AU2002337277B2 - Compositions for the treatment of Parkinson's disease containing CB1 receptor antagonist and a product that activates dopaminergic neurotransmission in the brain - Google Patents
Compositions for the treatment of Parkinson's disease containing CB1 receptor antagonist and a product that activates dopaminergic neurotransmission in the brain Download PDFInfo
- Publication number
- AU2002337277B2 AU2002337277B2 AU2002337277A AU2002337277A AU2002337277B2 AU 2002337277 B2 AU2002337277 B2 AU 2002337277B2 AU 2002337277 A AU2002337277 A AU 2002337277A AU 2002337277 A AU2002337277 A AU 2002337277A AU 2002337277 B2 AU2002337277 B2 AU 2002337277B2
- Authority
- AU
- Australia
- Prior art keywords
- radical
- bis
- chlorophenyl
- methyl
- azetidin
- Prior art date
- Legal status (The legal status 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 status listed.)
- Ceased
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- 210000004556 brain Anatomy 0.000 title claims description 21
- 230000015883 synaptic transmission, dopaminergic Effects 0.000 title claims description 18
- 208000018737 Parkinson disease Diseases 0.000 title claims description 15
- 239000000203 mixture Substances 0.000 title description 33
- 229940123158 Cannabinoid CB1 receptor antagonist Drugs 0.000 title description 4
- 239000003555 cannabinoid 1 receptor antagonist Substances 0.000 title description 4
- -1 duodopa Chemical compound 0.000 claims description 165
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 107
- 150000001875 compounds Chemical class 0.000 claims description 62
- 238000000034 method Methods 0.000 claims description 56
- 125000004567 azetidin-3-yl group Chemical group N1CC(C1)* 0.000 claims description 35
- 150000003839 salts Chemical class 0.000 claims description 25
- WTDRDQBEARUVNC-LURJTMIESA-N L-DOPA Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-LURJTMIESA-N 0.000 claims description 20
- WTDRDQBEARUVNC-UHFFFAOYSA-N L-Dopa Natural products OC(=O)C(N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-UHFFFAOYSA-N 0.000 claims description 20
- 150000001539 azetidines Chemical class 0.000 claims description 20
- 229960004502 levodopa Drugs 0.000 claims description 19
- HNQIVZYLYMDVSB-UHFFFAOYSA-N methanesulfonimidic acid Chemical compound CS(N)(=O)=O HNQIVZYLYMDVSB-UHFFFAOYSA-N 0.000 claims description 15
- 239000008194 pharmaceutical composition Substances 0.000 claims description 15
- 229940124802 CB1 antagonist Drugs 0.000 claims description 10
- 239000003814 drug Substances 0.000 claims description 8
- DRTQHJPVMGBUCF-XVFCMESISA-N Uridine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-XVFCMESISA-N 0.000 claims description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 6
- MNIXOHSBCFNRSH-UQGUCNKVSA-N (6ar,9r,10ar)-7-methyl-9-(1,2,4-triazol-1-ylmethyl)-6,6a,8,9,10,10a-hexahydro-4h-indolo[4,3-fg]quinoline;(z)-but-2-enedioic acid Chemical compound OC(=O)\C=C/C(O)=O.C([C@H]1CN([C@H]2[C@@H](C=3C=CC=C4NC=C(C=34)C2)C1)C)N1C=NC=N1 MNIXOHSBCFNRSH-UQGUCNKVSA-N 0.000 claims description 3
- KORNTPPJEAJQIU-KJXAQDMKSA-N Cabaser Chemical compound C1=CC([C@H]2C[C@H](CN(CC=C)[C@@H]2C2)C(=O)N(CCCN(C)C)C(=O)NCC)=C3C2=CNC3=C1 KORNTPPJEAJQIU-KJXAQDMKSA-N 0.000 claims description 3
- 229950007871 adrogolide Drugs 0.000 claims description 3
- KTEBZVJGMARTOQ-GCJKJVERSA-N adrogolide Chemical compound CC(=O)OC1=C(OC(C)=O)C=C2[C@H]3C(C=C(S4)CCC)=C4CN[C@@H]3CCC2=C1 KTEBZVJGMARTOQ-GCJKJVERSA-N 0.000 claims description 3
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- OZVBMTJYIDMWIL-AYFBDAFISA-N bromocriptine Chemical compound C1=CC(C=2[C@H](N(C)C[C@@H](C=2)C(=O)N[C@]2(C(=O)N3[C@H](C(N4CCC[C@H]4[C@]3(O)O2)=O)CC(C)C)C(C)C)C2)=C3C2=C(Br)NC3=C1 OZVBMTJYIDMWIL-AYFBDAFISA-N 0.000 claims description 3
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- MEZLKOACVSPNER-GFCCVEGCSA-N selegiline Chemical compound C#CCN(C)[C@H](C)CC1=CC=CC=C1 MEZLKOACVSPNER-GFCCVEGCSA-N 0.000 claims description 3
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- RKZSNTNMEFVBDT-MRVPVSSYSA-N sumanirole Chemical compound C([C@H](C1)NC)C2=CC=CC3=C2N1C(=O)N3 RKZSNTNMEFVBDT-MRVPVSSYSA-N 0.000 claims description 3
- MIQPIUSUKVNLNT-UHFFFAOYSA-N tolcapone Chemical compound C1=CC(C)=CC=C1C(=O)C1=CC(O)=C(O)C([N+]([O-])=O)=C1 MIQPIUSUKVNLNT-UHFFFAOYSA-N 0.000 claims description 3
- 229960004603 tolcapone Drugs 0.000 claims description 3
- DRTQHJPVMGBUCF-UHFFFAOYSA-N uracil arabinoside Natural products OC1C(O)C(CO)OC1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-UHFFFAOYSA-N 0.000 claims description 3
- 229940045145 uridine Drugs 0.000 claims description 3
- UGGBYJSPWKGTIZ-UHFFFAOYSA-N C1=CC(Cl)=CC=C1C(C=1C=CC(Cl)=CC=1)N1CC(N(CC=2C=NC=CC=2)S(=O)=O)C1 Chemical group C1=CC(Cl)=CC=C1C(C=1C=CC(Cl)=CC=1)N1CC(N(CC=2C=NC=CC=2)S(=O)=O)C1 UGGBYJSPWKGTIZ-UHFFFAOYSA-N 0.000 claims description 2
- PGDDYDAGRXBVAI-UHFFFAOYSA-N FC1=CC(F)=CC(CN(C2CN(C2)C(C=2C=CC(Cl)=CC=2)C=2C=CC(Cl)=CC=2)S(=O)=O)=C1 Chemical group FC1=CC(F)=CC(CN(C2CN(C2)C(C=2C=CC(Cl)=CC=2)C=2C=CC(Cl)=CC=2)S(=O)=O)=C1 PGDDYDAGRXBVAI-UHFFFAOYSA-N 0.000 claims description 2
- 230000003213 activating effect Effects 0.000 claims 3
- DHSSDEDRBUKTQY-UHFFFAOYSA-N 6-prop-2-enyl-4,5,7,8-tetrahydrothiazolo[4,5-d]azepin-2-amine Chemical compound C1CN(CC=C)CCC2=C1N=C(N)S2 DHSSDEDRBUKTQY-UHFFFAOYSA-N 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- XBBDACCLCFWBSI-ZETCQYMHSA-N melevodopa Chemical compound COC(=O)[C@@H](N)CC1=CC=C(O)C(O)=C1 XBBDACCLCFWBSI-ZETCQYMHSA-N 0.000 claims 1
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- 150000003254 radicals Chemical class 0.000 description 169
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 122
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 98
- 238000006243 chemical reaction Methods 0.000 description 98
- 239000012442 inert solvent Substances 0.000 description 77
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 73
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 72
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 63
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 60
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 57
- 125000000217 alkyl group Chemical group 0.000 description 55
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 54
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 49
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 49
- 238000009835 boiling Methods 0.000 description 47
- 239000002904 solvent Substances 0.000 description 47
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- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 39
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- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 19
- 229910052736 halogen Inorganic materials 0.000 description 19
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
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- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4858—Organic compounds
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- 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
- A61K31/397—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having four-membered rings, e.g. azetidine
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- 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
- A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- 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
-
- 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
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
-
- 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
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- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Life Sciences & Earth Sciences (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Psychology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Plural Heterocyclic Compounds (AREA)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AU2008212039A AU2008212039A1 (en) | 2001-08-29 | 2008-09-05 | Combination of a CB1 receptor antagonist and of a product which activates dopaminergic neurotransmission in the brian, the pharmaceutical compositions comprising them and their use in the treatment of Parkinson's disease |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR0111200A FR2829028B1 (fr) | 2001-08-29 | 2001-08-29 | Association d'un antagoniste du recepteur cb1 et d'un produit qui active la neurotransmission dopaminergique dans le cerveau, les compositions pharmaceutiques les contenant et leur utilisation pour le traitement de la maladie de |
| FR01/11200 | 2001-08-29 | ||
| PCT/FR2002/002946 WO2003020314A1 (fr) | 2001-08-29 | 2002-08-28 | Compositions pour le traitement de la maladie de parkinson contenant un antagoniste du recepteur cb1 et un produit qui active la neurotransmission dopaminergique dans le cerveau |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU2008212039A Division AU2008212039A1 (en) | 2001-08-29 | 2008-09-05 | Combination of a CB1 receptor antagonist and of a product which activates dopaminergic neurotransmission in the brian, the pharmaceutical compositions comprising them and their use in the treatment of Parkinson's disease |
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| AU2002337277A1 AU2002337277A1 (en) | 2003-06-05 |
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| AU2002337277A Ceased AU2002337277B2 (en) | 2001-08-29 | 2002-08-28 | Compositions for the treatment of Parkinson's disease containing CB1 receptor antagonist and a product that activates dopaminergic neurotransmission in the brain |
| AU2008212039A Abandoned AU2008212039A1 (en) | 2001-08-29 | 2008-09-05 | Combination of a CB1 receptor antagonist and of a product which activates dopaminergic neurotransmission in the brian, the pharmaceutical compositions comprising them and their use in the treatment of Parkinson's disease |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
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| AU2008212039A Abandoned AU2008212039A1 (en) | 2001-08-29 | 2008-09-05 | Combination of a CB1 receptor antagonist and of a product which activates dopaminergic neurotransmission in the brian, the pharmaceutical compositions comprising them and their use in the treatment of Parkinson's disease |
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| PT (1) | PT1423145E (enExample) |
| WO (1) | WO2003020314A1 (enExample) |
Families Citing this family (53)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE19814084B4 (de) | 1998-03-30 | 2005-12-22 | Lts Lohmann Therapie-Systeme Ag | D2-Agonist enthaltendes transdermales therapeutisches System zur Behandlung des Parkinson-Syndroms und Verfahren zu seiner Herstellung |
| DE10043321B4 (de) * | 2000-08-24 | 2005-07-28 | Neurobiotec Gmbh | Verwendung eines transdermalen therapeutischen Systems zur Behandlung der Parkinsonschen Krankheit, zur Behandlung und Prävention des prämenstruellen Syndroms und zur Lactationshemmung |
| DE10041479A1 (de) * | 2000-08-24 | 2002-03-14 | Sanol Arznei Schwarz Gmbh | Neue pharmazeutische Zusammensetzung zur Verabreichung von N-0923 |
| DE10053397A1 (de) | 2000-10-20 | 2002-05-02 | Schering Ag | Verwendung eines dopaminergen Wirkstoffes zur Behandlung von dopaminerg behandelbaren Erkrankungen |
| US20030027793A1 (en) * | 2001-05-08 | 2003-02-06 | Thomas Lauterback | Transdermal treatment of parkinson's disease |
| US20030026830A1 (en) * | 2001-05-08 | 2003-02-06 | Thomas Lauterback | Transdermal therapeutic system for parkinson's disease inducing high plasma levels of rotigotine |
| US20030139386A1 (en) * | 2001-12-21 | 2003-07-24 | Sophie Cote | Pharmaceutical compositions based on azetidine derivatives |
| US20060263419A1 (en) * | 2002-03-12 | 2006-11-23 | Hans-Michael Wolff | Transdermal therapeutic system for Parkinson's Disease |
| US20040048779A1 (en) * | 2002-05-06 | 2004-03-11 | Erwin Schollmayer | Use of rotigotine for treating the restless leg syndrome |
| DE10234673B4 (de) * | 2002-07-30 | 2007-08-16 | Schwarz Pharma Ag | Heißschmelz-TTS zur Verabreichung von Rotigotin und Verfahren zu seiner Herstellung sowie Verwendung von Rotigotin bei der Herstellung eines TTS im Heißschmelzverfahren |
| US8246980B2 (en) * | 2002-07-30 | 2012-08-21 | Ucb Pharma Gmbh | Transdermal delivery system |
| US8211462B2 (en) * | 2002-07-30 | 2012-07-03 | Ucb Pharma Gmbh | Hot-melt TTS for administering rotigotine |
| US7129239B2 (en) | 2002-10-28 | 2006-10-31 | Pfizer Inc. | Purine compounds and uses thereof |
| US7247628B2 (en) | 2002-12-12 | 2007-07-24 | Pfizer, Inc. | Cannabinoid receptor ligands and uses thereof |
| DE10261696A1 (de) | 2002-12-30 | 2004-07-15 | Schwarz Pharma Ag | Vorrichtung zur transdermalen Verabreichung von Rotigotin-Base |
| US7329658B2 (en) | 2003-02-06 | 2008-02-12 | Pfizer Inc | Cannabinoid receptor ligands and uses thereof |
| US7176210B2 (en) | 2003-02-10 | 2007-02-13 | Pfizer Inc. | Cannabinoid receptor ligands and uses thereof |
| US7145012B2 (en) | 2003-04-23 | 2006-12-05 | Pfizer Inc. | Cannabinoid receptor ligands and uses thereof |
| US7268133B2 (en) | 2003-04-23 | 2007-09-11 | Pfizer, Inc. Patent Department | Cannabinoid receptor ligands and uses thereof |
| US7141669B2 (en) | 2003-04-23 | 2006-11-28 | Pfizer Inc. | Cannabiniod receptor ligands and uses thereof |
| US7232823B2 (en) | 2003-06-09 | 2007-06-19 | Pfizer, Inc. | Cannabinoid receptor ligands and uses thereof |
| EP1636181A1 (en) | 2003-06-11 | 2006-03-22 | Merck & Co., Inc. | Substituted 3-alkyl and 3-alkenyl azetidine derivatives |
| DE10334188B4 (de) * | 2003-07-26 | 2007-07-05 | Schwarz Pharma Ag | Verwendung von Rotigotin zur Behandlung von Depressionen |
| DE10334187A1 (de) * | 2003-07-26 | 2005-03-03 | Schwarz Pharma Ag | Substituierte 2-Aminotetraline zur Behandlung von Depressionen |
| DE10359528A1 (de) * | 2003-12-18 | 2005-07-28 | Schwarz Pharma Ag | (S)-2-N-Propylamino-5-hydroxytetralin als D3-agonistisches Therapeutikum |
| EP1547592A1 (en) * | 2003-12-23 | 2005-06-29 | Schwarz Pharma Ag | Intranasal formulation of rotigotine |
| DE10361258A1 (de) * | 2003-12-24 | 2005-07-28 | Schwarz Pharma Ag | Verwendung von substituierten 2-Aminotetralinen zur vorbeugenden Behandlung von Morbus Parkinson |
| ES2244314B1 (es) * | 2004-02-17 | 2007-02-01 | Laboratorios Del Dr. Esteve, S.A. | Compuestos azetidinicos sustituidos, su preparacion y su aplicacion como medicamentos. |
| RU2006133258A (ru) * | 2004-02-17 | 2008-04-10 | Лабораториос Дель Др. Эстеве С.А. (Es) | Замещенные азетидиновые производные, их получение и применение в качестве лекарственных средств |
| US20050197385A1 (en) * | 2004-02-20 | 2005-09-08 | Schwarz Pharma Ag | Use of rotigotine for treatment or prevention of dopaminergic neuron loss |
| DE102004014841B4 (de) * | 2004-03-24 | 2006-07-06 | Schwarz Pharma Ag | Verwendung von Rotigotin zur Behandlung und Prävention des Parkinson-Plus-Syndroms |
| TW200602314A (en) | 2004-05-28 | 2006-01-16 | Tanabe Seiyaku Co | A novel pyrrolidine compound and a process for preparing the same |
| JP2008545009A (ja) | 2005-06-30 | 2008-12-11 | プロシディオン・リミテッド | Ｇｐｃｒアゴニスト |
| US20070060638A1 (en) * | 2005-08-26 | 2007-03-15 | Olmstead Mary C | Methods and therapies for potentiating therapeutic activities of a cannabinoid receptor agonist via administration of a cannabinoid receptor antagonist |
| US7906652B2 (en) | 2005-11-28 | 2011-03-15 | Merck Sharp & Dohme Corp. | Heterocycle-substituted 3-alkyl azetidine derivatives |
| TWI392670B (zh) * | 2006-06-22 | 2013-04-11 | Ucb Pharma Gmbh | 經取代的２-胺基萘滿之於製造用於預防、減緩及／或治療各種類型疼痛之藥物上的用途 |
| GB0700122D0 (en) | 2007-01-04 | 2007-02-14 | Prosidion Ltd | GPCR agonists |
| WO2008081208A1 (en) | 2007-01-04 | 2008-07-10 | Prosidion Limited | Piperidine gpcr agonists |
| CL2008000017A1 (es) | 2007-01-04 | 2008-08-01 | Prosidion Ltd | Compuestos derivados de heterociclos de nitrogeno y oxigeno, agonistas de gpcr; composicion farmaceutica que comprende a dicho compuesto; y uso del compuesto para el tratamiento de la obesidad, diabetes, sindrome metabolico, hiperlipidemia, toleranci |
| PE20081659A1 (es) | 2007-01-04 | 2008-10-24 | Prosidion Ltd | Agonistas de gpcr |
| US20100048632A1 (en) | 2007-01-04 | 2010-02-25 | Matthew Colin Thor Fyfe | Piperidine GPCR Agonists |
| EP1987815A1 (en) * | 2007-05-04 | 2008-11-05 | Schwarz Pharma Ag | Oronasopharyngeally deliverable pharmaceutical compositions of dopamine agonists for the prevention and/or treatment of restless limb disorders |
| GB0720390D0 (en) | 2007-10-18 | 2007-11-28 | Prosidion Ltd | G-Protein coupled receptor agonists |
| GB0720389D0 (en) | 2007-10-18 | 2008-11-12 | Prosidion Ltd | G-Protein Coupled Receptor Agonists |
| SI2215072T1 (sl) * | 2007-11-28 | 2015-10-30 | Ucb Pharma Gmbh | Polimorfna oblika rotigotina |
| US20090247537A1 (en) * | 2008-03-25 | 2009-10-01 | William Dale Overfield | Methods for preventing or treating bruxism using dopaminergic agents |
| PL2421825T3 (pl) | 2009-04-22 | 2014-06-30 | Janssen Pharmaceutica Nv | Diamidy azetydynylowe jako inhibitory lipazy monoacyloglicerolowej |
| EP2281559A1 (en) | 2009-06-26 | 2011-02-09 | UCB Pharma GmbH | Pharmaceutical composition comprising rotigotine salts (acid or Na), especially for iontophoresis |
| KR20160055971A (ko) | 2009-12-22 | 2016-05-18 | 유씨비 파르마 게엠베하 | 비결정질형 로티고틴의 고체 분산체의 안정화를 위한 폴리비닐피롤리돈 |
| AU2011316975A1 (en) | 2010-10-22 | 2013-05-23 | Janssen Pharmaceutica Nv | Amino-pyrrolidine-azetidine diamides as monoacylglycerol lipase inhibitors |
| US8513423B2 (en) | 2010-10-22 | 2013-08-20 | Janssen Pharmaceutica, Nv | Piperidin-4-yl-azetidine diamides as monoacylglycerol lipase inhibitors |
| US9248111B2 (en) * | 2011-03-01 | 2016-02-02 | Pharnext | Therapeutic approaches for treating parkinson's disease |
| US20250082586A1 (en) * | 2021-05-21 | 2025-03-13 | Brian Stuart Murphy | Compositions for treating inflammatory, neurologic and/or vascular conditions and methods of use thereof |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB9405304D0 (en) * | 1994-03-16 | 1994-04-27 | Scherer Ltd R P | Delivery systems for hydrophobic drugs |
| US5635159A (en) * | 1994-08-26 | 1997-06-03 | Abbott Laboratories | Aerosol drug formulations containing polyglycolyzed glycerides |
| US5562917A (en) * | 1994-12-23 | 1996-10-08 | Pentech Pharmaceuticals, Inc. | Transdermal administration of apomorphine |
| FR2783246B1 (fr) * | 1998-09-11 | 2000-11-17 | Aventis Pharma Sa | Derives d'azetidine, leur preparation et les medicaments les contenant |
| EP1236476A1 (en) * | 1999-12-10 | 2002-09-04 | Takeda Chemical Industries, Ltd. | Medicinal compositions for oral use |
| US6355631B1 (en) * | 2000-03-03 | 2002-03-12 | Aventis Pharma S.A. | Pharmaceutical compositions containing azetidine derivatives, novel azetidine derivatives and their preparation |
-
2001
- 2001-08-29 FR FR0111200A patent/FR2829028B1/fr not_active Expired - Fee Related
-
2002
- 2002-08-27 AR ARP020103211A patent/AR036302A1/es not_active Application Discontinuation
- 2002-08-28 AU AU2002337277A patent/AU2002337277B2/en not_active Ceased
- 2002-08-28 ES ES02772514T patent/ES2263816T3/es not_active Expired - Lifetime
- 2002-08-28 CA CA002458348A patent/CA2458348A1/en not_active Abandoned
- 2002-08-28 EP EP06000097A patent/EP1649849A3/fr not_active Withdrawn
- 2002-08-28 DK DK02772514T patent/DK1423145T3/da active
- 2002-08-28 EP EP02772514A patent/EP1423145B1/fr not_active Expired - Lifetime
- 2002-08-28 PT PT02772514T patent/PT1423145E/pt unknown
- 2002-08-28 IL IL16055702A patent/IL160557A0/xx unknown
- 2002-08-28 JP JP2003524621A patent/JP2005505551A/ja not_active Ceased
- 2002-08-28 DE DE60212148T patent/DE60212148T2/de not_active Expired - Lifetime
- 2002-08-28 WO PCT/FR2002/002946 patent/WO2003020314A1/fr not_active Ceased
- 2002-08-28 MX MXPA04001645A patent/MXPA04001645A/es not_active Application Discontinuation
- 2002-08-28 AT AT02772514T patent/ATE328609T1/de not_active IP Right Cessation
-
2004
- 2004-02-25 US US10/786,810 patent/US7217705B2/en not_active Expired - Fee Related
-
2006
- 2006-08-31 CY CY20061101241T patent/CY1105341T1/el unknown
-
2007
- 2007-04-04 US US11/696,485 patent/US20070197654A1/en not_active Abandoned
-
2008
- 2008-08-07 IL IL193325A patent/IL193325A0/en unknown
- 2008-09-05 AU AU2008212039A patent/AU2008212039A1/en not_active Abandoned
-
2009
- 2009-12-09 JP JP2009279071A patent/JP2010053153A/ja active Pending
Non-Patent Citations (2)
| Title |
|---|
| British Journal of Pharmacology, 1998, 123, suppl 66P * |
| FASEB Journal, 2000, 4(10), 1432-8 * |
Also Published As
| Publication number | Publication date |
|---|---|
| EP1423145A1 (fr) | 2004-06-02 |
| FR2829028A1 (fr) | 2003-03-07 |
| IL193325A0 (en) | 2009-02-11 |
| EP1649849A3 (fr) | 2006-11-02 |
| AR036302A1 (es) | 2004-08-25 |
| WO2003020314A1 (fr) | 2003-03-13 |
| EP1649849A2 (fr) | 2006-04-26 |
| AU2008212039A1 (en) | 2008-10-09 |
| FR2829028B1 (fr) | 2004-12-17 |
| CY1105341T1 (el) | 2010-03-03 |
| US7217705B2 (en) | 2007-05-15 |
| US20070197654A1 (en) | 2007-08-23 |
| CA2458348A1 (en) | 2003-03-13 |
| DK1423145T3 (da) | 2006-10-02 |
| DE60212148D1 (de) | 2006-07-20 |
| US20040209861A1 (en) | 2004-10-21 |
| DE60212148T2 (de) | 2007-04-19 |
| IL160557A0 (en) | 2004-07-25 |
| JP2010053153A (ja) | 2010-03-11 |
| ATE328609T1 (de) | 2006-06-15 |
| MXPA04001645A (es) | 2004-05-31 |
| EP1423145B1 (fr) | 2006-06-07 |
| PT1423145E (pt) | 2006-09-29 |
| JP2005505551A (ja) | 2005-02-24 |
| ES2263816T3 (es) | 2006-12-16 |
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| FGA | Letters patent sealed or granted (standard patent) | ||
| MK14 | Patent ceased section 143(a) (annual fees not paid) or expired |