Organic compounds -- part of the class 532-570 series – Organic compounds – Four or more ring nitrogens in the bicyclo ring system
Reexamination Certificate
1996-12-09
2002-04-23
Rotman, Alan L. (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Four or more ring nitrogens in the bicyclo ring system
C544S370000, C546S199000, C548S307100
Reexamination Certificate
active
06376666
ABSTRACT:
THE FIELD OF TECHNIQUES
The invention relates to new S- and N,S-substituted 2-mercaptobenzimidazoles which can be useful as the pharmaceutical agents and pharmacological compositions including these compounds. The applied compounds are the pharmacologically active drugs which possess psychotropic and cardiovascular actions depending on their structure. They can be used in medicine for treatment of different neuropsychiatric disturbances and ischemic heart disease.
THE PRECEDING LEVEL OF TECHNIQUES
The preparation of numerous substituted 2-mercaptobenzimidazoles possessing different biological activities is known in the literature. The first information about the activity of this series appeared in 1958 when Knobloch W. et al. [Arch.Pharmaz., 1958, 291, p.113-118] and Nakajima S. et al. [Yakugaku Zasshi, 1958, 78, p.1378-1388] described the synthesis of different 2-alkyl-, alkenyl-, aralkyl-, dialkylaminoalkylbenzimidazoles having anti-fungal activity. In the following numerous papers [Nakajima S. et al., Jap.Pat., 10978 ('61), (1961); Hideg K. et al., Brit.Pat., 1234058, (1971); Xin Tao et al., Zhongguo Yiyao Gongye Zazhi, 1990, 21 (8), p.347-350; Johnson C. A. et al., Med.Chem.Rec., 1992, 2 (4), p.247-255; Onkol et al., J.Fac.Pharm.Gazz.Univ., 1992, 9 (1), p.47-57; etc.] there were discribed 2-mercaptobenzimidazoles with different substitutions in S-, N- and benzol ring possessing bacteriostatic, insecticidal and anthelminthic activities.
There was reported about Anti-inflammatory, antipyretic and antidepressant activities of different S-substituted-2-mercaptobenzimidazoles were reported in French Special Medicament Patent. The data about anti-inflammatory and analgetic activities of the 2-mercaptobenzimidazole derivatives are described in papers of Seki et al. [Yakugaku Zasshi, 1962, 82, p.1620-1624], Hasegawa H. et al. [Jap.Pat., 7441198 (1974)], Aka T. et al. [Jap.Pat., 9888 ('64) (1964)], Lafon V. et al. [Ger.Offen 2246429 (1978)], Rao V., Madhusudan et al. [Indian Drugs, 1987, 24 (12), p.545-548], Lazer E. S. et al. [J.Med.Chem., 1987, 30, p.726-729].
The synthesis of 2-dialkylaminoalkylbenzimidazoles substituted in N-atom with anti-histaminic and anti-allergic properties was described by Giani R. et al. [Eur.Pat.Appl. EP334818 (1989)] and Dini S. et al. [Agents Actions, 1990, 30, p.174-177].
There have been patented many different S-substituted-2-mercaptobenzimidazoles with anti-ulcerous activity [Machinami T. et al., Eur.Pat.Appl. EP 452076 (1991); Lang H. J. et al., Eur.Pat.Appl. EP 213474 (1987); Adelstein G. W. et al., Eur.Pat.Appl. EP 204215 (1986); Okitsu M., Jpn. Kokai Tokkyo Koho JP 62230773 (1987); Hirai K. et al., Jpn. Kokai Tokkyo Koho JP 62331158 (1987); Okabe S. et al., Jpn. Kokai Tokkyo Koho JP 03227927 (1991); Riedel R. et al., PCT Int.Appl. WO 87/01114 (1986); Klemm K. et al., PCT Int.Appl. WO 9204898 (1992) etc.]. Some of them—omeprazol, lansoprazol are widely used in clinical practice.
Synthesis of N-substituted-2-alkylthiobenzimidazoles possessing the properties of antagonists of angiotensin II and inhibitors of dopamine-&bgr;-hydroxylase was reported in the patents of Hauel et al. [Eur.Pat.Appl. EP 502314 (1992)] and Smithkline Beckman Corp. [Jpn. Kokai Tokkyo Koho JP 61161267 (1986)].
There are known some papers describing the synthesis of some 2-mercaptobenzimidazole derivatives with cardiotonic, vasodilative, anti-hypertensive, anti-atherosclerotic and anti-agglutinate properties [Osawa Y. et al., Yakugaku Zasshi, 1968, 88 (6), p.747-754; Brukshtus A. B. et al., Khimiko-Farmatcevt.Zhurnal, 1992, N 11-12, p.50-53; 1994, N 6, p.24-26; Bru-Magniez N. et al., Eur.Pat.Appl. EP 385850 (1990); Harsanyi K. et al., UK Pat.Appl. GB 217319A (1986)]. There were revealed some compounds with anti-ischemic, anti-arrhythmic and anti-hypoxant activities among synthesized 2-dialkylamino-alkylthiobenzimidazoles [Patent of Russia, 2027709 (1991)].
Some substituted 2-mercaptobenzimidaziles with butyrophenon in the 1st position are characterised by psychotropic properties including the tranquilising and neuroleptic types of activity [Sato Makoto et al., Japan Kokai 7584578 (1975); 76136674 (1976); 76146473 (1976)].
The bemityl-2-ethylbenzimidazole hydrobromide is used in clinical practice as the psychostimulator and antihypoxant for the treatment of asthenic and asthenic-depressant disturbances according to the data of Bobkov Yu. G. et al. [Author Certificate of USSR 1251374 (1986)] and Neznamov G. G. et al. [Physiol.Active Drugs, 1993, 25, p.45-49]. According to Losinskyi M. O. et al. [Author Certificate of USSR 1259652 (1986)] the bemityl's analogue-5-ethoxy-2-ethylthiobenzimidazole produces the stress-protective and antihypoxant activities. Plotnikov E. M. et al. [Physiol.Active Drugs, 1993, 25, p.30-34] and Ratnikov L. I. et al. [Physiol.Active Drugs, 1993, 25, p.27-29] have shown that these compounds may be used for the treatment of acute cerebrovascular disturbances and acute respiratory viral infections.
DISCLOSURE OF THE INVENTION
The compounds of the present invention are derivatives of 2-mercaptobenzimidazole general formula
where in n=0,2,3; R-hydrogen atom, aralkyls; R
1
-lower alkyls, alkenyls, dialkylamino, monocyclic saturated amino group, which can contain additional heteroatom; R
2
and R
3
-identical or different and represent hydrogen atoms. lower alkyls, alkoxy in various positions. These compounds have tranquilising activity with selective component, sedative, anti-ischaemic and anti-arrithmic activity and can be used in medicine.
The applied compounds and their pharmaceutically acceptable salts were synthesized by standard method of alkylation 2-mercaptobenzimidazoles by corresponding agents in ethanol-water medium in the presence of base (sodium hydroxide) with following treatment of obtaining oily or crystalline bases in the solution of absolute ethanol or ether with ethanolic or etherial solution of gaseous hydrogen chloride:
wherein n, R, R
1
, R
2
, R
3
have foregoing sense; X-atom of chlorine or bromine; m=1,2,3.
Variant of the Realization of the Invention
The reaction processes were controlled by using TLC—Silufol UV 254 or DC-Alufolien Aluminiumoxid 60 F 254 (Merk), spots were detected by uv absorbance or iodine vapor. Melting points were determined in the opened cappilaries and were not corrected. NMR spectra were recorded with AC-250 Bruker using CDCl
3
or D
2
O as solvent and tetramethylsilane as internal reference.
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Hasegawa, et al “B
Blednov Jury Alexeevich
Chichkanov Gennady Georgievich
Kaverina Natalia Veniaminova
Kirsanova Galina Jurievna
Mozhaeva Tatyana Yakovlevna
Ladas & Parry
Nauchno-Issledovatelsky Institut Farmakologii Rossiiskoi Akademi
Rotman Alan L.
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