JP2002524508A - 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. A composition comprising a first component (a) and a second component (b) which is paroxetine in the form of a free base or a pharmaceutically acceptable salt and / or a solvate thereof, a process for preparing the same, The present invention relates to a pharmaceutical composition comprising the composition, a use of the composition and a method for treating emotional disorders such as mood disorders and anxiety disorders using the composition, and a kit comprising the composition.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

【Technical field】

The present invention relates to (2R, 3R) -hydrogen (R) -3-tartrate-N, N-dicyclobutylamino-8-fluoro-3,4-dihydro-2H-1-benzopyran-5-carboxamide monohydrate. A composition comprising a first component (a) and a second component (b) that is paroxetine or a pharmaceutically acceptable salt and / or solvate thereof. 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- which antagonizes HT _1A mediated response
It is disclosed that N, N-dicyclobutylamino-3,4-dihydro-2H-1-benzopyran provides 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, N-
A first component (a) which is dicyclobutylamino-8-fluoro-3,4-dihydro-2H-1-benzopyran-5-carboxamide monohydrate and a free base or a pharmaceutically acceptable salt and / or Or a new composition comprising a second component (b) which is paroxetine in the form of a solvate thereof. This composition exhibits a more rapid onset of action, which allows for 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 effects of 5-HT reuptake inhibitors (SSRIs), affect emotional 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-tartrate-3-N, N-dicyclobutylamino-8-fluoro-3,4-dihydro-2H-1-benzopyran-5 -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 bitartrate (R) -3-N, N-dicyclobutylamino-8-fluoro-3,4-dihydro-2H-1-benzopyran-5-carboxamide monohydrate is Has high affinity for certain subgroups of 5-HT _1A receptors in the CNS, acts as an antagonist for the 5-HT _1A receptor, and has good bioavailability after oral administration Shows sex.

[0008] Paroxetine is a commercially available 5-HT reuptake inhibitor (SSRI). Pharmaceutically acceptable salts of paroxetine such as hydrochloride, hydrobromide, maleate, tartrate, acetate and the like are also included in the compositions of the present invention. Hydrate forms such as salt 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 is component (a) and the other is 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 invention also relates to (2R, 3R) -hydrogen tartrate (R) -3-N, N-dicyclobutylamino-8-fluoro-3,4-dihydro-2H-1-benzopyran-5-carboxamide monohydrate And a method for improving the onset of a therapeutic effect by co-administering a composition containing paroxetine.

Another embodiment of the present invention is a process for preparing (2R, 3R) -hydrogen (R) -3-N, N-dicyclobutylamino-8-fluoro-3,4-dihydrogen, optionally with instructions for use. It is a kit comprising a dosage unit of -2H-1-benzopyran-5-carboxamide monohydrate and a dosage unit of paroxetine.

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, eg, 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 and 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. These coatings include:
Dyes may be added, 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 suppository containing the active substance as a mixture with a base of neutral fat or the active substance as a mixture with a vegetable or paraffin oil. 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.

[0017] Suitable daily doses of the active compound in the composition according to the invention in the treatment of humans are 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-5-
The daily dose of carboxamide monohydrate can vary significantly from the daily dose of active ingredient paroxetine, but the dose can be the same for both active ingredients.

Pharmaceutical Uses In another aspect, the invention is directed to the use of (2R, 3R) -hydrogentartrate (R) -3-N, N-dicyclobutylamino- in the treatment of 5-hydroxytryptamine-mediated disorders such as affective disorders. Use of a composition containing a first component (a) that is 8-fluoro-3,4-dihydro-2H-1-benzopyran-5-carboxamide monohydrate and a second component (b) that is paroxetine I will provide a. Examples of emotional disorders are 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,
Trichothyromanny) and sleep disorders. CNS
Other disorders in, such as eating disorders (obesity, anorexia, bulimia), premenstrual syndrome, sexual dysfunction, 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, thermoregulatory disorders, 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 bitartrate (R) -3-N, N-dicyclobutylamino-8-fluoro-3, inhibits paroxetine-induced inhibition of dorsal raphe firing. Antagonism by 4-dihydro-2H-1-benzopyran-5-carboxamide monohydrate (NAD 299) Materials and Methods Mature male Sprague Dawley rats (B & K Universal, Sollentuna, Sweden)
Were bred under controlled weather conditions. Animals were prepared for electrophysiological recordings according to standard procedures. Briefly, rats were deeply anesthetized with chloral hydrate and placed in a stereotaxic frame. The extracellular recording electrode was lowered into the posterior raphe along the stereotactic axis and target neurons were detected by the firing properties of serotonin neurons in this nucleus. Animals were anesthetized throughout the experiment and drugs were administered intravenously via a tail vein catheter. Paroxetine (0.1 mg kg ^-1 iv) is NAD 299 (50 n
It was administered 3 minutes before the administration of mol kg ^-1 iv).

Results NAD 299 was able to antagonize paroxetine-induced suppression of firing in rat serotonergic posterior raphe neurons (FIG. 1).
. FIG. 1 shows the range between the median ± quartile based on recorded values obtained from 5 animals per group. The statistical evaluation of the difference between the administration group and the control, performed by the Mann-Whitney μ-test, is also shown in FIG. In addition, paroxetine-induced suppression was due to NAD 299
Administration was statistically significantly antagonized (p <0.05).

DISCUSSION AND CONCLUSIONS Selective serotonin reuptake inhibitors (SSRIs) such as paroxetine exert their antidepressant effects on the synaptic availability of serotonin in the frontal target area of serotonergic protrusions from the midbrain raphe nucleus It depends on its ability to enhance. However, the affected 5-hydroxytryptamine (5-HT) transport protein is present in both the somatic dendrites and terminal regions, and initially the inhibitory 5-hydroxytryptamine (5-HT) transport protein is increased due to increased availability of serotonin in the former regions. Activation of HT _1A autoreceptors suppresses neuronal activity and the synthesis and release of frontal 5-HT. As these receptors become desensitized over time, the release of serotonin in the forehead gradually increases, as observed in animal studies, and the time course of this phenomenon is probably due to the action of antidepressants. This is considered to explain clinically the delayed onset.

There is a hypothesis that de-suppression of the self-suppressive effect of SSRIs by blocking inhibitory 5-HT _1A autoreceptors results in a more rapid onset of action and also generally increases the effects of these drugs. . According to the data, (2R, 3R) -hydrogen tartrate (R) -3-N, N-dicyclobutylamino-8-fluoro-3,4-dihydro-2H-1-benzopyran-5-carboxamide monohydrate (NAD299) effectively antagonizes the suppression of firing in serotonergic neurons induced by acute administration of paroxetine in rats. 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]

FIG. 1 shows the range between median ± quartile based on recorded values obtained from 5 animals per group.
In addition, the statistical evaluation of the difference between the administration group and the control performed by the Mann-Whitney μ-test is also shown.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification code FI Theme coat ゛ (Reference) A61P 43/00 A61P 43/00 // C07D 311/04 C07D 311/04 405/12 405/12 (81) Designated countries 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), E A (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AE, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, CA, CH, CN, R, 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. AstraZeneca. R & D Söderteier F-term (reference) 4C062 EE99 4C063 AA01 BB08 CC81 DD10 EE01 4C086 AA01 AA02 BA08 BC21 GA02 GA07 GA15 MA02 MA03 MA04 MA05 NA05 ZA05 ZA18 ZA84 ZC42 ZC75

Claims (22)

[Claims] (1) (2R, 3R) -hydrogen tartrate (R) -3-N, N-dicyclobutylamino-8-fluoro-3,4-dihydro-2H-1-benzopyran-5-carboxamide monohydrate (A) and paroxetine in the form of a free base or a pharmaceutically acceptable salt and / or a solvate thereof (
A composition containing b). 2. Use of a composition according to claim 1 for the manufacture of a medicament for the treatment of a 5-HT mediated disorder. 3. Use of a composition according to claim 2 for the manufacture of a medicament for the treatment of emotional disorders. 4. Use according to claim 3, for the manufacture of a medicament for the treatment of mood disorders. 5. Use according to claim 4, for the manufacture of a medicament for the treatment of depression. 6. Use according to claim 2, for the manufacture of a medicament in the prevention or treatment of urinary incontinence. 7. A method for treating a 5-HT-mediated disorder by administering the composition of claim 1 to the patient. 8. The method according to claim 7, for treating emotional disorders. 9. The method according to claim 7, for treating a mood disorder. 10. The method according to claim 9, for treating depression. 11. The method according to claim 7, for preventing or treating urinary incontinence. 12. A method for improving the expression of a therapeutic effect by co-administration of the composition according to claim 1. 13. Pharmaceutical formulation, wherein the active ingredient is a substance in the composition according to claim 1, optionally in combination with auxiliaries, excipients and / or inert carriers. 14. The pharmaceutical preparation according to claim 13, wherein the first component (a) is administered simultaneously with the second component (b). 15. The pharmaceutical preparation according to claim 13 or 14 for use in the treatment of a 5-HT mediated disorder. 16. The pharmaceutical preparation according to claim 13 or 14 for use in treating an emotional disorder. 17. The pharmaceutical preparation according to claim 13 or 14 for use in the treatment of a mood disorder. 18. The method of claim 13 or 14 for use in treating depression.
Pharmaceutical preparation of Claim. 19. Use according to claim 13 or 1 for use in the treatment of urinary incontinence.
5. The pharmaceutical preparation according to 4. 20. 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). 21. The method of preparing a composition according to claim 1, wherein the first component (a) is in one pharmaceutical formulation and is combined with the second component (b) in another pharmaceutical formulation. . 22. (2R, 3R) -hydrogen (R) -3-N, N-dicyclobutylamino-8-fluoro-3,4-dihydro-2H-1-benzopyran, optionally with instructions for use. First component (a) which is -5-carboxamide monohydrate
And a dosage unit of the second component (b), which is paroxetine in the form of a free base or a pharmaceutically acceptable salt and / or a solvate thereof.