WO2009002770A1 - 6.5-pyrrolopiperidine tachykinin receptor antagonists - Google Patents
6.5-pyrrolopiperidine tachykinin receptor antagonists Download PDFInfo
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- WO2009002770A1 WO2009002770A1 PCT/US2008/067270 US2008067270W WO2009002770A1 WO 2009002770 A1 WO2009002770 A1 WO 2009002770A1 US 2008067270 W US2008067270 W US 2008067270W WO 2009002770 A1 WO2009002770 A1 WO 2009002770A1
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- 0 CC(c1cc(CC(*(CCC2C3C*(Cc4ccccc4)C2)C3c2ccc(C)cc2)=O)cc(C(C)(N)N)c1)(N)N Chemical compound CC(c1cc(CC(*(CCC2C3C*(Cc4ccccc4)C2)C3c2ccc(C)cc2)=O)cc(C(C)(N)N)c1)(N)N 0.000 description 4
- SVSVCYZPFWDAPW-UHFFFAOYSA-N CC(OC1)=NC1=O Chemical compound CC(OC1)=NC1=O SVSVCYZPFWDAPW-UHFFFAOYSA-N 0.000 description 1
- VRWMXYPHKHMXRU-CQKQJRMFSA-N C[C@H](c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N(C)C(NCCC1[C@H](Cc2ccccc2C)CN(Cc2ccccc2)C1)=O Chemical compound C[C@H](c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N(C)C(NCCC1[C@H](Cc2ccccc2C)CN(Cc2ccccc2)C1)=O VRWMXYPHKHMXRU-CQKQJRMFSA-N 0.000 description 1
- PXHFLWCSJYTAFU-UHFFFAOYSA-N O=C1NCOC1 Chemical compound O=C1NCOC1 PXHFLWCSJYTAFU-UHFFFAOYSA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/06—Antimigraine agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/22—Anxiolytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Definitions
- Substance P is a naturally occurring undecapeptide belonging to the tachykinin family of peptides, the latter being so-named because of their prompt contractile action on extravascular smooth muscle tissue.
- the tachykinins are distinguished by a conserved carboxyl- terminal sequence.
- the known mammalian tachykinins include neurokinin A and neurokinin B.
- the current nomenclature designates the receptors for substance P, neurokinin A, and neurokinin B as neurokinin- 1 (NK-I), neurokinin-2 (NK-2), and neurokinin-3 (NK-3), respectively.
- Tachykinin, and in particular substance P, antagonists are useful in the treatment of clinical conditions which are characterized by the presence of an excess of tachykinin, in particular substance P, activity, including disorders of the central nervous system, nociception and pain, gastrointestinal disorders, disorders of bladder function and respiratory diseases.
- the present invention is directed to certain hydroxvmethyl ether hydroisoindoline compounds of Formula (I) which are useful as neurokinin- 1 (NK-I) receptor antagonists, and inhibitors of tachykinin and in particular substance P.
- the invention is also concerned with pharmaceutical formulations comprising these compounds as active ingredients and the use of the compounds and their formulations in the treatment of certain disorders, including emesis, urinary incontinence, LUTS, depression, and anxiety.
- X is N or CH
- R 1 is selected from the group consisting of:
- HET is selected from the group consisting of
- Ra is selected from H, and C 1 -3 alkyl and Rb is selected fromH, C 1-4 alkyl, -(CO)-CH3 and -(CO)-NH 2 ,
- R 2 , R 3 , R 4 and R 5 are each independently selected from the group consisting of:
- R 6 is independently selected from the group consisting of:
- R 1 R 2 R 3 R 4 R 5 R 6 and X are defined herein or a pharmaceutically acceptable salt thereof and individual enantiomers and diastereomers thereof.
- R.1 is selected from the group consisting of:
- alkyl portion of choices (4), (6) and (7) of Rl are optionally substituted with halo, hydroxyl or phenyl.
- R* is selected from the group consisting of: (1) hydrogen,
- RI is selected from the group consisting of:
- R 6 is independently selected from the group consisting of:
- R 5 is independently selected from the group consisting of: (2) methyl.
- X is N.
- Specific embodiments of the present invention include a compound which is selected from the group consisting of the subject compounds of the Examples herein and pharmaceutically acceptable salts thereof and individual enantiomers and diastereomers thereof.
- Specific embodiments of the present invention include a compound which is selected from the group consisting of the subject compounds of the Examples herein and pharmaceutically acceptable salts thereof and individual enantiomers and diastereomers thereof.
- the compounds of the present invention may contain one or more asymmetric centers and can thus occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. Additional asymmetric centers may be present depending upon the nature of the various substituents on the molecule. Each such asymmetric center will independently produce two optical isomers and it is intended that all of the possible optical isomers and diastereomers in mixtures and as pure or partially purified compounds are included within the ambit of this invention. The present invention is meant to comprehend all such isomeric forms of these compounds.
- Formula I shows the structure of the class of compounds without preferred stereochemistry.
- the coupling reaction is often the formation of salts using an enantiomerically pure acid or base.
- the diasteromeric derivatives may then be converted to the pure enantiomers by cleavage of the added chiral residue.
- the racemic mixture of the compounds can also be separated directly by chromatographic methods utilizing chiral stationary phases, which methods are well known in the art.
- any enantiomer of a compound may be obtained by stereoselective synthesis using optically pure starting materials or reagents of known configuration by methods well known in the art.
- the above compound can be named either as "(3aR,4R,5S,7aR) tert- butyl-5 -hydroxy-4-(2-methyIphenyl)octahydro-2H-isoindole-2-carboxylate” or 'tert-butyl (3aR,4R,5S,7aR)-5-hydroxy-4-phenyIoctahydro-2H-isoindole-2-carboxylate".
- the core structure may be generally referred to as octahydroisoindole, hexahydroisoindoline, perhydroisoindoline, hydroisomdoline, or hydroisoindole compounds.
- halo or halogen as used herein are intended to include fluoro, chloro, bromo and iodo.
- C 1-6 as in C 1-6 alkyl is defined to identify the group as having 1, 2, 3, 4, 5 or 6 carbons in a linear or branched arrangement, such that C 1-6 alkyl specifically includes methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert- butyl, pentyl, and hexyl.
- a group which is designated as being independently substituted with substituents may be independently substituted with multiple numbers of such substituents.
- salts refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic or organic bases and inorganic or organic acids.
- Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc, and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium, and sodium salts. Salts in the solid form may exist in more than one crystal structure, and may also be in the form of hydrates.
- Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylene-diam ⁇ ne, diethylamine, 2- diethylaminoethanol, 2-dimethylamino-ethanol, ethanolamine, ethylenediamine, N-ethyl- morpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamme, trimethylamine, tripropylamine, tromethamine, and the like.
- salts may be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids.
- acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid, and the like.
- Particularly preferred are citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, fumaric, and tartaric acids.
- Exemplifying the invention is the use of the compounds disclosed in the Examples and herein.
- Specific compounds within the present invention include a compound which selected from the group consisting of the compounds disclosed in the following Examples and pharmaceutically acceptable salts thereof and individual diastereomers thereof.
- the compounds of the present invention are useful in the prevention and treatment of a wide variety of clinical conditions which are characterized by the presence of an excess of tachykinin, in particular substance P, activity.
- an excess of tachykinin, and in particular substance P, activity is implicated in a variety of disorders of the central nervous system.
- Such disorders include mood disorders, such as depression or more particularly depressive disorders, for example, single episodic or recurrent major depressive disorders and dysthymic disorders, or bipolar disorders, for example, bipolar I disorder, bipolar II disorder and cyclothymic disorder; anxiety disorders, such as panic disorder with or without agoraphobia, agoraphobia without history of panic disorder, specific phobias, for example, specific animal phobias, social phobias, obsessive-compulsive disorder, stress disorders including post-traumatic stress disorder and acute stress disorder, and generalised anxiety disorders; schizophrenia and other psychotic disorders, for example, schizophreniform disorders, schizoaffective disorders, delusional disorders, brief psychotic disorders, shared psychotic disorders and psychotic disorders with delusions or hallucinations; delerium, dementia, and amnestic and other cognitive or neurodegenerative disorders, such as Alzheimer's disease, senile dementia, dementia of the Alzheimer's type, vascular dementia, and other dementias, for example, due to HIV disease, head trauma, Parkinson
- Tachykinin, and in particular substance P, activity is also involved in nociception and pain.
- the compounds of the present invention will therefore be of use in the prevention or treatment of diseases and conditions in which pain predominates, including soft tissue and peripheral damage, such as acute trauma, osteoarthritis, rheumatoid arthritis, musculo- skeletal pain, particularly after trauma, spinal pain, myofascial pain syndromes, headache, episiotomy pain, and burns; deep and visceral pain, such as heart pain, muscle pain, eye pain, orofacial pain, for example, odontalgia, abdominal pain, gynaecological pain, for example, dysmenorrhoea, and labour pain; pain associated with nerve and root damage, such as pain associated with peripheral nerve disorders, for example, nerve entrapment and brachial plexus avulsions, amputation, peripheral neuropathies, tic douloureux, atypical facial pain, nerve root damage, and arachnoidit
- Tachykinin, and in particular substance P, antagonists may also be of use in the treatment of respiratory diseases, particularly those associated with excess mucus secretion, such as chronic obstructive airways disease, bronchopneumonia, chronic bronchitis, cystic fibrosis and asthma, adult respiratory distress syndrome, and bronchospasm; inflammatory diseases such as inflammatory bowel disease, psoriasis, fibrositis, osteoarthritis, rheumatoid arthritis, pruritis and sunburn; allergies such as eczema and rhinitis; hypersensitivity disorders such as poison ivy; ophthalmic diseases such as conjunctivitis, vernal conjunctivitis, and the like; ophthalmic conditions associated with cell proliferation such as proliferative vitreoretinopathy; cutaneous diseases such as contact dermatitis, atopic dermatitis, urticaria, and other eczematoid dermatitis.
- respiratory diseases
- Tachykinin, and in particular substance P, antagonists may also be of use in the treatment of neoplasms, including breast tumours, neuroganglioblastomas and small cell carcinomas such as small cell lung cancer.
- Tachykinin, and in particular substance P, antagonists may also be of use in the treatment of gastrointestinal (GI) disorders, including inflammatory disorders and diseases of the GI tract such as gastritis, gastroduodenal ulcers, gastric carcinomas, gastric lymphomas, disorders associated with the neuronal control of viscera, ulcerative colitis, Crohn's disease, irritable bowel syndrome and emesis, including acute, delayed or anticipatory emesis such as emesis induced by chemotherapy, radiation, toxins, viral or bacterial infections, pregnancy, vestibular disorders, for example motion sickness vertigo dizziness and Meniere's disease surgery migraine variations in intercranial pressure, gastro-oesophageal reflux disease, acid indigestion, over indulgence in food or drink, acid stomach, waterbrash or regurgitation, heartburn, for example, episodic, nocturnal or meal-induced heartburn, and dyspepsia.
- GI gastrointestinal
- Tachykinin, and in particular substance P, antagonists may also be of use in the treatment of a variety of other conditions including stress related somatic disorders; reflex sympathetic dystrophy such as shoulder/hand syndrome; adverse immunological reactions such as rejection of transplanted tissues and disorders related to immune enhancement or suppression such as systemic lupus erythematosus; plasma extravasation resulting from cytokine chemotherapy, disorders of bladder function such as cystitis, bladder detrusor hyper-reflexia, frequent urination, urinary incontinence and LUTS, including the prevention or treatment of overactive bladder with symptoms of urge urinary incontinence, urgency, and frequency; fibrosing and collagen diseases such as scleroderma and eosinophilic fascioliasis; disorders of blood flow caused by vasodilation and vasospastic diseases such as angina, vascular headache, migraine and Reynaud's disease; and pain or nociception attributable to or associated with any of the foregoing conditions, especially the transmission
- the term "urinary incontinence" is intended to include a range of conditions including urge incontinence, stress incontinence, overflow incontinence, functional incontinence, neurogenic incontinence, post-prostatectomy incontinence, urinary frequency, urinary urgency, nocturia, enuresis, and related conditions in mammalian subjects.
- the lower urinary tract disorder, or targeted symptoms for treatment arising therefrom may include overactive bladder, including neurogenic and non-neurogenic overactive bladder, interstitial cystitis, prostatitis, prostadynia, and benign prostatic hyperplasia.
- the methods and compositions of the invention are effective for preventing or treating excessive micturition in subjects suffering from lower urinary tract disorders.
- the compounds of the present invention are also of value in the treatment of a combination of the above conditions, in particular in the treatment of combined post-operative pain and post-operative nausea and vomiting.
- the compounds of the present invention are particularly useful in the prevention or treatment of emesis, including acute, delayed or anticipatory emesis, such as emesis induced by chemotherapy, radiation, toxins, pregnancy, vestibular disorders, motion, surgery, migraine, and variations in intercranial pressure.
- emesis including acute, delayed or anticipatory emesis, such as emesis induced by chemotherapy, radiation, toxins, pregnancy, vestibular disorders, motion, surgery, migraine, and variations in intercranial pressure.
- the compounds of the present invention are of use optionally in combination with other antiemetic agents for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of moderate or highly emetogenic cancer chemotherapy, including high-dose cisplatin.
- the compounds of the present invention are of use in the treatment of emesis induced by antineoplastic (cytotoxic) agents including those routinely used in cancer chemotherapy and emesis induced by other pharmacological agents, for example, rolipram.
- chemotherapeutic agents include alkylating agents, for example, ethyleneimine compounds, alkyl sulphonates and other compounds with an alkylating action such as nitrosoureas, cisplatin and dacarbazine; antimetabolites, for example, folic acid, purine or pyrimidine antagonists; mitotic inhibitors, for example, vinca alkaloids and derivatives of podophyllotoxin; and cytotoxic antibiotics.
- chemotherapeutic agents are described, for instance, by D. J. Stewart in Nausea and Vomiting: Recent Research and Clinical Advances, Eds. J. Kucharczyk et al, CRC Press Inc., Boca Raton, Florida, USA (1991) pages 177-203, especially page 188.
- chemotherapeutic agents include cisplatin, dacarbazine (DTIC), dactinomycin, mechlorethamine, streptozocin, cyclophosphamide, carmustine (BCNU), lomustine (CCNU), doxorubicin (adriamycin), daunorubicm, procarbazine, mitomycin, cytarabine, etoposide, methotrexate, 5-fiuorouracil, vinblastine, vincristine, bleomycin and chlorambucil [R. .T. Gralla et al in Cancer Treatment Reports (1984) 68(1), 163-172].
- a further aspect of the present invention comprises the use of a compound of the present invention for achieving a chronobiologic (circadian rhythm phase- shifting) effect and alleviating circadian rhythm disorders in a mammal.
- the present invention is further directed to the use of a compound of the present invention for blocking the phase-shifting effects of light in a mammal.
- a further aspect of the present invention comprises the use of a compound of the present invention in the treatment of Lower urinary tract symptoms (LUTS).
- LUTS in men include, but are not, restricted to a complex of obstructive (voiding) and irritative (storage or filling) symptoms, which include increased frequency, nocturia, poor urinary stream and hesitancy or delay in starting urinary flow.
- LUTS are recognized as arising from changes in urethral resistance induced by the enlarging prostate as well as contraction of the prostatic smooth muscle. The resulting increase in urethral resistance restricts the outflow of urine and causes secondary changes are induced in the bladder.
- a characteristic pattern of unstable bladder contractions is often observed in men with morphological BPH.
- the present invention is further directed to the use of a compound of the present invention or a pharmaceutically acceptable salt thereof, for enhancing or improving sleep quality as well as preventing and treating sleep disorders and sleep disturbances in a mammal.
- the present invention provides a method for enhancing or improving sleep quality by increasing sleep efficiency and augmenting sleep maintenance.
- the present invention provides a method for preventing and treating sleep disorders and sleep disturbances in a mammal which comprising the administration of a compound of the present invention or a pharmaceutically acceptable salt thereof.
- the present invention is useful for the treatment of sleep disorders, including Disorders of Initiating and Maintaining Sleep (insomnias) (“DIMS”) which can arise from psychophysiological causes as a consequence of psychiatric disorders (particularly related to anxiety), from drugs and alcohol use and abuse (particularly during withdrawal stages), childhood onset DIMS, nocturnal myoclonus and restless legs and non specific REM disturbances as seen in ageing.
- DIMS Disorders of Initiating and Maintaining Sleep
- the particularly preferred embodiments of the instant invention are the treatment of eraesis, urinary incontinence, depression or anxiety by administration of the compounds of the present invention to a subject (human or animal) in need of such treatment.
- the present invention is directed to a method for the manufacture of a medicament for antagonizing the effect of substance P at its receptor site or for the blockade of neurokinin- 1 receptors in a mammal comprising combining a compound of the present invention with a pharmaceutical carrier or diluent.
- the present invention is further directed to a method for the manufacture of a medicament for the treatment of a physiological disorder associated with an excess of tachykinins in a mammal comprising combining a compound of the present invention with a pharmaceutical carrier or diluent.
- the present invention also provides a method for the treatment or prevention of physiological disorders associated with an excess of tachykinins, especially substance P, which method comprises administration to a patient in need thereof of a tachykinin reducing amount of a compound of the present invention or a composition comprising a compound of the present invention.
- treatment refers to the administration of the compounds of the present invention to reduce, ameliorate, or eliminate either the symptoms or underlying cause of the noted disease conditions, in a subject (human or animal) that suffers from that condition or displays clinical indicators thereof.
- prevention refers to the administration of the compounds of the present invention to reduce, ameliorate, or eliminate the risk or likelihood of occurrence of the noted disease conditions, in a subject (human or animal) susceptible or predisposed to that condition.
- the compounds of this invention are useful for antagonizing tachykinins, in particular substance P in the treatment of gastrointestinal disorders, central nervous system disorders, inflammatory diseases, pain or migraine and asthma in a mammal in need of such treatment. This activity can be demonstrated by the following assays.
- NKlR human neurokinin- 1 receptor
- pCDM9 which was derived from ⁇ CDM8 (INVITROGEN) by inserting the ampicillin resistance gene (nucleotide 1973 to 2964 from BLUESCRIPT SK+) into the Sac II site.
- Transfection of 20 ug of the plasmid DNA into 10 million COS cells was achieved by electroporation in 800 ul of transfection buffer (135 mM NaCl, 1.2 mM CaCl2, 1.2 mM MgCl2, 2.4 mM K2HPO4, 0.6 mM KH2PO4, 10 mM glucose, 10 mM HEPES pH 7.4) at 260 V and 950 uF using the IBI GENEZAPPER (IBI, New Haven, CT).
- the cells were incubated in 10% fetal calf serum, 2 mM glutamine, 100U/ml penicillin-streptomycin, and 90% DMEM media (GIBCO, Grand Island, NY) in 5% C02 at 37 °C for three days before the binding assay.
- Transfection of 20 ug of the plasmid DNA into CHO cells was achieved by electroporation in 800 ul of transfection buffer suplemented with 0.625 mg/ml Herring sperm DNA at 300 V and 950 uF using the IBI GENEZAPPER (IBI).
- the transfected cells were incubated in CHO media [10 % fetal calf serum, 100 U/ml pennicilin-streptomycin, 2 mM glutamine, 1/500 hypoxanthine- thymidine (ATCC), 90% IMDM media (JRH BIOSCIENCES, Lenexa, ICS), 0.7 mg/ml G418 (GIBCO)] in 5% CO2 at 37°C until colonies were visible. Each colony was separated and propagated. The cell clone with the highest number of human NKlR was selected for subsequent applications such as drug screening.
- the binding assay of human NKlR expressed in either COS or CHO cells is based on the use of 125 I-substance P ( 125 I-SP, from DU PONT, Boston, MA) as a radioactively labeled ligand which competes with unlabeled substance P or any other ligand for binding to the human NKlR.
- 125 I-substance P 125 I-SP, from DU PONT, Boston, MA
- Monolayer cell cultures of COS or CHO were dissociated by the non-enzymatic solution (SPECIALTY MEDIA, Lavallette, NJ) and resuspended in appropriate volume of the binding buffer (50 mM Tris pH 7.5, 5 mM MnCl2, 150 mM NaCl, 0.04 mg/ml bacitracin, 0.004 mg/ml leupeptin, 0.2 mg/ml BSA, 0.01 mM phosphoramidon) such that 200 ul of the cell suspension would give rise to about 10,000 cpm of specific 125 I-SP binding (approximately 50,000 to 200,000 cells).
- the binding buffer 50 mM Tris pH 7.5, 5 mM MnCl2, 150 mM NaCl, 0.04 mg/ml bacitracin, 0.004 mg/ml leupeptin, 0.2 mg/ml BSA, 0.01 mM phosphoramidon
- the binding assay 200 ul of cells were added to a tube containing 20 ul of 1.5 to 2.5 nM of 125 I-SP and 20 ul of unlabeled substance P or any other test compound. The tubes were incubated at 4°C or at room temperature for 1 hour with gentle shaking. The bound radioactivity was separated from unbound radioactivity by GF/C filter (BRANDEL, Gaithersburg, MD) which was pre-wetted with 0.1 % polyethylenimine. The filter was washed with 3 ml of wash buffer (50 mM Tris pH 7.5, 5 mM MnCl2, 150 mM NaCl) three times and its radioactivity was determined by gamma counter.
- wash buffer 50 mM Tris pH 7.5, 5 mM MnCl2, 150 mM NaCl
- NKlR The activation of phospho lipase C by NKlR may also be measured in CHO cells expressing the human NKl R by determining the accumulation of inositol monophosphate which is a degradation product of IP3. CHO cells are seeded in 12-well plate at 250,000 cells per well.
- the aqueous phase is applied to a 1 ml Dowex AG 1X8 ion exchange column.
- the column is washed with 0.1 N formic acid followed hy 0.025 M ammonium formate-0.1 N formic acid.
- the inositol monophosphate is eluted with 0.2 M ammonium formate-0.1 N formic acid and quantitated by beta counter.
- the intrinsic tachykinin receptor antagonist activities of the compounds of the present invention may be demonstrated by this assay.
- the compounds of the invention have activity in the aforementioned assay in the range of 0.05 nM to 10 ⁇ M.
- the Examples hereinunder were found to have the following activity:
- the activity of the present compounds may also be demonstrated by the assay disclosed by Lei, et al., British J. Pharmacol., 105, 261-262 (1992).
- the present invention provides a compound of the present invention for use as a composition that may be administered to a subject in need of a reduction of the amount of tachykinin or substance P in their body.
- composition as used herein is intended to encompass a product comprising specified ingredients in predetermined amounts or proportions, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
- This term in relation to pharmaceutical compositions is intended to encompass a product comprising one or more active ingredients, and an optional carrier comprising inert ingredients, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of uniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation.
- the active object compound is included in an amount sufficient to produce the desired effect upon the process or condition of diseases.
- the pharmaceutical compositions of the present invention encompass any composition made by admixing a compound of the present invention and a pharmaceutically acceptable carrier.
- pharmaceutically acceptable it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
- Pharmaceutical compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations.
- Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
- excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc.
- the tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
- compositions for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
- an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
- water or an oil medium for example peanut oil, liquid paraffin, or olive oil.
- Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions.
- Oily suspensions may be formulated by suspending the active ingredient in a suitable oil.
- Oil-in- water emulsions may also be employed.
- Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives.
- compositions of the present compounds may be in the form of a sterile injectable aqueous or oleagenous suspension.
- the compounds of the present invention may also be administered in the form of suppositories for rectal administration.
- creams, ointments, jellies, solutions or suspensions, etc., containing the compounds of the present invention may be employed.
- the compounds of the present invention may also be formulated for administered by inhalation.
- the compounds of the present invention may also be administered by a transdermal patch by methods known in the art.
- compositions containing compounds of the present invention may be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy.
- unit dosage form is taken to mean a single dose wherein all active and inactive ingredients are combined in a suitable system, such that the patient or person adminstering the drug to the patient can open a single container or package with the entire dose contained therein, and does not have to mix any components together from two or more containers or packages.
- Typical examples of unit dosage forms are tablets or capsules for oral administration, single dose vials for injection, or suppositories for rectal administration. This list of unit dosage forms is not intended to be limiting in any way, but merely to represent typical examples in the pharmacy arts of unit dosage forms.
- compositions containing compounds of the present invention may also be presented as a kit, whereby two or more components, which may be active or inactive ingredients, carriers, diluents, and the like, are provided with instructions for preparation of the actual dosage form by the patient or person administering the drug to the patient.
- kits may be provided with all necessary materials and ingredients contained therein, or they may contain instructions for using or making materials or components that must be obtained independently by the patient or person administering the drug to the patient.
- pharmaceutically acceptable it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
- administering a should be understood to mean providing a compound of the invention to ⁇ xe individual in need of treatment in a form that can be introduced into that individuals body in a therapeutically useful form and therapeutically effective amount, including, but not limited to: oral dosage forms, such as tablets, capsules, syrups, suspensions, and the like; injectable dosage forms, such as IV, IM, or IP, and the like; transdermal dosage forms, including creams, jellies, powders, or patches; buccal dosage forms; inhalation powders, sprays, suspensions, and the like; and rectal suppositories.
- therapeutically effective amount refers to a sufficient quantity of the compounds of the present invention, in a suitable composition, and in a suitable dosage form to treat or prevent the noted disease conditions.
- the compounds of the present invention may be administered in combination with another substance that has a complimentary effect to the tachykinin and substance P inhibitors of the present invention.
- a compound of the present invention may be used in conjunction with other anti-emetic agents, especially 5HT3 receptor antagonists, such as ondansetron, granisetron, tropisetron, palenosetron and zatisetron, a corticosteroid, such as dexamethasone, or GABA B receptor agonists, such as baclofen.
- 5HT3 receptor antagonists such as ondansetron, granisetron, tropisetron, palenosetron and zatisetron
- a corticosteroid such as dexamethasone
- GABA B receptor agonists such as baclofen.
- a compound of the present invention may be used in conjunction with other anti-migraine agents, such as ergotamines or 5HTi agonists, especially sumatriptan, naratriptan, zolmatriptan or rizatriptan.
- a compound of the present invention may be used in conjunction with other anti-depressant or anti-anxiety agents, such as norepinephrine reuptake inhibitors, selective serotonin reuptake inhibitors (SSRJs), monoamine oxidase inhibitors (MAOIs), reversible inhibitors of monoamine oxidase (RIMAs), serotonin and noradrenaline reuptake inhibitors (SNRIs), ⁇ -adrenoreceptor antagonists, atypical anti-depressants, benzodiazepines, 5-HT 1 A agonists or antagonists, especially 5-HT IA partial agonists, corticotropin releasing factor (CRF) antagonists, and pharmaceutically acceptable salts thereof.
- anti-depressant or anti-anxiety agents such as norepinephrine reuptake inhibitors, selective serotonin reuptake inhibitors (SSRJs), monoamine oxidase inhibitors (MAOIs), reversible inhibitor
- a compound of the present invention may be used in conjunction with other anorectic agents.
- an antiinflammatory or analgesic agent such as an opiate agonist, a lipoxygenase inhibitor, such as an inhibitor of 5-Iipoxygenase, a cyclooxygenase inhibitor, such as a cyclooxygenase-2 inhibitor, an interleukin inhibitor, such as an interleukin- 1 inhibitor, an NMDA antagonist, an inhibitor of nitric oxide or an inhibitor of the synthesis of nitric oxide, a non-steroidal antiinflammatory agent, or a cytokine-suppressing antiinflammatory agent.
- an antiinflammatory or analgesic agent such as an opiate agonist, a lipoxygenase inhibitor, such as an inhibitor of 5-Iipoxygenase, a cyclooxygenase inhibitor, such as a cyclooxygenase-2 inhibitor, an interleukin inhibitor, such as an interleukin- 1 inhibitor,
- a compound of the invention may be used in combination with a ⁇ 3 adrenergic receptor ( ⁇ 3AR) agonist ( ⁇ 3 agonist), and/or an anti-muscatinic and optionally an alpha- 1 adrenergic antagonist, or a steroid type II 5-alpha- reductase inhibitor.
- ⁇ 3AR ⁇ 3 adrenergic receptor
- ⁇ 3 agonist ⁇ 3 agonist
- an anti-muscatinic and optionally an alpha- 1 adrenergic antagonist or a steroid type II 5-alpha- reductase inhibitor.
- the ⁇ 3 agonist is intended to include N- [4- [2- [[2-hydroxy-2-(pyridin-3-yl)ethyl]amino]ethyl]phenyl]-4-[4-(3-cyclo ⁇ entyl ⁇ ropyl)-5-tetrazolon- 1 -yl]benzenesulfonamide.
- ⁇ 3 agonist 2N-[4-[2-[[2-hydroxy-2-(pyridin-3-yl)ethyl]amino]ethyl]phenyl]-4-[4-[4- (trifluoromethyl)phenyl]thiazol-2-yl]benzenesulfonamide.
- Appropriate daily amounts of the ⁇ 3 agonist include lOmg, 25,mg, 50mg, lOOmg, 125mg, 200mg, 250mg and 375mg. These beta 3 agonists are discussed and may be prepared as disclosed in US 5,561 , 142 and US 6,011 ,048, which are hereby incorporated by reference.
- anti-rauscarinc agents included, but are not limited to tolterodine, oxybutynin, trospium, vaiericamide, solifenacin, propiverine, S- oxybutynin, temiverine, sanctura, staybla, fesoterodine, SVT40776, 202405 by GlaxoSmithKline, TD6301, RBX9841, DDP200, and PLD179.
- these drugs may be administered orally or topically in standard or extended release forms, such as extended release tolterodine, extended relesase oxybutynin and transdermal oxybutynin.
- the anti-muscarmic agent is selected from tolterodine, oxybutynin, trospium, vamicamide, solifenacin, propiverine, S-oxybutynin, temiverine, sanctura, staybla, fesoterodine, SVT40776, 202405 by GlaxoSmithKline, TD6301, RBX9841, DDP200, and PLD179.
- the anti-muscarinic agent is selected from the group consisting of trospium chloride, darifenacin and imidafenacin.
- the anti-muscarinic agent is selected from the group consisting of extended release tolterodine, extended relsease oxybutynin and transdermal oxybutynin.
- the 5-alpha reductase inhibitor includes, but is not limited to finasteride, dutasteride, turosteride and epristeride.
- finasteride as used here is meant the compound as designated by 4- azaandrost-l-ene-17-carboxamide, N-(l,l-dimethylethyl)-3-oxo-,(5 ⁇ ,17 ⁇ ).
- FDA approved doses for finasteride are lmg and 5mg, once a day.
- dutasteride as used herein is meant the compound as designated by (5 ⁇ , 17 ⁇ )-N- ⁇ 2, 5 bis(trifluoromelhyl)phenyl ⁇ -3-oxo-4-azaandrost-l-ene-17-carboxamide.
- FDA approved doses for finasteride are lmg and 5mg, once a day.
- the FDA approved dose for dutasteride is 0.5mg, once a day.
- the FDA approved dose for dutasteride is 0.5mg, once a day.
- the alpha- adrenergic receptor antagonist is selected from amsulosin, terazosin, doxazosin, alfuzosin, indoramin and prazosin.
- amsulosin e.g. Flomax or tamsulosm hydrochloride
- amsulosin e.g. Flomax or tamsulosm hydrochloride
- amsulosin e.g. Flomax or tamsulosm hydrochloride
- Amsulosin is disclosed in U.S. Pat. No. 4,703,063 and claimed in U.S. Pat. No. 4,987,152 as being useful in treating lower urinary tract dysfunction.
- FDA approved doses include 0.4mg once a day for tamsulosin hydrochloride.
- terazosin as used herein is meant the compound l-(4-amino-6,7- dimethoxy-2quinazolinyl)-4-[(tetrahydro-2-furoyl)carbonyl]p iperazine and salts, hydrates and solvates thereof.
- Terazosin is disclosed in U.S. Pat. No. 4,251,532.
- FDA approved doses include 1, 2, 5 and lOmg once a day for terazosin hydrochloride.
- doxazosin as used herein is meant the compound ⁇ -(4-amino-6,7- dimethoxy-2-quinazolinyl)-4-[(2,3-dihydro-l,4-benzodioxin-2 -yl)carbonyl]-piperazine and salts, hydrates and solvates thereof.
- Doxazosin is disclosed in U.S. Pat. No. 4,188,390. FDA approved doses include 1, 2, 4 and 8 mg once a day for doxazosin mesylate.
- alfuzosin e.g. Uroxatral
- alfuzosin the compound N- [3-[(4-amino-6,7-dimemoxy-2-quinazolinyl)methylamino]propyI]tetrahydro- 2- furancarboxamide and salts, hydrates and solvates thereof.
- Alfuzosin is disclosed in U.S. Pat. No. 4,315,007. FDA approved doses include 10 mg once a day for alfuzosin hydrochloride.
- indoramin as used herein is meant the compound N-[[l-[2-(lH- indol-3-yl)ethyl]-4-pi ⁇ eridmyl]benzamme. Indoramin is disclosed in U.S. Pat. No. 3,527,761.
- prazosin as used herein is meant a compound of the formula l-(4- amino-6,7-dimethoxy-2-quinazolinyl)-4-(2-furanylcarbonyl)piperazine. and solvates thereof.
- Prazosin is disclosed in U.S. Pat. No. 3,511,836. FDA approved doses include 1, 2 and 5 mg once a day for prazosin hydrochloride.
- both the compound of the present invention and the other active agent(s) will be administered to a patient, within a reasonable period of time.
- the compounds may be in the same pharmaceutically acceptable carrier and therefore administered simultaneously They may be in separate pharmaceutical carriers such as conventional oral dosage forms which are taken simultaneously.
- the term “combination” also refers to the case where the compounds are provided in separate dosage forms and are administered sequentially. Therefore, by way of example, one active component may be administered as a tablet and then, within a reasonable period of time, the second active component may be administered either as an oral dosage form such as a tablet or a fast-dissolving oral dosage form.
- a fast dissolving oral formulation is meant, an oral delivery form which when placed on the tongue of a patient, dissolves within about 10 seconds.
- reactionable period of time is meant a time period that is not in excess of about 1 hour. That is, for example, if the first active component is provided as a tablet, then within one hour, the second active component should be administered, either in the same type of dosage form, or another dosage form which provides effective delivery of the medicament
- the compounds of this invention may be administered to patients (animals and humans) in need of such treatment in dosages that will provide optimal pharmaceutical efficacy. It will be appreciated that the dose required for use in any particular application will vary from patient to patient, not only with the particular compound or composition selected, but also with the route of administration, the nature of the condition being treated, the age and condition of the patient, concurrent medication or special diets then being followed by the patient, and other factors which those skilled in the art will recognize, with the appropriate dosage ultimately being at the discretion of the attendant physician.
- a suitable dosage level of the compounds of the present invention, or pharmaceutically acceptable salts thereof is about 0.001 to 50 mg/kg per day, in particular about 0.01 to about 25 mg/kg, such as from about 0.05 to about 10 mg/kg per day.
- the dosage range will generally be about 0.5 to 1000 mg per patient per day, which may be administered in single or multiple doses.
- the dosage range will be about 0.5 mg to 500 mg per patient per day; more preferably about 0.5 mg to 200 mg per patient per day; and even more preferably about 5 mg to 50 mg per patient per day.
- Specific dosages of the compounds of the present invention, or pharmaceutically acceptable salts thereof, for administration include 1 mg, 5 mg, 10 mg, 30 mg, 100 mg, and 500 mg.
- Pharmaceutical compositions of the present invention may be provided in a formulation comprising about 0.5 mg to 1000 mg active ingredient; more preferably comprising about 0.5 mg to 500 mg active ingredient; or 0.5 mg to 250 mg active ingredient; or 1 mg to 100 mg active ingredient.
- Specific pharmaceutical compositions for treatment or prevention of excess tachykinins comprise about 1 mg, 5 mg, 10 mg, 30 mg, 100 mg, and 500 mg of active ingredient.
- Step A N-[(1E)-(4-fluorophenyI)methylene]-1-[(trimethylsilyl)oxy]ethylenamine
- Step C tert-butyl (2RS,3RS,4SR)-2-(4-fluorophenyl)-3,4-bis(hydroxymethyl)piperidine- 1 - carboxylate
- Step D tert-butyl (3aSR,4RS,7aSR)-2-benzyl-4-(4-fluorophenyl)octahydro-5H- pyrrolo[3,4-c]pyridine-5-carboxylate
- Step G (3aSR,4RS,7aSR)-5- ⁇ [3,5-bis(trifluoromethyl)phenyl]acetyl ⁇ -4-(4- fluorophenyl)octahydro-1H-pyrrolo [3 ,4-c]pyridine
- Step H 3-[(3aSR,4RS,7aSR)-5- ⁇ [3,5-bis(trifluoromethyI)phenyl]acetyl ⁇ -4-(4- fluorophenyl)octahydro-2H-pyrrolo [3 ,4-c]pyridin-2-yl] cyclopent-2-en- 1 -one
- Step A ⁇ l-[3,5-bis(trifluoromethyl)phenyl]ethyl ⁇ methylcarbamic chloride
- Step B (3aSR,4RS,7aSR)-2-benzyl-N- ⁇ 1 - [3,5 -bis(trifluoromethyl)phenyl] ethyl ⁇ -4-(4- fluorophenyl)-N-methyloctahydro-5H-pyrrolo [3 ,4-c] pyridine- 5 -carboxamide
- Step D (3aSR,4RS,7aSR)-N- ⁇ 1-[3,5-bis(trifluoromethyl)phenyl]ethyl ⁇ -4-(4-fluorophenyl)- N-methyl-2-(3-oxocyclopent-1-en-1-yl)octahydro-5H-pyrrolo [3 ,4-c] pyridine- 5 - carboxamide
- the title compound was prepared from (3aSR,4RS,7aSR)-N- ⁇ l-[3,5- bis(trifluoromethyl)phenyl]ethyl ⁇ -4-(4-fluorophenyl)-N-methyloctahydro-5H-pyrrolo[3,4- c]pyridine-5 -carboxamide and tetrahydro-2H-pyran-4-carboxylic acid by the procedure in
- Step A N-[(1E)-(2-methylphenyl)methylene]-1-[(trimelhylsilyl)oxy]ethylenamine
- Step B dimethyl (2RS,3RS,4SR)-2-(2-methylphenyl)-6-oxopiperidine-3,4-dicarboxylate
- Step D tert-butyl (3aSR,4RS,7aSR)-2-benzyl-4-(2-methylphenyl)octaliydro-5H- pyrrolo[3,4-c]pyridine-5-carboxylate
- Step E (3aSR,4RS,7aSR)-2-ben2yl-4-(2-methylphenyl)octahydro-1H-pyrrolo[3,4- c] pyridine
- Step B /erf-butyl (3a5/.,4 ⁇ JaS.?)-2-[3-(acetyloxy)-2 ⁇ -dimethylpropyl3-4-(2- methylphenyl)octahydro'5 ⁇ yiTolo[3,4 ⁇ ]pyridine-5-caiboxylale
- Step C 3-[(3aS,4 ⁇ ,7aS)-5- ⁇ [ ⁇ (ltf)-l-[3,5 ⁇ bis(trifIuoromethyl)phenyl]ethyl ⁇ (methyl)amino]carbonyl ⁇ -4-(2- methylphenyl)c ⁇ rtahydro-2i7 ⁇ yriOlo[3,4 ⁇ ]pyridin-2-yl]-2,2-dimethylpropyl acetate
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Abstract
Description
Claims
Priority Applications (5)
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CA2690737A CA2690737A1 (en) | 2007-06-22 | 2008-06-18 | 6.5-pyrrolopiperidine tachykinin receptor antagonists |
JP2010513364A JP2010530874A (en) | 2007-06-22 | 2008-06-18 | 6,5-pyrrolopiperidine tachykinin receptor antagonist |
EP08771300A EP2170064A4 (en) | 2007-06-22 | 2008-06-18 | 6.5-pyrrolopiperidine tachykinin receptor antagonists |
AU2008268667A AU2008268667A1 (en) | 2007-06-22 | 2008-06-18 | 6.5-pyrrolopiperidine tachykinin receptor antagonists |
US12/665,088 US20100197724A1 (en) | 2007-06-22 | 2008-06-18 | 6.5 -pyrrolopiperidine tachykinin receptor antagonists |
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US93686407P | 2007-06-22 | 2007-06-22 | |
US60/936,864 | 2007-06-22 |
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PCT/US2008/067270 WO2009002770A1 (en) | 2007-06-22 | 2008-06-18 | 6.5-pyrrolopiperidine tachykinin receptor antagonists |
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EP (1) | EP2170064A4 (en) |
JP (1) | JP2010530874A (en) |
AU (1) | AU2008268667A1 (en) |
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Cited By (14)
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WO2011062614A1 (en) * | 2009-11-20 | 2011-05-26 | Tonix Pharmaceuticals, Inc. | Methods and compositions for treating symptoms associated with post-traumatic stress disorder using cyclobenzaprine |
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US20140081064A1 (en) * | 2007-01-18 | 2014-03-20 | Sk Innovation Co., Ltd. & Sk Global Chemical Co. Ltd. | Ethylene tetramerization catalyst systems and method for preparing 1-octene using the same |
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- 2008-06-18 WO PCT/US2008/067270 patent/WO2009002770A1/en active Application Filing
- 2008-06-18 CA CA2690737A patent/CA2690737A1/en not_active Abandoned
- 2008-06-18 EP EP08771300A patent/EP2170064A4/en not_active Withdrawn
- 2008-06-18 JP JP2010513364A patent/JP2010530874A/en not_active Withdrawn
- 2008-06-18 AU AU2008268667A patent/AU2008268667A1/en not_active Abandoned
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US20070099914A1 (en) * | 2002-02-08 | 2007-05-03 | Giuseppe Alvaro | Piperidine Derivatives |
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Also Published As
Publication number | Publication date |
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EP2170064A1 (en) | 2010-04-07 |
JP2010530874A (en) | 2010-09-16 |
CA2690737A1 (en) | 2008-12-31 |
EP2170064A4 (en) | 2010-08-04 |
AU2008268667A1 (en) | 2008-12-31 |
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