Organic compounds -- part of the class 532-570 series – Organic compounds – Unsubstituted hydrocarbyl chain between the ring and the -c-...
Reexamination Certificate
1994-10-17
2001-03-13
Shah, Mukund J. (Department: 1624)
Organic compounds -- part of the class 532-570 series
Organic compounds
Unsubstituted hydrocarbyl chain between the ring and the -c-...
Reexamination Certificate
active
06201119
ABSTRACT:
BACKGROUND OF THE INVENTION
In the Eur. J. Med. Chem. 1978, 13 53-59, there are described three tetrahydroimidazo[4,5,1-jk][1,4]benzodiazepines. The compounds of the present invention differ there-from by the fact that the imidazo-moiety is substituted with an oxo or thio group and that said compounds show antiviral activity.
DESCRIPTION OF THE INVENTION
The present invention is concerned with tetrahydroimidazo[1,4]benzodiazepin-2-(thi)ones having the formula:
the pharmaceutically acceptable acid addition salts and the stereochernically isomeric forms thereof, wherein:
X is O or S;
R
1
is C
1-6
alkyl optionally substituted with aryl; C
3-6
alkynyl; C
3-6
cycloalkyl; or a radical of formula:
Alk is C-
1-6
alkanediyl;
R
8
and R
9
each independently are hydrogen, halo, C
3-6
cycloalkyl, trifluoromethyl, 2,2,2-trifluoroethyl, C
1-4
alkyl optionally substituted with
C
1-4
alkyloxy;
R
10
is hydrogen, halo or C
1-4
alkyl;
each R
11
independently is hydrogen or C
1-4
alkyl; or both R
11
taken together may form a C
1-6
alkanediyl radical;
R
12
is hydrogen, halo or C
1-4
alkyl;
n is 2, 3, 4, 5 or 6;
each R
13
independently is hydrogen or C
1-4
alkyl; or both R
13
taken together may form a C
1-6
alkanediyl radical;
R
14
is hydrogen or C
2-6
alkenyl;
R
2
is hydrogen or methyl;
R
3
is hydrogen or C
1-6
alkyl;
R
4
and R
5
each independently are hydrogen, C
1-6
alkyl, halo, cyano, nitro, trifluoromethyl, hydroxy, C
1-6
alkyloxy, amino, mono-or di(C
1-6
alkyl)amino or C
1-6
alkylcarbonylamino;
R
6
is hydrogen or methyl;
R
7
is hydrogen or methyl;
each aryl is phenyl optionally substituted with from 1 to 3 substituents independently selected from C
1-6
alkyl, halo, hydroxy, C
1-6
alkyloxy, amino, nitro and trifluoromethyl.
The compounds of formula (I) may also exist in their tautomeric form. Said tautomeric form, indicated below, is intended to be included within the scope of the present invention.
In the foregoing definitions the term halo is generic to fluoro, chloro, bromo and iodo; C
1-4
alkyl defines straight and branched chain saturated hydrocarbon radicals having from 1 to 4 carbon atoms such as, for example, methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl and the like; C
1-6
alkyl defines C
1-4
alkyl radicals as defined hereinabove and the higher homologs thereof having from 5 to 6 carbon atoms; C
1-6
alkanediyl defines bivalent straight or branched chain hydrocarbon radicals containing 1 to 6 carbon atoms such as, for example, 1,2-ethanediyl, 1,3-propanediyl, 1,4-butanediyl, 1,5-pentanediyl, 1,6-hexanediyl and the branched isomers thereof; C
2-6
alkenyl defines straight and branched hydrocarbon radicals containing one double bond and having from 2 to 6 carbon atoms such as, for example, ethenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-methyl-2-propenyl, pentenyl, hexenyl and the like; C
3-6
alkynyl defines straight and branched chain hydrocarbon radicals containing a triple bond and having from 3 to 6 carbon atoms such as, for example, 2-propynyl, 2-butynyl, 3-butynyl, pentynyl, hexynyl and the like; C
3-6
cycloalkyl defines cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
Each R
11
, R
13
and R
14
in the radicals of formula (a-2) and (a-3), when being as defined hereinbefore but other than hydrogen, is meant to replace a hydrogen atom of the —(CH
2
)
n
— or the —CH— moiety in said radicals.
Depending on the nature of the various substituents, the compounds of formula (I) may have several asymmetric carbon atoms. Unless otherwise mentioned or indicated, the chemical designation of compounds denotes the mixture of all possible stereo-chemically isomeric forms, said mixtures containing all diastereomers and enantiomers of the basic molecular structure. The absolute configuration of each chiral center may be indicated by the stereochemical descriptors R and S, this R and S notation corresponding to the rules described in Pure Appl. Chem. 1976, 45, 11-30. Stereochemically isomeric forms of the compounds of formula (I) are obviously intended to be embraced within the scope of the invention.
The compounds of formula (I) have basic properties and, consequently, they may be converted 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, sulfuic 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-dihydroxybutanedioic, 2-hydroxy-1,2,3-propanetricarboxylic, methanesulfonic, ethanesulfonic, benzenesulfonic, 4methyl-benzenesulfonic, cyclohexanesulfamic, 2-hydroxybenzoic, 4-amino-2-hydroxybenzoic and the like acids. Conversely the salt form can be converted by treatment with alki into the free base form. The term pharmaceutically acceptable acid addition salts also comprises the solvates which the compounds of formula (I) may form and said solvates are intended to be included within the scope of the present invention. Examples of such solvates are e.g. the hydrates, alcoholates and the like.
A first interesting group of compounds of formula (I) are those wherein R
1
is C
1-6
alkyl, C
3-6
alkenyl, C
3-6
alkynyl, C
3-6
cycloalkyl or C
1-6
alkyl substituted with C
3-6
cycloalkyl; and/or R
4
and R
5
each independently are hydrogen, C
1-6
alkyl, halo, cyano, nitro, trifluoromethyl, hydroxy, C
1-6
alkyloxy, amino or mono- or di(C
1-6
alkyl)amino; and/or R
6
and R
7
are hydrogen; and R
2
, R
3
, X and aryl are as defined under formula (I).
A second interesting group of compounds of formula (I) are those wherein R
1
is C
1-6
alkyl, C
3-6
alkenyl, C
3-6
alkynyl, C
3-6
cycloalkyl or C
1-6
alkyl substituted with C
3-6
cycloalkyl; and/or R
4
and R
5
each independently are hydrogen, C
1-6
alkyl, halo, cyano, nitro, trifluoromethyl, hydroxy, C
1-6
alkyloxy, amino or mono- or di(C
1-6
alkyl)amino; and/or R
6
is methyl, R
7
is hydrogen; and R
2
, R
3
, X and aryl are as defined under formula (I).
More interesting compounds are those compounds of formula (I) or those compounds comprised within the abovementioned interesting groups, wherein R
1
is C
1-6
alkyl, C
3- 6
alkynyl or a radical of formula (a-1), (a-2) or (a-3); and/or R
4
and R
5
each independently are hydrogen, C
1-6
alkyl, halo, cyano, nitro, amino, trifluoromethyl, hydroxy or C
1-6
alkyloxy.
A first particular subgroup comprises those more interesting compounds wherein R
2
and R
3
each independently are hydrogen or methyl; and/or X is O.
A second particular subgroup comprises those more interesting compounds wherein R
2
and R
3
each independently are hydrogen or methyl; and/or X is S.
More particular compounds are those compounds comprised within the above-mentioned particular subgroups wherein R
1
is C
3-6
alkyl or a radical of formula (a-1) wherein R
8
and R
9
each independently are C
3-6
cycloalkyl, trifluoromethyl or C
1-4
alkyl; or a radical of formula (a-3) wherein n is 2 or 3; and/or R
5
and R
7
are hydrogen.
Preferred compounds are those more particular compounds wherein R
8
and R
9
each independently are C
1-3
alkyl; and/or each R
13
and R
14
are hydrogen; and/or R
6
is hydrogen.
More preferred compounds are those preferred compounds wherein R
1
is propyl; 3,3-dimethylbutyl; methylcyclopropyl optionally substituted with one or two methyl groups and/or one 2-methylpropenyl group; methylcyclobutyl; 2-propenyl; 2-butenyl; 2-methyl-2-butenyl; 3-methyl-2-butenyl, 2,3 dinethyl-2-butenyl or 3-ethyl-2-pentenyl; and/or R
4
is hydrogen, methyl, chloro or bromo.
The most preferred compounds are
(+)-(S)-9-chloro-4,5,6,7-tetrahydro-5-methyl-6-(3-methyl-2-butenyl)imidazo[4,5,1-jk][1,4]benzodiazepine-2(1H)-thione;
(+)-(S)4,5,6,7-tetrahydro-5,8-dimethyl-6-(3-methyl-2-butenyl)imidazo[4,5,1-jk][1,4]benzodiazepine-2(1H)-thione;
(+)-(S)-8-
Breslin Henry Joseph
Janssen Paul Adriaan Jan
Kukla Michael Joseph
Raeymaekers Alfons H. M.
Van Gelder Josephus L. H.
Ciambrone Coletti Ellen
Coleman Brenda
Janssen Pharmaceutica N.V.
Shah Mukund J.
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