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
  • A61K31/352—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 condensed with carbocyclic rings, e.g. methantheline 
  • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
• • 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
  • 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
• • 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
  • A61P25/22—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 a first component (a) which is R 3-N,N-dicyclobutylamino-8-fluoro-3,4-dihydro-2H- 1 -benzopyran-5- carboxamide hydrogen (2R,3R)-tartrate monohydrate and a second component (b) which is l-[3-(dimethylamino)propyl]-l-(p-fluorophenyl)-5-phthalancarbonitrile, as the racemate or an enantiomer thereof, in the form of the free base, or a pharmaceutically acceptable salt and/or solvate thereof.
• a first component (a) which is R 3-N,N-dicyclobutylamino-8-fluoro-3,4-dihydro-2H- 1 -benzopyran-5- carboxamide hydrogen (2R,3R)-tartrate monohydrate
• a second component (b) which is l-[3-(dimethylamino)propyl
• 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
• a new composition comprising of a first component (a) which is the specific 5-HT ⁇ antagonist (R ⁇ -3-N,N-dicyclobutylamino-8-fluoro-3,4- dihydro-2H-l-benzopyran-5-carboxamide hydrogen (2R,3R)-tartrate monohydrate and a second component (b) which is l-[3-(dimethylamino)propyl]-l-(p-fluorophenyl)-5- phthalancarbonitrile, as the racemate or an enantiomer thereof, in the form of the free base, or a pharmaceutically acceptable salt and/or solvate thereof, which is a 5- ⁇ T reuptake inhibitor.
• 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)-3-N,N-dicyclobutylamino-8-fluoro-3,4-dihydro-2H-l-benzopyran-5- carboxamide hydrogen (2R,3R)-tartrate monohydrate (NAD 299) disclosed herein is described in J. Pharmacolog. Exp. Ther., 283, 216-225, (1997), as a selective 5- ⁇ T 1A receptor antagonist.
• l-[3-(dimethylamino)propyl]-l-(p-fluorophenyl)-5-phthalancarbonitrile is a 5-HT reuptake inhibitor (SSRI).
• SSRI 5-HT reuptake inhibitor
• l-[3-(dimethylamino)propyl]- l-(p-fluorophenyl)-5-phthalancarbonitrile in the racemic form is known as citalopram, which is commercially available.
• the enantiomer (+)-l-[3-(dimethylamino)propyl]-l-(p- fluorophenyl)-5-phthalancarbonitrile disclosed herein, is described in US 4,943,590.
• salts of l-[3-(dimethylamino)propyl]-l-(p-fluorophenyl)-5- phthalancarbonitrile in the racemic or enantiomeric forms may be hydrochlorides, hydrobromides, maleates, tartrates, acetates, oxalates, fumarates etc. and are also included in the inventive composition. Also solvate forms such as the hydrate and hemihydrate are included.
• composition according to the present invention may exist in one pharmaceutical formulation comprising the component (a) and component (b), or in two different pharmaceutical formulations, one for component (a) and one for component (b).
• 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.
• the composition of the present invention can be prepared such that component (a) is inco ⁇ orated into the same pharmaceutical formulation as component (b) 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 of (R)-3-N,N- dicyclobutylamino-8-fluoro-3,4-dihydro-2H- 1 -benzopyran-5-carboxamide hydrogen (2R,3/?)-tartrate monohydrate and l-[3-(dimethylamino)propyl]-l-(p-fluorophenyl)-5- phthalancarbonitrile, as the racemate or an enantiomer thereof, 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)-3- N,N-dicyclobutylamino-8-fluoro-3,4-dihydro-2H-l-benzopyran-5-carboxamide hydrogen (2R,3R)-tartrate monohydrate and a dosage unit of l-[3-(dimethylamino)propyI]-l-(p- fluorophenyl)-5-phthalancarbonitrile, as the racemate or an enantiomer thereof, in the form of the free base, or a pharmaceutically acceptable salt and/or solvate thereof, optionally with instructions for use.
• 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 ingredients 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, excipients e.g. diluents, 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; 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 starch
• 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 gelatin 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, polyetheneglycol, waxes, lipids or gelatine. 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 veget- able 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 tR > )-3-N,N-dicyclobutylamino-8-fluoro-3,4-dihydro-2H-l- benzopyran-5-carboxamide hydrogen (2R,3R)-tartrate monohydrate may very well differ from the daily doses of the active ingredient l-[3-(dimethylamino)propyl]-l-(p- fluoropheny ⁇ )-5-phthalancarbonitrile, as the racemate or an enantiomer thereof, in the form of free the 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
• a which is (7?j-3-N,N-dicyclobutylamino-8-fluoro-3,4-dihydro-2H-l- benzopyran-5-carboxamide hydrogen (2R,3R)-tartrate monohydrate
• a second component (b) which is l-[3-(dimethylamino)propyl]-l-(p-fluorophenyl)-5- phthalancarbonitrile, as the racemate or an enantiomer thereof, 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 CNS 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 CNS 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 hyperprolactinaemia), stroke, dyskinesia, Parkinson's disease, thermoregulatory disorders, pain and hypertension may also be treated with the combination described herein.
• hydroxytryptamine mediated disorders are urinary incontinence, vasospasm and growth control of tumors (e g lung carcinoma) and it may be possible to treat those with the combination described herein as well.
• the rats were anaesthetised with a mixture of ketamine HC1 (67 mg/kg intraperitoneal (IP);
• the microdialysis studies were performed in conscious animals after a 40-48 h recovery period, during which they were kept individually. Food and water were allowed ad libitum in the plastic cages subsequently used in the experimental sessions. On the day of the experiment, the probe inlets were connected to a syringe perfusion pump (CMA/100; CMA Microdialysis AB, Sweden), delivering artificial CSF (Hjorth, S., J. Neurochem. 60:776-779 (1993)) at a speed of 1.3 ⁇ l/min. Twenty-min dialysate fractions were collected from the probe outlet tubing, and immediately analysed for 5-HT and 5-HLAA by standard HPLC-EC methods.
• CMA/100 CMA Microdialysis AB, Sweden
• NAD 299 (0.3 mg/kg SC) administered 60 minutes after citalopram (5 mg/kg SC), strongly potentiated the 5-HT-elevating action of citalopram vs. controls (receiving citalopram +
• a suitable pharmaceutical composition comprising a first component (a) and a second component (b) in a single dosage form include the following:

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Cited By (5)

Citations (1)

• 1998
  • 1998-09-16 SE SE9803157A patent/SE9803157D0/xx unknown
• 1999
  • 1999-09-13 WO PCT/SE1999/001598 patent/WO2000015219A1/en not_active Application Discontinuation
  • 1999-09-13 BR BR9913765-8A patent/BR9913765A/pt not_active Application Discontinuation
  • 1999-09-13 KR KR1020017003338A patent/KR20010099648A/ko not_active Application Discontinuation
  • 1999-09-13 CA CA002342585A patent/CA2342585A1/en not_active Abandoned
  • 1999-09-13 HU HU0103569A patent/HUP0103569A3/hu unknown
  • 1999-09-13 IL IL14152099A patent/IL141520A0/xx unknown
  • 1999-09-13 EP EP99951320A patent/EP1121119A1/en not_active Withdrawn
  • 1999-09-13 JP JP2000569803A patent/JP2002524509A/ja active Pending
  • 1999-09-13 AU AU63781/99A patent/AU6378199A/en not_active Abandoned
  • 1999-09-13 PL PL99346769A patent/PL346769A1/xx unknown
  • 1999-09-13 CN CN99811007A patent/CN1317963A/zh active Pending
  • 1999-09-13 TR TR2001/00769T patent/TR200100769T2/xx unknown
  • 1999-09-13 EE EEP200100156A patent/EE200100156A/xx unknown
  • 1999-09-13 SK SK327-2001A patent/SK3272001A3/sk unknown
  • 1999-09-13 CZ CZ2001962A patent/CZ2001962A3/cs unknown
  • 1999-09-13 ID IDW20010580A patent/ID28359A/id unknown
  • 1999-09-15 AR ARP990104627A patent/AR023657A1/es unknown
• 2001
  • 2001-03-05 IS IS5877A patent/IS5877A/is unknown
  • 2001-03-08 ZA ZA200101951A patent/ZA200101951B/xx unknown
  • 2001-03-15 NO NO20011313A patent/NO20011313L/no unknown

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