Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1998-04-21
2000-01-11
Rotman, Alan L.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
546 94, 546 95, 546 96, A61K 3144, A61K 31435, C07D22106
Patent
active
060136537
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
This invention relates to processes for the preparation of pyridoindole derivatives and salts thereof which are pharmaceutically effective as a 5-hydroxytryptamine (5-HT) antagonism.
BACKGROUND ART
Some pyridoindole derivatives indicated by the following general formula (III) and salts thereof are publicly known in the Japanese Kokai Tokkyo Koho 2-117675. These pyridoindole derivatives and salts thereof possess a 5-HT antagonism and are effective in the treatment and the prevention of central nervous system (CNS) disorders such as psychosis (e.g., schizophrenia, mania, etc.), anxiety, depression and so forth; pains such as headaches (e.g., migraine headaches, cluster headaches, vascular headaches, etc.), neuralgia (e.g., trigeminal neuralgia, etc.) and so forth; gastrointestinal disorders such as symptoms of gastrointestinal dysfunction accompanying dyspepsia, peptic ulcer, reflux esophagitis, meteorism, and the like, irritable bowel syndrome (IBS), and the like; nausea or vomiting accompanying cancer treatment; motion sickness; and so forth. ##STR1## wherein R.sup.1 is hydrogen, a lower alkyl group or a lower alkenyl group, R.sup.2 is hydrogen, a lower alkyl group or a halogen, and R.sup.3 is an imidazolyl group which may have a suitable substituent (s).
A process for the synthesis of (.+-.)-8,9-dihydro-10-methyl-7-[(5-methyl-1H-imidazol-4-yl)methyl]pyrido[1 ,2-a]indol-6(7H)-one (IIIa) is described in Japanese Kokai Tokkyo Koho 2-117675 through the following 5 steps which are illustrated below specifically as an example of the process for the synthesis of pyridoindole derivatives (IIIa). ##STR2##
In the above described conventional processes, the object compound (IIIa) is obtained from the compound (Ia) by means of processes through five steps, which comprises an alkylation first being carried out through an aldol reaction with an aldehyde (V), followed by acetylation, deacetoxification, detosylation, and reduction to synthesize the compound (IIIa). Here, the yield from the compound (Ia) to the object compound (IIIa) is 68%. The processes for producing the pyridoindole derivatives shown by the general formula (III) which are disclosed in the aforesaid Japanese Tokkyo Koho have drawbacks in the complicated processes due to the large number of steps, in the low yield, and in the higher cost, and so forth.
Furthermore, the aforesaid pyridoindole derivative is generally obtained as a racemic mixture. Moreover, the stereoisomers of said pyridoindole derivatives are generally obtained by the resolution process involving a reaction with an optically active reagent such as, for example, diparatoluoyltartaric acid or the like. However, the conventional optical resolution processes using diparatoluoyltartaric acid or the like have the drawback not only in the low yield but also in the use of a large amount of the solvent for the crystallization, and also are inavoidable to use chloroform which is in trouble for its safety.
DISCLOSURE OF INVENTION
The present invention provides a process for producing a pyridoindole derivative (III) or a salt thereof in one single step illustrated in the Process 1, shown below; which comprises a direct alkylation of a compound (I) or a salt thereof with an alkylating agent (II) or a salt thereof. This process is superior in it's simplicity and it's yield to the process disclosed in the aforesaid Japanese Kokai Tokkyo Koho. ##STR3## wherein R.sup.1 is hydrogen, a lower alkyl group or a lower alkenyl group, R.sup.2 is hydrogen, a lower alkyl group or a halogen, R.sup.3.sub.a is an imidazolyl group substituted with an imino protective group, which may have a suitable substituent (s), R.sup.3 is an imidazolyl group which may have a suitable substituent (s), and X is a halogen.
In addition, the present invention also provides a process for producing an optically active pyridoindole derivative (IV) or a salt thereof from a racemic mixture of the pyridoindole derivative (III) or a salt thereof by means of the following process, which is superior to the process in the
REFERENCES:
New 5HT3 (Serotin-3) receptor Antagonist II. Chem .Pharm. Bull. vol. 42 (12) pp. 2556-2564; by Masyuki Kato et al, Aug. 18, 1994.
New 5HT3 (Serotin-3) receptor Antagonist I. Chem .Pharm. Bull. vol 42 (12) pp. 2546-2555; by Masyuki Kato et al, Aug. 18, 1994.
New 5HT3 (Serotin-3) receptor Antagonist III. Chem .Pharm. Bull. vol. 43 (8) pp. 1346-1350; by Masyuki Kato et al, Apr. 4, 1995.
Ieda Shigeru
Kagara Kooji
Kawai Nobutaka
Machiya Koji
Nakamura Takashi
Desai Rita
Fujisawa Pharmaceuticals Co., Ltd.
Rotman Alan L.
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