U.S. patent application number 13/020079 was filed with the patent office on 2011-05-26 for novel mycobacterial inhibitors.
Invention is credited to Jerome Emile Georges GUILLEMONT, David Francis Alain Lancois, Elisabeth Therese Jeanne Pasquier.
Application Number | 20110124870 13/020079 |
Document ID | / |
Family ID | 34807238 |
Filed Date | 2011-05-26 |
United States Patent
Application |
20110124870 |
Kind Code |
A1 |
GUILLEMONT; Jerome Emile Georges ;
et al. |
May 26, 2011 |
NOVEL MYCOBACTERIAL INHIBITORS
Abstract
The present invention relates to novel substituted quinoline
derivatives according to the general Formula (Ia) or the general
Formula (Ib) ##STR00001## the pharmaceutically acceptable acid or
base addition salts thereof, the quaternary amines thereof, the
stereochemically isomeric forms thereof, the tautomeric forms
thereof and the N-oxide forms thereof. The claimed compounds are
useful for the treatment of mycobacterial diseases. In particular,
compounds are claimed in which, independently from each other,
R.sup.1 is halo; p=1; R.sup.2 is optionally substituted alkyloxy,
alkyl, Ar, Het, or a radical of formula ##STR00002## R.sup.3 is
optionally substituted Ar or Het; q=1, R.sup.4 and R.sup.5 each
independently are alkyl; R.sup.6 is hydrogen or a radical of
formula ##STR00003## r is equal to 0 or 1 and R.sup.7 is hydrogen
or Ar. Also claimed is a composition comprising a pharmaceutically
acceptable carrier and, as active ingredient, a therapeutically
effective amount of the claimed compounds, the use of the claimed
compounds or compositions for the manufacture of a medicament for
the treatment of mycobacterial diseases and a process for preparing
the claimed compounds.
Inventors: |
GUILLEMONT; Jerome Emile
Georges; (Ande, FR) ; Pasquier; Elisabeth Therese
Jeanne; (Le Neubourg, FR) ; Lancois; David Francis
Alain; (Louviers, FR) |
Family ID: |
34807238 |
Appl. No.: |
13/020079 |
Filed: |
February 3, 2011 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10596270 |
Jun 7, 2006 |
7902225 |
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PCT/EP05/50271 |
Jan 21, 2005 |
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13020079 |
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60538907 |
Jan 23, 2004 |
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Current U.S.
Class: |
546/167 ;
546/173 |
Current CPC
Class: |
A61P 31/04 20180101;
C07D 409/14 20130101; C07D 215/38 20130101; C07D 215/14 20130101;
C07D 401/14 20130101; C07D 405/12 20130101; C07D 215/227 20130101;
C07D 405/06 20130101; C07D 401/12 20130101; C07D 409/04 20130101;
C07D 401/04 20130101; C07D 405/04 20130101; C07D 405/14 20130101;
A61P 31/06 20180101 |
Class at
Publication: |
546/167 ;
546/173 |
International
Class: |
C07D 405/04 20060101
C07D405/04; C07D 409/04 20060101 C07D409/04; C07D 215/14 20060101
C07D215/14 |
Claims
1-16. (canceled)
17. A compound having the formula; ##STR00130## the
pharmaceutically acceptable acid or base addition salts thereof,
the quaternary amines thereof, the stereochemically isomeric forms
thereof, the tautomeric forms thereof and the N-oxide forms
thereof.
18. A compound having the formula; ##STR00131## the
pharmaceutically acceptable acid or base addition salts thereof,
the quaternary amines thereof, the stereochemically isomeric forms
thereof, the tautomeric forms thereof and the N-oxide forms
thereof.
19. A compound having the formula; ##STR00132## the
pharmaceutically acceptable acid or base addition salts thereof,
the quaternary amines thereof, the stereochemically isomeric forms
thereof, the tautomeric forms thereof and the N-oxide forms
thereof.
20. A compound having the formula; ##STR00133## the
pharmaceutically acceptable acid or base addition salts thereof,
the quaternary amines thereof, the stereochemically isomeric forms
thereof, the tautomeric forms thereof and the N-oxide forms
thereof.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] The present application claims the benefits of the filing of
U.S. application Ser. No. 10/596,270 filed Jun. 7, 2006, Patent
Application No.: PCT/EPOS/50271 filed Jan. 21, 2005 and U.S.
Provisional Application No. 60/538,907 filed Jan. 23, 2004. The
complete disclosures of the aforementioned related patent
applications are hereby incorporated herein by reference for all
purposes.
[0002] The present invention relates to novel substituted quinoline
derivatives useful for the treatment of mycobacterial diseases,
particularly those diseases caused by pathogenic mycobacteria such
as Mycobacterium tuberculosis (M.), M. bovis, M. avium and M.
marinum.
BACKGROUND OF THE INVENTION
[0003] Mycobacterium tuberculosis is the causative agent of
tuberculosis (TB), a serious and potentially fatal infection with a
world-wide distribution. Estimates from the World Health
Organization indicate that more than 8 million people contract TB
each year, and 2 million people die from tuberculosis yearly. In
the last decade, TB cases have grown 20% worldwide with the highest
burden in the most impoverished communities. If these trends
continue, TB incidence will increase by 41% in the next twenty
years. Fifty years since the introduction of an effective
chemotherapy, TB remains after AIDS, the leading infectious cause
of adult mortality in the world. Complicating the TB epidemic is
the rising tide of multi-drug-resistant strains, and the deadly
symbiosis with HIV. People who are HIV-positive and infected with
TB are 30 times more likely to develop active TB than people who
are HIV-negative and TB is responsible for the death of one out of
every three people with HIV/AIDS worldwide.
[0004] Existing approaches to treatment of tuberculosis all involve
the combination of multiple agents. For example, the regimen
recommended by the U.S. Public Health Service is a combination of
isoniazid, rifampicin and pyrazinamide for two months, followed by
isoniazid and rifampicin alone for a further four months. These
drugs are continued for a further seven months in patients infected
with HIV. For patients infected with multi-drug resistant strains
of M. tuberculosis, agents such as ethambutol, streptomycin,
kanamycin, amikacin, capreomycin, ethionamide, cycloserine,
ciprofoxacin and ofloxacin are added to the combination therapies.
There exists no single agent that is effective in the clinical
treatment of tuberculosis, nor any combination of agents that
offers the possibility of therapy of less than six months'
duration.
[0005] There is a high medical need for new drugs that improve
current treatment by enabling regimens that facilitate patient and
provider compliance. Shorter regimens and those that require less
supervision are the best way to achieve this. Most of the benefit
from treatment comes in the first 2 months, during the intensive,
or bactericidal, phase when four drugs are given together; the
bacterial burden is greatly reduced, and patients become
noninfectious. The 4- to 6-month continuation, or sterilizing,
phase is required to eliminate persisting bacilli and to minimize
the risk of relapse. A potent sterilizing drug that shortens
treatment to 2 months or less would be extremely beneficial. Drugs
that facilitate compliance by requiring less intensive supervision
also are needed. Obviously, a compound that reduces both the total
length of treatment and the frequency of drug administration would
provide the greatest benefit.
[0006] Complicating the TB epidemic is the increasing incidence of
multi-drug-resistant strains or MDR-TB. Up to four percent of all
cases worldwide are considered MDR-TB--those resistant to the most
effective drugs of the four-drug standard, isoniazid and rifampin.
MDR-TB is lethal when untreated and can not be adequately treated
through the standard therapy, so treatment requires up to 2 years
of "second-line" drugs. These drugs are often toxic, expensive and
marginally effective. In the absence of an effective therapy,
infectious MDR-TB patients continue to spread the disease,
producing new infections with MDR-TB strains. There is a high
medical need for a new drug with a new mechanism of action, which
is likely to demonstrate activity against MDR strains.
[0007] The term "drug resistant" as used hereinbefore or
hereinafter is a term well understood by the person skilled in
microbiology. A drug resistant Mycobacterium is a Mycobacterium
which is no longer susceptible to at least one previously effective
drug; which has developed the ability to withstand antibiotic
attack by at least one previously effective drug. A drug resistant
strain may relay that ability to withstand to its progeny.
[0008] Said resistance may be due to random genetic mutations in
the bacterial cell that alters its sensitivity to a single drug or
to different drugs.
[0009] MDR tuberculosis is a specific form of drug resistant
tuberculosis due to a bacterium resistant to at least isoniazid and
rifampicin (with or without resistance to other drugs), which are
at present the two most powerful anti-TB drugs.
[0010] The purpose of the present invention is to provide novel
compounds, in particular substituted quinoline derivatives, having
the property of inhibiting growth of Mycobacteria including drug
resistant or multi drug resistant Mycobacteria, and therefore
useful for the treatment of mycobacterial diseases, particularly
those diseases caused by pathogenic mycobacteria such as
Mycobacterium tuberculosis, M. bovis, M. avium, M. smegmatis and M.
marinum.
[0011] Substituted quinolines were already disclosed in U.S. Pat.
No. 5,965,572 (The United States of America) for treating
antibiotic resistant infections and in WO 00/34265 to inhibit the
growth of bacterial microorganisms. WO 2004/011436 describes
quinoline derivatives as antimycobacterial agents.
SUMMARY OF THE INVENTION
[0012] The present invention relates to novel substituted quinoline
derivatives according to Formula (Ia) and (I-b).
##STR00004##
the pharmaceutically acceptable acid or base addition salts
thereof, the quaternary amines thereof, the stereochemically
isomeric forms thereof, the tautomeric forms thereof and the
N-oxide forms thereof, wherein: [0013] R.sup.1 is hydrogen, halo,
haloalkyl, cyano, hydroxy, Ar, Het, alkyl, alkyloxy, alkylthio,
alkyloxyalkyl, alkylthioalkyl, Ar-alkyl or di(Ar)alkyl; [0014] p is
an integer equal to 1, 2 or 3; [0015] R.sup.2 is hydrogen; alkyl;
hydroxy; thio; alkyloxy optionally substituted with amino or mono
or di(alkyl)amino or a radical of formula
##STR00005##
[0015] wherein Z is CH.sub.2, CH--R.sup.10, O, S, N--R.sup.10 and t
is an integer equal to 1 or 2 and the dotted line represents an
optional bond; alkyloxyalkyloxy; alkylthio; mono or di(alkyl)amino
wherein alkyl may optionally be substituted with one or two
substituents each independently be selected from alkyloxy or Ar or
Het or morpholinyl or 2-oxopyrrolidinyl; Ar; Het or a radical of
formula
##STR00006##
wherein Z is CH.sub.2, CH--R.sup.10, O, S, N--R.sup.10; t is an
integer equal to 1 or 2; and the dotted line represents an optional
bond; [0016] R.sup.3 is alkyl, Ar, Ar-alkyl, Het or Het-alkyl;
[0017] q is an integer equal to zero, 1, 2, 3 or 4; [0018] X is a
direct bond or CH.sub.2; [0019] R.sup.4 and R.sup.5 each
independently are hydrogen, alkyl or benzyl; or [0020] R.sup.4 and
R.sup.5 together and including the N to which they are attached may
form a radical selected from the group of pyrrolidinyl,
2H-pyrrolyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolyl, imidazolidinyl,
pyrazolidinyl, 2-imidazolinyl, 2-pyrazolinyl, imidazolyl,
pyrazolyl, triazolyl, piperidinyl, pyridinyl, piperazinyl,
imidazolidinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl,
morpholinyl and thiomorpholinyl, each of said rings optionally
being substituted with alkyl, halo, haloalkyl, hydroxy, alkyloxy,
amino, mono- or dialkylamino, alkylthio, alkyloxyalkyl,
alkylthioalkyl and pyrimidinyl; [0021] R.sup.6 is hydrogen or a
radical of formula
##STR00007##
[0021] wherein s is an integer equal to zero, 1, 2, 3 or 4; r is an
integer equal to 1, 2, 3, 4 or 5; and R.sup.11 is hydrogen, halo,
haloalkyl, hydroxy, Ar, alkyl, alkyloxy, alkylthio, alkyloxyalkyl,
alkylthioalkyl, Ar-alkyl or di(Ar)alkyl; or two vicinal R.sup.11
radicals may be taken together to form together with the phenyl
ring to which they are attached a naphthyl; [0022] R.sup.7 is
hydrogen, alkyl, Ar or Het; [0023] R.sup.8 is hydrogen or alkyl;
[0024] R.sup.9 is oxo; or [0025] R.sup.8 and R.sup.9 together form
the radical --CH.dbd.CH--N.dbd.; [0026] R.sup.10 is hydrogen,
alkyl, hydroxyl, aminocarbonyl, mono- or di(alkyl)aminocarbonyl,
Ar, Het, alkyl substituted with one or two Het, alkyl substituted
with one or two Ar, Het-C(.dbd.O)--, Ar--C(.dbd.O)--; [0027] alkyl
is a straight or branched saturated hydrocarbon radical having from
1 to 6 carbon atoms; or is a cyclic saturated hydrocarbon radical
having from 3 to 6 carbon atoms; or is a a cyclic saturated
hydrocarbon radical having from 3 to 6 carbon atoms attached to a
straight or branched saturated hydrocarbon radical having from 1 to
6 carbon atoms; wherein each carbon atom can be optionally
substituted with halo, hydroxy, alkyloxy or oxo; [0028] Ar is a
homocycle selected from the group of phenyl, naphthyl, acenaphthyl,
tetrahydronaphthyl, each optionally substituted with 1, 2 or 3
substituents, each substituent independently selected from the
group of hydroxy, halo, cyano, nitro, amino, mono- or dialkylamino,
alkyl, haloalkyl, alkyloxy, haloalkyloxy, carboxyl,
alkyloxycarbonyl, alkylcarbonyl, aminocarbonyl, morpholinyl and
mono- or dialkylaminocarbonyl; [0029] Het is a monocyclic
heterocycle selected from the group of N-phenoxypiperidinyl,
pyrrolyl, pyrazolyl, imidazolyl, furanyl, thienyl, oxazolyl,
isoxazolyl, thiazolyl, isothiazolyl, triazolyl, pyridinyl,
pyrimidinyl, pyrazinyl and pyridazinyl; or a bicyclic heterocycle
selected from the group of quinolinyl, isoquinolinyl,
1,2,3,4-tetrahydroisoquinolinyl, quinoxalinyl, indolyl, indazolyl,
benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl,
benzisothiazolyl, benzofuranyl, benzothienyl,
2,3-dihydrobenzo[1,4]dioxinyl or benzo[1,3]dioxolyl; each
monocyclic and bicyclic heterocycle may optionally be substituted
on a carbon atom with 1, 2 or 3 substituents selected from the
group of halo, hydroxy, alkyl or alkyloxy; [0030] halo is a
substituent selected from the group of fluoro, chloro, bromo and
iodo and [0031] haloalkyl is a straight or branched saturated
hydrocarbon radical having from 1 to 6 carbon atoms or a cyclic
saturated hydrocarbon radical having from 3 to 6 carbon atoms,
wherein one or more carbon atoms are substituted with one or more
halo-atoms. provided that when R.sup.7 is hydrogen then the
##STR00008##
[0031] radical may also be placed in position 3 of the quinoline
ring.
[0032] The compounds according to Formula (Ia) and (Ib) are
interrelated in that e.g. a compound according to Formula (Ib),
with R.sup.9 equal to oxo is the tautomeric equivalent of a
compound according to Formula (Ia) with R.sup.2 equal to hydroxy
(keto-enol tautomerism).
DETAILED DESCRIPTION
[0033] In the framework of this application, alkyl is a straight or
branched saturated hydrocarbon radical having from 1 to 6 carbon
atoms; or is a cyclic saturated hydrocarbon radical having from 3
to 6 carbon atoms; or is a a cyclic saturated hydrocarbon radical
having from 3 to 6 carbon atoms attached to a straight or branched
saturated hydrocarbon radical having from 1 to 6 carbon atoms;
wherein each carbon atom can be optionally substituted with halo,
hydroxy, alkyloxy or oxo. Preferably, alkyl is methyl, ethyl or
cyclohexylmethyl.
[0034] C.sub.1-6alkyl as a group or part of a group encompasses the
straight and branched chain saturated hydrocarbon radicals having
from 1 to 6 carbon atoms such as, methyl, ethyl, butyl, pentyl,
hexyl, 2-methylbutyl and the like.
[0035] In the framework of this application, Ar is a homocycle
selected from the group of phenyl, naphthyl, acenaphthyl,
tetrahydronaphthyl, each optionally substituted with 1, 2 or 3
substituents, each substituent independently selected from the
group of hydroxy, halo, cyano, nitro, amino, mono- or dialkylamino,
alkyl, haloalkyl, alkyloxy, haloalkyloxy, carboxyl,
alkyloxycarbonyl, aminocarbonyl, morpholinyl and mono- or
dialkylaminocarbonyl. Preferably, Ar is naphthyl or phenyl, each
optionally substituted with 1 or 2 substituents selected from halo
or alkyl, preferably halo.
[0036] In the framework of this application, Het is a monocyclic
heterocycle selected from the group of N-phenoxypiperidinyl,
pyrrolyl, pyrazolyl, imidazolyl, furanyl, thienyl, oxazolyl,
isoxazolyl, thiazolyl, isothiazolyl, triazolyl, pyridinyl,
pyrimidinyl, pyrazinyl and pyridazinyl; or a bicyclic heterocycle
selected from the group of quinolinyl, isoquinolinyl,
1,2,3,4-tetrahydroisoquinolinyl, quinoxalinyl, indolyl, indazolyl,
benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl,
benzisothiazolyl, benzofuranyl, benzothienyl,
2,3-dihydrobenzo[1,4]dioxinyl or benzo[1,3]dioxolyl; each
monocyclic and bicyclic heterocycle may optionally be substituted
on a carbon atom with 1, 2 or 3 substituents selected from the
group of halo, hydroxy, alkyl or alkyloxy. Preferably, Het is
thienyl, furanyl, imidazolyl, pyridyl, triazolyl,
benzo[1,3]dioxolyl, indazolyl, isoquinolinyl,
1,2,3,4-tetrahydroisoquinolinyl, benzofuranyl.
[0037] In the framework of this application, halo is a substituent
selected from the group of fluoro, chloro, bromo and iodo and
haloalkyl is a straight or branched saturated hydrocarbon radical
having from 1 to 6 carbon atoms or a cyclic saturated hydrocarbon
radical having from 3 to 6 carbon atoms, wherein one or more
carbonatoms are substituted with one or more halo-atoms.
Preferably, halo is bromo, fluoro or chloro and preferably,
haloalkyl is trifluoromethyl.
[0038] In the framework of this application, the quinoline ring of
the compounds of formula (Ia) or (Ib) is numbered as follows:
##STR00009##
[0039] The
##STR00010##
radical may be placed on any available position of the quinoline
moiety.
[0040] Whenever used hereinafter, the term "compounds of formula
(Ia) or (Ib)" is meant to also include their N-oxide forms, their
salts, their quaternary amines, their tautomeric forms and their
stereochemically isomeric forms. Of special interest are those
compounds of formula (Ia) or (Ib) which are stereochemically
pure.
[0041] An interesting embodiment of the present invention relates
to those compounds of formula (Ia) or (Ib), the pharmaceutically
acceptable acid or base addition salts thereof, the
stereochemically isomeric forms thereof, the tautomeric forms
thereof and the N-oxide forms thereof, wherein [0042] R.sup.1 is
hydrogen, halo, haloalkyl, cyano, hydroxy, Ar, Het, alkyl,
alkyloxy, alkylthio, alkyloxyalkyl, alkylthioalkyl, Ar-alkyl or
di(Ar)alkyl; [0043] p is an integer equal to 1, 2 or 3; [0044]
R.sup.2 is hydrogen; alkyl; hydroxy; thio; alkyloxy optionally
substituted with amino or mono or di(alkyl)amino or a radical of
formula
##STR00011##
[0044] wherein Z is CH.sub.2, CH--R.sup.10, O, S, N--R.sup.10 and t
is an integer equal to 1 or 2 and the dotted line represents an
optional bond; alkyloxyalkyloxy; alkylthio; mono or di(alkyl)amino
wherein alkyl may optionally be substituted with one or two
substituents each independently be selected from alkyloxy or Ar or
Het or morpholinyl or 2-oxopyrrolidinyl; Het or a radical of
formula
##STR00012##
wherein Z is CH.sub.2, CH--R.sup.10, O, S, N--R.sup.10; t is an
integer equal to 1 or 2; and the dotted line represents an optional
bond; [0045] R.sup.3 is alkyl, Ar, Ar-alkyl, Het or Het-alkyl;
[0046] q is an integer equal to zero, 1, 2, 3 or 4; [0047] X is a
direct bond; [0048] R.sup.4 and R.sup.5 each independently are
hydrogen, alkyl or benzyl; or [0049] R.sup.4 and R.sup.5 together
and including the N to which they are attached may form a radical
selected from the group of pyrrolidinyl, 2H-pyrrolyl, 2-pyrrolinyl,
3-pyrrolinyl, pyrrolyl, imidazolidinyl, pyrazolidinyl,
2-imidazolinyl, 2-pyrazolinyl, imidazolyl, pyrazolyl, triazolyl,
piperidinyl, pyridinyl, piperazinyl, imidazolidinyl, pyridazinyl,
pyrimidinyl, pyrazinyl, triazinyl, morpholinyl and thiomorpholinyl,
each of said rings optionally being substituted with alkyl, halo,
haloalkyl, hydroxy, alkyloxy, amino, mono- or dialkylamino,
alkylthio, alkyloxyalkyl, alkylthioalkyl and pyrimidinyl; [0050]
R.sup.6 is a radical of formula
##STR00013##
[0050] wherein s is an integer equal to zero, 1, 2, 3 or 4; r is an
integer equal to 1, 2, 3, 4 or 5; and R.sup.11 is hydrogen, halo,
haloalkyl, hydroxy, Ar, alkyl, alkyloxy, alkylthio, alkyloxyalkyl,
alkylthioalkyl, Ar-alkyl or di(Ar)alkyl; or two vicinal R.sup.11
radicals may be taken together to form together with the phenyl
ring to which they are attached a naphthyl; [0051] R.sup.7 is
hydrogen, alkyl, Ar or Het; [0052] R.sup.8 is hydrogen or alkyl;
[0053] R.sup.9 is oxo; or [0054] R.sup.8 and R.sup.9 together form
the radical --CH.dbd.CH--N.dbd.; [0055] R.sup.10 is hydrogen,
alkyl, aminocarbonyl, mono- or di(alkyl)aminocarbonyl, Ar, Het,
alkyl substituted with one or two Het, alkyl substituted with one
or two Ar, Het-C(.dbd.O)--; [0056] alkyl is a straight or branched
saturated hydrocarbon radical having from 1 to 6 carbon atoms; or
is a cyclic saturated hydrocarbon radical having from 3 to 6 carbon
atoms; or is a a cyclic saturated hydrocarbon radical having from 3
to 6 carbon atoms attached to a straight or branched saturated
hydrocarbon radical having from 1 to 6 carbon atoms; wherein each
carbon atom can be optionally substituted with halo, hydroxy,
alkyloxy or oxo; [0057] Ar is a homocycle selected from the group
of phenyl, naphthyl, acenaphthyl, tetrahydronaphthyl, each
optionally substituted with 1, 2 or 3 substituents, each
substituent independently selected from the group of hydroxy, halo,
cyano, nitro, amino, mono- or dialkylamino, alkyl, haloalkyl,
alkyloxy, haloalkyloxy, carboxyl, alkyloxycarbonyl, alkylcarbonyl,
aminocarbonyl, morpholinyl and mono- or dialkylaminocarbonyl;
[0058] Het is a monocyclic heterocycle selected from the group of
N-phenoxypiperidinyl, pyrrolyl, pyrazolyl, imidazolyl, furanyl,
thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl,
pyridinyl, pyrimidinyl, pyrazinyl and pyridazinyl; or a bicyclic
heterocycle selected from the group of quinolinyl, quinoxalinyl,
indolyl, indazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl,
benzothiazolyl, benzisothiazolyl, benzofuranyl, benzothienyl,
2,3-dihydrobenzo[1,4]dioxinyl or benzo[1,3]dioxolyl; each
monocyclic and bicyclic heterocycle may optionally be substituted
on a carbon atom with 1, 2 or 3 substituents selected from the
group of halo, hydroxy, alkyl or alkyloxy; [0059] halo is a
substituent selected from the group of fluoro, chloro, bromo and
iodo and [0060] haloalkyl is a straight or branched saturated
hydrocarbon radical having from 1 to 6 carbon atoms or a cyclic
saturated hydrocarbon radical having from 3 to 6 carbon atoms,
wherein one or more carbon atoms are substituted with one or more
halo-atoms. Preferably, R.sup.11 is hydrogen, halo, haloalkyl,
hydroxy, Ar, alkyl, alkyloxy, alkylthio, alkyloxyalkyl,
alkylthioalkyl, Ar-alkyl or di(Ar)alkyl.
[0061] Preferably, when R.sup.6 is other than hydrogen then R.sup.2
is hydrogen and when R.sup.2 is other than hydrogen then R.sup.6 is
hydrogen.
[0062] Preferably, R.sup.6 is other than hydrogen and R.sup.2 is
hydrogen.
[0063] Preferably, R.sup.2 is other than hydrogen and R.sup.6 is
hydrogen.
[0064] Preferably, the invention relates to compounds of Formula
(Ia) and (Ib) wherein: [0065] R.sup.1 is hydrogen, halo, cyano, Ar,
Het, alkyl, and alkyloxy; [0066] p is an integer equal to 1, 2 or
3; [0067] R.sup.2 is hydrogen; alkyl; hydroxy; alkyloxy optionally
substituted with amino or mono or di(alkyl)amino or a radical of
formula
##STR00014##
[0067] wherein Z is CH.sub.2, CH--R.sup.10, O, S, N--R.sup.10 and t
is an integer equal to 1 or 2 and the dotted line represents an
optional bond; alkyloxyalkyloxy; alkylthio; mono or di(alkyl)amino;
Ar; Het or a radical of formula
##STR00015##
wherein Z is CH.sub.2, CH--R.sup.10, O, S, N--R.sup.16; t is an
integer equal to 1 or 2; and the dotted line represents an optional
bond; [0068] R.sup.3 is alkyl, Ar, Ar-alkyl or Het; [0069] q is an
integer equal to zero, 1, 2, or 3 [0070] X is a direct bond or
CH.sub.2; [0071] R.sup.4 and R.sup.5 each independently are
hydrogen, alkyl or benzyl; or [0072] R.sup.4 and R.sup.5 together
and including the N to which they are attached may form a radical
selected from the group of pyrrolidinyl, imidazolyl, triazolyl,
piperidinyl, piperazinyl, pyrazinyl, morpholinyl and
thiomorpholinyl, optionally substituted with alkyl and pyrimidinyl;
[0073] R.sup.6 is hydrogen or a radical of formula
##STR00016##
[0073] wherein s is an integer equal zero, 1, 2, 3 or 4; r is an
integer equal to 1, 2, 3, 4 or 5; and R.sup.11 is hydrogen, halo,
or alkyl; or two vicinal R.sup.11 radicals may be taken together to
form together with the phenyl ring to which they are attached a
naphthyl; preferably R.sup.11 is hydrogen, halo, or alkyl; [0074] r
is an integer equal to 1; [0075] R.sup.7 is hydrogen or Ar; [0076]
R.sup.8 is hydrogen or alkyl; [0077] R.sup.9 is oxo; or [0078]
R.sup.8 and R.sup.9 together form the radical --CH.dbd.CH--N.dbd.;
[0079] alkyl is a straight or branched saturated hydrocarbon
radical having from 1 to 6 carbon atoms; or is a cyclic saturated
hydrocarbon radical having from 3 to 6 carbon atoms; or is a a
cyclic saturated hydrocarbon radical having from 3 to 6 carbon
atoms attached to a straight or branched saturated hydrocarbon
radical having from 1 to 6 carbon atoms; wherein each carbon atom
can be optionally substituted with halo or hydroxy; [0080] Ar is a
homocycle selected from the group of phenyl, naphthyl, acenaphthyl,
tetrahydronaphthyl, each optionally substituted with 1, 2 or 3
substituents, each substituent independently selected from the
group of halo, haloalkyl, cyano, alkyloxy and morpholinyl; [0081]
Het is a monocyclic heterocycle selected from the group of
N-phenoxypiperidinyl, pyrrolyl, pyrazolyl, imidazolyl, furanyl,
thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl,
pyridinyl, pyrimidinyl, pyrazinyl and pyridazinyl; or a bicyclic
heterocycle selected from the group of quinolinyl, isoquinolinyl,
1,2,3,4-tetrahydroisoquinolinyl, quinoxalinyl, indolyl, indazolyl,
benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl,
benzisothiazolyl, benzofuranyl, benzothienyl,
2,3-dihydrobenzo[1,4]dioxinyl or benzo[1,3]dioxolyl; each
monocyclic and bicyclic heterocycle may optionally be substituted
on a carbon atom with 1, 2 or 3 substituents selected from the
group of halo, hydroxy, alkyl or alkyloxy; and [0082] halo is a
substituent selected from the group of fluoro, chloro and
bromo.
[0083] For compounds according to either Formula (Ia) and (Ib),
preferably, R.sup.1 is hydrogen, halo, Ar, Het, alkyl or alkyloxy.
More preferably, R.sup.1 is hydrogen, halo, alkyl or Het. Even more
in particular R.sup.1 is hydrogen, halo or Het. Most preferably,
R.sup.1 is halo, in particular bromo.
[0084] Preferably, p is equal to 1.
[0085] Preferably, R.sup.2 is hydrogen; alkyl; alkyloxy optionally
substituted with amino or mono or di(alkyl)amino or a radical of
formula
##STR00017##
wherein Z is CH.sub.2, CH--R.sup.10, O, S, N--R.sup.10 and t is an
integer equal to 1 or 2 and the dotted line represents an optional
bond; mono or di(alkyl)amino; Ar; Het or a radical of formula
##STR00018##
wherein Z is CH.sub.2, CH--R.sup.10, O, S, N--R.sup.10; t is an
integer equal to 1 or 2; and the dotted line represents an optional
bond. More preferably, R.sup.2 is alkyloxy, Het, Ar, alkyl, mono or
di(alkyl)amino, a radical of formula
##STR00019##
wherein Z is CH.sub.2, CH--R.sup.10, O, N--R.sup.10; t is an
integer equal to 1 or 2; alkyloxy substituted with amino or mono or
di(alkyl)amino or a radical of formula
##STR00020##
wherein Z is CH.sub.2, CH--R.sup.10, O, N--R.sup.10 and t is an
integer equal to 1 or 2. Most preferably, R.sup.2 is alkyloxy, e.g.
methyloxy; Het or a radical of formula
##STR00021##
wherein Z is CH.sub.2, CH--R.sup.10, O, N--R.sup.10 and t is 1 or
2.
[0086] Preferably, R.sup.3 is naphthyl, phenyl or Het, each
optionally substituted with 1 or 2 substituents, that substituent
preferably being a halo or haloalkyl, most preferably being a halo.
More preferably, R.sup.3 is naphthyl, phenyl, 3,5-dihalophenyl,
1,6-dihalophenyl, thienyl, furanyl, benzofuranyl, pyridyl. Most
preferably, R.sup.3 is optionally substituted phenyl, e.g.
3,5-dihalophenyl, or naphthyl.
[0087] Preferably, q is equal to zero, 1 or 2. More preferably, q
is equal to 1.
[0088] Preferably, R.sup.4 and R.sup.5 each independently are
hydrogen or alkyl, more preferably hydrogen, methyl or ethyl, most
preferably methyl.
[0089] Preferably R.sup.4 and R.sup.5 together and including the N
to which they are attached form a radical selected from the group
of imidazolyl, triazolyl, piperidinyl, piperazinyl and
thiomorpholinyl, optionally substituted with alkyl, halo,
haloalkyl, hydroxy, alkyloxy, alkylthio, alkyloxyalkyl or
alkylthioalkyl, preferably substituted with alkyl, most preferably
substituted with methyl or ethyl.
##STR00022##
[0090] Preferably, R.sup.6 is hydrogen or a radical of formula
wherein s is an integer equal to zero, 1 or 2, preferably zero or
1; r is an integer equal to 1 or 2, preferably 1; and R.sup.11 is
hydrogen, halo, or alkyl, preferably hydrogen or alkyl. More
preferably, R.sup.6 is a radical of formula
##STR00023##
Most preferably, R.sup.6 is benzyl or phenyl. Preferably r is 1 and
R.sup.11 is hydrogen.
[0091] Preferably, R.sup.7 is hydrogen, alkyl or Ar. More
preferably hydrogen or Ar, in particular hydrogen or phenyl. Most
preferably R.sup.7 is hydrogen.
[0092] For compounds according to Formula (Ib) only, preferably,
R.sup.8 is alkyl or hydrogen, preferably hydrogen, and R.sup.9 is
oxygen.
[0093] Preferably, R.sup.10 is hydrogen, alkyl, hydroxyl, alkyl
substituted with one or two Het, alkyl substituted with one or two
Ar, Het-C(.dbd.O)--. Most preferably R.sup.10 is hydroxyl, Het,
alkyl substituted with one Het, alkyl substituted with one Ar.
[0094] Preferably the compounds of the present invention are
compounds according to Formula (Ia), the pharmaceutically
acceptable acid or base addition salts thereof, the quaternary
amines thereof, the stereochemically isomeric forms thereof, the
tautomeric forms thereof and the N-oxide forms thereof.
[0095] Preferably X is a direct bond.
[0096] Preferably X is CH.sub.2.
[0097] An interesting group of compounds are those compounds
according to Formula (Ia) or (Ib), preferably (Ia), the
pharmaceutically acceptable acid or base addition salts thereof,
the quaternary amines thereof, the stereochemically isomeric forms
thereof, the tautomeric forms thereof and the N-oxide forms
thereof, in which R.sup.1 is hydrogen, halo, Ar, alkyl or alkyloxy;
p=1; R.sup.2 is hydrogen, alkyloxy or alkylthio, R.sup.3 is
naphthyl, phenyl or thienyl, each optionally substituted with 1 or
2 substituents selected from the group of halo and haloalkyl; q=0,
1, 2 or 3; R.sup.4 and R.sup.5 each independently are hydrogen or
alkyl or R.sup.4 and R.sup.5 together and including the N to which
they are attached form a radical selected from the group of
imidazolyl, triazolyl, piperidinyl, piperazinyl and
thiomorpholinyl; R.sup.6 is hydrogen, alkyl or halo; r is equal to
1 and R.sup.7 is hydrogen.
[0098] Also an interesting group of compounds are those compounds
according to Formula (Ia) or (Ib), preferably (Ia), the
pharmaceutically acceptable acid or base addition salts thereof,
the quaternary amines thereof, the stereochemically isomeric forms
thereof, the tautomeric forms thereof and the N-oxide forms
thereof, wherein R.sup.1 is hydrogen, halo, alkyl or Het, wherein
Het is preferably pyridyl; R.sup.2 is alkyl, alkyloxy optionally
substituted with mono or di(alkyl)amino or a radical of formula
##STR00024##
wherein
[0099] Z is CH.sub.2, CH--R.sup.10, O, N--R.sup.10, preferably Z is
CH.sub.2, t is an integer equal to 1 or 2, and R.sup.10 is
hydrogen, alkyl, hydroxyl, alkyl substituted with one or two Het,
alkyl substituted with one or two Ar, Het-C(.dbd.O)--, preferably
R.sup.10 is hydrogen; Ar; Het; a radical of formula
##STR00025##
wherein Z is CH.sub.2, CH--R.sup.10, O, N--R.sup.10, t is an
integer equal to 1 or 2, wherein R.sup.16 is hydrogen, alkyl,
hydroxyl, alkyl substituted with one or two Het, alkyl substituted
with one or two Ar, Het-C(.dbd.O)--; R.sup.3 is Ar, preferably
phenyl or naphthyl, or Het, preferably thienyl, furanyl, pyridyl,
benzofuranyl, each of said Ar or Het optionally substituted with 1
or 2 substituents that substituent preferably being a halo; R.sup.4
and R.sup.5 are each alkyl, preferably methyl; R.sup.6 is hydrogen,
phenyl, benzyl or 4-methylbenzyl; R.sup.7 is hydrogen or phenyl;
R.sup.8 is hydrogen; R.sup.9 is oxo.
[0100] Interesting intermediates of the present invention are
intermediates of formula
##STR00026##
wherein W.sub.1 represents a suitable leaving group, such as for
example halo, e.g. chloro, bromo and the like, and wherein R.sup.1,
R.sup.3 to R.sup.7, X, q and p are as defined hereinabove.
[0101] The pharmaceutically acceptable acid addition salts are
defined to comprise the therapeutically active non-toxic acid
addition salt forms which the compounds according to either Formula
(Ia) or (Ib) are able to form. Said acid addition salts can be
obtained by treating the base form of the compounds according to
either Formula (Ia) or (Ib) with appropriate acids, for example
inorganic acids, for example hydrohalic acid, in particular
hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and
phosphoric acid; organic acids, for example acetic acid,
hydroxyacetic acid, propanoic acid, lactic acid, pyruvic acid,
oxalic acid, malonic acid, succinic acid, maleic acid, fumaric
acid, malic acid, tartaric acid, citric acid, methanesulfonic acid,
ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid,
cyclamic acid, salicyclic acid, p-aminosalicylic acid and pamoic
acid.
[0102] The compounds according to either Formula (Ia) or (Ib)
containing acidic protons may also be converted into their
therapeutically active non-toxic base addition salt forms by
treatment with appropriate organic and inorganic bases. Appropriate
base salts forms comprise, for example, the ammonium salts, the
alkaline and earth alkaline metal salts, in particular lithium,
sodium, potassium, magnesium and calcium salts, salts with organic
bases, e.g. the benzathine, N-methyl-D-glucamine, hybramine salts,
and salts with amino acids, for example arginine and lysine.
[0103] Conversely, said acid or base addition salt forms can be
converted into the free forms by treatment with an appropriate base
or acid.
[0104] The term addition salt as used in the framework of this
application also comprises the solvates which the compounds
according to either Formula (Ia) or (Ib) as well as the salts
thereof, are able to form. Such solvates are, for example, hydrates
and alcoholates.
[0105] The term "quaternary amine" as used hereinbefore defines the
quaternary ammonium salts which the compounds of formula (Ia) or
(Ib) are able to form by reaction between a basic nitrogen of a
compound of formula (Ia) or (Ib) and an appropriate quaternizing
agent, such as, for example, an optionally substituted alkylhalide,
arylhalide or arylalkylhalide, e.g. methyliodide or benzyliodide.
Other reactants with good leaving groups may also be used, such as
alkyl trifluoromethanesulfonates, alkyl methanesulfonates, 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.
[0106] The term "stereochemically isomeric forms" as used herein
defines all possible isomeric forms which the compounds of either
Formula (Ia) or (Ib) may possess. Unless otherwise mentioned or
indicated, the chemical designation of compounds denotes the
mixture of all possible stereochemically isomeric forms, said
mixtures containing all diastereomers and enantiomers of the basic
molecular structure. More in particular, stereogenic centers may
have the R- or S-configuration; substituents on bivalent cyclic
(partially) saturated radicals may have either the cis- or
trans-configuration. Stereochemically isomeric forms of the
compounds of either Formula (Ia) or (Ib) are obviously intended to
be embraced within the scope of this invention.
[0107] Following CAS-nomenclature conventions, when two stereogenic
centers of known absolute configuration are present in a molecule,
an R or S descriptor is assigned (based on Cahn-Ingold-Prelog
sequence rule) to the lowest-numbered chiral center, the reference
center. The configuration of the second stereogenic center is
indicated using relative descriptors [R*,R*] or [R*,S*], where R*
is always specified as the reference center and [R *,R *] indicates
centers with the same chirality and [R *,S*] indicates centers of
unlike chirality. For example, if the lowest-numbered chiral center
in the molecule has an S configuration and the second center is R,
the stereo descriptor would be specified as S--[R*,S*]. If "<"
and ".RTM." are used: the position of the highest priority
substituent on the asymmetric carbon atom in the ring system having
the lowest ring number, is arbitrarily always in the "<"
position of the mean plane determined by the ring system. The
position of the highest priority substituent on the other
asymmetric carbon atom in the ring system relative to the position
of the highest priority substituent on the reference atom is
denominated "<", if it is on the same side of the mean plane
determined by the ring system, or ".RTM.", if it is on the other
side of the mean plane determined by the ring system.
[0108] Compounds of either Formula (Ia) and (Ib) and some of the
intermediate compounds invariably have at least one stereogenic
centers in their structure which may lead to at least 2
stereochemically different structures.
[0109] The compounds of either Formula (Ia) or (Ib) as prepared in
the processes described below may be synthesized in the form of
racemic mixtures of enantiomers which can be separated from one
another following art-known resolution procedures. The racemic
compounds of either Formula (Ia) or (Ib) may be converted into the
corresponding diastereomeric salt forms by reaction with a suitable
chiral acid. Said diastereomeric salt forms are subsequently
separated, for example, by selective or fractional crystallization
and the enantiomers are liberated therefrom by alkali. An
alternative manner of separating the enantiomeric forms of the
compounds of either Formula (Ia) or (Ib) involves liquid
chromatography using a chiral stationary phase. 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 will be synthesized by stereospecific
methods of preparation. These methods will advantageously employ
enantiomerically pure starting materials.
[0110] The tautomeric forms of the compounds of either Formula (Ia)
or (Ib) are meant to comprise those compounds of either Formula
(Ia) or (Ib) wherein e.g. an enol group is converted into a keto
group (keto-enol tautomerism).
[0111] The N-oxide forms of the compounds according to either
Formula (Ia) or (Ib) are meant to comprise those compounds of
either Formula (Ia) or (Ib) wherein one or several nitrogen atoms
are oxidized to the so-called N-oxide, particularly those N-oxides
wherein the nitrogen of the amine radical is oxidized.
[0112] The invention also comprises derivative compounds (usually
called "pro-drugs") of the pharmacologically-active compounds
according to the invention, which are degraded in vivo to yield the
compounds according to the invention. Pro-drugs are usually (but
not always) of lower potency at the target receptor than the
compounds to which they are degraded. Pro-drugs are particularly
useful when the desired compound has chemical or physical
properties that make its administration difficult or inefficient.
For example, the desired compound may be only poorly soluble, it
may be poorly transported across the mucosal epithelium, or it may
have an undesirably short plasma half-life. Further discussion on
pro-drugs may be found in Stella, V. J. et al., "Prodrugs", Drug
Delivery Systems, 1985, pp. 112-176, and Drugs, 1985, 29, pp.
455-473.
[0113] Pro-drugs forms of the pharmacologically-active compounds
according to the invention will generally be compounds according to
either Formula (Ia) or (Ib), the pharmaceutically acceptable acid
or base addition salts thereof, the stereochemically isomeric forms
thereof, the tautomeric forms thereof and the N-oxide forms
thereof, having an acid group which is esterified or amidated.
Included in such esterified acid groups are groups of the formula
--COOR.sup.x, where R.sup.x is a C.sub.1-6alkyl, phenyl, benzyl or
one of the following groups:
##STR00027##
[0114] Amidated groups include groups of the formula
--CONR.sup.yR.sup.z, wherein R.sup.y is H, C.sub.1-6alkyl, phenyl
or benzyl and R.sup.z is --OH, H, C.sub.1-6alkyl, phenyl or
benzyl.
[0115] Compounds according to the invention having an amino group
may be derivatised with a ketone or an aldehyde such as
formaldehyde to form a Mannich base. This base will hydrolyze with
first order kinetics in aqueous solution.
[0116] The compounds according to the invention have surprisingly
been shown to be suitable for the treatment of mycobacterial
diseases, particularly those diseases caused by pathogenic
mycobacteria, including drug resistant and multi drug resistant
mycobacteria, such as Mycobacterium tuberculosis, M. bovis, M.
avium, M. smegmatis and M. marinum. The present invention thus also
relates to compounds of either Formula (Ia) or (Ib) as defined
hereinabove, the pharmaceutically acceptable acid or base addition
salts thereof, the stereochemically isomeric forms thereof, the
tautomeric forms thereof and the N-oxide forms thereof, for use as
a medicine. The invention also relates to a composition comprising
a pharmaceutically acceptable carrier and, as active ingredient, a
therapeutically effective amount of a compound according to the
invention. The compounds according to the invention may be
formulated into various pharmaceutical forms for administration
purposes. As appropriate compositions there may be cited all
compositions usually employed for systemically administering drugs.
To prepare the pharmaceutical compositions of this invention, an
effective amount of the particular compound, optionally in addition
salt form, as the active ingredient is combined in intimate
admixture with a pharmaceutically acceptable carrier, which carrier
may take a wide variety of forms depending on the form of
preparation desired for administration. These pharmaceutical
compositions are desirable in unitary dosage form suitable, in
particular, for administration orally or by parenteral injection.
For example, in preparing the compositions in oral dosage form, any
of the usual pharmaceutical media may be employed such as, for
example, water, glycols, oils, alcohols and the like in the case of
oral liquid preparations such as suspensions, syrups, elixirs,
emulsions and solutions; or solid carriers such as starches,
sugars, kaolin, diluents, lubricants, binders, disintegrating
agents and the like in the case of powders, pills, capsules and
tablets. Because of their ease in administration, tablets and
capsules represent the most advantageous oral dosage unit forms in
which case solid pharmaceutical carriers are obviously employed.
For parenteral compositions, the carrier will usually comprise
sterile water, at least in large part, though other ingredients,
for example, to aid solubility, may be included. Injectable
solutions, for example, may be prepared in which the carrier
comprises saline solution, glucose solution or a mixture of saline
and glucose solution. Injectable suspensions may also be prepared
in which case appropriate liquid carriers, suspending agents and
the like may be employed. Also included are solid form preparations
which are intended to be converted, shortly before use, to liquid
form preparations.
[0117] Depending on the mode of administration, the pharmaceutical
composition will preferably comprise from 0.05 to 99% by weight,
more preferably from 0.1 to 70% by weight of the active ingredient
of formula (Ia) or (Ib), and, from 1 to 99.95% by weight, more
preferably from 30 to 99.9 weight % of a pharmaceutically
acceptable carrier, all percentages being based on the total
composition.
[0118] The pharmaceutical composition may additionally contain
various other ingredients known in the art, for example, a
lubricant, stabilising agent, buffering agent, emulsifying agent,
viscosity-regulating agent, surfactant, preservative, flavouring or
colorant.
[0119] It is especially advantageous to formulate the
aforementioned pharmaceutical compositions in unit dosage form for
ease of administration and uniformity of dosage. Unit dosage form
as used herein refers to physically discrete units suitable as
unitary dosages, each unit containing a predetermined quantity of
active ingredient calculated to produce the desired therapeutic
effect in association with the required pharmaceutical carrier.
Examples of such unit dosage forms are tablets (including scored or
coated tablets), capsules, pills, powder packets, wafers,
suppositories, injectable solutions or suspensions and the like,
and segregated multiples thereof. The daily dosage of the compound
according to the invention will, of course, vary with the compound
employed, the mode of administration, the treatment desired and the
mycobacterial disease indicated. However, in general, satisfactory
results will be obtained when the compound according to the
invention is administered at a daily dosage not exceeding 1 gram,
e.g. in the range from 10 to 50 mg/kg body weight.
[0120] Further, the present invention also relates to the use of a
compound of either Formula (Ia) or (Ib), the pharmaceutically
acceptable acid or base addition salts thereof, the
stereochemically isomeric forms thereof, the tautomeric forms
thereof and the N-oxide forms thereof, as well as any of the
aforementioned pharmaceutical compositions thereof for the
manufacture of a medicament for the prevention or the treatment of
mycobacterial diseases.
[0121] Accordingly, in another aspect, the invention provides a
method of treating a patient suffering from, or at risk of, a
mycobacterial disease, which comprises administering to the patient
a therapeutically effective amount of a compound or pharmaceutical
composition according to the invention.
[0122] The compounds of the present invention may also be combined
with one or more other antimycobacterial agents.
[0123] Therefore, the present invention also relates to a
combination of (a) a compound of formula (Ia) or (Ib) and (b) one
or more other antimycobacterial agents.
[0124] The present invention also relates to a combination of (a) a
compound of formula (Ia) or (Ib) and (b) one or more other
antimycobacterial agents for use as a medicine.
[0125] A pharmaceutical composition comprising a pharmaceutically
acceptable carrier and, as active ingredient, a therapeutically
effective amount of (a) a compound of formula (Ia) or (Ib) and (b)
one or more other antimycobacterial agents is also comprised by the
present invention.
[0126] The other Mycobacterial agents which may be combined with
the compounds of formula (Ia) or (Ib) are for example rifampicin
(=rifampin); isoniazid; pyrazinamide; amikacin; ethionamide;
moxifloxacin; ethambutol; streptomycin; para-aminosalicylic acid;
cycloserine; capreomycin; kanamycin; thioacetazone; PA-824;
quinolones/fluoroquinolones such as for example ofloxacin,
ciprofloxacin, sparfloxacin; macrolides such as for example
clarithromycin, clofazimine, amoxycillin with clavulanic acid;
rifamycins; rifabutin; rifapentine.
[0127] Preferably, the present compounds of formula (Ia) or (Ib)
are combined with rifapentin and moxifloxacin.
General Preparation
[0128] The compounds according to the invention can generally be
prepared by a succession of steps, each of which is known to the
skilled person.
[0129] Compounds of formula (Ia) wherein R.sup.2 represents alkoxy;
a radical of formula
##STR00028##
wherein t and Z are defined as hereinabove; alkyloxy substituted
with a radical of formula
##STR00029##
wherein t and Z are defined as hereinabove; mono or di(alkyl)amino
wherein alkyl may optionally be substituted with one or two
substituents each independently be selected from alkyloxy or Ar or
Het or morpholinyl or 2-oxopyrrolidinyl, said R.sup.2 being
represented by R.sup.2a, and said compounds being represented by
formula (Ia-1), can be prepared by reacting an intermediate of
formula (II), wherein W.sub.1 represents a suitable leaving group,
such as for example halo, e.g. chloro and the like, with
H--R.sup.2a or with a suitable salt form of R.sup.2a--H optionally
in the presence of a suitable solvent, such as for example an
alcohol, e.g. methanol and the like, acetonitrile, and optionally
in the presence of a suitable base, such as for example KOH,
dipotassium carbonate.
##STR00030##
[0130] Compounds of formula (Ia) wherein R.sup.2 represents Het or
alkyl, said R.sup.2 being represented by formula R.sup.2b and said
compounds being represented by formula (Ia-2), can be prepared by
reacting an intermediate of formula (II) with
R.sup.2b--B(OH).sub.2, in the presence of a suitable catalyst, such
as for example Pd(PPh.sub.3).sub.4, a suitable solvent, such as for
example dimethylether or an alcohol, e.g. methanol and the like,
and a suitable base, such as for example disodium carbonate or
dipotassium carbonate.
##STR00031##
[0131] Compounds of formula (Ia) wherein R.sup.2 represents Het,
e.g. pyridyl, said R.sup.2 being represented by Het and said
intermediates being represented by formula (Ia-3), can be prepared
by reacting an intermediate of formula (II) with
##STR00032##
in the presence of a suitable catalyst, such as for example
Pd(PPh.sub.3).sub.4, a suitable solvent, such as for example
dimethylether or an alcohol, e.g. methanol and the like, and a
suitable base, such as for example disodium carbonate or
dipotassium carbonate.
##STR00033##
[0132] Compounds of formula (Ia) wherein X is a direct bond, said
intermediates being represented by formula (Ia-4), can be prepared
by reacting an intermediate of formula (III) wherein W.sub.2
represents a suitable leaving group, such as for example halo, e.g.
bromo, chloro and the like, with an intermediate of formula (IV) in
the presence of a suitable coupling agent, such as for example
n-butyl lithium, secBuLi, and in the presence of a suitable
solvent, such as for example tetrahydrofuran, and optionally in the
presence of a suitable base, such as for example
2,2,6,6-tetramethylpiperidine, NH(CH.sub.2CH.sub.2CH.sub.3).sub.2,
N,N-diisopropylamine or trimethylethylenediamine
##STR00034##
[0133] Compounds of formula (Ib) wherein R.sup.9 represents oxo,
can be prepared by reacting an intermediate of formula (II) with a
suitable acid, such as for example HCl, in the presence of a
suitable solvent, such as for example tetrahydrofuran.
##STR00035##
[0134] In the above reactions, the obtained compound of formula
(Ia) or (Ib) can be isolated, and, if necessary, purified according
to methodologies generally known in the art such as, for example,
extraction, crystallization, distillation, trituration and
chromatography.
[0135] In case the compound of formula (Ia) or (Ib) crystallizes
out, it can be isolated by filtration. Otherwise, crystallization
can be caused by the addition of an appropriate solvent, such as
for example water; acetonitrile; an alcohol, such as for example
methanol, ethanol; and combinations of said solvents.
Alternatively, the reaction mixture can also be evaporated to
dryness, followed by purification of the residue by chromatography
(e.g. reverse phase HPLC, flash chromatography and the like). The
reaction mixture can also be purified by chromatography without
previously evaporating the solvent. The compound of formula (Ia) or
(Ib) can also be isolated by evaporation of the solvent followed by
recrystallisation in an appropriate solvent, such as for example
water; acetonitrile; an alcohol, such as for example methanol; and
combinations of said solvents.
[0136] The person skilled in the art will recognise which method
should be used, which solvent is the most appropriate to use or it
belongs to routine experimentation to find the most suitable
isolation method.
[0137] The compounds of formula (Ia) or (Ib) may further be
prepared by converting compounds of formula (Ia) or (Ib) into each
other according to art-known group transformation reactions.
[0138] The compounds of formula (Ia) or (Ib) may be converted to
the corresponding N-oxide forms following art-known procedures for
converting a trivalent nitrogen into its N-oxide form. Said
N-oxidation reaction may generally be carried out by reacting the
starting material of formula (Ia) or (Ib) with an appropriate
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-chlorobenzenecarboperoxoic acid,
peroxoalkanoic acids, e.g. peroxoacetic acid, alkylhydroperoxides,
e.g. t.butyl hydro-peroxide. Suitable solvents are, for example,
water, lower alcohols, 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.
[0139] Compounds of formula (Ia) wherein R.sup.1 represents halo,
said compounds being represented by formula (Ia-5), can be
converted into a compound of formula (Ia) wherein R.sup.1
represents Het, e.g. pyridyl, said compounds being represented by
formula (Ia-6), by reaction with
##STR00036##
n the presence of a suitable catalyst, such as for example
Pd(PPh.sub.3).sub.4, a suitable solvent, such as for example
dimethylether or an alcohol, e.g. methanol and the like, and a
suitable base, such as for example disodium carbonate or
dipotassium carbonate.
##STR00037##
[0140] Compounds of formula (Ia-5) can also be converted into a
compound of formula (Ia) wherein R.sup.1 represents methyl, said
compound being represented by formula (Ia-7), by reaction with
Sn(CH.sub.3).sub.4 in the presence of a suitable catalyst, such as
for example Pd(PPh.sub.3).sub.4, a suitable solvent, such as for
example toluene.
##STR00038##
[0141] Some of the compounds of formula (I) and some of the
intermediates in the present invention may consist of a mixture of
stereochemically isomeric forms. Pure stereochemically isomeric
forms of said compounds and said intermediates can be obtained by
the application of art-known procedures. For example,
diastereoisomers can be separated by physical methods such as
selective crystallization or chromatographic techniques, e.g.
counter current distribution, liquid chromatography and the like
methods. Enantiomers can be obtained from racemic mixtures by first
converting said racemic mixtures with suitable resolving agents
such as, for example, chiral acids, to mixtures of diastereomeric
salts or compounds; then physically separating said mixtures of
diastereomeric salts or compounds by, for example, selective
crystallization or chromatographic techniques, e.g. liquid
chromatography and the like methods; and finally converting said
separated diastereomeric salts or compounds into the corresponding
enantiomers. Pure stereochemically isomeric forms may also be
obtained from the pure stereochemically isomeric forms of the
appropriate intermediates and starting materials, provided that the
intervening reactions occur stereospecifically.
[0142] An alternative manner of separating the enantiomeric forms
of the compounds of formula (I) and intermediates involves liquid
chromatography, in particular liquid chromatography using a chiral
stationary phase.
[0143] It is to be understood that in the above or the following
preparations, the reaction products may be isolated from the
reaction medium and, if necessary, further purified according to
methodologies generally known in the art such as, for example,
extraction, crystallization, distillation, trituration and
chromatography.
[0144] Some of the intermediates and starting materials are known
compounds and may be commercially available or may be prepared
according to art-known procedures.
[0145] Intermediates of formula (II) wherein X is a direct bond,
such intermediates being represented by formula (II-a), can be
prepared by reacting an intermediate of formula (V) wherein W.sub.1
is as defined hereinabove, with an intermediate of formula (IV) in
the presence of a suitable coupling agent, such as nBuLi, secBuLi,
and in the presence of a suitable solvent, such as for example
tetrahydrofuran, and a suitable base, such as for example
2,2,6,6-tetramethylpiperidine, NH(CH.sub.2CH.sub.2CH.sub.3).sub.2,
N,N-diisopropylamine or trimethylethylenediamine
##STR00039##
[0146] Intermediates of formula (II) wherein X represents CH.sub.2,
said intermediates being represented by formula (II-b), can be
prepared by reacting an intermediate of formula (VI) with an
intermediate of formula (IV) in the presence of a suitable coupling
agent, such as nBuLi, secBuLi, and in the presence of a suitable
solvent, such as for example tetrahydrofuran, and a suitable base,
such as for example 2,2,6,6-tetramethylpiperidine,
NH(CH.sub.2CH.sub.2CH.sub.3).sub.2, N,N-diisopropylamine or
trimethylethylenediamine
##STR00040##
[0147] Intermediates of formula (II) wherein R' is hydrogen, said
intermediates being represented by formula (II-c), can be prepared
by reacting an intermediate of formula (V) wherein R.sup.1 is halo,
said intermediates being represented by formula (V-a), with an
intermediate of formula (IV), in the presence of a suitable strong
base, such as for example nBuLi, secBuLi, and in the presence of a
suitable solvent, such as for example tetrahydrofuran.
##STR00041##
[0148] The intermediates of formula (V) are compounds that are
either commercially available or may be prepared according to
conventional reaction procedures generally known in the art. For
example, intermediates of formula (V) wherein R.sup.7 is hydrogen,
R.sup.6 is a radical of formula
##STR00042##
wherein s is an integer equal to 1 and W.sub.1 is chloro, said
intermediates being represented by formula (V-b) may be prepared
according to the following reaction scheme (1):
##STR00043##
wherein all variables are defined as in Formula (Ia). Reaction
scheme (1) comprises step (a) in which an appropriately substituted
aniline is reacted with an appropriate acylchloride such as
3-phenylpropionyl chloride, 3-fluorobenzenepropionyl chloride or
p-chlorobenzenepropionyl chloride, in the presence of a suitable
base, such as triethylamine and a suitable reaction-inert solvent,
such as methylene chloride or ethylene dichloride. The reaction may
conveniently be carried out at a temperature ranging between room
temperature and reflux temperature. In a next step (b) the adduct
obtained in step (a) is reacted with phosphoryl chloride
(POCl.sub.3) in the presence of a suitable solvent, such as for
example N,N-dimethylformamide (Vilsmeier-Haack formylation followed
by cyclization). The reaction may conveniently be carried out at a
temperature ranging between room temperature and reflux
temperature. It is evident that in the foregoing and in the
following reactions, the reaction products may be isolated from the
reaction medium and, if necessary, further purified according to
methodologies generally known in the art, such as extraction,
crystallization and chromatography. It is further evident that
reaction products that exist in more than one enantiomeric form,
may be isolated from their mixture by known techniques, in
particular preparative chromatography, such as preparative HPLC.
Typically, compounds of Formula (Ia) and (Ib) may be separated into
their isomeric forms.
[0149] Intermediates of formula (V-a) wherein W.sub.i represents
chloro, said intermediates being represented by formula (V-a-1),
can be prepared by reacting an intermediate of formula (VII) with
POCl.sub.3.
##STR00044##
[0150] Intermediates of formula (VII) can be prepared by reacting
an intermediate of formula (VIII) with 4-methylbenzenesulfonyl
chloride in the presence of a suitable solvent, such as for example
methylene chloride, and a suitable base, such as for example
dipotassium carbonate.
##STR00045##
[0151] Intermediates of formula (VIII) can be prepared by reacting
an intermediate of formula (IX) with a suitable oxidizing agent,
such as for example 3-chlorobenzenecarboperoxoic acid, in the
presence of a suitable solvent, such as for example methylene
chloride.
##STR00046##
[0152] Intermediates of formula (IX) wherein R.sup.6 is hydrogen
and R.sup.7 is phenyl, said intermediates being represented by
formula (IX-a), can be prepared by reacting an intermediate of
formula (X) with 3-chloro-1-phenyl-1-propanone in the presence of a
suitable acid, such as for example hydrochloric acid, iron chloride
hexahydrate, zinc chloride and a suitable solvent, such as for
example diethyl ether and a suitable alcohol, e.g. ethanol.
##STR00047##
[0153] Intermediates of formula (IX) wherein R.sup.7 is hydrogen
and R.sup.6 is a radical of formula
##STR00048##
wherein s is an integer equal to 1, said intermediates being
represented by formula (IX-b), can be prepared by reacting an
intermediate of formula (XI) in the presence of diphenyl ether.
##STR00049##
[0154] Intermediates of formula (XI) can be prepared by reacting an
intermediate of formula (XII) with an intermediate of formula
(XIII) in the presence of a suitable base, such as for example
sodium hydroxide
##STR00050##
[0155] Intermediates of formula (IV) are compounds that are either
commercially available or may be prepared according to conventional
reaction procedures generally known in the art. For example,
intermediate compounds of Formula (IV) wherein q is equal to 1,
said intermediates being represented by formula (IV-a), can be
prepared according to the following reaction scheme (2):
##STR00051##
[0156] Reaction scheme (2) comprises step (a) in which an
appropriately R.sup.3 is reacted by Friedel-Craft reaction with an
appropriate acylchloride such as 3-chloropropionyl chloride or
4-chlorobutyryl chloride, in the presence of a suitable Lewis acid,
such as AlCl.sub.3, FeCl.sub.3, SnCl.sub.4, TiCl.sub.4 or
ZnCl.sub.2 and a suitable reaction-inert solvent, such as methylene
chloride or ethylene dichloride. The reaction may conveniently be
carried out at a temperature ranging between room temperature and
reflux temperature. In a next step (b) an amino group (e.g.
--NR.sup.4R.sup.5) is introduced by reacting the intermediate
compound obtained in step (a) with an appropriate amine.
[0157] Intermediates of formula (IV-a) can also be prepared by
reacting an intermediate of formula (XIV) with HC(.dbd.O)H and a
suitable aminogroup HNR.sup.4R.sup.5, such as for example
NH(CH.sub.3).sub.2.HCl in the presence of a suitable solvent, such
as for example an alcohol, e.g. methanol, ethanol and the like, and
a suitable acid, such as for example hydrochloric acid.
##STR00052##
[0158] Intermediates of formula (VI) wherein W.sub.1 represents
chloro, said intermediates being represented by formula (VI-a) can
be prepared by reacting an intermediate of formula (XV) with
POCl.sub.3 in the presence of benzyltriethylammonium chloride
(Phase transfert agent) and a suitable solvent, such as for example
acetonitrile.
##STR00053##
##STR00054##
[0159] Intermediates of formula (XV) wherein R.sup.6 represents a
radical of formula wherein s is an integer equal to 1, said
intermediates being represented by formula (XV-a), can be prepared
by reacting an intermediate of formula (XVI) with
NH.sub.2--NH.sub.2 in the presence of a suitable base, such as for
example potassium hydroxide and a suitable solvent, such as for
example 1,2-ethanediol.
##STR00055##
which is an intermediate of formula (XVI) can be prepared by
reacting 1-(2-aminophenyl)ethanone and .beta.-oxobenzenepropanoic
acid ethyl ester.
[0160] Intermediates of formula (III) wherein R.sup.2 represents
C.sub.1-6alkyloxy. said intermediates being represented by formula
(III-a), can be prepared by reacting an intermediate of formula
(XVII) with the appropriate C.sub.1-6alkylO-- salt in the presence
of a suitable solvent, such as for example the corresponding
C.sub.1-6alkylOH.
##STR00056##
[0161] Intermediates of formula (XVII) can be prepared by reacting
an intermediate of formula (XVIII) with POCl.sub.3.
##STR00057##
[0162] Intermediates of formula (XVIII) wherein R.sup.7 is hydrogen
and R.sup.6 represents a radical of formula
##STR00058##
wherein s is an integer equal to 0, said intermediates being
represented by formula (XVIII-a), can be prepared by cyclization of
an intermediate of formula (XIX) in the presence of AlCl.sub.3 and
a suitable solvent, such as for example chlorobenzene.
##STR00059##
[0163] In the intermediates of formula (III) the R.sup.1
substituent may represent halo and then this halo substituent may
take the place of the W.sub.2 leaving group. Said intermediates of
formula (III) being represented by formula
##STR00060##
[0164] The following examples illustrate the present invention
without being limited thereto.
EXPERIMENTAL PART
[0165] Of some compounds the absolute stereochemical configuration
of the stereogenic carbon atom(s) therein was not experimentally
determined. In those cases the stereochemically isomeric form which
was first isolated is designated as "A" and the second as "B",
without further reference to the actual stereochemical
configuration. However, said "A" and "B" isomeric forms can be
unambiguously characterized by a person skilled in the art, using
art-known methods such as, for example, X-ray diffraction. The
isolation method is described in detail below.
[0166] Hereinafter, the term `M.P.` means melting point, `DIPE`
means diisopropyl ether, `DMF` means N,N-dimethylformamide, `THF`
means tetrahydrofuran, `EtOAc` means ethyl acetate, `DCM` means
dichloromethane.
A. Preparation of the Intermediates
Example A1
Preparation of Intermediate 1
##STR00061##
[0168] Benzenepropanoyl chloride (0.488 mol) was added dropwise at
room temperature to a solution of 4-bromo benzenamine (0.407 mol)
in Et.sub.3N (70 ml) and DCM (700 ml) and the mixture was stirred
at room temperature overnight. The mixture was poured out into
water and concentrated NH.sub.4OH, and extracted with DCM. The
organic layer was dried (MgSO.sub.4), filtered, and the solvent was
evaporated. The residue was crystallized from diethyl ether. The
residue (119.67 g) was taken up in DCM and washed with HCl N. The
organic layer was dried (MgSO.sub.4), filtered, and the solvent was
evaporated, yielding 107.67 g of intermediate 1 (87%).
Example A2
Preparation of Intermediate 2
##STR00062##
[0170] Phosphoric trichloride (1.225 mol) was added dropwise at
10.degree. C. to DMF (0.525 mol). Then intermediate 1 (0.175 mol)
was added at room temperature. The mixture was stirred overnight at
80.degree. C., poured out on ice and extracted with DCM. The
organic layer was dried (MgSO.sub.4), filtered, and the solvent was
evaporated. The product was used without further purification,
yielding 77.62 g of intermediate 2 (67%).
Example A3
a) Preparation of Intermediate 3
##STR00063##
[0172] A mixture of intermediate 2 (0.233 mol) in a 30% MeONa in
MeOH solution (222.32 ml) and MeOH (776 ml) was stirred and
refluxed overnight, then poured out on ice and extracted with DCM.
The organic layer was separated, dried (MgSO.sub.4), filtered and
the solvent was evaporated. The residue was purified by column
chromatography over silica gel (eluent: DCM/cyclohexane 20/80 and
then 100/0; 20-45 .mu.m). The pure fractions were collected and the
solvent was evaporated, yielding 25 g of intermediate 3 (33%).
[0173] The following intermediate was prepared according to the
method described above.
##STR00064##
b) Preparation of Intermediate 4
##STR00065##
[0175] A mixture of intermediate 2 (0.045 mol) in a 21% EtONa in
EtOH solution (50 ml) and EtOH (150 ml) was stirred and refluxed
for 12 hours. The mixture was poured out on ice and extracted with
DCM. The organic layer was separated, dried (MgSO.sub.4), filtered
and the solvent was evaporated, yielding 15.2 g of intermediate 4
(98%).
Example A4
a) Preparation of Intermediate 5
##STR00066##
[0177] Aluminum chloride (1.31 mol) was added at room temperature
to a mixture of
N-(3-bromophenyl)-.alpha.-(phenylmethylene)benzeneacetamide (0.1311
mol) in chlorobenzene (500 ml). The mixture was stirred and
refluxed for 3 hours, then cooled to room temperature, poured out
into ice water and filtered. The filtrate was washed with H.sub.2O,
then with cyclohexane and dried, yielding 35.5 g of intermediate 5
(95%).
b) Preparation of Intermediate 6 and Intermediate 7
##STR00067##
[0179] A mixture of intermediate 5 (0.2815 mol) in phosphoric
trichloride (320 ml) was stirred and refluxed for 1 hour, then
cooled to room temperature and the solvent was evaporated till
dryness. The residue was taken up in H.sub.2O. The mixture was
extracted with DCM. The organic layer was separated, dried
(MgSO.sub.4), filtered, and the solvent was evaporated till
dryness. The residue (58.2 g) was purified by column chromatography
over silica gel (eluent: toluene/cyclohexane 80/20; 15-35 .mu.m).
Two fractions were collected and the solvent was evaporated,
yielding 21 g of intermediate 6 and 34.5 g of intermediate 7.
c) Preparation of Intermediate 8
##STR00068##
[0181] A mixture of intermediate 6 (0.0659 mol) and a 30% MeONa in
MeOH solution (0.329 mol) in MeOH (300 ml) was stirred and refluxed
for 2 days, then cooled to room temperature, poured out into ice
water and filtered. The filtrate was washed with H.sub.2O and
dried, yielding 19 g of intermediate 8 (92%).
Example A5
a) Preparation of INTERMEDIATE 9
##STR00069##
[0183] A mixture of 5-bromo-1H-indole-2,3-dione (0.28 mol) in 3N
NaOH (650 ml) was stirred and heated at 80.degree. C. for 30
minutes, then cooled to room temperature. Benzenepropanal (0.28
mol) was added and the mixture was stirred and refluxed overnight.
The mixture was allowed to cool to room temperature and acidified
till pH 5 with HOAc. The precipitate was filtered off, washed with
H.sub.2O and dried (vacuum), yielding 50 g of intermediate 9
(52%).
b) Preparation of Intermediate 10
##STR00070##
[0185] A mixture of intermediate 9 (0.035 mol) in
1,1'-oxybisbenzene (100 ml) was stirred and heated at 300.degree.
C. for 8 hours, then allowed to cool to room temperature. This
procedure was carried out four times. The four mixtures were
combined and then purified by column chromatography over silica gel
(eluent: DCM/MeOH 100/0, then 99/1). The pure fractions were
collected and the solvent was evaporated, yielding 25.6 g of
intermediate 10 (61%).
Example A6
a) Preparation of Intermediate 11
##STR00071##
[0187] HCl/diethyl ether (30 ml) was added to a solution of
4-bromobenzenamine (0.139 mol) in EtOH (250 ml) and the mixture was
stirred for 30 minutes. Iron chloride hexahydrate (0.237 mol) and
then zinc chloride (0.014 mol) were added and the mixture was
stirred at 80.degree. C. for 30 minutes.
3-Chloro-1-phenyl-1-propanone (0.146 mol) was added and the mixture
was stirred at 80.degree. C. for one night. The mixture was poured
into water and extracted with EtOAc. The organic layer was washed
with water, then with K.sub.2CO.sub.3 10%, dried (MgSO.sub.4),
filtered off and evaporated. The residue (25 g) was purified by
column chromatography over silica gel (eluent: DCM/MeOH 100/0 and
then 97/3) (35-70 .mu.m). The pure fractions were collected and
evaporated, yielding 17.5 g of intermediate 11 (44%).
b) Preparation of Intermediate 12
##STR00072##
[0189] 3-Chlorobenzenecarboperoxoic acid (0.12 mol) was added
portionwise at room temperature to a solution of intermediate 11
(0.0598 mol) in DCM (200 ml) and the mixture was stirred at room
temperature for one night. K.sub.2CO.sub.3 10% was added, the
organic layer was decanted, dried (MgSO.sub.4), filtered off and
evaporated till a volume of 150 ml of intermediate 12 was left.
c) Preparation of Intermediate 13
##STR00073##
[0191] 4-Methylbenzenesulfonyl chloride (0.075 mol) was added
portionwise at room temperature to a solution of intermediate 12
(0.0598 mol) in a 10% K.sub.2CO.sub.3 solution (150 ml) and DCM
(150 ml) and the mixture was stirred at room temperature for one
night. Diethyl ether was added and filtered off. The precipitate
was washed with diethyl ether and evaporated till dryness, yielding
14 g of intermediate 13 (78%).
d) Preparation of Intermediate 14
##STR00074##
[0193] A mixture of intermediate 13 (0.047 mol) in phosphoric
trichloride (150 ml) was stirred and refluxed for 48 hours. The
mixture was evaporated, the residue was taken up in NH.sub.4OH and
extracted with DCM. The organic layer was dried (MgSO.sub.4),
filtered off and evaporated, yielding 13 g of intermediate 14
(87%).
Example A7
a) Preparation of Intermediate 15
##STR00075##
[0195] A mixture of 1-(2-aminophenyl)ethanone (0.37 mol) and
.beta.-oxobenzenepropanoic acid ethyl ester (1.48 mol) was stirred
at 180.degree. C. overnight. The mixture was brought to room
temperature. The precipitate was filtered, washed with diethyl
ether and dried. The residue was crystallized from DIPE. The
precipitate was filtered off and dried, yielding 56.6 g of
intermediate 15 (58%).
b) Preparation of Intermediate 16
##STR00076##
[0197] A mixture of intermediate 15 (0.076 mol) and hydrazine (0.76
mol) in 1,2-ethanediol (240 ml) was stirred at 100.degree. C. for 1
hour. KOH (0.266 mol) was added. The mixture was stirred at
180.degree. C. overnight. H.sub.2O was added. The mixture was
acidified and extracted with DCM. The organic layer was separated,
dried (MgSO.sub.4), filtered, and the solvent was evaporated. The
residue (12.05 g) was crystallized from DIPE. The precipitate was
filtered off and dried, yielding 4.74 g of intermediate 16.
c) Preparation of Intermediate 17
##STR00077##
[0199] Phosphoric trichloride (0.057 mol) was added slowly at
80.degree. C. to a mixture of intermediate 16 (0.019 mol) and
benzyltriethylammonium chloride (0.0532 mol) in acetonitrile (50
ml). The mixture was stirred overnight. The solvent was evaporated.
The mixture was poured out into ice and Na.sub.2CO.sub.3 10% and
extracted with DCM. The organic layer was separated, dried
(MgSO.sub.4), filtered, and the solvent was evaporated, yielding
4.08 g of intermediate 17.
Example A8
a) Preparation of Intermediate 18 and Intermediate 19
##STR00078##
[0201] A mixture of aluminium chloride (0.257 mol) and
3-chloropropanoyl chloride (0.234 mol) in 1,2-dichloroethane (100
ml) was stirred at 0.degree. C. A solution of naphthalene (0.234
mol) in 1,2-dichloroethane (100 ml) was added. The mixture was
stirred at 0.degree. C. for 1 hour and poured out into ice water.
The organic layer was separated, dried (MgSO.sub.4), filtered, and
the solvent was evaporated. The residue (56 g) was purified by
column chromatography over silica gel (eluent: cyclohexane/DCM
60/40; 20-45 .mu.m). Two fractions were collected and the solvent
was evaporated, yielding 2 fractions, 31 g of fraction 1 as
intermediate 18 (61%) and 14 g of fraction 2. Fraction 2 was taken
up in DIPE, then the resulting precipitate was filtered off and
dried, yielding 8.2 g of intermediate 19
b) Preparation of Intermediate 20
##STR00079##
[0203] A mixture of intermediate 18 (0.0137 mol),
N-methylbenzenemethanamine (0.015 mol) and K.sub.2CO.sub.3 (2 g) in
acetonitrile (100 ml) was stirred at 80.degree. C. for 2 hours.
H.sub.2O was added. The mixture was extracted with DCM. The organic
layer was separated, dried (MgSO.sub.4), filtered, and the solvent
was evaporated, yielding 4.2 g of intermediate 20 (100%).
Example A9
Preparation of Intermediate 21
##STR00080##
[0205] A mixture of 1-(3,5-difluorophenyl)ethanone (0.013 mol),
formaldehyde (0.05 mol) and N-methylmethanamine hydrochloride
(0.052 mol) in concentrated HCl (0.1 ml) in EtOH (20 ml) was
stirred at 80.degree. C. for 20 hours, then cooled to room
temperature. The solvent was evaporated till dryness. The residue
was taken up in HCl 3N. The mixture was washed with diethyl ether,
basified with K.sub.2CO.sub.3 and extracted with diethyl ether. The
organic layer was separated, dried (MgSO.sub.4), filtered, and the
solvent was evaporated, yielding 2 g of intermediate 21.
Example A10
a) Preparation of Intermediate 22 and Intermediate 23
##STR00081##
[0207] 1.6M Butyllithium (0.12 mol) was added dropwise at
-10.degree. C. under N.sub.2 flow to a solution of
2,2,6,6-tetramethylpiperidine (0.12 mol) in THF (200 ml). The
mixture was stirred at -10.degree. C. for 20 minutes and then
cooled to -70.degree. C. A mixture of intermediate 2 (0.1 mol) in
THF (100 ml) was added. The mixture was stirred at -70.degree. C.
for 45 minutes. A solution of
3-(dimethylamino)-1-phenyl-1-propanone (0.1 mol) in THF (100 ml)
was added. The mixture was stirred at -70.degree. C. for 1 hour,
brought to -50.degree. C. and hydrolysed. H.sub.2O (100 ml) was
added at -50.degree. C. The mixture was stirred at room temperature
for 30 minutes and extracted with EtOAc. The organic layer was
separated, dried (MgSO.sub.4), filtered and the solvent was
evaporated. The residue was taken up in EtOAc. The precipitate was
filtered off, washed with EtOAc and diethyl ether and dried in
vacuo, yielding 4 g of intermediate 23 (8%). The mother layer was
evaporated. The residue (26 g) was purified by column
chromatography over silica gel (eluent: DCM/MeOH/NH.sub.4OH
97/3/0.1; 15-40 .mu.m). The desired fractions were collected and
the solvent was evaporated. The residue was crystallized from
diethyl ether. The precipitate was filtered off and dried, yielding
1 g of intermediate 22
[0208] The following intermediates were prepared according to the
method described above.
##STR00082##
b) Preparation of Intermediate 24
##STR00083##
[0210] 1.6M Butyllithium (0.0094 mol) was added dropwise at
-20.degree. C. to a mixture of 2,2,6,6-tetramethylpiperidine
(0.0094 mol) in THF (20 ml) under N.sub.2 flow. The mixture was
stirred at -20.degree. C. for 20 minutes, then cooled to
-70.degree. C. A solution of 6-bromo-2-chloro-3-phenylquinoline
(0.0062 mol) in THF (40 ml) was added. The mixture was stirred at
-70.degree. C. for 1 hour. A solution of intermediate 21 (0.0094
mol) in THF (25 ml) was added. The mixture was stirred from
-70.degree. C. to room temperature for 18 hours. H.sub.2O and EtOAc
were added. The organic layer was washed with saturated NaCl, dried
(MgSO.sub.4), filtered, and the solvent was evaporated. The residue
(4.3 g) was purified by column chromatography over silica gel
(eluent: DCM/MeOH/NH.sub.4OH 97/3/0.1; 10 .mu.m). The pure
fractions were collected and the solvent was evaporated, yielding
0.77 g of intermediate 24 (23%).
[0211] The following intermediates were prepared according to the
method described above.
##STR00084##
c) Preparation of Intermediate 28
##STR00085##
[0213] 1.6M Butyllithium (0.029 mol) was added at -10.degree. C. to
a solution of N-propyl-1-propanamine (0.029 mol) in THF (50 ml)
under N.sub.2 flow. The mixture was stirred for 20 minutes, then
cooled to -70.degree. C. A solution of intermediate 2 (0.024 mol)
in THF (30 ml) was added. The mixture was stirred at -70.degree. C.
for 1 hour. A solution of
3-(dimethylamino)-1-(2-thienyl)-1-propanone (0.029 mol) in THF (20
ml) was added. The mixture was stirred at -70.degree. C. for 1
hour, then brought to -20.degree. C. and extracted with EtOAc. The
organic layer was separated, dried (MgSO.sub.4), filtered, and the
solvent was evaporated. The residue was purified by column
chromatography over silica gel (eluent: DCM/MeOH/NH.sub.4OH
96/4/0.1; 20-45 .mu.m). The pure fractions were collected and the
solvent was evaporated. The residue (4.65 g) was crystallized from
DIPE. The precipitate was filtered off and dried, yielding 2.7 g of
intermediate 28 (M.P.: 168.degree. C.). The mother layer was
evaporated, yielding another 1.7 g of intermediate 28.
d) Preparation of Intermediate 25
##STR00086##
[0215] 1.6M Butyllithium (0.0112 mol) was added dropwise at
-20.degree. C. to a solution of N-(1-methylethyl)-2-propanamine
(0.0112 mol) in THF (20 ml) under N.sub.2 flow. The mixture was
stirred at -20.degree. C. for 30 minutes, then cooled to
-70.degree. C. A solution of intermediate (0.0094 mol) in THF (20
ml) was added. The mixture was stirred for 45 minutes. A solution
of intermediate 21 (0.0112 mol) in THF (10 ml) was added. The
mixture was stirred at -70.degree. C. for 2 hours, poured out into
H.sub.2O at -30.degree. C. and extracted with EtOAc. The organic
layer was separated, dried (MgSO.sub.4), filtered, and the solvent
was evaporated. The residue (4 g) was purified by column
chromatography over silica gel (eluent: DCM/MeOH 98/2; 15-40
.mu.m). The pure fractions were collected and the solvent was
evaporated. The residue (3 g) was crystallized from DIPE. The
precipitate was filtered off and dried, yielding 1.94 g of
intermediate 25 (43%) (M.P.: 140.degree. C.).
e) Preparation of Intermediate 26
##STR00087##
[0217] 1.6M Butyllithium (0.013 mol) was added dropwise at
-30.degree. C. to a mixture of N-(1-methylethyl)-2-propanamine
(0.013 mol) in THF (20 ml) under N.sub.2 flow. The mixture stirred
at -20.degree. C. for 30 minutes, then cooled to -70.degree. C. A
solution of 2-chloro-4-methyl-3-phenylquinoline (0.011 mol) in THF
(20 ml) was added. The mixture was stirred for 45 minutes. A
solution of intermediate 21 (0.013 mol) in THF (10 ml) was added.
The mixture was stirred at -70.degree. C. for 2 hours, poured out
into H.sub.2O and extracted with EtOAc. The organic layer was
separated, dried (MgSO.sub.4), filtered, and the solvent was
evaporated. The residue (5 g) was purified by column chromatography
over silica gel (eluent: DCM/MeOH 98/2; 15-40 .mu.m). The pure
fractions were collected and the solvent was evaporated, yielding 4
g of intermediate 26 (78%).
f) Preparation of Intermediate 27
##STR00088##
[0219] 1.6M Butyllithium in hexane (0.0075 mol) was added dropwise
at -70.degree. C. to a mixture of intermediate 14 (0.0062 mol) in
THF (20 ml) under N.sub.2 flow. The mixture was stirred at
-70.degree. C. for 1 hour. A solution of intermediate 21 (0.0075
mol) in THF (10 ml) was added at -70.degree. C. The mixture was
stirred from -70.degree. C. to room temperature then stirred for 18
hours. H.sub.2O was added. The mixture was extracted with EtOAc.
The organic layer was washed with saturated NaCl, dried
(MgSO.sub.4), filtered and the solvent was evaporated. The residue
(3 g) was purified by column chromatography over silica gel
(eluent: DCM/MeOH/NH.sub.4OH 97/3/0.1; 15-40 .mu.m). The pure
fractions were collected and the solvent was evaporated, yielding
1.1 g of intermediate 27 (39%).
[0220] The following intermediates were prepared according to the
method described above.
##STR00089##
B. Preparation of the Final Compounds
Example B1
a) Preparation of Compound 1
##STR00090##
[0222] 1.6M Butyllithium (0.0019 mol) was added dropwise at
-70.degree. C. to a mixture of intermediate 8 (0.0016 mol) in THF
(5 ml) under N.sub.2 flow. The mixture was stirred at -70.degree.
C. for 1 hour. A solution of intermediate 21 (0.0019 mol) in THF (2
ml) was added. H.sub.2O was added. The mixture was extracted with
DCM. The organic layer was separated, dried (MgSO.sub.4), filtered,
and the solvent was evaporated The residue was purified by column
chromatography over silica gel (eluent: DCM/MeOH/NH.sub.4OH
98/2/0.1; 10 .mu.m). The pure fractions were collected and the
solvent was evaporated, yielding 0.2 g of compound 1 (28%, MH+:
449).
[0223] The following final compounds were prepared according to the
method described above.
##STR00091## ##STR00092##
b) Preparation of Compound 2
##STR00093##
[0225] Butyllithium (0.0035 mol) was added dropwise at -20.degree.
C. to a solution of N-(1-methylethyl)-2-propanamine (0.0034 mol) in
THF (10 ml) under N.sub.2 flow. The mixture was stirred at
-20.degree. C. for 20 minutes, then cooled to -70.degree. C. A
solution of intermediate (0.0029 mol) in THF (10 ml) was added. The
mixture was stirred at -70.degree. C. for 2 hours. A solution of
intermediate 21 (0.0032 mol) in THF (10 ml) was added at
-70.degree. C. The mixture was stirred at -70.degree. C. for 3
hours, poured out into ice water and extracted with DCM. The
organic layer was separated, dried (MgSO.sub.4), filtered, and the
solvent was evaporated. The residue (1.4 g) was purified by column
chromatography over silica gel (eluent: DCM/MeOH/NH.sub.4OH
99/1/0.1; 15-40 .mu.m). The desired fraction was collected and the
solvent was evaporated. The residue (0.968 g) was purified by
column chromatography over silica gel (eluent: DCM/MeOH/NH.sub.4OH
98/2/0.2; 15-40 .mu.m). The pure fractions were collected and the
solvent was evaporated. The residue was dried, yielding 0.151 g of
compound 2 (11%, oil).
Example B2
a) Preparation of Compound 3
##STR00094##
[0227] A 30% MeONa solution (2 ml) was added at room temperature to
a mixture of intermediate 23 (0.002 mol) in MeOH (2 ml). The
mixture was stirred and refluxed overnight, poured out on ice and
extracted with DCM. The organic layer was separated, dried
(MgSO.sub.4), filtered, and the solvent was evaporated. The residue
(0.62 g) was purified by column chromatography over silica gel
(eluent: DCM/MeOH/NH.sub.4OH 95/5/0.5; 15-40 .mu.m). The pure
fractions were collected and the solvent was evaporated. The
obtained residue (0.39 g) was crystallized from DIPE. The
precipitate was filtered off and dried, yielding 0.15 g of compound
3 (M.P.: 66.degree. C.).
[0228] The following final compounds were prepared according to the
method described above.
##STR00095## ##STR00096##
b) Preparation of Compound 4
##STR00097##
[0230] A mixture of intermediate 25 (0.0004 mol) and pyrrolidine
(0.0021 mol) was stirred at 90.degree. C. overnight, then poured
out into H.sub.2O and extracted with DCM. The organic layer was
separated, dried (MgSO.sub.4), filtered, and the solvent was
evaporated. The residue (0.18 g) was purified by column
chromatography over silica gel (eluent: DCM/MeOH/NH.sub.4OH
98/2/0.1; 10 .mu.m). The desired fraction was collected and the
solvent was evaporated, yielding 0.043 g of compound 4 (20%, MH+:
516).
[0231] The following final compounds were prepared according to the
method described above.
##STR00098## ##STR00099##
c) Preparation of compound 5
##STR00100##
[0233] A mixture of intermediate 25, 2-furanylboronic acid (0.0012
mol), tetrakis(triphenylphosphine)palladium (0.0013 mol) and a 2M
Na.sub.2CO.sub.3 solution (0.002 mol) in dimethyl ether (7 ml) was
stirred at 90.degree. C. overnight, then poured out into H.sub.2O
and extracted with DCM. The organic layer was separated, dried
(MgSO.sub.4), filtered, and the solvent was evaporated. The residue
(0.2 g) was purified by column chromatography over silica gel
(eluent: DCM/MeOH 95/5; 15-40 .mu.m). The pure fractions were
collected and the solvent was evaporated. The residue (0.12 g) was
purified by column chromatography over silica gel (eluent:
DCM/MeOH/NH.sub.4OH 99/1/0.1; 20 .mu.m). The pure fractions were
collected and the solvent was evaporated, yielding 0.06 g of
compound 5 (28%, M.P.: 130.degree. C.).
[0234] The following final compounds were prepared according to the
method described above.
##STR00101##
d) Preparation of Compound 6
##STR00102##
[0236] A mixture of intermediate 35 (0.0005 mol), methylboronic
acid (0.0011 mol), tetrakis(triphenylphosphine)palladium (0.0005
mol) and a 2M K.sub.2CO.sub.3 solution (0.0028 mol) in dimethyl
ether (10 ml) and MeOH (3 ml) was stirred at 100.degree. C. for 24
hours, then cooled to room temperature. H.sub.2O was added. The
mixture was extracted with EtOAc. The organic layer was washed with
saturated NaCl, dried (MgSO.sub.4), filtered and the solvent was
evaporated. The residue (0.19 g) was purified by column
chromatography over kromasil (eluent: DCM/MeOH/NH.sub.4OH 95/5/0.1;
10 .mu.m). The pure fractions were collected and the solvent was
evaporated, yielding 0.06 g of compound 6 (28%, MH+: 387, oil).
[0237] The following final compound was prepared according to the
method described above.
##STR00103##
e) Preparation of Compound 7
##STR00104##
[0239] A mixture of intermediate 23 (0.0019 mol), morpholine
(0.0021 mol) and K.sub.2CO.sub.3 (0.3 g) in acetonitrile (10 ml)
was stirred and refluxed overnight, poured out on ice and extracted
with DCM. The organic layer was separated, dried (MgSO.sub.4),
filtered, and the solvent was evaporated. The residue (0.58 g) was
purified by column chromatography over silica gel (eluent:
DCM/MeOH/NH.sub.4OH 95/5/01 to 94/6/0.5; 15-40 .mu.m). The desired
fraction was collected and the solvent was evaporated. The obtained
residue (0.04 g) was crystallized from DIPE. The precipitate was
filtered off and dried, yielding 0.023 g of compound 7 (M.P.:
70.degree. C.).
[0240] The following final compounds were prepared according to the
method described above.
##STR00105## ##STR00106## ##STR00107## ##STR00108## ##STR00109##
##STR00110## ##STR00111##
f) Preparation of Compound 8
##STR00112##
[0242] A mixture of intermediate 27 (0.0005 mol),
3-(1,3,2-dioxaborinan-2-yl)pyridine (0.0008 mol),
tetrakis(triphenylphosphine)palladium (0.0005 mol) and a 2M
K.sub.2CO.sub.3 solution (0.0027 mol) in dimethyl ether (7 ml) and
MeOH (3 ml) was stirred at 100.degree. C. for 18 hours under
N.sub.2 flow, then cooled to room temperature. H.sub.2O was added.
The mixture was extracted with EtOAc. The organic layer was washed
with saturated NaCl, dried (MgSO.sub.4), filtered, and the solvent
was evaporated. The residue (0.34 g) was taken up in 2-propanone (6
ml). Oxalic acid was added. The mixture was stirred. The
precipitate was filtered off and dried at 60.degree. C. under a
vacuo, yielding 0.29 g of compound 8 as an ethanedioic acid salt
(1:2) (80%, M.P.: 151.degree. C.).
[0243] The following final compounds were prepared according to the
method described above.
##STR00113##
g) Preparation of Compound 9
##STR00114##
[0245] A mixture of intermediate 25 (0.0004 mol),
3-(1,3,2-dioxaborinan-2-yl)pyridine (0.0012 mol),
tetrakis(triphenylphosphine)palladium (0.00004 mol) and a 2M
Na.sub.2CO.sub.3 solution (0.002 mol) in dimethyl ether (6 ml) was
stirred at 90.degree. C. overnight, poured out into H.sub.2O and
extracted with DCM. The organic layer was separated, dried
(MgSO.sub.4), filtered, and the solvent was evaporated. The residue
(0.33 g) was purified by column chromatography over silica gel
(eluent: DCM/MeOH/NH.sub.4OH 97/3/0.1; 20 .mu.m). The desired
fraction was collected and the solvent was evaporated, yielding
0.03 g of compound 9 (14%, M.P.: 164.degree. C.).
h) Preparation of Compound 10
##STR00115##
[0247] A mixture of intermediate 37 (0.0007 mol) in
N-methylmethanamine (10 ml) and acetonitrile (10 ml) was stirred at
90.degree. C. for 12 hours, poured out into
H.sub.2O/K.sub.2CO.sub.3 and extracted with DCM. The organic layer
was separated, dried (MgSO.sub.4), filtered, and the solvent was
evaporated. The obtained fraction (0.25 g) was stirred at
90.degree. C. for 72 hours and purified by column chromatography
over kromasil (eluent: DCM/MeOH 99/1; 10 .mu.m). The desired
product fraction was collected and the solvent was evaporated. The
residue (0.08 g) was dissolved in oxalic acid/2-propanol and
converted into the ethanedioic acid salt (1:2.5). The precipitate
was filtered off and dried, yielding 0.07 g of compound 10 (14%,
M.P.: 136.degree. C.).
[0248] The following final compounds were prepared according to the
method described above.
##STR00116##
i) Preparation of Compound 11
##STR00117##
[0250] A mixture of KOH (0.0011 mol) in 1-piperidineethanol (2 ml)
was stirred at 80.degree. C. till KOH disappeared. Intermediate 23
(0.0009 mol) was added. The mixture was stirred at 80.degree. C.
overnight, poured out on ice and extracted with DCM. The organic
layer was separated, dried (MgSO.sub.4), filtered, and the solvent
was evaporated. The residue (2.49 g) was crystallized from DIPE.
The precipitate was filtered off and dried, yielding 0.308 g of
compound 11 (M.P.: 131.degree. C.).
[0251] The following final compound was prepared according to the
method described above.
##STR00118##
j) Preparation of Compound 78
##STR00119##
[0253] A mixture of intermediate 23 (0.000137 mol),
N-methylmethanamine (0.000412 mol, 3 equiv.) and K.sub.2CO.sub.3 (3
equiv.) in acetonitrile (2 ml) was stirred at 80.degree. C. for 12
hours, poured out into H.sub.2O and extracted with DCM. The organic
layer was separated, dried (MgSO.sub.4), filtered, and the solvent
was evaporated. The obtained fraction was purified by column
chromatography over silica gel, then the desired product fraction
was collected and the solvent was evaporated, yielding 0.07 g of
compound 78 (54.79%, MH+: 518).
[0254] The following final compounds were prepared according to the
method described above.
##STR00120## ##STR00121## ##STR00122## ##STR00123##
Example B3
a) Preparation of Compound 13
##STR00124##
[0256] A mixture of compound 12 (0.0003 mol),
3-(1,3,2-dioxaborinan-2-yl)pyridine (0.0006 mol),
tetrakis(triphenylphosphine)palladium (0.00003 mol) and a 2M
K.sub.2CO.sub.3 solution (0.0015 mol) in dimethyl ether (6 ml) and
MeOH (2 ml) was stirred at 100.degree. C. for 18 hours under
N.sub.2 flow, then cooled to room temperature. H.sub.2O was added.
The mixture was extracted with EtOAc. The organic layer was washed
with saturated NaCl, dried (MgSO.sub.4), filtered, and the solvent
was evaporated. The residue (0.14 g) was taken up in 2-propanone (2
ml). Oxalic acid (2 equivalents) was added. The mixture was stirred
for 10 minutes. The precipitate was filtered, washed with
2-propanone and dried at 70.degree. C. under a vacuo, yielding
0.077 g of compound 13 as ethanedioic acid salt (1:1.5) (38%, M.P.:
156.degree. C.).
[0257] The following final compound was prepared according to the
method described above.
##STR00125##
b) Preparation of Compound 14
##STR00126##
[0259] A mixture of compound 3 (0.0003 mol),
tetrakis(triphenylphosphine)palladium (0.00003 mol), a 2M
Na.sub.2CO.sub.3 solution (0.0019 mol) and
3-(1,3,2-dioxaborinan-2-yl)pyridine (0.0011 mol) in dimethyl ether
(6 ml) was stirred at 100.degree. C. overnight, then poured out
into H.sub.2O and extracted with DCM. The organic layer was
separated, dried (MgSO.sub.4), filtered, and the solvent was
evaporated. The residue was purified by column chromatography over
kromasil (eluent: toluene/2-propanol/NH.sub.4OH 80/20/1; 10 .mu.m).
The pure fractions were collected and the solvent was evaporated.
The residue (0.1 g, 51%) was crystallized from DIPE/acetonitrile.
The precipitate was filtered off and dried, yielding 0.057 g of
compound 14 (M.P.: 180.degree. C.).
[0260] The following final compound was prepared according to the
method described above.
##STR00127##
c) Preparation of Compound 16
##STR00128##
[0262] A mixture of compound 15 (0.0007 mol),
tetrakis(triphenylphosphine)palladium (0.00007 mol) and
tetramethylstannane (0.0016 mol) in toluene (6 ml) was stirred and
refluxed overnight. H.sub.2O was added. The mixture was extracted
with DCM. The organic layer was separated, dried (MgSO.sub.4),
filtered, and the solvent was evaporated. The residue was purified
by column chromatography over silica gel (eluent:
DCM/MeOH/NH.sub.4OH 95/5/0.3; 20 .mu.m). The pure fractions were
collected and the solvent was evaporated, yielding 0.038 g of
compound 16 (11%, MH+: 447).
Example B4
Preparation of Compound 17
##STR00129##
[0264] A mixture of intermediate 32 (0.0016 mol) in 6N HCl (5 ml)
and THF (10 ml) was stirred at 80.degree. C. for 48 hours, then
cooled to room temperature, poured out into a 10% K.sub.2CO.sub.3
solution and extracted with EtOAc. The organic layer was washed
with saturated NaCl, dried (MgSO.sub.4), filtered and the solvent
was evaporated. The residue was crystallized from diethyl
ether/2-propanone. The precipitate was filtered off and dried. Part
of this fraction (0.3 g of 0.6 g (44%)) was taken up in hot
2-propanone. The precipitate was filtered off and dried, yielding
0.2 g of compound 17 (15%, M.P.: 190.degree. C.).
C. Analytical Methods
[0265] The mass of the compounds was recorded with LCMS (liquid
chromatography mass spectrometry). Three methods were used which
are described below. The data are gathered in Table 1 below.
[0266] LCMS-Method 1
[0267] LCMS analysis was carried out (electrospray ionization in
positive mode, scanning mode from 100 to 900 amu) on a Kromasil C18
column (Interchim, Montlucon, FR; 5 .mu.m, 4.6.times.150 mm) with a
flow rate of 1 ml/minute. Two mobile phases (mobile phase A: 30%
6.5 mM ammonium acetate+40% acetonitrile+30% formic acid (2 ml/1);
mobile phase B: 100% acetonitrile) were employed to run a gradient
condition from 100% A for 1 minute to 100% B in 4 minutes, 100% B
for 5 minutes to 100% A in 3 minutes, and reequilibrate with 100% A
for 2 minutes.
[0268] LCMS-Method 2
[0269] LCMS analysis was carried out (electrospray ionization in
both positive and negative (pulsed) mode scanning from 100 to 1000
amu) on a Kromasil C18 column (Interchim, Montlucon, FR; 3.5 .mu.m,
4.6.times.100 mm) with a flow rate of 0.8 ml/minute. Two mobile
phases (mobile phase A: 35% 6.5 mM ammonium acetate+30%
acetonitrile+35% formic acid (2 ml/1); mobile phase B: 100%
acetonitrile) were employed to run a gradient condition from 100% A
for 1 minute to 100% B in 4 minutes, 100% B at a flow rate of 1.2
ml/minute for 4 minutes to 100% A at 0.8 ml/minute in 3 minutes,
and reequilibrate with 100% A for 1.5 minute.
[0270] LCMS-Method 3
[0271] LCMS analysis was carried out (electrospray ionization in
positive mode, scanning from 100 to 900 amu) on a Xterra MS C18
column (Waters, Milford, Mass.; 5 .mu.m, 4.6.times.150 mm) with a
flow rate of 1 ml/minute. Two mobile phases (mobile phase A: 85%
6.5 mM ammonium acetate+15% acetonitrile; mobile phase B: 20% 6.5
mM ammonium acetate+80% acetonitrile) were employed to run a
gradient condition from 100% A for 3 minutes to 100% B in 5
minutes, 100% B at a flow rate of 1.2 ml/minute for 6 minutes to
100% A at 0.8 ml/minute in 3 minutes, and reequilibrate with 100% A
for 3 minutes.
TABLE-US-00001 TABLE 1 LCMS parent peak Compound LC/GC/MS No Method
1 1 4 3 6 2 16 2 18 1 19 1 21 1 22 1 23 1 28 1 29 1 31 1 35 1 43 3
45 2 47 2 48 2 49 2 50 2 51 2 52 2 54 2 55 1 57 2 58 1 59 1 60 1 61
1 64 2 65 1 67 1 69 2 71 3 72 3 73 1 74 3 78 1 79 1 80 1 81 1 82 1
83 1 84 1 85 1 86 1 87 1 88 1 89 1 90 1 91 1 92 1 93 1 94 1
D. Pharmacological Examples
[0272] D.1. In-Vitro Method for Testing Compounds Against M.
tuberculosis.
[0273] Flat-bottom, sterile 96-well plastic microtiter plates were
filled with 100 .mu.l of Middlebrook (1.times.) broth medium.
Subsequently, stock solutions (10.times. final test concentration)
of compounds were added in 25 .mu.l volumes to a series of
duplicate wells in column 2 so as to allow evaluation of their
effects on bacterial growth. Serial five-fold dilutions were made
directly in the microtiter plates from column 2 to 11 using a
customised robot system (Zymark Corp., Hopkinton, Mass.). Pipette
tips were changed after every 3 dilutions to minimize pipetting
errors with high hydrophobic compounds. Untreated control samples
with (column 1) and without (column 12) inoculum were included in
each microtiter plate. Approximately 5000 CFU per well of
Mycobacterium tuberculosis (strain H37RV), in a volume of 100 .mu.l
in Middlebrook (1.times.) broth medium, was added to the rows A to
H, except column 12. The same volume of broth medium without
inoculum was added to column 12 in row A to H. The cultures were
incubated at 37.degree. C. for 7 days in a humidified atmosphere
(incubator with open air valve and continuous ventilation). One day
before the end of incubation, 6 days after inoculation, Resazurin
(1:5) was added to all wells in a volume of 20 .mu.l and plates
were incubated for another 24 hours at 37.degree. C. On day 7 the
bacterial growth was quantitated fluorometrically.
[0274] The fluorescence was read in a computer-controlled
fluorometer (Spectramax Gemini EM, Molecular Devices) at an
excitation wavelength of 530 nm and an emission wavelength of 590
nm. The percentage growth inhibition achieved by the compounds was
calculated according to standard methods, and MIC data
(representing IC90's expressed in microgram/ml) were
calculated.
[0275] D.2. In-Vitro Method for Testing Compounds for
Anti-Bacterial Activity Against Strain M. Smegmatis ATCC607.
[0276] Flat-bottom, sterile 96-well plastic microtiter plates were
filled with 180 .mu.l of sterile deionized water, supplemented with
0.25% BSA. Subsequently, stock solutions (7.8.times. final test
concentration) of compounds were added in 45 .mu.l volumes to a
series of duplicate wells in column 2 so as to allow evaluation of
their effects on bacterial growth. Serial five-fold dilutions (45
.mu.l in 180 .mu.l) were made directly in the microtiter plates
from column 2 to 11 using a customised robot system (Zymark Corp.,
Hopkinton, Mass.). Pipette tips were changed after every 3
dilutions to minimize pipetting errors with high hydrophobic
compounds. Untreated control samples with (column 1) and without
(column 12) inoculum were included in each microtiter plate.
Approximately 250 CFU per well of bacteria inoculum, in a volume of
100 .mu.l in 2.8.times. Mueller-Hinton broth medium, was added to
the rows A to H, except column 12. The same volume of broth medium
without inoculum was added to column 12 in row A to H. The cultures
were incubated at 37.degree. C. for 48 hours in a humidified 5%
CO.sub.2 atmosphere (incubator with open air valve and continuous
ventilation). At the end of incubation, two days after inoculation,
the bacterial growth was quantitated fluorometrically. Therefore
Alamar Blue (10.times.) was added to all wells in a volume of 20
.mu.l and plates were incubated for another 2 hours at 50.degree.
C.
[0277] The fluorescence was read in a computer-controlled
fluorometer (Cytofluor, Biosearch) at an excitation wavelength of
530 nm and an emission wavelength of 590 nm (gain 30). The % growth
inhibition achieved by the compounds was calculated according to
standard methods. The pIC.sub.50 was defined as the 50% inhibitory
concentration for bacterial growth. The results are shown in Table
2
TABLE-US-00002 TABLE 2 Results (pIC.sub.50) of an in
vitro-screening of the compounds according to the invention for M.
smegmatis and M. tuberculosis. M. smegmatis M. tuberculosis Co. No.
(pIC.sub.50) (pIC.sub.50) 1 5.9 2 5.9 3 5.9 4 6.6 5 6.4 6 4.5 7 5.8
8 5.8 9 5.2 10 5.7 11 5.5 5.5 12 5.8 13 6.4 14 5.1 15 5.1 16 5.8 18
5.8 19 5.1 20 4.5 21 4.5 26 5.7 27 5.2 28 5.1 29 4.5 31 5.9 32 5.0
33 4.5 35 5.8 36 5.0 37 4.1 39 5.9 40 5.1 41 4.5 42 4.4 43 4.9 44
5.9 45 6.6 46 6.6 47 6.4 48 6.2 49 6.1 50 6.1 51 6.0 52 6.0 53 5.9
54 5.9 55 5.9 56 5.8 57 5.8 58 5.8 59 5.8 60 5.7 61 5.3 62 5.3 63
5.2 64 5.2 65 5.2 66 4.9 67 4.7 68 4.5 69 4.4 71 5.8 72 5.2 73 5.8
75 5.2 5.3 76 5.8 77 4.9 78 5.8 79 6.2 4.6 80 6.1 5.05 81 5.9 82
5.8 83 5.8 84 5.7 85 5.7 86 5.7 87 5.6 88 5.6 89 5.6 90 5.5 91 5.3
92 5.2 93 5.1 94 5.1
* * * * *