U.S. patent application number 12/576761 was filed with the patent office on 2010-02-04 for 6,7,8,9-substituted 1-phenyl-1,5-dihydro-pyrido[3,2-b]indol-2-ones useful as anti-infective pharmaceutical agents.
Invention is credited to Bart Rudolf Romanie Kesteleyn, Natalie Maria Francisca Kindermans, Annick Ann Peeters, Pierre Jean-Marie Bernard Raboisson, Dominique Louis Nestor Ghislai Surleraux, Sandrine Marie Helene Vendeville, Piet Tom Bert Paul Wigerinck.
Application Number | 20100029635 12/576761 |
Document ID | / |
Family ID | 34929105 |
Filed Date | 2010-02-04 |
United States Patent
Application |
20100029635 |
Kind Code |
A1 |
Kesteleyn; Bart Rudolf Romanie ;
et al. |
February 4, 2010 |
6,7,8,9-SUBSTITUTED 1-PHENYL-1,5-DIHYDRO-PYRIDO[3,2-B]INDOL-2-ONES
USEFUL AS ANTI-INFECTIVE PHARMACEUTICAL AGENTS
Abstract
This invention concerns the compounds ##STR00001## the N-oxides,
salts, stereoisomeric forms, racemic mixtures, prodrugs, esters and
metabolites thereof, wherein X is NR.sup.2, O, S, SO, SO.sub.2;
R.sup.1 is hydrogen, cyano, halo, substituted carbonyl,
methanimidamidyl, N-hydroxy-methanimidamidyl, mono- or
di(C.sub.1-4alkyl)methanimidamidyl, Het.sub.1 or Het.sub.2; n is 1,
2 or 3; R.sup.2 is hydrogen, aryl substituted with a radical
--COOR.sup.4; or R.sup.2 is substituted C.sub.1-10alkyl,
C.sub.2-10alkenyl or C.sub.3-7cycloalkyl; or R.sup.2 is a radical
of formula: ##STR00002##
--C.sub.pH.sub.2p--CH(OR.sup.14)--C.sub.qH.sub.2q--R.sup.15 (b-3);
--CH.sub.2--CH.sub.2--(O--CH.sub.2--CH.sub.2).sub.m--OR.sup.14
(b-4);
--CH.sub.2--CH.sub.2--(O--CH.sub.2--CH.sub.2).sub.m--NR.sup.5aR.sup.5b(b--
5) -a.sup.1=a.sup.2-a.sup.3=a.sup.4- is --CH.dbd.CH--CH.dbd.CH--;
--N.dbd.CH--CH.dbd.CH--; --CH.dbd.N--CH.dbd.CH--;
--CH.dbd.CH--N.dbd.CH--; --CH.dbd.CH--CH.dbd.N-- (c-5); wherein one
of the hydrogen atoms in (c-1)-(c-5) is replaced by particular
radicals; R.sup.3 is nitro, cyano, amino, halo, hydroxy,
C.sub.1-4alkyloxy, hydroxycarbonyl, substituted carbonyl,
methanimidamidyl, mono- or di(C.sub.1-4alkyl)methanimidamidyl,
N-hydroxy-methanimidamidyl or Het.sub.1.
Inventors: |
Kesteleyn; Bart Rudolf Romanie;
(Berlare, BE) ; Vendeville; Sandrine Marie Helene;
(Etterbeek, BE) ; Kindermans; Natalie Maria
Francisca; (Mechelen, BE) ; Surleraux; Dominique
Louis Nestor Ghislai; (Braine-le-chateau, BE) ;
Raboisson; Pierre Jean-Marie Bernard; (Sterrebeek, BE)
; Wigerinck; Piet Tom Bert Paul; (Terhagen, BE) ;
Peeters; Annick Ann; (Wilrijk, BE) |
Correspondence
Address: |
PHILIP S. JOHNSON;JOHNSON & JOHNSON
ONE JOHNSON & JOHNSON PLAZA
NEW BRUNSWICK
NJ
08933-7003
US
|
Family ID: |
34929105 |
Appl. No.: |
12/576761 |
Filed: |
October 9, 2009 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
11568840 |
Nov 8, 2006 |
7622581 |
|
|
PCT/EP05/52263 |
May 17, 2005 |
|
|
|
12576761 |
|
|
|
|
Current U.S.
Class: |
514/232.8 ;
514/253.03; 514/292; 544/126; 544/361; 546/81 |
Current CPC
Class: |
A61P 31/16 20180101;
A61P 31/18 20180101; C07D 471/04 20130101 |
Class at
Publication: |
514/232.8 ;
546/81; 544/126; 544/361; 514/292; 514/253.03 |
International
Class: |
A61K 31/5377 20060101
A61K031/5377; C07D 471/04 20060101 C07D471/04; C07D 413/14 20060101
C07D413/14; C07D 401/14 20060101 C07D401/14; A61K 31/437 20060101
A61K031/437; A61K 31/497 20060101 A61K031/497; A61P 31/16 20060101
A61P031/16 |
Foreign Application Data
Date |
Code |
Application Number |
May 17, 2004 |
EP |
04102170.0 |
Claims
1-16. (canceled)
17. A process for preparing a compound of formula (I): ##STR00052##
the N-oxides, salts, quaternary ammonium salts, stereoisomeric
forms, racemic mixtures, prodrugs, esters and metabolites thereof,
wherein n is 1, 2 or 3; R.sup.1 is hydrogen, cyano, halo,
aminocarbonyl hydroxycarbonyl C.sub.1-4alkyloxycarbonyl,
C.sub.1-4alkylcarbonyl mono- or di(C.sub.1-4alkyl)aminocarbonyl
arylaminocarbonyl N-(aryl)-N--(C.sub.1-4alkyl)aminocarbonyl,
methanimidamidyl, N-hydroxy-methanimidamidyl, mono- or
di(C.sub.1-4alkyl)methanimidamidyl, Het.sub.1 or Het.sub.2; X is a
bivalent radical NR.sup.2, O, S SO, SO.sub.2; R.sup.2 is: i)
hydrogen, C.sub.1-10alkyl, C.sub.2-10alkenyl, C.sub.3-7cycloalkyl,
wherein said C.sub.1-10alkyl, C.sub.2-10alkenyl, and
C.sub.3-7cycloalkyl, each individually and independently, may be
optionally substituted with a substituent selected from the group
consisting of cyano, N(R.sup.16aR.sup.16b) pyrrolidinyl,
piperidinyl, homopiperidinyl, piperazinyl,
4-(C.sub.1-4alkyl)-piperazinyl, morpholinyl, thiomorpholinyl,
1-oxothiomorpholinyl, 1,1-dioxo-thiomorpholinyl, aryl, furanyl,
thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl,
isothiazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl,
tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl,
triazinyl, hydroxy-carbonyl, C.sub.1-4alkylcarbonyl,
N(R.sup.16aR.sup.16b)carbonyl, C.sub.1-4alkyloxycarbonyl,
pyrrolidin-1-ylcarbonyl, piperidin-1-ylcarbonyl,
homopiperidin-1-ylcarbonyl, piperazin-1-ylcarbonyl,
4-(C.sub.1-4alkyl)-piperazin-1-ylcarbonyl, morpholin-1-yl-carbonyl,
thiomorpholin-1-ylcarbonyl, 1-oxothiomorpholin-1-ylcarbonyl and
1,1-dioxo-thiomorpholin-1-ylcarbonyl; or R.sup.2 is ii) aryl
substituted with a radical --COOR.sup.4; or R.sup.2 is iii)
C.sub.1-10alkyl, C.sub.2-10alkenyl, C.sub.3-7cycloalkyl, each of
said C.sub.1-10alkyl, C.sub.2-10alkenyl, C.sub.3-7cycloalkyl each
individually and independently, being substituted with aryl wherein
said aryl is substituted with a radical --COOR.sup.4; or R.sup.2 is
iv) C.sub.1-10alkyl, C.sub.2-10alkenyl, C.sub.3-7cycloalkyl, each
individually and independently, substituted with a radical selected
from --NR.sup.5a--C(.dbd.NR.sup.5b)--NR.sup.5cR.sup.5d,
--NR.sup.5a--C(.dbd.NR.sup.5e)--R.sup.5f,
--O--NR.sup.5a--C(.dbd.NR.sup.5b)--NR.sup.5cR.sup.5d,
--O--NR.sup.5a--C(.dbd.NR.sup.5e)--R.sup.5f, -sulfonyl-R.sup.6,
--NR.sup.7R.sup.8, --NR.sup.9R.sup.10, a radical ##STR00053##
wherein each Q.sup.1 independently is a direct bond, --CH.sub.2--,
or --CH.sub.2--CH.sub.2--; each Q.sup.2 independently is O, S, SO
or SO.sub.2; each R.sup.4 independently is hydrogen,
C.sub.1-4alkyl, arylC.sub.1-4alkyl; each R.sup.5a, R.sup.5b,
R.sup.5c, R.sup.5d independently is hydrogen, C.sub.1-4alkyl or
arylC.sub.1-4alkyl; each R.sup.5e, R.sup.5f independently is
hydrogen, C.sub.1-4alkyl or arylC.sub.1-4alkyl, or R.sup.5e and
R.sup.5f taken together may form a bivalent alkanediyl radical of
formula --CH.sub.2--CH.sub.2-- or --CH.sub.2--CH.sub.2--CH.sub.2--;
R.sup.6 is C.sub.1-4alkyl, --N(R.sup.5aR.sup.5b),
C.sub.1-4alkyloxy, pyrrolidin-1-yl, piperidin-1-yl,
homopiperidin-1-yl, piperazin-1-yl,
4-(C.sub.1-4alkyl)-piperazin-1-yl, morpholin-4-yl-,
thiomorpholin-4-yl-, 1-oxothiomorpholin-4-yl and
1,1-dioxo-thiomorpholin-4-yl; R.sup.7 is hydrogen C.sub.1-4alkyl,
hydroxyC.sub.1-4alkyl, C.sub.1-4alkoxyC.sub.1-4alkyl or
C.sub.1-4alkylcarbonyloxyC.sub.1-4alkyl; R.sup.8 is hydrogen
C.sub.1-4alkyl, C.sub.1-4alkoxyC.sub.1-4alkyl,
C.sub.1-4alkoxycarbonyloxyC.sub.1-4alkyl or arylC.sub.4alkyl;
R.sup.9 is hydrogen or C.sub.1-4alkyl; R.sup.10 is Het.sub.1,
Het.sub.2 or a radical ##STR00054## R.sup.11 is aryl,
arylC.sub.1-4alkyl, formyl, C.sub.1-4alkylcarbonyl, arylcarbonyl,
arylC.sub.1-4alkyl-carbonyl, C.sub.1-4alkyloxycarbonyl,
arylC.sub.1-4alkyloxycarbonyl, R.sup.5aR.sup.5bN-carbonyl,
hydroxyC.sub.1-4alkyl, C.sub.1-4alkyloxyC.sub.1-4alkyl,
arylC.sub.1-4alkyloxyC.sub.1-4alkyl, aryloxyC.sub.1-4alkyl,
Het.sub.2; each R.sup.12 independently is hydroxy, C.sub.1-4alkyl,
arylC.sub.1-4alkyl, C.sub.1-4alkyloxy, arylC.sub.1-4alkyloxy oxo,
spiro(C.sub.2-4alkanedioxy), spiro(diC.sub.1-4alkyloxy),
--NR.sup.5aR.sup.5b; R.sup.13 is hydrogen, hydroxy, C.sub.1-4alkyl,
C.sub.1-4alkyloxy, or arylC.sub.1-4alkyloxy; or R.sup.13a is
C.sub.1-4alkyl, arylC.sub.1-4alkyl, C.sub.1-4alkyloxycarbonyl or
arylC.sub.1-4alkyloxycarbonyl; each R.sup.13b is hydrogen or
C.sub.1-4alkyl; or R.sup.2 is iv) a radical of formula:
##STR00055##
C.sub.pH.sub.2p--CH(OR.sup.14)--C.sub.qH.sub.2q--R.sup.15 (b-3);
--CH.sub.2--CH.sub.2--(O--CH.sub.2--CH.sub.2).sub.m--OR.sup.14
(b-4);
--CH.sub.2--CH.sub.2--(O--CH.sub.2--CH.sub.2).sub.m--NR.sup.17aR.sup.17b
(b-5); wherein in radical (b-3) one of the hydrogen atoms in
--C.sub.pH.sub.2p-- and one of the hydrogen atoms in
--CH(OR.sup.14)--C.sub.qH.sub.2q--, that is not part of R.sup.14,
may be replaced by a direct bond or a C.sub.1-4alkanediyl group; p
is 1, 2 or 3; q is 0, 1, 2 or 3; each m independently is 1 to 10;
each R.sup.14 independently is hydrogen, C.sub.1-4alkyl aryl
C.sub.1-4alkyl, aryl C.sub.1-4alkylcarbonyl, --SO.sub.3H,
--PO.sub.3H.sub.2. R.sup.15 is a substituent selected from the
group consisting of cyano, NR.sup.16aR.sup.16b, pyrrolidinyl,
piperidinyl, homopiperidinyl, piperazinyl,
4-(C.sub.1-4alkyl)-piperazinyl
4-(C.sub.1-4alkylcarbonyl)-piperazinyl,
4-(C.sub.1-4alkyloxycarbonyl)-piperazinyl, morpholinyl,
thiomorpholinyl, 1-oxothiomorpholinyl, 1,1-dioxo-thiomorpholinyl,
aryl, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl,
isoxazolyl, isothiazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl,
triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl,
pyridazinyl, triazinyl, hydroxy-carbonyl, C.sub.1-4alkylcarbonyl
N(R.sup.16aR.sup.16b)carbonyl C.sub.1-4alkyloxycarbonyl
pyrrolidin-1-yl-carbonyl, piperidin-1-ylcarbonyl,
homopiperidin-1-ylcarbonyl, piperazin-1-yl-carbonyl
4-(C.sub.1-4alkyl)-piperazin-1-ylcarbonyl morpholin-1-yl-carbonyl
thiomorpholin-1-yl-carbonyl, 1-oxothiomorpholin-1-ylcarbonyl and
1,1-dioxo-thiomorpholin-1-ylcarbonyl; or R.sup.15 may additionally
be aryl substituted with a radical --COOR.sup.4; or a radical
selected from --NR.sup.5a--C(.dbd.NR.sup.5b)--NR.sup.5cR.sup.5d,
--NR.sup.5a--C(.dbd.NR.sup.5e)--R.sup.5f,
--O--NR.sup.5a--C(.dbd.NR.sup.5b)--NR.sup.5cR.sup.5d,
--O--NR.sup.5a--C(.dbd.NR.sup.5e)--R.sup.5f, -sulfonyl-R.sup.6,
--NR.sup.7R.sup.8, --NR.sup.9R.sup.10, a radical (a-1), (a-2),
(a-3), (a-4) or (a-5); wherein R.sup.4R.sup.5a, R.sup.5b, R.sup.5c,
R.sup.5d, R.sup.6, R.sup.7, R.sup.8, R.sup.9, R.sup.10, and the
radicals (a-1), (a-2) (a-3), (a-4), (a-5) independently are as
defined above: R.sup.16a and R.sup.16b independently from one
another are hydrogen, C.sub.1-6alkyl or C.sub.1-6alkyl substituted
with a substituent selected from the group consisting of amino,
mono- or di(C.sub.1-4alkyl)amino, pyrrolidinyl, piperidinyl,
homopiperidinyl, piperazinyl, 4-(C.sub.1-4alkyl)-piperazinyl,
morpholinyl, thiomorpholinyl, 1-oxothiomorpholinyl,
1,1-dioxo-thiomorpholinyl and aryl; R.sup.17a and R.sup.17b
independently from one another are hydrogen, C.sub.1-4alkyl or
arylC.sub.1-4alkyl; or R.sup.17a and R.sup.17b together with the
nitrogen atom to which they are attached form a pyrrolidinyl,
piperidinyl, homopiperidinyl, morpholinyl, thiomorpholinyl,
1-oxothio-mompholinyl 1,1-dioxo-thiomompholinyl piperazinyl
4-C.sub.1-4alkyl-piperazinyl,
4-(C.sub.1-4alkylcarbonyl)-piperazinyl,
4-(C.sub.1-4alkyloxycarbonyl)-piperazinyl ring; each R.sup.18
independently is hydrogen, C.sub.1-4alkyl, arylC.sub.1-4alkyl,
C.sub.1-4alkylcarbonyl or C.sub.1-4alkyloxycarbonyl; R.sup.19 is
hydrogen, hydroxy, C.sub.1-4alkyl or a radical --COOR.sup.4;
-a.sup.1=a.sup.2-a.sup.3=a.sup.4- represents a bivalent radical of
formula --CH.dbd.CH--CH.dbd.CH-- (c-1); --N.dbd.CH--CH.dbd.CH--
(c-2): --CH.dbd.N--CH.dbd.CH-- (c-3); --CH.dbd.CH--N.dbd.CH--
(c-4): --CH.dbd.CH--CH.dbd.N-- (c-5); wherein one, two, three or
four of the hydrogen atoms in (c-1) is replaced by a radical,
C.sub.1-6alkyl C.sub.1-4alkoxy, halo, hydroxy, (R.sup.5g)(R.sup.5h)
N--(C.sub.1-4alkanediyl)-O--,
(R.sup.7)(R.sup.8)N--(C.sub.1-4alkanediyl)-O--
(R.sup.8)(R.sup.9)N--(C.sub.1-4alkanediyl)-O-, trifluoromethyl
cyano, a radical --COOR.sup.4, (R.sup.5a)(R.sup.5)N-carbonyl,
(R.sup.5a)(R.sup.5b)N-sulfonyl, pyrrolidinylsulfonyl,
piperidinylsulfonyl, homopiperidinylsulfonyl, formyl,
C.sub.1-6alkylcarbonyl, nitro, hydroxyC.sub.1-6alkyl,
C.sub.1-4alkoxyC.sub.1-6alkyl, (R.sup.4OOC)--C.sub.1-6alkyl a
radical --N(R.sup.5a)(R.sup.5b)--N(R.sup.7)(R.sup.8),
--N(R.sup.9)(R.sup.10), a radical ##STR00056## mompholinyl,
thiomompholinyl, 1-oxothiomorpholinyl 1,1-dioxo-thiomorpholinyl,
(R.sup.5g)(R.sup.5h) N--(C.sub.1-4alkanediyl)-N(R.sup.5c)--,
(R.sup.7)(R.sup.8)N--(C.sub.1-4alkanediyl)-N(R.sup.5c)--,
(R.sup.9)(R.sup.10)N--(C.sub.1-4alkanediyl)-N(R.sup.5c)--,
C.sub.1-6alkylcarbonylamino, C.sub.1-6alkyloxycarbonylamino,
trifluoroacetylamino, C.sub.1-6alkylsulfonylamino,
(R.sup.5a)(R.sup.5b)N--C.sub.1-4alkyl; aryl; Het.sub.1 or
Het.sub.2; R.sup.20 is hydrogen, hydroxy, C.sub.1-4, alkyl,
arylC.sub.1-4alkyl, C.sub.1-4alkyloxy, arylC.sub.1-4alkyloxy, oxo,
spiro(C.sub.2-4alkylenedioxy), spiro(diC.sub.1-4alkyloxy),
--NR.sup.5gR.sup.5h; each R.sup.5g or R.sup.5h independently is
hydrogen, C.sub.1-4alkyl or arylC.sub.1-4alkyl, or R.sup.5g and
R.sup.5h together with the nitrogen to which they attached form a
pyrrolidinyl, piperidinyl, homopiperidinyl, morfolinyl, piperazinyl
or 4-C.sub.1-4alkylpiperazinyl radical; wherein each of said
pyrrolidinyl, piperidinyl, homopiperidinyl, morfolinyl, piperazinyl
or 4-C.sub.1-4alkylpiperazinyl radical may optionally be
substituted with hydroxy or oxo; or wherein one or more of the
hydrogen atoms in (c-2) (c-3) (c-4) or (c-5) may be replaced with a
radical selected from halo and C.sub.1-6alkyl R.sup.3 is nitro,
cyano, amino, halo, hydroxy C.sub.1-4alkyloxy, hydroxycarbonyl,
amino-carbonyl, C.sub.1-4alkyloxycarbonyl, mono- or di(C
alkyl)aminocarbonyl, C.sub.1-4alkyl-carbonyl, methanimidamidyl,
mono- or di(C.sub.1-4alkyl)methanimidamidyl,
N-hydroxy-methanimidamidyl or Het.sub.1; aryl is phenyl optionally
substituted with one or more substituents each individually
selected from the group consisting of C.sub.1-6alkyl,
C.sub.1-4alkoxy, halo, hydroxy, amino, trifluoromethyl, cyano,
nitro, hydroxyC.sub.1-6alkyl, cyanoC.sub.1-6alkyl, mono- or
di(C.sub.1-4alkyl)amino, aminoC.sub.1-4alkyl, mono- or
di(C.sub.1-4alkyl)aminoC.sub.1-4alkyl; Het.sub.1 is a 5-membered
ring system wherein one, two, three or four ring members are
heteroatoms each individually and independently selected from the
group consisting of nitrogen oxygen and sulfur, and wherein the
remaining ring members are carbon atoms; and, where possible any
nitrogen ring member may optionally be substituted with
C.sub.1-4alkyl; any ring carbon atom may, each individually and
independently optionally be substituted with a substituent selected
from the group consisting of C.sub.1-4alkyl, C.sub.2-6alkenyl,
C.sub.3-7cycloalkyl, hydroxy, C.sub.1-4alkoxy, halo, amino, cyano,
trifluoromethyl, hydroxyC.sub.1-4alkyl, cyanoC.sub.1-4alkyl, mono-
or di(C.sub.4alkyl)amino, aminoC.sub.1-4alkyl, mono- or
di(C.sub.1-4alkyl)aminoC.sub.1-4alkyl, arylC.sub.1-4alkyl, amino
C.sub.2-6alkenyl, mono- or di(C.sub.1-4alkyl)aminoC.sub.2-6alkenyl,
furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl,
isoxazolyl, isothiazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl,
triazolyl, tetrazolyl, aryl, hydroxycarbonyl, aminocarbonyl,
C.sub.1-4alkyloxycarbonyl mono- or di(C.sub.1-4alkyl)aminocarbonyl
C.sub.1-4alkylcarbonyl oxo, thio; and wherein any of the foregoing
furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl,
isoxazolyl, isothiazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, and
triazolyl moieties may optionally be substituted with
C.sub.1-4alkyl; and Het.sub.2 is pyridyl pyrimidinyl pyrazinyl
pyridazinyl or triazinyl wherein any ring carbon atom of each of
said 6-membered nitrogen containing aromatic rings may optionally
be substituted with a substituent selected from the group
consisting of C.sub.1-4alkyl said process comprising: (a) cyclizing
an intermediate (II-5) to obtain a compound of formula (I-b):
##STR00057## and optionally N-alkylating the compound of formula
(I-b) to obtain a compound of formula (I-e): ##STR00058## (b)
cyclizing an intermediate (VII-d) thus obtaining compounds of
formula (I-f): ##STR00059## c) halogenating an intermediate
(VIII-a) to obtain a compound of formula (I-g) and if desired
reacting the compound (I-g) with an amine HNR.sup.cR.sup.d to
obtain a compound (I-h): ##STR00060## d) alkoxycarbonylating a
compound (I-g) with CO in the presence of C.sub.1-4alkyl-OH to
obtain a compound (I-i): ##STR00061## e) and if desired, preparing
salts of the compounds of formula (I) by treating the free forms
with an acid or with a base; or conversely treating the salt form
with an acid or base to prepare the free form.
18. A method of treating a subject infected with human
immunodeficiency virus (HIV), said method comprising the systemic
administration to said HIV-infected subject of an amount of a
compound of formula (I) effective in the treatment of the
conditions associated with HIV infection, wherein the compound of
formula (I) comprises: ##STR00062## the N-oxides, salts, quaternary
ammonium salts, stereoisomeric forms, racemic mixtures, prodrugs,
esters and metabolites thereof, wherein n is 1, 2 or 3; R.sup.1 is
hydrogen, cyano, halo, aminocarbonyl, hydroxycarbonyl,
C.sub.1-4alkyloxycarbonyl, C.sub.1-4alkylcarbonyl, mono- or
di(C.sub.1-4alkyl)aminocarbonyl, arylaminocarbonyl,
N-(aryl)-N--(C.sub.1-4alkyl)aminocarbonyl, methanimidamidyl,
N-hydroxy-methanimidamidyl, mono- or
di(C.sub.1-4alkyl)methanimidamidyl, Het.sub.1 or Het.sub.2; X is a
bivalent radical NR.sup.2, O, S, SO, SO.sub.2; R.sup.2 is: i)
hydrogen, C.sub.1-10alkyl, C.sub.2-10alkenyl, C.sub.3-7cycloalkyl,
wherein said C.sub.1-10alkyl, C.sub.2-10alkenyl and
C.sub.3-7cycloalkyl, each individually and independently, may be
optionally substituted with a substituent selected from the group
consisting of cyano, N(R.sup.16aR.sup.16b), pyrrolidinyl,
piperidinyl, homopiperidinyl, piperazinyl,
4-(C.sub.1-4alkyl)-piperazinyl, morpholinyl, thiomorpholinyl,
1-oxothiomorpholinyl, 1,1-dioxo-thiomorpholinyl, aryl, furanyl,
thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl,
isothiazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl,
tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl,
triazinyl, hydroxy-carbonyl, C.sub.1-4alkylcarbonyl,
N(R.sup.16aR.sup.16b)carbonyl, C.sub.1-4alkyloxycarbonyl,
pyrrolidin-1-ylcarbonyl, piperidin-1-ylcarbonyl,
homopiperidin-1-ylcarbonyl, piperazin-1-ylcarbonyl,
4-(C.sub.1-4alkyl)-piperazin-1-ylcarbonyl, morpholin-1-yl-carbonyl,
thiomorpholin-1-ylcarbonyl, 1-oxothiomorpholin-1-ylcarbonyl and
1,1-dioxo-thiomorpholin-1-ylcarbonyl; or R.sup.2 is ii) aryl
substituted with a radical --COOR.sup.4; or R.sup.2 is iii)
C.sub.1-10alkyl, C.sub.2-10alkenyl, C.sub.3-7cycloalkyl, each of
said C.sub.1-10alkyl, C.sub.2-10alkenyl, C.sub.3-7cycloalkyl, each
individually and independently, being substituted with aryl wherein
said aryl is substituted with a radical --COOR.sup.4; or R.sup.2 is
iv) C.sub.1-10alkyl, C.sub.2-10alkenyl, C.sub.3-7cycloalkyl, each
individually and independently, substituted with a radical selected
from --NR.sup.5a--C(.dbd.NR.sup.5b)--NR.sup.5cR.sup.5d,
--NR.sup.5a--C(.dbd.NR.sup.5e)--R.sup.5f,
--O--NR.sup.5a--C(.dbd.NR.sup.5b)--NR.sup.5cR.sup.5d,
--O--NR.sup.5a--C(.dbd.NR.sup.5e)--R.sup.5f, -sulfonyl-R.sup.6,
--NR.sup.7R.sup.8, --NR.sup.9R.sup.10, a radical ##STR00063##
wherein each Q.sup.1 independently is a direct bond, --CH.sub.2--,
or --CH.sub.2--CH.sub.2--; each Q.sup.2 independently is O, S, SO
or SO.sub.2; each R.sup.4 independently is hydrogen,
C.sub.1-4alkyl, arylC.sub.1-4alkyl; each R.sup.5, R.sup.5b,
R.sup.5c, R.sup.5d independently is hydrogen, C.sub.1-4alkyl or
arylC.sub.1-4alkyl; each R.sup.5e, R.sup.5f independently is
hydrogen, C.sub.1-4alkyl or arylC.sub.1-4alkyl, or R.sup.5e and
R.sup.5f, taken together may form a bivalent alkanediyl radical of
formula --CH.sub.2--CH.sub.2-- or --CH.sub.2--CH.sub.2--CH.sub.2--;
R.sup.6 is C.sub.1-4alkyl, --N(R.sup.5aR.sup.5b),
C.sub.1-4alkyloxy, pyrrolidin-1-yl, piperidin-1-yl,
homopiperidin-1-yl, piperazin-1-yl,
4-(C.sub.1-4alkyl)-piperazin-1-yl, morpholin-4-yl-,
thiomorpholin-4-yl-, 1-oxothiomorpholin-4-yl and
1,1-dioxo-thiomorpholin-4-yl; R.sup.7 is hydrogen, C.sub.1-4alkyl,
hydroxyC.sub.1-4alkyl, C.sub.1-4alkoxyC.sub.1-4alkyl or
C.sub.1-4alkylcarbonyloxyC.sub.1-4alkyl; R.sup.8 is
hydroxyC.sub.1-4alkyl, C.sub.1-4alkoxyC.sub.1-4alkyl,
C.sub.1-4alkylcarbonyloxyC.sub.1-4alkyl, aryl or
arylC.sub.1-4alkyl; R.sup.9 is hydrogen or C.sub.1-4alkyl; R.sup.10
is Het.sub.1, Het.sub.2 or a radical ##STR00064## R.sup.11 is aryl,
arylC.sub.1-4alkyl, formyl, C.sub.1-4alkylcarbonyl, arylcarbonyl,
arylC.sub.1-4alkyl-carbonyl, C.sub.1-4alkyloxycarbonyl,
arylC.sub.1-4alkyloxycarbonyl, R.sup.5aR.sup.5bN-carbonyl,
hydroxyC.sub.1-4alkyl, C.sub.1-4alkyloxyC.sub.1-4alkyl,
arylC.sub.1-4alkyloxyC.sub.1-4alkyl, aryloxyC.sub.1-4alkyl,
Het.sub.2; each R.sup.12 independently is hydroxy, C.sub.1-4alkyl,
arylC.sub.1-4alkyl, C.sub.1-4alkyloxy, arylC.sub.1-4alkyloxy, oxo,
spiro(C.sub.2-4alkanedioxy), spiro(diC.sub.1-4alkyloxy),
--NR.sup.5aR.sup.5b; R.sup.13 is hydrogen, hydroxy, C.sub.1-4alkyl,
C.sub.1-4alkyloxy, or arylC.sub.1-4alkyloxy; or R.sup.13a is
C.sub.1-4alkyl, arylC.sub.1-4alkyl, C.sub.1-4alkyloxycarbonyl or
arylC.sub.1-4alkyloxycarbonyl; each R.sup.13b is hydrogen or
C.sub.1-4alkyl; or R.sup.2 is iv) a radical of formula:
##STR00065##
--C.sub.pCH.sub.2p--CH(OR.sup.14)--C.sub.qH.sub.2q--R.sup.15 (b-3)
--CH.sub.2--CH.sub.2--(O--CH.sub.2--CH.sub.2).sub.m--OR.sup.14
(b-4);
--CH.sub.2--CH.sub.2--(O--CH.sub.2--CH.sub.2).sub.m--NR.sup.17aR.sup.17b
(b-5); wherein in radical (b-3) one of the hydrogen atoms in
--C.sub.pH.sub.2p and one of the hydrogen atoms in
--CH(OR.sup.14)--C.sub.qH.sub.2q--, that is not part of R.sup.14,
may be replaced by a direct bond or a C.sub.1-4alkanediyl group; p
is 1, 2 or 3; q is 0, 1, 2 or 3; each m independently is 1 to 10;
each R.sup.14 independently is hydrogen, C.sub.1-4alkyl, aryl
C.sub.1-4alkyl, aryl, C.sub.1-4alkylcarbonyl, --SO.sub.3H,
--PO.sub.3H.sub.2; R.sup.15 is a substituent selected from the
group consisting of cyano, NR.sup.16aR.sup.16b, pyrrolidinyl,
piperidinyl, homopiperidinyl, piperazinyl,
4-(C.sub.1-4alkyl)-piperazinyl,
4-(C.sub.1-4alkylcarbonyl)-piperazinyl,
4-(C.sub.1-4alkyloxycarbonyl)-piperazinyl, morpholinyl,
thiomorpholinyl, 1-oxothiomorpholinyl, 1,1-dioxo-thiomorpholinyl,
aryl, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl,
isoxazolyl, isothiazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl,
triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl,
pyridazinyl, triazinyl, hydroxy-carbonyl, C.sub.1-4alkylcarbonyl,
N(R.sup.16aR.sup.16b)carbonyl, C.sub.1-4alkyloxycarbonyl,
pyrrolidin-1-yl-carbonyl, piperidin-1-ylcarbonyl,
homopiperidin-1-ylcarbonyl, piperazin-1-yl-carbonyl,
4-(C.sub.1-4alkyl)-piperazin-1-ylcarbonyl, morpholin-1-yl-carbonyl,
thiomorpholin-1-yl-carbonyl, 1-oxothiomorpholin-1-ylcarbonyl and
1,1-dioxo-thiomorpholin-1-ylcarbonyl; or R.sup.15 may additionally
be aryl substituted with a radical --COOR.sup.4; or a radical
selected from --NR.sup.5a--C(.dbd.NR.sup.5b)--NR.sup.5cR.sup.5d,
--NR.sup.5a--C(.dbd.NR.sup.5e)--R.sup.5f,
--O--NR.sup.5a--C(.dbd.NR.sup.5b)--NR.sup.5cR.sup.5d,
--O--NR.sup.5a--C(.dbd.NR.sup.5e)--R.sup.5f, -sulfonyl-R.sup.6,
--NR.sup.7R.sup.8, --NR.sup.9R.sup.10, a radical (a-1), (a-2),
(a-3), (a-4) or (a-5); wherein R.sup.4R.sup.5a, R.sup.5b, R.sup.5c,
R.sup.5d, R.sup.6, R.sup.7, R.sup.8, R.sup.9, R.sup.10, and the
radicals (a-1), (a-2), (a-3), (a-4), (a-5) independently are as
defined above; R.sup.16a and R.sup.16b independently from one
another are hydrogen, C.sub.1-6alkyl or C.sub.1-6alkyl substituted
with a substituent selected from the group consisting of amino,
mono- or di(C.sub.1-4alkyl)amino, pyrrolidinyl, piperidinyl,
homopiperidinyl, piperazinyl, 4-(C.sub.1-4alkyl)-piperazinyl,
morpholinyl, thiomorpholinyl, 1-oxothiomorpholinyl,
1,1-dioxo-thiomorpholinyl and aryl; R.sup.17a and R.sup.17b
independently from one another are hydrogen, C.sub.1-4alkyl or
arylC.sub.1-4alkyl; or R.sup.17a and R.sup.17b together with the
nitrogen atom to which they are attached form a pyrrolidinyl,
piperidinyl, homopiperidinyl, morpholinyl, thiomorpholinyl,
1-oxothio-morpholinyl, 1,1-dioxo-thiomorpholinyl, piperazinyl,
4-C.sub.1-4alkyl-piperazinyl,
4-(C.sub.1-4alkylcarbonyl)-piperazinyl,
4-(C.sub.1-4alkyloxycarbonyl)-piperazinyl ring; each R.sup.18
independently is hydrogen, C.sub.1-4alkyl, arylC.sub.1-4alkyl,
C.sub.1-4alkylcarbonyl or C.sub.1-4alkyloxycarbonyl; R.sup.19 is
hydrogen, hydroxy, C.sub.1-4alkyl or a radical --COOR.sup.4;
-a.sup.1=a.sup.2-a.sup.3=a.sup.4- represents a bivalent radical of
formula --CH.dbd.CH--CH.dbd.CH-- (c-1); --N.dbd.CH--CH.dbd.CH--
(c-2); --CH.dbd.N--CH.dbd.CH-- (c-3); --CH.dbd.CH--N.dbd.CH--
(c-4); --CH.dbd.CH--CH.dbd.N-- (c-5); wherein one, two, three or
four of the hydrogen atoms in (c-1) is replaced by a radical,
C.sub.1-6alkyl, C.sub.1-4alkoxy, halo, hydroxy,
(R.sup.5g)(R.sup.5h)N--(C.sub.1-4alkanediyl)-O--,
(R.sup.7)(R.sup.8)N--(C.sub.1-4alkanediyl)-O--,
(R.sup.8)(R.sup.9)N--(C.sub.1-4alkanediyl)-O--, trifluoromethyl,
cyano, a radical --COOR.sup.4, (R.sup.5a)(R.sup.5b)N-carbonyl,
(R.sup.5a)(R.sup.5b)N-sulfonyl, pyrrolidinylsulfonyl,
piperidinylsulfonyl, homopiperidinylsulfonyl, formyl,
C.sub.1-6alkylcarbonyl, nitro, hydroxyC.sub.1-6alkyl,
C.sub.1-4alkoxyC.sub.1-6alkyl, (R.sup.4OOC)--C.sub.1-6alkyl, a
radical --N(R.sup.5a)(R.sup.5b), --N(R.sup.7)(R.sup.8),
--N(R.sup.9)(R.sup.10), a radical ##STR00066## morpholinyl,
thiomorpholinyl, 1-oxothiomorpholinyl, 1,1-dioxo-thiomorpholinyl,
(R.sup.5g)(R.sup.5h)N--(C.sub.1-4alkanediyl)-N(R.sup.5c)--,
(R.sup.7)(R.sup.8)N--(C.sub.1-4alkanediyl)-N(R.sup.5c),
(R.sup.9)(R.sup.10)N--(C.sub.1-4alkanediyl)-N(R.sup.5c)--,
C.sub.1-6alkylcarbonylamino, C.sub.1-6alkyloxycarbonylamino,
trifluoroacetylamino, C.sub.1-6alkylsulfonylamino,
(R.sup.5a)(R.sup.5b)N--C.sub.1-4alkyl; aryl; Het.sub.1 or
Het.sub.2; R.sup.20 is hydrogen, hydroxy, C.sub.1-4alkyl,
arylC.sub.1-4alkyl, C.sub.1-4alkyloxy, arylC.sub.1-4alkyloxy, oxo,
spiro(C.sub.2-4alkylenedioxy), spiro(diC.sub.1-4alkyloxy),
--NR.sup.5gR.sup.5h; each R.sup.5g or R.sup.5h independently is
hydrogen, C.sub.1-4alkyl or arylC.sub.1-4alkyl, or R.sup.5g and
R.sup.5h together with the nitrogen to which they attached form a
pyrrolidinyl, piperidinyl, homopiperidinyl, morfolinyl, piperazinyl
or 4-C.sub.1-4alkylpiperazinyl radical; wherein each of said
pyrrolidinyl, piperidinyl, homopiperidinyl, morfolinyl, piperazinyl
or 4-C.sub.1-4alkylpiperazinyl radical may optionally be
substituted with hydroxy or oxo; or wherein one or more of the
hydrogen atoms in (c-2), (c-3), (c-4) or (c-5) may be replaced with
a radical selected from halo and C.sub.1-6alkyl; R.sup.3 is nitro,
cyano, amino, halo, hydroxy, C.sub.1-4alkyloxy, hydroxycarbonyl,
amino-carbonyl, C.sub.1-4alkyloxycarbonyl, mono- or
di(C.sub.1-4alkyl)aminocarbonyl, C.sub.1-4alkyl-carbonyl,
methanimidamidyl, mono- or di(C.sub.1-4alkyl)methanimidamidyl,
N-hydroxy-methanimidamidyl or Het.sub.1; aryl is phenyl optionally
substituted with one or more substituents each individually
selected from the group consisting of C.sub.1-6alkyl,
C.sub.1-4alkoxy, halo, hydroxy, amino, trifluoromethyl, cyano,
nitro, hydroxyC.sub.1-6alkyl, cyanoC.sub.1-6alkyl, mono- or
di(C.sub.1-4alkyl)amino, aminoC.sub.1-4alkyl, mono- or
di(C.sub.1-4alkyl)aminoC.sub.1-4alkyl; Het.sub.1 is a 5-membered
ring system wherein one, two, three or four ring members are
heteroatoms each individually and independently selected from the
group consisting of nitrogen, oxygen and sulfur, and wherein the
remaining ring members are carbon atoms; and, where possible, any
nitrogen ring member may optionally be substituted with
C.sub.1-4alkyl; any ring carbon atom may, each individually and
independently, optionally be substituted with a substituent
selected from the group consisting of C.sub.1-4alkyl,
C.sub.2-6alkenyl, C.sub.3-7cycloalkyl, hydroxy, C.sub.1-4alkoxy,
halo, amino, cyano, trifluoromethyl, hydroxyC.sub.1-4alkyl,
cyanoC.sub.1-4alkyl, mono- or di(C.sub.1-4alkyl)amino,
aminoC.sub.1-4alkyl, mono- or
di(C.sub.1-4alkyl)aminoC.sub.1-4alkyl, arylC.sub.1-4alkyl,
aminoC.sub.2-6alkenyl, mono- or
di(C.sub.1-4alkyl)aminoC.sub.2-6alkenyl, furanyl, thienyl,
pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl,
isothiazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl,
tetrazolyl, aryl, hydroxycarbonyl, aminocarbonyl,
C.sub.1-4alkyloxycarbonyl, mono- or
di(C.sub.1-4alkyl)aminocarbonyl, C.sub.1-4alkylcarbonyl, oxo, thio;
and wherein any of the foregoing furanyl, thienyl, pyrrolyl,
oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl,
pyrazolyl, oxadiazolyl, thiadiazolyl and triazolyl moieties may
optionally be substituted with C.sub.1-4alkyl; and Het.sub.2 is
pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl or triazinyl, wherein
any ring carbon atom of each of said 6-membered nitrogen containing
aromatic rings may optionally be substituted with a substituent
selected from the group consisting of C.sub.1-4alkyl
Description
[0001] This invention relates to 6,7,8,9-Substituted
1-phenyl-1,5-dihydro-pyrido[3,2-b]indol-2-ones, the use of these
compounds as HIV inhibitors, to pharmaceutical compositions
containing these compounds and to processes for preparing these
compounds and compositions.
[0002] The virus causing the acquired immunodeficiency syndrome
(AIDS) is known by different names, including T-lymphocyte virus
III (HTLV-III), lymphadenopathy-associated virus (LAV),
AIDS-related virus (ARV) or human immunodeficiency virus (HIV). Up
until now, two distinct classes have been identified, i.e. HIV-1
and HIV-2. Hereinafter, the term HIV will be used to generically
denote both these classes.
[0003] HIV infected patients are currently treated with HIV
protease inhibitors (PIs), nucleoside reverse transcriptase
inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors
(NNRTIs) and nucleotide reverse transcriptase inhibitors (NtRTIs).
Despite the fact that these antiretrovirals are very useful, they
have a common limitation, namely, the targeted enzymes in the HIV
virus are able to mutate in such a way that the known drugs become
less effective, or even ineffective against these mutant HIV
viruses. Or, in other words, the HIV virus creates an
ever-increasing resistance against any available drugs, which is a
major cause of therapy failure. Moreover, it has been shown that
resistant virus is carried over to newly infected individuals,
resulting in severely limited therapy options for these drug-naive
patients.
[0004] Current HIV therapy comprises in most cases the
administration of drug cocktails comprising two or more active
ingredients selected from the above classes of HIV inhibitors. But
even when using combination therapy, drug resistance arises
resulting in the combination becoming less effective. This often
may force the treating physician to boost the plasma levels of the
active drugs in order for said antiretrovirals to regain
effectivity against the mutated HIV viruses, the consequence of
which is an undesirable increase in pill burden. The latter in turn
may also lead to an increased risk of non-compliance with the
prescribed therapy.
[0005] Therefore, there is a continuous general need for new
combinations of HIV inhibitors that comprise new types of HIV
inhibitory agents. Hence there is a need for new HIV inhibitors
that differ from existing inhibitors in terms of chemical structure
as well as mode of action or both. There is a particular need for
compounds that are active not only against wild type HIV virus, but
also against the increasingly more common resistant HIV
viruses.
[0006] Currently used HIV reverse transcriptase inhibitors belong
to three different classes. These include the NRTIs, which are
intracellularly converted to nucleoside triphosphates that compete
with the natural nucleoside triphosphates for incorporation into
elongating viral DNA by reverse transcriptase. Chemical
modifications that distinguish these compounds from natural
nucleosides result in DNA chain termination events. NRTIs that are
currently available include zidovudine (AZT), didanosine (ddI),
zalcitabine (ddC), stavudine (d4T), lamivudine (3TC) and abacavir
(ABC). A second class comprises the NtRTIs such as tenofovir, which
have a similar mode of action as the NRZTIs. Emergence of mutations
causes the NRTIs and NtRTIs to become ineffective. A third class
comprises the NNRTIs, which interact with the NNRTI binding site
and thereby block the RT mechanism. Currently available NNRTIs
include nevirapine, delavirdine and efavirenz, known to be
susceptible to relative rapid emergence of resistance due to
mutations at amino acids that surround the NNRTI-binding site.
[0007] Thus, there is a medical need for further anti-infective
compounds that target HIV reverse transcriptase, in particular
anti-retroviral compounds that are able to delay the occurrence of
resistance and that combat a broad spectrum of mutants of the HIV
virus.
[0008] WO02/055520 and WO02/059123 disclose
benzoylalkylindolepyridinium compounds as antiviral compounds.
Ryabova et al. disclose the synthesis of certain
benzoylalkyl-indolepyridinium compounds (Russian Chem. Bull. 2001,
50(8), 1449-1456; and Chem. Heterocycl. Compd. (Engl. Translat.)
36; 3; 2000; 301-306; Khim. Geterotsikl. Soedcin.; RU; 3; 2000;
362-367).
[0009] The compounds of this invention differ from these prior art
compounds in terms of chemical structure as well as by the fact
that they interact via a mechanism that differs from known RT
inhibitors. They not only are active against wild type HIV virus
but also against mutant HIV viruses, in particular mutant HIV
viruses exhibiting resistance against currently available reverse
transcriptase (RT) inhibitors.
[0010] Thus in one aspect the present invention concerns
6,7,8,9-substituted 1-phenyl-1,5-dihydro-pyrido[3,2-b]indol-2-ones
which can be represented by formula (I):
##STR00003##
the N-oxides, salts, quaternary ammonium salts, stereoisomeric
forms, prodrugs, esters and metabolites thereof, wherein [0011] n
is 1, 2 or 3; [0012] R.sup.1 is hydrogen, cyano, halo,
aminocarbonyl, hydroxycarbonyl, C.sub.1-4alkyloxycarbonyl,
C.sub.1-4alkylcarbonyl, mono- or di(C.sub.1-4alkyl)aminocarbonyl,
arylaminocarbonyl, N-(aryl)-N--(C.sub.1-4alkyl)aminocarbonyl,
methanimidamidyl, N-hydroxy-methanimidamidyl, mono- or
di(C.sub.1-4alkyl)methanimidamidyl, Het.sub.1 or Het.sub.2; [0013]
X is a bivalent radical NR.sup.2, O, S, SO, SO.sub.2; [0014]
R.sup.2 is: [0015] i) hydrogen, C.sub.1-10alkyl, C.sub.2-10alkenyl,
C.sub.3-7cycloalkyl, wherein said C.sub.1-10alkyl,
C.sub.2-10alkenyl and C.sub.3-7cycloalkyl, each individually and
independently, may be optionally substituted with a substituent
selected from the group consisting of cyano, N(R.sup.16aR.sup.16b),
pyrrolidinyl, piperidinyl, homopiperidinyl, piperazinyl,
4-(C.sub.1-4alkyl)-piperazinyl, morpholinyl, thiomorpholinyl,
1-oxothiomorpholinyl, 1,1-dioxo-tbiomorpholinyl, aryl, furanyl,
thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl,
isothiazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl,
tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl,
triazinyl, hydroxy-carbonyl, C.sub.1-4alkylcarbonyl,
N(R.sup.16aR.sup.16b)carbonyl, C.sub.1-4alkyloxycarbonyl,
pyrrolidin-1-ylcarbonyl, piperidin-1-ylcarbonyl,
homopiperidin-1-ylcarbonyl, piperazin-1-ylcarbonyl,
4-(C.sub.1-4alkyl)-piperazin-1-ylcarbonyl, morpholin-1-yl-carbonyl,
thiomorpholin-1-ylcarbonyl, 1-oxothiomorpholin-1-ylcarbonyl and
1,1-dioxo-thiomorpholin-1-ylcarbonyl; or R.sup.2 is [0016] ii) aryl
substituted with a radical --COOR.sup.4; or R.sup.2 is [0017] iii)
C.sub.1-10alkyl, C.sub.2-10alkenyl, C.sub.3-7cycloalkyl, each of
said C.sub.1-10alkyl, C.sub.2-10alkenyl, C.sub.3-7cycloalkyl, each
individually and independently, being substituted with aryl wherein
said aryl is substituted with a radical --COOR.sup.4; or R.sup.2 is
[0018] iv) C.sub.1-10alkyl, C.sub.2-10alkenyl, C.sub.3-7cycloalkyl,
each individually and independently, substituted with a radical
selected from --NR.sup.5a--C(.dbd.NR.sup.5b)--NR.sup.5cR.sup.5d,
--NR.sup.5a--C(.dbd.NR.sup.5e)--R.sup.5f,
--O--NR.sup.5a--C(.dbd.NR.sup.5b)--NR.sup.5cR.sup.5d,
--O--NR.sup.5a--C(.dbd.NR.sup.5e)--R.sup.5f, -sulfonyl-R.sup.6,
--NR.sup.7R.sup.8, --NR.sup.9R.sup.10, a radical
##STR00004##
[0018] wherein [0019] each Q.sup.1 independently is a direct bond,
--CH.sub.2--, or --CH.sub.2--CH.sub.2--; [0020] each Q.sup.2
independently is O, S, SO or SO.sub.2; [0021] each R.sup.4
independently is hydrogen, C.sub.1-4alkyl, arylC.sub.1-4alkyl;
[0022] each R.sup.5a, R.sup.5b, R.sup.5c, R.sup.5d independently is
hydrogen, C.sub.1-4alkyl or arylC.sub.1-4alkyl; [0023] each
R.sup.5e, R.sup.5f independently is hydrogen, C.sub.1-4alkyl or
arylC.sub.1-4alkyl, or R.sup.5e and R.sup.5f, taken together may
form a bivalent alkanediyl radical of formula --CH.sub.2CH.sub.2--
or --CH.sub.2--CH.sub.2--CH.sub.2--; [0024] R.sup.6 is
C.sub.1-4alkyl, --N(R.sup.5aR.sup.5b), C.sub.1-4alkyloxy,
pyrrolidin-1-yl, piperidin-1-yl, homopiperidin-1-yl,
piperazin-1-yl, 4-(C.sub.1-4alkyl)-piperazin-1-yl, morpholin-4-yl-,
thiomorpholinyl-, 1-oxothiomorpholin-4-yl and
1,1-dioxo-thiomorpholin-4-yl; [0025] R.sup.7 is hydrogen,
C.sub.1-4alkyl, hydroxyC.sub.1-4alkyl,
C.sub.1-4alkoxyC.sub.1-4alkyl or
C.sub.1-4alkylcarbonyloxyC.sub.1-4alkyl; [0026] R.sup.8 is
hydroxyC.sub.1-4alkyl, C.sub.1-4alkoxyC.sub.1-4alkyl,
C.sub.1-4alkylcarbonyloxyC.sub.1-4alkyl, aryl or
arylC.sub.1-4alkyl; [0027] R.sup.9 is hydrogen or C.sub.1-4alkyl;
[0028] R.sup.10 is Het.sub.1, Het.sub.2 or a radical
[0028] ##STR00005## [0029] R.sup.11 is aryl, arylC.sub.1-4alkyl,
formyl, C.sub.1-4alkylcarbonyl, arylcarbonyl,
arylC.sub.1-4alkyl-carbonyl, C.sub.1-4alkyloxycarbonyl,
arylC.sub.1-4alkyloxycarbonyl, R.sup.5aR.sup.5bN-carbonyl,
hydroxyC.sub.1-4alkyl, C.sub.1-4alkyloxyC.sub.1-4alkyl
arylC.sub.1-4alkyloxyC.sub.1-4alkyl, aryloxyC.sub.1-4alkyl,
Het.sub.2; [0030] each R.sup.12 independently is hydroxy,
C.sub.1-4alkyl, arylC.sub.1-4alkyl, C.sub.1-4alkyloxy,
arylC.sub.1-4alkyloxy, oxo, spiro(C.sub.2-4alkanedioxy),
spiro(diC.sub.1-4alkyloxy), --NR.sup.5aR.sup.5b; R.sup.13 is
hydrogen, hydroxy, C.sub.1-4alkyl, C.sub.1-4alkyloxy, or
arylC.sub.1-4alkyloxy; or R.sup.13a is C.sub.1-4alkyl,
arylC.sub.1-4alkyl, C.sub.1-4alkyloxycarbonyl or
arylC.sub.1-4alkyloxycarbonyl; each R.sup.13b is hydrogen or
C.sub.1-4alkyl; or R.sup.2 is [0031] v) a radical of formula:
[0031] ##STR00006##
--C.sub.pH.sub.2p--CH(OR.sup.14)--C.sub.qH.sub.2q--R.sup.15
(b-3);
--CH.sub.2--CH.sub.2--(O--CH.sub.2--CH.sub.2).sub.m--OR.sup.14
(b-4);
--CH.sub.2--CH.sub.2--(O--CH.sub.2--CH.sub.2).sub.m--NR.sup.17aR.sup.17b
(b-5);
wherein in radical (b-3) one of the hydrogen atoms in
--C.sub.pH.sub.2p-- and one of the hydrogen atoms in
--CH(OR.sup.14)C.sub.qH.sub.2q, that is not part of R.sup.14, may
be replaced by a direct bond or a C.sub.1-4alkanediyl group; [0032]
p is 1, 2 or 3; [0033] q is 0, 1, 2 or 3; [0034] each m
independently is 1 to 10; [0035] each R.sup.14 independently is
hydrogen, C.sub.1-4alkyl, aryl C.sub.1-4alkyl, aryl,
C.sub.1-4alkylcarbonyl, --SO.sub.3H, --PO.sub.3H.sub.2; [0036]
R.sup.15 is a substituent selected from the group consisting of
cyano, NR.sup.16aR.sup.16b, pyrrolidinyl, piperidinyl,
homopiperidinyl, piperazinyl, 4-(C.sub.1-4alkyl)-piperazinyl,
4-(C.sub.1-4alkylcarbonyl)-piperazinyl,
4-(C.sub.1-4alkyloxycarbonyl)-piperazinyl, morpholinyl,
thiomorpholinyl, 1-oxothiomorpholinyl, 1,1-dioxo-thiomorpholinyl,
aryl, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl,
isoxazolyl, isothiazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl,
triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl,
pyridazinyl, triazinyl, hydroxycarbonyl, C.sub.1-4alkylcarbonyl,
N(R.sup.16aR.sup.16b)carbonyl, C.sub.1-4alkyloxycarbonyl,
pyrrolidin-1-yl-carbonyl, piperidin-1-ylcarbonyl,
homopiperidin-1-ylcarbonyl, piperazin-1-yl-carbonyl,
4-(C.sub.1-4alkyl)-piperazin-1-ylcarbonyl, morpholin-1-yl-carbonyl,
thiomorpholin-1-yl-carbonyl, 1-oxothiomorpholin-1-ylcarbonyl and
1,1-dioxo-thiomorpholin-1-ylcarbonyl; or R.sup.15 may additionally
be aryl substituted with a radical --COOR.sup.4; or a radical
selected from --NR.sup.5a--C(.dbd.NR.sup.5b)--NR.sup.5cR.sup.5d,
--NR.sup.5a--C(.dbd.NR.sup.5e)--R.sup.5f,
--O--NR.sup.5a--C(.dbd.NR.sup.5b)--NR.sup.5cR.sup.5d,
--O--NR.sup.5a--C(.dbd.NR.sup.5e)--R.sup.5f, -sulfonyl-R.sup.6,
--NR.sup.7R.sup.8, --NR.sup.9R.sup.10, a radical (a-1), (a-2),
(a-3), (a-4) or (a-5); wherein R.sup.4, R.sup.5a, R.sup.5b,
R.sup.5c, R.sup.5d, R.sup.6, R.sup.7, R.sup.8, R.sup.9, R.sup.10,
and the radicals (a-1), (a-2), (a-3), (a-4), (a-5) independently
are as defined above; [0037] R.sup.16a and R.sup.16b independently
from one another are hydrogen, C.sub.1-6alkyl or C.sub.1-6alkyl
substituted with a substituent selected from the group consisting
of amino, mono- or di(C.sub.1-4alkyl)amino, pyrrolidinyl,
piperidinyl, homopiperidinyl, piperazinyl,
4-(C.sub.1-4alkyl)-piperazinyl, morpholinyl, thiomorpholinyl,
1-oxothiomorpholinyl, 1,1-dioxo-thiomorpholinyl and aryl; [0038]
R.sup.17a and R.sup.17b independently from one another are
hydrogen, C.sub.1-4alkyl or arylC.sub.1-4alkyl; or R.sup.17a and
R.sup.17b together with the nitrogen atom to which they are
attached form a pyrrolidinyl, piperidinyl, homopiperidinyl,
morpholinyl, thiomorpholinyl, 1-oxothio-morpholinyl,
1,1-dioxo-thiomorpholinyl, piperazinyl,
4-C.sub.1-4alkyl-piperazinyl,
4-(C.sub.1-4alkylcarbonyl)-piperazinyl,
4-(C.sub.1-4alkyloxycarbonyl)-piperazinyl ring; each R.sup.18
independently is hydrogen, C.sub.1-4alkyl, arylC.sub.1-4alkyl,
C.sub.1-4alkylcarbonyl or C.sub.1-4alkyloxycarbonyl; [0039]
R.sup.19 is hydrogen, hydroxy, C.sub.1-4alkyl or a radical
--COOR.sup.4; [0040] -a.sup.1=a.sup.2-a.sup.3=a.sup.4- represents a
bivalent radical of formula
[0040] --CH.dbd.CH--CH.dbd.CH-- (c-1);
--N.dbd.CH--CH.dbd.CH-- (c-2);
--CH.dbd.N--CH.dbd.CH-- (c-3);
--CH.dbd.CH--N--CH-- (c-4);
--CH.dbd.CH--CH.dbd.N-- (c-5); [0041] wherein one, two, three or
four of the hydrogen atoms in (c-1) is replaced by a radical
C.sub.1-6alkyl, C.sub.1-4alkoxy, halo, hydroxy,
(R.sup.5g)(R.sup.5h)N--(C.sub.1-4alkanediyl)-O--,
(R.sup.7)(R.sup.8)N--(C.sub.1-4alkanediyl)-O--,
(R.sup.8)(R.sup.9)N--(C.sub.1-4alkanediyl)-O--, trifluoromethyl,
cyano, a radical --COOR.sup.4, (R.sup.5a)(R.sup.5b)N-carbonyl,
(R.sup.5a)(R.sup.5b)N-sulfonyl, pyrrolidinylsulfonyl,
piperidinylsulfonyl, homopiperidinylsulfonyl, formyl,
C.sub.1-6alkylcarbonyl, nitro, hydroxyC.sub.1-6alkyl,
C.sub.1-4alkoxyC.sub.1-6alkyl, (R.sup.4OOC)--C.sub.1-6alkyl, a
radical --N(R.sup.5a)(R.sup.5b), --N(R.sup.7)(R.sup.8),
--N(R.sup.9)(R.sup.10), a radical
##STR00007##
[0041] morpholinyl, thiomorpholinyl, 1-oxothiomorpholinyl,
1,1-dioxo-thiomorpholinyl,
(R.sup.5g)(R.sup.5h)N--(C.sub.1-4alkanediyl)-N(R.sup.5c)--,
(R.sup.7)(R.sup.8)N--(C.sub.1-4alkanediyl)-N(R.sup.5c)--,
(R.sup.9)(R.sup.10)N--(C.sub.1-4alkanediyl)-N(R.sup.5c)--,
C.sub.1-6alkylcarbonylamino, C.sub.1-6alkyloxycarbonylamino,
trifluoroacetylamino, C.sub.1-6alkylsulfonylamino,
(R.sup.5a)(R.sup.5b)N--C.sub.1-4alkyl aryl; Het.sub.1 or Het.sub.2;
[0042] R.sup.20 is hydrogen, hydroxy, C.sub.1-4alkyl,
arylC.sub.1-4alkyl, C.sub.1-4alkyloxy, arylC.sub.1-4alkyloxy, oxo,
spiro(C.sub.1-24alkylenedioxy), spiro(diC.sub.1-4alkyloxy),
NR.sup.5gR.sup.5h; [0043] each R.sup.5g or R.sup.5h independently
is hydrogen, C.sub.1-4alkyl or arylC.sub.1-4alkyl, or R.sup.5g and
R.sup.5h together with the nitrogen to which they attached form a
pyrrolidinyl, piperidinyl, homopiperidinyl, morfolinyl, piperazinyl
or 4-C.sub.1-4alkylpiperazinyl radical; wherein each of said
pyrrolidinyl, piperidinyl, homopiperidinyl, morfolinyl, piperazinyl
or 4-C.sub.1-4alkylpiperazinyl radical may optionally be
substituted with hydroxy or oxo; or [0044] wherein one or more of
the hydrogen atoms in (c-2), (c-3), (c-4) or (c-5) may be replaced
with a radical selected from halo and C.sub.1-6alkyl;
[0045] R.sup.3 is nitro, cyano, amino, halo, hydroxy,
C.sub.1-4alkyloxy, hydroxycarbonyl, amino carbonyl,
C.sub.1-4alkyloxycarbonyl, mono- or
di(C.sub.1-4alkyl)aminocarbonyl, C.sub.1-4alkyl-carbonyl,
methanimidamidyl, mono- or di(C.sub.1-4alkyl)methanimidamidyl,
N-hydroxy-methanimidamidyl or Het.sub.1; [0046] aryl is phenyl
optionally substituted with one or more substituents each
individually selected from the group consisting of C.sub.1-6alkyl,
C.sub.1-4alkoxy, halo, hydroxy, amino, trifluoromethyl, cyano,
nitro, hydroxyC.sub.1-6alkyl, cyanoC.sub.1-6alkyl, mono or
di(C.sub.1-4alkyl)amino, aminoC.sub.1-4alkyl, mono- or
di(C.sub.1-4alkyl)aminoC.sub.1-4alkyl; [0047] Het.sub.1 is a
5-membered ring system wherein one, two, three or four ring members
are heteroatoms each individually and independently selected from
the group consisting of nitrogen, oxygen and sulfur, and wherein
the remaining ring members are carbon atoms; and, where possible,
any nitrogen ring member may optionally be substituted with
C.sub.1-4alkyl; any ring carbon atom may, each individually and
independently, optionally be substituted with a substituent
selected from the group consisting of C.sub.1-4alkyl,
C.sub.2-6alkenyl, C.sub.3-7cycloalkyl, hydroxy, C.sub.1-4alkoxy,
halo, amino, cyano, trifluoromethyl, hydroxyC.sub.1-4alkyl,
cyanoC.sub.1-4alkyl, mono- or di(C.sub.1-4alkyl)amino,
aminoC.sub.1-4alkyl, mono or di(C.sub.1-4alkyl)aminoC.sub.1-4alkyl,
arylC.sub.1-4alkyl, aminoC.sub.2-6alkenyl, mono- or
di(C.sub.1-4alkyl)aminoC.sub.2-6alkenyl, furanyl, thienyl,
pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl,
isothiazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl,
tetrazolyl, aryl, hydroxycarbonyl, aminocarbonyl,
C.sub.1-4alkyloxycarbonyl, mono- or
di(C.sub.1-4alkyl)aminocarbonyl, C.sub.1-4alkylcarbonyl, oxo, thio;
and wherein any of the foregoing furanyl, thienyl, pyrrolyl,
oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl,
pyrazolyl, oxadiazolyl, thiadiazolyl and triazolyl moieties may
optionally be substituted with C.sub.1-4alkyl; [0048] Het.sub.2 is
pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl or triazinyl, wherein
any ring carbon atom of each of said 6-membered nitrogen containing
aromatic rings may optionally be substituted with a substituent
selected from the group consisting of C.sub.1-4alkyl.
[0049] In a particular aspect this invention concerns compounds of
formula (I) wherein R.sub.1 is cyano; X is O or NR.sup.2 wherein
R.sup.2 is a C.sub.1-10alkyl radical substituted as specified above
or R.sup.2 is a linear radical of formula (b-3) or (b-4); n is 1
and R.sub.3 is nitro.
[0050] As used herein "C.sub.1-4alkyl" as a group or part of a
group defines straight or branched chain saturated hydrocarbon
radicals having from 1 to 4 carbon atoms such as for example
methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl,
2-methyl-1-propyl; "C.sub.1-6alkyl" encompasses C.sub.1-4alkyl
radicals and the higher homologues thereof having 5 or 6 carbon
atoms such as, for example, 1-pentyl, 2-pentyl, 3-pentyl, 1-hexyl,
2-hexyl, 2-methyl-1-butyl, 2-methyl-1-pentyl, 2-ethyl-1-butyl,
3-methyl-2-pentyl, and the like. The term "C.sub.1-10alkyl" as a
group or part of a group encompasses C.sub.1-6alkyl radicals and
the higher homologues thereof having from 7 to 10 carbon atoms such
as, for example, 1-heptyl, 2-heptyl, 2-methyl-1-hexyl,
2-ethyl-1-hexyl, 1-octyl, 2-octyl, 2-methyl-1-heptyl,
2-methyl-2-heptyl, 1-nonyl, 2-nonyl, 2-methyl-1-octyl,
2-methyl-2-octyl, 1-decyl, 2-decyl, 3-decyl, 2-methyl-1-decyl and
the like.
[0051] The term "C.sub.2-6alkenyl" as a group or part of a group
defines straight and branched chained hydrocarbon radicals having
saturated carbon-carbon bonds and at least one double bond, and
having from 2 to 6 carbon atoms, such as, for example, propenyl,
buten-1-yl, buten-2-yl, 2-buten-1-yl, 3-buten-1-yl, penten-1-yl,
penten-2-yl, 2-penten-2-yl, hexen-1-yl, hexen-2-yl, hexen-3-yl,
2-methylbuten-1-yl, 1-methyl-2-penten-1-yl and the like. The term
"C.sub.2-10alkenyl" as a group or part of a group defines comprises
C.sub.2-6alkenyl groups and the higher homologues thereof having
from 7 to 10 carbon atoms and at least one double bond such as, for
example, hepten-1-yl, 2-hepten-1-yl, 3-hepten-1-yl, octen-1-yl,
2-octen-1-yl, 3-octen-1-yl, nonen-1-yl, 2-nonen-1-yl, 3-nonen-1-yl,
4-nonen-1-yl, decen-1-yl, 2-decen-1-yl, 3-decen-1-yl, 4-decen-1-yl,
1-methyl-2-hexen-1-yl and the like. Preferred are C.sub.2-6alkenyl
or C.sub.2-10alkenyl groups having one double bond. Whenever linked
to a heteroatom, the C.sub.2-6alkenyl or C.sub.2-10alkenyl groups
by preference are linked to the hetero atom by a saturated carbon
atom. Preferred subgroups amongst C.sub.2-6alkenyl or
C.sub.2-10alkenyl are C.sub.3-6alkenyl or C.sub.3-10alkenyl which
are alkenyl groups as specified herein having from 3 to 6 or from 3
to 10 carbon atoms.
[0052] The term "C.sub.3-7cycloalkyl" is generic to cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
[0053] The term "C.sub.1-4alkanediyl" defines bivalent straight and
branched chain saturated hydrocarbon radicals having from 1 to 4
carbon atoms such as, for example, methylene, 1,2-ethanediyl,
1,3-propanediyl, 1,4-butanediyl, 1,2-propanediyl, 2,3-butanediyl,
and the like, refers to bivalent C.sub.1-4alkyl radicals having
from one to four carbon atoms, in particular methylene,
1,2-ethanediyl, 1,1-ethanediyl, 1,2-propanediyl, 1,3-propanediyl,
1,2-butanediyl, 1,3-butanediyl, 1,4-butanediyl,
"C.sub.2-4alkanediyl" similarly refers to bivalent hydrocarbon
atoms having 2 to 4 carbon atoms. Of particular interest are the
C.sub.1-4alkanediyl groups in which the carbon atoms bearing the
connecting bond are next to one another (in vicinal position),
these groups sometimes being referred to as ethylene, propylene and
butylene.
[0054] "C.sub.2-4alkanedioxy" refers to straight and branched chain
saturated hydrocarbon radicals having 2-4 carbon atoms and two oxy
(--O--) groups, e.g. 1,2-ethanedioxy
(--O--CH.sub.2--CH.sub.2--O--), 1,3-propanedioxy
(--O--CH.sub.2CH.sub.2CH.sub.2--O--), 1,2-propanedioxy
(--O--CH.sub.2--CH(CH.sub.3)--O--), 1,4-butanedioxy
(--O--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--O--), and the like.
[0055] The terms "spiro(C.sub.2-4alkanedioxy)" and
"spiro(diC.sub.1-4alkyloxy)" refer to a linkage of the
C.sub.2-4alkanedioxy and diC.sub.1-4alkyloxy groups to the same
carbon atom, whereby in the former instance a ring is formed.
[0056] The term "halo" is generic to fluoro, chloro, bromo or
iodo.
[0057] A hydroxyC.sub.1-6alkyl group when substituted on an oxygen
atom or a nitrogen atom preferably is a hydroxyC.sub.2-6alkyl group
wherein the hydroxy group and the oxygen or nitrogen are separated
by at least two carbon atoms.
[0058] The term "methanimidamidyl" is used in accordance with the
Chemical Abstracts Nomenclature (CAS) and refers to the radical of
formula H.sub.2N--C(.dbd.NH)--, which radical can also be referred
to as "amidine". Likewise N-hydroxy-methanimidamidyl is used in
accordance with the CAS nomenclature and refers to the radical of
formula H.sub.2N--C(.dbd.N--OH)-- or its tautomer
HN.dbd.C(--NH--OH)--, which radical can also be referred to as
"hydroxyamidine".
[0059] The term "hydroxycarbonyl" refers to a carboxyl group
(--COOH).
[0060] The aryl group is phenyl optionally substituted with one or
more substituents and in particular is phenyl optionally
substituted with one, two, three, four or five substituents,
preferably phenyl substituted with one, two or three
substituents.
[0061] Het.sub.1 in particular is a 5-membered ring system as
specified above wherein the ring system is aromatic. More
particularly, Het.sub.1 is a 5-membered ring system as specified
above wherein the ring system contains one oxygen, sulfur or
nitrogen, and optionally one, two or three further nitrogen atoms
and wherein the remaining ring members are carbon atoms. Further in
particular, Het.sub.1 is an aromatic 5-membered ring system as
specified above wherein the ring system contains one oxygen, sulfur
or nitrogen atom, and optionally one, two or three further nitrogen
atoms and wherein the remaining ring members are carbon atoms. In
each of the instances mentioned in this paragraph, Het.sub.1 may be
optionally substituted with any of substituents specified herein in
the definitions of the compounds of formula (I) as well as any of
the subgroups of compounds of formula (I).
[0062] Examples of Het.sub.1 rings are furanyl, thienyl, pyrrolyl,
oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl,
pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, each
of which individually and independently may be optionally
substituted with a substituent selected from the group consisting
of C.sub.1-4alkyl, C.sub.2-6alkenyl, C.sub.3-7cycloalkyl, hydroxy,
C.sub.1-4alkoxy, halo, amino, cyano, trifluoromethyl,
hydroxyC.sub.1-4alkyl, cyano-C.sub.1-4alkyl, mono- or
di(C.sub.1-4alkyl)amino, aminoC.sub.1-4alkyl, mono- or
di(C.sub.1-4alkyl)amino-C.sub.1-4alkyl, arylC.sub.1-4alkyl,
aminoC.sub.2-6alkenyl, mono- or
di(C.sub.1-4alkyl)aminoC.sub.2-6alkenyl, furanyl, thienyl,
pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl,
isothiazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl,
tetrazolyl, aryl, hydroxycarbonyl, aminocarbonyl,
C.sub.1-4alkyloxycarbonyl, mono- or
di(C.sub.1-4alkyl)aminocarbonyl, C.sub.1-4alkyl-carbonyl, oxo,
thio; and wherein any of the foregoing furanyl, thienyl, pyrrolyl,
oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl,
pyrazolyl, oxadiazolyl, thiadiazolyl and triazolyl moieties may
optionally be substituted with C.sub.1-4alkyl.
[0063] The substituents R.sup.12, R.sup.13, --COOR.sup.4,
R.sup.13b, R.sup.18, R.sup.19, R.sup.20 on radicals (a-2), (a-3),
(a-5), (a-6), (a-7) and (b-1) may be positioned at any ring carbon
atom, including the atoms of radicals Q.sup.1. Preferably, the
substituents R.sup.12, R.sup.13, R.sup.13b, R.sup.18, R.sup.19 or
R.sup.20 are not in .alpha.-position from the ring nitrogen atom,
in particular where any of said substituents is oxo,
spiro(C.sub.2-4alkanediyldioxy), spiro(diC.sub.1-4alkyloxy),
--NR.sup.5aR.sup.5b, hydroxy or C.sub.1-4alkyloxy. Of particular
interest are radicals (a-2), (a-3), (a-6), (a-7) or (b-1) wherein
substituents R.sup.12, R.sup.13, R.sup.18 or R.sup.19 are
positioned on a carbon atom of Q.sup.1 or where Q.sup.1 is a direct
bond, on the ring carbon atom to which Q.sup.1 is linked.
[0064] The connecting bond in radicals (a-3), (a-4), (a-6), (b-1)
or (b-2) may be positioned at any ring carbon atom, including the
atoms of radicals Q.sup.1.
[0065] One or more of the hydrogen atoms in (c-2), (c-3), (c-4) or
(c-5) may be replaced with a radical selected from halo and
C.sub.1-6alkyl; this is meant to comprise instances where one, two
or three of the nitrogen atoms of these radicals is replaced; in
particular it refers to the instance where one or two, more in
particular where one, of the nitrogen atoms of these radicals is
replaced.
[0066] It should be noted that different isomers of the various
heterocycles may exist within the definitions as used throughout
the specification. For example, oxadiazolyl may be
1,2,4-oxadiazolyl or 1,3,4-oxadiazolyl or 1,2,3-oxadiazolyl;
likewise for thiadiazolyl which may be 1,2,4-thiadiazolyl or
1,3,4-thiadiazolyl or 1,2,3-thiadiazolyl; pyrrolyl may be
1H-pyrrolyl or 2H-pyrrolyl.
[0067] It should also be noted that the radical positions on any
molecular moiety used in the definitions may be anywhere on such
moiety as long as it is chemically stable. For instance pyridyl
includes 2-pyridyl, 3-pyridyl and 4-pyridyl; pentyl includes
1-pentyl, 2-pentyl and 3-pentyl; morpholinyl includes
4-morpholinyl, 3-morpholinyl and 2-morpholinyl.
[0068] When any variable (e.g. halogen or C.sub.1-4alkyl) occurs
more than one time in any constituent, each definition is
independent.
[0069] The term "prodrug" as used throughout this text means the
pharmacologically acceptable derivatives such as esters, amides and
phosphates, such that the resulting in vivo biotransformation
product of the derivative is the active drug as defined in the
compounds of formula (I). The reference by Goodman and Gilman (The
Pharmacological Basis of Therapeutics, 8.sup.th ed, McGraw-Hill,
Int. Ed. 1992, "Biotransformation of Drugs", p 13-15) describing
prodrugs generally is hereby incorporated. Prodrugs preferably have
excellent aqueous solubility, increased bioavailability and are
readily metabolized into the active inhibitors in vivo. Prodrugs of
a compound of the present invention are prepared by modifying
functional groups present in the compound in such a way that the
modifications are cleaved, either by routine manipulation or in
vivo, to the parent compound.
[0070] Preferred are pharmaceutically acceptable ester prodrugs
that are hydrolysable in vivo and are derived from those compounds
of formula (I) having a hydroxy or a carboxyl groups. An in vivo
hydrolysable ester is an ester, which is hydrolysed in the human or
animal body to produce the parent acid or alcohol. Suitable
pharmaceutically acceptable esters for carboxy include
C.sub.1-6alkoxymethyl esters for example methoxymethyl,
C.sub.1-6alkanoyloxymethyl esters for example pivaloyloxymethyl,
phthalidyl esters, C.sub.3-8cycloalkoxycarbonyloxyC.sub.1-6 alkyl
esters for example 1-cyclohexylcarbonyloxyethyl;
1,3-dioxolen-2-onylmethyl esters for example
5-methyl-1,3-dioxolen-2-onylmethyl; and
C.sub.1-6alkoxycarbonyloxyethyl esters for example
1-methoxycarbonyloxyethyl and may be formed at any carboxy group in
the compounds of this invention.
[0071] An in vivo hydrolysable ester of a compound of the formula
(I) containing a hydroxy group includes inorganic esters such as
phosphate esters and .alpha.-acyloxyalkyl ethers and related
compounds which as a result of the in vivo hydrolysis of the ester
breakdown to give the parent hydroxy group. Examples of
a-acyloxyalkyl ethers include acetoxymethoxy and
2,2-dimethylpropionyloxy-methoxy. A selection of in vivo
hydrolysable ester forming groups for hydroxy include alkanoyl,
benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl,
alkoxycarbonyl (to give alkyl carbonate esters), dialkylcarbamoyl
and N-(dialkylaminoethyl)-N-alkylcarbamoyl (to give carbamates),
dialkylaminoacetyl and carboxyacetyl. Examples of substituents on
benzoyl include morpholino and piperazino linked from a ring
nitrogen atom via a methylene group to the 3- or 4-position of the
benzoyl ring.
[0072] For therapeutic use, the salts of the compounds of formula
(I) are those wherein the counterion is pharmaceutically or
physiologically acceptable. However, salts having a
pharmaceutically unacceptable counterion may also find use, for
example, in the preparation or purification of a pharmaceutically
acceptable compound of formula (I). All salts, whether
pharmaceutically acceptable or not are included within the ambit of
the present invention.
[0073] The pharmaceutically acceptable or physiologically tolerable
addition salt forms which the compounds of the present invention
are able to form can conveniently be prepared using the appropriate
acids, such as, for example, inorganic acids such as hydrohalic
acids, e.g. hydrochloric or hydrobromic acid; sulfuric;
hemisulphuric, nitric; phosphoric and the like acids; or organic
acids such as, for example, acetic, aspartic, dodecyl-sulphuric,
heptanoic, hexanoic, nicotinic, propanoic, hydroxyacetic, lactic,
pyruvic, oxalic, malonic, succinic, maleic, fumaric, malic,
tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic,
p-toluenesulfonic, cyclamic, salicylic, p-amino-salicylic, pamoic
and the like acids.
[0074] Conversely said acid addition salt forms can be converted by
treatment with an appropriate base into the free base form.
[0075] The compounds of formula (I) containing an acidic proton may
also be converted into their non-toxic metal or amine addition base
salt form by treatment with appropriate organic and inorganic
bases. Appropriate base salt forms comprise, for example, the
ammonium salts, the alkali and earth alkaline metal salts, e.g. the
lithium, sodium, potassium, magnesium, calcium salts and the like,
salts with organic bases, e.g. the benzathine,
N-methyl-D-glucamine, hydrabamine salts, and salts with amino acids
such as, for example, arginine, lysine and the like.
[0076] Conversely said base addition salt forms can be converted by
treatment with an appropriate acid into the free acid form.
[0077] The term "salts" also comprises the hydrates and the solvent
addition forms that the compounds of the present invention are able
to form. Examples of such forms are e.g. hydrates, alcoholates and
the like.
[0078] The term "quaternary ammonium salt" as used herein defines
the quaternary ammonium salts which the compounds of formula (I)
are able to form by reaction between a basic nitrogen of a compound
of formula (I) and an appropriate quaternizing agent, such as, for
example, an optionally substituted alkyl halide, aryl halide or
arylalkyl halide, e.g. methyliodide or benzyliodide. Other
reactants with good leaving groups may also be used, such as alkyl
trifluoromethane sulfonates, alkyl methane sulfonates, and alkyl
p-toluenesulfonates. A quaternary amine has a positively charged
nitrogen. Pharmaceutically acceptable counterions include chloro,
bromo, iodo, trifluoroacetate and acetate. The counterion of choice
can be introduced using ion exchange resins.
[0079] Particular quaternary ammonium salts are those derived from
the groups --NR.sup.7R.sup.8, --NR.sup.9R.sup.10,
--N(R.sup.5aR.sup.5b), pyrrolidin-1-yl, piperidin-1-yl,
homopiperidin-1-yl, 4-(C.sub.1-4alkyl)-piperazin-1-yl,
morpholin-4-yl-, NR.sup.16aR.sup.16b; or NR.sup.17aR.sup.17b. These
quaternized groups can be represented by the formulae
--(NR.sup.7R.sup.8R.sup.8a).sup.+,
--(NR.sup.9R.sup.10R.sup.8a).sup.+,
--(NR.sup.5aR.sup.5bR.sup.8a).sup.+,
--(NR.sup.16aR.sup.16bR.sup.8a).sup.+;
--(NR.sup.17aR.sup.17bR.sup.8a).sup.+,
##STR00008##
wherein each R.sup.8a independently is C.sub.1-6alkyl,
arylC.sub.1-6alkyl or hydroxyC.sub.1-6alkyl, in particular each
R.sup.8a independently is C.sub.1-6alkyl or arylC.sub.1-6alkyl.
[0080] The N-oxide forms of the present compounds are meant to
comprise the compounds of formula (I) wherein one or several
nitrogen atoms are oxidized to the so-called N-oxide.
[0081] Some of the present compounds may also exist in tautomeric
forms. Such forms, although not explicitly indicated in the above
formula are intended to be included within the scope of the present
invention. For example, within the definition of Het, a 5 membered
aromatic heterocycle such as for example an 1,2,4-oxadiazole may be
substituted with a hydroxy or a thio group in the 5-position, thus
being in equilibrium with its respective tautomeric form as
depicted below.
##STR00009##
[0082] The term stereochemically isomeric forms of compounds of the
present invention, as used hereinbefore, defines all possible
compounds made up of the same atoms bonded by the same sequence of
bonds but having different three-dimensional structures which are
not interchangeable, which the compounds of the present invention
may possess. Unless otherwise mentioned or indicated, the chemical
designation of a compound encompasses the mixture of all possible
stereochemically isomeric forms which said compound may possess.
Said mixture may contain all diastereomers and/or enantiomers of
the basic molecular structure of said compound. All
stereochemically isomeric forms of the compounds of the present
invention both in pure form or in admixture with each other are
intended to be embraced within the scope of the present
invention.
[0083] Pure stereoisomeric forms of the compounds and intermediates
as mentioned herein are defined as isomers substantially free of
other enantiomeric or diastereomeric forms of the same basic
molecular structure of said compounds or intermediates. In
particular, the term `stereoisomerically pure` concerns compounds
or intermediates having a stereoisomeric excess of at least 80%
(i.e. minimum 90% of one isomer and maximum 10% of the other
possible isomers) up to a stereoisomeric excess of 100% (i.e. 100%
of one isomer and none of the other), more in particular, compounds
or intermediates having a stereoisomeric excess of 90% up to 100%,
even more in particular having a stereoisomeric excess of 94% up to
100% and most in particular having a stereoisomeric excess of 97%
up to 100%. The terms `enantiomerically pure` and
`diastereomerically pure` should be understood in a similar way,
but then having regard to the enantiomeric excess, respectively the
diastereomeric excess of the mixture in question.
[0084] Pure stereoisomeric forms of the compounds and intermediates
of this invention may be obtained by the application of art-known
procedures. For instance, enantiomers may be separated from each
other by the selective crystallization of their diastereomeric
salts with optically active acids or bases. Examples thereof are
tartaric acid, dibenzoyl-tartaric acid, ditoluoyltartaric acid and
camphosulfonic acid. Alternatively, enantiomers may be separated by
chromatographic techniques using chiral stationary phases. Said
pure stereochemically isomeric forms may also be derived from the
corresponding pure stereochemically isomeric forms of the
appropriate starting materials, provided that the reaction occurs
stereospecifically. Preferably, if a specific stereoisomer is
desired, said compound are synthesized by stereospecific methods of
preparation. These methods may advantageously employ
enantiomerically pure starting materials.
[0085] The diastereomeric racemates of formula (I) can be obtained
separately by conventional methods. Appropriate physical separation
methods that may advantageously be employed are, for example,
selective crystallization and chromatography, e.g. column
chromatography.
[0086] The present invention is also intended to include all
isotopes of atoms occurring on the present compounds. Isotopes
include those atoms having the same atomic number but different
mass numbers. By way of general example and without limitation,
isotopes of hydrogen include tritium and deuterium. Isotopes of
carbon include C-13 and C-14.
[0087] Whenever used hereinafter, the term "compounds of formula
(I)", or "the present compounds" or similar term is meant to
include the compounds of general formula (I), their N-oxides,
salts, stereoisomeric forms, racemic mixtures, prodrugs, esters and
metabolites, as well as their quaternized nitrogen analogues. One
embodiment of the invention are the subgroups comprising the
N-oxides of the compounds of formula (I) or of any subgroup of the
compounds of formula (I) specified herein, including any salts or
stereoisomeric forms thereof.
[0088] It is to be understood that any of the subgroups of
compounds of formulae (I) is meant to also comprise any prodrugs,
N-oxides, addition salts, quaternary amines and stereochemically
isomeric forms of such compounds.
[0089] Embodiments of the present invention are those compounds of
formula (I) or any of the subgroups of compounds of formula (I)
specified herein, wherein [0090] (1) n is 1 or 2; or wherein:
[0091] (1-a) n is 1.
[0092] Further embodiments of the present invention are those
compounds of formula (I) or any of the subgroups of compounds of
formula (I) specified herein, wherein [0093] (2) R.sup.1 is
hydrogen, cyano, halo, aminocarbonyl, C.sub.1-4alkylaminocarbonyl,
hydroxycarbonyl, C.sub.1-4alkyloxycarbonyl, arylaminocarbonyl,
N-hydroxy-methanimidamidyl, mono- or
di(C.sub.1-4alkyl)methanimidamidyl, Het.sub.1 or Het.sub.2; [0094]
(2-a) R.sup.1 is hydrogen, cyano, halo, aminocarbonyl,
C.sub.1-4alkylaminocarbonyl, arylamino-carbonyl,
C.sub.1-4alkyloxycarbonyl, N-hydroxy-methanimidamidyl, Het, or
pyridinyl; [0095] (2-b) R.sup.1 is hydrogen, cyano, halo,
aminocarbonyl, C.sub.1-4alkylaminocarbonyl, arylamino-carbonyl,
C.sub.1-4alkyloxycarbonyl, N-hydroxy-methanimidamidyl, pyridinyl,
furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl,
isoxazolyl, isothiazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl,
triazolyl, tetrazolyl, each of which individually and independently
may be optionally substituted with a substituent selected from the
group consisting of C.sub.1-4alkyl, C.sub.1-6alkenyl,
C.sub.3-7cycloalkyl, hydroxy, C.sub.1-4alkoxy, halo, amino, cyano,
trifluoromethyl, hydroxyC.sub.1-4alkyl, cyanoC.sub.1-4alkyl, mono-
or di(C.sub.1-4alkyl)amino, aminoC.sub.1-4alkyl, mono- or
di(C.sub.1-4alkyl)aminoC.sub.1-4alkyl, arylC.sub.1-4alkyl,
aminoC.sub.2-6alkenyl, mono- or
di(C.sub.1-4alkyl)aminoC.sub.2-6alkenyl, furanyl, thienyl,
pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl,
isothiazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl,
tetrazolyl, aryl, hydroxycarbonyl, aminocarbonyl,
C.sub.1-4alkyloxycarbonyl, mono- or
di(C.sub.1-4alkyl)aminocarbonyl, C.sub.1-4alkylcarbonyl, oxo, thio;
and wherein any of the foregoing furanyl, thienyl, pyrrolyl,
oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl,
pyrazolyl, oxadiazolyl, thiadiazolyl and triazolyl moieties may
optionally be substituted with C.sub.1-4alkyl; [0096] (2-c) R.sup.1
is hydrogen, cyano, halo, aminocarbonyl,
C.sub.1-4alkylaminocarbonyl, arylamino-carbonyl,
C.sub.1-4alkyloxycarbonyl, N-hydroxy-methanimidamidyl, pyridinyl,
furanyl, thienyl, oxadiazolyl, tetrazolyl, wherein the latter four
may be optionally substituted with C.sub.1-4alkyl,
C.sub.2-6alkenyl, C.sub.3-7cycloalkyl, hydroxy, C.sub.1-4alkoxy,
halo, amino, cyano, trifluoromethyl, hydroxyC.sub.1-4alkyl,
cyanoC.sub.1-4alkyl, mono- or di(C.sub.1-4alkyl)amino,
aminoC.sub.1-4alkyl, mono- or
di(C.sub.1-4alkyl)aminoC.sub.1-4alkyl, arylC.sub.1-4alkyl,
aminoC.sub.2-6alkenyl, mono- or
di(C.sub.1-4alkyl)aminoC.sub.2-6alkenyl, aryl, hydroxycarbonyl,
aminocarbonyl, C.sub.1-4alkyloxycarbonyl, mono- or
di(C.sub.1-4alkyl)-aminocarbonyl, C.sub.1-4alkylcarbonyl, oxo,
thio; [0097] (2-d) R.sup.1 is hydrogen, cyano, bromo, tetrazolyl or
oxadiazolyl optionally substituted with a substituent selected from
the group consisting of C.sub.1-4alkyl, C.sub.2-6alkenyl,
C.sub.3-7cycloalkyl, hydroxy, C.sub.1-4alkoxy, amino, cyano,
trifluoromethyl, hydroxyl-C.sub.1-4alkyl, cyanoC.sub.1-4alkyl,
mono- or di(C.sub.1-4alkyl)amino, aminoC.sub.1-4alkyl, mono- or
di(C.sub.1-4alkyl)aminoC.sub.1-4alkyl, arylC.sub.1-4alkyl,
aminoC.sub.2-6alkenyl, mono- or
di(C.sub.1-4alkyl)aminoC.sub.2-6alkenyl, furanyl, thienyl,
pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl,
isothiazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl,
tetrazolyl, aryl, hydroxycarbonyl, aminocarbonyl,
C.sub.1-4alkyloxycarbonyl, mono- or
di(C.sub.1-4alkyl)aminocarbonyl, C.sub.1-4alkylcarbonyl, oxo, thio;
[0098] (2-e) R.sup.1 is hydrogen, cyano, halo, aminocarbonyl,
C.sub.1-4alkylaminocarbonyl, arylamino-carbonyl,
C.sub.1-4alkyloxycarbonyl, N-hydroxy-methanimidamidyl, pyridinyl,
furanyl, tetrazolyl, oxadiazolyl, wherein the latter may be
optionally substituted with C.sub.1-4alkyl, halo, amino, cyano,
trifluoromethyl, hydroxyC.sub.1-4alkyl, cyano-C.sub.1-4alkyl,
aminoC.sub.1-4alkyl, mono- or
di(C.sub.1-4alkyl)aminoC.sub.1-4alkyl, arylC.sub.1-4alkyl,
aminoC.sub.2-6alkenyl, mono- or
di(C.sub.1-4alkyl)aminoC.sub.2-6alkenyl, oxo, thio; [0099] (2-f)
R.sup.1 is hydrogen, cyano, halo, aminocarbonyl,
C.sub.1-4alkylaminocarbonyl, arylaminocarbonyl,
C.sub.1-4alkyloxycarbonyl, N-hydroxy-methanimidamidyl, pyridinyl,
furanyl, tetrazolyl, oxadiazolyl, wherein the latter may be
optionally substituted with C.sub.1-4alkyl, trifluoromethyl,
aminoC.sub.2-6alkenyl, mono- or
di(C.sub.1-4alkyl)aminoC.sub.2-6alkenyl, oxo, thio; [0100] (2-g)
R.sup.1 is cyano, aminocarbonyl, C.sub.1-4alkylaminocarbonyl;
[0101] (2-h) R.sup.1 is cyano, methyloxycarbonyl,
methylaminocarbonyl, ethyloxycarbonyl or ethylaminocarbonyl; or
[0102] (2-i) R.sup.1 is cyano and ethylaminocarbonyl; or [0103]
(2-j) R.sup.1 is cyano.
[0104] Further embodiments of the present invention are those
compounds of formula (I) or any of the subgroups of compounds of
formula (I) specified herein, wherein: [0105] (3) X is O or S; or
[0106] (3-a) X is O;
[0107] Further embodiments of the present invention are those
compounds of formula (I) or any of the subgroups of compounds of
formula (I) specified herein, wherein. [0108] (4) X is NR.sup.2,
wherein R.sup.2 is hydrogen, C.sub.1-10alkyl, C.sub.2-10alkenyl,
C.sub.3-7cycloalkyl, wherein said C.sub.1-10alkyl,
C.sub.2-10alkenyl and C.sub.3-7cycloalkyl, each individually and
independently, may be optionally substituted with a substituent
selected from the group consisting of cyano, N(R.sup.16aR.sup.16b),
pyrrolidinyl, piperidinyl, homopiperidinyl, piperazinyl,
4-(C.sub.1-4alkyl)-piperazinyl, morpholinyl, thiomorpholinyl,
1-oxothiomorpholinyl, 1,1-dioxo-thiomorpholinyl, aryl, furanyl,
thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl,
isothiazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl,
tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl,
triazinyl, hydroxycarbonyl, C.sub.1-4alkylcarbonyl,
N(R.sup.16aR.sup.16b)carbonyl, C.sub.1-4alkyloxycarbonyl,
pyrrolidin-1-ylcarbonyl, piperidin-1-yl-carbonyl,
homopiperidin-1-ylcarbonyl, piperazin-1-ylcarbonyl,
4-(C.sub.1-4alkyl)-piperazin-1-ylcarbonyl, morpholin-1-ylcarbonyl,
thiomorpholin-1-ylcarbonyl, 1-oxothiomorpholin-1-ylcarbonyl and
1,1-dioxo-thiomorpholin-1-ylcarbonyl; or wherein R.sup.2 is aryl
substituted with a radical --COOR.sup.4; or [0109] R.sup.2 is
C.sub.1-10alkyl, C.sub.2-10alkenyl, C.sub.3-7cycloalkyl, wherein
said C.sub.1-10alkyl, C.sub.2-10alkenyl, C.sub.3-7cycloalkyl, each
individually and independently, is substituted with aryl wherein
said aryl is substituted with a radical --COOR.sup.4; or [0110]
wherein said C.sub.1-10alkyl, C.sub.2-10alkenyl,
C.sub.3-7cycloalkyl, each individually and independently, is
substituted with a radical selected from [0111]
NR.sup.5a--C(.dbd.NR.sup.5b)NR.sup.5cR.sup.5d,
--NR.sup.5a--C(.dbd.NR.sup.5e)--R.sup.5f--O--NR.sup.5a--C(.dbd.NR.sup.5b)-
--NR.sup.5cR.sup.5d, O--NR.sup.5a--C(.dbd.NR.sup.5e)--R.sup.5f,
-sulfonyl-R.sup.6, --NR.sup.7R.sup.8, --NR.sup.9R.sup.10, a
radical
[0111] ##STR00010## [0112] wherein [0113] each Q.sup.1
independently is a direct bond, --CH.sub.2--, or
--CH.sub.2--CH.sub.2--; [0114] each R.sup.4 independently is
hydrogen, C.sub.1-4alkyl, arylC.sub.1-4alkyl; [0115] each R.sup.5a,
R.sup.5b, R.sup.5c, R.sup.5d independently is hydrogen,
C.sub.1-4alkyl or arylC.sub.1-4alkyl; [0116] each R.sup.5e,
R.sup.5f independently is hydrogen, C.sub.1-4alkyl or
arylC.sub.1-4alkyl, or R.sup.5e and R.sup.5f, taken together may
form a bivalent alkylene radical of formula --CH.sub.2--CH.sub.2--
or --CH.sub.2--CH.sub.2--CH.sub.2--; [0117] R.sup.6 is
C.sub.1-4alkyl, --N(R.sup.5aR.sup.5b), C.sub.1-4alkyloxy,
pyrrolidin-1-yl, piperidin-1-yl, homopiperidin-1-yl,
piperazin-1-yl, 4-(C.sub.1-4alkyl)-piperazin-1-yl, morpholin-4-yl-,
thiomorpholinyl-, 1-oxothiomorpholin-4-yl and
1,1-dioxo-thiomorpholin-4-yl; [0118] R.sup.7 is hydrogen or
hydroxyC.sub.1-4alkyl; [0119] R.sup.8 is hydroxyC.sub.1-4alkyl;
[0120] R.sup.9 is hydrogen or C.sub.1-4alkyl; [0121] R.sup.10 is
Het.sub.1, Het.sub.2 or a radical
[0121] ##STR00011## [0122] R.sup.11 is aryl, arylC.sub.1-4alkyl,
formyl, C.sub.1-4alkylcarbonyl, arylcarbonyl,
arylC.sub.1-4alkyl-carbonyl, C.sub.1-4alkyloxycarbonyl,
arylC.sub.1-4alkyloxycarbonyl, R.sup.5aR.sup.5bN-carbonyl,
hydroxyC.sub.1-4alkyl, C.sub.1-4alkyloxyC.sub.1-4alkyl,
arylC.sub.1-4alkyloxyC.sub.1-4alkyl, aryloxyC.sub.1-4alkyl,
Het.sub.2; [0123] R.sup.12 is hydroxy, C.sub.1-4alkyl,
arylC.sub.1-4alkyl, C.sub.1-4alkyloxy, arylC.sub.1-4alkyloxy, oxo,
spiro(C.sub.2-4alkylenedioxy), spiro(diC.sub.1-4alkyloxy),
--NR.sup.5aR.sup.5b; [0124] R.sup.13 is hydrogen, hydroxy,
C.sub.1-4alkyl, C.sub.1-4alkyloxy, or arylC.sub.1-4alkyloxy; or
[0125] R.sup.2 is a radical of formula:
[0125] ##STR00012##
--C.sub.pH.sub.2p--CH(OR.sup.14)--C.sub.qH.sub.2q--R.sup.15
(b-3);
--CH.sub.2CH.sub.2--(O--CH.sub.2--CH.sub.2).sub.m--OR.sup.14
(b-4);
--CH.sub.2--CH.sub.2--(O--CH.sub.2--CH.sub.2).sub.m--NR.sup.5aR.sup.5b
(b-5); [0126] wherein in radical (b-3) one of the hydrogen atoms in
--C.sub.pH.sub.2p-- and one of the hydrogen atoms in
--CH(OR.sup.14)--C.sub.qH.sub.2q--, that is not part of R.sup.14,
may be replaced by a direct bond or a C.sub.1-4alkanediyl group;
[0127] p is 1, 2 or 3; [0128] q is 0, 1, 2 or 3; [0129] m is 1 to
10; [0130] each R.sup.14 independently is hydrogen, C.sub.1-4alkyl,
aryl C.sub.1-4alkyl, aryl, C.sub.1-4alkyl-carbonyl, --SO.sub.3H,
--PO.sub.3H.sub.2; [0131] R.sup.15 is a substituent selected from
the group consisting of cyano, NR.sup.16aR.sup.16b, pyrrolidinyl,
piperidinyl, homopiperidinyl, piperazinyl,
4-(C.sub.1-4alkyl)-piperazinyl, morpholinyl, thiomorpholinyl,
1-oxothiomorpholinyl, 1,1-dioxo-thiomorpholinyl, aryl, furanyl,
thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl,
isothiazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl,
tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl,
triazinyl, hydroxy-carbonyl, C.sub.1-4alkylcarbonyl,
N(R.sup.16aR.sup.16b)carbonyl, C.sub.1-4alkyloxy-carbonyl,
pyrrolidin-1-ylcarbonyl, piperidin-1-ylcarbonyl,
homopiperidin-1-ylcarbonyl, piperazin-1-ylcarbonyl,
4-(C.sub.1-4alkyl)-piperazin-1-ylcarbonyl, morpholin-1-yl-carbonyl,
thiomorpholin-1-yl-carbonyl, 1-oxothiomorpholin-1-ylcarbonyl and
1,1-dioxo-thiomorpholin-1-ylcarbonyl; and wherein R.sup.15 may
additionally be aryl substituted with a radical --COOR.sup.4; or a
radical selected from
--NR.sup.5a--C(--NR.sup.5b)--NR.sup.5cR.sup.5d,
--NR.sup.5a--C(.dbd.NR.sup.5e)--R.sup.5f--,
O--NR.sup.5a--C(.dbd.NR.sup.5b)--NR.sup.5cR.sup.5d,
--O--NR.sup.5a--C(.dbd.NR.sup.5e)--R.sup.5f, -sulfonyl-R.sup.6,
--NR.sup.7R.sup.8, --NR.sup.9R.sup.10, a radical (a-1), (a-2),
(a-3); wherein R.sup.4, R.sup.5a, R.sup.5b, R.sup.5c, R.sup.5d,
R.sup.6, R.sup.7, R.sup.8, R.sup.9, R.sup.10, and the radicals
(a-1), (a-2), (a-3) independently are as defined above; [0132]
R.sup.16a is hydrogen, C.sub.1-4alkyl or C.sub.1-4alkyl substituted
with a substituent selected from the group consisting of amino,
mono- or di(C.sub.1-4alkyl)amino, pyrrolidinyl, piperidinyl,
homopiperidinyl, piperazinyl, 4-(C.sub.1-4alkyl)-piperazinyl,
morpholinyl, thiomorpholinyl, 1-oxothiomorpholinyl and
1,1-dioxo-thiomorpholinyl; [0133] R.sup.16b is hydrogen,
C.sub.1-4alkyl or C.sub.1-4alkyl substituted with a substituent
selected from the group consisting of amino, mono- or
di(C.sub.1-4alkyl)amino, pyrrolidinyl, piperidinyl,
homopiperidinyl, piperazinyl, 4-(C.sub.1-4alkyl)-piperazinyl,
morpholinyl, thiomorpholinyl, 1-oxothiomorpholinyl and
1,1-dioxo-thiomorpholinyl; [0134] each R.sup.18 independently is
hydrogen, C.sub.1-4alkyl or arylC.sub.1-4alkyl; [0135] R.sup.19 is
hydrogen, hydroxy, C.sub.1-4alkyl or a radical --COOR.sup.4; or
wherein [0136] (4-a) X is NR.sup.2 wherein R.sup.2 is
C.sub.1-10alkyl, C.sub.2-10alkenyl, C.sub.3-7cycloalkyl, each of
the former three radicals being independently substituted with
aryl, wherein said aryl is substituted with a radical --COOR.sup.4;
or [0137] (4-a-1) X is NR.sup.2 wherein R.sup.2 is C.sub.1-10alkyl
being substituted with aryl, wherein said aryl is substituted with
a radical --COOR.sup.4; or [0138] (4-a-2) X is NR.sup.2 wherein
R.sup.2 is C.sub.1-6alkyl being substituted with phenyl substituted
with a radical --COOR.sup.4; or [0139] (4-a-3) X is NR.sup.2
wherein R.sup.2 is C.sub.1-6alkyl being substituted with phenyl
substituted in para position with a radical --COOR.sup.4; or
wherein [0140] (4-b) X is NR.sup.2 wherein R.sup.2 is
C.sub.1-10alkyl, C.sub.2-10alkenyl, C.sub.3-7cycloalkyl, each of
the former three radicals being independently substituted with a
radical selected from
--NR.sup.5a--C(.dbd.NR.sup.5b)--NR.sup.5cR.sup.5d,
--O--NR.sup.5a--C(.dbd.NR.sup.5b)--NR.sup.5cR.sup.5d,
-sulfonyl-R.sup.6, --NR.sup.7R.sup.8, --NR.sup.9R.sup.10, a radical
(a-1), (a-2), (a-3), (a-4) and (a-5); [0141] (4-b-1) X is NR.sup.2
wherein R.sup.2 is C.sub.1-10alkyl substituted with a radical
selected from --NR.sup.5a--C(.dbd.NR.sup.5b)--NR.sup.5cR.sup.5d,
--NR.sup.5a--C(.dbd.NR.sup.5b)--NR.sup.5cR.sup.5d,
-sulfonyl-R.sup.6, --NR.sup.7R.sup.8, --NR.sup.9R.sup.10, a radical
(a-1), (a-2), (a-3), (a-4) and (a-5); [0142] (4-b-2) X is NR.sup.2
wherein R.sup.2 is C.sub.1-10alkyl substituted with a radical
selected from --NR.sup.5a--C(.dbd.NR.sup.5b)--NR.sup.5cR.sup.5d,
--O--NR.sup.5a--C(.dbd.NR.sup.5b)--NR.sup.5cR.sup.5d,
-sulfonyl-R.sup.6, --NR.sup.7R.sup.8, --NR.sup.9R.sup.10, a radical
(a-1), (a-2) and (a-3); [0143] (4-b-3) X is NR.sup.2 wherein
R.sup.2 is C.sub.1-6alkyl substituted with the radicals mentioned
in (4-b-1) or in (4-b-2); [0144] (4-b-4) X is NR.sup.2, wherein
R.sup.2 is C.sub.1-6alkyl substituted with a radical selected from
--NR.sup.5a--C(.dbd.NR.sup.5b)--NR.sup.5cR.sup.5d,
--NR.sup.7R.sup.8, --NR.sup.9R.sup.10, a radical (a-1), (a-2),
(a-3), (a-4) and (a-5); [0145] (4-b-5) X is NR.sup.2, wherein
R.sup.2 is C.sub.1-6alkyl substituted with a radical selected from
--NR.sup.5a--C(.dbd.NR.sup.5b)--NR.sup.5cR.sup.5d,
--NR.sup.7R.sup.8, --NR.sup.9R.sup.10, a radical (a-1), (a-2),
(a-3); [0146] (4-c) X is NR.sup.2 wherein R.sup.2 is a radical
(b-1); [0147] (4-c-1) X is NR.sup.2 wherein R.sup.2 is a radical
(b-1), wherein R.sup.19 is hydrogen or --COOR.sup.4 and wherein
Q.sup.1 in radical (b-1) is a direct bond or --CH.sub.2--; [0148]
(4-d) X is NR.sup.2 wherein R.sup.2 is a radical (b-2); [0149]
(4-d-1) X is NR.sup.2 wherein R.sup.2 is a radical (b-2), wherein
Q.sup.2 is O; [0150] (4-e) X is NR.sup.2 wherein R.sup.2 is a
radical (b-3) wherein q is 1, 2 or 3; [0151] (4-e-1) X is NR.sup.2
wherein R.sup.2 is a radical (b-3) wherein p is 1 and q is 1;
[0152] (4-e-2) X is NR.sup.2 wherein R.sup.2 is a radical (b-3)
wherein R.sup.15 is cyano, NR.sup.16aR.sup.16b, pyrrolidinyl,
piperidinyl, 4-(C.sub.1-4alkyl)-piperazinyl, morpholinyl, aryl,
imidazolyl, pyridyl, hydroxycarbonyl,
N(R.sup.16aR.sup.16b)carbonyl, C.sub.1-4alkyloxy-carbonyl
4-(C.sub.1-4alkyl)-piperazin-1-ylcarbonyl, --NR.sup.7R.sup.8,
--NR.sup.9R.sup.10, a radical (a-1), (a-2), (a-3), (a-4) or (a-5);
[0153] (4-e-3) X is NR.sup.2 wherein R.sup.2 is a radical (b-3)
wherein R.sup.14 is hydrogen and R.sup.15 is cyano,
NR.sup.16aR.sup.16b, pyrrolidinyl, piperidinyl,
4-(C.sub.1-4alkyl)-piperazinyl, morpholinyl, aryl, imidazolyl,
pyridyl, hydroxycarbonyl, N(R.sup.16aR.sup.16b)carbonyl,
C.sub.1-4alkyloxycarbonyl or
4-(C.sub.1-4alkyl)-piperazin-1-ylcarbonyl; [0154] (4-e-4) X is
NR.sup.2 wherein R.sup.2 is a radical (b-3) wherein p is 1 and q is
1, and R.sup.15 is cyano, NR.sup.16aR.sup.16b, pyrrolidinyl,
piperidinyl, 4-morpholinyl, aryl, imidazolyl, pyridyl,
hydroxycarbonyl or N(R.sup.16aR.sup.6b)carbonyl; [0155] (4-e-5) X
is NR.sup.2 wherein R.sup.2 is a radical (b-3) R.sup.15 is
NR.sup.16aR.sup.16b, pyrrolidinyl, piperidinyl, 4-morpholinyl;
[0156] (4-e-6) X is NR.sup.2 wherein R.sup.2 is a radical (b-3)
wherein R.sup.15 is pyrrolidinyl, piperidinyl, 4-morpholinyl;
[0157] (4-e-6) X is NR.sup.2 wherein R.sup.2 is a radical (b-3)
wherein R.sup.15 is pyrrolidinyl; [0158] (4-f) X is NR.sup.2
wherein R.sup.2 is a radical (b-4) wherein m is 1-6; [0159] (4-f-1)
X is NR.sup.2 wherein R.sup.2 is a radical (b-4) wherein R.sup.14
is hydrogen or C.sub.1-4alkyl; [0160] (4-f-2) X is NR.sup.2 wherein
R.sup.2 is a radical (b-4) wherein m is 1-5 and R.sup.14 is
hydrogen or C.sub.1-4alkyl; [0161] (4-g) X is NR.sup.2 wherein
R.sup.2 is a radical (b-5); [0162] (4-g-1) X is NR.sup.2 wherein
R.sup.2 is a radical (b-5) wherein m is 1-5. [0163] (4-h) X is
NR.sup.2, wherein R.sup.2 is hydrogen, C.sub.1-10alkyl, which may
be optionally substituted with a substituent selected from the
group consisting of cyano, N(R.sup.16aR.sup.16b), pyrrolidinyl,
piperidinyl, homopiperidinyl, piperazinyl,
4-(C.sub.1-4alkyl)-piperazinyl, morpholinyl, thiomorpholinyl,
1-oxothio-morpholinyl, 1,1-dioxo-thiomorpholinyl, aryl, furanyl,
thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl,
isothiazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl,
tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl,
triazinyl, hydroxycarbonyl, C.sub.1-4alkylcarbonyl,
N(R.sup.16aR.sup.16b)carbonyl, C.sub.1-4alkyloxycarbonyl,
pyrrolidin-1-ylcarbonyl, piperidin-1-ylcarbonyl,
homopiperidin-1-ylcarbonyl, piperazin-1-ylcarbonyl,
4-(C.sub.1-4alkyl)-piperazin-1-ylcarbonyl, morpholin-1-ylcarbonyl,
thiomorpholin-1-ylcarbonyl, 1-oxothiomorpholin-1-ylcarbonyl and
1,1-dioxo-thiomorpholin-1-ylcarbonyl; [0164] (4-h-1) X is NR.sup.2,
wherein R.sup.2 is hydrogen, C.sub.1-10alkyl, which may be
optionally substituted with cyano, N(R.sup.16aR.sup.16b),
pyrrolidinyl, piperidinyl, homopiperidinyl, piperazinyl,
4-(C.sub.1-4alkyl)-piperazinyl, morpholinyl, thiomorpholinyl,
1-oxothiomorpholinyl, 1,1-dioxo-thiomorpholinyl, aryl, furanyl,
thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridyl,
pyrimidinyl, hydroxy-carbonyl, C.sub.1-4alkylcarbonyl,
N(R.sup.16aR.sup.16b)carbonyl, C.sub.1-4alkyloxycarbonyl,
pyrrolidin-1-ylcarbonyl, piperidin-1-ylcarbonyl,
homopiperidin-1-ylcarbonyl, piperazin-1-ylcarbonyl,
4-(C.sub.1-4alkyl)-piperazin-1-ylcarbonyl, morpholin-1-yl-carbonyl,
thiomorpholin-1-ylcarbonyl; [0165] (4-h-2) X is NR.sup.2, wherein
R.sup.2 is hydrogen, C.sub.1-10alkyl, which may be optionally
substituted with cyano, N(R.sup.16aR.sup.16b), pyrrolidinyl,
piperidinyl, homopiperidinyl, piperazinyl,
4-(C.sub.1-4alkyl)-piperazinyl, morpholinyl, thiomorpholinyl,
1-oxothiomorpholinyl, 1,1-dioxo-thiomorpholinyl, aryl, pyridyl,
pyrimidinyl, hydroxycarbonyl, C.sub.1-4alkylcarbonyl,
N(R.sup.16aR.sup.16b)carbonyl, C.sub.1-4alkyloxy-carbonyl; [0166]
(4-h-3) X is NR.sup.2, wherein R.sup.2 is hydrogen, C.sub.1-6alkyl,
which may be optionally substituted with cyano,
N(R.sup.16aR.sup.16b), pyrrolidinyl, piperidinyl, homopiperidinyl,
piperazinyl, 4-(C.sub.1-4alkyl)-piperazinyl, morpholinyl,
thiomorpholinyl, aryl, hydroxycarbonyl, C.sub.1-4alkylcarbonyl;
[0167] (4-h-4) X is NR.sup.2, wherein R.sup.2 is hydrogen,
C.sub.1-6alkyl, which may be optionally substituted with
N(R.sup.16aR.sup.16b), pyrrolidinyl, piperidinyl, homopiperidinyl,
piperazinyl, 4-(C.sub.1-4alkyl)-piperazinyl, morpholinyl,
thiomorpholinyl; [0168] (4-h-5) X is NR.sup.2 wherein R.sup.2 is
C.sub.1-6alkyl, which may be optionally substituted with
N(R.sup.16aR.sup.16b), pyrrolidinyl, piperidinyl; [0169] (4-h-6) X
is NR.sup.2, wherein R.sup.2 is C.sub.1-6alkyl, which may be
optionally substituted with N(R.sup.16aR.sup.16b),
pyrrolidinyl.
[0170] Further embodiments of the present invention are those
compounds of formula (I) or any of the subgroups of compounds of
formula (I) specified herein, wherein [0171] (5) R.sup.3 is
hydrogen, nitro, cyano, amino, halo, hydroxy, C.sub.1-4alkyloxy,
C.sub.1-4alkyl, hydroxycarbonyl, aminocarbonyl, mono- or
di(C.sub.1-4alkyl)aminocarbonyl, aminothiocarbonyl,
C.sub.1-4alkyloxycarbonyl, C.sub.1-4alkylcarbonyl, mono- or
di(C.sub.1-4alkyl)methanimidamidyl, N-hydroxy-methanimidamidyl or
Het.sub.1; [0172] (5-a) R.sup.3 is nitro, cyano, amino, halo,
hydroxy, C.sub.1-4alkyloxy, C.sub.1-4alkyl, hydroxy-carbonyl,
aminocarbonyl, di(C.sub.1-4alkyl)aminocarbonyl,
C.sub.1-4alkyloxycarbonyl, mono- or
di(C.sub.1-4alkyl)methanimidamidyl, N-hydroxy-methanimidamidyl or
Het.sub.1; [0173] (5-b) R.sup.3 is nitro, cyano, halo,
C.sub.1-4alkyloxy, hydroxycarbonyl, aminocarbonyl, mono- or
di(C.sub.1-4alkyl)methanimidamidyl, N-hydroxy-methanimidamidyl or
Het.sub.1; [0174] (5-c) R.sup.3 is nitro, cyano, halo,
C.sub.1-4alkyloxy, hydroxycarbonyl, aminocarbonyl, mono- or
di(C.sub.1-4alkyl)methanimidamidyl, N-hydroxy-methanimidamidyl,
furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl,
isoxazolyl, isothiazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl,
triazolyl, tetrazolyl wherein each of said furanyl, thienyl,
pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl,
isothiazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl,
tetrazolyl may optionally be substituted with one or two
substituents selected from the group consisting of C.sub.1-4alkyl,
C.sub.2-6alkenyl, C.sub.3-7cycloalkyl, hydroxy, C.sub.1-4alkoxy,
amino, cyano, trifluoromethyl, hydroxyC.sub.1-4alkyl,
cyanoC.sub.1-4alkyl, mono- or di(C.sub.1-4alkyl)amino,
aminoC.sub.1-4alkyl, mono- or
di(C.sub.1-4alkyl)aminoC.sub.1-4alkyl, arylC.sub.1-4alkyl,
aminoC.sub.2-6alkenyl, mono- or
di(C.sub.1-4alkyl)aminoC.sub.2-6alkenyl, furanyl, thienyl,
pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl,
isothiazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl,
tetrazolyl, aryl, hydroxycarbonyl, aminocarbonyl,
C.sub.1-4alkyloxycarbonyl, mono- or
di(C.sub.1-4alkyl)aminocarbonyl, C.sub.1-4alkylcarbonyl, oxo, thio;
and wherein any of the foregoing furanyl, thienyl, pyrrolyl,
oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl,
pyrazolyl, oxadiazolyl, thiadiazolyl and triazolyl moieties may
optionally be substituted with C.sub.1-4alkyl. [0175] (5-d) R.sup.3
is nitro, cyano, halo, C.sub.1-4alkyloxy, hydroxycarbonyl,
aminocarbonyl, mono- or di(C.sub.1-4alkyl)methanimidamidyl,
N-hydroxy-methanimidamidyl, oxadiazolyl, thienyl, thiazolyl,
furanyl, isoxazolyl wherein each of said oxadiazolyl, thienyl,
thiazolyl, furanyl, isoxazolyl may be substituted with a
substituent selected from the group consisting of C.sub.1-4alkyl,
C.sub.2-6alkenyl, C.sub.3-7cycloalkyl, hydroxy, C.sub.1-4alkoxy,
amino, cyano, trifluoromethyl, hydroxyC.sub.1-4alkyl,
cyanoC.sub.1-4alkyl, mono- or di(C.sub.1-4alkyl)amino,
aminoC.sub.1-4alkyl, mono- or
di(C.sub.1-4alkyl)amino-C.sub.1-4alkyl, arylC.sub.1-4alkyl,
aminoC.sub.2-6alkenyl, mono- or
di(C.sub.1-4alkyl)amino-C.sub.2-6alkenyl, furanyl, thienyl,
pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl,
isothiazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl,
tetrazolyl, aryl, hydroxycarbonyl, aminocarbonyl,
C.sub.1-4alkyloxycarbonyl, mono- or
di(C.sub.1-4alkyl)aminocarbonyl, C.sub.1-4alkylcarbonyl, oxo, thio;
and wherein any of the foregoing furanyl, thienyl, pyrrolyl,
oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl,
pyrazolyl, oxadiazolyl, thiadiazolyl and triazolyl moieties may
optionally be substituted with C.sub.1-4alkyl. [0176] (5-e) R.sup.3
is nitro, cyano, halo, C.sub.1-4alkyloxy, hydroxycarbonyl,
aminocarbonyl, mono- or di(C.sub.1-4alkyl)methanimidamidyl,
N-hydroxy-methanimidamidyl, oxadiazolyl, isoxazolyl, thienyl,
pyrrolyl, triazolyl, thiazolyl, furanyl, isoxazolyl, tetrazolyl,
wherein each of said oxadiazolyl, isoxazolyl, thienyl, pyrrolyl,
triazolyl, thiazolyl, furanyl, isoxazolyl, tetrazolyl may
optionally be substituted with C.sub.1-4alkyl, C.sub.2-6alkenyl,
C.sub.3-7cycloalkyl, hydroxy, C.sub.1-4alkoxy, amino, cyano,
trifluoromethyl, hydroxyC.sub.1-4alkyl, cyanoC.sub.1-4alkyl, mono-
or di(C.sub.1-4alkyl)amino, aminoC.sub.1-4alkyl, mono- or
di(C.sub.1-4alkyl)aminoC.sub.1-4alkyl, arylC.sub.1-4alkyl,
amino-C.sub.2-6alkenyl, mono- or
di(C.sub.1-4alkyl)aminoC.sub.2-6alkenyl, furanyl, isoxazolyl,
C.sub.1-4alkyl substituted isoxazolyl, aryl, hydroxycarbonyl,
aminocarbonyl, C.sub.1-4alkyloxycarbonyl, mono- or
di(C.sub.1-4alkyl)aminocarbonyl, C.sub.1-4alkylcarbonyl, oxo, thio;
[0177] (5-f) R.sup.3 is nitro, cyano, halo, C.sub.1-4alkyloxy,
hydroxycarbonyl, aminocarbonyl, mono- or
di(C.sub.1-4alkyl)methanimidamidyl, N-hydroxy-methanimidamidyl,
oxadiazolyl, isoxazolyl, thienyl, pyrrolyl, triazolyl, thiazolyl,
furanyl, isoxazolyl, tetrazolyl, wherein each of said oxadiazolyl,
isoxazolyl, thienyl, pyrrolyl, triazolyl, thiazolyl, furanyl,
isoxazolyl, tetrazolyl may optionally be substituted with
C.sub.1-4alkyl, C.sub.3-7cycloalkyl, hydroxy, cyano,
trifluoromethyl, cyanoC.sub.1-4alkyl, mono- or
di(C.sub.1-4alkyl)amino, arylC.sub.1-4alkyl,
di(C.sub.1-4alkyl)aminoC.sub.2-6alkenyl, furanyl, isoxazolyl,
C.sub.1-4alkyl substituted isoxazolyl, aryl, hydroxycarbonyl,
aminocarbonyl, C.sub.1-4alkyloxycarbonyl, mono- or
di(C.sub.1-4alkyl)aminocarbonyl, C.sub.1-4alkylcarbonyl, oxo, thio;
[0178] (5-g) R.sup.3 is nitro, cyano, halo, C.sub.1-4alkyloxy,
hydroxycarbonyl, aminocarbonyl, mono- or
di(C.sub.1-4alkyl)methanimidamidyl, N-hydroxy-methanimidamidyl,
oxadiazolyl, isoxazolyl, thiazolyl, furanyl, isoxazolyl,
tetrazolyl, wherein each of said oxadiazolyl, isoxazolyl,
thiazolyl, furanyl, isoxazolyl, tetrazolyl may optionally be
substituted with C.sub.1-4alkyl, hydroxy, cyano, trifluoromethyl;
[0179] (5-h) R.sup.3 is nitro, cyano, halo, C.sub.1-4alkyloxy,
hydroxycarbonyl, aminocarbonyl [0180] (5-i) R.sup.3 is nitro;
[0181] (5-j) the R.sup.3 group on the phenyl ring is in the
position vis-a-vis the nitrogen atom in the fused pyridine
moiety.
[0182] Further embodiments of the present invention are those
compounds of formula (I) or any of the subgroups of compounds of
formula (I) specified herein, wherein: [0183] (6) R.sup.4 is
hydrogen or C.sub.1-4alkyl; or wherein [0184] (6-a) R.sup.4 is
hydrogen.
[0185] Further embodiments of the present invention are those
compounds of formula (I) or any of the subgroups of compounds of
formula (I) specified herein, wherein: [0186] (7) each R.sup.5a,
R.sup.5b, R.sup.5c, R.sup.5d, R.sup.5e and R.sup.5f independently
is hydrogen or C.sub.1-4alkyl; or R.sup.5e and R.sup.5f, taken
together may form a bivalent alkanediyl radical of formula
--CH.sub.2--CH.sub.2-- or --CH.sub.2--CH.sub.2--CH.sub.2--; [0187]
(7-a) each R.sup.5a, R.sup.5b, R.sup.5c, R.sup.5d, R.sup.5e and
R.sup.5f independently is hydrogen or C.sub.1-4alkyl; [0188] (7-b)
each R.sup.5a, R.sup.5b, R.sup.5c, R.sup.5d, R.sup.5e and R.sup.5f
independently is hydrogen.
[0189] Further embodiments of the present invention are those
compounds of formula (I) or any of the subgroups of compounds of
formula (I) specified herein, wherein: [0190] (8) R.sup.6 is
C.sub.1-4alkyl, --N(R.sup.5aR.sup.5b), C.sub.1-4alkyloxy,
pyrrolidin-1-yl, piperidin-1-yl, homopiperidin-1-yl,
piperazin-1-yl, 4-(C.sub.1-4alkyl)-piperazin-1-yl, morpholin-4-yl-;
[0191] (8-a) R.sup.6 is C.sub.1-4alkyl, --N(R.sup.5aR.sup.5b),
C.sub.1-4alkyloxy, pyrrolidin-1-yl, piperidin-1-yl,
morpholin-4-yl-; [0192] (8-b) R.sup.6 is C.sub.1-4alkyl,
N(R.sup.5aR.sup.5b), pyrrolidin-1-yl, piperidin-1-yl,
morpholin-4-yl-; wherein R.sup.5a and R.sup.5b independently are
hydrogen or C.sub.1-4alkyl.
[0193] Other embodiments of the present invention are those
compounds of formula (I) or any of the subgroups of compounds of
formula (I) specified herein, wherein one or more of the following
restrictions apply: [0194] (9-a) R.sup.7 is hydrogen or
hydroxyC.sub.1-4alkyl; [0195] (9-b) R.sup.8 is
hydroxyC.sub.1-4alkyl; [0196] (9-c) R.sup.9 is hydrogen.
[0197] Still other embodiments of the present invention are those
compounds of formula (I) or any of the subgroups of compounds of
formula (I) specified herein, wherein: [0198] (10) R.sup.10 is
Het.sub.1, pyridyl, pyrimidinyl or a radical (a-6); [0199] (10-a)
R.sup.10 is imidazolyl, isoxazolyl, pyrazolyl, triazolyl, each of
which may be optionally substituted with C.sub.1-4alkyl; or
R.sup.10 is pyrimidyl or pyrimidinyl or a radical (a-6); [0200]
(10-b) R.sup.10 is pyrimidyl, pyrimidinyl or a radical (a-6);
[0201] (10-c) R.sup.10 is a radical (a-6).
[0202] Still other embodiments of the present invention are those
compounds of formula (I) or any of the subgroups of compounds of
formula (I) specified herein, wherein: [0203] (11) R.sup.11 is
aryl, arylC.sub.1-4alkyl, formyl, C.sub.1-4alkylcarbonyl,
arylcarbonyl, C.sub.1-4alkyloxycarbonyl,
arylC.sub.1-4alkyloxycarbonyl, mono- and
diC.sub.1-4alkylaminocarbonyl, C.sub.1-4alkyloxyC.sub.1-4alkyl,
arylC.sub.1-4alkyloxyC.sub.1-4alkyl, pyridyl or pyrimidinyl; [0204]
(11-a) R.sup.11 is aryl, arylC.sub.1-4alkyl, formyl,
C.sub.1-4alkylcarbonyl, arylcarbonyl, C.sub.1-4alkyloxycarbonyl,
C.sub.1-4alkyloxyC.sub.1-4alkyl,
arylC.sub.1-4alkyloxyC.sub.1-4alkyl, pyridyl or pyrimidinyl. [0205]
(11-b) R.sup.11 is aryl, C.sub.1-4alkylcarbonyl,
C.sub.1-4alkyloxycarbonyl, hydroxyC.sub.1-4alkyl or pyridyl.
[0206] Still other embodiments of the present invention are those
compounds of formula (I) or any of the subgroups of compounds of
formula (I) specified herein, wherein: [0207] (12) R.sup.12 is
hydroxy, C.sub.1-4alkyl, C.sub.1-4alkyloxy, oxo,
spiro(C.sub.2-4alkanediyldioxy), spiro(diC.sub.1-4alkyloxy),
--NR.sup.5aR.sup.5b; [0208] (12-a) when in radical (a-2) one
R.sup.12 radical is present, R.sup.12 is hydroxy, C.sub.1-4alkyl,
C.sub.1-4alkyloxy, oxo, --NR.sup.5R.sup.5b; or when in radical
(a-2) two R.sup.12 radicals are present both independently are
C.sub.1-4alkyl, spiro(C.sub.2-4alkanediyldioxy) or
spiro(diC.sub.1-4alkyloxy); and [0209] (12-b) R.sup.2 is hydroxy or
C.sub.1-4alkyl.
[0210] Still other embodiments of the present invention are those
compounds of formula (I) or any of the subgroups of compounds of
formula (I) specified herein, wherein one or more of the following
restrictions apply: [0211] (13-a) Q.sup.1 is a direct bond or
--CH.sub.2--; or [0212] (13-b) Q.sup.2 is O or S; or (13-b-1)
Q.sup.2 is O,
[0213] Still other embodiments of the present invention are those
compounds of formula (I) or any of the subgroups of compounds of
formula (I) specified herein, wherein one or more of the following
restrictions apply: [0214] (14-a) R.sup.13 is hydrogen or hydroxy;
[0215] (14-b) R.sup.13a is C.sub.1-4alkyl; [0216] (14-c) R.sup.13b
is hydrogen;
[0217] Still other embodiments of the present invention are those
compounds of formula (I) or any of the subgroups of compounds of
formula (I) specified herein, wherein: [0218] (15) R.sup.14 is
hydrogen, C.sub.1-4alkyl or arylC.sub.1-4alkyl; [0219] (15-a)
R.sup.14 is hydrogen or C.sub.1-4alkyl; [0220] (15-b) R.sup.14 is
hydrogen.
[0221] Still further embodiments of the present invention are those
compounds of formula (I) or any of the subgroups of compounds of
formula (I) specified herein, wherein: [0222] (16) R.sup.15 is
selected from the group consisting of cyano, NR.sup.16aR.sup.16b,
pyrrolidinyl, piperidinyl, homopiperidinyl, piperazinyl,
4-(C.sub.1-4alkyl)-piperazinyl,
4-(C.sub.1-4alkylcarbonyl)-piperazinyl,
4-(C.sub.1-4alkyloxycarbonyl)-piperazinyl, morpholinyl,
thiomorpholinyl, 1-oxothiomorpholinyl, 1,1-dioxo-thiomorpholinyl,
aryl, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl,
isoxazolyl, isothiazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl,
triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl,
pyridazinyl, triazinyl, hydroxy-carbonyl, C.sub.1-4alkylcarbonyl,
N(R.sup.16aR.sup.16b)carbonyl, C.sub.1-4alkyloxycarbonyl,
pyrrolidin-1-ylcarbonyl, piperidin-1-ylcarbonyl,
homopiperidin-1-ylcarbonyl, piperazin-1-ylcarbonyl,
4-(C.sub.1-4alkyl)-piperazin-1-ylcarbonyl, morpholin-1-yl-carbonyl,
thiomorpholin-1-yl-carbonyl, 1-oxothiomorpholin-1-ylcarbonyl and
1,1-dioxo-thiomorpholin-1-ylcarbonyl; or R.sup.15 may additionally
be aryl substituted with a radical --COOR.sup.4; or a radical
selected from --NR.sup.5a--C(.dbd.NR.sup.5b)--NR.sup.5cR.sup.5d,
NR.sup.5a--C(.dbd.NR.sup.5e)--R.sup.5f,
--O--NR.sup.5a--C(.dbd.NR.sup.5b)--NR.sup.5cR.sup.5d,
--O--NR.sup.5a--C(.dbd.NR.sup.5e)--R.sup.5f, -sulfonyl-R.sup.6,
--NR.sup.7R.sup.8, --NR.sup.9R.sup.10, a radical (a-1), (a-2),
(a-3); [0223] (16-a) R.sup.15 is selected from the group consisting
of cyano, NR.sup.16aNR.sup.16b, pyrrolidinyl, piperidinyl,
homopiperidinyl, piperazinyl, 4-(C.sub.1-4alkyl)-piperazinyl,
4-(C.sub.1-4alkylcarbonyl)-piperazinyl,
4-(C.sub.1-4alkyloxycarbonyl)-piperazinyl, morpholinyl,
thiomorpholinyl, 1-oxothiomorpholinyl, 1,1-dioxo-thiomorpholinyl,
aryl, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl,
isoxazolyl, isothiazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl,
triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl,
pyridazinyl, triazinyl, hydroxy-carbonyl, C.sub.1-4alkylcarbonyl,
N(R.sup.16aR.sup.16b) carbonyl, C.sub.1-4alkyloxycarbonyl,
pyrrolidin-1-ylcarbonyl, piperidin-1-ylcarbonyl,
homopiperidin-1-ylcarbonyl, piperazin-1-ylcarbonyl,
4-(C.sub.1-4alkyl)-piperazin-1-ylcarbonyl, morpholin-1-yl-carbonyl,
thiomorpholin-1-yl-carbonyl, 1-oxothiomorpholin-1-ylcarbonyl and
1,1-dioxo-thiomorpholin-1-ylcarbonyl; [0224] (16-b) R.sup.15 is
selected from the group consisting of cyano, NR.sup.16aR.sup.16b,
pyrrolidinyl, piperidinyl, homopiperidinyl, piperazinyl,
4-(C.sub.1-4alkyl)-piperazinyl,
4-(C.sub.1-4alkylcarbonyl)-piperazinyl,
4-(C.sub.1-4alkyloxycarbonyl)-piperazinyl, morpholinyl,
thiomorpholinyl, 1-oxothiomorpholinyl, 1,1-dioxo-thiomorpholinyl,
aryl, hydroxy-carbonyl, C.sub.1-4alkylcarbonyl,
N(R.sup.16aR.sup.16b)carbonyl, C.sub.1-4alkyloxycarbonyl; [0225]
(16-c) R.sup.15 is selected from the group consisting of
NR.sup.16aR.sup.16b, pyrrolidinyl, piperidinyl, homopiperidinyl,
piperazinyl, 4-(C.sub.1-4alkyl)-piperazinyl,
4-(C.sub.1-4alkylcarbonyl)-piperazinyl, morpholinyl,
thiomorpholinyl, 1-oxothiomorpholinyl, 1,1-dioxo-thiomorpholinyl;
[0226] (16-d) R.sup.15 is selected from the group consisting of
NR.sup.16aR.sup.16b, pyrrolidinyl, piperidinyl, piperazinyl,
4-(C.sub.1-4alkyl)-piperazinyl, morpholinyl, thiomorpholinyl,
1,1-dioxo-thiomorpholinyl; [0227] (16-e) R.sup.15 is selected from
the group consisting of pyrrolidinyl, piperidinyl.
[0228] Further embodiments of the present invention are those
compounds of formula (I) or any of the subgroups of compounds of
formula (I) specified herein, wherein: [0229] (17) R.sup.16a and
R.sup.16b independently from one another are hydrogen,
C.sub.1-4alkyl or C.sub.1-4alkyl substituted with a substituent
selected from the group consisting of amino, mono- or
di(C.sub.1-4alkyl)amino, pyrrolidinyl, piperidinyl,
homopiperidinyl, piperazinyl, 4-(C.sub.1-4alkyl)-piperazinyl,
morpholinyl, thiomorpholinyl, 1-oxothiomorpholinyl,
1,1-dioxo-thiomorpholinyl and aryl; [0230] (17-a) R.sup.16a and
R.sup.16b independently from one another are hydrogen,
C.sub.1-4alkyl or C.sub.1-4alkyl substituted with a substituent
selected from the group consisting of amino, mono- or
di(C.sub.1-4alkyl)amino, pyrrolidinyl, piperidinyl,
homopiperidinyl, piperazinyl, 4-(C.sub.1-4alkyl)-piperazinyl,
morpholinyl, thiomorpholinyl, 1-oxothiomorpholinyl,
1,1-dioxo-thiomorpholinyl; [0231] (17-b) R.sup.16a and R.sup.16b
independently from one another are hydrogen or C.sub.1-4alkyl.
[0232] Further embodiments of the present invention are those
compounds of formula (I) or any of the subgroups of compounds of
formula (I) specified herein, wherein: [0233] (18) R.sup.17a and
R.sup.17b independently from one another are hydrogen,
C.sub.1-4alkyl or arylC.sub.1-4alkyl; or R.sup.17a and R.sup.17b
together with the nitrogen atom to which they are attached form a
pyrrolidinyl, piperidinyl, homopiperidinyl, morpholinyl,
thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, piperazinyl or
4-C.sub.1-4alkyl-piperazinyl ring; [0234] (18-a) R.sup.17a and
R.sup.17b independently from one another are hydrogen,
C.sub.1-4alkyl or aryl-C.sub.1-4alkyl; [0235] (18-b) R.sup.17a and
R.sup.17b independently from one another are hydrogen,
C.sub.1-4alkyl or aryl-C.sub.1-4alkyl.
[0236] Further embodiments of the present invention are those
compounds of formula (I) or any of the subgroups of compounds of
formula (I) specified herein, wherein: [0237] (19) each R.sup.15
independently is hydrogen, C.sub.1-4alkyl or arylC.sub.1-4alkyl;
[0238] (19-a) each R.sup.18 independently is hydrogen.
[0239] Further embodiments of the present invention are those
compounds of formula (I) or any of the subgroups of compounds of
formula (I) specified herein, wherein: [0240] (20) R.sup.19 is
hydrogen, C.sub.1-4alkyl or a radical COOR.sup.4; [0241] (20-a)
R.sup.19 is hydrogen.
[0242] Further embodiments of the present invention are those
compounds of formula (I) or any of the subgroups of compounds of
formula (I) specified herein, wherein: [0243] (21) aryl is phenyl
optionally substituted with one or more substituents each
individually selected from the group consisting of C.sub.1-6alkyl,
C.sub.1-4alkoxy, cyano, nitro; [0244] (21-a) aryl is phenyl
optionally substituted with one, two or three substituents each
independently selected from C.sub.1-6alkyl, C.sub.1-4alkoxy, cyano
and nitro;
[0245] Further embodiments of the present invention are those
compounds of formula (I) or any of the subgroups of compounds of
formula (I) specified herein, wherein: [0246] (22) Het.sub.1 is an
aromatic 5-membered ring system wherein one, two, three or four
ring members are heteroatoms each individually and independently
selected from the group consisting of nitrogen, oxygen and sulfur,
and wherein the remaining ring members are carbon atoms; and, where
possible, any nitrogen ring member may optionally be substituted
with C.sub.1-4alkyl; any ring carbon atom may, each individually
and independently, optionally be substituted with a substituent
selected from the group consisting of C.sub.1-4alkyl,
C.sub.3-7cycloalkyl, halo, cyano, trifluoromethyl,
cyanoC.sub.1-4alkyl, mono- or di(C.sub.1-4alkyl)amino, mono- or
di(C.sub.1-4alkyl)aminoC.sub.2-6alkenyl, isoxazolyl, aryl,
hydroxycarbonyl, C.sub.1-4alkyloxycarbonyl, oxo, thio; and wherein
the foregoing isoxazolyl may optionally he substituted with
C.sub.1-4alkyl; [0247] (22-a) Het.sub.1 is furanyl, thienyl,
pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl,
isothiazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl,
tetrazolyl, each of which individually and independently may be
optionally substituted with a substituent selected from the group
consisting of C.sub.1-4alkyl, C.sub.2-6alkenyl,
C.sub.3-7cycloalkyl, hydroxy, C.sub.1-4alkoxy, halo, amino, cyano,
trifluoromethyl, hydroxyC.sub.1-4alkyl, cyanoC.sub.1-4alkyl, mono-
or di(C.sub.1-4alkyl)amino, aminoC.sub.1-4alkyl, mono- or
di(C.sub.1-4alkyl)aminoC.sub.1-4alkyl, arylC.sub.1-4alkyl,
aminoC.sub.2-6alkenyl, mono- or
di(C.sub.1-4alkyl)aminoC.sub.2-6alkenyl, furanyl, thienyl,
pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl,
isothiazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl,
tetrazolyl, aryl, hydroxycarbonyl, aminocarbonyl,
C.sub.1-4alkyloxy-carbonyl, mono- or
di(C.sub.1-4alkyl)aminocarbonyl, C.sub.1-4alkylcarbonyl, oxo, thio;
and wherein any of the foregoing furanyl, thienyl, pyrrolyl,
oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl,
pyrazolyl, oxadiazolyl, thiadiazolyl and triazolyl moieties may
optionally be substituted with C.sub.1-4alkyl.
[0248] Further embodiments of the present invention are those
compounds of formula (I) or any of the subgroups of compounds of
formula (I) specified herein, wherein: [0249] (23) Het.sub.2 is
pyridyl or pyrimidinyl both optionally substituted with
C.sub.1-4alkyl. [0250] (23-a) Het.sub.2 is pyridyl or pyrimidinyl;
[0251] (23-b) Het.sub.2 is pyridyl.
[0252] Further embodiments of the present invention are those
compounds of formula (I) or any of the subgroups of compounds of
formula (I) specified herein, wherein: [0253] (24) p is 1, 2;
[0254] (24-a) p is 1.
[0255] Further embodiments of the present invention are those
compounds of formula (I) or any of the subgroups of compounds of
formula (I) specified herein, wherein. [0256] (25) p is 1, 2, 3;
[0257] (25-a) q is 1, 2; [0258] (25-b) q is 1.
[0259] Further embodiments of the present invention are those
compounds of formula (I) or any of the subgroups of compounds of
formula (I) specified herein, wherein: [0260] (26) m is 1-8; [0261]
(26-a) m is 1-6; [0262] (26-b) m is 1-4 ; [0263] (26-c) m is 1-3 ;
[0264] (26-d) m is 1-2.
[0265] Further embodiments of the present invention are those
compounds of formula (I) or any of the subgroups of compounds of
formula (I) specified herein, wherein: [0266] (27)
-a.sup.1=a.sup.2-a.sup.3=a.sup.4- represents a bivalent radical of
formula
[0266] --CH.dbd.CH--CH.dbd.CH-- (c-1);
--N.dbd.CH--CH.dbd.CH-- (c-2);
--CH.dbd.N--CH.dbd.CH-- (c-3);
--CH.dbd.CH--N.dbd.CH-- (c-4);
--CH.dbd.CH--CH.dbd.N-- (c-5);
wherein one of the hydrogen atoms in (c-1) is replaced by a radical
[0267] C.sub.1-6alkyl, C.sub.1-4alkoxy, halo, hydroxy,
(R.sup.5g)(R.sup.5h)N--(C.sub.1-4alkanediyl)-O--,
(R.sup.7)(R.sup.8)N--(C.sub.1-4alkanediyl)-O--,
(R.sup.8)(R.sup.9)N--(C.sub.1-4alkanediyl)-O--, trifluoromethyl,
cyano, a radical --COOR.sup.4, (R.sup.5a)(R.sup.5b)N-carbonyl,
(R.sup.5a)(R.sup.5b)N-sulfonyl, formyl, C.sub.1-6alkylcarbonyl,
nitro, hydroxyC.sub.1-6alkyl, C.sub.1-4alkoxyC.sub.1-6alkyl,
(R.sup.4OOC)--C.sub.1-6alkyl, a radical --N(R.sup.5a)(R.sup.5b),
--N(R.sup.7)(R.sup.8), --N(R.sup.9)(R.sup.10), a radical (a-1), a
radical
##STR00013##
[0267] morpholinyl, thiomorpholinyl, 1-oxothiomorpholinyl,
1,1-dioxo-thiomorpholinyl,
(R.sup.5g)(R.sup.5h)N--(C.sub.1-4alkanediyl)-N(R.sup.5c)--,
(R.sup.7)(R.sup.8)N--(C.sub.1-4alkainediyl)-N(R.sup.5c)--,
(R.sup.9)(R.sup.10)N--(C.sub.1-4alkanediyl)-N(R.sup.5c)--,
C.sub.1-6alkylcarbonylamino, C.sub.1-6alkyloxycarbonylamino,
(R.sup.5a)(R.sup.5b)N--C.sub.1-4alkyl; aryl; Het.sub.1 or
Het.sub.2; [0268] R.sup.20 is hydrogen, hydroxy, C.sub.1-4alkyl,
arylC.sub.1-4alkyl, C.sub.1-4alkyloxy, arylC.sub.1-4alkyloxy, oxo,
spiro(C.sub.2-4alkylenedioxy), spiro(diC.sub.1-4alkyloxy),
--NR.sup.5gR.sup.5h; [0269] each R.sup.5g or R.sup.5h independently
is hydrogen, C.sub.1-4alkyl or arylC.sub.1-4alkyl, or R.sup.5g and
R.sup.5h together with the nitrogen to which they attached form a
pyrrolidinyl, piperidinyl, homopiperidinyl, morfolinyl, piperazinyl
or 4-C.sub.1-4alkylpiperazinyl radical; wherein each of said
pyrrolidinyl, piperidinyl, homopiperidinyl, morfolinyl, piperazinyl
or 4-C.sub.1-4alkylpiperazinyl radical may optionally be
substituted with hydroxy or oxo; or [0270] wherein one or more of
the hydrogen atoms in (c-2), (c-3), (c-4) or (c-5) may be replaced
with a radical selected from halo and C.sub.1-6alkyl; [0271] (27-a)
-a.sup.1=a.sup.2-a.sup.3=a.sup.4- represents a bivalent radical of
formula (c-1) wherein one, two or three (or one or two; or one) of
the hydrogen atoms in (c-1) is replaced by a radical
C.sub.1-6alkyl, C.sub.1-4alkoxy, halo, hydroxy,
(R.sup.5a)(R.sup.5b)N--(C.sub.1-4alkanediyl)oxy, trifluoromethyl,
cyano, a radical --COOR.sup.4, (R.sup.5a)(R.sup.5b)N-carbonyl,
C.sub.1-6alkyl-carbonyl, nitro, hydroxyC.sub.1-6alkyl,
C.sub.1-4alkoxyC.sub.1-6alkyl, (R.sup.4OOC)--C.sub.1-6alkyl, a
radical N(R.sup.5a)(R.sup.5b), a radical (a-1), a radical (a-7),
morpholinyl, (R.sup.5a)(R.sup.5b)N--(C.sub.1-4alkanediyl)amino,
(R.sup.5a)(R.sup.5b)N--(C.sub.1-4alkanediyl)-(C.sub.1-4alkyl-amino),
C.sub.1-6alkylcarbonylamino, C.sub.1-6alkyloxycarbonylamino,
(R.sup.5a)(R.sup.5b)N--C.sub.1-4alkyl; or [0272] wherein one of the
hydrogen atoms in (c-2), (c-3), (c-4) or (c-5) may be replaced with
a radical selected from halo and C.sub.1-6alkyl; [0273] (27-b)
-a.sup.1=a.sup.2-a.sup.3=a.sup.4- represents a bivalent radical of
formula (c-1) wherein one of the hydrogen atoms in (c-1) is
replaced by a radical C.sub.1-6alkyl, halo, a radical --COOR.sup.4,
a radical --N(R.sup.5a)(R.sup.5b), (R.sup.5a)
(R.sup.5b)N--(C.sub.1-4alkanediyl)amino,
C.sub.1-6alkyloxycarbonylamino, a radical (a-1) wherein R.sup.19 is
hydrogen or C.sub.1-4alkyl, a radical (a-7) wherein R.sup.19 is
hydrogen; or -a.sup.1=a.sup.2-a.sup.3=a.sup.4- represents a
bivalent radical of formula (c-2), (c-3) (c-4) or (c-5) that is
unsubstituted; [0274] (27-c) -a.sup.1=a.sup.2-a.sup.3=a.sup.4-
represents a bivalent radical of formula (c-1); (c-2); (c-3);
(c-4); (c-5); wherein one, two or three (or one or two; or one) of
the hydrogen atoms in (c-1) is replaced by C.sub.1-6alkyl,
C.sub.1-4alkoxy, halo, hydroxy,
(R.sup.5g)(R.sup.5h)N--(C.sub.1-4alkanediyl)-O--, cyano,
--COOR.sup.4, (R.sup.5a)(R.sup.5b)N-carbonyl
(R.sup.5a)(R.sup.5b)N-sulfonyl, formyl, C.sub.1-6alkylcarbonyl,
nitro, hydroxyC.sub.1-6alkyl, C.sub.1-4alkoxyC.sub.1-6alkyl,
(R.sup.4OOC)--C.sub.1-6alkyl, --N(R.sup.5a)(R.sup.5b),
--N(R.sup.7)(R.sup.8), --N(R.sup.9)(R.sup.10), a radical (a-1), a
radical (a-7), morpholinyl, thiomorpholinyl,
(R.sup.5g)(R.sup.5h)N--(C.sub.1-4alkanediyl)-N(R.sup.5c)--,
C.sub.1-6alkylcarbonylamino, C.sub.1-6alkyloxycarbonylamino,
trifluoroacetylaminio, (R.sup.5a)(R.sup.5b)N--C.sub.1-4alkyl;
wherein one of the hydrogen atoms in (c-2), (c-3), (c-4) or (c-5)
may be replaced with a radical selected from halo and
C.sub.1-6alkyl; [0275] (27-d) -a.sup.1=a.sup.2-a.sup.3=a.sup.4-
represents a bivalent radical of formula (c-1); wherein one, two or
three (or one or two; or one) of the hydrogen atoms is replaced by
C.sub.1-6alkyl, C.sub.1-4alkoxy, halo, hydroxy,
(R.sup.5g)(R.sup.5h)N--(C.sub.1-4alkanediyl)-O--, a radical
--COOR.sup.4, (R.sup.5a)(R.sup.5b)N-sulfonyl,
N(R.sup.5a)(R.sup.5b), --N(R.sup.7)(R.sup.8), a radical (a-1), a
radical (a-7), morpholinyl,
(R.sup.5g)(R.sup.5h)N--(C.sub.1-4alkanediyl)-N(R.sup.5c)--,
C.sub.1-6alkyloxycarbonylamino, trifluoroacetylamino,
(R.sup.5a)(R.sup.5b)N--C.sub.1-4alkyl; or [0276]
-a.sup.1=a.sup.2-a.sup.3=a.sup.4- represents a bivalent radical of
formula (c-2), (c-3), (c-4) or (c-5) that is unsubstituted; [0277]
(27-e) -a.sup.1=a.sup.2-a.sup.3=a.sup.4- represents a bivalent
radical of formula (c-1); wherein one or two of the hydrogen atoms
is replaced by C.sub.1-6alkyl, C.sub.1-4alkoxy, halo, hydroxy,
(R.sup.5g)(R.sup.5h)N--(C.sub.1-4alkanediyl)-O--, --COOR.sup.4,
--N(R.sup.5a)(R.sup.5b), --N(R.sup.7)(R.sup.8), a radical (a-1), a
radical (a-7), morpholinyl,
(R.sup.5g)(R.sup.5h)N--(C.sub.1-4alkanediyl)-N(R.sup.5c)--,
C.sub.1-6alkyloxycarbonylamino, trifluoroacetylamino or
-a.sup.1=a.sup.2-a.sup.3=a.sup.4- represents a bivalent radical of
formula (c-2), (c-3), (c-4) or (c-5) that is unsubstituted; [0278]
(27-f) -a.sup.1=a.sup.2-a.sup.3=a.sup.4- represents a bivalent
radical of formula (c-1); wherein one or two of the hydrogen atoms
is replaced by C.sub.1-6alkyl, C.sub.1-4alkoxy, halo, hydroxy,
(R.sup.5g)(R.sup.5h)N--(C.sub.1-4alkanediyl)-O--COOR.sup.4,
--N(R.sup.5a)(R.sup.5b), a radical (a-1), a radical (a-7),
morpholinyl,
(R.sup.5g)(R.sup.5h)N--(C.sub.1-4alkanediyl)-N(R.sup.5c)--; [0279]
(27-g) -a.sup.1=a.sup.2-a.sup.3=a.sup.4- represents a bivalent
radical of formula (c-1); wherein one or two of the hydrogen atoms
is replaced by hydroxy,
(R.sup.5g)(R.sup.5h)N--(C.sub.1-4alkanediyl)-O--,
--N(R.sup.5a)(R.sup.5b), a radical (a-1),
(R.sup.5g)(R.sup.5f)N--(C.sub.1-4alkanediyl)-N(R.sup.5c)--; [0280]
(27-h) -a.sup.1=a.sup.2-a.sup.3=a.sup.4- represents a bivalent
radical of formula (c-1); wherein one or two of the hydrogen atoms
is replaced by hydroxy,
(R.sup.5g)(R.sup.5h)N--(C.sub.1-4alkanediyl)-O--,
(R.sup.5g)(R.sup.5h)N--(C.sub.1-4alkanediyl)-N(R.sup.5c)--; [0281]
(27-i) -a.sup.1-=a.sup.2-a.sup.3=a.sup.4- represents a bivalent
radical of formula (c-1); wherein one (or two) of the hydrogen
atoms is replaced by hydroxy,
(R.sup.5g)(R.sup.5h)N--(C.sub.1-4alkanediyl)-N(R.sup.5c)--.
[0282] Further embodiments of the present invention are those
compounds of formula (I) or any of the subgroups of compounds of
formula (I) specified herein, wherein: [0283] (28) R.sup.20 is
hydrogen, hydroxy, C.sub.1-4alkyl, spiro(C.sub.2-4alkylenedioxy),
spiro(diC.sub.1-4alkyloxy), --NR.sup.5gR.sup.5h; [0284] (28-a)
R.sup.20 is hydrogen, hydroxy, C.sub.1-4alkyl,
spiro(C.sub.2-4alkylenedioxy), --NR.sup.5gR.sup.5h; [0285] (28-a)
R.sup.20 is hydrogen, hydroxy, C.sub.1-4alkyl; or [0286] (28-a)
R.sup.20 is hydrogen.
[0287] Further embodiments of the present invention are those
compounds of formula (I) or any of the subgroups of compounds of
formula (I) specified herein, wherein: [0288] (29) R.sup.5g or
R.sup.5h independently is hydrogen, C.sub.1-4alkyl or
arylC.sub.1-4alkyl, or R.sup.5g and R.sup.5h together with the
nitrogen to which they attached form a pyrrolidinyl, piperidinyl,
homopiperidinyl, morfolinyl, piperazinyl or
4-C.sub.1-4alkylpiperazinyl radical; wherein each of said
pyrrolidinyl, piperidinyl, homopiperidinyl, morfolinyl, piperazinyl
or 4-C.sub.1-4alkylpiperazinyl radical may optionally be
substituted with hydroxy or oxo; or [0289] (29-a) R.sup.5g or
R.sup.5h independently is hydrogen or C.sub.1-4alkyl, or R.sup.5g
and R.sup.5h together with the nitrogen to which they attached form
a pyrrolidinyl, piperidinyl, homopiperidinyl, morfolinyl,
piperazinyl or 4-C.sub.1-4alkylpiperazinyl radical; [0290] (29-b)
R.sup.5g or R.sup.5h independently is hydrogen or
C.sub.1-4alkyl.
[0291] It is to be understood that subgroups of compounds of
formula (I) comprise those groups of compounds of formula (I)
wherein one or more of the above restrictions apply in whatever
combination. If within a definition of a restriction one or more
variables are present, each of these variables can have any of the
meanings given in the restrictions relating to these variables. For
example if within the restrictions for R.sup.2 a radical
NR.sup.5aR.sup.5b is mentioned the radicals R.sup.5a and R.sup.5b
can have any of the meanings listed in the restrictions relating to
R.sup.5a and R.sup.5b.
[0292] A particular group of compounds of formula (I) is this
wherein R.sup.1, R.sup.3 and n are as specified in the definition
of the compounds of formula (J); and R.sup.2 is as in restriction
(4); and/or -a.sup.1=a.sup.2-a.sup.3=a.sup.4- is as in restriction
(27).
[0293] In one embodiment, n is 1 and the R.sup.3 group on the
phenyl ring in the compounds of formula (I) or any subgroup
specified herein, is in para-position vis-a-vis the nitrogen atom
in the fused pyridine moiety as depicted herein below and
hereinafter referred to as compounds of formula (I-a):
##STR00014##
[0294] Another subgroup of the compounds of formula (I-a) comprises
those compounds of formula (I-a), hereinafter referred to compounds
of formula (c-1), wherein R.sup.3 is nitro.
[0295] Examples of subgroups of compounds are the following:
[0296] (i) those compounds of formula (I-a) wherein R.sup.3 is
nitro and R.sup.1 is cyano, halo, aminocarbonyl,
N-hydroxy-methanimidamidyl, Het.sub.1; further among the latter
compounds are those compounds of formula (I-a) wherein R.sup.3 is
nitro, X is O, or X is NR.sup.2 wherein R.sup.2 is a radical (b-3)
wherein R.sup.14 is hydrogen and R.sup.15 is cyano,
NR.sup.16aR.sup.16b, pyrrolidinyl, piperidinyl,
4-(C.sub.1-4alkyl)-piperazinyl, morpholinyl, hydroxycarbonyl; or X
is NR.sup.2 wherein R.sup.2 is a radical (b-4) wherein R.sup.14 is
hydrogen or C.sub.1-4alkyl; and R.sup.1 is as in restrictions (2-d)
to (2-j).
[0297] (ii) those compounds of formula (I-a) wherein R.sup.3 is
nitro and R.sup.1 is cyano and X is O, Suitable compounds are those
compounds of formula (I-a) wherein R.sup.1 is cyano and R.sup.3 is
nitro, cyano, halo, C.sub.1-4alkyloxy, hydroxycarbonyl,
aminocarbonyl, mono- or di(C.sub.1-4alkyl)methanimidamidyl,
N-hydroxy-methanimidamidyl or Het.sub.1;
[0298] (iii) those compounds of formula (I-a) wherein
[0299] R.sup.1 is cyano;
[0300] X is O; or X is NR.sup.2 wherein R.sup.2 is a radical of
formula (b-3) wherein p is 1, q is 1, R.sup.14 is hydrogen,
R.sup.15 is cyano, NR.sup.16aR.sup.16b, pyrrolidinyl, piperidinyl,
4-(C.sub.1-4alkyl)-piperazinyl, morpholinyl, aryl, imidazolyl,
pyridyl, hydroxycarbonyl, N(R.sup.16aR.sup.16b)carbonyl,
C.sub.1-4alkyloxycarbonyl or
4-(C.sub.1-4alkyl)-piperazin-1-ylcarbonyl; or X is NR.sup.2 wherein
R.sup.2 is a radical of formula (b-4) wherein m is 1, 2 or 3,
R.sup.14 is hydrogen or C.sub.1-4alkyl; and R.sup.3 is as in
restrictions (5-d), (5-e), (5-f) or (5-g).
[0301] Another subgroup of compounds comprises those compounds of
formula (I) as a salt, wherein the salt is selected from
trifluoroacetate, fumarate, chloroacetate, methanesulfonate,
oxalate, acetate and citrate.
[0302] Preferred compounds are any of the compounds listed in
tables 1 and 2, more in particular the compounds having numbers 1,
3-7, 11, 12, 15-18, 23-26, 28, 30, 32, 33, 35, 36.
[0303] Compounds of particular interest are: [0304]
8-bromo-5-methyl-1-(4-nitro-phenyl)-2-oxo-2,5-dihydro-1H-pyrido[3,2-b]ind-
ole-3-carbonitrile, [0305]
8-morpholin-5-methyl-1-(4-nitro-phenyl)-2-oxo-2,5-dihydro-1H-pyrido[3,2-b-
]indole-3-carbonitrile, [0306]
8-hydroxy-5-methyl-1-(4-nitro-phenyl)-2-oxo-2,5-dihydro-1H-pyrido[3,2-b]i-
ndole-3-carbonitrile, [0307]
8-hydroxy-1-(4-nitro-phenyl)-2-oxo-2,5-dihydro-1H-pyrido[3,2-b]indole-3-c-
arbonitrile, [0308]
8-methoxy-5-methyl-1-(4-nitro-phenyl)-2-oxo-2,5-dihydro-1H-pyrido[3,2-b]i-
ndole-3-carbonitrile, [0309]
8-[(3-Dimethylamino-propyl)-methylamino]-5-methyl-1-(4-nitro-phenyl)-2-ox-
o-2,5-dihydro-1H-pyrido[3,2-b]indole-3-carbonitrile; [0310]
8-[(3-Dimethylamino-propyl)-oxy]-5-methyl-1-(4-nitro-phenyl)-2-oxo-2,5-di-
hydro-1H-pyrido[3,2-b]indole-3-carbonitrile.
[0311] Other compounds of interest comprise the above compounds of
interest and the salts and possible stereoisomers thereof; or the
above compounds of interest and the N-oxides, salts and possible
stereoisomers thereof.
[0312] The compounds of the present invention inhibit HIV reverse
transcriptase and may also inhibit reverse transcriptases having
similarity to HIV reverse transcriptase. Such similarity may be
determined using programs known in the art including BLAST. In one
embodiment, the similarity at the amino acid level is at least 25%,
interestingly at least 50%, more interestingly at least 75%. In
another embodiment, the similarity at the amino acid level at the
binding pocket, for the compounds of the present invention, is at
least 75%, in particular at least 90% as compared to HIV reverse
transcriptase.
[0313] Compounds of the present invention may be tested in other
lentivirusses besides HIV-1, such as, for example, SIV and
HIV-2.
[0314] The compounds of the present invention may have a good
selectivity as measured by the ratio between EC.sub.50 and
CC.sub.50 as described and exemplified in the antiviral analysis
example. The compounds of the present invention have also a
favorable specificity.
[0315] There exists a high dissociation between the activity on
lentiviruses versus other retroviridae, such as MLV, and versus
non-viral pathogens.
[0316] The standard of "sensitivity" or alternatively "resistance"
of a HIV reverse transcriptase enzyme to a drug is set by the
commercially available HIV reverse transcriptase inhibitors.
Existing commercial HIV reverse transcriptase inhibitors including
efavirenz, nevirapine and delavirdine may loose effectivity over
time against a population of HIV virus in a patient. The reason
being that under pressure of the presence of a particular HIV
reverse transcriptase inhibitor, the existing population of HIV
virus, usually mainly wild type HIV reverse transcriptase enzyme,
mutates into different mutants which are far less sensitive to that
same HIV reverse transcriptase inhibitor. If this phenomenon
occurs, one talks about resistant mutants. If those mutants are not
only resistant to that one particular HIV reverse transcriptase
inhibitors but also to multiple other commercially available HIV
reverse transcriptase inhibitors, one talks about multi-drug
resistant HIV reverse transcriptase. One way of expressing the
resistance of a mutant to a particular HIV reverse transcriptase
inhibitor is making the ratio between the EC.sub.50 of said HIV
reverse transcriptase inhibitor against mutant HIV reverse
transcriptase over EC.sub.50 of said HIV reverse transcriptase
inhibitor against wild type HIV reverse transcriptase. Said ratio
is also called fold change in resistance (FR). The EC.sub.50 value
represents the amount of the compound required to protect 50% of
the cells from the cytopathogenic effect of the virus.
[0317] Many of the mutants occurring in the clinic have a fold
resistance of 100 or more against the commercially available HIV
reverse transcriptase inhibitors, like nevirapine, efavirenz,
delavirdine. Clinically relevant mutants of the HIV reverse
transcriptase enzyme may be characterized by a mutation at codon
position 100, 103 and 181. As used herein a codon position means a
position of an amino acid in a protein sequence. Mutations at
positions 100, 103 and 181 relate to non-nucleoside RT inhibitors
(D'Aquila et al. Topics in HIV medicine, 2002, 10, 11-15). Examples
of such clinical relevant mutant HIV reverse transcriptases are
listed in Table 1.
TABLE-US-00001 TABLE 1 List of mutations present in reverse
transcriptase of the HIV strains used. A Y181C B KI03N C L100I;
K103N D L100I; K103N E F227C F Y188L G V106A, F227L H K103N, Y181C
I K101E, K103N J I31L, L100I, K103N, E138G, Y181C, L214F K K2OR,
E28K, M41L, E44A, D67N, L74I, K103N, V118I, D123N, S162C, Y181C,
G196K, Q207E, L210W, L214F, T215Y, K219N, P225H, D250E, P272A,
R277K, I293V, P297K, K311R, R358K, T376A, E399D, T400L
[0318] An interesting group of compounds are those compounds of
formula (I) having a fold resistance ranging between 0.01 and 100
against at least one mutant HIV reverse transcriptase, suitably
ranging between 0.1 and 100, more suitably ranging between 0.1 and
50, and even more suitably ranging between 0.1 and 30. Of
particular interest are the compounds of formula (I) showing a fold
resistance against at least one mutant HIV reverse transcriptase
ranging between 0.1 and 20, and even more interesting are those
compounds of formula (I) showing a fold resistance against at least
one mutant HIV reverse transcriptase ranging between 0.1 and
10.
[0319] An interesting group of compounds are those compounds of
formula (I) having a fold resistance, determined according to the
methods herein described, in the range of 0.01 to 100 against HIV
species having at least one mutation in the amino acid sequence of
HIV reverse transcriptase as compared to the wild type sequence
(genbank accession e.g. M38432, K03455, gi 327742) at a position
selected from 100, 103 and 181; in particular at least two
mutations selected from the positions 100, 103 and 181. Even more
interesting are those compounds within said interesting group of
compounds having a fold resistance in the range of 0.1 to 100, in
particular in the range 0.1 to 50, more in particular in the range
0.1 to 30. Most interesting are those compounds within said
interesting group of compounds having a fold resistance in the
range of 0.1 and 20, especially ranging between 0.1 and 10.
[0320] One embodiment relates to compounds of the present invention
showing a fold resistance in the ranges mentioned herein against at
least one clinically relevant mutant HIV reverse
transcriptases.
[0321] A particular subgroup of compounds are those compounds of
formula (I) having an IC.sub.50 of 1 .mu.M or lower, suitably an
IC.sub.50 of 100 nM or lower vis-a-vis the wild type virus upon in
vitro screening according to the methods described herein.
[0322] The ability of the present compounds to inhibit HIV-1,
HIV-2, SIV and HIV viruses with reverse transcriptase (RT) enzymes
having mutated under pressure of the currently known RT inhibitors,
together with the absence of cross resistance with currently known
RT inhibitors, indicate that the present compounds bind differently
to the RT enzyme when compared to known NNRTIs and NRTIs. Other
indicators of a different mode of action are the ribonucleotide
sensitivity of the compounds of this invention as can be shown by
their increased activity when administered in the presence of ATP
and by their nucleoside competitive behaviour. The compounds of
this invention therefore can be classified as nucleoside
competitive reverse transcriptase inhibitors.
[0323] The compounds of the present invention show antiretroviral
properties, in particular against Human Immunodeficiency Virus
(HIV), which is the aetiological agent of Acquired Immune
Deficiency Syndrome (AIDS) in humans. The HIV virus preferably
infects CD4 receptor containing cells such as human T4 cells and
destroys them or changes their normal function, particularly the
coordination of the immune system. As a result, an infected patient
has an ever-decreasing number of T4 cells, which moreover behave
abnormally. Hence, the immunological defence system is unable to
combat infections and/or neoplasms and the HIV infected subject
usually dies by opportunistic infections such as pneumonia, or by
cancers. Other diseases associated with HIV infection include
thrombocytopaenia, Kaposi's sarcoma and infection of the central
nervous system characterized by progressive demyelination,
resulting in dementia and symptoms such as, progressive dysarthria,
ataxia and disorientation. HIV infection further has also been
associated with peripheral neuropathy, progressive generalized
lymphadenopathy (PGL) and AIDS-related complex (ARC). The HIV virus
also infects CD8-receptor containing cells. Other target cells for
HIV virus include microglia, dendritic cells, B-cells and
macrophages.
[0324] Due to these favourable pharmacological properties, the
compounds of the present invention or any subgroup thereof may be
used as a medicine against the above-mentioned diseases or in the
prophylaxis thereof, or used in a method of treatment of the
above-mentioned diseases or in the prophylaxis thereof. Said use as
a medicine or method of treatment comprises the systemic
administration to HIV-infected subjects, in particular human
patients, of an amount of a compound of formula (I) or of a
compound of a subgroup of compounds of formula (I), effective in
the prophylaxis or treatment of the conditions associated with HIV
infection.
[0325] In a further aspect, the present invention concerns the use
of a compound of formula (I) or any subgroup thereof in the
manufacture of a medicament useful for preventing, treating or
combating infection or disease associated with HIV infection.
[0326] In another aspect, the present invention concerns the use of
a compound of formula (I) or any subgroup thereof in the
manufacture of a medicament useful for inhibiting replication of a
HIV virus, in particular a HIV virus having a mutant HIV reverse
transcriptase, more in particular having a multi-drug resistant
mutant HIV reverse transcriptase.
[0327] In yet another aspect, the present invention relates to the
use of a compound of formula (I) or any subgroup thereof in the
manufacture of a medicament useful for preventing, treating or
combating a disease associated with HIV viral infection wherein the
reverse transcriptase of the HIV virus is mutant, in particular a
multi-drug resistant mutant HIV reverse transcriptase.
[0328] The compounds of formula (I) or any subgroup thereof are
also useful in a method for preventing, treating or combating
infection or disease associated with HIV infection in a mammal,
comprising administering to said mammal an effective amount of a
compound of formula (I) or any subgroup thereof.
[0329] In another aspect, the compounds of formula (I) or any
subgroup thereof are useful in a method for preventing, treating or
combating infection or disease associated with infection of a
mammal with a mutant HIV virus, comprising administering to said
mammal an effective amount of a compound of formula (I) or any
subgroup thereof.
[0330] In another aspect, the compounds of formula (I) or any
subgroup thereof are useful in a method for preventing, treating or
combating infection or disease associated with infection of a
mammal with a multi drug-resistant HIV virus, comprising
administering to said mammal an effective amount of a compound of
formula (I) or any subgroup thereof.
[0331] In yet another aspect, the compounds of formula (I) or any
subgroup thereof are useful in a method for inhibiting replication
of a HIV virus, in particular a HIV virus having a mutant HIV
reverse transcriptase, more in particular a multi-drug resistant
mutant HIV reverse transcriptase, comprising administering to a
mammal in need thereof an effective amount of a compound of formula
(I) or any subgroup thereof.
[0332] Preferably, a mammal as mentioned in the methods of this
invention is a human being.
[0333] The compounds of the present invention may also find use in
inhibiting ex vivo samples containing HIV or expected to be exposed
to HIV, Hence, the present compounds may be used to inhibit HIV
present in a body fluid sample that contains or is suspected to
contain or be exposed to HIV.
[0334] Particular reaction procedures to make the present compounds
are described below. In the preparations described below, the
reaction products may be isolated from the medium and, if
necessary, further purified according to methodologies generally
known in the art such as, for example, extraction, crystallization,
trituration and chromatography.
[0335] In the following reaction schemes each W independently
represents a leaving group such as halo, e.g. chloro or bromo,
tosylate, mesylate, and the like.
[0336] The compounds of formula (I) wherein X is a group NH, which
compounds may be represented by formula (I-b), can be prepared by a
cyclization procedure, as outlined in the following reaction
scheme.
##STR00015##
[0337] The synthesis of intermediates ( I-b) starts from a
1-C.sub.1-6alkylcarbonyl-3-hydroxy-indole (II-1), which is
condensed with a substituted aniline yielding
3-(phenylamino)indoles (II-2). This condensation reaction may be
conducted at elevated temperatures and in acidic circumstances e.g.
by using an acidic solvent such as acetic acid, or using a solvent
such as toluene, benzene, an alcohol and the like, with a suitable
acid such as toluene sulfonic acid. Intermediate (II-2)
subsequently is deacylated with a base, such as for example
triethylamine, sodium or potassium hydroxide, sodium acetate,
potassium acetate or potassium carbonate and the like, in a
suitable solvent, such as for example methanol or ethanol,
preferably at elevated temperature, yielding intermediates (II-3).
Formylation of intermediates (II-3), for instance by applying a
Vilsmeier reaction, results in indole aldehydes (II-4).
Condensation of intermediates (II-4) with an acetic acid ester
results in intermediate (II-5). In one embodiment, this
condensation may be performed with an substituted acetic acid ester
of formula R.sup.1--CH.sub.2--COOR.sup.4a, wherein R.sup.4a is
C.sub.1-6alkyl or arylC.sub.1-6alkyl, using a base such as for
example triethylamine, sodium acetate, potassium acetate,
piperidine and the like, in a wide variety of solvents.
Alternatively use may be made of a Wittig reaction or a
Wittig-Horner reaction. In the former instance a Wittig type
reagent, such as a triphenylphosphoniumylide is used. The Wittig
conversion is conducted in a suitable reaction-inert solvent such
as an ether, starting from triphenylphosphine and a halo acitic
acid ester of formula R.sup.1--CH(Halo)-COOR.sup.4a. The
Wittig-Horner reaction is performed using a phosphonate, such as
e.g. a reagent of formula
di(C.sub.1-6alkyloxy)-P(.dbd.O)--CH(R.sup.1)--COOR.sup.4a in the
presence of a base, preferably a strong base, in an aprotic organic
solvent.
[0338] Subsequent cyclisation of intermediates (II-5) at elevated
temperature and in a solvent like ethyleneglycol, dioxane,
N,N-dimethylformamide, dimethylsulfoxide, glyme, diglyme and the
like, yields compounds (I-b).
[0339] The order of the reaction steps in the process set out in
the above reaction scheme may be different. For instance the
formylation may be performed prior to deacylation.
[0340] This synthesis pathway is particularly useful for preparing
compounds of formula (I-b) wherein R.sup.3 is nitro or cyano. In
one embodiment, R.sup.3 is para-nitro and the process starts from
para-nitroaniline. It may also be used to prepare intermediates
wherein R.sup.1 is aminocarbonyl, C.sub.1-4alkyloxycarbonyl, mono-
or di(C.sub.1-4alkyl)aminocarbonyl, arylaminocarbonyl,
N-(aryl)-N--(C.sub.1-4alkyl)aminocarbonyl, Het.sub.1 or Het.sub.2.
The intermediates of formula (II) obtained through this reaction
pathway may be converted to analogous intermediates of formula (II)
wherein R.sup.1 has the other meanings by functional group
transformation reactions such as cyano to carboxyl hydrolysis,
carboxyl to amide conversion, etc.
[0341] This synthesis pathway moreover is particularly useful to
prepare intermediates of formula (II) wherein R.sup.3 is nitro or
cyano. In one embodiment, R.sup.3 is para-nitro and the process
starts from para-nitroaniline.
[0342] The compounds of formula (I-c), which are compounds of
formula (I-b) wherein R.sup.1 is cyano, may alternatively be
prepared as outlined in the following reaction scheme.
##STR00016##
[0343] Intermediate (II-2), which is prepared as described in the
previous reaction scheme, is reacted with chloroacetyl chloride or
a functional derivative thereof, suitably at elevated temperature,
to yield an intermediate of formula (III-a). The latter
intermediate of formula (III-a) is deprotected using a suitable
base such as trietylamine, sodium acetate, potassium acetate,
sodium hydroxide, potassium hydroxide, potassium carbonate and the
like, in a solvent like methanol or ethanol. The thus formed
intermediate (III-b) is converted to the corresponding cyano
derivative (III-b) using potassium cyanide or
tetrabutylammoniumcyanide. The cyano derivative (III-b) is cyclized
in a two step procedure comprising first a Vilsmeier formylation
using POCl.sub.3 in N,N-dimethylformamide and subsequent
cyclization to form compound (I-c).
[0344] Compounds of formula (I-d), which are compounds of formula
(I-b) wherein R.sup.1 is hydrogen, can be prepared as outlined in
the following reaction scheme.
##STR00017##
[0345] Intermediate (II-2), which is prepared as outlined above, is
reacted with acetic anhydride in the presence of a catalyst such as
for example pyridine or dimethylamino-pyridine or the like,
suitably at elevated temperature, to yield an intermediate of
formula (IV-a). The thus formed intermediate of formula (IV-a) is
formylated using a Vilsmeier reaction with POCl.sub.3 in
N,N-dimethylformamide, to form intermediate (IV-b) which in turn
can be further cyclized to a compound (II-b), e.g. in an aqueous
acidic environment, e.g. in aqueous HCl.
[0346] Compounds of formula (I-b), (I-c) or (I-d) may be
transformed into other compounds of formula (I) using art-known
functional group transformation reactions. For example where
R.sup.3 is Br, Br may be transformed into a heterocyclic ring using
heterocyclic borates and palladium. Or where R.sup.3 is
C.sub.1-6alkyloxycarbonyl this radical may be transformed to the
equivalent carboxylic acid or amide using a hydrolysis reaction, or
respectively, an ester or carboxylic acid to amide reaction. Also
R.sup.3 being cyano may be transformed to a heterocycle such as a
tetrazolyl, oxadiazolyl, thiazolyl etc. using art-known cyclization
procedures.
[0347] The compounds of formula (I) wherein X is a group NR.sup.2,
which compounds may be represented by formula (I-e), can be
prepared by N-alkylating intermediates of formula (I-b), (I-c) or
(I-d) with a suitable N-alkylating agent, the reaction starting
from (I-b) being outlined in the following reaction scheme.
##STR00018##
[0348] In one embodiment, the N-alkylating reagent is a reagent,
which can be represented by formula R.sup.2--W (V-a), wherein W is
a leaving group. Suitable leaving groups are halo, in particular
chloro, bromo and iodo, or other leaving groups such as for example
sulfonates, e.g. tosylates, mesylates and the like. This type of
N-alkylation reaction may be performed in an appropriate solvent in
the presence of a suitable base such as an alkali metal hydride,
e.g. sodium or potassium hydride, or an alkali or earth alkaline
metal hydroxide, carbonate or hydrogencarbonate, e.g. sodium or
potassium carbonate, sodium or potassium hydroxide, calcium
hydroxide, sodium or potassium hydrogencarbonate and the like.
[0349] Some of the compounds of formula (I-c) may also, where
appropriate, be prepared by a reductive amination reaction which
comprises reacting intermediates (II-a) with an intermediate
R.sup.2-a.dbd.O (V-b), wherein R.sup.2-a has the same meanings of
R.sup.2 provided that it has a carbon atom that can form an
aldehyde of ketone functionality. This reaction may be conducted in
the presence of hydrogen and a suitable catalyst, in particular a
noble metal catalyst such as Pd or Pt, usually in a suitable
solvent such as an ether or alcohol.
[0350] Some of the R.sup.2 groups may also be introduced using
R.sup.2 groups derived from an epoxide. This type of reaction is
particularly suited for introducing R.sup.2 groups wherein R.sup.2
is a radical (b-3), (b-4) or (b-5).
##STR00019##
[0351] For example, compounds of formula (I-e), wherein R.sup.2 is
a radical (b-3) wherein p is 1 and wherein the group
--NR.sup.aR.sup.b are certain radicals amongst R.sup.15 such as
--NR.sup.16aR.sup.16b pyrrolidinyl, piperidinyl, homopiperidinyl,
piperazinyl, 4-(C.sub.1-4alkyl)-piperazinyl, morpholinyl,
thiomorpholinyl, 1-oxothiomorpholinyl, 1,1-dioxo-thiomorpholinyl,
pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl,
isothiazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl,
tetrazolyl, a radical (a-1), (a-2), (a-3), or (a-5); wherein any of
the foregoing heterocycles such as pyrrolidinyl, piperidinyl,
homopiperidinyl, etc. is substituted on the C.sub.qH.sub.2q moiety
via a nitrogen atom; which compounds can be represented by formula
(I-e-1); can be prepared by reacting a compound of formula (I-b)
with an epoxide of formula (V-c). The resulting intermediates of
formula (VI-a) can be converted into compounds of formula (c-1)
wherein --NR.sup.aR.sup.b is as specified above by an appropriate
alcohol (C--OH) to amine (C--N) conversion reaction. The alcohol
group may be converted into a suitable leaving group and
subsequently reacted with an amine H--NR.sup.aR.sup.b. In an
alternative execution, the alcohol group may be converted to an
amine bond by a Mitsonobu-type reaction using an
azodicarboxylate/triphenyl phosphine reagent, for example
diisopropyl-azodicarboxylate (DIAD), and subsequent reaction with
the appropriate amine. The thus obtained compounds of formula
(I-e-1) can be O-alkylated or O-acylated in order to obtain the
analogs of the compounds (I-e-1) wherein R.sup.14 is other than
hydrogen.
[0352] In a similar process, intermediates (II) are reacted with a
epoxide (V-d) using a hydroxyl to amino conversion reaction such as
the above describe Mitsonobu reaction to obtain an epoxide (VI-b),
The latter is reacted with an amine to yield compounds of formula
(I-e-2) as outlined in the following reaction scheme. The compounds
of formula (I-e-2) can also be O-alkylated or O-acylated as
described in the previous paragraph.
##STR00020##
[0353] In an alternative procedure, compound (I-b) can be reacted
with an epoxide having formula
##STR00021##
to directly obtain compounds of formula (I) wherein R.sup.2 is a
radical (b-3) wherein R.sup.15 is an amino substituent
--NR.sup.aR.sup.b
[0354] The intermediates of formula (VI-b) can also be reacted with
an alkanolamine to obtain compounds of formula (I-e-3), which are
cyclized to obtain compounds (I-e-4), which are compounds of
formula (I) wherein R.sup.2 is alkyl substituted with a radical of
formula (a-4). The cyclization may be conducted in the presence an
acid such as hydrochloric acid with removal of water or in the
presence of a suitable dehydrating agent for example sulfonyl amide
such as an arylsulfonyl imidazole. These reactions are represented
in the following reaction scheme wherein R.sup.a has the meanings
of R.sup.13a, provided that it is other than hydrogen. R.sup.a can
also be a N-protecting group, which is removed afterwards, thus
giving access to compounds wherein R.sup.13a is hydrogen.
##STR00022##
[0355] Compounds wherein R.sup.2 is a group (b-4) can be prepared
starting from ethylene oxide followed by controlled addition of
further ethylene oxide moieties. The resulting compounds may be
alkylated to yield compounds of formula (I) having a (b-4) group
with a R.sup.14 radical that is other than hydrogen or converted
into the corresponding amines (b-5) using a suitable alcohol to
amine conversion reaction.
[0356] Compounds of formula (I) wherein is a phenyl group
substituted with a --COOR.sup.4 group can be obtained by suitable
N-arylation reactions.
[0357] Compounds wherein R.sup.2 is a group (b-1) can be prepared
starting from a pyrrolidine, piperidine or homopiperidine
derivative having a suitable leaving group. Similarly compounds
wherein R.sup.2 is a group (b-2) can be prepared starting from a
morpholine having a suitable leaving group.
[0358] Compounds wherein R.sup.2 is C.sub.1-10alkyl,
C.sub.2-10alkenyl, C.sub.3-7cycloalkyl, substituted with a radical
selected from NR.sup.5a--C(.dbd.NR.sup.5b)--NR.sup.5cR.sup.5d,
--O--NR.sup.5a--C(.dbd.NR.sup.5b)--NR.sup.5cR.sup.5d,
-sulfonyl-R.sup.6, --NR.sup.7R.sup.8, --NR.sup.9R.sup.10, a radical
(a-1), (a-2), or (a-3), as defined above, can be prepared starting
from a C.sub.1-10alkyl, C.sub.2-10alkenyl, C.sub.3-7cycloalkyl
bearing two leaving groups which is reacted with a compound (I-b)
in a controlled manner such that only one of the leaving groups is
substituted. Subsequently the thus obtained intermediate is reacted
with an appropriate amine or amineoxide thus substituting the
second leaving group. For example compound of formula (I-b) may be
reacted with a C.sub.1-10alkylene dihalide and subsequently reacted
with an amine H--NR.sup.7R.sup.8, H--NR.sup.9R.sup.10 or another
amine. Other similar process variants may be used in which some or
several functionalities are protected and subsequently
deprotected.
[0359] The compounds of formula (I) wherein X is O, wherein R.sup.2
is cyano, which compounds are represented by formula (I-f), can be
prepared as outlined in the following reaction scheme.
##STR00023##
[0360] 3-Hydroxybenzofuran (VII-a) is condensed with a suitable
aniline derivative to result in a 3-phenylaminobenzofuran (VII-b)
[see V. A. Azimov, S. Yu. Ryabova, L. M. Alekseeva and V. G.
Granik, Chemistry of heterocyclic compounds 2000, 36, 1272-1275].
The conversion from (VII-a) to (VII-b) may be conducted in a
suitable solvent such as a hydrocarbon, for example toluene,
typically in the presence of a catalytic amount of acid such as
e.g. p-toluenesulfonic acid. The 3-phenylaminobenzofuran (VII-b) is
formylated, for example by using phosphorus oxychloride in DMF
followed by hydrolysis. The formylated derivative (VII-c) may be
converted to a compound (VII-d) by using a cyano acetate
derivative, typically in a suitable solvent such as an alcohol,
e.g. iso-propanol, in the presence of a base, preferably a tertiary
amine base such as triethylamine. Intermediate (VII-d) subsequently
is cyclized at elevated temperature to yield compound (I-f). A
suitable solvent for this cyclization reaction is a glycol such as,
e.g., ethylene glycol.
[0361] This synthesis route may also be used to prepare analogs of
the compounds (I-e) wherein R.sup.1 is other than cyano, in
particular compounds of formula (I-e) wherein R.sup.1 is
C.sub.1-4alkyloxycarbonyl, by reacting (VI-c) with a
di(C.sub.1-4alkyl)malonic acid ester.
[0362] The compounds of formula (I) wherein X is S can be prepared
from the sulfur analogs of intermediate (VII-a), i.e.
3-hydroxybenzothiene, following the same procedures outlined above
yielding the sulfur analogs of compounds (I-f). The latter can be
converted to the corresponding sulfoxides (X is SO) or sulfones (X
is SO.sub.2) using art known oxidation procedures, e.g. by
treatment with a suitable peroxide.
[0363] The compounds of formula (I) wherein
-a.sup.1=a.sup.2-a.sup.3=a.sup.4- is a radical (c-1), which is
substituted with amino groups, said compounds being represented by
formula (I-h), can be prepared as outlined in the following
reaction scheme.
##STR00024##
[0364] Starting intermediate (VIII-a) can be prepared following
procedures described above for the preparation of compounds (I-b),
starting from intermediates wherein
-a.sup.1=a.sup.2-a.sup.3=a.sup.4- (c-1) is an unsubstituted
CH.dbd.CH--CH.dbd.CH radical, followed by an N-alkylation reaction
to introduce substituent R.sup.2. Intermediates (VIII-a) are
halogenated using a suitable halogenating agent such as
N-halosuccinimide (NHS), e.g. N-bromosuccinimide, to a compound
(I-j).
[0365] The resulting compound (I-g) may be converted to analogs
wherein radical (c-1) is substituted with a group
--NR.sup.cR.sup.d, wherein --NR.sup.cR.sup.d is an amino
substituent on radical -a.sup.1=a.sup.2-a.sup.3=a.sup.4- (c-1), by
a suitable substitution reaction replacing the halogen atom by the
desired amino group. In preferred execution use can be made of
suitable catalyst such as a bis(diphenylphosphino) palladium
complex e.g. 2,2'-bis(diphenylphosphino)-1,1'-binaphtyl palladium
complex. This reaction is typically conducted in a suitable solvent
such as 1,4-dioxane in the presence of a base such as potassium
t.butoxide or cesium carnbonate. An unsubstituted amino group
(--NH.sub.2) can be obtained using benzophenon imine and subsequent
removal of the benzophenon group.
[0366] The compounds of formula (I) wherein
-a.sup.1=a.sup.2-a.sup.3=a.sup.4- is a radical (c-1), which is
substituted with alkoxycarbonyl groups, said compounds being
represented by formulae (I-i), can be prepared by recating
compounds of formula (I-g) with CO gas in the presence of a
suitable catalyst e.g. [1,1'-bis(diphenylphosphino)ferrocene]
dichloropalladium(II) in a suitable solvent, e.g.
dimethylformamide, in the presence of C.sub.1-4alkyl alcohol, e.g.
methanol or ethanol. This reaction may be conducted under pressure
e.g. in a Parr reactor at higher temperature.
##STR00025##
[0367] When using this reaction procedure with compounds wherein
R.sup.3 is a nitro group, the nitro group is reduced during the CO
addition reaction to the corresponding amino group. The latter can
be converted into a nitro group by using a suitable oxidant such as
a perborate, e.g. sodium perborate monohydrate.
##STR00026##
[0368] The compounds of formula (I) may be transferred into other
compounds of formula (X) with different substitution using
art-known transformation techniques. For instance, the compounds of
formula (I) wherein R.sup.3 is nitro may be reduced to R.sup.3
being amino, and may then be further derivatized. Further examples
of transformation reactions are given in the experimental part.
[0369] The compounds of formula (I) wherein R.sup.1 is cyano may be
hydrolysed to the corresponding compounds of formula (I) wherein
R.sup.1 is hydroxycarbonyl, which in turn may be esterified to
obtain compounds of formula (I) wherein R.sup.1 is
C.sub.1-4alkyloxy-carbonyl. The latter or the hydroxycarbonyl
derivatives may be converted to the corresponding amides using
art-known carboxyl to amide or alkylester to amide transformation
reactions.
[0370] Compounds of formula (I) having a --COOR.sup.4 group wherein
R.sup.4 is hydrogen may be converted to the corresponding esters
using art-known esterification procedures. Vice versa, the esters
can be conveted to the free acid by suitable hydrolysis procedures,
e.g. by hydrolysis in acidic or basic media.
[0371] Compounds of formula (I) having a thiomorpholinyl group can
be oxidized to the corresponding 1-oxothiomorpholinyl or
1,1-dioxothiomorpholinyl containing compounds using a suitable
organic or inorganic peroxide. Appropriate inorganic peroxides
comprise, for example, hydrogen peroxide, alkali metal or earth
alkaline metal peroxides, e.g. sodium peroxide, potassium peroxide;
appropriate organic peroxides may comprise peroxy acids such as,
for example, benzenecarboperoxoic acid or halo substituted
benzenecarboperoxoic acid, e.g. 3-chloro-benzenecarboperoxoic acid,
peroxoalkanoic acids, e.g. peroxoacetic acid, alkylhydroperoxides,
e.g. tert-butyl hydroperoxide. The 1-oxothiomorpholinyl analogs are
preferably obtained using controlled oxidation procedures.
[0372] The compounds of formula (I) may also be converted to the
corresponding K-oxide forms following art-known procedures for
converting a tri-substituted nitrogen into its N-oxide form. Said
N-oxidation reaction may generally be carried out by reacting the
starting material of formula (I) with a suitable organic or
inorganic peroxide. Appropriate inorganic peroxides comprise, for
example, hydrogen peroxide, alkali metal or earth alkaline metal
peroxides, e.g. sodium peroxide, potassium peroxide; appropriate
organic peroxides may comprise peroxy acids such as, for example,
benzenecarboperoxoic acid or halo substituted benzenecarboperoxoic
acid, e.g. 3-chloro-benzenecarboperoxoic acid, peroxoalkanoic
acids, e.g. peroxoacetic acid, alkylhydroperoxides, e.g. tert-butyl
hydroperoxide. Suitable solvents are, for example, water, lower
alkanols, e.g. ethanol and the like, hydrocarbons, e.g. toluene,
ketones, e.g. 2-butanone, halogenated hydrocarbons, e.g.
dichloromethane, and mixtures of such solvents.
[0373] A basic nitrogen occurring in the present compounds can be
quaternized with any agent known to those of ordinary skill in the
art including, for instance, lower alkyl halides, dialkyl sulfates,
long chain halides and aralkyl halides according to art-known
procedures.
[0374] The compounds of the present invention may be used in
animals, preferably in mammals, and in particular in humans as
pharmaceuticals per se, in mixtures with one another or in the form
of pharmaceutical preparations.
[0375] Consequently, the present invention relates to
pharmaceutical formulations containing as active ingredients an
effective dose of at least one of the compounds of formula (I) in
addition to customary pharmaceutically innocuous excipients and
auxiliaries. The pharmaceutical preparations may contain 0.1 to 90%
by weight of a compound of formula (I). The pharmaceutical
preparations can be prepared in a manner known per se to one of
skill in the art. For this purpose, a compound of formula (I),
together with one or more solid or liquid pharmaceutical excipients
and/or auxiliaries and, if desired, in combination with other
pharmaceutical active compounds, are brought into a suitable
administration form or dosage form which can then be used as a
pharmaceutical product in human medicine or veterinary
medicine.
[0376] Pharmaceuticals which contain a compound according to the
invention can be administered orally, parenterally, e.g.,
intravenously, rectally, by inhalation, or topically, the preferred
route of administration being dependent on the individual case,
e.g., the particular course of the disorder to be treated. Oral
administration is preferred.
[0377] The person skilled in the art is familiar on the basis of
his expert knowledge with the auxiliaries that are suitable for the
desired pharmaceutical formulation. Beside solvents, gel-forming
agents, suppository bases, tablet auxiliaries and other active
compound carriers, antioxidants, dispersants, emulsifiers,
antifoams, flavor corrigents, preservatives, solubilizers, agents
for achieving a depot effect, buffer substances or colorants are
also useful.
[0378] Also, the combination of an antiretroviral compound and a
compound of the present invention can be used. Thus, to prevent,
combat or treat HIV infections and the diseases associated with HIV
infection, such as Acquired Immunodeficiency Syndrome (AIDS) or
AIDS Related Complex (ARC), the compounds of this invention may be
co-administered in combination with for instance, binding
inhibitors, fusion inhibitors, co-receptor binding inhibitors; RT
inhibitors; nucleoside RTIs; nucleotide RTIs; NNRTIs; RNAse H
inhibitors; TAT inhibitors; integrase inhibitors; protease
inhibitors; glycosylation inhibitors; entry inhibitors.
[0379] Any of these combinations may provide a synergistic effect,
whereby viral infectivity and its associated symptoms may be
prevented, substantially reduced, or eliminated completely.
[0380] Thus in a further aspect, the present invention also relates
to combinations containing: [0381] (a) a compound of the present
invention, in particular a compound of formula (I) as defined
herein, or a compound of formula (I) of any of the subgroups
specified herein; an N-oxide, salt, stereoisomeric form, prodrug,
ester or metabolite thereof, and [0382] (b) another anti-retroviral
compound, in particular another HIV inhibitor.
[0383] The present invention additionally relates to combinations
containing [0384] (a) (a) a compound of the present invention, in
particular a compound of formula (I) as defined herein, or a
compound of formula (I) of any of the subgroups specified herein,
an N-oxide, salt, stereoisomeric form, prodrug, ester or metabolite
thereof, and [0385] (b) any of the agents selected from binding
inhibitors, such as, for example, dextran sulfate, suramine,
polyanions, soluble CD4, PRO-542, BMS-806; fusion inhibitors, such
as, for example, T20, T1249, RPR 103611, YK-FH312, IC 9564,
5-helix, D-peptide ADS-J1; co-receptor binding inhibitors, such as,
for example, AMD 3100, AMD-3465, AMD7049, AMD3451 (Bicyclams), TAK
779, T-22, ALX40-4C; SHC-C(SCH351125), SHC-D, PRO-140, RPR103611;
RT inhibitors, such as, for example, foscarnet and prodrugs;
nucleoside RTIs, such as, for example, AZT, 3TC, DDC, DDI, D4T,
Abacavir, FTC, DAPD (Amdoxovir), dOTC (BCH-10652), fozivudine, DPC
817; nucleotide RTIs, such as, for example, PMEA, PMPA (tenofovir);
NNRTIs, such as, for example, nevirapine, delavirdine, efavirenz, 8
and 9-Cl TIBO (tivirapine), loviride, TMC-125, dapivirine, MKC-442,
UC 781, UC 782, Capravirine, QM96521, GW420867X, DPC 961, DPC963,
DPC082, DPC083, calanolide A, SJ-3366, TSAO, 4''-deaminated TSAO,
MV150, MV026048, PNU-142721; RNAse H inhibitors, such as, for
example, SP1093V, PD126338; TAT inhibitors, such as, for example,
RO-5-3335, K12, K37; integrase inhibitors, such as, for example, L
708906, L 731988, S-1360; protease inhibitors, such as, for
example, amprenavir and fosamprenavir, ritonavir, nelfinavir,
saquinavir, indinavir, lopinavir, palinavir, BMS 186316,
atazanavir, DPC 681, DPC 684, tipranavir, AG1776, mozenavir,
DMP-323, GS3333, KNI-413, KNI-272, L754394, L756425, LG-71350,
PD161374, PD173606, PD177298, PD178390, PD178392, PNU 140135,
TMC-114, maslinic acid, U-140690; glycosylation inhibitors, such
as, for example, castanospermine, deoxynojirimycine; entry
inhibitors CGP64222; hereafter referred to as agents belonging to
group (b).
[0386] In one embodiment there are provided combinations containing
ingredients (a) and (b), as specified above, wherein the compound
of the present invention is a compound (I-a), an N-oxide, salt,
stereoisomeric form, prodrug, ester or metabolite thereof.
[0387] In another embodiment there are provided combinations
containing ingredients (a) and (b), as specified above, wherein the
compound of the present invention is selected from the group
consisting of: [0388]
8-bromo-5-methyl-1-(4-nitro-phenyl)-2-oxo-2,5-dihydro-1H-pyrido[3,2-b]ind-
ole-3-carbonitrile, [0389]
8-morpholin-5-methyl-1-(4-nitro-phenyl)-2-oxo-2,5-dihydro-1H-pyrido[3,2-b-
]indole-3-carbonitrile, [0390]
8-hydroxy-5-methyl-1-(4-nitro-phenyl)-2-oxo-2,5-dihydro-1H-pyrido[3,2-b]i-
ndole-3-carbonitrile, [0391]
8-hydroxy-1-(4-nitro-phenyl)-2-oxo-2,5-dihydro-1H-pyrido[3,2-b]indole-3-c-
arbonitrile, [0392]
8-methoxy-5-methyl-1-(4-nitro-phenyl)-2-oxo-2,5-dihydro-1H-pyrido[3,2-b]i-
ndole-3-carbonitrile, [0393]
8-[(3-Dimethylamino-propyl)-methylamino]-5-methyl-1-(4-nitro-phenyl)-2-ox-
o-2,5-dihydro-1H-pyrido[3,2-b]indole-3-carbonitrile; [0394]
8-[(3-Dimethylamino-propyl)-oxy]-5-methyl-1-(4-nitro-phenyl)-2-oxo-2,5-di-
hydro-1H-pyrido[3,2-b]indole-3-carbonitrile; and their N-oxides,
salts and possible stereoisomers, said group hereafter being
referred to as "group of compounds (I-j)".
[0395] Embodiments of this invention are combinations comprising
(a) one or more compounds of formula (I), or compounds of any of
the subgroups of compounds of formula (I), as specified herein, in
particular of the subgroups of compounds of formula (I-a), or the
group of compounds (I-j), including the N-oxides, salts,
stereoisomeric forms, prodrugs, esters and metabolites thereof; and
(b) one or more HIV inhibitors selected from: [0396] (i) one or
more fusion inhibitors, such as, for example, T20, T1249, RPR
103611, YK-FH312, IC 9564, 5-helix, D-peptide ADS-J1, enfuvirtide
(ENF), GSK-873, 140, PRO-542, SCH-417,690. TNX-355, maraviroc
(UK-427,857); preferably one or more fusion inhibitors, such as,
for example, enfuvirtide (ENF), GSK-873,140, PRO-542, SCH-417,690,
TNX-355, maraviroc (UK-427,857); [0397] (ii) one or more nucleoside
RTIs, such as for example AZT, 3TC, zalcitabine (ddC), ddI, d4T,
Abacavir (ABC), FTC, DAPD (Amdoxovir), dOTC (BCH-10652),
fozivudine, D-D4FC (DPC 817 or Reverset.TM.), alovudine (MIV-310 or
FLT), elvucitabine (ACH-126,443); preferably one or more nucleoside
RTIs, such as for example, AZT, 3TC, zalcitabine (ddC), ddI, d4T,
Abacavir (ABC), FTC, DAPD (Amdoxovir), D-D4FC (DPC 817 or
Reverset.TM.), alovudine (MIV-310 or FLT), elvucitabine
(ACH-126,443); [0398] (iii) nucleotide RTIs, such as, for example,
PMEA, PMPA (TDF or tenofovir) or tenofovir disoproxil fumarate;
preferably tenofovir or tenofovir disoproxil fumarate; [0399] (iv)
one or more NNRTIs such as, for example, nevirapine, delavirdine,
efavirenz, 8 and 9-Cl TIBO (tivirapine), loviride, TMC125,
4-[[4-[[4-(2-cyanoethenyl)-2,6-diphenyl]amino]-2-pyrimidinyl]amino]-benzo-
nitrile (TMC278 or R278474), dapivirine (R147681 or TMC120),
MKC-442, UC 781, UC 782, Capravirine, QM96521, GW420867X, DPC 961,
DPC963, DPC082, DPC083 (or BMS-561390), calanolide A, SJ-3366,
TSAO, 4''-deaminated TSAO, MV150, MV026048, PNU-14272; or
preferably one or more NNRTIs such as for example nevirapine,
delavirdine, efavirenz, TMC125, TMC278, TMC120, capravirine,
DPC083, calanolide A; [0400] (v) one or more protease inhibitors,
such as, for example, amprenavir and fosamprenavir, lopinavir,
ritonavir (as well as combinations of ritonavir and lopinavir such
as Kaletra.TM.), nelfinavir, saquinavir, indinavir, palinavir, BMS
186316, atazanavir, DPC 681, DPC 684, tipranavir, AG 1776,
mozenavir, DMP-323, GS3333, KNI-413, KNI-272, L754394, L756425,
LG-71350, PD161374, PD173606, PD177298, PD178390, PD178392, PNU
140135, TMC-114, maslinic acid, U-140690; in particular one or more
protease inhibitors, such as, for example, amprenavir and
fosamprenavir, lopinavir, ritonavir (as well as combinations of
ritonavir and lopinavir), nelfinavir, saquinavir, indinavir,
atazanavir, tipranavir, TMC-114.
[0401] In a further aspect the present invention provides
combinations comprising at least one compound of formula (I) or
compounds of any of the subgroups of compounds of formula (I), as
specified herein, in particular of the subgroups of compounds of
formula (I-a), or the group of compounds (I-j), including the
N-oxides, salts, stereoisomeric forms, prodrugs, esters and
metabolites thereof, and at least two different other
antiretroviral agents.
[0402] One embodiment are combinations as specified in the previous
paragraph wherein said two different other antiretroviral agents
are
(i) two nucleoside transcriptase inhibitors (NRTIs); (ii) a
nucleoside (NRTIs) and a nucleotide reverse transcriptase inhibitor
(NtRTI); (iii) an NRTI and an NNRTI; (iv) an NRTI and a protease
inhibitor (PI);
(v) two NRTIs and a PI;
[0403] (vi) an NRTI and a fusion inhibitor.
[0404] The NRTIs, NtRTIs, NNRTIs, PIs and fusion inhibitors in the
combinations mentioned in the previous paragraph may be selected
from the groups of NRTIs, NtRTIs, NNRTIs, PIs and fusion inhibitors
(i), (ii), (iii), (iv) or (v) mentioned above in relation to
embodiments which are combinations comprising ingredients (a) and
(b).
[0405] Of particular interest among the combinations mentioned
above are those comprising a compound of the present invention
having the formula (I) or (I-a), or belonging to or the group of
compounds (I-j), as specified above, and: [0406] (1) a fusion
inhibitor selected from enfuvirtide (ENF), GSK-873,140, PRO-542,
SCH-417,690. TNX-355, maraviroc (UK-427,857); [0407] (2) an NNRTI
selected from nevirapine, delavirdine, efavirenz, TMC125, TMC278,
TMC120, capravirine, DPC083, calanolide A; [0408] (3) an NRTI
selected from AZT, 3TC, zalcitabine (ddC), ddI, d4T, Abacavir
(ABC), FTC, DAPD (Amdoxovir), D-D4FC (DPC 817 or Reverset.TM.),
alovudine (MIV-310 or FLT), elvucitabine (ACH-126,443). [0409] (4)
an NtRTI selected from tenofovir or tenofovir disoproxil fumarate;
[0410] (5) a PI selected from amprenavir and fosamprenavir,
lopinavir, ritonavir (as well as combinations of ritonavir and
lopinavir), nelfinavir, saquinavir, indinavir, atazanavir,
tipranavir, TMC-114; [0411] (6) a NRTI as in (3) and a PI as in
(5); [0412] (7) two different NRTIs as in (3); [0413] (8) an NRTI
as in (3) and an NNRTI as in (2); [0414] (9) two different NRTIs as
in (3) and an NNRTI as in (2); [0415] (10) two different NRTIs as
in (3) and a PI as in (5); [0416] (11) a NRTI as in (3) and an
NtRTI as in (4); or [0417] (12) a NRTI and a fusion inhibitor as in
(1).
[0418] One type of embodiments of this invention are those
combinations as outlined herein that do not contain 3TC.
[0419] The present invention also relates to a product containing
(a) a compound of the present invention, in particular a compound
of formula (I) as defined herein, or a compound of formula (I) of
any of the subgroups defined herein, its N-oxides, salts,
stereoisomeric forms, prodrugs, esters and metabolites, or any
compound of a subgroup as specified herein, and (b) another
antiretroviral compound, as a combined preparation for
simultaneous, separate or sequential use in treatment of retroviral
infections such as HIV infection, in particular, in the treatment
of infections with multi-drug resistant retroviruses.
[0420] Any of the above combinations may provide a synergistic
effect, whereby viral infectivity and its associated symptoms may
be prevented, substantially reduced, or eliminated completely.
[0421] Any of the above mentioned combinations or products may be
used to prevent, combat or treat HIV infections and the disease
associated with HIV infections, such as Acquired Immunodeficiency
Syndrome (AIDS) or AIDS Related Complex (ARC). Therefore in a
further aspect there are provided methods of treating mammals, in
particular humans, being infected with HIV or at risk of being
infected with HIV, said method comprising administering to said
mammals, or in particular to said humans, a combination or a
product as specified herein.
[0422] The compounds of the present invention may also be
administered in combination with immunomodulators (e.g.,
bropirimine, anti-human alpha interferon antibody, IL-2, methionine
enkephalin, interferon alpha, and naltrexone) with antibiotics
(e.g., pentamidine isothiorate) cytokines (e.g. Th2), modulators of
cytokines, chemokines or modulators of chemokines, chemokine
receptors (e.g. CCR5, CXCR4), modulators chemokine receptors, or
hormones (e.g. growth hormone) to ameliorate, combat, or eliminate
HIV infection and its symptoms. Such combination therapy in
different formulations, may be administered simultaneously,
sequentially or independently of each other. Alternatively, such
combination may be administered as a single formulation, whereby
the active ingredients are released from the formulation
simultaneously or separately.
[0423] The compounds of the present invention may also be
administered in combination with modulators of the metabolization
following application of the drug to an individual. These
modulators include compounds that interfere with the metabolization
at cytochromes, such as cytochrome P450. It is known that several
isoenzymes exist of cytochrome P450, one of which is cytochrome
P450 3A4. Ritonavir is an example of a modulator of metabolization
via cytochrome P450. Such combination therapy in different
formulations, may be administered simultaneously, sequentially or
independently of each other. Alternatively, such combination may be
administered as a single formulation, whereby the active
ingredients are released from the formulation simultaneously or
separately. Such modulator may be administered at the same or
different ratio as the compound of the present invention.
Preferably, the weight ratio of such modulator vis-a-vis the
compound of the present invention (modulator:compound of the
present invention) is 1:1 or lower, more preferable the ratio is
1:3 or lower, suitably the ratio is 1:10 or lower, more suitably
the ratio is 1:30 or lower.
[0424] For an oral administration form, compounds of the present
invention are mixed with suitable additives, such as excipients,
stabilizers or inert diluents, and brought by means of the
customary methods into the suitable administration forms, such as
tablets, coated tablets, hard capsules, aqueous, alcoholic, or oily
solutions. Examples of suitable inert carriers are gum arabic,
magnesia, magnesium carbonate, potassium phosphate, lactose,
glucose, or starch, in particular, corn starch. In this case the
preparation can be carried out both as dry and as moist granules.
Suitable oily excipients or solvents are vegetable or animal oils,
such as sunflower oil or cod liver oil. Suitable solvents for
aqueous or alcoholic solutions are water, ethanol, sugar solutions,
or mixtures thereof. Polyethylene glycols and polypropylene glycols
are also useful as further auxiliaries for other administration
forms.
[0425] For subcutaneous or intravenous administration, the active
compounds, if desired with the substances customary therefore such
as solubilizers, emulsifiers or further auxiliaries, are brought
into solution, suspension, or emulsion. The compounds of formula
(I) can also be lyophilized and the lyophilizates obtained used,
for example, for the production of injection or infusion
preparations. Suitable solvents are, for example, water,
physiological saline solution or alcohols, e.g. ethanol, propanol,
glycerol, in addition also sugar solutions such as glucose or
mannitol solutions, or alternatively mixtures of the various
solvents mentioned.
[0426] Suitable pharmaceutical formulations for administration in
the form of aerosols or sprays are, for example, solutions,
suspensions or emulsions of the compounds of formula (I) or their
physiologically tolerable salts in a pharmaceutically acceptable
solvent, such as ethanol or water, or a mixture of such solvents.
If required, the formulation can also additionally contain other
pharmaceutical auxiliaries such as surfactants, emulsifiers and
stabilizers as well as a propellant. Such a preparation customarily
contains the active compound in a concentration from approximately
0.1 to 50%, in particular from approximately 0.3 to 3% by
weight.
[0427] In order to enhance the solubility and/or the stability of
the compounds of formula (I) in pharmaceutical compositions, it can
be advantageous to employ .alpha.-, .beta.- or
.gamma.-cyclo-dextrins or their derivatives. Also co-solvents such
as alcohols may improve the solubility and/or the stability of the
compounds of formula (I) in pharmaceutical compositions. In the
preparation of aqueous compositions, addition salts of the subject
compounds are obviously more suitable due to their increased water
solubility.
[0428] Appropriate cyclodextrins are .alpha.-, .beta.- or
.gamma.-cyclodextrins (CDs) or ethers and mixed ethers thereof
wherein one or more of the hydroxy groups of the anihydroglucose
units of the cyclodextrin are substituted with C.sub.1-6alkyl,
particularly methyl, ethyl or isopropyl, e.g. randomly methylated
.beta.-CD; hydroxyC.sub.1-6alkyl, particularly hydroxy-ethyl,
hydroxypropyl or hydroxybutyl; carboxyC.sub.1-6alkyl, particularly
carboxymethyl or carboxyethyl; C.sub.1-6alkyl-carbonyl,
particularly acetyl; C.sub.1-6alkyloxycarbonylC.sub.1-6alkyl or
carboxyC.sub.1-6alkyloxyC.sub.1-6-alkyl, particularly
carboxymethoxypropyl or carboxyethoxy-propyl;
C.sub.1-6alkylcarbonyloxyC.sub.1-6alkyl, particularly
2-acetyloxypropyl. Especially noteworthy as complexants and/or
solubilizers are .beta.-CD, randomly methylated .beta.-CD,
2,6-dimethyl-.beta.-CD, 2-hydroxyethyl-.beta.-CD,
2-hydroxyethyl-.gamma.-CD, 2-hydroxypropyl-.gamma.-CD and
(2-carboxymethoxy)propyl-.beta.-CD, and in particular
2-hydroxypropyl-.beta.-CD (2-HP- .beta.-CD).
[0429] The term mixed ether denotes cyclodextrin derivatives
wherein at least two cyclodextrin hydroxy groups are etherified
with different groups such as, for example, hydroxy-propyl and
hydroxyethyl.
[0430] An interesting way of formulating the present compounds in
combination with a cyclodextrin or a derivative thereof has been
described in EP-A-721,331. Although the formulations described
therein are with antifungal active ingredients, they are equally
interesting for formulating the compounds of the present invention.
The formulations described therein are particularly suitable for
oral administration and comprise an antifungal as active
ingredient, a sufficient amount of a cyclodextrin or a derivative
thereof as a solubilizer, an aqueous acidic medium as bulk liquid
carrier and an alcoholic co-solvent that greatly simplifies the
preparation of the composition. Said formulations may also be
rendered more palatable by adding pharmaceutically acceptable
sweeteners and/or flavours.
[0431] Other convenient ways to enhance the solubility of the
compounds of the present invention in pharmaceutical compositions
are described in WO 94/05263, WO 98/42318, EP-A-499,299 and WO
97/44014, all incorporated herein by reference.
[0432] More in particular, the present compounds may be formulated
in a pharmaceutical composition comprising a therapeutically
effective amount of particles consisting of a solid dispersion
comprising (a) a compound of formula (I), and (b) one or more
pharmaceutically acceptable water-soluble polymers.
[0433] The term "a solid dispersion" defines a system in a solid
state (as opposed to a liquid or gaseous state) comprising at least
two components, wherein one component is dispersed more or less
evenly throughout the other component or components. When said
dispersion of the components is such that the system is chemically
and physically uniform or homogenous throughout or consists of one
phase as defined in thermo-dynamics, such a solid dispersion is
referred to as "a solid solution". Solid solutions are preferred
physical systems because the components therein are usually readily
bioavailable to the organisms to which they are administered.
[0434] The term "a solid dispersion" also comprises dispersions,
which are less homogenous throughout than solid solutions. Such
dispersions are not chemically and physically uniform throughout or
comprise more than one phase.
[0435] The water-soluble polymer in the particles is conveniently a
polymer that has an apparent viscosity of 1 to 100 mPas when
dissolved in a 2% aqueous solution at 20.degree. C. solution.
[0436] Preferred water-soluble polymers are hydroxypropyl
methylcelluloses or HPMC. HPMC having a methoxy degree of
substitution from about 0.8 to about 2.5 and a hydroxypropyl molar
substitution from about 0.05 to about 3.0 are generally water
soluble. Methoxy degree of substitution refers to the average
number of methyl ether groups present per anhydroglucose unit of
the cellulose molecule. Hydroxy-propyl molar substitution refers to
the average number of moles of propylene oxide which have reacted
with each anhydroglucose unit of the cellulose molecule.
[0437] The particles as defined hereinabove can be prepared by
first preparing a solid dispersion of the components, and then
optionally grinding or milling that dispersion. Various techniques
exist for preparing solid dispersions including melt-extrusion,
spray-drying and solution-evaporation, melt-extrusion being
preferred.
[0438] It may further be convenient to formulate the present
compounds in the form of nanoparticles which have a surface
modifier adsorbed on the surface thereof in an amount sufficient to
maintain an effective average particle size of less than 1000 nm.
Useful surface modifiers are believed to include those that
physically adhere to the surface of the antiretroviral agent but do
not chemically bond to the antiretroviral agent.
[0439] Suitable surface modifiers can preferably be selected from
known organic and inorganic pharmaceutical excipients. Such
excipients include various polymers, low molecular weight
oligomers, natural products and surfactants. Preferred surface
modifiers include nonionic and anionic surfactants.
[0440] Yet another interesting way of formulating the present
compounds involves a pharmaceutical composition whereby the present
compounds are incorporated in hydrophilic polymers and applying
this mixture as a coat film over many small beads, thus yielding a
composition with good bioavailability which can conveniently be
manufactured and which is suitable for preparing pharmaceutical
dosage forms for oral administration.
[0441] Said beads comprise (a) a central, rounded or spherical
core, (b) a coating film of a hydrophilic polymer and an
antiretroviral agent and (c) a seal-coating polymer layer.
[0442] Materials suitable for use as cores in the beads are
manifold, provided that said materials are pharmaceutically
acceptable and have appropriate dimensions and firmness. Examples
of such materials are polymers, inorganic substances, organic
substances, and saccharides and derivatives thereof.
[0443] The route of administration may depend on the condition of
the subject, co-medication and the like.
[0444] Another aspect of the present invention concerns a kit or
container comprising a compound of formula (I) in an amount
effective for use as a standard or reagent in a test or assay for
determining the ability of a potential pharmaceutical to inhibit
HIV reverse transcriptase, HIV growth, or both. This aspect of the
invention may find its use in pharmaceutical research programs.
[0445] The compounds of the present invention can be used in
phenotypic resistance monitoring assays, such as known recombinant
assays, in the clinical management of resistance developing
diseases such as HIV. A particularly useful resistance monitoring
system is a recombinant assay known as the Antivirogram.RTM.. The
Antivirogram.RTM. is a highly automated, high throughput, second
generation, recombinant assay that can measure susceptibility,
especially viral susceptibility, to the compounds of the present
invention. (Hertogs K et al. Antimicrob Agents Chemother, 1998;
42(2):269-276, incorporated by reference).
[0446] The compounds of the present invention may comprise
chemically reactive moieties capable of forming covalent bonds to
localized sites such that said compound have increased tissue
retention and half-lives. The term "chemically reactive group" as
used herein refers to chemical groups capable of forming a covalent
bond. Reactive groups will generally be stable in an aqueous
environment and will usually be carboxy, phosphoryl, or convenient
acyl group, either as an ester or a mixed anhydride, or an imidate,
or a maleimidate thereby capable of forming a covalent bond with
functionalities such as an amino group, a hydroxy or a thiol at the
target site on for example blood components such as albumine. The
compounds of the present invention may be linked to maleimide or
derivatives thereof to form conjugates.
[0447] In still a further aspect, the present invention provides a
method of treating patients who are infected by the HIV virus or at
risk of becoming infected by the HIV virus, said method comprising
the administration of an effective amount of a combination of a
compound of formula (I) or a compound of a subgroup of compounds of
formula (I), as specified herein, and another HIV-inhibitor, which
can be any of the HIV-inhibitors mentioned herein.
[0448] The dose of the present compounds or of the physiologically
tolerable salt(s) thereof to be administered depends on the
individual case and, as customary, is to be adapted to the
conditions of the individual case for an optimum effect. Thus it
depends, of course, on the frequency of administration and on the
potency and duration of action of the compounds employed in each
case for therapy or prophylaxis, but also on the nature and
severity of the infection and symptoms, and on the sex, age, weight
co-medication and individual responsiveness of the human or animal
to be treated and on whether the therapy is acute or prophylactic.
Customarily, the daily dose of a compound of formula (I) in the
case of administration to a patient approximately 75 kg in weight
is 1 mg to 3 g, preferably 3 mg to 1 g, more preferably, 5 mg to
0.5 g. The dose can be administered in the form of an individual
dose, or divided into several, e.g. two, three, or four, individual
doses.
EXAMPLES
[0449] The following examples illustrate the preparation of the
compounds of formula (I) and their intermediates as well as their
pharmacological properties. These examples should not be construed
as a limitation of the scope of the present invention.
Example 1
##STR00027##
[0451] The synthesis of intermediates g started from the
commercially available 1-acetyl-3-hydroxyindole a. Condensation of
intermediate a with 4-nitroaniline, under refluxing conditions in
acetic acid, yielded 3-((4-nitrophenyl)amino)indole (b) (Valezheva
et al.; Chem. Heterocycl. Compd. (Engl. Transl.); 14; 1978;
757,759,760; Khim. Geterotsikl. Soedin.; 14; 1978; 939).
Deacylation of intermediate b with triethylamine in refluxing
methanol and formylation of intermediate c using phosphorus
oxychloride in dimethylformamide resulted in intermediate d
(Ryabova, S. Yu.; Tugusheva, N. Z.; Alekseeva, L. M.; Granik, V.
G.; Pharm. Chem. J. (Engl. Transl.); EN; 30; 7; 1996; 472-477;
Khim. Farm. Zh.; RU; 30; 7; 1996; 42-46). Knoevenagel condensation
of intermediate d with ethyl cyanoacetate in the presence of a
catalytic amount of triethylamine and subsequent intramolecular
cyclisation of intermediate e under reflux in 1,2-ethanediol,
yielded intermediate f
(1-(4-nitro-phenyl)-2-oxo-2,5-dihydro-1H-pyrido[3,2-b]indole-3-carbonitri-
le) (Ryabova, S. Yu.; Alekseeva, L. M.; Granik, B. G.; Chem.
Heterocycl. Compd. (Engl. Translat.)36; 3; 2000; 301-306;
Khim.Geterotsikl.Soedin.; RU; 3; 2000; 362-367). N-methylation
using methyl iodide led to intermediate g
(5-methyl-1-(4-nitro-phenyl)-2-oxo-2,5-dihydro-1H-pyrido[3,2-b]indole-3-c-
arbonitrile).
[0452] More in particular, to a mixture of N-acetyl-3-hydroxyindole
(a) (0.114 mol, 20 g) in acetic acid (150 ml), was added
4-nitroaniline (1.5 equiv., 0.171 mol, 23.65 g). The mixture was
heated at reflux for 5 hours and cooled to room temperature. An
orange precipitate was filtered off and washed with isopropanol and
diisopropyl ether, affording intermediate b.
[0453] Intermediate b (0.070 mol, 20.71 g) was mixed with methanol
(200 ml) and triethylamine (3 equiv., 0.210 mol, 21.27 g) and the
mixture was heated at reflux for 4 hours, cooled to room
temperature and evaporated under reduced pressure to a dry powder.
The crude product c (purity (LC)>95%) was used as such in the
next step.
[0454] To ice-cooled N,N-dimethylformamide (hereinafter referred to
as DMF) (50 ml) was added dropwise phosphorus oxychloride (3
equiv., 0.210 mol, 32.22 g) keeping the internal temperature
<10.degree. C. and the cooled mixture was stirred for 1 hour.
Then, a solution of c in DMF (100 ml) was added dropwise, keeping
the reaction temperature<10.degree. C. during the addition. The
ice-bath was removed and the reaction mixture was stirred at room
temperature for 1.5 hours. The mixture was poured into ice-water (1
liter) and then heated overnight at 60.degree. C. and cooled to
room temperature. The precipitate was isolated by filtration,
washed successively with water, isopropanol and diisopropyl ether
to afford intermediate d (15.93 g, yield=81%, purity
(LC)>95%).
[0455] To a mixture of d (0.056 mol, 15.93 g) in isopropanol (15
ml) was added triethylamine (1.5 equiv., 0.085 mol, 8.59 g) and
ethyl cyanoacetate (0.068 mol, 7.69 g). The mixture was heated at
reflux for 2 hours, cooled to room temperature, filtered and the
residue was successively washed with isopropanol and diisopropyl
ether to afford intermediate e.
[0456] A stirred suspension of d (0.043 mol, 16.42 g) in
ethyleneglycol (200 ml) was heated at reflux for 2 hours and cooled
to room temperature. The precipitate was isolated by filtration and
washed successively with isopropanol and diisopropyl ether. Crude
intermediate f was crystallised from DMF/water as follows: the
crude precipitate was dissolved in warm DMF (250 ml). To the warm
solution, water (100 ml) was added and the solution was cooled to
room temperature, allowing intermediate f to precipitate. The
precipitate was isolated by filtration and washed successively with
isopropanol and diisopropyl ether to afford intermediate f (10.52
g, yield=73%, purity (LC)>98%). .sup.1H NMR (.delta., DMSO-D6):
6.11 (1H, d, J.apprxeq.8 Hz), 6.86 (11, t, J.apprxeq.8 Hz), 7.38
(1H, t, J.apprxeq.8 Hz), 7.54 (1H, d, J.apprxeq.8 Hz), 7.91 (2H, d,
J=8.6 Hz), 8.55 (2H, d, J=8.6 Hz), 8.70 (1H, s), 12.00 (1H, br
s).
[0457] To a mixture of intermediate f (6.05 mmol, 2.0 g) in DMF (20
ml) was added potassium carbonate (2 equiv., 12.11 mmol, 1.674 g)
and methyl iodide (1.5 equiv., 9.08 mmol, 1.289 g) and the mixture
was heated at reflux for 2 hours. The warm suspension was further
diluted with DMF (40 ml). Water (40 ml) was added dropwise to the
warm solution and the mixture was cooled to room temperature,
allowing compound g to crystallise. The precipitate was isolated by
filtration and washed successively with isopropanol and diisopropyl
ether, affording intermediate g (2.085 g, yield=91%, purity
(LC)>98%). .sup.1H NMR (.delta., DMSO-D6): 3.93 (3H, s), 6.12
(1H, d, J.apprxeq.8 Hz), 6.89 (1H, t, J.apprxeq.8 Hz), 7.45 (1H, t,
J.apprxeq.8 Hz), 7.64 (1H, d, J.apprxeq.8 Hz), 7.89 (2H, d,
J.apprxeq.8.5 Hz), 8.54 (2H, d, J=8.5 Hz), 8.99 (1H, s)
Example 2
##STR00028##
[0459] To a mixture of intermediate g (4.00 g, 11.62 mmol) in DMF
(150 ml) was added N-bromosuccinimide (1.2 equiv., 13.94 mmol, 2.48
g). The mixture was stirred overnight at room temperature. The
mixture was filtered and the residue was dried overnight at
50.degree. C. in a vacuum oven to afford compound 1 (4.35 g,
yield=82%, purity (LC)=92%).
[0460] A mixture of palladium(II) acetate (0.2 equiv., 0.1336 mmol,
0.030 g) and rac-2,2'-bis(diphenylphosphino)-1,1'-binaphtyl (0.3
equiv., 0.213 mmol, 0.132 g) in dry 1,4-dioxane (3 ml) was stirred
under nitrogen at 100.degree. C. for 20 min. This mixture was added
to a stirred suspension of compound 1 (0.7089 mmol, 0.300 g),
N-methyl-piperazine (1.7 equiv. 1.20 mmol, 0.121 g) and cesium
carbonate (2.3 equiv., 1.63 mmol, 0.531 g) in dry 1,4-dioxane (5
ml). The reaction mixture was stirred under nitrogen at 100.degree.
C. for 4 days. After cooling the reaction mixture was filtered over
celite and the celite was washed with dimethylformamide
(2.times.100 ml). The filtrate was evaporated under reduced
pressure to a residual volume of 2 ml. The product was precipitated
by the addition of water (20 ml). The product was crystallized from
dimethylformamide/methanol affording compound 4 (0.038 g,
yield=12%, purity (LC)>95%).
Example 3
##STR00029##
[0462] A mixture of palladium(II) acetate (0.189 equiv., 0.044
mmol, 0.010 g) and rac-2,2'-bis(diphenylphosphino)-1,1'-binaphtyl
(0.3 equiv., 0.071 mmol, 0.044 g) in dry 1,4-dioxane (1 ml) was
stirred under nitrogen at 100.degree. C. for 20 min. This mixture
was added to a stirred suspension of compound 1 (0.2363 mmol, 0.100
g), benzophenon imine (1.798 equiv., 0.425 mmol, 0.077 g) and
cesium carbonate (1.948 equiv., 0.4604, 0.150 g) in dry 1,4-dioxane
(1 ml). The reaction mixture was stirred under nitrogen at
100.degree. C. for 84 h. A second mixture of palladium(II) acetate
(0.1885 equiv., 0.04454 mmol, 0.010 g) and
rac-2,2'-bis(diphenylphosphino)-1,1'-binaphtyl (0.3 equiv., 0.071
mmol, 0.044 g) in dry 1,4-dioxane (1 ml) was stirred under nitrogen
at 100.degree. C. for 20 min. This mixture was added to the
reaction mixture and stirred at 100.degree. C. under nitrogen for 5
h. After cooling, 2 N hydrochloric acid (1 ml) was added to the
reaction mixture and it was stirred at room temperature for 2 h.
The reaction mixture was diluted with dichloromethane (50 ml) and
washed with a saturated aqueous sodium bicarbonate solution
(3.times.100 ml). The organic phase was evaporated under reduced
pressure. The dark brown solid residue was mixed with water (25 ml)
and stirred for 1/2 h at room temperature. After filtration, the
precipitate was washed with isopropanol and diisopropylether and
purified by preparative HPLC affording compound 8 (0.112 g,
yield=116%, purity (LC)=88%). The product may contain water and
salts.
Example 4
##STR00030##
[0464] A mixture of compound 1 (0.728 mmol, 0.308 g), triethylamine
(1 equiv., 0.728 mmol, 0.074 g) and
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.13
equiv., 0.098 mmol, 0.080 g) in dimethylformamide (75 ml) and
methanol (25 ml) was stirred overnight in a Parr reactor at
120.degree. C. at a pressure of 35 bar of carbon monooxide. Then,
another portion of [1,1'bis(diphenylphosphino)ferrocene]
dichloropalladium(II) (0.084 equiv., 0.061 mmol, 0.050 g) was added
to the reaction mixture and it was stirred overnight at 140.degree.
C. at a pressure of 35 bar of carbon monoxide. The reaction mixture
was evaporated under reduced pressure. The black residue was mixed
with dichloromethane (100 ml) and filtered. The filtrate was
evaporated under reduced pressure. The dark brown solid residue was
dissolved in dimethylformamide (4 ml). This mixture was poured into
water (40 ml) and stirred for 1/2 h. at room temperature. After
filtration, the precipitate was washed with water, isopropanol and
diisopropylether, affording compound 9 (0.144 g, yield=53%, purity
(LC)=83%).
[0465] A mixture of compound 9 (0.1343 mmol, 0.050 g) in acetic
acid (2 ml) was added dropwise to a mixture of sodium perborate
monohydrate (16 equiv., 2.15 mmol, 0.214 g) in acetic acid (2 ml)
and stirred for 40 h at room temperature in a reaction vial
provided with a calcium chloride tube. After filtration, the
filtrate was evaporated under reduced pressure. The yellow-brown
solid crude mixture was mixed with water (10 ml) and stirred for
1/2 h. at room temperature. After filtration, the precipitate was
purified by preparative HPLC affording compound 12 (0.0046 g,
yield=9%, purity (LC)>95%).
Example 5
##STR00031##
[0467] To a stirred solution of compound 8 (0.16 mmol, 57 mg) in
DMF (2 ml) was added triethylamine (1.25 equiv., 0.2 mmol, 20 mg)
and trifluoroacetyl chloride (1.25 equiv., 0.2 mmol, 26 mg) and the
mixture was stirred at room temperature for 2 hours. The solvent
was evaporated under reduced pressure and the reaction product was
purified by preparative reversed phase HPLC yielding compound 36
(40 mg, yield=55%, purity (LC)>95%).
Example 6
##STR00032##
[0469] Compound g (0.25 mmol, 86 mg) was added to cooled (0.degree.
C.) chlorosulfonic acid (3 ml) and the mixture was stirred
overnight at room temperature. The mixture was poured into a
vigorously stirred biphasic system of saturated aqueous potassium
carbonate and ethyl acetate. The organic phase was isolated and
evaporated under reduced pressure and the residue was taken up in 3
ml DMF. To the resulting solution was added dimethylamine (2 ml of
40% dimethylamine in water) and reaction mixture was stirred for 2
hours at room temperature. The mixture was poured in water (50 ml),
the precipitate was filtered off, washed with water, isopropanol
and diisopropyl ether to afford compound 13 (12 mg, yield=10%,
purity (LC)>95%).
Example 7
##STR00033##
[0471] 2-Amino-5-methoxybenzoic acid (i) (34.1 mmol, 5.70 g) was
mixed with water (10 ml) and ethanol (45 ml). Ethyl bromoacetate
(1.2 equiv., 41.0 mmol, 6.80 g) and sodium hydroxide (2.50 equiv.,
85.2 mmol, 3.41 g) were added and the reaction mixture was stirred
at 60.degree. C. for 1 hour. More sodium hydroxide (0.73 equiv.,
25.0 mmol, 1.00 g) was added and the reaction mixture was stirred
at 60.degree. C. for 1.5 hours. The reaction mixture was cooled to
room temperature, allowing the reaction product to crystallize. The
precipitate was filtered off and washed with isopropanol and
diisopropylether, affording compound j (5.93 g, yield=65%, purity
(LC)=90%).
[0472] Acetic anhydride (50 equiv., 1171.1 mmol, 119.60 g) was
added to a solution of compound j (23.4 mmol, 5.93 g) in ethyl
acetate (60 ml) and the mixture was heated at 70.degree. C. for 2
hours under N.sub.2-atmosphere. After cooling to room temperature,
the reaction mixture was filtered and the filtrate was evaporated
under reduced pressure. The residue was dissolved in chloroform
(200 ml) and washed with water and an aqueous saturated sodium
bicarbonate solution. The organic phase was dried (MgSO.sub.4) and
evaporated to afford compound k (2.12 g, yield=37%, purity
(LC)=70%).
[0473] A solution of compound k (9.2 mmol, 2.12 g) in ethanol (20
ml) was heated to reflux temperature under N.sub.2-atmosphere. To
this stirred mixture, a hot (75.degree. C.) solution of sodium
sulfite (1.5 equiv., 13.75 mmol, 1.73 g) in water (30 ml) was added
and the mixture was heated under reflux for 30 min. After cooling
to room temperature, the reaction mixture was concentrated to half
of the original volume. The aqueous solution was extracted with
chloroform (4.times.). The combined organic fractions were dried
(MgSO.sub.4) and evaporated, affording compound 1 [Sugasawa,
Tsutomu; Adachi, Makoto; Sasakura, Kazuyuki; Kitagawa, Akiko.
Journal of Organic Chemistry 1979, 44(4), 578-86] (1.00 g,
yield=53%, purity (LC)>95%).
[0474] 4-Nitroaniline (1.2 equiv., 4.85 mmol, 0.67 g) and
para-toluenesulfonic acid (a catalytic amount) were added to a
mixture of compound 1 (4.045 mmol, 1.00 g) in toluene (10 ml). The
mixture was heated at reflux for 2 hours and cooled to room
temperature. The precipitate was filtered off and washed with
isopropanol and diisopropylether, affording compound m (1.0479 g,
yield=80%, purity (LC)>95%).
[0475] Compound m (3.22 mmol, 1.0479 g) was mixed with methanol (10
ml) and triethylamine (1.2 equiv., 3.90 mmol, 0.39 g) and heated
under reflux overnight. After cooling to room temperature, the
reaction mixture was evaporated, affording compound n (purity
(LC)>95%). Phosphorus oxychloride (3 equiv., 9.66 mmol, 1.482 g)
was added dropwise to ice-cooled DMF (2 ml), keeping the internal
temperature <5.degree. C. This solution was stirred for 1/2 h at
0.degree. C. Then, a solution of compound n in DMF (8 ml) was added
dropwise, keeping the reaction temperature <5.degree. C. After
stirring for 1/2 hour at 0.degree. C., the reaction mixture was
poured into water (100 ml) and heated overnight at 70.degree. C.
After cooling to room temperature, the precipitate was filtered
off, washed successively with isopropanol and diisopropylether,
affording compound o (0.804 g, yield=80%, purity (LC)>95%).
[0476] To a mixture of compound o (2.58 mmol, 0.804 g) in
isopropanol (10 ml) was added triethylamine (1.5 equiv., 3.94 mmol,
0.399 g) and ethyl cyanoacetate (1.25 equiv., 3.24 mol, 0.366 g).
The mixture was heated at reflux for 1 hour and cooled to room
temperature. The precipitate was filtered off and washed with
isopropanol and diisopropylether to afford compound p (0.841 g,
yield=80%, purity (LC)>95%).
[0477] A stirred suspension of compound p (2.07 mmol, 0.841 g) and
1,8-diazabicyclo-[5.4.0]undec-7-ene (a catalytic amount) in
ethyleneglycol (15 ml) was heated at 185.degree. C. for 1 h and
cooled to room temperature. The precipitate was isolated by
filtration and washed successively with isopropanol and
diisopropylether, affording compound q (0.604 g, yield=81%, purity
(LC)>95%).
[0478] A mixture of compound q (100 mg, 0.278 mmol) and
dimethylformamide dimethyl acetal (DMFDMA) (5 equiv., 1.39 mmol,
165 mg) in DMF (2 ml) was heated to reflux for 2 h. The reaction
mixture was poured into ice-water (20 ml) and stirred for 30 min.
The precipitate was filtered off and washed with water, isopropanol
and diisopropyl ether to afford compound 31 (87 mg, yield=84%,
purity (LC)=95%).
Example 8
##STR00034##
[0480] To a cooled 0.degree. C. solution of compound 31 (0.90 mmol,
337 mg) in dichloromethane (10 ml) was added dropwise boron
tribromide (20 equiv., 18 mmol, 18 ml of a 1N solution of BBr.sub.3
in dichloromethane) and the reaction mixture was stirred at room
temperature for 24 h under N.sub.2-atmosphere. The reaction mixture
was poured into a vigorously stirred aqueous saturated sodium
bicarbonate solution, the precipitate was filtered off, washed with
water, isopropanol and diisopropyl ether to afford compound 29 (155
mg, yield=48%, purity=91%) as a yellow solid.
[0481] Compound 29 (155 mg, 0.43 mmol), 3-dimethylaminopropyl
chloride hydrochloride [0482] (204 mg, 1.29 mmol, 3 equiv.) and
potassium carbonate (300 mg, 2.15 mmol, 5 equiv.) were refluxed in
DMF (5 ml) for 4 h. The reaction mixture was cooled to room
temperature, poured into ice-water. The precipitate was filtered
off, washed with isopropanol and diisopropyl ether, to give the
desired compound 18 (28 mg, yield 15%) as a brown powder.
Example 9
##STR00035##
[0484] To an ice-cooled solution of boron trichloride (18 ml of 1N
BCl.sub.3 in dichloromethane, 18 mmol, 1.1 equiv.) under
N.sub.2-atmosphere was added subsequently a solution of m-anisidine
r (2 g, 16 mmol, 1 equiv.) in dichloromethane (5 ml), followed by
chloro-acetonitrile (1.5 g, 19 mmol, 1.2 equiv.) and finally
aluminum (III) chloride (2.4 g, 18 mmol, 1.1 equiv.) in several
portions. The reaction mixture was refluxed for 3 h. After cooling
to room temperature, the reaction mixture was quenched by addition
of 1N hydrochloric acid at 0.degree. C. A yellow precipitate
appeared. The mixture was heated at 50.degree. C. until the
precipitate disappeared. The mixture was extracted with
dichloromethane, washed with aqueous saturated sodium bicarbonate
and brine, dried (MgSO.sub.4), filtered and concentrated to give
compound s [Sugasawa, Tsutomu; Adachi, Makoto; Sasakura, Kazuyuki;
Kitagawa, Akiko. Journal of Organic Chemistry 1979, 44(4), 578-86]
(2.2 g, yield=65%) as a green solid. The compound was used without
further purification in the next step.
[0485] Intermediate s (2.6 g, 13 mmol) was dissolved in acetic
anhydride (25 ml) and heated at 85.degree. C. for 2 h. The reaction
mixture was concentrated to dryness, the residue was taken up in
dichloromethane, washed with water and brine, dried (MgSO.sub.4),
filtered and concentrated to give compound t [Sugasawa, Tsutomu,
Adachi, Makoto; Sasakura, Kazuyuki; Kitagawa, Akiko. Journal of
Organic Chemistry 1979, 44(4), 578-86] (3.05 g, yield=97%) as an
orange solid. The crude material t was used as such in the next
step.
[0486] To a cooled (0.degree. C.) stirred suspension of sodium
hydride (14 mmol, 1.1 equiv., 0.56 g of a dispersion of 60% NaH in
mineral oil) in dry tetrahydrofuran (20 ml), was added dropwise, a
solution of intermediate t (3.05 g, 13 mmol) in dry tetrahydrofuran
(10 ml) and the mixture was heated for 2 h under reflux. The
reaction mixture was cooled to 0.degree. C. and quenched by the
addition of 1N hydrochloric acid. The reaction mixture was
extracted with dichloromethane, washed with brine, dried
(MgSO.sub.4), filtered and concentrated. Recrystallization from
isopropanol/DCM/diisopropyl ether gave the desired product u
[Sugasawa, Tsutomu; Adachi, Makoto; Sasakura, Kazuyuki; Kitagawa,
Akiko. Journal of Organic Chemistry 1979, 44(4), 578-86] (735 mg,
yield=28%) as a red solid.
[0487] The conversion of compound u to compound 30 was performed
using the same procedures as described in example 1 for the
conversion of compound a to compound g. Compound 30 was obtained as
an orange powder (257 mg, purity (LC)>95%.
[0488] Compound 30 (100 mg, 0.27 mmol) was dissolved in
dichloromethane (5 ml) under N.sub.2-atmosphere, and the reaction
mixture was cooled to 0.degree. C. Boron tribromide (5.3 ml of a 1M
solution of BBr.sub.3 in dichloromethane, 5.3 mmol, 20 equiv.) was
added and the reaction was allowed to warm to room temperature.
After 4 h, the reaction mixture was poured into a mixture of ice
and a saturated solution of sodium bicarbonate under vigorous
stirring. The precipitate was filtered off, washed with water,
isopropanol and diisopropyl ether to give the desired phenol 32 (50
mg, yield=52%) of as an orange powder.
Example 10
##STR00036##
[0490] Phosphorus oxychloride (1.30 equiv., 104 mmol, 15.90 g) was
added dropwise to dimethylacetamide (30 ml) while the reaction
temperature was kept under 20.degree. C. After stirring for 1/2 h,
a solution of 5-methoxyindole A (80 mmol, 11.80 g) in
dimethyl-acetamide (30 ml) was added and reaction mixture was
heated at 90.degree. C. for 2 h and subsequently stirred at room
temperature for 16 h. The mixture was poured into ice-water (500
ml). The aqueous layer was basified with 50% NaOH (30 ml) until
pH=14 and filtered. The precipitate was washed with water and
recrystallized from methanol (200 ml), affording compound B (7.83
g, yield=52%, purity (LC)>95%).
[0491] To a mixture of 3-acetyl-5-methoxyindole B (0.038 mol. 7.2
g) in dry DMF (20 ml), was added diazabicyclo[2.2.2]octane (0.10
equiv., 0.004 mol, 0.43 g) and dimethylcarbonate (2.0 equiv., 0.076
mol, 6.86 g). The reaction mixture was heated at 100.degree. C. for
one week and evaporated under reduced pressure. The residue was
mixed with water (100 ml) and the pH was adjusted to 3 with 1N
hydrochloric acid. The aqueous solution was extracted with
dichloromethane (2.times.300 ml), dried (MgSO.sub.4) and evaporated
under reduced pressure, affording compound C (7.64 g,
yield=98%).
[0492] To a mixture of compound C (38 mmol, 7.64 g) in ethanol (70
ml) and water (35 ml) was added sodium acetate (2.40 equiv., 90
mmol, 7.4 g) and hydroxylamine hydrochloride (3.0 equiv., 113 mmol,
7.8 g). The reaction mixture was heated at reflux for 3 hours,
cooled to room temperature and most of the ethanol was stripped off
under reduced pressure. The remaining aqueous suspension was mixed
with a saturated sodium bicarbonate solution to pH=7. The
precipitate was filtered off and washed with water. The solid was
taken up in toluene and evaporated under reduced pressure to afford
7.7 g of a mixture of compound D (91%) and compound E (8.5%). Thus,
the mixture was dissolved in acetic acid (30 ml) and heated at
reflux for 2 hours. The solvent was evaporated under reduced
pressure, and the residue was purified using column chromatography
on silica gel (eluent: ethylacetate:dichloromethane 2:8) to afford
intermediate E (3.75 g, yield=49%).
[0493] To a mixture of compound E (19.2 mmol, 4.20 g) and
2-hydroxymethylene 3,3-dimethoxypropionitrile sodium salt.sup.ref
(1.50 equiv., 28.9 mmol, 4.77 g) in methanol (50-ml), concentrated
hydrochloric acid (15 ml) was added. The reaction mixture was
heated under reflux for 4 h. After cooling to room temperature, the
precipitate was isolated by filtration, and washed with isopropanol
and diisopropyl ether affording compound F (5.20 mg, yield=98%,
purity (LC)=99%) as its hydrochlorate.
[0494] Compound F (20.0 mmol, 5.47 g) was mixed with chloroform
(1.5 liters) and an aqueous saturated sodium carbonate solution
(200 ml) and vigorously stirred for 15 min. The organic layer was
isolated and concentrated to a residual volume of 150 ml,
3-chloroperbenzoic acid (1.2 equiv., 24 mmol, 5.92 of 70% mCPBA)
was added and the mixture was heated to reflux for 2 h. The
reaction mixture was cooled to room temperature, diluted with
chloroform to a total volume of 800 ml and washed with an aqueous
sodium carbonate solution (2.times.200 ml). The organic layer was
dried (MgSO.sub.4), filtered and evaporated to a dry residue. The
residue was dissolved in acetic anhydride (60 ml) and heated to
reflux for 3 h. The reaction mixture was evaporated under reduced
pressure to a dry dark residue. The residue was mixed with methanol
(100 ml) and triethylamine (2 ml) and heated under reflux for 4 h.
The mixture was allowed to cool to room temperature, the
precipitate was filtered off and washed with isopropanol and
diisopropylether to afford compound I (1.92 g, yield=38%, purity
(LC)=99%) as a yellow powder.
Example 11
##STR00037##
[0496] To a mixture of compound 1 (0.24 mmol, 100 mg) in
dichloromethane (3.0 ml) was added powdered molecular sieves (600
mg), copper(II) acetate (2.0 equiv., 0.48 mmol, 86 mg),
4-cyanophenyl boronic acid (2.0 equiv., 0.48 mmol, 70 mg), pyridine
(2.0 equiv., 0.48 mmol, 37 mg) and triethylamine (2.0 equiv., 0.48
mmol, 48 mg. Air was allowed to enter the reaction mixture via a
CaCl.sub.2-tube on top of the flask. The mixture was stirred at
room temperature for 8 days. The reaction mixture was filtered over
a short path of decalite and washed with a mixture of
tetrahydrofurane/dichloro-methane (9/1). The filtrate was washed
with a saturated sodium bicarbonate solution (2.times.100 ml) and
water (100 ml). The organic layer was evaporated under reduced
pressure and the residue was purified by chromatography on a silica
gel eluting with a mixture of tetrahydrofurane/dichloromethane
(99/1) affording compound 17 (47 mg, yield=49%, purity
(LC)=88%).
[0497] To an ice-cooled mixture of compound 17 (0.13 mmol, 0.45 mg)
in dichloromethane (2 ml) was added boron tribromide (20 equiv.,
2.6 mmol, 2.6 ml of a solution of 1M BBr.sub.3 in dichloromethane)
dropwise under a nitrogen atmosphere. The mixture was stirred at
room temperature for 3 hours and then poured into an ice-cooled
saturated sodium bicarbonate solution (50 ml). The precipitate was
filtered, washed successively with water and diisopropyl ether and
chromatographed on a silica gel column eluting with a mixture of
tetrahydrofurane/dichloromethane (98/2) affording compound 33 (9
mg, yield=21%, purity (LC)=99%).
Example 12
##STR00038##
[0499] To an ice-cooled solution of boron trichloride (1.2 equiv.,
10 mmol, 10 ml of a solution of 1M BCl.sub.3 in dichloromethane)
under N.sub.2-atmosphere was added dropwise a solution of J (1 g, 8
mmol,) in dichloromethane (5 ml). Then, chloroacetonitrile (0.7 g,
10 mmol, 1.2 equiv.) was added dropwise, followed by aluminum (III)
chloride (0.5 g, 4 mmol, 0.5 equiv.) in one portion. The reaction
mixture was allowed to warm up to room temperature and was stirred
for 6 h. The reaction mixture was diluted with dichloromethane and
quenched with 1N hydrochloric acid at 0.degree. C. After stirring
for 10 min, the aqueous layer was extracted with dichloromethane.
The combined organic layers were washed with brine, dried
(MgSO.sub.4) and concentrated. Purification by flash chromatography
on silica gel (eluent: dichloromethane) afforded the desired
product K [Hammond, Milton L.; Zambias, Robert A.; Chang, Michael
N.; Jensen, Norman P.; McDonald, John; Thompson, Kathryn; Boulton,
David A.; Kopka, Ihor E.; Hand, Karen M. Journal of Medicinal
Chemistry 1990, 33(3), 908-18] (1 g, yield=60%).
[0500] Intermediate K (0.15 g, 0.75 mmol, 1 equiv.) and potassium
acetate (0.22 g, 2.2 mmol, 3 equiv.) were refluxed in ethanol (10
ml) for 1 h. After cooling, the reaction mixture was filtered and
concentrated. The residue was mixed with water, and acidified with
1N hydrochloric acid to pH=1. The aqueous solution was extracted
with ethyl acetate, the combined extracts were dried (MgSO.sub.4),
filtered and concentrated to afford the desired product L [Hammond,
Milton L.; Zambias, Robert A.; Chang, Michael N.; Jensen, Norman
P.; McDonald, John; Thompson, Kathryn; Boulton, David A.; Kopka,
Ihor E.; Hand, Karen M. Journal of Medicinal Chemistry 1990, 33(3),
908-18] (110 mg, yield=90%) as a pink solid.
[0501] The experimental procedures for the condensation reaction of
compound L with 4-nitroaniline in acetic acid to form compound M,
followed by Vilsmeier-Haack formulation and subsequent Knoevenagel
condensation of the benzofuran carbaldehyde N with ethyl
cyanoacetate to form compound O, and finally, intramolecular
cyclisation to compound 37 were performed using analogous
procedures as exemplified in example 1 for the synthesis of
compound f starting from compound a. Compound 37 was obtained as a
yellow powder (30 mg, purity (LC)=80%).
[0502] The following tables list examples of compounds of the
present invention which compounds are prepared analogous those of
the foregoing synthesis schemes. In the following tables the column
headed "rf" lists the retention times and the column "(M+H).sup.+"
lists the mass of the molecule ions.
[0503] Retention times were measured using the following equipment:
HPLC-system:
[0504] Waters Alliance 2790 (pump+auto sampler), Waters 996(Photo
diode array-detector);
[0505] Column: Waters XTerra MS CIS 2.5 .mu.m 50.times.4.6 mm. The
following were the measurement parameters:
[0506] Temperature: 30.degree. C.
[0507] Mobile phase: [0508] A: 10 mM HCOONH4+0.1% HCOOH in H.sub.2O
[0509] B: 0.1% HCOOH in CH.sub.3CN
[0510] Gradient: 0 min: 15% B, 5 min: 95% B, 7 min: 95% B
[0511] Equilibration time: 2 min
[0512] Flow: 1.2 ml/min
[0513] Injection volume: 3 ul of a 1 mg/ml solution
[0514] The molecular ion was determined using the following
MS-detector: Waters LCT; ionisation: electrospray in positive or
negative mode.
TABLE-US-00002 TABLE I ##STR00039## Comp. Synthesis No. Example
R.sup.2 R.sup.3 R.sup.20 R.sup.21 rf (M + H).sup.+ 1 2 CH.sub.3
NO.sub.2 Br H 3.94 423 2 2 CH.sub.3 CN Br H 3 2 CH.sub.3 NO.sub.2
4-morpholinyl H 4 2 CH.sub.3 NO.sub.2 4-methyl-piperazin-1-yl H
1.99 443 5 2 CH.sub.3 NO.sub.2 ##STR00040## H 3.37 486 6 2 CH.sub.3
NO.sub.2 C.sub.6H.sub.5--CH.sub.2--N(CH.sub.3)-- H 4.31 464 7 2
CH.sub.3 NO.sub.2 ##STR00041## H 2.26 459 8 3 CH.sub.3 NO.sub.2
--NH.sub.2 H 2.18 360 9 4 CH.sub.3 NH.sub.2 --COOCH.sub.3 H 2.85
373 10 2 CH.sub.3 NO.sub.2 t.Bu-OOC--NH-- H 11 2 CH.sub.3 NO.sub.2
(CH.sub.3).sub.2CH--(CH.sub.2).sub.2--NH-- H 4.05 430 12 4 CH.sub.3
NO.sub.2 --COOCH.sub.3 H 3.48 4.03 13 6 CH.sub.3 NO.sub.2
--SO.sub.2--N(CH.sub.3).sub.2 H 14 6 CH.sub.3 NO.sub.2 ##STR00042##
H 15 7 CH.sub.3 NO.sub.2 F F 3.7 381 16 7 CH.sub.3 NO.sub.2 F
--OCH.sub.3 3.51 393 17 11 CH.sub.3 CN OCH.sub.3 H 18 8 CH.sub.3
NO.sub.2 --O--(CH.sub.2).sub.3--N(CH.sub.3).sub.2 H 2.14 446 19 6
CH.sub.3 NO.sub.2 ##STR00043## H 20 6 CH.sub.3 NO.sub.2
--SO.sub.2--NH--(CH.sub.2).sub.5--CH.sub.3 H 21 2 CH.sub.3 NO.sub.2
##STR00044## H 2.38 501 22 2 CH.sub.3 NO.sub.2 ##STR00045## H 2.35
511 23 2 CH.sub.3 NO.sub.2 ##STR00046## H 2.39 485 24 2 CH.sub.3
NO.sub.2 ##STR00047## H 2.86 506 25 2 CH.sub.3 NO.sub.2
##STR00048## H 4.42 523 26 7 CH.sub.3 NO.sub.2 --CH.sub.3-- H 3.8
359 27 7 CH.sub.3 NO.sub.2 --OCH.sub.3 H 3.59 375 28 7 H NO.sub.2 F
F 3.42 367 29 8 CH.sub.3 NO.sub.2 OH H 2.85 361 30 9 CH.sub.3
NO.sub.2 H --OCH.sub.3 3.56 375 31 11 CH.sub.3 NO.sub.2 --OCH.sub.3
H 3.59 375 32 9 CH.sub.3 NO.sub.2 H OH 2.88 361 33 11 CH.sub.3 CN
OH H 2.73 341 34 5 CH.sub.3 NO.sub.2 --NH--SO.sub.2--CH.sub.3 H 35
2 CH.sub.3 NO.sub.2 ##STR00049## H 3.89 460 36 5 CH.sub.3 NO.sub.2
##STR00050## H
TABLE-US-00003 TABLE 2 ##STR00051## Comp. Synthesis No. Example X
R.sup.3 R.sup.20 R.sup.21 rf (M + H).sup.+ 37 12 O NO.sub.2
--O--CH.sub.3 H 3.74 362
Example 13
In Vitro Inhibition of HIV Reverse Transcriptase
[0515] The assay was run using kit IRK 1022 (Amersham Life
Sciences) according to the manufacturer's instructions with slight
modifications. Compounds were diluted in steps of 1/4 in 100% DMSO
and subsequently transferred to Medium A (1/50 dilution; medium A:
RPMI 1640+10% FetalClone II+Gentamycin 20 mg/L). 25 .mu.l of
compound (in 2% DMSO in Medium A) or 25 .mu.l of 2% DMSO in medium
A was added to wells. To each well was added 25.5 .mu.l master mix
(master mix: 5 .mu.l primer/template beads, 10 .mu.l assay buffer,
0.5 .mu.l tracer (3H-TTP), 5 .mu.l HIV RT enzyme solution at a
final enzyme activity of 15 mU per 50 .mu.l reaction, 5 .mu.l
medium A). The plates were sealed, marked as radioactive and
incubated during 4 hours at 37.degree. C. Subsequently, 100 .mu.l
stop solution was added to each well (except R.sup.1). The
radioactivity was counted in a TopCount.
Example 14
Cellular Assay
[0516] The compounds of the present invention were examined for
anti-viral activity in a cellular assay, which was performed
according to the following procedure.
[0517] HIV- or mock-infected MT4 cells were incubated for five days
in the presence of various concentrations of the inhibitor. At the
end of the incubation period, the replicating virus in the control
cultures has killed all HIV-infected cells in the absence of any
inhibitor. Cell viability was determined by measuring the
concentration of MTT, a yellow, water soluble tetrazolium dye that
is converted to a purple, water insoluble formazan in the
mitochondria of living cells only. Upon solubilization of the
resulting formazan crystals with isopropanol, the absorbance of the
solution was monitored at 540 nm. The values correlate directly to
the number of living cells remaining in the culture at the
completion of the five day incubation. The inhibitory activity of
the compound was monitored on the virus-infected cells and was
expressed as EC.sub.50 and EC.sub.90. These values represent the
amount of the compound required to protect 50% and 90%,
respectively, of the cells from the cytopathogenic effect of the
virus. The toxicity of the compound was measured on the
mock-infected cells and was expressed as CC.sub.50, which
represents the concentration of compound required to inhibit the
growth of the cells by 50%. The selectivity index (SI) (ratio
CC.sub.50/EC.sub.50) is an indication of the selectivity of the
anti-HIV activity of the inhibitor. Wherever results are reported
as e.g. pEC.sub.50 or pCC.sub.50 values, the result is expressed as
the negative logarithm of the result expressed as EC.sub.50 or
CC.sub.50 respectively.
[0518] The pEC.sub.50 values for a number of compounds of this
invention are listed in the following table.
TABLE-US-00004 Comp. No. pEC.sub.50 3 5.6 4 6.5 5 5.7 6 5.7 7 6.8 8
4.7 9 4.8 10 5.9 11 5.2 12 5.7 15 6.4 16 5.4 18 6.6 21 4.8 23 7.1
24 5.2 25 5.5 26 4.8 27 7.1 28 5.6 29 6.7 32 5.9 36 6.8
Example 15
Formulations
Capsules
[0519] A compound of formula (I), is dissolved in organic solvent
such as ethanol, methanol or methylene chloride, preferably, a
mixture of ethanol and methylene chloride. Polymers such as
polyvinylpyrrolidone copolymer with vinyl acetate (PVP-VA) or
hydroxypropylmethylcellulose (HPMC), typically 5 mPas, are
dissolved in organic solvents such as ethanol, methanol methylene
chloride. Suitably the polymer is dissolved in ethanol. The polymer
and compound solutions are mixed and subsequently spray dried. The
ratio of compound/polymer is selected from 1/1 to 1/6. Intermediate
ranges can be 1/1.5 and 1/3. A suitable ratio can be 1/6. The
spray-dried powder, a solid dispersion, is subsequently filled in
capsules for administration. The drug load in one capsule ranges
between 50 and 100 mg depending on the capsule size used.
Film-Coated Tablets
Preparation of Tablet Core
[0520] A mixture of 100 g of a compound of formula (I), 570 g
lactose and 200 g starch are mixed well and thereafter humidified
with a solution of 5 g sodium dodecyl sulfate and 10 g
polyvinylpyrrolidone in about 200 ml of water. The wet powder
mixture is sieved, dried and sieved again. Then there is added 100
g microcrystalline cellulose and 15 g hydrogenated vegetable oil.
The whole is mixed well and compressed into tablets, giving 10.000
tablets, each comprising 10 mg of the active ingredient.
Coating
[0521] To a solution of 10 g methylcellulose in 75 ml of
denaturated ethanol there is added a solution of 5 g of
ethylcellulose in 150 ml of dichloromethane. Then there is added 75
ml of dichloromethane and 2.5 ml 1,2,3-propanetriol. 10 g of
polyethylene glycol is molten and dissolved in 75 ml of
dichloromethane. The latter solution is added to the former and
then there is added 2.5 g of magnesium octadecanoate, 5 g of
polyvinylpyrrolidone and 30 ml of concentrated color suspension and
the whole is homogenated. The tablet cores are coated with the thus
obtained mixture in a coating apparatus.
* * * * *