JP2002524509A - New composition - Google Patents

Abstract

  (57) [Summary] The present invention relates to (2R, 3R) -hydrogen tartrate (R) -3-N, N-dicyclobutylamino-8-fluoro-3,4-dihydro-2H-1-benzopyran-5-carboxamide monohydrate. Certain first component (a) and 1- [3- (dimethylamino) propyl] -1 in the form of a free base or a pharmaceutically acceptable salt and / or a solvate thereof as a racemate or an enantiomer thereof A composition comprising the second component (b) which is-(p-fluorophenyl) -5-phthalanecarbonitrile, a method for preparing the same, a pharmaceutical composition comprising the composition, use of the composition and The present invention relates to a method for treating an emotional disorder such as mood disorder and anxiety disorder, and a kit containing the composition.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

【Technical field】

The present invention relates to (2R, 3R) -hydrogen tartrate (R) -3-N, N-dicyclobutylamino-8-fluoro-3,4-dihydro-2H-1-benzopyran-5-carboxamide monohydrate. Certain first component (a) and 1- [3- (dimethylamino) propyl] -1 in the form of a free base or a pharmaceutically acceptable salt and / or a solvate thereof as a racemate or an enantiomer thereof A composition comprising a second component (b) which is-(p-fluorophenyl) -5-phthalanecarbonitrile. The present invention also relates to methods of preparing the compositions of the invention, pharmaceutical compositions containing the compositions, co-administration or separate administration as an improved method of treating emotional disorders such as depression, anxiety, obsessive-compulsive disorder (OCD) and the like. The use of the above composition according to any of the above.

[0002]

BACKGROUND OF THE INVENTION

In recent years, it is generally considered that it takes 2 to 4 weeks for an antidepressant to exert its full clinical effect. On the other hand, side effects are immediate. That is, since the onset of the action of the antidepressant is slow, the patient is given a severe period in which he / she can experience side effects but cannot experience the therapeutic action of the drug. Convincing the patient to continue treatment during this period places a heavy burden on the attending physician. Furthermore, in patients at risk of suicide, the onset of action is slow, so decision-making is restored without experiencing complete regression of the symptoms, the risk of suicide remains, and the need for hospitalization is frequent. I do. Antidepressants with rapid onset of action not only benefit from more rapid symptom reduction, but are also more tolerated by patients and physicians, reducing the need and duration of hospitalization. An equally long time to full clinical effect has been observed in the treatment of anxiety and other affective disorders such as OCD.

[0003]

[Prior art]

WO 96/33710, which has a high affinity for the 5-HT receptor,
Compound (R) -5-carbamoyl-8-fluoro-3 that antagonizes HT _1A mediated response
It is disclosed that -N, N-dicyclobutylamino-3,4-dihydro-2H-1-benzopyran results in a rapid improvement in depressed patients receiving serotonin reuptake inhibitors.

[0004]

DISCLOSURE OF THE INVENTION

The present invention provides a specific 5-HT _1A antagonist (2R, 3R) -hydrogen tartrate (R) -3-N,
First component (a) which is N-dicyclobutylamino-8-fluoro-3,4-dihydro-2H-1-benzopyran-5-carboxamide monohydrate and racemic which is a 5-HT reuptake inhibitor 1- [3- (Dimethylamino) propyl] -1- (p-fluorophenyl) -5-in the form of a free base or a pharmaceutically acceptable salt and / or a solvate thereof as a compound or its enantiomer It relates to a new composition containing a second component (b), which is phthalanecarbonitrile. The composition exhibits a more rapid onset of action, thereby enabling more effective treatment of patients suffering from emotional disorders, especially depression.

In animal studies, acute administration of a selective 5-HT reuptake inhibitor (SSRI) is via a negative feedback response, possibly mediated by collateral 5-HT axon release 5-HT in the raphe nucleus. Have been shown to reduce electrical impulse propagation in 5-HT neurons. Somato dendrites in the raphe nucleus (somato
dendritic) By inhibiting 5-HT _1A autoreceptors, selective antagonists
Acts against the reduced transmission caused by HT reuptake inhibitors. This suggests that selective blockage of somatic dendritic autoreceptors, ie, 5-HT _1A antagonists have clinical potential to improve the action of 5-HT reuptake inhibitors (SSRIs), affective disorders Has shown a new basis for the rapid onset of action in the treatment of, for example, antidepressant effects.

The compounds disclosed herein (2R, 3R) -hydrogen (R) -3-N, N-dicyclobutylamino-8-fluoro-3,4-dihydro-2H-1-benzopyran-5 bitartrate -Carboxamide monohydrate (NAD 299) is described as a selective 5-HT _1A receptor antagonist in J. Pharmacol. Exp. Ther., 283, 216-225 (1997).

(2R, 3R) -hydrogen (R) -3-tartrate-3-N, N-dicyclobutylamino-8-
Fluoro-3,4-dihydro-2H-1-benzopyran-5-carboxamide 1
Hydrates have a high affinity for certain subgroups of 5-HT _1A receptors in the CNS, act as antagonists on the 5-HT _1A receptor, and
Shows good bioavailability after oral administration.

[0008] 1- [3- (dimethylamino) propyl] -1- (p-fluorophenyl) in the form of a free base or a pharmaceutically acceptable salt and / or a solvate thereof as a racemate or an enantiomer thereof ) -5-phthalanecarbonitrile is 5-H
It is a T reuptake inhibitor (SSRI). 1- [3- (Dimethylamino) propyl] -1- (p-fluorophenyl) -5-phthalanecarbonitrile as a racemate is known as titalopram and is commercially available. The enantiomer (+)-1- [3- (dimethylamino) propyl] -1- (p-fluorophenyl) -5-phthalanecarbonitrile is disclosed herein and described in U.S. Pat. No. 4,943,590. ing.

The pharmaceutically acceptable salts of 1- [3- (dimethylamino) propyl] -1- (p-fluorophenyl) -5-phthalanecarbonitrile in racemic or enantiomeric form include hydrochloride, bromide It may be a hydrochloride, maleate, tartrate, acetate, oxalate, fumarate, and the like, and is also included in the compositions of the present invention.
Solvate forms such as hydrates and hemihydrates are also included.

The composition of the present invention is present in one pharmaceutical composition containing component (a) and component (b), or one component (a) and another component (b) May be present in two pharmaceutical compositions containing The pharmaceutical compositions may be in the form of tablets or capsules, powders, mixtures, solutions or other suitable pharmaceutical forms such as patches or nasal preparations. The composition of the present invention can be prepared, for example, by mixing the component (a) into the same pharmaceutical composition as the component (b) by mixing by a conventional method.

The present invention also relates to (2R, 3R) -hydrogen tartrate (R) -3-N, N-dicyclobutylamino-8-fluoro-3,4-dihydro-2H-1-benzopyran-5-carboxamide 1 1- [3-] in the form of a free base or a pharmaceutically acceptable salt and / or a solvate thereof as a hydrate and a racemate or an enantiomer thereof
A method for improving the onset of the therapeutic effect by co-administering a composition containing (dimethylamino) propyl] -1- (p-fluorophenyl) -5-phthalanecarbonitrile is also included.

Another embodiment of the present invention relates to a (2R, 3R)-
Hydrogen tartrate (R) -3-N, N-dicyclobutylamino-8-fluoro-3,4-
1- [1] in the form of a free base or a pharmaceutically acceptable salt and / or a solvate thereof as a dosage unit of dihydro-2H-1-benzopyran-5-carboxamide monohydrate and as a racemate or an enantiomer thereof. 3- (dimethylamino) propyl] -1- (p-fluorophenyl) -5-phthalanecarbonitrile.

Pharmaceutical Compositions According to the present invention, the compounds in the compositions are orally, rectally, transdermally, nasally, in the form of pharmaceutical compositions containing the active ingredient, usually in a pharmaceutically acceptable dosage form. Or it is administered by injection. The dosage form may be a solid, semi-solid or liquid formulation. Usually the active substance will comprise from 0.1 to 99% by weight of the formulation, especially from 0.5 to 20% by weight in injectable formulations
In oral preparations, it constitutes 0.2 to 50% by weight. The pharmaceutical composition will contain the active ingredient optionally in combination with adjuvants, excipients, for example, diluents and / or inert carriers.

For preparing pharmaceutical compositions of the compositions of the present invention in dosage unit form for oral administration, the selected compound (s) may be a solid excipient such as lactose, saccharose, sorbitol, mannitol, starch, Potato starch, corn starch or amylopectin, cellulose derivatives, binders such as gelatin or polyvinylpyrrolidone, tablet disintegrants such as sodium starch glycolate, cross-linked PVP and sodium croscaramellose, lubricants such as magnesium stearate, calcium stearate, polyethylene glycol , Wax, paraffin and the like, and an anti-adhesion agent, such as talc or colloidal silicon dioxide, and then compressed into tablets. If a coated tablet is required, the core prepared as described above may be coated with a polymer known to those skilled in the art, for example, HPMC, HC or other cellulose derivatives or PVP, wherein the polymer is Dissolves in water or readily volatile organic solvents or mixtures of organic solvents. Alternatively, tablets can be coated with a concentrated sugar solution, which can contain, for example, gum arabic, gelatin, talcum, titanium dioxide, and the like. Dyes may be added to these coatings, for example, to facilitate differentiation between tablets containing different active substances or different amounts of active compound.

For the preparation of soft gelatin capsules, the active substances may be mixed with, for example, vegetable oils or polyethylene glycols. Hard gelatin capsules may contain any of the above-mentioned excipients for tablets, such as lactose, saccharose, sorbitol, mannitol, starch (eg, potato starch, corn starch or amylopectin), cellulose derivatives, plasticizers, polyethylene glycol, wax, lipids or gelatin. May be used to contain the granules of the active substance. Liquid or semisolid drugs can also be filled into hard gelatin capsules.

The dosage unit for rectal administration can be a solution or suspension, or the active substance as a suppository or a mixture with vegetable or paraffin oil containing the active substance as a mixture with a neutral fat base. Can be prepared in the form of gelatin rectal capsules. Oral liquid preparations may be solutions, syrups or suspensions, for example from about 0.2 to about 20% by weight of the above active substance and the balance being sugar and ethanol,
It can be in the form of a solution containing a mixture of water, glycerol and polyethylene glycol. In some cases, such liquid preparations may contain colorants, flavors,
It may contain saccharin and carboxymethylcellulose as a thickening agent, or other excipients known to those skilled in the art.

Solutions for parenteral administration by injection may be prepared as an aqueous solution of a water-soluble pharmaceutically acceptable salt of the active substance, preferably at a concentration of about 0.5 to about 10% by weight.
These solutions may also contain stabilizers and / or buffers and may conveniently be provided in various dosage unit ampoules.

Suitable daily doses of the active compound in the compositions of the invention in the treatment of humans are from about 0.01 to 100 mg / kg body weight for oral administration and 0.001 to 100 mg / kg for parenteral administration.
kg weight. Active ingredient (2R, 3R) -hydrogen tartrate (R) -3-N, N-dicyclobutylamino-8-fluoro-3,4-dihydro-2H-1-benzopyran-
The daily dose of 5-carboxamide monohydrate is 1- [3- () in the form of a free base or a pharmaceutically acceptable salt and / or a solvate thereof as the active ingredient, racemate or its enantiomer. Dimethylamino) propyl] -1- (p
The daily dosage of the (-fluorophenyl) -5-phthalanecarbonitrile may vary greatly, but the dosage can be the same for both active ingredients.

Pharmaceutical Uses In another aspect, the invention provides (2R, 3R) -hydrogen tartrate (R) -3-N, N
The first component (a), which is dicyclobutylamino-8-fluoro-3,4-dihydro-2H-1-benzopyran-5-carboxamide monohydrate, and the free base as a racemate or an enantiomer thereof Or 1- [3- (dimethylamino) propyl] -1- in the form of a pharmaceutically acceptable salt and / or a solvate thereof.
A second component (b) which is (p-fluorophenyl) -5-phthalanecarbonitrile
) And the use in the treatment of 5-hydroxytryptamine-mediated disorders such as emotional disorders. Examples of emotional disorders include mood disorders (depression, major depressive symptoms, mood swings, seasonal affective disorder, depression in bipolar disorder), anxiety disorders (
Obsessive-compulsive disorder, panic disorder with or without agoraphobia, social aversion, specific aversion, general anxiety disorder, post-traumatic stress disorder), personality disorder (suppression disorder, trichothromoney) and sleep disorders Such an obstacle in the CNS. Other disorders in the CNS, such as eating disorders (obesity, anorexia, bulimia), premenstrual syndrome, sexual disorders, alcoholism, excessive smoking, autism, lack of attention, hyperactivity, migraine, memory impairment (Age-related memory impairment, presenile and senile dementia, such as Alzheimer's disease), pathological aggression, schizophrenia, endocrine disorders (eg, hyperprolactinemia), stroke, movement disorders, Parkinson's disease, impaired thermoregulation , Pain and hypertension may also be treated with the combinations described herein. Examples of other hydroxytryptamine-mediated disorders are urinary incontinence, vasospasm and growth control of tumors (eg, lung cancer), which may also be treatable with the combinations described herein.

Pharmacology (2R, 3R) -hydrogen tartrate (R) -3-N, N-dicyclobutylamino-8-fluoro-3,4-dihydro-2H-1-benzopyran-5-carboxamide monohydrate Enhancement of 5-HT _1A Autoreceptor Blocking Effect of 5-HT of Citalopram Using (NAD 299) Materials and Methods Animals Tests were performed in male Sprague-Dawley rats (290-450 g; B & K Universal, So
llentuna, Sweden). The test animals were bred for at least 3 weeks after they were obtained before they were used for the experiment.

Methods The study was performed using intracerebral microdialysis in awake rats. Dialysis probes were tested with frontal cortex (FCx) and posterior hippocampus (D) to determine if there were any virtual regional differences between the posterior and midline raphe innervated 5-HT protrusion regions.
H) were implanted simultaneously.

Microdialysis Rats were treated with ketamine hydrochloride (67 mg / kg intraperitoneally (IP); Ketalar®, Park-D ⁾ .
avis) and xylazine hydrochloride ^{(13mg / kg IP; Rompun (} R), Bayer-Levekusen
The mixture was anesthetized. U type microdialysis probe (total dialysis fiber length 4mm, O
D 220 μm) in the frontal cortex (FCx) and posterior hippocampus (DH).
At this time, the tip of the probe was AP + 3.5 with respect to the bregma and dura surface
ML-3.0, DV-4.2 and -4.3, ML + 2.5, DV-4.2 (Paxinos et al., The Rat Brain in Stereotaxic Coordinates, 2nd Ed., Academic
Press, San Diego (1996)). Microdialysis tests were performed on awake animals after a recovery period of 40-48 hours housed individually. Food and drinking water were provided ad libitum in plastic cages used later in the experimental procedure. On the day of the experiment, the inlet of the probe was connected to a syringe perfusion pump (CMA / 100; CMA Microdialysis AB, Sweden), and an artificial CSF (Hjorth, S., J. Neurochem. 60: 776-779 (1993)) was used. It was supplied at a rate of 3 μL / min. The 20 minute dialysate fraction was collected from the probe drain tubing and immediately analyzed for 5-HT and 5-HIAA by standard HPLC-EC methods. Drug administration was performed after establishing a stable 5-HT dialysate concentration of 5-HT by allowing 2-3 hours after the start of perfusion. At 2 o'clock in the rat group, titalopram (
5.0 mg / kg SC). After 60 minutes, NaCl (control) was given to one group,
NAD 299 (0.3 mg / kg SC) was given to the other group. The dialysate concentration of 5-HT in the frontal cortex (FXc), expressed as the corresponding pre-injection baseline, is shown in FIG.

Results: NAD 299 (0.3 mg / kg SC) administered 60 minutes after titalopram (5 mg / kg SC)
kgSC) compared to the control group (citalopram + NaCl).
The ascending effect was strongly enhanced.

Conclusions According to the data shown in FIG. 1, an endogenous agonist (5-5) at the 5-HT _1A autoreceptor, induced by citalopram, thereby enhancing the citalopram-induced 5-HT elevation in the frontal region. -HT) (2R, 3R) -hydrogen (R) -3-N, N-dicyclobutylamino-8-fluoro-3,4-dihydro-2H, as evident from its ability to antagonize increased tone. -1-benzopyran-5
-Carboxamide monohydrate (NAD 299) exhibits potent 5-HT _1A autoreceptor blocking properties. Via its 5-HT _1A autoreceptor blockade, (2R, 3R) -hydrogen tartrate (R) -3-N, N-dicyclobutylamino-8-fluoro-3,4-dihydro-2H-1- Benzopyran-5-carboxamide monohydrate may be clinically useful in treating 5-HT mediated disorders, especially mood disorders. The following non-limiting examples illustrate the invention.

EXAMPLES A suitable pharmaceutical composition containing a first component (a) and a second component (b) in a single dosage form comprises the following components: Composition: mg / tablet Active pharmaceutical ingredient (a) 5 Active pharmaceutical ingredient (b) 20 Microcrystalline cellulose 100 Corn starch 40 Povidone 4 Water 50 Sodium starch glycolate 8 Magnesium stearate 1

[Brief description of the drawings]

BRIEF DESCRIPTION OF THE FIGURES FIG. 1: Two groups of rats were injected with titalopram (5.0 mg / kg SC) at time 0, and 60 minutes later, N
Dialysis of 5-HT in the frontal cortex (FXc), given as aCl (control) in one group and NAD 299 (0.3 mg / kg SC) in the other group, expressed as% of the corresponding pre-injection baseline. Indicates the substance concentration.

──────────────────────────────────────────────────続 き Continuation of front page (81) Designated country EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE ), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, SD, SL, SZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AE, AL, AM, AT, AU, AZ, BA, BB, BG, BR , BY, CA, CH, CN, CR, CU, CZ, DE, DK, DM, EE, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL , IN, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, UA, UG, US, UZ, VN, YU, ZA, ZW (72) Inventor Set-Urov・ Torberg S-151 85 Sweden. AstraZeneca. R & D Söderteier F-term (reference) 4C086 AA02 BA06 BA08 MA02 MA04 NA05 ZA12 ZA18 ZC01 ZC75

Claims (24)

[Claims] (1) (2R, 3R) -hydrogen tartrate (R) -3-N, N-dicyclobutylamino-8-fluoro-3,4-dihydro-2H-1-benzopyran-5-
1- [3- (dimethyl) in the form of a free base or a pharmaceutically acceptable salt and / or a solvate thereof as the first component (a) which is carboxamide monohydrate and the racemate or its enantiomer. A composition comprising a second component (b) which is amino) propyl] -1- (p-fluorophenyl) -5-phthalanecarbonitrile. 2. The composition according to claim 1, wherein the second component (b) is racemic 1- [3- (dimethylamino) propyl] -1- (p-fluorophenyl) -5-phthalanecarbonitrile. Composition. 3. The method according to claim 2, wherein the second component (b) is (+)-1- [3- (dimethylamino)
Propyl] -1- (p-fluorophenyl) -5-phthalanecarbonitrile. 4. A method for the manufacture of a medicament for treating 5-HT-mediated disorders.
Use of a composition according to any one of the preceding claims. 5. Use according to claim 4, for the manufacture of a medicament for the treatment of emotional disorders. 6. Use according to claim 5, for the manufacture of a medicament for the treatment of mood disorders. 7. Use according to claim 6, for the manufacture of a medicament for the treatment of depression. 8. Use according to claim 4, for the manufacture of a medicament in the prevention or treatment of urinary incontinence. 9. A method for treating a 5-HT mediated disorder by administering the composition according to any one of claims 1 to 3 to a patient suffering from the disorder. 10. The method according to claim 9, for treating an emotional disorder. 11. The method according to claim 10, for treating a mood disorder. 12. The method according to claim 11, for treating depression. 13. The method according to claim 9, for the prevention or treatment of urinary incontinence. 14. A method for improving the expression of a therapeutic effect by co-administration of the composition according to any one of claims 1 to 3. 15. Pharmaceutical formulation, wherein the active ingredient is a substance in a composition according to any one of claims 1 to 3, optionally in combination with auxiliaries, excipients and / or inert carriers. 16. The pharmaceutical preparation according to claim 15, wherein the first component (a) is administered simultaneously with the second component (b). 17. A pharmaceutical preparation according to claim 15 or 16 for use in the treatment of a 5-HT mediated disorder. 18. A pharmaceutical preparation according to claim 15 or 16 for use in the treatment of an emotional disorder. 19. The pharmaceutical preparation according to claim 15 or 16 for use in the treatment of a mood disorder. 20. A method according to claim 15 for use in the treatment of depression.
Pharmaceutical preparation of Claim. 21. The use according to claim 15 or 1 for use in the treatment of urinary incontinence.
7. The pharmaceutical preparation according to 6. 22. The method for preparing a composition according to claim 1, wherein the first component (a) is blended with the same pharmaceutical preparation as the second component (b). 23. The method according to claim 1, wherein the first component (a) is in one pharmaceutical preparation and is combined with the second component (b) in another pharmaceutical preparation.
A method for preparing the composition described in the section. 24. (2R, 3R) -Hydrogen (R) -3-N, N-dicyclobutylamino-8-fluoro-3,4-dihydro-2H-1-benzopyran, optionally with instructions for use. A free base or a pharmaceutically acceptable salt and / or a solvate thereof in the form of a dosage unit of the first component (a) which is -5-carboxamide monohydrate and a racemate or an enantiomer thereof. − [3- (
Kit comprising a dosage unit of the second component (b) which is dimethylamino) propyl] -1- (p-fluorophenyl) -5-phthalanecarbonitrile.