WO2009100994A1 - Piperidine sulfonamide derivatives - Google Patents
Piperidine sulfonamide derivatives Download PDFInfo
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- WO2009100994A1 WO2009100994A1 PCT/EP2009/051135 EP2009051135W WO2009100994A1 WO 2009100994 A1 WO2009100994 A1 WO 2009100994A1 EP 2009051135 W EP2009051135 W EP 2009051135W WO 2009100994 A1 WO2009100994 A1 WO 2009100994A1
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- 0 CCC(N(CC)C(C(CCC1)CN1S([Al]*)(=O)=O)=O)[Al](*)C(C)* Chemical compound CCC(N(CC)C(C(CCC1)CN1S([Al]*)(=O)=O)=O)[Al](*)C(C)* 0.000 description 1
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- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/92—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with a hetero atom directly attached to the ring nitrogen atom
- C07D211/96—Sulfur atom
Definitions
- PIPERIDINE SULFONAMIDE DERIVATIVES The present invention relates to compounds of formula
- Ar 1 and Ar 2 are independently from each other unsubstituted or substituted aryl or heteroaryl;
- R 1 and R 2 are independently from each other hydroxy, halogen, lower alkyl, lower alkyl substituted by halogen, lower alkoxy, lower alkoxy substituted by halogen or cyano; m is 0, 1, 2 or 3; n is 1 or 2;
- the compounds of formula I are orexin receptor antagonists and the related compounds may be useful in the treatment of disorders, in which orexin pathways are involved like sleep disorders including sleep apnea, narcolepsy, insomnia, parasomnia, jet lag syndrome, circadian rhythms disorder, restless leg syndrome, psychiatric, neurological and neurodegenerative disorders including anxiety, depression, manic depression, obsessive compulsive disorders, affective neurosis, depressive neurosis, anxiety neurosis, mood disorder, delirium, panic-attack disorder, posttraumatic stress disorders, sexual dysfunction, schizophrenia, psychosis, cognitive disorders, Alzheimer's and Parkinson's diseases, dementia, mental retardation, dyskinesias such as Huntington's disease and Tourette syndrome, addictions, craving associated with drug abuse, seizure disorders, epilepsy, metabolic diseases such as obesity, diabetes, eating disorders including anorexia and bulimia, asthma, migraine, headache, pain, neuropathic pain, sleep disorders associated with psychiatric, neurological disorders and neurode
- Orexins hypocretins
- hypocretins a family of hypothalamic neuropeptides
- the orexin-A / hypocretinl (OX-A, 33 amino acids) and orexin-B / hypocretin2 (OX-B, 28 amino acids) are derived from the same precursor by proteolytic processing of 130 amino acids prepro-orexin (de Lecea et at, Proc Natl Acad Sd US A, 95, 322-327, 1998; Sakurai T. et at, Cell, 92, 573-585, 1998).
- orexin levels show a diurnal variation being highest during the active cycle.
- Two receptor subtypes termed orexin- 1 receptor (OXiR) and orexin-2 receptor (OX2R) have been identified.
- OX2R is a non-selective receptor for both OX-A and -B
- OXiR is selective for OX-A
- OX-B is selective and has a higher affinity for OX2R ⁇ Sakurai T. et at, Cell, 92, 573-585, 1998).
- Both receptors belong to the class A family of G-protein-coupled receptors (GPCRs) that couple via G q/ ⁇ to the activation of phospholipase C leading to phosphoinositide (PI) hydrolysis and elevation of intracellular Ca 2+ levels.
- GPCRs G-protein-coupled receptors
- OX2R could also couple via G ⁇ 0 to cAMP pathway (Sakurai, Regulatory Peptides, 126, 3-10, 2005).
- Northern blot analysis of adult rat tissues showed that the prepro-orexin mRNA is detected exclusively in the brain (except for a small amount in the testis) and that the OXiR and OX2R transcripts are also exclusively detected in the brain (Sakurai T.
- a disrupted orexin system is suggested to be the cause of narcolepsy based on following lines of evidence: (a) Prepro-orexin knockout mice possessed a phenotype with characteristics remarkably similar to narcolepsy (Chemelli et al, Cell, 98, 437-451, 1999), (b) a mutation (canarc-1), which disrupts the gene encoding OX2R, was found to be responsible for canine narcolepsy (Lin et al., Cell, 98, 365-376, 1999), (c) lack of OX-A and OX-B was observed in human narcoleptic patients (Nishino et al., Lancet, 355, 39-40, 2000; Peyron et al, Nature Medicine, 6, 991-997, 2000), (d) it has been shown that Modafinil, an anti-narcoleptic drug with unknown mechanism of action, activates orexin neurons (Mignot et al, Sleep, 11, 1012
- Orexin plays an important role in stress and anxiety via its interaction with the corticotropin-releasing factor (CRF) system in hypothalamus (Sakamoto et al, Regul Pept, 118, 183-91, 2004).
- CRF corticotropin-releasing factor
- the icv injection of OX-A induces grooming (stress-response) which is blocked in part by a CRF antagonist (Ida et al, Biochem. Biophys. Res. Comm., 270, 318- 323, 2000).
- OX2R is highly expressed in adrenal medulla, whereas OXiR is high in adrenal cortex.
- OX-A and OX-B stimulate corticosterone release in plasma and induce c-Fos in paraventricular nucleus (PVN) in the hypothalamus (Kuru et al, Neuroreport, 11, 1977- 1980, 2000). Furthermore, orexin neurons projecting to CRF neurons express mainly the OX 2 R (Winsky-Sommerer et al, J. Neuroscience, 24, 11439-11448, 2004). Therefore, OX2R stimulation activates the hypothalamo-pituitary-adrenal (HPA) axis.
- HPA hypothalamo-pituitary-adrenal
- lower alkyl denotes a straight- or branched-chain alkyl group containing from 1-4 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, n-butyl, i-butyl, t-butyl and the like.
- alkyl denotes a straight- or branched- chain alkyl group containing from 1-7 carbon atoms.
- lower alkoxy denotes a group wherein the alkyl residues are as defined above, and which is attached via an oxygen atom.
- halogen denotes chlorine, iodine, fluorine and bromine.
- aryl means the monovalent cyclic aromatic hydrocarbon group consisting of one or more fused rings in which at least one ring is aromatic in nature. Examples of aryl radicals include, but are not limited to, phenyl, naphthyl, 5,6,7,8- tetrahydro-naphthalenyl, biphenyl, indanyl, anthraquinolyl, and the like.
- Heteroaryl means a carbocyclic group having one or more rings, wherein at least one ring is aromatic in nature, incorporating one, two, or three heteroatoms within the ring (chosen from nitrogen, oxygen, or sulfur).
- heteroaryl radicals include, but are not limited to, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiophenyl, furanyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinolinyl, isoquinolinyl, benzofuryl, benzothiophenyl, benzothiopyranyl, benzimidazolyl, benzooxazolyl, benzothiazolyl, benzopyranyl, indazolyl, indolyl, isoindolyl, chromanyl, naphtyridinyl, 2,3-dihydro
- lower alkyl substituted by halogen denotes an alkyl group as defined above, wherein at least one hydrogen atom is replaced by halogen, for example CF 3 , CHF 2 , CH 2 F, CH 2 CF 3 , CH 2 CH 2 CF 3 , CH 2 CF 2 CF 3 and the like.
- lower alkoxy substituted by halogen denotes a group wherein a lower alkyl substituted by halogen residue as defined above is attached via an oxygen atom.
- pharmaceutically acceptable acid addition salts embraces salts with inorganic and organic acids, such as hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, fumaric acid, maleic acid, acetic acid, succinic acid, tartaric acid, methanesulfonic acid, p-toluenesulfonic acid and the like.
- Preferred compounds of formula I are those wherein n is 1.
- Preferred compounds from this group are for example the following compounds
- Preferred compounds of formula I are further those wherein n is 2.
- Preferred compounds from this group are for example the following compounds
- present compounds of formula I and their pharmaceutically acceptable salts can be prepared by methods known in the art, for example, by processes described below, which process comprises a) reacting a compound of formula
- Ar 1 , Ar 2 , R 1 , R 2 , m and n are as described above, or
- Ar 1 , Ar 2 , R 1 , R 2 , m and n are as described above, and if desired, converting the compounds obtained into pharmaceutically acceptable acid addition salts.
- the compounds of formula I can be manufactured by the methods given below, by the methods given in the examples or by analogous methods.
- Appropriate reaction conditions for the individual reaction steps are known to a person skilled in the art.
- the reaction sequence is not limited to the one displayed in scheme 1, however, depending on the starting materials and their respective reactivity the sequence of reaction steps can be freely altered.
- Starting materials are either commercially available or can be prepared by methods analogous to the methods given below, by methods described in references cited in the description or in the examples, or by methods known in the art.
- l-(tert-Butoxycarbonyl)-3-piperidinecarboxylic acid II is commercially available and can be coupled with 2-phenyl pyrrolidines or piperidenes VI, which are commercially available or can be accessed by methods described in literature like in: Basha, F. Z.; Debernardis, J. F.; Tetrahedron Lett 1984, 25, 527 or Walter, G.; Chem Ber 1951, 84, 304.
- the coupling of carboxylic acids with amines is widely described in literature and the procedures are known to those in the art (For reaction conditions described in literature affecting such reactions see for example: Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 2 nd Edition, Richard C. Larock.
- the acid can conveniently be transformed to the respective amide through coupling with an amine by employing the usage of coupling reagents.
- coupling reagents like N,N'-carbonyldiimidazole (CDI), N,N'- dicyclohexylcarbodiimide (DCC), l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI), l-[bis(dimethylamino)methylene] -IH-1, 2,3-triazolo [4,5- b]pyridinium-3-oxide hexafluorophosphate (HATU), l-hydroxy-l,2,3-benzotriazole (HOBT), O-benzotriazol-l-yl-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU) and the like can equally well be employed to
- reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. We find it convenient to carry out the reaction with heating from ambient temperature to reflux. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents.
- any base commonly used in this type of reaction may equally be employed here.
- bases include triethylamine and diisopropylethylamine, and the like.
- the reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. We find it convenient to carry out the reaction with heating from ambient temperature to reflux. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents. However, a period of from 0.5 h to several days will usually suffice to yield piperidine sulfonamides I.
- Piperidine-3-carboxylic acid ethyl ester IV is commercially available and can be coupled with sulfonylchlorides VII (either commercially available or accessible through methods described in literature) in the presence of a base and a solvent to yield the piperidine uspend mide ester V.
- a base and a solvent to yield the piperidine uspend mide ester V.
- suitable solvents include: DMF, dichloromethane (DCM), dioxane, THF, and the like.
- reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. We find it convenient to carry out the reaction with heating from ambient temperature to reflux. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents. However, a period of from 0.5 h to several days will usually suffice to yield piperidine uspend mide ester V.
- reaction temperature we find it convenient to carry out the reaction with heating from ambient temperature to reflux.
- the time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents. However, a period of from 0.5 h to several days will usually suffice to yield piperidine uspend mide ester V.
- piperidine uspend mide ester V.
- Piperidine sulfonamide ester V can be transformed to the final piperidine sulfonamides I in analogy to procedures described in literature. However, we find it convenient to employ a two step reaction sequence in which the ester functionality in V is cleaved under aqueous basic conditions and the liberated acid functionality converted with the respective amines VI under coupling conditions.
- aqueous base there is no particular restriction on the nature of the aqueous base to be employed, provided that it has no adverse effect on the reaction or the reagents involved and that it can dissolve the reagents, at least to some extent.
- suitable aqueous bases include NaOH, LiOH and the like. Any commonly used co-solvent can be employed. Examples include methanol, THF water, and the like.
- HATU [bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate
- HOBT l-hydroxy-l,2,3-benzotriazole
- TBTU O-benzotriazol-1- yl-N,N,N',N'-tetramethyluronium tetrafluoroborate
- solvent there is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or the reagents involved and that it can dissolve the reagents, at least to some extent.
- suitable solvents include: DMF, dichloromethane (DCM), dioxane, THF, and the like.
- base used in this stage, and any base commonly used in this type of reaction may equally be employed here. Examples of such bases include triethylamine and diisopropylethylamine, and the like.
- the reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. We find it convenient to carry out the reaction with heating from ambient temperature to reflux. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents. However, a period of from 0.5 h to several days will usually suffice to yield piperidine sulfonamides I.
- the Chinese Hamster Ovary (dHFr-) mutant cell line stably expressing human orexin-1
- hOXl human orexin-2 receptors were maintained in Dulbecco's Modified Eagle Medium ( IX) with GlutaMaxTMl, 4500 mg/L D-Glucose and Sodium Pyruvate
- F- 14202 F- 14202, Molecular Probes, Eugene, OR) in FLIPR buffer (IxHBSS, 20 mM HEPES, 2.5 mM Probenecid).
- FLIPR buffer IxHBSS, 20 mM HEPES, 2.5 mM Probenecid.
- Hanks' Balanced Salt Solution (HBSS) (10X) (catalog No. 14065-049) and HEPES (IM) (catalog No. 15630-056) were purchased from Invitrogen, Carlsbad, CA.
- Probenecid (250 mM) (catalog No. P8761) was from Sigma, Buchs, Switzerland.
- the cells were washed five times with FLIPR buffer to remove excess dye and intracellular calcium mobilization, [Ca 2+ ] i were measured using a Fluorometric Imaging Plate Reader (FLIPR-96, Molecular Devices, Menlo Park, CA) as described previously (Malherbe et al., MoI. Pharmacol., 64, 823-832, 2003). Orexin A (catalog No. 1455, Toris Cookson Ltd, Bristol, UK) was used as agonist. Orexin A (50 mM stock solution in DMSO) was diluted in FLIPR buffer + 0.1% BSA.
- FLIPR-96 Fluorometric Imaging Plate Reader
- the EC50 and EC ⁇ o values of orexin-A were measured daily from standard agonist concentration-response curves in CHO(dHFr-)-OXlR and -OX2R cell lines. All compounds were dissolved in 100 % DMSO. Inhibition curves were determined by addition of 11 concentrations (0.0001-10 ⁇ M) of inhibitory compounds and using EC ⁇ o value of orexin-A as agonist (a concentration which gave 80% of max agonist response, determined daily). The antagonists were applied 25 min (incubation at 37°C) before the application of the agonist.
- the compounds show a K b value ( ⁇ M) ⁇ 0.1 in human on orexin receptor as shown in the table below.
- the compounds of formula I and the pharmaceutically acceptable salts of the compounds of formula I can be used as medicaments, e.g. in the form of pharmaceutical preparations.
- the pharmaceutical preparations can be administered orally, e.g. in the form of tablets, coated tablets, dragees, hard and soft gelatine capsules, solutions, emulsions or uspend- sions.
- the administration can, however, also be effected rectally, e.g. in the form of suppositories, or parenterally, e.g. in the form of injection solutions.
- the compounds of formula I can be processed with pharmaceutically inert, inorganic or organic carriers for the production of pharmaceutical preparations.
- Lactose, corn starch or derivatives thereof, talc, stearic acids or its salts and the like can be used, for example, as such carriers for tablets, coated tablets, dragees and hard gelatine capsules.
- Suitable carriers for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like. Depending on the nature of the active substance no carriers are however usually required in the case of soft gelatine capsules.
- Suitable carriers for the production of solutions and syrups are, for example, water, polyols, glycerol, vegetable oil and the like.
- Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like.
- the pharmaceutical preparations can, moreover, contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances.
- Medicaments containing a compound of formula I or a pharmaceutically acceptable salt thereof and a therapeutically inert carrier are also an object of the present invention, as is a process for their production, which comprises bringing one or more compounds of formula I and/or pharmaceutically acceptable acid addition salts and, if desired, one or more other therapeutically valuable substances into a galenical administration form together with one or more therapeutically inert carriers.
- the most preferred indications in accordance with the present invention are those, which include sleep disorders including sleep apnea, narcolepsy, insomnia, parasomnia, jet lag syndrome, circadian rhythms disorder, restless leg syndrome, psychiatric, neurological and neurodegenerative disorders including anxiety, depression, manic depression, obsessive compulsive disorders, affective neurosis, depressive neurosis, anxiety neurosis, mood disorder, delirium, panic-attack disorder, posttraumatic stress disorders, sexual dysfunction, schizophrenia, psychosis, cognitive disorders, Alzheimer's and Parkinson's diseases, dementia, mental retardation, dyskinesias such as Huntington's disease and Tourette syndrome, addictions, craving associated with drug abuse, seizure disorders, epilepsy, metabolic diseases such as obesity, diabetes, eating disorders including anorexia and bulimia, asthma, migraine, pain, headache, neuropathic pain, sleep disorders associated with psychiatric, neurological and neurodegenerative disorders, neuropathic pain, enhanced or exaggerated sensitivity to
- the dosage can vary within wide limits and will, of course, have to be adjusted to the individual requirements in each particular case.
- the dosage for adults can vary from about 0.01 mg to about 1000 mg per day of a compound of general formula I or of the corresponding amount of a pharmaceutically acceptable salt thereof.
- the daily dosage may be administered as single dose or in divided doses and, in addition, the upper limit can also be exceeded when this is found to be indicated.
- Tablet Formulation (Wet Granulation) Item Ingredients mg/ tablet
- step 1 l-(2-Chloro-benzenesulfonyl)-piperidine-3-carboxylic acid ethyl ester
- step 2 Lithium l-(2-chloro-benzene sulfonyl)-piperidine-3 carboxylate
- Step 3 [l-(2-Chloro-benzenesulfonyl)-piperidin-3-yll-(2-m-tolyl-pyrrolidin-l-yl)-methanone
- DCM dimethyl sulfoxide
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Abstract
Description
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Priority Applications (10)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN200980102624.1A CN101918361B (en) | 2008-02-12 | 2009-02-02 | Piperidine sulfonamide derivatives |
CA2713713A CA2713713C (en) | 2008-02-12 | 2009-02-02 | Piperidine sulfonamide derivatives |
BRPI0907627-1A BRPI0907627A2 (en) | 2008-02-12 | 2009-02-02 | Piperidine Sulphonamides Derivatives |
EP09711149A EP2252587B1 (en) | 2008-02-12 | 2009-02-02 | Piperidine sulfonamide derivatives |
AT09711149T ATE517090T1 (en) | 2008-02-12 | 2009-02-02 | PIPERIDINE SULPHONAMIDE DERIVATIVES |
JP2010546286A JP5346043B2 (en) | 2008-02-12 | 2009-02-02 | Piperidinesulfonamide derivatives |
MX2010007968A MX2010007968A (en) | 2008-02-12 | 2009-02-02 | Piperidine sulfonamide derivatives. |
KR1020107017153A KR101229603B1 (en) | 2008-02-12 | 2009-02-02 | Piperidine sulfonamide derivatives |
AU2009214244A AU2009214244B2 (en) | 2008-02-12 | 2009-02-02 | Piperidine sulfonamide derivatives |
IL206615A IL206615A (en) | 2008-02-12 | 2010-06-24 | Piperidine sulfonamide derivatives, process for their preparation, medicaments containing them and use thereof for the preparation of medicaments for therapy |
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JP (1) | JP5346043B2 (en) |
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CN (1) | CN101918361B (en) |
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AU (1) | AU2009214244B2 (en) |
BR (1) | BRPI0907627A2 (en) |
CA (1) | CA2713713C (en) |
ES (1) | ES2367341T3 (en) |
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WO (1) | WO2009100994A1 (en) |
Cited By (1)
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JP2013538206A (en) * | 2010-08-24 | 2013-10-10 | アクテリオン ファーマシューティカルズ リミテッド | Proline sulfonamide derivatives as orexin receptor antagonists |
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US9440982B2 (en) | 2012-02-07 | 2016-09-13 | Eolas Therapeutics, Inc. | Substituted prolines/piperidines as orexin receptor antagonists |
EP2811997B1 (en) | 2012-02-07 | 2018-04-11 | Eolas Therapeutics Inc. | Substituted prolines/piperidines as orexin receptor antagonists |
JP6663909B2 (en) | 2014-08-13 | 2020-03-13 | エオラス セラピューティクス, インコーポレイテッド | Difluoropyrrolidine as an orexin receptor modulator |
AU2017217931B2 (en) | 2016-02-12 | 2020-10-22 | Astrazeneca Ab | Halo-substituted piperidines as orexin receptor modulators |
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2009
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- 2009-02-02 EP EP09711149A patent/EP2252587B1/en not_active Not-in-force
- 2009-02-02 JP JP2010546286A patent/JP5346043B2/en not_active Expired - Fee Related
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- 2009-02-02 CN CN200980102624.1A patent/CN101918361B/en not_active Expired - Fee Related
- 2009-02-02 WO PCT/EP2009/051135 patent/WO2009100994A1/en active Application Filing
- 2009-02-02 KR KR1020107017153A patent/KR101229603B1/en not_active IP Right Cessation
- 2009-02-02 ES ES09711149T patent/ES2367341T3/en active Active
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US20050288317A1 (en) * | 2004-06-24 | 2005-12-29 | Wenqing Yao | Amido compounds and their use as pharmaceuticals |
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Cited By (1)
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JP2013538206A (en) * | 2010-08-24 | 2013-10-10 | アクテリオン ファーマシューティカルズ リミテッド | Proline sulfonamide derivatives as orexin receptor antagonists |
Also Published As
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JP2011511822A (en) | 2011-04-14 |
IL206615A (en) | 2015-10-29 |
ATE517090T1 (en) | 2011-08-15 |
US8202888B2 (en) | 2012-06-19 |
US20090203736A1 (en) | 2009-08-13 |
MX2010007968A (en) | 2010-08-04 |
JP5346043B2 (en) | 2013-11-20 |
BRPI0907627A2 (en) | 2015-07-21 |
US8691846B2 (en) | 2014-04-08 |
EP2252587B1 (en) | 2011-07-20 |
CA2713713A1 (en) | 2009-08-20 |
US20130217729A1 (en) | 2013-08-22 |
AU2009214244A1 (en) | 2009-08-20 |
KR101229603B1 (en) | 2013-02-04 |
US20120238602A1 (en) | 2012-09-20 |
AU2009214244B2 (en) | 2013-02-07 |
CA2713713C (en) | 2016-05-24 |
ES2367341T3 (en) | 2011-11-02 |
IL206615A0 (en) | 2010-12-30 |
KR20100111709A (en) | 2010-10-15 |
EP2252587A1 (en) | 2010-11-24 |
CN101918361B (en) | 2014-05-28 |
CN101918361A (en) | 2010-12-15 |
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