Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2003-01-17
2004-09-07
Aulakh, Charanjit S. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S232000, C546S236000, C546S229000, C546S210000, C546S201000, C546S197000, C546S192000, C544S180000, C540S484000, C548S570000, C514S323000, C514S321000, C514S212010, C514S408000
Reexamination Certificate
active
06787560
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a serotonin reuptake inhibitor. The serotonin reuptake inhibitor of the present invention is a selective serotonin reuptake inhibitor that has affinity for serotonin 1A receptors, has a small inhibitory effect on the reuptake of dopamine and noradrenaline, and strongly inhibits serotonin reuptake. In addition, the present invention relates to a novel compound having such a selective inhibitory effect on serotonin reuptake. Furthermore, the present invention relates to a novel benzylpiperidine derivative that is an intermediate for synthesizing such a compound, and a process for producing the derivative.
BACKGROUND ART
Depression is a chronic disease that affects persons of all ages. Of various antidepressants used at present, the most successful antidepressants are selective serotonin reuptake inhibitors (hereinafter abbreviated as SSRI in some cases). SSRI has serotonin reuptake inhibitory effect more selective than dopamine and noradrenaline reuptake inhibitory effect. The first drug put on the market as SSRI is zimelidine. Other SSRIs that have been put on the market or are under development include, for example, fluoxetine, fluvoxamine, citalopram, cericlamine, femoxetine, ifoxetine, cyanodothiepin, sertraline, paroxetine and lotoxetine.
Although SSRIs are the most successful as antidepressants at present, several problems in them are pointed out. Of these problems, the following two problems are typical: about one-third of all melancholiacs are so difficult to cure that SSRIs are not sufficiently effective, and the exhibition of a sufficient clinical effect of SSRI requires 3 to 8 weeks. In particular, this slow exhibition of antidepressant effect causes the following problems. Since side effects are brought about immediately though the exhibition of antidepressant effect is slow, there is a vulnerable period in which the patient undergoes only the side effects without obtaining the therapeutic effect of the drug. Therefore, persuading the patient into continuing the same treatment also in this period is often a heavy burden for a doctor in charge. In addition, because of the gradual beginning of experience of the effect, a patient who tends to commit suicide resumes initiative before experiencing sufficient improvement of depressive condition. Therefore, there are, for example, a risk of suicide and a necessity for frequent admission into a hospital. Accordingly, the development of an antidepressant capable of exhibiting its effect rapidly is desired.
The reason why the exhibition of the antidepressant effect of SSRI requires several weeks is as follows.
SSRI inhibits rapid serotonin reuptake in serotonin metabolic turnover. Since this action takes place at the nerve ending of each serotonergic neuron, neurotransmission due to serotonin is enhanced. The inhibition of rapid serotonin reuptake by SSRI, however, takes place also in serotonergic neuron cell bodies and dendrites, which are present in raphe nucleus. Therefore, the firing auto-inhibition (the negative feedback reaction) of the serotonergic neuron through 5-HT
1A
auto-receptor is also enhanced in the raphe nucleus. As a result, the neurotransmission in the serotonergic neuron is not enhanced to an expected degree as a whole by initial administration of SSRI. On the other hand, in the course of continuous taking of SSRI for several weeks, serotonin 1A auto-receptors present on serotonergic neuronal cell bodies and dendrites in the raphe nucleus are desensitized, so that the negative feed back reaction is abolished. As a result, the firing inhibition of the serotonergic neuron is broken down, so that the enhancement of the activity of the serotonergic neuron and the inhibition of serotonin uptake at the nerve ending succeed cooperatively. Therefore, the serotonin neurotransmission is enhanced, resulting in exhibition of the antidepressant effect.
Accordingly, the reduction of a period required for the exhibition of the effect of SSRI or the enhancement of the antidepressant effect can be achieved either by stopping the negative feedback reaction of serotonin by inhibiting the serotonin 1A auto-receptor by the use of a serotonin 1A receptor antagonist, or by reducing a period required for the desensitization by positively stimulating the serotonin 1A auto-receptor by the use of a serotonin 1A receptor agonist. That is, a compound having affinity for serotonin 1A receptors and a selective inhibitory effect on serotonin reuptake has a marked antidepressant effect and hence can be used as a therapeutic agent for psychiatric diseases which exhibits its effect after a reduced period. In fact, it has been reported that, for example, pindolol having a high affinity for serotonin 1A receptors increases the effect of a serotonin reuptake inhibitor in a melancholiac and reduces a period required for the onset of the effect (Arch, Gen. Psychiatry, (1994), 51, 248-251).
There are many references concerning nitrogen-containing saturated heterocyclic derivatives substituted by a benzyl group which include nitrogen-containing saturated heterocyclic derivatives substituted by an N-aralkyl group and a benzyl group. As to the nitrogen-containing saturated heterocyclic derivatives substituted by an N-aralkyl group and a benzyl group, Arch. Pharm. (Weinheim, Ger.)(1979), 312, 670-681, for example, describes benzylpiperidine derivatives having psychotropic effect like dopamine. Japanese Patent No. 2573195 discloses cyclic amine derivatives as therapeutic agents for psychiatric symptoms accompanying a cerebrovascular accident. Med. Chem. Res. (1992), 2, 368-375 describes N-aralkyl-substituted 4-benzylpiperidines as sigma receptor ligands. International Publication No. WO 93/97216 discloses N-aralkyl-substituted 4-benzylpiperidines as NMDA receptor antagonists. None of these prior art references, however, report that the compounds described therein have inhibitory effect on serotonin reuptake. As 4-benzylpiperidines substituted by a substituted alkyl group having a heterocyclic group as the substituent, there are compounds disclosed in JP-A-63-183576. This reference, however, does not report either that these substituted 4-benzylpiperidines have inhibitory effect on serotonin reuptake. In addition, as 4-benzylpiperidines substituted by a cycloalkylalkyl group, there are the compounds disclosed in DE3614907. This reference, however, does not report either that these substituted 4-benzylpiperidines have inhibitory effect on serotonin reuptake.
Various derivatives have been known as only nitrogen-containing saturated heterocyclic derivatives substituted by a substituted benzyl group, in particular, 4-substituted benzylpiperidines. For example, J. Org. Chem. (1999), 64, 3763-3766 and CA2188485 disclose synthesis processes of the derivatives. Neither of these prior art references, however, reports a 2-substituted benzylpiperidine containing a bromine atom. Moreover, this compound cannot be synthesized according to the disclosed process.
DISCLOSURE OF THE INVENTION
The present invention is intended to provide a selective serotonin reuptake inhibitor having affinity for serotonin 1A receptors. Specifically, the present invention is intended to provide a selective serotonin reuptake inhibitor having affinity for serotonin 1A receptors which is useful as a therapeutic agent for mood disorders including depression, seasonal affective disorder and dysthymia in human beings and animals; anxiety disorders including generalized anxiety disorder, obsessive-compulsive disorder and panic disorder; agoraphobia and avoidant personality disorder; social phobia; compulsive reaction; post-traumatic stress disorder; psychosomatic disorder; retention defects including dementia, forgetfulness and retention defect associated with aging; eating disorders including anorexia nervosa and bulimia nervosa; obesity; somnipathy; schizophrenia; chemical dependency due to alcohol, tobacco, nicotine or the like; cluster headache; migraine; pains; Alzheimer's disease; chronic paroxysmal migraine; headache associated wit
Kinomura Naoya
Kodo Toru
Koyama Koji
Masumoto Shuji
Aulakh Charanjit S.
Sumitomo Pharmaceuticals Company Limited
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