetate and water, and the ethyl acetate solution was washed with brine, dried (MgSO ₄₎ and evaporated in vacuo to produce an oil. The oil was purified by flash column chromatography (ethyl acetate: heptane-1:1) to give a white solid, which was recrystallized (ethyl acetate /hexane) to afford white solid. The target compound.

Melting point 76-78 ° C. MS 273 (MH ⁺ ) Elemental analysis: Calculated: C, 48.52; H, 5.92; N, 10.29; S, 11.78 Analysis: C, 48.63; H, 5.62; N, 10.20; , 11.90 ¹ H NMR (CDCl ₃ ) δ 6.87 (m, 4H), 4.59 (bd m, 1H, NH), 4.35 (m, 1H), 4.27 (dd, J = 2.3, 11.4 Hz, 1H), 4.04 ( Dd, J = 7.0, 11.4 Hz, 1H), 3.36 (m, 2H), 2.82 (s, 6H).

Example 6

N-(2,3-dihydro-benzo[1,4] Oct-2-ylmethyl)-N-methylsulfonamide (Compound #7)

Racemic 2,3-dihydro-1,4-benzoic Oct-2-ylmethylamine (825 mg, 5 mmol) was dissolved in ethyl formate (15 mL), refluxed for 30 min and evaporated in vacuo to give N- (2, 3- Hydrogen-benzo[1,4] Oct-2-ylmethyl)-carbenamide.

The oil containing diethyl ether (25 mL) was taken in EtOAc (EtOAc (EtOAc) The reaction was cooled in an ice-bath and EtOAc (EtOAc)EtOAc The mixture was then stirred at room temperature for 1 hour. The solid was filtered off and the filtrate was evaporated in vacuo to give a crystallite. The aqueous phase was basified with 1N NaOH and extracted with diethyl ether. The organic phase was dried (MgSO ₄₎ and evaporated in vacuo to give an oil of (2,3-dihydro - benzo [1,4] Oct-2-ylmethyl)-methyl-amine.

MS 180 (MH ⁺ ) ¹ H NMR (CDCl ₃ ) δ 6.85 (m, 4H), 4.30 (m, 2H), 4.02 (dd, J = 7.9, 11.6 Hz, 1H), 2.85 (m, 2H), 2.50 (s, 3H).

Combine oil (380 mg, 2.1 mmol) with sulfonamide (820 mg, 8.5 mmol) in two Alkane (15 mL) was refluxed for 1.5 h and evaporated in vacuo to give crude residue. The residue was purified by column chromatography (ethyl acetate / hexanes 1:1), and the obtained solid was recrystallized from ethyl acetate /hexane to give the compound as a white solid.

Melting point 97-98 ° C. MS 257 (M ^-1 ) Elemental analysis: C, 46.50; H, 5.64; N, 10.85; S, 12.41. Analysis: C, 46.48; H, 5.65; N, 10.90; S, 12.07 ¹ H NMR (CDCl ₃ ) δ 6.86 (m, 4H), 4.52 (bs, 2H), 4.46 (m, 1H), 4.29 (dd, J = 2.3, 11.5 Hz, 1H), 4.05 (dd, J = 6.5, 11.5 Hz, 1H), 3.51 (dd, J = 6.7, 14.9 Hz, 1H), 3.40 (dd, J = 5.9, 14.9 Hz, 1H), 2.99 (s, 3H).

Example 7

(2S)-(-)-N-(6-chloro-2,3-dihydro-benzo[1,4] Oct-2-ylmethyl)-sulfonamide (Compound #8)

4-Chlorol catechol was reacted according to the method described in Example 4 above to obtain (2S)-C-(7-chloro-2,3-dihydro-benzo[1,4] Oct-2-yl)-methylamine and (2S)-C-(6-chloro-2,3-dihydro-benzo[1,4] A mixture of oct-2-yl)-methylamine (by RP HPLC, the ratio of 6-chloro:7-chloro isomer is about 3:1).

The mixture was dissolved in 2-propanol (100 mL) and 1N HCl was added in diethyl ether until pH = 1.0. The precipitated hydrochloride was filtered (2.65 g) and recrystallized from methanol/IPA to give white crystals. White crystals were distributed between DCM and dilute NaOH. The DCM was dried and evaporated in vacuo to give purified (2S)-C-(6-chloro-2,3-dihydro-benzo[1,4] Oct-2-yl)-methylamine.

[α] _D = -67.8 (c = 1.51, CHCl ₃ )

Combine oil (7.75 millimoles) and sulfonamide (1.50 grams, 15.5 millimoles) into two The mixture was refluxed for EtOAc (50 mL). The product was purified via flash column using DCM /MeOH 20:1 to yield the title compound as white solid.

MS 277(M ^-1 )[α] _D = -59.9° (c = 1.11, M) ¹ H NMR (CDCl ₃ ) δ 6.90 (d, J = 2.2 Hz, 1H), 6.81 (m, 2H), 4.76 (m, 1H), 4.55 (s, 2H), 4.40 (m, 1H), 4.29 (dd, J = 2.4, 11.5 Hz, 1H), 4.05 (dd, J = 7.1, 11.5 Hz, 1H), 3.45 ( m, 2H).

Elemental analysis: calculated value analysis: C, 38.78; H, 3.98; N, 10.05 Measured value analysis: C, 38.80; H, 3.67; N, 9.99

(2S)-C-(6-Chloro-2,3-dihydro-benzo[1,4] The filtrate of the crystalline hydrochloride hydrochloride of oct-2-yl)-methylamine was recovered (6-chloro: 7-chloro isomer about 1:1) and evaporated in vacuo to give a solid, which was taken in DCM (200 ml ) and distribution between dilute NaOH (0.5M, 50 ml). The DCM solution was washed once with brine, dried (Na ₂ SO ₄₎ and evaporated in vacuo to give an oil, which was to be via reverse phase HPLC (0.16% TFA containing the CNA 10-50% water containing 0.20% of TFA) Purification to give (2S)-C-(7-chloro-2,3-dihydro-benzo[1,4] Oct-2-yl)-methylamine.

Combine the residue with sulfonamide (0.90 g, 9.4 mmol) in two The mixture was refluxed for 2.5 hours in hexanes (25 mL), cooled to room temperature and evaporated in vacuo. The oil was purified by flash column chromatography using DCM/MeOH-10:1 to afford (2S)-(-)-N-(7-chloro-2,3-dihydro as a white solid. -Benzo[1,4] Oct-2-ylmethyl)-sulfonamide.

MS 277(M ^-1 ) ¹ H NMR (CDCl ₃ /CD ₃ OD) δ 6.88 (d, J = 0.7 Hz, 1H), 6.81 (m, 2H), 4.37 (m, 1H), 4.30 (dd, J = 2.3, 11.6 Hz, 1H), 4.04 (dd, J = 7.0, 11.6 Hz, 1H), 3.38 (m, 2H).

Example 8

-2-ylmethylsulfonamide (compound #10)

will 2-carboxylic acid (4.5 g, 25 mmol) and HOBT (3.86 g, 25 mmol) were combined in DCM (40 mL) and DMF (10 mL). Dimethylaminopropylethylcarbodiimide (EDC, 4.84 g, 25 mmol) was added at room temperature and the reaction mixture was stirred for 30 min. Ammonium hydroxide (2.26 mL, 33.4 mmol) was added and the reaction mixture was stirred for 16 h. The reaction mixture was diluted with DCM (50 mL) and water (50 mL) and the pH of mixture mixture was adjusted to about pH = 3.0 with 1 N HCl. The DCM was separated and the aqueous phase was extracted twice with DCM. The combined DCM phases were dried (Na ₂ SO ₄₎ and evaporated to give an oil in vacuo to give an oil, which were purified by flash column chromatography (ethyl acetate).

The oil (5.35 g, 30 mmol) in THF (90 mL) was stirred and then stirred at room temperature for 20 hr. The reaction was quenched with water, stirred for 2 hours, the solution decanted, dried (Na ₂ SO ₄₎ and evaporated in vacuo to give an oily form an amine C- -2-yl-methylamine.

Combine oily amine (1.63 g, 10 mmol) and sulfonamide (1.92 g, 20 mmol) in two The alkane (50 ml) was refluxed for 2 hours. The solution was cooled and evaporated in vacuo to give EtOAc (EtOAc) The solid was recrystallized from ethyl acetate/hexane to give a white solid. -2-yl-methylsulfonamide.

Melting point 100-101 ° C. MS 241 (M ^-1 ) Elemental analysis: C, 49.57; H, 5.82; N, 11.56; S, 13.23 Analysis of measured value: C, 49.57; H, 5.80; N, 11.75; S, 13.33.

Example 9

2-(2,3-dihydro-benzo[1,4]di Oct-2-yl)-ethylsulfonamide (Compound #16)

Potassium cyanide (2.05 g, 31.5 mmol) was added to contain 2-bromomethyl-(2,3 dihydrobenzo[1,4] Xin (6.87 g, 30 mmol) in DMSO (90 mL) and stirred at ambient temperature for 20 hours. The reaction mixture was then diluted with water (250 mL) and twice with diethyl ether. The diethyl ether was washed with water, then washed twice with brine, dried (Na ₂ SO ₄₎ and evaporated in vacuo to give a white solid of methyl 2-cyano - (2,3-dihydro-benzo [l, 4 ]two Xin).

¹ H NMR (CDCl ₃ ) δ 6.89 (m, 4H), 4.50 (m, 1H), 4.31 (dd, J = 2.3, 11.5 Hz, 1H), 4.08 (dd, J = 6.2, 11.6 Hz, 1H), 2.78 (d, J = 6.1 Hz, 2H).

2-cyanomethyl-(2,3 dihydrobenzo[1,4] Oct) was dissolved in THF (50 mL) was added and containing 1M of BH THF ₃ (80 mL, 80 mmol) and the reaction mixture was refluxed for 5 hours, then stirred at ambient temperature for 16 hours. After cooling with an ice bath, 2N HCl was added until pH = 1.0 was reached. The reaction mixture was then stirred at room temperature for 1 hour and evaporated in vacuo to give an oil. The oil between 3N NaOH and diethyl ether distributed, and the diethyl ether solution was washed with brine, dried (Na ₂ SO ₄₎ and evaporated in vacuo to give crude 2- (2,3 dihydrobenzo [1, 4] two Oct-2-yl)ethylamine.

MS (M+H) ⁺ 180.

Will contain crude 2-(2,3 dihydrobenzo[1,4] Octan-2-yl)ethylamine The alkane (100 mL) was combined with sulfonamide (3.0 g, 31 mmol) and heated to reflux for 2 h. The solution was cooled and evaporated in vacuo to give crystals crystals crystals crystals The solid was recrystallized from DCM to give the title compound as a solid.

MS (M-1) 257 mp 101-103 ° C (m.) ¹ H NMR (CDCl ₃ ) δ 6.86 (m, 4H), 4.70 (m, 1H), 4.52 (s, 2H), 4.30 (m, 2H) , 3.94 (dd, J = 7.4, 11.3 Hz, 1H), 3.43 (dd, J = 6.4, 12.9 Hz, 2H), 1.94 (dd, J = 6.5, 12.9 Hz, 2H).

Elemental analysis: Analysis of calculated values: C, 46.48; H, 5.60; N, 10.81; S, 12.41 Analysis of measured values: C, 46.50; H, 5.46; N, 10.85; S, 12.41

Example 10

(2S)-(-)-N-(6,7-dichloro-2,3-dihydro-benzo[1,4] Oct-2-ylmethyl)-sulfonamide (Compound #29)

4,5-Dichlorocatechol (8.6 g, 48 mmol) and potassium carbonate (6.64 g, 48 mmol) were stirred in DMF (200 mL). (2R)-glycidyl sulfonate (9.12 g, 40 mmol) was added and the reaction mixture was stirred at 60 ° C for 24 hours. The reaction mixture was cooled to room temperature and then diluted with EtOAc (EtOAc) The combined organic solution was washed three times with 10% potassium carbonate, washed twice with brine, dried (MgSO ₄₎ and evaporated in vacuo to give (2S) -2- (6,7- dichloro-2,3- Hydrogen-benzo[1,4] Xin) Methanol viscous oil.

(2S)-2-(6,7-dichloro-2,3-dihydro-benzo[1,4] Methanol oil (6.4 g, 27 mmol) was dissolved in pyridine (50 mL) and cooled to 0 °C. Then, p-toluenesulfonium chloride (5.2 g, 27 mmol) was added and the reaction mixture was stirred at room temperature for 20 hours. The reaction mixture was diluted with diethyl ether and be 1N HCl (750 mL) and the organic layer was separated and washed twice with water (150 mL) with 1N HCl (250 mL), washed once, washed twice with brine, dried (MgSO ₄ And evaporating in vacuo to give toluene-4-sulfonic acid (2S)-6,7-dichloro-2,3-dihydro-benzo[1,4] A pale yellow solid of oct-2-ylmethyl ester.

¹ H NMR (CDCl ₃ ) δ 7.79 (d, J = 8.3 Hz, 2H), 7.36 (d, J = 8.0 Hz, 2H), 6.94 (s, 1H), 6.83 (s, 1H), 4.37 (m, 1H), 4.2 (m, 3H), 4.03 (dd, J = 6.3, 11.7 Hz, 1H), 2.47 (s, 3H).

Toluene-4-sulfonic acid (2S)-6,7-dichloro-2,3-dihydro-benzo[1,4] Octan-2-ylmethyl ester (8.0 g, 20.5 mmol) and potassium decylamine (6.1 g, 33 mmol) were combined in DMF (75 mL) and heated to reflux for 1 hour, cooled to room temperature Pour into vigorously stirred water (0.5 L) and then stir for 30 minutes. The white solid was filtered off and the solid was washed with water, 2% EtOAc EtOAc EtOAc EtOAc Dihydro-benzo[1,4] Oct-2-ylmethyl)-isoindole-1,3-dione (6.0 g, 80%).

The white powdery solid was combined with hydrazine (1.06 g, <RTI ID=0.0>> 1N HCl was added to adjust the pH of the reaction mixture to pH 1.0 and then the reaction mixture was stirred for 15 min. The white solid was filtered and taken up in EtOAc EtOAc (EtOAc)EtOAc. The diethyl ether solution was dried (Na ₂ SO ₄ ) and evaporated in vacuo to give (2S)-2-aminomethyl-(6,7-dichloro-2,3-dihydro-benzo[1,4 ]two Xin) viscous oil.

¹ H NMR (CDCl ₃ ): δ 6.98 (s, 1H), 6.96 (s, 1H), 4.25 (dd, J = 2.0, 11.2 Hz, 1H), 4.15 (m, 1H), 4.0 (m, 1H) , 2.97 (d, J = 5.5 Hz, 2H).

A portion of the oil (3.8 grams, 16 millimoles) and sulfonamide (3.1 grams, 32.4 millimoles) in two The alkane (100 ml) was refluxed for 2 h and the crude was purified by flash column chromatography (DCM:MeOH 20:1) to afford Recrystallization from hexane gave the title compound as a white crystalline solid.

MS[M-H] ^- 311.0 mp 119-121 ° C [α] _D = -53.4 (c = 1.17, M) ¹ H NMR (DMSOd ₆ ): δ 7.22 (s, 1H), 7.20 (s, 1H) , 6.91 (bd s, 1H), 6.68 (bd s, 2H), 4.35 (m, 2H), 4.05 (dd, J = 6.5, 11.5 Hz, 1H), 3.15 (m, 2H).

Elemental analysis: Analysis of calculated values: C, 34.52; H, 3.22; N, 8.95; Cl, 22.64; S, 10.24. Found: C, 34.64; H, 2.68; N, 8.87; Cl, 22.94; S, 10.35.

Example 11

(2S)-(-)-N-(7-Amino-2,3-dihydro-benzo[1,4] Oct-2-ylmethyl)-sulfonamide (Compound #36)

(2S)-(-)-N-(2,3-dihydro-7-nitro-benzo[1,4] Oct-2-ylmethyl)-sulfonamide (1.2 g, 4.15 mmol) was prepared from 4-nitrocatechol according to the procedure described in Example 4. Then (2S)-(-)-N-(2,3-dihydro-7-nitro-benzo[1,4] Oct-2-ylmethyl)-sulphonamide was combined with 10% Pd/C in methanol (120 mL) and was shaken under hydrogen (39 psi) at room temperature for 3 hours. The solid was filtered and washed with EtOAc (EtOAc)EtOAc The crude product was dissolved in 0.2N EtOAc (25 mL).

MS (M+H) ⁺ 260 ¹ H NMR (DMSO d ₆ ): δ 10.2 (bd s, 3H), 6.86 (m, 1H), 6.85 (s, 1H), 6.74 (dd, J = 2.5, 8.4 Hz, 1H ), 4.22 (m, 2H), 3.88 (dd, J = 6.7, 11.4 Hz, 1H), 3.04 (m, 2H).

Example 12

(2S)-(-)-N-(7-methyl-2,3-dihydro-benzo[1,4] Oct-2-ylmethyl)-sulfonamide (Compound #19)

The title compound was prepared according to the method described in Example 4 above, starting from 4-methyl catechol to give a white solid, which was recrystallized from ethyl acetate/hexane to give the compound as a white solid. .

MS[M-H] ^- 257 ¹ H NMR (CDCl ₃ ): δ 6.76 (m, 1H), 6.66 (m, 2H), 4.80 (m, 1H), 4.57 (bd s, 1H), 4.40 (m, 1H), 4.28 (m, 1H), 4.03 (dd, J = 6.9, 11.4 Hz, 1H), 3.45 (m, 2H), 2.25 (s, 3H).

Elemental analysis: Calculated value analysis: C, 46.50; H, 5.46; N, 10.85; S, 12.41. Found: C, 46.65; H, 5.60; N, 10.84; S, 12.61.

Example 13

The Little Mouse Formalin Analysis (NINDS) Miniature Mouse Famaline Test is an acute and chronic mode used to test the ability of test compounds to treat pain.

In the small mouse fumarin test, 0.5% fumarin was injected subcutaneously into the ankle area of the hind paw of an adult male mouse to induce a pain response mediated by inflammatory. Pain was expressed in a two-mode manner - the acute and chronic mid-injection zone. The acute phase occurs immediately after injection and lasts for approximately 20 minutes, representing direct stimulation of pain fibers. After about 10 minutes (~20 minutes after injection), the sputum behavior begins for 10-15 minutes, representing the chronic phase, assuming that it is caused by the release of an inflammatory mediator such as cytokines.

The activity in the acute phase of the formalin test is considered to be consistent with the peripheral pain pathway and is an indicator of acute pain. The activity in the chronic phase of the formalin test represents the centralization and sensitization of pain in the path of higher pain and has demonstrated efficacy and chronic neuropathic pain in the Bennett chronic obstructive mode with neuropathic pain. The clinical efficacy is quite consistent (Viers et al., 2003).

Compound #8 was evaluated in the Famaline test of the small mouse as described above. Compound #8 was administered intraperitoneally at 110 mg/kg 15 minutes prior to the injection of formalin and a significant decrease in acute and chronic phase response was observed. In the acute phase, it was 52% lower than the control group (p<0.01), while the chronic phase was 43% lower than the control group (p<0.01). Compound #8 showed similar analgesic activity when administered intraperitoneally at 60 mg/kg, which was 30% lower in the acute phase than in the control group (p<0.05) and 40% lower in the chronic phase than in the control group (p<0.01). %.

Therefore, in this analysis, Compound #8 has analgesic activity, particularly regarding acute and chronic inflammatory pain.

Example 14

Big mouse model of neuropathic pain The Big Mouse model is used to determine whether a compound has an analysis for the treatment of neuropathic pain (Jin and Chung, 1994; Chapland et al., 1994).

In this study, male Sprague Dawley rats (145-165 g, Harlan) were anesthetized and L5 nerves were isolated and ligated with silk material to cause mechanical dissociation pain. After six weeks of ligation, the rats were orally administered with a vehicle (0.5% aqueous solution of methylcellulose) or compound #8 120 and 240 mg/kg. Mechanical (tactile) dissociation pain was administered for 30 minutes, and after 1, 2, 4, 6, 8, and 24 hours, the affected paws were recorded and quantified from the pressure of the graded stimulus (Farfoley). The results were normalized and the results were expressed as % MPE (maximum protective effect) of the drug.

Oral treatment with Compound #8 120 mg/kg resulted in a 42% increase in %MPE relative to control animals. The effect was observed at 30 minutes, peaked at 1 hour and continued 4 hours after dosing. Oral treatment with Compound #8 240 mg/kg resulted in a 66% increase in %MPE relative to control animals. The effect was observed at 30 minutes, peaked at 2-4 hours and continued 4 hours after dosing. (The large mice treated with the vehicle have no effect.)

It should be noted that in this analysis, gabapentin was orally administered at 480 mg/kg as a positive control group. The effect of carbapanidine was equivalent to the activity of Compound #8 administered at 240 mg/kg.

Therefore, in this analysis, Compound #8 has analgesic activity, particularly regarding chronic inflammation and/or neuropathic pain.

Example 15-18

Lumbar 5 of the neuropathic pain (L5) Spinal nerve ligation (Chung's) model The large mouse Chung's model is used to determine whether the compound has an analysis for the treatment of neuropathic pain (Jin and Chung, 1994; Chapland et al., 1994) ). In this analysis, the injury to the sciatic nerve was caused by loosening the ligated chromosomal suture of the ligature, tightening the L5 spinal nerve with a silk suture or tightening the wire with a silk thread, resulting in a number of stimulating sensations for several weeks. Allergies (eg, contact, stress, temperature) occur for several months. The heterosexual pain and hyperalgesia observed in the clinical conditions of neuropathic pain caused by mechanical nerve damage, diabetes, and chemotherapy caused by such injuries are reminiscent. This analysis predicts the analgesic, anti-heterostatic and/or anti-hyperalgesic effects of the test compound.

Test compounds and control groups were dissolved in an appropriate volume of 0.5% HPMC or 10% Solutol in 0.5% hydroxypropyl methylcellulose (HPMC). HPMC was used as a carrier in the preparation of carbapantin solution (as a positive control group). The solution was prepared to provide a final dose of 2.5 ml/kg or 5 ml/kg for oral administration to large mice. Will be obtained from Harlan Industries (Indian Napoli, Indiana) weighing 150 to 250 grams for males of surgery, and Spark-Dawley rats for L ₅ SNL studies.

All animals have a weekly quarantine/environmental adaptation period prior to transfer to a common storage room. The large rats in the SNL study were housed and tested in the same room. Animals were housed in small-isolated cages, four large mice per cage or five small mice per cage, with corn shaft bedding and free access to food and water. The environment is maintained at a constant temperature of 21 ° C and a 12-hour light/dark cycle. Large rats undergoing L ₅ SNL surgery were placed in individual cages with alpha dry bedding and free access to hearty food, food pellets and water. Animals were allowed to recover for four to six weeks after surgery and no trials were performed after more than eight weeks of surgery. L ₅ SNL testing at the time, only the pressure response is below 4 g in animals comprising further testing and analysis, and the date of the study were randomly divided into treatment groups. In all of the trials, the investigator who performed the behavioral analysis was completely unaware of the administration of any individual animal.

At L ₅ SNL surgery, large rats were induced and maintained on isoflurane inhalation anesthetics. L ₄ -S n to the left of the midline on the back surface of the vertebral cut 2- ₂ cm skin incision, followed by separation of the muscles from the spinal side of the cable in the ratchet projections (process). Then carefully removed transverse projection of L ₆ and L ₅ spinal nerve was confirmed. Then left L ₅ spinal nerve was tightly enclosed with 6-0 silk thread, the muscle with 4-0 suture Vic, and adhesion with the skin to be wound clips.

Behavioral tests done at a time between 3-6 weeks after ligation of the rat L ₅ SNL. Research to date, the large L ₅ SNL rats orally with vehicle, Compound # 8 or Kabapanting (as a positive control), based on the baseline where Frey assay to confirm the presence of mechanical pain decapitated. Tactile ectopic pain was recorded at 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, and/or 24 hours after administration. Paws from the ipsilateral side of the ligated nerve were administered from a series of calculated Favre lines. (0.4, 0.7, 1.2, 2.0, 3.6, 5.5, 8.5, and 15.1 grams, Stodoin, Wooldale, Ill.) quantified the strength of retraction. Starting at moderate stiffness (2.0 grams), a fine line was applied to the hind paw - ankle for about 5 seconds. A slight retraction of the paw results in a milder one stimulus presentation and a lack of a retraction response resulting in a stronger next stimulus to determine the response threshold. A total of four responses were obtained after the first threshold detection. The 50% retraction threshold is interpolated by the Dickson method (eg, TF. Merter and HA. Vermeer, Pharmacology, Biochemistry, Behavior; 2005, 80(2), pp. 309-326) And when the response threshold falls above or below the detection range, it is specified as a value of 15.0 or 0.25 gram, respectively.

Threshold data from the Van Fleel thin line test is recorded in grams back to the threshold or according to the formula: %MPE = [(post-dose threshold) - (baseline threshold)] / [(15-gram break value) - (baseline Threshold)] x 100 is converted to the maximum possible effect percentage (%MPE). The effective dose (ED ₅₀ ) that produced the 50% effect and related statistics were calculated using the PharmTools Plus software (Mark Cali Group). Statistical analysis of acetic acid analysis (double-direction ANOVA) was calculated using Graph Pad Prism v4.0. Data from time course studies in the SNL model derived from neuropathic pain were analyzed by individual-intra, repeated assays, single-to-ANOVA. A significant main effect (p < 0.05) was further analyzed using the Dunnett multiple comparison test. Data are presented as mean +/- SEM below. The results of many studies are detailed below.

Example 15/Study A : In the first study, Compound #8 was evaluated at 120 mg/kg and 240 mg/kg and compared with carbapenetine at 480 mg/kg and vehicle.

In the untreated rats, the mean retraction threshold was greater than 13 grams, and after 6 weeks of surgery, the retraction threshold was between 1.0 and 1.6 grams. The vector did not change the retraction threshold during the four hour study period.

The dose of 480 mg/kg carbapandin was significantly increased at 1 hour, 2 hours, and 4 hours after administration (73.2 ± 14.7 and 73.7 ± 16.6% were reversed at 2 hours and 4 hours, respectively). The effect of Compound #8 administered at 120 mg/kg was slightly lower than that observed with carbapantin, but after 1 hour (42.2 ± 13.8% reversal) and 4 hours (45.4 ± 12.2% reversal) after oral administration The baseline (time 〝0〞) is significantly different. The effect produced by the administration of 240 mg/kg of Compound #8 (65.6 ± 21.1% changed at 4 hours) was similar to that observed with carbapantin (73.4 ± 15.2 at 4 hours). Thus, both carbapantin and Compound #8 significantly increased the retraction threshold at 2 hours, 4 hours, and 6 hours after oral administration. The effect of the 8-hour effect was small and similar to the value of 24 hours after drug-treated treatment.

Example 16/Study B : In the second study, Compound #8 was administered daily for up to 7 days to assess whether subchronic administration would change the retraction threshold. Three weeks after surgery, baseline tactile hypersensitivity was assessed. Large rats were randomly divided into 5 groups and received vehicle (HPMC), compound #8 at 60 mg/kg, 120 mg/kg, 240 mg/kg or 480 mg/kg. The retraction threshold is 1 hour, 2 hours, 4 hours, 8 hours and 24 hours after the first day (starting dose), the third day (third dose) and the seventh day (seventh dose). to evaluate.

After the first dose of 480 mg/kg of compound #8, tactile hypersensitivity was significantly reversed and a peak effect occurred 4 hours after administration (64.3 ± 9.9% reversal). Although the lower dose of Compound #8 had a non-statistically significant trend in reversing the hypersensitivity, no significant differences were observed at this time point in the other treatment groups. At the time of administration on the third and seventh days, none of the treatment groups showed significant reversal of tactile hypersensitivity.

Example 17/Study C: In the third study, Compound #8 was orally administered at 100 mg/kg, 300 mg/kg and 560 mg/kg, and carbapenet was administered at 560 mg/kg as positive. The control group and mechanical dissociative pain were measured 2 hours, 4 hours and 6 hours after administration at the 4th week after surgery.

In this study, oral administration of Compound #8 at 100 mg/kg, 300 mg/kg or 560 mg/kg for 6 hours did not show a statistically significant effect. Compared with baseline, the results of administration of carbapenen 560 mg/kg (positive control group) were observed after mechanical administration (reversed 58.7 and 86.4%, respectively) at 2 hours and 4 hours. Reduced, but not 6 hours after administration. (It should be noted that this behavior with carbapandin does not seem to match the behavior of carbapantin expected in the Chung model).

Example 18/Research D : In the fourth study, Evaluation Compound #8 was used at a dose of 560 mg/kg using an effect containing 10% solitolite in HPMC solution. Carbapestine was administered as a positive control group at 560 mg/kg and mechanical dissociation pain was determined at selected time points up to 6 hours after administration.

Four weeks after the surgery, the vehicle (10% solubil in HPMC), Compound #8 was orally administered to mega-mouse at 560 mg/kg or carbapenen at 560 mg/kg. In this study, the vehicle produced a statistically significant increase in tactile allergy during the study compared to baseline, whereas carbapandin produced statistically on tactile allergy between 2 and 6 hours after dosing. Significantly reduced (55 to 77% reversal). The reduction in sensitivity at 4 hours and 6 hours after administration of Compound #8 large mice had a non-statistically significant trend. More specifically, oral treatment with Compound #8 at 560 mg/kg showed a reduction in mechanical dissociation pain at 4 hours and 6 hours after administration, but p=0.054.

It should be noted that the effects of the positive control group are varied in the Zhong's mode as described in the previous description. Therefore, the effect of Compound #8 should be interpreted in any given study with positive control responses in this paper.

Example 19

By Taxol Models of peripheral neuropathy induced by peripheral neuropathy are chronic symptoms of nerve damage caused by traumatic injury, disease, metabolic insufficiency, or by certain drugs and poisons. Sensory disorders and chemotherapeutic agents, for example, paclitaxel (Taxol) Related, ranging from a slight sting to spontaneous burning, typically in the hands and feet. Continued treatment makes the symptoms more intense and can lead to weakness, movement disorders, paralysis and pain, which can take weeks to months to eliminate.

In the experimental study, the evaluation of compound #8 was reduced by Taxol - the ability to induce mechanical dissociation pain and neurodegeneration of the sciatic nerve (RC. Polomano, AJ. Mannes, US. Clark, GJ. Bennett. Produced by chemotherapeutic agent, paclitaxel in mice) Painful peripheral neuropathy. Pain, 94: 293-304, 2001; SJL Furat, W-H Shaw, GJ Bennett. Acetyl-L-carnitine prevents and reduces pain induced by paclitaxel Peripheral neuropathy, Neuroscience 397: 219-223, 2006). In addition, the effect of the compound on the spontaneous movement activity was measured.

METHODS : Male Spock-Dawley rats (from Harlan Spark Dodley, 7 weeks old) were divided into two treatment groups (n=10/group): the first group used 2 mg/kg Taxol Transdermal treatment via intraperitoneal +0.5% HPMC (hydroxypropyl methylcellulose) carrier; second dose with 2 mg/kg Taxol Transdermally via intraperitoneal + 100 mg/kg Compound #8 (in HPMC vector). Animals were housed in polycarbonate plastic cages, 2 animals per cage, at 18-26 ° C, 30-70% humidity, 12-hour light/dark cycle, free access to food and water.

On days 1, 3, 5, and 7, mice received an intraperitoneal (intraperitoneal) injection of Taxol. (2 mg / kg). In addition, for the injection of Taxol Animals were started daily with po (oral) administration of Compound #8 or vehicle for 12 days.

Two behavioral tests were performed: tactile sensitivity and determination of spontaneous mobility. Animals at baseline and Taxol On the 5th and 12th day after the injection, the Van Frey test was performed to determine mechanical dissociation pain (according to SR. Chapland, FW. Baha, JW. Bogley, JM. Chung, TL. Quantitative assessment of tactile allodynia in rats' ankles, Journal of Neuroscience Methods, 53:55-63, 1994). Tactile sensitivity (i.e., mechanical dissimilar pain) is determined using a calculated fine line contacting the ankle surface of the affected limb to determine the paw retraction threshold. Briefly, mice were placed in a resin glass cage with a metal wire bottom and allowed to adjust for 10 minutes. Once the animal is ready, the sole surface of the right hind paw is contacted with a 2.0 gram vane line. When the paw does not have a retracting response to the initial selection of the thin line, a strong stimulus is present; if the paw is retracted, the next stimulus is selected to be weaker. In this fashion, the positive and negative response patterns that are generated are used to determine the paw retraction threshold. Data were analyzed using a two-way ANOVA, single-to-ANOVA and Duned's multiple comparison test with statistical significance at p < 0.05.

On the 11th day, Taxol After the start of the injection, the animals were subjected to an open space test to determine the degree of motor activity. Previous research has shown Taxol Treatment can result in reduced spontaneous mobility (eg, number of beam crossings) (D. Basco, C. Gecoya, M. Suyaz, MI. Martin. Cannabinoid agonist, WIN 55, 212-2, reduced neuropathic sensation induced by paclitaxel in mice. Pain 118: 23-34, 2005). The open space test was conducted by placing the animal in a 17" x 17" open chamber with an infrared light strip around the wall of the chamber. The light strip transmits the infrared beam of light to automatically record the movement (moving) and vertical (the hind legs standing up) of the animal every 100 milliseconds with a beam break. At the time of the study, the degree of mobility of the animals was recorded over a 20 minute period to assess the spontaneous activity in the new environment. Data were analyzed using one-way ANOVA and Duned's test and were statistically significant at p < 0.05.

On day 13, the animals were killed by carbon dioxide asphyxiation. The sciatic nerve and right hind paw were excised and placed in 10% neutral buffered formalin. The harvested tissue was cut into large pieces, embedded in paraffin, sectioned and stained with hemotoxylin and eosin. The tissue was examined using light microscopy and counted by an assessor who was blind to the treatment intake. The tissue is arranged on a scale of 0 to 3 of the degree and number of body axis divisions observed in the section, 0 is the normal body axis appearance, 1 to 2 is a slight to moderate body axis division and 3 is complete Splitting and body axis of Waller's degeneration (G. Cavaletti, G. Tridis, M. Braka, S. Tasari, by taking Taxol Repeated intraperitoneal administration to experimental peripheral neuropathy induced in adult mice. Experimental Neurology 133: 64-72, 1995). Data were analyzed using single-to-ANOVA and Duned's test and were statistically significant at p < 0.05.

RESULTS : Mechanical dissociative pain was at baseline, Taxol It was measured on the 5th day and the 12th day after administration. There were no significant differences between the groups at baseline or day 5; however, on day 12, compared to baseline responses, to Taxol (p<0.05) alone and Taxol Each group treated with +100 mg/kg Compound #8 (p < 0.001) was more pain-sensitive. With Taxol On a separate basis, Compound #8 appeared to be more effective in responding to pain; however, this difference was not statistically significant.

Spontaneous mobile activity is initiated at the administration of Taxol The test was carried out on the 11th day. There is no difference between treatment groups when moving horizontally; however, with Taxol Individual comparison, by Taxol + Compound #8 (p < 0.05) treated animals exhibited a reduced vertical hind leg erect.

The right hind paw and the sciatic nerve were sectioned for histopathological evaluation. Compound #8 in Taxol There was no effect on the severity of the induced right hind paw degeneration; however, although the difference was not statistically significant, there was a positive trend in reducing the degeneration in the sciatic nerve.

Discussion : Conduct a pilot study to evaluate the efficacy of Compound #8 on pain, movement changes, and nerve damage, as available by Taxol The result of the induced peripheral neuropathy. Typically, via Taxol The treated mice were evaluated several weeks after the injection because the mechanical dissociation pain was caused by Taxol. Occurs at any time between the 12th and 21st days after administration. In this study, the efficacy of the compound was in Taxol. The evaluation was performed on days 5 and 12 after administration, and the study period was shorter than the previously disclosed investigators; however, it should be noted that significant heterosexual pain may occur within this time frame.

The result shows the use of Taxol Treatment developed mechanical dissociation pain on day 12, although the extent of the effect was not complete (baseline: 16.42 ± 2.14 g, day 12: 12.11 ± 4.92 g). However, Compound #8 was not effective at preventing dissociation pain at the same time point. This result is considered inconclusive. Increase the duration of the study to show more obvious Taxol Effect and the protective effect of Compound #8. In addition, it should be noted that the positive control group is not included in the study.

Assessment of open space behavior indicated that mice treated with Compound #8 had reduced hind leg erect behavior, with Taxol When comparing individual, point to a lower degree of spontaneous vertical exploration. However, because of the level of horizontal activity, the compound #8 handler and Taxol There is no difference between the individual treatments, and the pain or sedation may not be the reason for the lower hind legs to stand upright. Histopathological analysis revealed that treatment of sciatic nerve injury with compound #8 had a tendency to decrease; however, it was not statistically significant.

All in all, this preliminary study showed that Compound #8 in mice can be confronted by Taxol The beneficial effects of induced peripheral neuropathy. It is recommended that follow-up studies should include longer Taxol The multiple administration concentration (eg, dose-response curve) of the test period (eg, ~6 cycles) and compound #8 after administration.

Example 20

By Taxol Models of peripheral neuropathy induced by peripheral neuropathy are chronic symptoms of nerve damage caused by traumatic injury, disease, metabolic insufficiency, or by certain drugs and poisons. Sensory disorders and chemotherapeutic agents, for example, paclitaxel (Taxol) Related, ranging from a slight sting to spontaneous burning, typically in the hands and feet. Continuous treatment makes the symptoms more intense and can lead to weakness, movement disorders, paralysis and pain that can take weeks to months to eliminate.

The use by Taxol The second of the induced peripheral neuropathy patterns, the longer-term study was completed as a follow-up to the preliminary study as illustrated in Example 19 above.

Method : Pacific Paclitaxel (Taxol) , must be treated with Squibb Pharmaceuticals; 6 mg / ml in a 50:50 mixture of Cremophor and ethanol) diluted to 2 mg / ml with saline before use and at 4 ml / kg in four intervals (D0, D2, D4 and D6) were injected intraperitoneally. Compound #8 was suspended in 0.1 N HCl: 0.5% methylcellulose (1:9) at a concentration of 60 mg/ml and 120 mg/ml immediately prior to each injection.

Adult male Spock-Dawley mice (Harlan, Indianapolis, Indiana; Frederick, MD stocking community) were placed in a cage of sawdust with 3-4 pairs , free access to food and water and a 12:12 hour light-dark cycle.

The paclitaxel-treated animals were divided into three groups, each group n=12: Group 1 was treated with Compound #8 at 60 mg/kg, and oral (oral feeding) for 20 days per day, starting on day D0 ( Same as the date when paclitaxel started to be administered). On days when both Compound #8 and Pacific Paclitaxel were administered, Compound #8 was administered at 0900 hours and the paclitaxel system was administered at 1300 hours.

Group 2 was treated with Compound #8 at 120 mg/kg, orally (orally), daily, starting on day D0 (same date as the start of paclitaxel administration). On days when both Compound #8 and Pacific Paclitaxel were administered, Compound #8 was administered at 0900 hours and the paclitaxel system was administered at 1300 hours. The third group was treated with an equal amount of vehicle, starting daily on day D0 (same date as starting paclitaxel).

Animals were accustomed to the test environment on three separate days and then three daily baseline periods were administered to determine the normal response rate for the application of 4 or 15 grams of pressure Flemish hair stimulation (4 grams of VFH and 15 grams of VFH). Normal mice are rare, if any, retracted from a stimulus with 4 grams of VFH; therefore, paclitaxel, which is increased in response to this stimulus, is an indication of mechanical dissociation pain after administration. Normal mice were retracted from 10-20% of the time with 15 grams of VFH stimulation; therefore, the increased frequency of response to this stimulus was indicative of mechanical dissociation pain.

Place the animal under the inverted plastic mouse cage on top of the ascending platform with a three metal wire-hole floor. Each VFH was applied to the mid-foot root hairless skin with or without retraction. This was repeated 5 times on each hind paw and the animal response was summarized as a response score percentage (eg, 5 retraction responses to 15 grams of FVH stimulation should yield a 50% score). The behavior is assessed by observers who are completely ignorant of the specific content of each group.

The paclitaxel effect behavior test was started on day 13 (D13) and repeated on D15, D17, D21, D24, D28, D31, D35 and D38. The trials on days 13-17 were during the 20 days of administration of Compound #8. During these periods, the drug was given at 0900 hours and the behavioral test started at 1300 hours. It is expected that significant mechanical-heterologous pain and mechanical-hyperalgesia caused by paclitaxel can be developed 10-14 days after the last injection of paclitaxel.

Results : As expected, paclitaxel-treated large mice received vehicle injection to develop mechanical-heterotopic pain (4 gram VFH test) and mechanical-hyperalgesia (15 gram VFH test).

Compound #8's 60 mg/kg and 120 mg/kg doses inhibited the development of mechanical-distal pain and mechanical-hyperalgesia. After the last injection of Compound #8, the effect of depression was evident at the onset of pain symptoms and continued for approximately 11 days; thereafter, the pain and hyperalgesia of the distraction recovered. There were no significant differences between the two dose groups. Treatment with Compound #8 did not produce significant side effects. The mechanical-disturbance pain block is clearly superior to the mechanical-hyperalgesia block.

Example 21

Visceral Pain in Abdominal Contraction Mode Induced by Acetic Acid - The purpose of this analysis was to determine whether Compound #8 reversed hyperalgesia in visceral, inflammatory, and neuropathic pain patterns.

Test compounds and control groups were dissolved in an appropriate volume of 0.5% HPMC or 10% solutazone in 0.5% hydroxypropyl methylcellulose (HPMC). HPMC was used as a carrier in the preparation of carbapantin solution (as a positive control group). The solution was prepared to provide a final dose of 10 ml/kg oral (oral) for the mice. Males suitable for research between Charles Rivier Laboratories (Potage, Maine) weighing between 25 and 30 grams, and CD-1 mice were used for the abdominal stretching study induced by acetic acid.

All animals had a weekly quarantine/environmental adaptation period prior to transfer to a common storage room. The mice in the acetic acid-induced abdominal stretching study were acclimated to the test room environment for 1 hour before the start of the study. Animals were housed in groups of 4 large mice per cage or 5 small mice per cage in small-isolated cages with corncobs and free access to food and water. The environment was maintained at a constant temperature of 21 ° C and a 12 hour light/dark cycle.

During the entire study period, the animal line used in the acetic acid-induced abdominal stretching test was maintained in the original cage (4 large mice per cage, 5 small mice per cage; the cage was Nalgene with corn shaft bedding) cage). Animals from several cages were randomly assigned to the cross-treatment group; that is, the small mice in a given cage were pseudo-randomly assigned to different treatment groups. In all trials, the investigator who performed the behavioral analysis was completely unaware of the administration to any individual animal.

On the day of the study, mice were orally administered with vehicle (mesoxi or 10% soritox: mesoxa), 560 mg/kg of compound #8 or 560 mg/kg of carbapanten as a positive control group. The mice were then injected intraperitoneally with 0.5 ml (2 x 0.25 ml / quarter of the abdomen) of 0.6% acetic acid, followed by treatment with vehicle, compound or positive control group for 1 hour, 2 hours, 3 hours or 4 hours. . After 5 minutes of intraperitoneal injection of acetic acid, 5 animals were placed in separate bell pots containing a small amount of potato leaf mat, and the number of abdominal stretches per animal was recorded for 5 minutes. Repeated in each group (N=10 mice/group).

The 50% effect effective dose (ED ₅₀ ) and related statistics were calculated using the Pharm Tools Plus software (McKali Group). Statistical analysis of acetic acid analysis (double-direction ANOVA) was calculated using Graph Pad Prism v4.0. The data obtained from the acetic acid-induced visceral pain pattern was analyzed by a 2-way analysis (ANOVA) of the variables. Significant main effects (p < 0.05) were further analyzed using Dunard's multiple comparison test. The data is expressed as the standard error (SEM) of the mean +/- mean.

Compound #8 was evaluated in an acetic acid-induced pattern of visceral-chemical pain. In the vehicle-treated mice, the average number of abdominal stretches in the 4 groups was between 13 and 16.2. Although carbapestine had a tendency to reduce the number of stretches 2 hours (11.00 ± 1.5 stretch) and 3 hours (10.0 ± 1.6 stretch) after oral administration, the effect was not statistically significant. Treatment with 560 mg/kg Compound #8 did not significantly alter the stretch induced by acetic acid when compared to vehicle- or carbapenatin-treated mice.

Compound #8 did not alter abdominal contractions produced by intraperitoneal injection of acetic acid. Similarly, carbapandin did not significantly reduce the contraction induced by acetic acid. These results indicate that the analysis may be insensitive to the analgesic effects of these anti-caries compounds.

Example 22

Inflammatory Pain Pattern Induced by Complete Freund's Adjuvant (CFA) - Intra-articular injection of CFA in large rats results in a persistent inflammatory response characterized by edema and significant thermal and mechanical stimuli Hyperalgesia. This hyperalgesia spike is between 24-72 hours after injection and can last for several weeks. This analysis predicts the analgesic, anti-heterostatic and/or anti-hyperalgesic effects of the test compound.

Test compounds and control groups were dissolved in an appropriate volume of 0.5% HPMC or 10% solutazone in 0.5% hydroxypropyl methylcellulose (HPMC). The solution was prepared to provide a final dose of 2.5 ml/kg volume or 5 ml/kg orally for large rats. It will be obtained from Charles Rivie Laboratories (Potage, Maine) between 250 and 350 grams of males suitable for research, and the Spark-Dawley rat is used for CFA paw radiant heat studies.

All animals had a weekly quarantine/environmental adaptation period prior to transfer to a common storage room. The large mice in the CFA study were transferred to the common storage room on the day of CFA injection and were retained here during the study period. Animals were housed in groups of 4 large mice per cage or 5 small mice per cage in small-isolated cages with corncobs and free access to food and water. The environment was maintained at a constant temperature of 21 ° C and a 12 hour light/dark cycle.

The animals used in the CFA-RH test throughout the study were maintained in the original cage (4 large mice per cage, 5 small mice per cage; the cage was Nalgene with corn shaft bedding) cage). Animals from several cages were randomly assigned to cross-treatment groups; that is, rodents in a given cage were pseudo-randomly assigned to different treatment groups. In the CFA trial, only large rats that exhibited at least a 25% reduction in baseline latency (ie, hyperalgesia) during the response incubation period were included in further testing and analysis. In all trials, the investigator who performed the behavioral analysis was completely unaware of the administration to any individual animal.

On the day of the study, 100 μl (1 μg/μl) of CFA (1:1 CFA: saline) was administered to the rats in their left hind paws. After 24 hours of incubation, response latency was obtained on a radiant heat paw stimulator (RH) and compared to baseline (pre-CFA) latency. The response is automatically recorded by the RH device when the rat lifts its paw from the glass surface. After the CFA-post-latency evaluation, large rats were orally administered with Compound #8 or vehicle (HPMC). The percentage of reversal of hyperalgesia in each animal was calculated as [(Process Response) - (CFA - Post Response)] / [(CFA - Pre Response) - (CFA - Post Response)] x 100. The mean reversal % of hyperalgesia in each treatment group (n=5-6 large mice/group) was then calculated.

The effective dose (ED ₅₀ ) that produced the 50% effect and related statistics were calculated using the Pharm Tools Plus software (Mark Cali Group). The statistics (double-way ANOVA) at the time of acetic acid analysis were calculated using Graph Pad Prism v4.0. The data obtained in the time course study in the CFA-induced inflammatory pain pattern was analyzed by intra- and intra-individual, single-to-ANOVA. A significant main effect (p < 0.05) was further analyzed using the Dunnett multiple comparison test. Data are presented as mean +/- SEM below.

Compound #8 was evaluated in the CFA mode of inflammatory pain. In normal large rats, the average paw retraction latency was between 14.6 and 15.6 seconds. Twenty-four hours after the CFA, the average paw retraction latency has increased to between 6.0 and 6.8 seconds, indicating that hypersensitivity has developed. Oral administration of the vehicle did not significantly alter the paw retraction latency. In contrast, oral administration of 560 mg/kg carbapenetine time-dependently reversed hypersensitivity, and a peak of 68.6% reversal was observed 4 hours after oral administration (with 24-hour CFA-post baseline) Compare). Oral dose 560 mg/kg Compound #8 also reversed thermosensitivity time-dependently and a peak 86.0% reversal was observed 4 hours after oral administration (compared to 24-hour CFA-post baseline).

Compound #8 time-dependently attenuated the hypersensitivity induced by CFA, indicating that Compound #8 should be expected to be useful in the treatment of inflammatory pain.

Example 23

The form of hyperalgesia induced by formalin. Adult males weighing 2-0 grams, CF-1 small mice were obtained from Charles Rivier Laboratories (Wilmington, MA). All animals were kept in a 12:12 light/dark cycle and allowed free access to both food and water, except when moving from the cage during the course of the experiment.

Compound #8 was ground in a small amount of 0.5% methylcellulose, sonicated for 10 minutes and brought to final volume with 0.5% methylcellulose. Compound #8 was administered intraperitoneally to the test mice in a volume of 0.01 mg/10 g body weight. After compound #8 or vehicle was administered intraperitoneally for 2 hours, 0.5% formalin was injected into the right hind paw and ankle area.

In this model, the injected formalin exerts a distinct two-way behavioral pattern characterized by the affected paws of the small mouse. The mice immediately licked their paws for about 10 minutes after the injection. This corresponds to phase 1 (acute response) and then a short incubation period, when the behavioral activity is small. Then a longer period of about 20-30 minutes occurs to form the second phase (inflammation).

Compound #8 at 15 mg/kg (n=8), 30 mg/kg (n=8), 200 mg/kg (n=8), 300 mg/kg (n=4) or vehicle (n=8) Prior to administration, each mouse was placed in one of several 6-inch high resin glass tubes (4 直径 in diameter) for a 15-minute adjustment before the microscope. After the acclimation period, Compound #8 or vehicle was administered intraperitoneally and the mice were returned to the original tubules. Two hours after the administration, formalin was injected subcutaneously (20 μl, 27 standard gauge needle) into the surface of the right hind leg. Place the bevel of the needle down to the surface of the skin. After the injection of formalin, each animal was observed for a total of 45 minutes 2 minutes before the 5 minute period. Record the cumulative length of 舔舐 every 2 minutes. Animals that received the necessary volume of vehicle, each small mouse was changed to dosing compound #8. Kill the animal and proceed to the conclusion of the experiment.

The area under the curve (AUC) was determined using GraphPad Prism version 3.03. The AUC of both the administration and control groups of both the acute and inflammatory phases was calculated. The total AUC of each animal for each period was also calculated and converted to the total AUC percentage of the control group. The average percentage of both Compound #8 and vehicle dose was calculated from the SEM and tested statistically significant.

Compound #8 is effective against acute, with the first stage of pain with formalin injection. After intraperitoneal administration, the component produced an effective dose (ED ₅₀ ) of 50% or less in the AUC and a 95% confidence interval (CI) calculated to be 111 mg/kg (with 62.0-245 mg/kg) range).

Compound #8 reduced the second-stage hyperalgesia induced by formalin in a dose-dependent manner. After intraperitoneal administration via the generated effective dose (ED ₅₀₎ and 95% confidence interval (CI) was calculated to be 101 mg / kg (with a range of 53.6-225 mg / kg of) in 50% or less equal to the AUC.

From the results of this study, it was pointed out that Compound #8 has the ability to reduce the hyperalgesia induced by formalin, and it is indicated that Compound #8 should be expected to be useful for the treatment of acute and chronic inflammatory pain.

Example 24

Compound #8 prepared as in Example 7 was formulated with a sufficient amount of the widely dispersed lactose to provide a total amount of 580 to 590 mg to fill the size 0 hard gelatin capsule.

The present invention has been described by way of illustration and example of the embodiments of the invention, and the invention of the invention Equal content.

Claims (14)

Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, Wherein R ¹ and R ² are each independently selected from the group consisting of hydrogen and a lower alkyl C _1-4 alkyl group; and R ⁴ is selected from the group consisting of hydrogen and a lower alkyl C _1-4 alkyl group; An integer from 1 to 2; Wherein b is an integer from 0 to 4; each R ⁵ is independently selected from the group consisting of halogen and lower alkyl C _1-4 alkyl; and is used in the manufacture of a medicament for treating pain. The use of claim 1, wherein R ¹ and R ² are each independently selected from the group consisting of hydrogen and lower alkyl C _1-4 alkyl; and R ⁴ is selected from the group consisting of hydrogen and lower alkyl C. _a group of _1-4 alkyl groups; a is an integer from 1 to 2; Wherein b is an integer from 0 to 2; each R ⁵ is independently selected from the group consisting of halogen and lower alkyl C _1-4 alkyl; or a pharmaceutically acceptable salt thereof. The use of claim 2, wherein R ¹ and R ² are each independently selected from the group consisting of hydrogen and lower alkyl C _1-4 alkyl; and R ⁴ is selected from the group consisting of hydrogen and methyl. ;a is an integer from 1 to 2; Is selected from the group consisting of 2-(2,3-dihydro-benzo[1,4] Dioxinyl, 2-(6-chloro-2,3-dihydro-benzo[1,4] Octyl), 2-(6-fluoro-2,3-dihydro-benzo[1,4] Octyl), 2-(5-fluoro-2,3-dihydro-benzo[1,4] Octyl), 2-(7-chloro-2,3-dihydro-benzo[1,4] Octyl), 2-(7-methyl-2,3-dihydro-benzo[1,4] Octyl), 2-(5-chloro-2,3-dihydro-benzo[1,4] Octyl), 2-(6-bromo-2,3-dihydro-benzo[1,4] Octyl), 2-(6,7-dichloro-2,3-dihydro-benzo[1,4] Octyl) and 2-(8-chloro-2,3-dihydro-benzo[1,4] Octyl); or a pharmaceutically acceptable salt thereof. The use of claim 3, wherein R ¹ and R ² are each independently selected from the group consisting of hydrogen and methyl; R ⁴ is selected from the group consisting of hydrogen and methyl; and a is from 1 to 2. Integer Is selected from the group consisting of 2-(2,3-dihydro-benzo[1,4] Octyl), 2-(6-chloro-2,3-dihydro-benzo[1,4] Octyl), 2-(7-chloro-2,3-dihydro-benzo[1,4] Octyl), 2-(7-methyl-2,3-dihydro-benzo[1,4] Octyl), 2-(6-bromo-2,3-dihydro-benzo[1,4] Octyl) and 2-(6,7-dichloro-2,3-dihydro-benzo[1,4] Octyl); or a pharmaceutically acceptable salt thereof. The use of the first aspect of the invention, wherein the compound of the formula (I) is selected from the group consisting of (2S)-(-)-N-(6-chloro-2,3-dihydro-benzo[1,4 ]two a group of oct-2-ylmethyl)-sulfonamide; and a pharmaceutically acceptable salt thereof. One selected from the group consisting of (2S)-(-)-N-(6-chloro-2,3-dihydro-benzo[1,4] A compound of oct-2-ylmethyl)-sulfonamide; and a pharmaceutically acceptable salt thereof for use in the manufacture of a medicament for the treatment of pain. The use of the first aspect of the patent application, wherein the pain is acute pain or chronic pain. The use of the first aspect of the patent application, wherein the pain is inflammatory pain. For example, the use of the scope of claim 1 wherein the pain is neuropathic pain. For example, the application of the scope of claim 9 wherein neuropathic pain It is a diabetic neuropathy. The use of the sixth aspect of the patent application, wherein the pain is acute pain or chronic pain. For example, the use of the scope of claim 6 wherein the pain is inflammatory pain. For example, the use of the scope of claim 6 wherein the pain is neuropathic pain. For example, the use of the scope of claim 13 wherein the neuropathic pain is diabetic neuropathy.