WO2000015220A1 - A new composition - Google Patents
A new composition Download PDFInfo
- Publication number
- WO2000015220A1 WO2000015220A1 PCT/SE1999/001599 SE9901599W WO0015220A1 WO 2000015220 A1 WO2000015220 A1 WO 2000015220A1 SE 9901599 W SE9901599 W SE 9901599W WO 0015220 A1 WO0015220 A1 WO 0015220A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- treatment
- solvate
- acceptable salt
- free base
- pharmaceutically acceptable
- Prior art date
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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
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
-
- 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
- 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
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Definitions
- the present invention relates to a composition which comprises fR)-5-carbamoyl-8-fluoro- 3-NN-dicyclobutylamino-3,4-dihydro-2H-l-benzopyrans in the form of the free base, or a pharmaceutically acceptable salt and/or solvate thereof, and (+)-l-[3- (dimethylamino)propyl]-l-(p-fluorophenyl)-5-phthalancarbonitrile in the form of the free base, or a pharmaceutically acceptable salt and/or solvate thereof.
- the present invention also relates to a process for the preparation of the inventive composition, pharmaceutical formulations containing said composition and to the use of said composition either by concomitant administration or by separate administration as an improvement of the treatment of affective disorders such as depression, anxiety, obsessive compulsive disorder (OCD), etc.
- affective disorders such as depression, anxiety, obsessive compulsive disorder (OCD), etc.
- antidepressants take 2-4 weeks to reach full clinical effect. In contrast, the side effects occur immediately. Thus, slow onset of action of antidepressants leads to a vulnerable period for patients in which they experience the side effects, but not the therapeutic effects of drugs. There is often a heavy burden on the treating physician to persuade the patient to continue with the treatment during this period. Furthermore, in suicidal patients, as the onset of action is gradual, initiative may be regained without the experiencing of full reversal of symptoms, leaving a window of risk for suicide and a frequent requirement for hospitalization.
- the present invention is directed to a new composition comprising of the specific 5-
- HTj Antagonist (7 ⁇ -5-carbamoyl-8-fluoro-3-NN-disubstituted-amino-3,4-dihydro-2H-l- benzopyran in the form of the free base, or a pharmaceutically acceptable salt and/or solvate thereof
- the specific 5- ⁇ T reuptake inhibitor (+)-l-[3-(dimethylamino)propyl]- l-(p-fluorophenyl)-5-phthalancarbonitrile in the form of the free base, or a pharmaceutically acceptable salt and/or solvate thereof.
- Said composition attains a faster onset of action and consequently, provides a more efficacious treatment of the patients suffering from affective disorders, particularly depression.
- 5- HT IA antagonist may have a clinical potential to improve the efficacy of 5-HT reuptake inhibitors (SSRIs) and offer a new rationale for rapid onset of effect in the treatment of affective disorders, for instance the antidepressant actions.
- SSRIs 5-HT reuptake inhibitors
- the compound (R)-5-carbamoyl-8-fluoro-3-N,N-dicyc butylamino-3,4-dihydro-2H-l- benzopyran in the form of the free base, and pharmaceutically acceptable salts thereof as disclosed herein is described in WO 95/11891, as a selective 5- ⁇ T1A receptor antagonist.
- the ( ? ) -5-carbamoyl-8-fluoro-3-NN-dicyclobutylamino-3,4-dihydro-2H-l-benzopyran is in the form of the free base, or a pharmaceutically acceptable salt and/or solvate thereof. Both organic and inorganic acids can be employed to form nontoxic pharmaceutically acceptable acid addition salts of the compounds of this invention.
- Illustrative acids are sulfuric, nitric, phosphoric, oxalic, hydrochloric, formic, hydrobromic, citric, acetic, lactic, tartaric, dibenzoyltartaric, diacetyltartaric, pamoic, ethanedisulfonic, sulfamic, succinic, propionic, glycollic, malic, gluconic, pyruvic, phenylacetic, 4-aminobenzoic, anthranilic, salicylic, 4-aminosalicylic, 4-hydroxybenzoic, 3,4-dihydroxybenzoic, 3,5- dihydroxybenzoic, 3-hydroxy-2-naphthoic, nicotinic, methanesulfonic, ethanesulfonic, hydroxyethanesulfonic, benzenesulfonic, p-toluenesulfonic, sulfanilic, naphthalenesulfonic
- the ( ?)-5-carbamoyl-8-fluoro-3-NN-dicyclobutylamino-3,4-dihydro-2H-l-benzopyran possesses a high affinity to the specific subgroup of 5- ⁇ T ⁇ A receptor in the C ⁇ S and acts as an antagonist on that 5-HT tA receptor, and as also shows favourable bioavailability after oral administration.
- composition according to the present invention may exist in one pharmaceutical formulation comprising of f7? -5-carbamoyl-8-fluoro-3-NN-dicyclobutylamino-3,4- dihydro-2H-l-benzopyran in the form of the free base, or a pharmaceutically acceptable salt and/or solvate thereof, and (+)-l-[3-(dimethylamino)propyl]-l-(p-fluorophenyl)-5- phthalancarbonitrile in the form of the free base, or a pharmaceutically acceptable salt and/or solvate thereof.
- the composition may exist in two different pharmaceutical formulations, one for fRj-5-carbamoyl-8-fluoro-3-NN-dicyclobutylamino- 3,4-dihydro-2H-l-benzopyran in the form of the free base, or a pharmaceutically acceptable- salt and/or solvate thereof and one for (+)-l-[3-(dimethylamino)propyl]-l-(p- fluorophenyl)-5-phthalancarbonitrile in the form of the free base, or a pharmaceutically acceptable salt and/or solvate thereof.
- the pharmaceutical formulation may be in the form of tablets or capsules, powders, mixtures, solutions or other suitable pharmaceutical formulation forms such as patches and nasal formulations.
- composition of the present invention can be prepared y that (7? 5-carbamoyl-8- fluoro-3-NN-dicyclobutylamino-3,4-dihydro-2H-l-benzopyran in the form of the free base. or a pharmaceutically acceptable salt and/or solvate thereof is incorporated into the same pharmaceutical formulation as (+)-l-[3-(dimethylamino)propyl]-l-(p-fluorophenyl)-5- phthalancarbonitrile in the form of the free base, or a pharmaceutically acceptable salt and/or solvate thereof by e.g. mixing in a conventional way.
- the present invention also includes a method of improving the onset of therapeutic action by concomitant administration of a composition
- a composition comprising (7?,)-5-carbamoyl-8-fluoro-3- NN-dicyclobutylamino-3,4-dihydro-2H-l-benzopyran in the form of the free base, or a pharmaceutically acceptable salt and/or solvate thereof and (+)-l-[3-(dimethylamino)- propyl]-l-(p-fluorophenyl)-5-phthalancarbonitrile in the form of the free base, or a pharmaceutically acceptable salt and/or solvate thereof.
- a further embodiment of the present invention is a kit containing a dosage unit of (R)-5- carbamoyl-8-fluoro-3-NN-dicyclbutylamino-3,4-dihydro-2H-l-benzopyrans in the form of the free base, or a pharmaceutically acceptable salt and/or solvate thereof, and a dosage unit of (+)-l-[3-(dimethylamino)propyl]-l-(p-fluorophenyl)-5-phthalancarbonitrile in the form of the free base, or a pharmaceutically acceptable salt and/or solvate thereof, optionally with instructions for use.
- Pharmaceutical formulations are examples of (R)-5- carbamoyl-8-fluoro-3-NN-dicyclbutylamino-3,4-dihydro-2H-l-benzopyrans in the form of the free base, or a pharmaceutically acceptable salt and/or solvate thereof, and a dosage unit of (+)-l-[3-(dimethyl
- the compounds in the composition will normally be administered orally, rectally, transdermally, nasally or by injection, in the form of pharmaceutical formulations comprising the active ingredient either as a free base, a solvate e.g. a hydrate or a pharmaceutically acceptable non-toxic acid addition salt, e.g. the hydrochloride, hydrobromide, lactate, acetate, phosphate, sulfate, sulfamate, citrate, tartrate, oxalate and the like in a pharmaceutically acceptable dosage form.
- the dosage form may be a solid, semisolid or liquid formulation.
- the active substances will constitute between 0.1 and 99% by weight of the formulation, more specifically between 0.5 and 20% by weight for formulations intended for injection and between 0.2 and 50% by weight for formulations suitable for oral administration.
- the pharmaceutical formulation comprises the active ingredients, optionally in association with adjuvants, diluents, excipients and/or inert carriers.
- the selected compounds may be mixed with a solid excipient, e.g. lactose, saccharose, sorbitol, mannitol, starches such as potato starch, corn starch or amylopectin, cellulose derivatives, a binder such as gelatin or poly- vinylpyrrolidone, disintegrants e.g. sodium starch glycolate, cross-linked PVP and cross- caramellose sodium; and a lubricant such as magnesium stearate, calcium stearate, polyethylene glycol, waxes, paraffin, and the like, and an antisticking agent such as talc or colloidal silicon dioxide, and then compressed into tablets.
- a solid excipient e.g. lactose, saccharose, sorbitol, mannitol, starches such as potato starch, corn starch or amylopectin, cellulose derivatives, a binder such as gelatin or poly- vinylpyrrolidone, disintegrants e.g. sodium star
- the cores may be coated with a polymer known to the man skilled in the art e.g. HPMC, HC or other cellulose derivatives or PVP, wherein the polymer is dissolved in water or a readily volatile organic solvent or mixture of organic solvents.
- a polymer known to the man skilled in the art e.g. HPMC, HC or other cellulose derivatives or PVP, wherein the polymer is dissolved in water or a readily volatile organic solvent or mixture of organic solvents.
- the tablets can be coated with a concentrated sugar solution which may contain e.g. gum arabic, gelatine, talcum, titanium dioxide, and the like.
- Dyestuffs may be added to these coatings for instance in order to readily distinguish between tablets ' containing different active substances or different amounts of the active compounds.
- the active substances may be admixed with e.g. a vegetable oil or polyethylene glycol.
- Hard gelatine capsules may contain granules of the active substances using any of the above mentioned excipients for tablets e.g. lactose, saccharose, sorbitol, mannitol, starches (e.g. potato starch, corn starch or amylopectin), cellulose derivatives, plasticizers, polyetheneglycole, waxes, lipids or gelatin. Also liquids or semisolids of the drug can be filled into hard gelatin capsules.
- Dosage units for rectal application can be solutions or suspensions or can be prepared in the form of suppositories comprising the active substances in a mixture with a neutral fatty base, or gelatin rectal capsules comprising the active substances in admixture with vegetable oil or paraffin oil.
- Liquid formulations for oral application may be in the form of solutions, syrups or suspensions, for example solutions containing from about 0.2% to about 20% by weight of the active substances herein described, the balance being sugar and a mixture of ethanol, water, glycerol and propylene glycol.
- such liquid formulations may contain colouring agents, flavouring agents, saccharin and carboxymethyl-cellulose as a thickening agent or other excipients known to a person skilled in the art.
- Solutions for parenteral applications by injection can be prepared in an aqueous solution of a water-soluble pharmaceutically acceptable salt of the active substances, preferably in a concentration of from about 0.5% to about 10% by weight. These solutions may also contain stabilizing agents and/or buffering agents and may conveniently be provided in various dosage unit ampoules.
- Suitable daily doses of the active compounds in the composition of the invention in therapeutic treatment of humans are about 0.01-100 mg/kg bodyweight for peroral administration and 0.001-100 mg/kg bodyweight for parenteral administration.
- the daily doses of the active ingredient fR>-5-carbamoyl-8-fluoro-3-NN-dicyclobutylamino-3,4- dihydro-2H-l-benzopyran in the form of the free base, or a pharmaceutically acceptable salt and/or solvate thereof may very well differ from the daily doses of the active ingredient (+)-l-[3-(dimethylamino)propyl]-l-(p-fluorophenyl)-5-phthalancarbonitrile in the form of the free base, or a pharmaceutically acceptable salt and/or solvate thereof but the doses can also be the same for both of the active ingredients.
- the present invention provides the use of the composition of (R)-5- carbamoyl-8-fluoro-3-NN-dicyclobutylamino-3,4-dihydro-2H-l-benzopyran in the form of the free base, or a pharmaceutically acceptable salt and/or solvate thereof and (+)-l-[3- (dimethylamino)propyl]-l-(p-fluorophenyl)-5-phthalancarbonitrile in the form of the free base, or a pharmaceutically acceptable salt and/or solvate thereof, and the use in the treatment of 5-hydroxytryptamine mediated disorders, such as affective disorders.
- affective disorders are disorders in the C ⁇ S such as mood disorders (depression, major depressive episodes, dysthymia, seasonal affective disorder, depressive phases of bipolar disorder), anxiety disorders (obsessive compulsive disorder, panic disorder with/without agoraphobia, social phobia, specific phobia, generalized anxiety disorder, posttraumatic stress disorder), personality disorders (disorders of impulse control, trichotellomania) and sleep disorders.
- disorders in the C ⁇ S such as eating disorders(obesity, anorexia, bulimia), premenstrual syndrome, sexual disturbances, alcoholism, tobacco abuse, autism, attention deficit, hyperactivity disorder, migraine, memory disorders (age associated memory impairment, presenile and senile dementia such as Alzheimer's disease), pathological aggression, schizophrenia, endocrine disorders (e g hyperprolactinaernia), stroke, dyskinesia, Parkinson's disease, thermoregulatory disorders, pain and hypertension may also be treated with the combination described herein.
- endocrine disorders e g hyperprolactinaernia
- stroke e g hyperkinesia
- Parkinson's disease Parkinson's disease
- thermoregulatory disorders e.g pain and hypertension
- pain and hypertension may also be treated with the combination described herein.
- examples of other hydroxytryptamine mediated disorders are urinary incontinence, vasospasm and growth control of tumors (e g lung carcinoma)
- the rats were anaesthetised with a mixture of ketamine HC1 (67 mg/kg intraperitoneal (IP); Ketalar , Park-Davis) and xylazine HC1 (13 mg kg IP; Rompun , Bayer-Leverkusen).
- U- shaped microdialysis probes (total dialysis fibre length 4 mm, OD 220 ⁇ m) were stereotaxically implanted in the frontal cortex (FCx) and dorsal hippocampus (DH); probe tips at AP +3.5, ML -3.0, DV -4.2 and -4.3, ML +2.5, DV -4.2, respectively, vs.
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- Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Neurology (AREA)
- Biomedical Technology (AREA)
- Neurosurgery (AREA)
- Pain & Pain Management (AREA)
- Psychiatry (AREA)
- Epidemiology (AREA)
- Urology & Nephrology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
Claims
Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP99951321A EP1113793A1 (en) | 1998-09-16 | 1999-09-13 | A new composition |
JP2000569804A JP2002524510A (en) | 1998-09-16 | 1999-09-13 | New composition |
CA002342233A CA2342233A1 (en) | 1998-09-16 | 1999-09-13 | A new composition |
AU63782/99A AU6378299A (en) | 1998-09-16 | 1999-09-13 | A new composition |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
SE9803158-6 | 1998-09-16 | ||
SE9803158A SE9803158D0 (en) | 1998-09-16 | 1998-09-16 | A new composition |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2000015220A1 true WO2000015220A1 (en) | 2000-03-23 |
Family
ID=20412629
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/SE1999/001599 WO2000015220A1 (en) | 1998-09-16 | 1999-09-13 | A new composition |
Country Status (6)
Country | Link |
---|---|
EP (1) | EP1113793A1 (en) |
JP (1) | JP2002524510A (en) |
AU (1) | AU6378299A (en) |
CA (1) | CA2342233A1 (en) |
SE (1) | SE9803158D0 (en) |
WO (1) | WO2000015220A1 (en) |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2001003694A1 (en) * | 1999-07-08 | 2001-01-18 | H. Lundbeck A/S | Treatment of neurotic disorders |
EA008372B1 (en) * | 2000-07-07 | 2007-04-27 | Х.Лундбекк А/С | Use of escitalopram for treating disorders associated with social anxiety disorder |
EA008373B1 (en) * | 2000-07-07 | 2007-04-27 | Х. Лундбекк А/С | Use of escitalopram useful in the treatment of disorders associated with post traumatic stress disorder |
WO2007124757A2 (en) * | 2006-05-02 | 2007-11-08 | H. Lundbeck A/S | Use of escitalopram for improving cognition |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1996033710A1 (en) * | 1995-04-27 | 1996-10-31 | Astra Aktiebolag | A combination of a 5-ht uptake inhibitor with a selective 5-ht1a antagonist |
-
1998
- 1998-09-16 SE SE9803158A patent/SE9803158D0/en unknown
-
1999
- 1999-09-13 WO PCT/SE1999/001599 patent/WO2000015220A1/en not_active Application Discontinuation
- 1999-09-13 JP JP2000569804A patent/JP2002524510A/en active Pending
- 1999-09-13 EP EP99951321A patent/EP1113793A1/en not_active Withdrawn
- 1999-09-13 AU AU63782/99A patent/AU6378299A/en not_active Abandoned
- 1999-09-13 CA CA002342233A patent/CA2342233A1/en not_active Abandoned
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1996033710A1 (en) * | 1995-04-27 | 1996-10-31 | Astra Aktiebolag | A combination of a 5-ht uptake inhibitor with a selective 5-ht1a antagonist |
Cited By (19)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1440691A3 (en) * | 1999-07-08 | 2004-08-25 | H.Lundbeck A/S | Treatment of neurotic disorders |
AU2005202685B2 (en) * | 1999-07-08 | 2009-01-15 | H Lundbeck A/S | Treatment of Neurotic disorders |
WO2001003694A1 (en) * | 1999-07-08 | 2001-01-18 | H. Lundbeck A/S | Treatment of neurotic disorders |
EP1440691A2 (en) * | 1999-07-08 | 2004-07-28 | H.Lundbeck A/S | Treatment of neurotic disorders |
EP1440690A2 (en) * | 1999-07-08 | 2004-07-28 | H.Lundbeck A/S | Treatment of neurotic disorders |
EP1440689A2 (en) * | 1999-07-08 | 2004-07-28 | H.Lundbeck A/S | Treatment of neurotic disorders |
EP1440690A3 (en) * | 1999-07-08 | 2004-08-18 | H.Lundbeck A/S | Treatment of neurotic disorders |
EP1440689A3 (en) * | 1999-07-08 | 2004-08-25 | H.Lundbeck A/S | Treatment of neurotic disorders |
JP2003504332A (en) * | 1999-07-08 | 2003-02-04 | ハー・ルンドベック・アクチエゼルスカベット | How to treat mental disorders |
EP1200081A1 (en) | 1999-07-08 | 2002-05-02 | H. Lundbeck A/S | Treatment of neurotic disorders |
US6960613B2 (en) | 1999-07-08 | 2005-11-01 | H. Lundbeck A/S | Treatment of neurotic disorders |
AU2005202686B2 (en) * | 1999-07-08 | 2009-01-15 | H Lundbeck A/S | Treatment of Neurotic disorders |
US7265151B2 (en) | 1999-07-08 | 2007-09-04 | H. Lundbeck A/S | Treatment of neurotic disorders |
US7271194B2 (en) | 1999-07-08 | 2007-09-18 | H. Lundbeck A/S | Treatment of neurotic disorders |
AU2005202684B2 (en) * | 1999-07-08 | 2009-01-15 | H Lundbeck A/S | Treatment of Neurotic disorders |
EA008372B1 (en) * | 2000-07-07 | 2007-04-27 | Х.Лундбекк А/С | Use of escitalopram for treating disorders associated with social anxiety disorder |
EA008373B1 (en) * | 2000-07-07 | 2007-04-27 | Х. Лундбекк А/С | Use of escitalopram useful in the treatment of disorders associated with post traumatic stress disorder |
WO2007124757A3 (en) * | 2006-05-02 | 2008-07-24 | Lundbeck & Co As H | Use of escitalopram for improving cognition |
WO2007124757A2 (en) * | 2006-05-02 | 2007-11-08 | H. Lundbeck A/S | Use of escitalopram for improving cognition |
Also Published As
Publication number | Publication date |
---|---|
JP2002524510A (en) | 2002-08-06 |
CA2342233A1 (en) | 2000-03-23 |
SE9803158D0 (en) | 1998-09-16 |
AU6378299A (en) | 2000-04-03 |
EP1113793A1 (en) | 2001-07-11 |
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