WO2007039797A1 - Utilisation d'antagonistes du recepteur cannabinoide de type 1 pour traiter les inflammations et l'arthrite - Google Patents

Utilisation d'antagonistes du recepteur cannabinoide de type 1 pour traiter les inflammations et l'arthrite Download PDF

Info

Publication number
WO2007039797A1
WO2007039797A1 PCT/IB2006/002623 IB2006002623W WO2007039797A1 WO 2007039797 A1 WO2007039797 A1 WO 2007039797A1 IB 2006002623 W IB2006002623 W IB 2006002623W WO 2007039797 A1 WO2007039797 A1 WO 2007039797A1
Authority
WO
WIPO (PCT)
Prior art keywords
phenyl
chloro
inflammatory
carboxamide
administering
Prior art date
Application number
PCT/IB2006/002623
Other languages
English (en)
Inventor
Shanmugam Muthian
Stephen John Mnich
Luz Amparo Cortes Burgos
Brian Michael Naiman
Original Assignee
Pfizer Products Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Pfizer Products Inc. filed Critical Pfizer Products Inc.
Publication of WO2007039797A1 publication Critical patent/WO2007039797A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • 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]

Definitions

  • the present invention relates to the treatment of inflammation, pain associated with inflammation and arthritis with cannabinoid receptor-1 (CB-1) antagonists.
  • CBD-1 cannabinoid receptor-1
  • Cannabis Sativa has been used for medicinal and recreational purposes for about 5000 years. Progress within the cannabinoid research field in the last 50 years has led to significant interest in the use of cannabinoid pharmacology for the treatment of a host of ailments including pain, inflammation, cancer and cachexia.
  • the mechanism of action of cannabinoids are thought to be mediated by cannabinoid receptors at the cell surface.
  • 2 receptors have been identified, CB1 (Nature, 346:561- 564 (1990); Matsuda et.al.) and CB2 (Nature, 365:61-65 (1993); Munro et.al) that couple to the Gi subtype of G-protein signaling pathways.
  • Multiple studies have demonstrated that activation of these receptors inhibit adenylate cyclase activity among other effects.
  • the distribution of these receptors appears to be fairly distinct with CB1 receptors primarily in the CNS and CB2 primarily in the periphery.
  • CB1 receptor activation leads to increased food consumption and weight gain
  • CB1 receptor blockade reduces food consumption and leads to weight loss
  • cannabinoids have also been suggested to be immunomodulatory; this effect has been attributed to the involvement of the CB2 receptor regulation of immune cell expansion and trafficking (Prostaglandin Leukot. Essent.
  • cannabinoid receptor ligands relate in inflammatory disorders, see, e.g., Rao GK, et al., J Leuko Biol 75, 884-892 (2004); Klein TW, et al., J Neuroimmunol, 147, 91-94 (2004); and Klein, TW, et al., Immunology Today, 19, 373-381 (1998).
  • cannabinoid receptor ligands relating to pain disorders, see e.g., Cravatt BF, et al., lnt J Neurobiol, 61,149-160 (2004); Richardson JD, et al.. Pain. 75,111-1 19 (1998); KeIIv S. et al., Eur J Neurosci. 18, 2239-2243 (2003); Clayton N, et al., Pajn, 96, 253-260 (2002); and Watts G.. Br Med J. 329, 257-258 (2004).
  • the data are equivocal in terms of the characteristics of the ligands required for anti-inflammatory activity (e.g., agonist vs. antagonist). See, e.g., Rao GK, et al., J Leuko Biol 75, 884-892 (2004); Klein, TW, et al., J Neuroimmunol, 147, 91-94 (2004); Klein, TW, et al., Immunology Today,19, 373-381 (1998);
  • CB1 receptor antagonists produce antiinflammatory activities beyond the suppression of TNF ⁇ .
  • the data reported herein demonstrates that CB1 receptor antagonists are active in both the mouse LPS challenge acute inflammation model as well as in the rat carrageenan-induced inflammation model.
  • the present invention provides a method for treating inflammatory diseases comprising the step of administering to an animal (preferably, a mammal, more preferably a human) in need thereof a therapeutically effective amount of a CB-1 antagonist (preferably, a selective CB-1 antagonist).
  • a CB-1 antagonist preferably, a selective CB-1 antagonist
  • Preferred inflammatory diseases include arthritis, inflammatory bowel disease and congestive obstructive pulmonary disorder.
  • the therapeutically effective amount is an amount sufficient to decrease the concentration of TNFoc or MIP-1oc and/or increase the concentration of IL-10 in the blood serum of the animal.
  • the reduction of TNFoc and/or M1P-1 «: that is significant or desirable is 40-60% (preferred), 60-80% (more preferred) and 80-100%
  • a method for reducing the symptoms of inflammation comprising the step of administering to an animal (preferably a mammal, more preferably a human) in need thereof a therapeutically effective amount of a CB-1 antagonist (preferably, a selective CB-1 antagonist).
  • a CB-1 antagonist preferably, a selective CB-1 antagonist.
  • the therapeutically effective amount is an amount sufficient to inhibit production of PGE 2 and TNFcc.
  • TNFoc or PGE 2 The reduction of TNFoc or PGE 2 that is significant or desirable is 40-60% (preferred), 60-80%
  • a method for treating inflammatory pain comprising the step of administering to an animal (preferably, a mammal, more preferably, a human) in need thereof a therapeutically effective amount of a CB-1 antagonist (preferably, a selective CB-1 antagonist).
  • a CB-1 antagonist preferably, a selective CB-1 antagonist
  • a method for treating arthritis comprising the step of administering to an animal
  • a CB-1 antagonist preferably, a selective CB-1 antagonist
  • terapéuticaally effective amount means an amount of a compound of the present invention that (i) treats or prevents the particular disease, condition, or disorder, (ii) attenuates, ameliorates, or eliminates one or more symptoms of the particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of the particular disease, condition, or disorder described herein.
  • animal refers to humans (male or female), companion animals (e.g., dogs, cats and horses), food-source animals, zoo animals, marine animals, birds and other similar animal species.
  • animal animals refers to food-source animals such as cows, pigs, sheep and poultry.
  • pharmaceutically acceptable indicates that the substance or composition must be compatible chemically and/or toxicologically, with the other ingredients comprising a formulation, and/or the mammal being treated therewith.
  • treating embrace both preventative, i.e., prophylactic, and palliative treatment.
  • a ligand may act as an agonist, partial agonist, inverse agonist, antagonist, or partial antagonist.
  • FIGURES Figure 1A, 1 B and 1C illustrate circulating TNFoc, MIP-1oc and IL-10 concentration, respectively, in serum of mice following low endotoxin challenge.
  • Mice were dosed intraperitoneally with 1 mg/kg of compounds 1 hour prior to LPS challenge (100 ng/mouse). Animals were terminated and blood collected 1 hour after LPS administration. The data represents 5 mice per group and reported as mean ⁇ SEM.
  • Figures 2A and 2B illustrate paw swelling and production of PGE 2 and TNFoc, respectively, following carrageenan stimuli in the rat. Rats were dosed intravenously with Compound C followed by carrageenan injection (1 mg/100uL/paw) into the right hind paw.
  • CB1 receptor antagonists produce antiinflammatory activities beyond the suppression of TNF ⁇ .
  • the data reported herein demonstrates that CB1 receptor antagonists are active in both the mouse LPS challenge acute inflammation model as well as in the rat carrageenan-induced inflammation model. Both models are standard well-established models that assess inhibition of acute inflammatory responses. Therefore, it is reasonable to believe that CB-1 receptor antagonists would be useful for treating inflammation, pain associated with inflammation and arthritis (in particular, rheumatoid arthritis). Consequently, the CB-1 antagonists described herein (including the compositions thereof) may be used in the manufacture of a medicament for the therapeutic applications described herein.
  • Cannabinoid-1 (CB-1) Receptor Antagonists CB-1 (CB-1) Receptor Antagonists:
  • CB-1 receptor refers to a G-protein coupled type 1 cannabinoid receptor.
  • antagonist includes both full antagonists and partial antagonists, as well as inverse agonists.
  • the CB-1 receptor antagonist is selective to the CB-1 receptor.
  • CB-1 receptor selective means that the compound has little or no activity to antagonize the cannabinoid-2 receptor (CB-2). More preferably, the CB-1 antagonist is at least about 10 fold selective for the CB-1 receptor in comparison to the CB-2 receptor.
  • the inhibitory concentration (IC 50 ) for antagonizing the CB-1 receptor is about 10 or more times lower than the IC 50 for antagonizing the CB-2 receptor.
  • Suitable CB-1 receptor antagonists include compounds disclosed in U.S. Patent Nos. 5,462,960; 5,596,106; 5,624,941 ; 5,747,524; 6,017,919; 6,028,084; 6,432,984; 6,476,060; 6,479,479; 6,518,264; and 6,566,356;
  • WO 03/075660 the hydrochloride, mesylate and besylate salt of 1 -[9-(4-chloro-phenyl)-8-(2-chloro-phenyl)-9H-purin-6-yl]-4-ethylamino-piperidine- 4-carboxylic acid which can be prepared as described in U.S. Patent Publication No.
  • Patent Publication No. 2004/0214855 3-(4-chloro-phenyl)-2-(2 ⁇ chIoro-phenyl)-7-(2,2-difluoro- propyl)-6,7-dihydro-2H,5H-4-oxa-1 ,2,7-triaza-azulen-8-one which can be prepared as described in U.S. Patent Publication No. 2005/0101592; 2-(2-chloro-phenyl)-6-(2,2,2-trifluoro-ethyl)-3-(4- trifluoromethyl-phenyl)-2,6-dihydro-pyrazolo[4,3-d]pyrimidin-7-one which can be prepared as described in U.S. Patent Publication No.
  • a typical formulation is prepared by mixing the CB-1 receptor antagonist with a carrier, diluent or excipient.
  • Suitable carriers, diluents and excipients are well known to those skilled in the art and include materials such as carbohydrates, waxes, water soluble and/or swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, and the like.
  • the particular carrier, diluent or excipient used will depend upon the means and purpose for which the compound of the present invention is being applied.
  • Solvents are generally selected based on solvents recognized by persons skilled in the art as safe (GRAS) to be administered to a mammal.
  • GRAS solvents recognized by persons skilled in the art as safe
  • safe solvents are non-toxic aqueous solvents such as water and other nontoxic solvents that are soluble or miscible in water.
  • Suitable aqueous solvents include water, ethanol, propylene glycol, polyethylene glycols (e.g., PEG400, PEG300), etc. and mixtures thereof.
  • the formulations may also include one or more buffers, stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents and other known additives to provide an elegant presentation of the drug or aid in the manufacturing of the pharmaceutical product (i.e., medicament).
  • the formulations may be prepared using conventional dissolution and mixing procedures.
  • the bulk drug substance (the compound or stabilized form of the compound (e.g., complex with a cyclodextrin derivative or other known complexation agent)) is dissolved in a suitable solvent in the presence of one or more of the excipients described above.
  • the compound is typically formulated into pharmaceutical dosage forms to provide an easily controllable dosage of the drug and to give the patient an elegant and easily handleable product.
  • the CB-1 receptor antagonist may be formulated into a single dosage form or separate dosage forms. To enhance dissolution rates, it may be advantageous to disperse poorly water-soluble compounds in a suitable dispersant prior to formulating into a dosage form.
  • the water-insoluble or partially water-insoluble compound may be spray-dried in the presence of a solubilizing or dispersing agent.
  • a solubilizing or dispersing agent See, e.g., Takeuchi, Hirofumi, et al., J Pharm Pharmacol, 39, 769-773 (1987).
  • Other techniques for improving bioavailability of poorly water-soluble compounds are described in Verreck, G., et al., J Pharm Sci, 93(5), 1217-1228 (2004).
  • typical dosage forms include tablets, dragees, capsules, granules, sachets and liquid solutions or suspensions where each contain a predetermined amount of the active ingredient(s) in the form of a powder or granules, or as a solution or a suspension in an aqueous liquid, a non-aqueous liquid, an oil-in-water emulsion or a water-in-oil liquid emulsion.
  • Compressed tablets may be prepared by compressing the active ingredient(s) in a free- flowing form such as a powder or granules with a binder, lubricant, inert diluent, surface active agent and/or dispersing agent.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs.
  • the liquid dosage form may contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents and emulsifiers, as for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1 ,3-butylene glycol, dimethylformamide, oils (e.g., cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil, sesame seed oil and the like), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, or mixtures of these substances, and the like.
  • the composition can also benzoate, propylene glycol, 1 ,3-buty
  • Suspensions in addition to the active ingredients, may further comprise suspending agents, e.g., ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth, or mixtures of these substances, and the like.
  • suspending agents e.g., ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth, or mixtures of these substances, and the like.
  • the pharmaceutical composition (or formulation) for application may be packaged in a variety of ways depending upon the method used for administering the drug.
  • an article for distribution includes a container having deposited therein the pharmaceutical formulation in an appropriate form.
  • Suitable containers are well-known to those skilled in the art and include materials such as bottles (plastic and glass), sachets, ampoules, plastic bags, metal cylinders, and the like.
  • the container may also include a tamper-proof assemblage to prevent indiscreet access to the contents of the package.
  • the container has deposited thereon a label that describes the contents of the container. The label may also include appropriate warnings.
  • the compounds can be administered by any method which delivers the compounds preferentially to the desired tissue (e.g., brain, renal or intestinal tissues).
  • the compounds are administered orally in single (e.g., once daily) or multiple doses.
  • the amount and timing of compounds administered will, of course, be dependent on the subject being treated, on the severity of the affliction, on the manner of administration and on the judgment of the prescribing physician.
  • the dosages given herein are a guideline and the physician may titrate doses of the drug to achieve the treatment that the physician considers appropriate for the patient.
  • the physician must balance a variety of factors such as age of the patient, presence of preexisting disease, as well as presence of other diseases (e.g., cardiovascular disease).
  • a daily dose of the CB-1 receptor antagonist is generally between about 0.01 mg to about 10 mg per kilogram of body weight, preferably between about 1 mg to about 10 mg per kilogram of body weight, more preferably between about 0.1 mg to about 1 mg per kilogram of body weight, most preferably between about 0.01 mg to about 0.1 mg per kilogram of body weight.
  • Suitable anti-inflammatory agents include COX-2 inhibitors (e.g., VioxxTM, CelebrexTM and BextraTM); non-selective anti-inflammatory agents (ibuprofen, naproxen), acetaminophen, and steroids such as prednisolone, and budesonide.
  • COX-2 inhibitors e.g., VioxxTM, CelebrexTM and BextraTM
  • non-selective anti-inflammatory agents ibuprofen, naproxen
  • acetaminophen acetaminophen
  • steroids such as prednisolone, and budesonide.
  • SSRIs serotonin reuptake inhibitors
  • CipramilTM or CelexaTM citalopram
  • EffexorTM venlafaxine HCI
  • ElavilTM amitriptyline
  • fluvoxamine maleate Lexapro® (escitalopram oxalate)
  • Lexapro® escitalopram oxalate
  • _PaxilTM _PaxilTM or AropaxTM.
  • SSNRIs selectrive seritonin and noradrenaline reuptake inhibitors
  • Both the acute inflammatory and carrageenan-induced inflammation models were used to test the inflammatory response of the test compounds (e.g., CB-1 antagonists).
  • the test compounds e.g., CB-1 antagonists.
  • the key cytokine, tumor necrosis factor ⁇ (TNF ⁇ ) was used as an indicator of the inflammatory response.
  • TNF ⁇ tumor necrosis factor ⁇
  • both paw swelling, and the production of PGE 2 and TNF ⁇ in the paw were used as indicators of the inflammatory response.
  • LPS Lipopolysaccharide
  • AALAC American Association for the Accreditation of Laboratory Animal Care
  • Test compounds were prepared in dimethylsulfoxide (DMSO):emulphor:saline (1 :1 :18). Compounds or vehicle alone were administered i.p. in 0.1 ml volume. LPS, at 100 ng/mouse, were administered 1 hour later by intravenous injection into the tail vein in 0.2 ml sterile saline. Blood was collected in serum separator tubes via cardiac puncture or orbital bleed 1 hour after LPS injection. Blood was allowed to clot, and serum obtained by centrifugation. Serum was stored at -80 0 C until assayed. This is a non-lethal dose of LPS, and therefore no adverse, reportable events, occurred.
  • DMSO dimethylsulfoxide
  • saline 1 :1 :18
  • Compounds or vehicle alone were administered i.p. in 0.1 ml volume.
  • LPS at 100 ng/mouse, were administered 1 hour later by intravenous injection into the tail vein in 0.2 ml
  • test compounds The anti-inflammatory activity of test compounds was determined as oedema measured by a UGO Basile water plethysmometer (volume displacement).
  • the paw volume due to oedema, increases approximately 1 ml after injection of the carrageenan. Withdrawal latencies and paw oedema were measured between 15 minutes to 3hours after the subplantar injection of carrageenan. At the conclusion of the above measurements, animals were terminated for analysis of inflammatory mediators in the paw exudates.
  • CB-1 antagonists provide a novel intervention/mechanism in the treatment of inflammatory diseases such as arthritis, inflammatory bowel disease and congestive obstructive pulmonary disorder.
  • inflammatory diseases such as arthritis, inflammatory bowel disease and congestive obstructive pulmonary disorder.
  • CB1 antagonists would be useful in reducing the mediators and symptoms of inflammation including swelling (see also, Figure 2A and 2B). Table 2A
  • cannabinoid agents may be used to alleviate pain associated with inflammation.
  • cannabinoid agents to impact pain disorders has overwhelmingly involved the use of agents that possess agonist activities at the cannabinoid receptors. Therefore, it is counterintuitive and unexpected that CB1 antagonists could lead to pain suppression.
  • CB1 receptor antagonist Compound C
  • cannabinoid receptor antagonists produce analgesic activities due to pain associated with inflammation.
  • Acute Inflammatory Pain Model In the acute inflammatory pain model, an inflammation-inducing agent (carrageenan) was administered in the plantar surface of the rat hind paw to initiate pain and swelling. This model has been shown to be effective in the assessment of anti-inflammatory and analgesic agents. See, Hargreaves K, et al., "A New and Sensitive Method for Measuring Thermal Nociception in Cutaneous Hyperalgesia," Pain, 32, 77-88 (1988). The following model is the standard model for acute inflammatory pain and oedema.
  • Analgesia was monitored via two behavioral endpoints.
  • rats were placed in a clear plastic chamber with a transparent glass floor.
  • a radiant heat source (a high intensity projector lamp bulb) , positioned under the chamber floor, was sequentially applied to each hindpaw. Withdrawal latency was the endpoint and it is defined as the time between onset of light and the behavioral response of lifting the paw.
  • the difference between the withdrawal latency of the non-injected hindpaw and the carrageenan-injected hindpaw was the measure of thermal hyperalgesia.
  • withdrawal latencies typically go from approximately 15 to 2 seconds. The maximum exposure was 20 seconds. To avoid potential acclimation to pain threshold, no more than 5 measurements per rat were taken. Therefore, animals were exposed to the light source only 1-5 times/paw/animal/experiment.
  • TNF ⁇ tumor necrosis factor ⁇
  • RA rheumatoid arthritis

Abstract

L'invention concerne le traitement des inflammations, de la douleur associée aux inflammations et de l'arthrite au moyen d'antagonistes du récepteur cannabinoïde de type 1 (CB-1).
PCT/IB2006/002623 2005-10-03 2006-09-20 Utilisation d'antagonistes du recepteur cannabinoide de type 1 pour traiter les inflammations et l'arthrite WO2007039797A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US72349305P 2005-10-03 2005-10-03
US60/723,493 2005-10-03

Publications (1)

Publication Number Publication Date
WO2007039797A1 true WO2007039797A1 (fr) 2007-04-12

Family

ID=37398673

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2006/002623 WO2007039797A1 (fr) 2005-10-03 2006-09-20 Utilisation d'antagonistes du recepteur cannabinoide de type 1 pour traiter les inflammations et l'arthrite

Country Status (1)

Country Link
WO (1) WO2007039797A1 (fr)

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101954084A (zh) * 2010-09-06 2011-01-26 北京大北农动物保健科技有限责任公司 一种治疗畜禽混合感染的药物组合物及其制备方法
WO2011113802A3 (fr) * 2010-03-17 2012-08-02 F. Hoffmann-La Roche Ag Composés d'imidazopyridine, compositions et procédés d'utilisation
US8637526B2 (en) 2008-10-31 2014-01-28 Genentech, Inc. Pyrazolopyrimidine JAK inhibitor compounds and methods
US8697708B2 (en) 2010-09-15 2014-04-15 F. Hoffmann-La Roche Ag Azabenzothiazole compounds, compositions and methods of use
US8999998B2 (en) 2009-07-02 2015-04-07 Genentech, Inc. Pyrazolopyrimidine JAK inhibitor compounds and methods
US9309240B2 (en) 2010-11-19 2016-04-12 Genentech, Inc. Pyrazolopyridine compounds, compositions and methods of use
US9346815B2 (en) 2014-05-23 2016-05-24 Genentech, Inc. 5-chloro-2-difluoromethoxyphenyl pyrazolopyrimidine compounds, compositions and methods of use thereof
US10307426B2 (en) 2017-05-22 2019-06-04 Genentech, Inc. Therapeutic compounds and compositions, and methods of use thereof
CN114805574A (zh) * 2015-09-30 2022-07-29 鸟石生物公司 结合人大麻素1(cb1)受体的抗体

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001085092A2 (fr) * 2000-05-12 2001-11-15 Sanofi-Synthelabo Antagoniste des recepteurs aux cannabinoides cb-1 antidiarrheique
WO2004045509A2 (fr) * 2002-11-18 2004-06-03 Pharmacia Corporation Methode de therapie combinee utilisant un inhibiteur de cox-2 et un modulateur du recepteur 5-ht1a
WO2005000817A2 (fr) * 2003-06-26 2005-01-06 Sanofi-Aventis Derives de diphenylpyridine, leur preparation et leur application en therapeutique

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001085092A2 (fr) * 2000-05-12 2001-11-15 Sanofi-Synthelabo Antagoniste des recepteurs aux cannabinoides cb-1 antidiarrheique
WO2004045509A2 (fr) * 2002-11-18 2004-06-03 Pharmacia Corporation Methode de therapie combinee utilisant un inhibiteur de cox-2 et un modulateur du recepteur 5-ht1a
WO2005000817A2 (fr) * 2003-06-26 2005-01-06 Sanofi-Aventis Derives de diphenylpyridine, leur preparation et leur application en therapeutique

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8637526B2 (en) 2008-10-31 2014-01-28 Genentech, Inc. Pyrazolopyrimidine JAK inhibitor compounds and methods
US8999998B2 (en) 2009-07-02 2015-04-07 Genentech, Inc. Pyrazolopyrimidine JAK inhibitor compounds and methods
WO2011113802A3 (fr) * 2010-03-17 2012-08-02 F. Hoffmann-La Roche Ag Composés d'imidazopyridine, compositions et procédés d'utilisation
CN101954084A (zh) * 2010-09-06 2011-01-26 北京大北农动物保健科技有限责任公司 一种治疗畜禽混合感染的药物组合物及其制备方法
CN101954084B (zh) * 2010-09-06 2015-06-17 北京大北农动物保健科技有限责任公司 一种治疗畜禽混合感染的药物组合物及其制备方法
US8697708B2 (en) 2010-09-15 2014-04-15 F. Hoffmann-La Roche Ag Azabenzothiazole compounds, compositions and methods of use
US9309240B2 (en) 2010-11-19 2016-04-12 Genentech, Inc. Pyrazolopyridine compounds, compositions and methods of use
US9346815B2 (en) 2014-05-23 2016-05-24 Genentech, Inc. 5-chloro-2-difluoromethoxyphenyl pyrazolopyrimidine compounds, compositions and methods of use thereof
US9604984B2 (en) 2014-05-23 2017-03-28 Genentech, Inc. 5-chloro-2-difluoromethoxyphenyl pyrazolopyrimidine compounds, compositions and methods of use thereof
CN114805574A (zh) * 2015-09-30 2022-07-29 鸟石生物公司 结合人大麻素1(cb1)受体的抗体
US10307426B2 (en) 2017-05-22 2019-06-04 Genentech, Inc. Therapeutic compounds and compositions, and methods of use thereof

Similar Documents

Publication Publication Date Title
WO2007039797A1 (fr) Utilisation d'antagonistes du recepteur cannabinoide de type 1 pour traiter les inflammations et l'arthrite
US20020077328A1 (en) Selective cyclooxygenase-2 inhibitors and vasomodulator compounds for generalized pain and headache pain
US20060258712A1 (en) Methods for modulating bladder function
CN1980658A (zh) 治疗自身炎性疾病的ice抑制剂
JP2010505774A (ja) 低体温誘導薬剤の使用方法
JP2008542255A (ja) 肥満症の治療または体重減量の維持のためのカンナビノイド−１受容体アンタゴニストおよびミクロソームトリグリセリド輸送タンパク質阻害物質の併用
JP2010522751A (ja) 下部尿路症状の治療のための併用療法
JP2010527984A (ja) 統合失調症を治療するための医薬組成物および方法
WO2009124552A2 (fr) Utilisation d’une combinaison de médicaments induisant une hypothermie
JP2015078240A (ja) 嘔吐および下痢などの状態を解消または軽減するためのコーティングされた薬物球状体およびその用途
US20030157061A1 (en) Combinations of a cyclooxygenase-2 selective inhibitor and a TNFalpha antagonist and therapeutic uses therefor
RU2308268C2 (ru) Производные арил- или гетероарилазолилкарбинолов для лечения недержания мочи
WO2005102380A2 (fr) Methodes d'inhibition de l'inflammation
CN109152767A (zh) 用血栓烷-a2受体拮抗剂治疗肌营养不良的组合物和方法
JP2000198734A (ja) 胃運動性減弱および関連疾患の治療のための運動性増強薬
EP2029139B1 (fr) Utilisation d'un inhibiteur de kinase p38 pour le traitement de troubles psychiatriques
CN111419800B (zh) 用于治疗红斑狼疮的药物制剂及其制备方法
JP2002535274A (ja) 抗アンドロゲン剤および疾病の治療方法
RU2118527C1 (ru) Фармацевтическая композиция, содержащая алкилсульфонамид-агонист 5ht1, для ректального введения
JP2009523778A (ja) 方法
EA007952B1 (ru) Применение ирбесартана для изготовления лекарств, которые пригодны для предупреждения или лечения лёгочной артериальной гипертензии
JP4418102B2 (ja) ジエノゲストを有効成分とする子宮筋腫治療剤
Leone Roberti Maggiore et al. An overview of early drug development for endometriosis
US9962400B2 (en) Methods and compositions for treating lupus
US20040022789A1 (en) Methods and compositions for treating T cell mediated inflammatory/autoimmune diseases and disorders in subjects having a glucocorticoid regulation deficiency

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application
NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 06795536

Country of ref document: EP

Kind code of ref document: A1