Organic compounds -- part of the class 532-570 series – Organic compounds – Unsubstituted hydrocarbyl chain between the ring and the -c-...
Patent
1994-02-15
1995-10-31
Ford, John M.
Organic compounds -- part of the class 532-570 series
Organic compounds
Unsubstituted hydrocarbyl chain between the ring and the -c-...
C07D48704
Patent
active
054630495
DESCRIPTION:
BRIEF SUMMARY
CROSS-REFERENCE TO RELATED APPLICATIONS
This application is based upon PCT application No. PCT/EP 92/02171, filed Sep. 18, 1992, which claims priority from EPO application Ser. No. 91.202.474.2, filed Sep. 24, 1991.
BACKGROUND OF THE INVENTION
In EP-A-0,348,522; Nature 1990, 343, 470; J. Med. Chem. 1991, 34, 746; and The Lancet 1991, 338, 140 there are described 4,5,6,7-tetrahydroimidazo[4,5,1-jk]-[1,4]benzodiazepin-2(1H)-thiones (TIBO) derivatives with potent activity against human immunodeficiency virus 1 (HIV-1) in vitro and showing encouraging results in vivo. A significant limitation to further assessment and eventual large-scale production of these novel drugs has hitherto been their long, difficult and insufficient synthesis. The fundamental problem in all approaches to the title compounds reported up till now relates to the use of benzoic acid derivatives and/or amino acid derivatives as starting materials. All said approaches necessarily involve one or two amide-to-amine reduction steps with violently reacting reagents such as lithium aluminum hydride or borane derivatives. Whereas such approaches may be suitable in the laboratory, (e.g.J. Org. Chem. 1991, 56, 4600), they are hardly amenable to large-scale production. In case enantiomeric amino acid derivatives are used as starting materials, the problems are further compounded by the possibility of racemisation at the chiral carbon atom.
The present invention is concerned with an improved process for preparing particular TIBO derivatives that avoids all problematic amide-to-amine reductions and rules out any possibility of racemisation at the chiral carbon atom. The process according to the present invention also represents a short and efficient industrial approach to particular TIBO compounds reported hitherto.
DESCRIPTION OF THE INVENTION
The present invention is concerned with a process of preparing enantiomerically pure 8-halo-4,5,6,7-tetrahydro-5-methylimidazo[4,5,1 -jk]-[1,4]benzodiazepin-2(1H)-thione derivatives having the formula ##STR3## and the pharmaceutically acceptable acid addition salt forms thereof, wherein
Said process is especially interesting for the preparation of (S)-8-halo-4,5,6,7-tetrahydro-5-methylimidazo[4,5,1-jk][1,4]benzodiazepin- 2(1H)-thione derivatives having the formula ##STR4## and the pharmaceutically acceptable acid addition salt forms thereof, wherein
The process according to the present invention is exceedingly interesting for the preparation of (S)-8-chloro-4,5,6,7-tetrahydro-5-methyl-6-(3-methyl-2-butenyl)-imidazo[4, 5,1-jk][1,4]benzodiazepine-2(1H)-thione having the formula ##STR5## In the foregoing definitions and hereinafter the term `enantiomerically pure` concerns compounds having an enantiomeric excess of at least 94% (i.e. minimum 97% of one enantiomer and maximum 3% of the other enantiomer) up to an enantiomeric excess of 100% (i.e. 100% of one enantiomer and none of the other), in particular compounds having an enantiomeric excess of 96% up to 100%, more in particular having an enantiomeric excess of 98% up to 100%; the term `halo` defines fluoro, chloro, bromo, iodo, in particular chloro or bromo and especially chloro; the term `C.sub.3-7 alkenyl` defines straight and branched hydrocarbon radicals containing one double bond and having from 3 to 7 carbon atoms such as, for example, 2-propenyl, 2-butenyl, 3-butenyl, 2-methyl-2-propenyl, 3-methyl-2-butenyl, 3-ethyl-2-pentenyl and the like, in particular 3-methyl-2-butenyl and 3-ethyl-2-pentenyl. The compounds of formula (I) have basic properties and, consequently, they may be convened to their therapeutically active non-toxic acid addition salt forms by treatment with appropriate acids, such as, for example, inorganic acids, e.g. hydrochloric, hydrobromic and the like acids, sulfuric acid, nitric acid, phosphoric acid and the like; or organic acids, such as, for example, acetic, propanoic, hydroxyacetic, 2-hydroxy-propanoic, 2-oxopropanoic, ethanedioic, propanedioic, butanedioic, (Z)-2-butenedioic, (E)-2-butenedioic, 2-hydroxybutanedioic, 2,3-di
De Knaep Alfons G. M.
Moens Luc J. R.
Vreysen Eduard J. C.
Ford John M.
Janssen Pharmaceutica N.V.
Metz Charles J.
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