Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-11-23
2004-04-13
Rotman, Alan L. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S318000, C514S320000, C544S129000, C546S196000, C546S205000
Reexamination Certificate
active
06720320
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a compound that acts on 5-hydroxytryptamine (5-HT) neurotransmission. More particularly, the present invention relates to a novel phenoxypropylamine compound having selective affinity for and simultaneous antagonistic activity against a 5-hydroxytryptamine 1A (5-HT
1A
) receptor in the central nervous system, as well as a 5-HT reuptake inhibitory activity, which is useful as a pharmaceutical agent, and to a therapeutic agent for depression and the like, which contains this compound. 5-Hydroxytryptamine (5-HT) is also known as “serotonin”.
BACKGROUND ART
As a compound having an antagonistic activity against 5-HT
1A
receptor as well as an inhibitory activity on the reuptake of 5-HT, there are known, for example, 1-(4-indolyloxy)-3-(4-(3,4-methylenedioxyphenyl)piperidino)-2-propanol derivative (EP 0722941), 4-(4-fluorophenyl)-1-((6-(methylamino)indan-1-yl)methyl)piperidine derivative (WO 95/33721), 3,6-dihydro-N-methyl-N-(5-chloro-2-pyridyl)-4-(1-naphthalenyl)-1-(2H)pyridine propanamine derivative (U.S. Pat. No. 5,472,966), 3-(5-chlorobenzo[b]thiophen-3-yl)-5,6-dihydroimidazo[2,1-b]thiazol derivative (WO 97/02269), S-(−)-N-(2-(3-(2-naphthyl)-pyrrolidino)ethyl)-N-(2-pyridyl)cyclohexanecarboxamide derivative (WO 97/40038), (R)-3-(N-cyclopentyl-N-n-propylamino)-8-fluoro-5-(N-methylcarbamoyl)-3,4-dihydro-2H-1-benzopyran derivative (WO 96/33710), 3-(2-(4-methylpiperazin-1-yl)benzylidene)-1,3-dihydroindol-2-one derivative (WO 97/36867), (S)-1-(4-indolyloxy)-3-[4-hydroxy-4-(2-naphthyl)piperidino]-propan-2-ol derivative (WO 97/48698) and the like.
JP-A-62-116557 discloses substituted benzyllactams, such as 2-hydroxy-1-[2-((2-oxo-4-pyrrolidinyl)methyl)phenoxy]-3-(4-diphenylmethyl-piperazin-1-yl)propane and the like, which have a binding ability with a serotonin receptor and a muscarinic acetylcholine receptor, and which can be used for the treatment of senile dementia, Alzheimer's disease, cerebrovascular dementia and the like.
Various diseases of the central nervous system (e.g., depression, anxiety) are considered to be caused by disorders of noradrenalin (NA) and 5-hydroxytryptamine (5-HT), which are neurotransmitters. Accordingly, augmentation of 5-HTergic neurotransmission is considered to mainly influence depressive mood and anxious, whereas augmentation of noradrenergic neurotransmission is considered to influence retardation in depressive patients. The pharmaceutical agents, such as imipramine, desipramine and the like, which are most frequently used for the treatment of depression, are considered to act on depressive patients by improving neurotransmission of one or both of these NA and 5-HT.
The activity of 5-HT is considered to relate to a number of various types of psychiatric disorders. In addition, 5-HT has been considered to be responsible for various conditions (e.g., eating disorder, gastrointestinal injury, control of cardiovascular system and sexual behavior). However, conventional antidepressants, such as imipramine, desipramine and the like, are defective in that they require 3-4 weeks or even longer time for the expression of an anti-depressive effect, which poses clinical problems.
A combined use of various pharmaceutical agents has been considered in an attempt to accelerate expression of effects of antidepressants or to increase their efficacy (Journal of Clinical Psychiatry, Vol. 57; Suppliment 7; pp 25-31). Therein, a noticeably shortened time for clinical expression of the effect by concurrent use of a selective serotonin (5-HT) reuptake inhibitor (SSRI) and a 5-HT
1A
antagonist, pindolol, has been reported (Journal of Clinical Psychopharmacology, Vol. 17, No. 6, pp. 446-450). It is known that the amount of 5-HT release in the brain does not increase much by SSRI alone, but when combined with a 5-HT
1A
antagonist, the amount increases markedly (Neurochemical Research, Vol. 21, No. 5, 1996, pp. 557-562). Under such circumstances, the “5-HT enhancement hypothesis” was proposed with regard to the expression of the action of antidepressants by Blier and de Montigny (Trends in Pharmacological Sciences, 1994, vol. 15, pp. 220-226). The 5-HT enhancement hypothesis means that the effector mechanism of antidepressant rests in the enhancement of 5-HT release at a terminal. It is based on the understanding that the conventional antidepressants decrease the 5-HT release by single administration, but increase the 5-HT release and express an anti-depressive effect only when they are administered consecutively. From those mentioned above, it is expected that a drug that promotes 5-HT release in the brain from the first can be a rapid onset antidepressant. In other words, a compound concurrently having a serotonin reuptake inhibitory action and a 5-HT
1A
antagonistic action is considered to be an antidepressant showing quick expression of an anti-depressive effect, namely, a rapid onset antidepressant.
It is an object of the present invention to find a subgroup of 5-hydroxytryptamine (5-HT) receptor, namely, a compound simultaneously having selective affinity for and antagonistic activity against 5-HT
1A
receptor in the central nervous system in mammals inclusive of human, which compound also having a 5-HT reuptake inhibitory activity.
It is therefore an object of the present invention to provide a compound that expresses an anti-depressive effect quickly, which is a so-called rapid onset antidepressant, and a compound useful for the treatment of 5-HT mediated diseases in the central nervous system, such as schizophrenia, anxiety neurosis, obsessive-compulsive disorder (OCD), panic disorder, social anxiety disorder, seasonal emotional disorder, Anorexia Nervosa, Bulimia Nervosa, nocturnal enuresis, children's hyperlocomotion, post-traumatic stress disorder(PTSD), senile dementia, hemicrania, stroke, Alzheimer's disease, recognition disorder, hypertension, gastrointestinal injury, feeding disorders, premenstrual syndrome (PMS), abnormal body temperature regulation, sexual disorder and pain, as well as for the treatment of abnormality in the cardiovascular system, treatment of drug abuse and the like.
SUMMARY OF THE INVENTION
The present inventors have conducted intensive studies, and as a result, found that a novel phenoxypropylamine compound of the formula (I), an optical isomer thereof and a pharmaceutically acceptable salt thereof have selective affinity for and simultaneous antagonistic activity against a 5-hydroxytryptamine 1A (5-HT
1A
) receptor, as well as 5-HT reuptake inhibitory activity, and can be a useful pharmaceutical agent that meets the above-mentioned objects, which resulted in the completion of the present invention. Moreover, the present inventors have also found novel compounds of the formulas (II) and (III) to be mentioned below, which are the synthetic intermediates for the phenoxypropylamine compound.
Accordingly, the present invention provides the following.
1. A phenoxypropylamine compound of the formula (I)
wherein each symbol in the formula means as follows:
a bond represented by a solid line and a dotted line shows a double bond or a single bond;
X is a hydrogen atom, a hydroxy group, a C
1
-C
8
alkoxy group, an acyloxy group or an oxo group;
provided that when R
1
is a group of the following formula (2), X should not be a hydrogen atom;
R
1
is a group of the following formula
wherein
Y is O or S,
Ar is optionally substituted aromatic hydrocarbon,
R is optionally substituted aryl group or optionally substituted aromatic heterocyclic group,
R
5
is optionally substituted aryl group or optionally substituted aromatic heterocyclic group,
Z is void or —CH
2
—, and
R
6
is hydrogen atom, hydroxy group, acetamido group, carboxyl group, alkoxycarbonyl group, cyano group or C
1
-C
8
alkoxy group;
R
3
is a hydrogen atom, a C
1
-C
18
alkyl group or a halogen atom;
V is —CH
2
—, —O—, —S— or the formula —N(R
4
)—
wherein R
4
is hydrogen atom, C
1
-C
18
alkyl group or optionally substituted aralkyl group;
W is void or —CH
2
— or —C(&
Bougauchi Masahiro
Kanzaki Kouji
Kuroita Takanobu
Minoguchi Masanori
Morio Yasunori
Mitsubishi Pharma Corporation
Rotman Alan L.
Small Andreä D.
Wenderoth , Lind & Ponack, L.L.P.
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