U.S. patent application number 09/865231 was filed with the patent office on 2001-09-27 for new pharmaceutical active compounds.
This patent application is currently assigned to Astra Aktiebolag, a Sweden corporation. Invention is credited to Bergstrand, Hakan, Karabelas, Kostas, Sjo, Peter.
Application Number | 20010025043 09/865231 |
Document ID | / |
Family ID | 26662759 |
Filed Date | 2001-09-27 |
United States Patent
Application |
20010025043 |
Kind Code |
A1 |
Bergstrand, Hakan ; et
al. |
September 27, 2001 |
New pharmaceutical active compounds
Abstract
The present invention provides optionally substituted and/or
annulated compounds of formula (I) 1 wherein X, Y, Z and A is each
independently carbon or nitrogen, and at least two of X, Y, Z and A
are carbon; and pharmaceutically acceptable salts thereof with the
proviso that: 3-(1H-Indol-3-yl)-1H-quinoxalin-2-one,
3-(2-Methyl-1H-indol-3-yl)-1H-quinoxalin-2-one, and
3-(1,2-Diphenyl-1H-indol-3-yl)-1H-quinoxalin-2-one are excluded
from compounds of formula (I). The invention includes the use of
compounds of formula (I) in medical therapy, particularly in the
therapy of conditions requiring inhibition of protein kinase C.
Inventors: |
Bergstrand, Hakan; (Bjarred,
SE) ; Karabelas, Kostas; (Lund, SE) ; Sjo,
Peter; (Lund, SE) |
Correspondence
Address: |
Janis K. Fraser
Fish & Richardson P.C.
225 Franklin Street
Boston
MA
02110-2804
US
|
Assignee: |
Astra Aktiebolag, a Sweden
corporation
|
Family ID: |
26662759 |
Appl. No.: |
09/865231 |
Filed: |
May 25, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
09865231 |
May 25, 2001 |
|
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|
08981266 |
Dec 18, 1997 |
|
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6271231 |
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Current U.S.
Class: |
514/250 ;
544/354 |
Current CPC
Class: |
C07H 19/04 20130101;
C07D 475/02 20130101; C07D 403/04 20130101; C07D 475/00 20130101;
C07D 405/14 20130101; C07D 471/04 20130101 |
Class at
Publication: |
514/250 ;
544/354 |
International
Class: |
A61K 031/498 |
Foreign Application Data
Date |
Code |
Application Number |
Sep 25, 1996 |
SE |
9603505-0 |
Jul 18, 1997 |
SE |
9702747-8 |
Sep 19, 1997 |
SE |
PCT/SE97/01582 |
Claims
1. An optionally substituted and/or annulated compound of formula
(I): 7wherein X, Y, Z and A is each independently carbon or
nitrogen, and at least two of X, Y, Z and A are carbon; and
pharmaceutically acceptable salts thereof, with the proviso that:
3-(1H-Indol-3-yl)-1H-quinoxalin-2-o- ne,
3-(2-Methyl-1H-indol-3-yl)-1H-quinoxalin-2-one, and
3-(1,2-Diphenyl-1H-indol-3-yl)-1H-quinoxalin-2-one are excluded
from compounds of formula (I).
2. A compound according to claim 1, of formula (IA): 8wherein X, Y,
Z and A are as defined in claim 1, R.sub.1, R.sub.2, R.sub.3, and
R.sub.4 is each independently H, hydroxy, amino, nitro, halo,
C.sub.1-6 alkyl, phenylC.sub.1-6 alkyl, C.sub.1-6 alkoxy,
haloC.sub.1-6 alkyl, carboxyC.sub.1-6 alkyl ester or R.sub.1 and
R.sub.2 or R.sub.2 and R.sub.3 or R.sub.3 and R.sub.4 form an
annulated aromatic ring, or when the atom to which it would be
attached is nitrogen, is absent; R.sub.5 and R.sub.6 is each
independently H, C.sub.1-6 alkyl, hydroxyC.sub.1-6 alkyl,
aminoC.sub.1-6 alkyl, phenylC.sub.1-6 alkyl, carboxyC.sub.1-6
alkyl, C.sub.1-6 alkenyl, (phenylC.sub.1-3 alkoxy)C.sub.1-3 alkyl,
(C.sub.1-6 acyloxy)C.sub.1-6 alkyl, (C.sub.1-6
alkoxycarbonyl)C.sub.1-6 alkyl, (mono- or di-C.sub.1-6
alkyl)aminoC.sub.1-6 alkyl, (C.sub.1-6 alkyl)aminocarbonylC.sub.1-6
alkyl, (C.sub.1-6 acylamino)C.sub.1-6 alkyl, (aminoC.sub.1-3
alkylphenyl)C.sub.1-3 alkyl, or aminodeoxysugar; R.sub.7 and
R.sub.8 is each independently H, amino, nitro, hydroxy, halogen,
C.sub.1-6 alkoxy, phenylC.sub.1-6 alkoxy or carboxyC.sub.1-6 alkyl
ester; R.sub.9 is H, C.sub.1-6 alkyl, phenyl, halophenyl or
phenylC.sub.1-6 alkyl and wherein when R.sub.5 and R.sub.9 together
comprise3-5 carbons they may be linked to generate a cyclic moiety
which may be aminoC.sub.1-6 alkyl substituted; and wherein at least
one of R.sub.1 to R.sub.9 is not H and wherein when the only one of
R.sub.1 to R.sub.9 which is not H is R.sub.9, R.sub.9 is not
methyl; and pharmaceutically acceptable salts thereof.
3. A compound according to claim 2, wherein at least one of R.sub.5
and R.sub.6 is aminoC.sub.1-6alkyl.
4. A compound according to any of claims 1 to 3, wherein at least
one of Y and Z is substituted.
5. A compound according to any one of claims 1 to 4, wherein at
least one of Y and Z is substituted with halo, methoxy or
carboxylic ester.
6. A compound according to any one of claims 1 to 5 wherein
position 5 of the indole is substituted.
7. A compound according to any one of claims 2 to 6 wherein R.sub.9
is H or alkyl.
8. A compound according to any one of claims 2 to 7 wherein R.sub.5
or R.sub.6 is an aminodeoxysugar, comprising a six membered
ring.
9. A compound according to any one of claims 2 to 7 wherein R.sub.5
and R.sub.9 together form a six membered ring.
10. A compound according to any one of claims 1 to 9 wherein three
or four of X,Y,Z and A are carbon.
11. A compound according to any one of claims 2 to 10 wherein
R.sub.1 and R.sub.2, or R.sub.2 and R.sub.3, or R.sub.3 and R.sub.4
form an annulated aromatic ring.
12. The compounds:
3-[3-(4-Methyl-3-oxo-3,4-dihydro-quinoxalin-2-yl)-indol-
-1-yl]propyl-ammonium acetate,
3-[3-(6,7-Dichloro-3-oxo-3,4-dihydro-quinox-
alin-2-yl)-indol-1-yl]-propyl-ammonium acetate,
3-[3-(6,7-Dichloro-3-oxo-3-
,4-dihydro-quinoxalin-2-yl)-5-methoxycarbonyl-indol-1-yl]-propyl-ammonium
acetate,
3-[3-(6,7-Dichloro-4-methyl-3-oxo-3,4-dihydro-quinoxalin-2-yl)-5-
-methoxycarbonyl-indol-1-yl]-propyl-ammonium acetate,
3-[5-Methoxycarbonyl-3-(7-methoxy-3-oxo-3,4-dihydro-quinoxalin-2-yl)-indo-
l-1-yl]-propyl-ammonium acetate,
3-[3-(4-tert-Butoxycarbonylmethyl-7-metho-
xy-3-oxo-3,4-dihydro-quinoxalin-2-yl)-5-methoxycarbonyl-indol-1-yl]propyl--
ammonium acetate,
3-[3-(4-(3-Ammoniumpropyl)-3-oxo-3,4-dihydro-quinoxalin--
2-yl)-indol-1-yl]propyl-ammonium bis trifluoroacetate,
Dimethyl-{3-[3-(1-methyl-1H-indol-3-yl)-2-oxo-2H-quinoxalin-1-yl]-propyl}-
-ammonium trifluoroacetate,
3-[3-(3-Oxo-3,4-dihydro-benzo[g]quinoxalin-2-y-
l)-indol-1-yl]-propyl-ammonium acetate,
3-[6-Benzyloxy-3-(7-methoxy-4-meth-
yl-3-oxo-3,4-dihydro-quinoxalin-2-yl)-indol-1-yl]-propyl-ammonium
acetate,
3-[5-Benzyloxy-3-(4-tert-butoxycarbonylmethyl-7-methoxy-3-oxo-3,4-dihydro-
-quinoxalin-2-yl)-indol-1-yl]-propyl-ammonium acetate,
3-[2-(4-Chloro-phenyl)-3-(7-methoxy-3-oxo-3,4-dihydro-quinoxalin-2-yl)-in-
dol-1-yl]-propyl-ammonium acetate,
3-[2-(4-Chloro-phenyl)-3-(7-methoxy-4-m-
ethyl-3-oxo-3,4-dihydro-quinoxalin-2-yl)-indol-1-yl]-propyl-ammonium
acetate,
3-[3-(6,7-Dichloro-4-methyl-3-oxo-3,4-dihydro-quinoxalin-2-yl)-2-
-ethyl-indol-1-yl]-propyl-ammonium acetate,
3-[3-(5-Methyl-3-oxo-3,4-dihyd-
ro-quinoxalin-2-yl)-6-nitro-indol-1-yl]-propyl-ammonium acetate,
3-[6-Nitro-3-(6-nitro-3-oxo-3,4-dihydro-quinoxalin-2-yl)-indol-1-yl]-prop-
yl-ammonium acetate,
4-[3-(3-Oxo-3,4-dihydro-quinoxalin-2-yl)-indol-1-ylme-
thyl]benzyl-ammonium acetate,
3-[3-(4-Methyl-3-oxo-3,4-dihydro-quinoxalin--
2-yl)-indol-1-ylmethyl]benzyl-ammonium trifluoroacetate,
3-[3-(4-Benzyl-3-oxo-3,4-dihydro-quinoxalin-2-yl)-indol-1-yl]-propyl-ammo-
nium trifluoroacetate; and other pharmaceutically acceptable salts
thereof.
13. The compound:
3-[3-(3-Oxo-3,4-dihydro-benzo[g]quinoxalin-2-yl)-indol-1-
-yl]-propyl-ammonium acetate, and other pharmaceutically acceptable
salts thereof.
14. A free amine of a compound according to claim 12.
15. A compound according to any one of claims 1 to 13, for use in
medical therapy.
16. A compound according to claim 15 wherein the medical therapy is
the treatment of inflammatory, immunological, bronchopulmonary,
cardiovascular, oncological or CNS-degenerative disorders.
17. Use of a compound according to any one of claims 1 to 13 in the
manufacture of a medicament for use in the treatment of
inflammatory, immunological, bronchopulmonary, cardiovascular,
oncological or CNS-degenerative disorders.
18. A method for the treatment of an inflammatory, immunological,
bronchopulmonary, cardiovascular, oncological or CNS-degenerative
disorder, wherein a therapeutically effective amount of a compound
according to any one of claims 1 to 13 is administered to a mammal
in the need of such treatment.
19. A pharmaceutical composition wherein the active ingredient is a
compound according to any one of claims 1 to 13.
20. A compound of formula (II): 9wherein X, Y, Z, A, are as defined
in claim 1; R.sub.1 to R.sub.9 are as defined in claim 2 and at
least one of R.sub.5 and R.sub.6 carries a protected amino, carboxy
or hydroxy group, or a compound of formula (III) 10wherein R.sub.5,
R.sub.7, R.sub.8, and R.sub.9 are as defined in claim 2, but when
R.sub.5 carries an amino, carboxy or hydroxy groups, such group is
in a protected form; and LG is a leaving group.
21. A process for the preparation of a compound according to claim
2 when at least one of R.sub.5 and R.sub.6 of formula (IA) carries
an amino, carboxy or hydroxy group, and pharmaceutically acceptable
salts thereof, comprising: a) deprotecting a compound of formula
(II) corresponding to formula (IA) but in which at least one of
R.sub.5 and R.sub.6 carries protected amino, carboxy or hydroxy
groups, or b) converting a compound of formula (IA), in which at
least one of R.sub.5 and R.sub.6 carries amino or carboxy groups i)
to a pharmaceutically acceptable salt thereof, or vice versa; or
ii) a pharmaceutically acceptable salt of a compound of formula
(IA) into a different pharmaceutically acceptable salt; or when
R.sub.6 is hydrogen, comprising reacting a compound of formula
(III): 11wherein R.sub.5, R.sub.7, R.sub.8, and R.sub.9 are as
defined in claim 2 and LG is a leaving group, with a compound of
formula (IV): 12wherein R.sub.1-R.sub.4 are as defined in claim 2
and A, X, Y, and Z are as defined in claim 1; and when R.sub.5 in
formula (III) carries an amino, carboxy or hydroxy groups such
groups are suitably protected and the protecting group removed in a
subsequent deprotecting step; or when R.sub.6 is other than H,
comprising reacting a compound of formula (II) which corresponds to
formula (I), but in which R.sub.6 is H, with a suitable alkylating
agent in the presence of a base and wherein when R.sub.5 in formula
(II) or the alkylating agent carries an amino, carboxy or hydroxy
group, such group is suitably protected and the protecting group
removed in a subsequent deprotecting step.
Description
[0001] The present invention relates to novel compounds which are
protein kinase C inhibitors, methods for their preparation,
intermediates therefor and pharmaceutical compositions comprising
them.
[0002] Protein kinase C (PKC) is a family of phospholipid-dependent
serine/threonine-specific protein kinases which play an important
role in cellular growth control, regulation and
differentiation.
[0003] Since the activation of PKC has been implicated in several
human disease processes, including various forms of cancer,
different forms of inflammatory and/or immunological disorders as
well as some neurological disorders, inhibition of PKC could be of
therapeutic value in treating these conditions.
[0004] Several classes of compounds have been identified as PKC
inhibitors, e.g. isoquinoline sulphonamides, sphingosine and
related sphingolipids, indolocarbazoles and
bisindolylmaleimides.
[0005] Although PKC inhibitors are described in the prior art,
there is a need for specific anti-inflammatory and
immunosuppressive compounds which are suitable for oral
administration, and for inhalation.
[0006] The present invention provides PKC inhibitors, methods for
their preparation and intermediates used for their preparation.
[0007] The present invention also provides the use of the compounds
of the present invention for the treatment of inflammatory,
immunological, bronchopulmonary, cardiovascular, oncological or
CNS-degenerative disorders.
[0008] Also provided by the present invention are pharmaceutical
compositions comprising a compound according to the present
invention, as active ingredient, together with a pharmaceutically
acceptable adjuvant, diluent or carrier.
[0009] The present invention provides optionally substituted and/or
annulated compounds of formula (I) 2
[0010] wherein X, Y, Z and A is each independently carbon or
nitrogen, and at least two of X, Y, Z and A are carbon;
[0011] and pharmaceutically acceptable salts thereof with the
proviso that the following compounds are not included in formula
(I):
[0012] 3-(1H-Indol-3-yl)-1H-quinoxalin-2-one,
[0013] 3-(2-Methyl-1H-indol-3-yl)-1H-quinoxalin-2-one, and
[0014] 3-(1,2-Diphenyl-1H-indol-3-yl)-1H-quinoxalin-2-one.
[0015] Preferred compounds of formula (I) are those of formula
(IA): 3
[0016] wherein
[0017] X, Y, Z and A are as defined above,
[0018] R.sub.1, R.sub.2, R.sub.3, and R.sub.4 is each independently
H, hydroxy, amino, nitro, halo, C.sub.1-6 alkyl, phenylC.sub.1-6
alkyl, C.sub.1-6 alkoxy, haloC.sub.1-6 alkyl, carboxyC.sub.1-6
alkyl ester or R.sub.1 and R.sub.2 or R.sub.2 and R.sub.3 or
R.sub.3 and R.sub.4 form an annulated aromatic ring, or when the
atom to which it would be attached is nitrogen, is absent;
[0019] R.sub.5 and R.sub.6 is each independently H, C.sub.1-6
alkyl, hydroxyC.sub.1-6 alkyl, aminoC.sub.1-6 alkyl,
phenylC.sub.1-6 alkyl, carboxyC.sub.1-6 alkyl, C.sub.1-6 alkenyl,
(phenylC.sub.1-3 alkoxy)C.sub.1-3 alkyl, (C.sub.1-6
acyloxy)C.sub.1-6 alkyl, (C.sub.1-6 alkoxycarbonyl)C.sub.1-6 alkyl,
(mono- or di-C.sub.1-6 alkyl)aminoC.sub.1-6 alkyl (C.sub.1-6
alkyl)aminocarbonylC.sub.1-6 alkyl, (C.sub.1-6 acylamino)C.sub.1-6
alkyl, (aminoC.sub.1-3 alkylphenyl)C.sub.1-3 alkyl, or
aminodeoxysugar;
[0020] R.sub.7 and R.sub.8 is each independently H, amino, nitro,
hydroxy, halogen, C.sub.1-6 alkoxy, phenylC.sub.1-6 alkoxy or
carboxyC.sub.1-6 alkyl ester;
[0021] R.sub.9 is H, C.sub.1-6 alkyl, phenyl, halophenyl or
phenylC.sub.1-6 alkyl and wherein when R.sub.5 and R.sub.9 together
comprise 3-5 carbons they may be linked to generate a cyclic moiety
which may be aminoC.sub.1-6 alkyl substituted;
[0022] and wherein at least one of R.sub.1 to R.sub.9 is not H and
wherein when the only one of R.sub.1 to R.sub.9 which is not H is
R.sub.9, R.sub.9 is not methyl;
[0023] and pharmaceutically acceptable salts thereof.
[0024] The compounds of formula (IA), in which at least one of
R.sub.5 and R.sub.6 carries an amino, carboxy or hydroxy group; and
pharmaceutically acceptable salts thereof, may be prepared by,
[0025] a) deprotecting a compound of formula (II) corresponding to
formula (IA) but in which at least one of R.sub.5 and R.sub.6
carries a protected amino, carboxy or hydroxy group, or
[0026] b) converting a compound of formula (IA), in which at least
one of R.sub.5 and R.sub.6 carries an amino or carboxy group
[0027] i) to a pharmaceutically acceptable salt thereof, or vice
versa; or
[0028] ii) a pharmaceutically acceptable salt of a compound of
formula (IA) into a different pharmaceutically acceptable salt.
[0029] The compounds of formula (IA), in which R.sub.6 is hydrogen,
may be prepared by reacting a compound of formula (III): 4
[0030] wherein R.sub.5, R.sub.7, R.sub.8, and R.sub.9 are as
defined in formula (IA) and LG is a leaving group, e.g: 5
[0031] with a compound of formula (IV): 6
[0032] wherein A, X, Y, and Z are as defined in formula (I), and
R.sub.1-R.sub.4 are as defined in formula (IA), in a suitable
solvent, e.g. THF, at about 10-30.degree. C., e.g. for about 16
hours.
[0033] When R.sub.5 in formula (III) carries an amino, carboxy or
hydroxy group, these groups should be suitably protected. The
protecting groups may be removed in a subsequent deprotecting
step.
[0034] The compounds of formula (IA), when R.sub.6 is other than H,
may be prepared by reacting a compound of formula (II) which
corresponds to formula (IA), but in which R.sub.6 is H, with a
suitable alkylating agent, e.g methyl iodide in the presence of a
base, e.g. sodium hydride. The alkylating step may be carried out
in a suitable solvent e.g dimethyl formamide at about 10-30.degree.
C. for e.g 2 hours.
[0035] When R.sub.5 in formula (II) and/or the alkylating agent
carries an amino, carboxy or hydroxy group, such groups should be
suitably protected. The protecting groups may be removed in a
subsequent deprotecting step.
[0036] The compounds of formula (II) may be prepared by
[0037] (i) reacting a compound of formula (III), as defined above,
with a compound of formula (IV), as defined above, in a suitable
solvent e.g. THF, at about 10-30.degree. C., e.g. for 16 h , or
[0038] (ii) by alkylating the product of (i) with a suitable
alkylating agent
[0039] when R.sub.5 in formula (III) and/or the alkylating agent
carries an amino, carboxy or hydroxy group, these should be in a
protected form.
[0040] In all processes above, the protecting groups and conditions
for deprotection are well known to those skilled in the art.
Suitable protecting groups for amino groups are e.g phthaloyl
groups and the deprotecting agent may be methylamine in e.g. water.
The deprotecting step may be carried out in a suitable solvent, e.g
tetrahydrofuran at about 10-30.degree. C., e.g for about 5 hours.
Suitable protecting groups for carboxy groups are e.g t-butyl
groups and the deprotection step may be carried out in trifluoro
acetic acid at about 10-30.degree. C., e.g for about 4 hours. The
hydroxy groups are protected as their corresponding acetoxy groups
and the deprotecting agent may be methylamine in e.g. water. The
deprotecting step may be carried out in a suitable solvent, e.g
tetrahydrofuran at about 10-30.degree. C., e.g for about 16
hours.
[0041] In process b) the conversion may be carried out by
conventional processes, e.g.
[0042] i) reaction of the free base with an acid containing the
desired anion, or by careful basification of the salt, or
[0043] ii) reaction of the free acid with a base containing the
desired cation, or by careful acidification of the salt.
[0044] The reaction may be carried out in a suitable solvent, e.g.
methanol or methylene chloride.
[0045] Compounds of formula (I) which are not of formula (IA) may
be made by analogous processes to those described above for
compounds of formula (IA).
[0046] The starting materials for the above processes may be made
by the methods set out in the Examples or by methods analogous
thereto. Other conventional methods for making the starting
materials will be evident to those skilled in the art.
[0047] The compounds of formula (I), and pharmaceutically
acceptable salts thereof, are useful because they demonstrate
pharmacological activity. In particular they demonstrate activity
as kinase inhibitors, especially PKC inhibitors, e.g. as is shown
by their activity in the in vitro assays described in Granet, R. A.
et al, Analyt. Biochem. 1987; 163, 458-463; Olsson, H. et al, Cell
Signal 1989, 1, 405-410; Chakravarthy, B. R. et al, Analyt.
Biochem. 1991, 196, 144-150 and Bergstrand, H et al, J. Pharm. Exp.
Ther. 1992; 263(3), 1334-1346.
[0048] In appropriate cellular systems, the compounds of formula
(I) and pharmaceutical acceptable salts thereof, can also reduce
the generation of inflammatory mediators. For example, the
compounds can inhibit oxygen radical generation and generation of
pro-inflammatory cytokines in monocytes. The compounds are
especially useful as inhibitors of one or more cytokines selected
from IL-1.beta., TNF-.alpha., GM-CSF or IL-8.
[0049] The compounds of the invention are indicated for use in the
treatment of inflammatory, immunological, bronchopulmonary,
cardiovascular, oncological or CNS-degenerative disorders.
Preferably for oral or topical treatment of inflammatory and/or
immunological disorders, such as the oral or topical treatment of
airway diseases involving inflammatory conditions, e.g. asthma,
bronchitis or atopic diseases, e.g. rhinitis or atopic dermatitis;
inflammatory bowel diseases, e.g. Crohn's disease or colitis;
autoimmune diseases e.g. multiple sclerosis, diabetes,
atherosclerosis, psoriasis, systemic lupus erythematosus or
rheumatoid arthritis; malignant diseases, e.g. skin or lung cancer;
HIV infections or AIDS; or for inhibiting rejection of
organs/transplants.
[0050] The dose of the compound to be administered will depend upon
the relevant indication, the age, weight and sex of the patient and
may be determined by a physician. The dosage will preferably be in
the range of from 0.1 mg/kg to 100 mg/kg.
[0051] The compounds may be administered topically, e.g. to the
lung and/or the airways, in the form of solutions, suspensions, HFA
areosols or dry powder formulations, e.g. formulations in the
inhaler denice known as the Turbuhaler.RTM.; or systemically, e.g.
by oral administration in the form of tablets, pills, capsules,
syrups, powders or granules, or by parenteral administration, e.g.
in the form of sterile parenteral solutions or suspensions, or by
rectal administration, e.g. in the form of suppositories.
[0052] The compounds of the invention may be administered on their
own or as a pharmaceutical composition comprising the compound of
the invention in combination with a pharmaceutically acceptable
diluent, adjuvant or carrier. Particularly preferred are
compositions not containing material capable of causing an adverse,
e.g. an allergic, reaction.
[0053] Dry powder formulations and pressurized HFA aerosols of the
compounds of the invention may be administred by oral or nasal
inhalation. For inhalation the compound is desireably finely
divided. The finely divided compound preferably has a mass median
diameter of less than 10 .mu.m, and may be suspended in a
propellant mixture with the assistance of a dispersant, such as a
C.sub.8-C.sub.20 fatty acid or salt thereof, (e.g. oleic acid), a
bile salt, a phospholipid, an alkyl saccharide, a perfluorinated or
polyethoxylated surfactant, or other pharmaceutically acceptable
dispersant.
[0054] The compounds of the invention may also be administered by
means of a dry powder inhaler. The inhaler may be a single or a
multi dose inhaler, and may be a breath actuated dry powder
inhaler.
[0055] One possibility is to mix the finely divided compound with a
carrier substance, e.g. a mono-, di- or polysaccharide, a sugar
alcohol, or an other polyol. Suitable carriers are sugars, e.g.
lactose, glucose, raffinose, melezitose, lactitol, maltitol,
trehalose, sucrose, mannitol; and starch. Alternatively the finely
divided compound may be coated by another substance. The powder
mixture may also be dispensed into hard gelatine capsules, each
containing the desired dose of the active compound.
[0056] Another possibility is to process the finely divided powder
into spheres which break up during the inhalation procedure. This
spheronized powder may be filled into the drug reservoir of a
multidose inhaler, e.g. that known as the Turbuhaler.RTM. in which
a dosing unit meters the desired dose which is then inhaled by the
patient. With this system the active compound, with or without a
carrier substance, is delivered to the patient.
[0057] For oral administration the active compound may be admixed
with an adjuvant or a carrier, e.g. lactose, saccharose, sorbitol,
mannitol; a starch, e.g. potato starch, corn starch or amylopectin;
a cellulose derivative; a binder, e.g. gelatine
orpolyvinylpyrrolidone, and/or a lubricant, e.g. magnesium
stearate, calcium stearate, polyethylene glycol, a wax, paraffin,
and the like, and then compressed into tablets. If coated tablets
are required, the cores, prepared as described above, may be coated
with a concentrated sugar solution which may contain e.g. gum
arabic, gelatine, talcum, titanium dioxide, and the like.
Alternatively, the tablet may be coated with a suitable polymer
dissolved in a readily volatile organic solvent.
[0058] For the preparation of soft gelatine capsules, the compound
may be admixed with e.g. a vegetable oil or polyethylene glycol.
Hard gelatine capsules may contain granules of the compound using
either the above mentioned excipients for tablets. Also liquid or
semisolid formulations of the drug may be filled into hard gelatine
capsules.
[0059] Liquid preparations for oral application may be in the form
of syrups or suspensions, for example solutions containing the
compound, the balance being sugar and a mixture of ethanol, water,
glycerol and propylene glycol. Optionally such liquid preparations
may contain colouring agents, flavouring agents, saccharine and/or
carboxymethylcellulose as a thickening agent or other excipients
known to those skilled in art.
[0060] The compounds of the invention may also be administered in
conjunction with other compounds used for the treatment of the
above conditions.
[0061] The term `medical therapy` as used herein is intended to
include prophylactic, diagnostic and therapeutic regimens carried
out in vivo or ex vivo on humans or other mammals.
[0062] Compounds of the present invention include all
stereoisomers, pure and mixed racemates, and mixtures thereof.
[0063] In compounds of formula (IA) of the present invention, the
following independent preferences apply:
[0064] R.sub.5 and/or R.sub.6 carries a hydroxy or amino group,
[0065] at least one of Y and Z are substituted,
[0066] position 5 of the indole is substituted,
[0067] at least one of Y and Z are substituted with halo, methoxy
or carboxylic ester,
[0068] R.sub.9 is H or alkyl and is most preferably H,
[0069] when R.sub.5 or R.sub.6 is an aminodeoxysugar, it is
preferably a six membered ring,
[0070] when R.sub.5 and R.sub.9 together form a cyclic moiety, it
is preferably a six membered ring,
[0071] three or four of X,Y,Z and A are carbon, and/or
[0072] R.sub.1 and R.sub.2, R.sub.2 and R.sub.3,or R.sub.3 and
R.sub.4; and most preferably R.sub.2 and R.sub.3, form an annulated
aromatic ring
[0073] The most preferred compounds of the present invention are as
follows:
[0074]
3-[3-(4-Methyl-3-oxo-3,4-dihydro-quinoxalin-2-yl)-indol-1-yl]-propy-
l-ammonium acetate,
[0075]
3-[3-(6,7-Dichloro-3-oxo-3,4-dihydro-quinoxalin-2-yl)-indol-1-yl]-p-
ropyl-ammonium acetate,
[0076]
3-[3-(6,7-Dichloro-3-oxo-3,4-dihydro-quinoxalin-2-yl)-5-methoxycarb-
onyl-indol-1-yl]-propyl-ammonium acetate,
[0077]
3-[3-(6,7-Dichloro-4-methyl-3-oxo-3,4-dihydro-quinoxalin-2-yl)-5-me-
thoxycarbonyl-indol-1-yl]-propyl-ammonium acetate,
[0078]
3-[5-Methoxycarbonyl-3-(7-methoxy-3-oxo-3,4-dihydro-quinoxalin-2-yl-
)-indol-1-yl]-propyl-ammonium acetate,
[0079]
3-[3-(4-tert-Butoxycarbonylmethyl-7-methoxy-3-oxo-3,4-dihydro-quino-
xalin-2-yl)-5-methoxycarbonyl-indol-1-yl]-propyl-ammonium
acetate,
[0080]
3-[3-(4-(3-Ammoniumpropyl)-3-oxo-3,4-dihydro-quinoxalin-2-yl)-indol-
-1-yl]propyl-ammonium bis trifluoroacetate,
[0081]
Dimethyl-{3-[3-(1-methyl-1H-indol-3-yl)-2-oxo-2H-quinoxalin-1-yl]-p-
ropyl}-ammonium trifluoroacetate,
[0082]
3-[3-(3-Oxo-3,4-dihydro-benzo[g]quinoxalin-2-yl)-indol-1-yl]-propyl-
-ammonium acetate,
[0083]
3-[6-Benzyloxy-3-(7-methoxy-4-methyl-3-oxo-3,4-dihydro-quinoxalin-2-
-yl)-indol-1-yl]-propyl-ammonium acetate,
[0084]
3-[5-Benzyloxy-3-(4-tert-butoxycarbonylmethyl-7-methoxy-3-oxo-3,4-d-
ihydro-quinoxalin-2-yl)-indol-1-yl]-propyl-ammonium acetate,
[0085]
3-[2-(4-Chloro-phenyl)-3-(7-methoxy-3-oxo-3,4-dihydro-quinoxalin-2--
yl)-indol-1-yl]-propyl-ammonium acetate,
[0086]
3-[2-(4-Chloro-phenyl)-3-(7-methoxy-4-methyl-3-oxo-3,4-dihydro-quin-
oxalin-2-yl)-indol-1-yl]-propyl-ammonium acetate,
[0087]
3-[3-(6,7-Dichloro-4-methyl-3-oxo-3,4-dihydro-quinoxalin-2-yl)-2-et-
hyl-indol-1-yl]-propyl-ammonium acetate,
[0088]
3-[3-(5-Methyl-3-oxo-3,4-dihydro-quinoxalin-2-yl)-6-nitro-indol-1-y-
l]-propyl-ammonium acetate,
[0089]
3-[6-Nitro-3-(6-nitro-3-oxo-3,4-dihydro-quinoxalin-2-yl)-indol-1-yl-
]-propyl-ammonium acetate,
[0090]
4-[3-(3-Oxo-3,4-dihydro-quinoxalin-2-yl)-indol-1-ylmethyl]benzyl-am-
monium acetate,
[0091]
3-[3-(4-Methyl-3-oxo-3,4-dihydro-quinoxalin-2-yl)-indol-1-ylmethyl]-
-benzyl-ammonium trifluoroacetate,
[0092]
3-[3-(4-Benzyl-3-oxo-3,4-dihydro-quinoxalin-2-yl)-indol-1-yl]propyl-
-ammonium trifluoroacetate;
[0093] and the corresponding free amines thereof and other
pharmaceutically acceptable salts thereof.
[0094] The most preferred compound of the present invention is:
[0095]
3-[3-(3-Oxo-3,4-dihydro-benzo[g]quinoxalin-2-yl)-indol-1-yl]-propyl-
-ammonium acetate,
[0096] and the corresponding free amines thereof and other
pharmaceutically acceptable salts thereof.
[0097] The following Examples illustrate, but in no way limit the
invention.
[0098] All reactions were performed in dried glassware under Ar or
N.sub.2 unless otherwise noted. Tetrahydrofuran was distilled from
sodium/benzophenone. Dimethyl formamide was distilled from calcium
hydride, or dried over molecular sieves. Other solvents and all
commercial reagents were used as received.
[0099] .sup.1H-NMR spectra were recorded on a Varian XL-300 or
Unity-500+instrument. The central solvent peaks of chloroform-d
(.delta..sub.H 7.24 ppm), methanol-d.sub.4 (.delta..sub.H 3.34 ppm)
and dimethyl sulphoxide-d.sub.6 (.delta..sub.H 2.50 ppm) were used
as internal references. Low-resolution mass spectra and accurate
mass determinations were recorded on an Autospec-Q, Fisons
Analytical, double focusing sector instrument equiped with a LSIMS
interface.
EXAMPLE 1
[0100]
{1-[3-(1,3-Dioxo-1,3-dihydroisoindol-2-yl)-propyl]-1H-indol-3-yl}-o-
xoacetic acid 2,5-dioxopyrrolidin-1-yl ester) [intermediate]
[0101] 1-[3-(1,3-Dioxo-1,3-dihydroisoindol-2-yl)-propyl]-1H-indol
(1.00 g, 3.29 mmol) was dissolved in dichloromethane (10 ml) and
cooled to 0.degree. C. Oxalylchloride (0.28 ml, 3.29 mmol) was
added and the reaction kept at 0.degree. C. for 30 minutes before
the addition of N-hydroxysuccinimide (0.38 g, 3.29 mmol) followed
by careful addition of pyridine (0.53 ml, 6.57 mmol).
[0102] After stirring the reaction for 1 hour at room temperature
brine (5%, 10 ml) was added and the phases separated, the organic
phase was washed with brine (5%, 2.times.10 ml), dried over
Na.sub.2SO.sub.4 followed by removal of the solvent in vacuo.
Crystallisation of the crude product from ethyl acetate--hexane
yields the title product, 1.06 g (69%).
[0103] .sup.1H-NMR (500 MHz, CDCl.sub.3): .delta. 2.36 (2H, p, J
6.9 Hz), 2.93 (4H, s), 3.82 (2H, t, J 6.5 Hz), 4.29 (2H, t, J 7.5
Hz), 7.33-7.44 (3H, m), 7.70-7.75 (2H, m), 7.78-7.83 (2H, m),
8.32-8.36 (1H, m), 8.50 (1H, s).
[0104] FAB-MS: m/z 474 [MH+]
EXAMPLE 2
[0105] A)
3-[3-(3-Oxo-3,4-dihydro-quinoxalin-2-yl)-indol-1-yl]propyl-ammon-
ium acetate
[0106] 1,2-Phenylenediamine (0.021 g, 0.20 mmol) and the product of
Example 1 (0.075 g, 0.16 mmol) was dissolved in tetrahydrofuran (1
ml). Stirring overnight yields
2-(3-(3-(3-oxo-3,4-dihydroquinoxalin-2-yl)-inol-
-1-yl)propyl)-isoindol-1,3-dione as a yellow precipitate that was
filtered off and washed with tetrahydrofuran.
[0107] .sup.1H-NMR (500, MHz, DMSO-d6): .delta. 2.18 (2H, p, J 7.1
Hz), 3.71 (2H, t, J 6.6 Hz), 4.44 (2H, t, J 7.4 Hz), 7.26-7.36 (4H,
m), 7.45 (1H, t, J 7.4 Hz), 7.67 (1H, d, J 8.3 Hz), 7.81-7.85 (2H,
m), 7.85-7.89 (3H, m), 8,91 (1H, d, J 7.5 Hz), 9.03 (1H, s), 12.44
(1H, s, NH).
[0108] FAB-MS: m/z 449.3 [MH+]
[0109] The precipitate was suspended in tetrahydrofuran (1 ml) and
aqueous methylamine (40%, 0.7 ml) was added. After stirring for 5
hours the solvent was removed in vacuo.
[0110] 3-(1-(3-Aminopropyl)-1H-indol-3-yl)-1H-quinoxalin-2-one was
crystallised from water and treated with aqueous acetic acid (1 M,
1 ml) to obtain the title compound as a yellow solid, 0.045 g
(75%), after freeze drying.
[0111] .sup.1H-NMR (500 MHz, CD.sub.3OD): .delta. 1.92 (3H, s),
2.26 (2H, dt, J 15.7, 7.0 Hz), 2.92-2.98 (2H, m), 4.43 (2H, t, J
6.9 Hz), 7.28-7.40 (4H, m), 7.46 (1H, t, J 7.5 Hz), 7.56 (1H, d, J
7.5 Hz), 7.92 (1H, d, J 8.0 Hz), 8.87 (1H, s), 8.96 (1H, d, J 7.6
Hz).
[0112] FAB-MS: m/z 319.1 [MH+]
[0113] B)
3-[3-(6-Fluoro-3-oxo-3,4-dihydro-quinoxalin-2-yl)-indol-1-yl]pro-
pyl-ammonium acetate
[0114] The title compound was prepared in 89% yield as described in
A) starting from 4-fluoro-1,2-phenylenediamine.
[0115] .sup.1H-NMR (500 MHz, DMSO-d.sub.6): .delta. 1.83 (3H, s),
1.99 (2H, p, J 7.1 Hz), 2.67 (2H, t, J 7.0 Hz), 4.42 (2H, t, J 7.0
Hz), 7.27-7.37 (4H, m), 7.67 (1H, d, J 7.6 Hz), 7.70 (1H, d, J 9.5
Hz), 8.91 (1H, d, J 7.9 Hz), 9.04 (1H, s).
[0116] FAB-MS: m/z 337.1 [MH+]
[0117] C)
3-[3-(7-Methoxy-3-oxo-3,4-dihydro-quinoxalin-2-yl)-indol-1-yl]-p-
ropyl-ammonium acetate
[0118] The title compound was prepared in 83% yield as described in
A) starting from 4-methoxy-1,2-phenylenediamine.
[0119] .sup.1H-NMR (500 MHz, CD.sub.3OD): .delta. 1.95 (3H, s),
2.29 (2H, dt, J 15.2, 6.8 Hz), 2.96-3.00 (2H, m), 3.96 (3H, s),
4.45 (2H, t, J 6.8 Hz), 7.13 (1H, dd, J 8.9, 2.6 Hz), 7.27 (1H, d,
J 9.2 Hz), 7.32-7.39 (2H, m), 7.44 (1H, d, J 2.6 Hz), 7.59 (1H, d,
J 7.9 Hz), 8.89 (1H, s), 8.99 (1H, d, J 7.5 Hz).
[0120] FAB-MS: m/z 349.1 [MH+]
[0121] D)
3-[3-(2-Oxo-1,2-dihydro-pyrido[2,3-b]pyrazin-3-yl)-indol-1-yl]pr-
opyl-ammonium acetate
[0122] The title compound was prepared in 85% yield as described in
A) starting from 2,3-diaminopyridine.
[0123] .sup.1H-NMR (500 MHz, CD.sub.3OD): .delta. 1.95 (3H, s),
2.30 (2H, dt, J 15.6, 7.1 Hz), 2.98-3.03 (2H, m), 4.47 (2H, t, J
7.0 Hz), 7.36-7.41 (2H, m), 7.58-7.62 (1H, m), 8.72 (1H, s), 8.96
(1H, s), 9.06-9.10 (1H, m), 9.18 (1H, s).
[0124] FAB-MS: m/z 320.1 [MH+]
[0125] E)
3-[3-(4-Hydroxy-6-oxo-5,6-dihydro-pteridin-7-yl)-indol-1-yl]-pro-
pyl-ammonium acetate
[0126] The title compound was prepared in 38% yield as described in
A) starting from 5,6-diamino-4-hydroxypyrimidine.
[0127] .sup.1H-NMR (500 MHz, DMSO-d.sub.6/D.sub.2O): .delta. 1.89
(3H, s), 2.08 (2H, p, J 7.0 Hz), 2.80 (2H, t, J 7.1 Hz), 4.45 (2H,
t, J 7.1 Hz), 7.26-7.33 (2H, m), 7.66 (1H, d, J 8.1 Hz), 8.00 (1H,
s), 8.91 (1H, d, J 7.5 Hz), 9.20 (1H, s).
[0128] FAB-MS: m/z 337.0 [M+]
[0129] F)
3-[3-(6-Oxo-5,6-dihydro-pteridin-7-yl)-indol-1-yl]-propyl-ammoni-
um acetate
[0130] The title compound was prepared in 38% yield as described in
A) starting from 5,6-diaminopyrimidine.
[0131] FAB-MS: m/z 320.2 [M+]
[0132] G)
3-[3-(5-Hydroxy-3-oxo-3,4-dihydro-quinoxalin-2-yl)-indol-1-yl]-p-
ropyl-ammonium acetate
[0133] The title compound was prepared in 22% yield as described in
A) starting from 2,3-diaminophenol.
[0134] FAB-MS: m/z 335.1 [MH+]
[0135] H)
3-[3-(3-Oxo-3,4-dihydro-pyrido[3,4-b]pyrazin-2-yl)-indol-1-yl]-p-
ropyl-ammonium acetate
[0136] The title compound was prepared in 38% yield as described in
A) starting from 3,4-diaminopyridine.
[0137] FAB-MS: m/z 320.2 [MH+]
[0138] I)
3-[3-(8-Nitro-3-oxo-3,4-dihydro-quinoxalin-2-yl)-indol-1-yl]prop-
yl-ammonium acetate
[0139] The title compound was prepared in 79% yield as described in
A) starting from 3-nitro-1,2-phenylenediamine.
[0140] FAB-MS: m/z 364.1 [MH+]
[0141] J)
3-[3-(6-Nitro-3-oxo-3,4-dihydro-quinoxalin-2-yl)-indol-1-yl]-pro-
pyl-ammonium acetate
[0142] The title compound was prepared in 55% yield as described in
A) starting from 4-nitro-1,2-phenylenediamine.
[0143] FAB-MS: m/z 364.1 [MH+]
[0144] K)
3-[3-(6,7-Dichloro-3-oxo-3,4-dihydro-quinoxalin-2-yl)-indol-1I-y-
l]-propyl-ammonium acetate
[0145] The title compound was prepared in 93% yield as described in
A) starting from 4,5-dichloro-1,2-phenylenediamine.
[0146] FAB-MS: m/z 387.0 [MH+]
[0147] L)
3-[3-(7-Methyl-3-oxo-3,4-dihydro-quinoxalin-2-yl)-indol-1-yl]-pr-
opyl-ammonium acetate
[0148] The title compound was prepared in 93% yield as described in
A) starting from 4-methyl-1,2-phenylenediamine.
[0149] FAB-MS: m/z 333.2 [MH+]
[0150] M)
3-[3-(5-Methyl-3-oxo-3,4-dihydro-quinoxalin-2-yl)-indol-1-yl]-pr-
opyl-ammonium acetate
[0151] The title compound was prepared in 87% yield as described in
A) starting from 3-methyl-1,2-phenylenediamine.
[0152] FAB-MS: m/z 333.2 [MH+]
[0153] N)
3-[3-(6,7-Dimethyl-3-oxo-3,4-dihydro-quinoxalin-2-yl)-indol-1-yl-
]-propyl-ammonium acetate
[0154] The title compound was prepared in 89% yield as described in
A) starting from 4,5-dimethyl-1,2-phenylenediaamine.
[0155] FAB-MS: m/z 347.2 [MH+]
[0156] O)
3-[3-(6-Methoxycarbonyl-3-oxo-3,4-dihydro-quinoxalin-2-yl)-indol-
-1-yl]-propyl-ammonium acetate
[0157] The title compound was prepared in 43% yield as described in
A) starting from methyl 3,4-diaminobensoate.
[0158] FAB-MS: m/z 377.1 [MH+]
[0159] P)
3-[3-(6-Ethoxycarbonyl-3-oxo-3,4-dihydro-quinoxalin-2-yl)-indol--
1-yl]propyl-ammonium acetate
[0160] The title compound was prepared in 78% yield as described in
A) starting from ethyl 3,4-diaminobensoate.
[0161] FAB-MS: m/z 391.0 [MH+]
[0162] Q)
3-[3-(3-Oxo-6-trifluoromethyl-3,4-dihydro-quinoxalin-2-yl)-indol-
-1-yl]propyl-ammonium acetate
[0163] The title compound was prepared in 85% yield as described in
A) starting from 4-trifluoromethyl-1,2-phenylenediamine.
[0164] FAB-MS: m/z 387.1 [MH+]
EXAMPLE 3
[0165]
3-[3-(4-Methyl-3-oxo-3,4-dihydro-quinoxalin-2-yl)-indol-1-yl]propyl-
-ammonium acetate
[0166] A dispersion of sodium hydride, 55-60% in oil, (0.0075 g,
0.17 mmol) in dry dimethyl formamide (2 ml) was cooled to
-20.degree. C. A solution
2-{3-[3-(3-oxo-3,4-dihydro-quinoxalin-2-yl)-indol-1-yl]-propyl}--
isoindol-1,3-dione (0.050 g, 0.11 mmol) in dry dimethyl formamide
(2 ml), was added dropwise and the resulting mixture kept at
-20.degree. C. for 5 min and then at room temperature for another
15 min. The reaction mixture was cooled to -20.degree. C. and
methyl iodide (0.017 g, 0.12 mmol, 7.7 .mu.l) was added via a
syringe. The resulting solution was allowed to reach room
temperature whereupon 12 ml of diethyl ether was added. After 2 h
at room temperature,
2-{3-[3-(4-methyl-3-oxo-3,4-dihydro-quinoxalin-2-
-yl)-indol-1-yl]-propyl}-isoindole-1,3-dione was precipitated.
[0167] The precipitate was collected by centrifugation, and then
suspended in tetrahydrofuran (2 ml). Aqueous methylamine (1 ml) was
added giving a homogenous light yellow solution. After stirring for
5 h, the free amine was precipitated. The solvent was evaporated
and the precipitate suspended in 4 ml of water and then collected
by centrifugation. The precipitate was treated with aqueous acetic
acid (1 M, 1 ml) and freeze dried to give 0.019 g (43%) of the
title compound as a yellow solid.
[0168] .sup.1H-NMR (400 MHz, CD.sub.3OD): .delta. 1.95 (3H, s),
2.28 (2H, quintet, J 7.0 Hz), 2.97 (2H, bs), 3.85 (3H, s), 4.46
(2H, t, J 7.0 Hz), 7.30-7.40 (2H, m), 7.46 (1H, ddd, J 8.0, 7.2,
2.4 Hz), 7.56-7.62 (3H, m), 7.98 (1H, d, J 7.7 Hz), 8.90 (1H, s),
8.99 (1H, d, J 7.3 Hz).
[0169] FAB-MS: m/z 333.0 [MH+]
EXAMPLE 4
[0170]
3-{1-(6-Amino-2,4,6-trideoxy-.beta.-D-threo-hexopyranosyl)-1H-indol-
-3-yl}-1H-quinoxazolin-2-one trifluoro acetic acid salt
[0171] a)
3-{1-(3-O-Benzoyl-6-phthalimido-2,4,6-trideoxy-.beta.-D-threo-he-
xopyranosyl)-1H-indol-3-yl}-1H-quinoxalin-2-one
[0172]
1-(3-O-Benzoyl-6-phthalimido-2,4,6-trideoxy-.beta.-D-threo-hexopyra-
nosyl)-1H-indole (0.30 g, 0.62 mmol) was dissolved in
dichloromethane (3 ml) and cooled to 0.degree. C. Oxalylchloride
(65 .mu.l, 0.74 mmol) was added and the reaction mixture kept at
0.degree. C. for 15 min and then stirred at room temperature for
another 45 minutes. N-hydroxysuccinimid (0.08 g 0.70 mmol) was
added followed by careful addition of pyridine (0.10 ml, 1.23
mmol). The reaction mixture was stirred at room temperature for 16
hours and then washed twice with water. The organic layer was
evaporated and the crude mixed with tetrahydrofuran (10 ml) and
1,2-diphenylenediamine (0.09 g, 0.80 mmol) and stirred at room
temperature for 16 hours. The resulting percipitate was collected
by centrifugation, washed twice with ether and dried to give 0.12 g
(32%) of the subtitle product.
[0173] .sup.1H-NMR (400 Mhz, DMSO-d.sub.6): .delta. 1.63-1.74 (1H,
m), 2.31-2.40 (2H, m), 2.55-2.62 (1H, m), 3.76 (1H, dd, J 14.2, 5.4
Hz), 3.86 (1H, dd, J 14.0, 7.3 Hz), 4.29-4.38 (1H, m), 5.41-5.53
(1H, m), 6.08 (1H, dd, J 11.0, 1.9 Hz), 7.00 (1H, t, J 7.5 Hz),
7.22 (1H, t, J 7.5 Hz), 7.29-7.37 (2H, m), 7.45 (1H, d, J 7.5 Hz),
7.49 (1H, d, J 7.9 Hz), 7.52-7.59 (2H, m), 7.69 (1H, t, J 7.5 Hz),
7.85 (4H, bs), 7.88 (1H, d, J 8.1 Hz), 8.01-8.06 (2H, m), 8.86 (1H,
d, J 8.1 Hz), 9.05 (1H, s), 12.49 (1H, s).
[0174] b) The product from step a) (52.0 mg, 0.08 mmol) was
dispersed in 2 ml of tetrahydrofuran. Aqueous methylamine was added
(1 ml) and the mixtrure stirred at room temperature for 17 hours.
The reaction mixture was eveporated and the crude filtered through
a short column of silica gel using CH.sub.2Cl.sub.2/MeOH/NH.sub.3
(100/10/1) as eluent. The solvents were evaporated and the crude
amine subjected to reverse-phase column chromatography using a
pre-packed column (Merck Lobar, LiChroprep RP-8) and
MeOH/H.sub.2O/TFA (70/30/0.1) as the eluent. The fractions
containing the product were partly evaporated and freeze dried to
give 0.01 g (24%) of the title product.
[0175] .sup.1H-NMR (500 Mhz, DMSO-d.sub.6): .delta. 1.27-1.37 (1H,
m), 1.95-2.05 (2H, m), 2.29-2.37 (1H, m), 2.88-3.00 (1H, m),
3.04-3.13 (1H, m), 3.93-4.08 (2H, m), 5.23 (1H, bs), 5.91 (1H, dd,
J 11.2, 1.8 Hz), 7.29-7.36 (4H, m), 7.46 (1H, t, J 7.4 Hz), 7.75
(1H, t, J 7.9 Hz), 7.79 (2H, bs), 7.89 (1H, d, J 8.0 Hz), 8.89-8.93
(1H, m), 9.09 (1H, s), 12.51 (1H, s).
[0176] FAB-MS: m/z 391 [MH+]
EXAMPLE 5
[0177]
3-[3-(4-(3-Ammoniumpropyl)-3-oxo-3,4-dihydro-quinoxalin-2-yl)-indol-
-1-yl]-propyl-ammonium bis trifluoroacetate
[0178] A mixture of sodium hydride, 55-60% in oil, (0.029 g, 0.67
mmol) and
2-{3-[3-(3-oxo-3,4-dihydro-quinoxalin-2-yl)-indol-1-yl]-propyl}-isoin-
dol-1,3-dione (0.25 g, 0.56 mmol) in dry dimethyl formamide (4 ml)
was stirred at -20.degree. C. for 10 min and then at room
temperature for another 30 min. A solution of
2-(3-Bromopropyl)-isoindole-1,3-dione (0.20 g 0.75 mmol) in 2 ml
dimethyl formamide was added and the rection mixture stirred at
room temperature for 30 min and then at 60.degree. C. for 3 hours.
The percipitate formed was separated by centrifuigation, washed
with ethyl acetate and dried. The crude percipitate was suspended
in tetrahydrofuran (5 ml) and aqeuous methylamine (3 ml) and
stirred at room temperature for 3.5 hours. The solvent was
evaporated and the residue washed with 10 ml of water. The crude
mixture was subjected to reverse-phase column chromatography using
a pre-packed column (Merck Lobar, LiChroprep RP-8) and
MeOH/H.sub.2O/TFA (70/30/0.1) as the eluent. The fractions
containing the product were partly evaporated and freeze dried to
give 0.02 g (6%) of the title product.
[0179] .sup.1H-NMR (500 Mhz, CD.sub.3OD): .delta. 2.29 (2H,
quintet, J 7.6 Hz), 2.39 (2H, quintet, J 7.1 Hz), 2.99 (2H, t, J
7.8 Hz), 3.20 (2H, t, J 7.3 Hz), 4.50 (2H, t, J 7.1 Hz), 4.844.89
(2H, triplett hidden under the solvent), 7.31 (1H, td, J 7.6 1.0
Hz), 7.36 (1H, td, J 7.8 1.2 Hz), 7.56-7.66 (3H, m), 7.78-7.84 (1H,
m), 8.04-8.09 (1H, m), 8.36 (1H, s), 8.94 (1H, d, J 7.9 Hz).
[0180] FAB-MS: m/z 376 [MH+]
[0181] The following examples were prepared following the methods
described above in Examples 1 to 4. Removal of protecting groups
were performed according to standard literature methods.
EXAMPLE 6
[0182]
3-[3-(4-tert-Butoxycarbonylmethyl-3-oxo-3,4-dihydro-quinoxalin-2-yl-
)-2-methyl-indol-1-yl]-propyl-ammonium acetate
[0183] FAB-MS: m/z 447 [MH+]
EXAMPLE 7
[0184]
3-[5-Benzyloxy-3-(4-methyl-3-oxo-3,4-dihydro-quinoxalin-2-yl)-indol-
-1-yl]-propyl-ammonium acetate
[0185] FAB-MS: m/z 439 [MH+]
EXAMPLE 8
[0186]
3-[3-(4-Methyl-3-oxo-3,4-dihydro-quinoxalin-2-yl)-6-nitro-indol-1-y-
l]propyl-ammonium acetate
[0187] FAB-MS: m/z 378 [MH+]
EXAMPLE 9
[0188]
3-[3-(4-tert-Butoxycarbonylmethyl-3-oxo-3,4-dihydro-quinoxalin-2-yl-
)-2-(4-chloro-phenyl)-indol-1-yl]-propyl-ammonium acetate
[0189] FAB-MS: m/z 544 [MH+]
EXAMPLE 10
[0190]
3-[2-Ethyl-3-(4-methyl-3-oxo-3,4-dihydro-quinoxalin-2-yl)-indol-1-y-
l]propyl-ammonium acetate
[0191] FAB-MS: m/z 361 [MH+]
EXAMPLE 11
[0192]
3-[6-Benzyloxy-3-(4-tert-butoxycarbonylmethyl-3-oxo-3,4-dihydro-qui-
noxalin-2-yl)-indol-1-yl]-propyl-ammonium acetate
[0193] FAB-MS: m/z 539 [MH+]
EXAMPLE 12
[0194]
3-[5-Methoxycarbonyl-3-(4-methyl-3-oxo-3,4-dihydro-quinoxalin-2-yl)-
-indol-1-yl]propyl-ammonium acetate
[0195] FAB-MS: m/z 391 [MH+]
EXAMPLE 13
[0196]
3-[3-(4,7-Dimethyl-3-oxo-3,4-dihydro-quinoxalin-2-yl)-2-methyl-indo-
l-1-yl]-propyl-ammonium acetate
[0197] FAB-MS: ml/z 361 [MH+]
EXAMPLE 14
[0198]
3-[5-Benzyloxy-3-(4-tert-butoxycarbonylmethyl-7-methyl-3-oxo-3,4-di-
hydro-quinoxalin-2-yl)-indol-1-yl]-propyl-ammonium acetate
[0199] FAB-MS: m/z 553 [MH+]
EXAMPLE 15
[0200]
3-[3-(4-tert-Butoxycarbonylmethyl-7-methyl-3-oxo-3,4-dihydro-quinox-
alin-2-yl)-6-nitro-indol-1-yl]-propyl-ammonium acetate
[0201] FAB-MS: m/z 492 [MH+]
EXAMPLE 16
[0202]
3-[2-(4-Chloro-phenyl)-3-(4,7-dimethyl-3-oxo-3,4-dihydro-quinoxalin-
-2-yl)-indol-1-yl]-propyl-ammonium acetate
[0203] FAB-MS: m/z 457 [MH+]
EXAMPLE 17
[0204]
3-[3-(4-tert-Butoxycarbonylmethyl-7-methyl-3-oxo-3,4-dihydro-quinox-
alin-2-yl)-2-ethyl-indol-1-yl]-propyl-ammonium acetate
[0205] FAB-MS: m/z 475 [MH+]
EXAMPLE 18
[0206]
3-[6-Benzyloxy-3-(4,7-dimethyl-3-oxo-3,4-dihydro-quinoxalin-2-yl)-i-
ndol-1-yl]propyl-ammonium acetate
[0207] 453 [MH+]
EXAMPLE 19
[0208]
3-[3-(4-tert-Butoxycarbonylmethyl-7-methyl-3-oxo-3,4-dihydro-quinox-
alin-2-yl)-5-methoxycarbonyl-indol-1-yl]propyl-ammonium acetate
[0209] 505 [MH+]
EXAMPLE 20
[0210]
3-[3-(4-tert-Butoxycarbonylmethyl-6,7-dichloro-3-oxo-3,4-dihydro-qu-
inoxalin-2-yl)-2-methyl-indol-1-yl]-propyl-ammonium acetate
[0211] 516 [MH+]
EXAMPLE 21
[0212]
3-[5-Benzyloxy-3-(6,7-dichloro-4-methyl-3-oxo-3,4-dihydro-quinoxali-
n-2-yl)-indol-1-yl]-propyl-ammonium acetate
[0213] 508 [MH+]
EXAMPLE 22
[0214]
3-[3-(6,7-Dichloro-4-methyl-3-oxo-3,4-dihydro-quinoxalin-2-yl)-2-et-
hyl-indol-1-yl]-propyl-ammonium acetate
[0215] FAB-MS: m/z 430 [MH+]
EXAMPLE 23
[0216]
3-[3-(6,7-Dichloro-4-methyl-3-oxo-3,4-dihydro-quinoxalin-2-yl)-5-me-
thoxycarbonyl-indol-1-yl]-propyl-ammonium acetate
[0217] FAB-MS: m/z 460 [MH+]
EXAMPLE 24
[0218]
3-[5-Benzyloxy-3-(4-tert-butoxycarbonylmethyl-6-nitro-3-oxo-3,4-dih-
ydro-quinoxalin-2-yl)-indol-1-yl]-propyl-ammonium acetate
[0219] FAB-MS: m/z 584 [MH+]
EXAMPLE 25
[0220]
3-[3-(4-tert-Butoxycarbonylmethyl-6-nitro-3-oxo-3,4-dihydro-quinoxa-
lin-2-yl)-6-nitro-indol-1-yl]-propyl-ammonium acetate
[0221] FAB-MS: m/z 523 [MH+]
EXAMPLE 26
[0222]
3-[3-(4-tert-Butoxycarbonylmethyl-6-nitro-3-oxo-3,4-dihydro-quinoxa-
lin-2-yl)-5-methoxycarbonyl-indol-1-yl]-propyl-ammonium acetate
[0223] FAB-MS: m/z 536 [MH+]
EXAMPLE 27
[0224]
3-[5-Benzyloxy-3-(4,5-dimethyl-3-oxo-3,4-dihydro-quinoxalin-2-yl)-i-
ndol-1-yl]propyl-ammonium acetate
[0225] FAB-MS: m/z 453 [MH+]
EXAMPLE 28
[0226]
3-[3-(4,5-Dimethyl-3-oxo-3,4-dihydro-quinoxalin-2-yl)-6-nitro-indol-
-1-yl]-propyl-ammonium acetate
[0227] FAB-MS: m/z 392 [MH+]
EXAMPLE 29
[0228]
3-[3-(4-tert-Butoxycarbonylmethyl-5-methyl-3-oxo-3,4-dihydro-quinox-
alin-2-yl)-2-(4-chloro-phenyl)-indol-1-yl]-propyl-ammonium
acetate
[0229] FAB-MS: m/z 558 [MH+]
EXAMPLE 30
[0230]
3-[5-Benzyloxy-3-(4-tert-butoxycarbonylmethyl-7-methoxy-3-oxo-3,4-d-
ihydro-quinoxalin-2-yl)-indol-1-yl]-propyl-ammonium acetate
[0231] FAB-MS: m/z 569 [MH+]
EXAMPLE 31
[0232]
3-[3-(4-tert-Butoxycarbonylmethyl-7-methoxy-3-oxo-3,4-dihydro-quino-
xalin-2-yl)-6-nitro-indol-1-yl]-propyl-ammonium acetate
[0233] FAB-MS: m/z 508 [MH+]
EXAMPLE 32
[0234]
3-[2-(4-Chloro-phenyl)-3-(7-methoxy-4-methyl-3-oxo-3,4-dihydro-quin-
oxalin-2-yl)-indol-1-yl]-propyl-ammonium acetate
[0235] FAB-MS: m/z 473 [MH+]
EXAMPLE 33
[0236]
3-[3-(4-tert-Butoxycarbonylmethyl-7-methoxy-3-oxo-3,4-dihydro-quino-
xalin-2-yl)-2-ethyl-indol-1-yl]-propyl-ammonium acetate
[0237] FAB-MS: m/z 491 [MH+]
EXAMPLE 34
[0238]
3-[6-Benzyloxy-3-(7-methoxy-4-methyl-3-oxo-3,4-dihydro-quinoxalin-2-
-yl)-indol-1-yl]-propyl-ammonium acetate
[0239] FAB-MS: m/z 469 [MH+]
EXAMPLE 35
[0240]
3-[3-(4-tert-Butoxycarbonylmethyl-7-methoxy-3-oxo-3,4-dihydro-quino-
xalin-2-yl)-5-methoxycarbonyl-indol-1-yl]-propyl-ammonium
acetate
[0241] FAB-MS: m/z 521 [MH+]
EXAMPLE 36
[0242]
3-[6-Hydroxy-3-(7-methoxy-4-methyl-3-oxo-3,4-dihydro-quinoxalin-2-y-
l)-indol-1-yl]-propyl-ammonium acetate
[0243] FAB-MS: m/z 379 [MH+]
EXAMPLE 37
[0244]
5-[3-(1H-Indol-3-yl)-6,7-dimethyl-2-oxo-2H-quinoxalin-1-yl]-pentyl--
ammonium trifluoroacetate
[0245] FAB-MS: m/z 357 [MH+]
EXAMPLE 38
[0246] 3-(1-Butyl-5-methoxy-1H-indol-3-yl)-1H-quinoxalin-2-one
[0247] FAB-MS: m/z 348 [MH+]
EXAMPLE 39
[0248]
3-[5-Bromo-3-(3-oxo-3,4-dihydro-quinoxalin-2-yl)-indol-1-ylmethyl]b-
enzyl-ammonium acetate
[0249] FAB-MS: m/z 459 [MH+]
EXAMPLE 40
[0250] Acetic acid
3-[3-(3-oxo-3,4-dihydro-quinoxalin-2-yl)-indol-1-yl]-pr- opyl
ester
[0251] FAB-MS: m/z 362 [MH+]
EXAMPLE 41
[0252]
3-[3-(3-Oxo-3,4-dihydro-quinoxalin-2-yl)-2-phenyl-indol-1-yl]-propy-
l-ammonium acetate
[0253] FAB-MS: m/z 395 [MH+]
EXAMPLE 42
[0254]
10-(3-Oxo-3,4-dihydro-quinoxalin-2-yl)-6,7,8,9-tetrahydro-pyrido[1,-
2-a]indol-8-ylmethyl-ammonium acetate
[0255] FAB-MS: m/z 345 [MH+]
EXAMPLE 43
[0256] 1-Methyl-3-(1-methyl-1H-indol-3-yl)-1H-quinoxalin-2-one
[0257] FAB-MS: m/z 290 [MH+]
EXAMPLE 44
[0258]
N-{3-[3-(3-Oxo-3,4-dihydro-quinoxalin-2-yl)-indol-1-yl]-propyl}-ace-
tamide
[0259] FAB-MS: m/z 361 [MH+]
EXAMPLE 45
[0260]
3-[3-(4-Methyl-3-oxo-3,4-dihydro-quinoxalin-2-yl)-indol-1-yl]-propy-
l-ammonium acetate
[0261] FAB-MS: m/z 333 [MH+]
EXAMPLE 46
[0262]
3-[3-(4-Methyl-3-oxo-3,4-dihydro-quinoxalin-2-yl)-indol-1-yl]-propy-
l-ammonium trifluoroacetate
[0263] FAB-MS: m/z 333 [MH+]
EXAMPLE 47
[0264] 3-(1-Benzyl-1H-indol-3-yl)-1H-quinoxalin-2-one
[0265] FAB-MS: m/z 352 [MH+]
EXAMPLE 48
[0266]
4-[3-(3-Oxo-3,4-dihydro-quinoxalin-2-yl)-indol-1-yl]-butyl-ammonium
acetate
[0267] FAB-MS: m/z 333 [MH+]
EXAMPLE 49
[0268]
3-[3-(4-Benzyloxymethyl-3-oxo-3,4-dihydro-quinoxalin-2-yl)-indol-1--
yl]propyl-ammonium acetate
[0269] FAB-MS: m/z 439 [MH+]
EXAMPLE 50
[0270]
3-[3-(4-Ethyl-3-oxo-3,4-dihydro-quinoxalin-2-yl)-indol-1-yl]-propyl-
-ammonium trifluoroacetate
[0271] FAB-MS: m/z 347 [MH+]
EXAMPLE 51
[0272]
3-[3-(7-Benzyl-4-methyl-3-oxo-3,4-dihydro-quinoxalin-2-yl)-indol-1--
yl]-propyl-ammonium acetate
[0273] FAB-MS: m/z 423 [MH+]
EXAMPLE 52
[0274]
3-[3-(4-Benzyl-3-oxo-3,4-dihydro-quinoxalin-2-yl)-indol-1-yl]propyl-
-ammonium trifluoroacetate
[0275] FAB-MS: m/z 409 [MH+]
EXAMPLE 53
[0276]
3-[3-(4-Butyl-3-oxo-3,4-dihydro-quinoxalin-2-yl)-indol-1-yl]-propyl-
-ammonium trifluoroacetate
[0277] FAB-MS: m/z 375 [MH+]
EXAMPLE 54
[0278]
3-[3-(4-Allyl-3-oxo-3,4-dihydro-quinoxalin-2-yl)-indol-1-yl]-propyl-
-ammonium trifluoroacetate
[0279] FAB-MS: m/z 359 [MH+]
EXAMPLE 55
[0280]
3-[3-(4-Methylcarbamoylmethyl-3-oxo-3,4-dihydro-quinoxalin-2-yl)-in-
dol-1-yl]propyl-ammonium trifluoroacetate
[0281] FAB-MS: m/z 390 [MH+]
EXAMPLE 56
[0282]
3-[3-(4-tert-Butoxycarbonylmethyl-3-oxo-3,4-dihydro-quinoxalin-2-yl-
)-indol-1-yl]-propyl-ammonium trifluoroacetate
[0283] FAB-MS: m/z 433 [MH+]
EXAMPLE 57
[0284]
3-[3-(4-Carboxymethyl-3-oxo-3,4-dihydro-quinoxalin-2-yl)-indol-1-yl-
]-propyl-ammonium trifluoroacetate
[0285] FAB-MS: m/z 377 [MH+]
EXAMPLE 58
[0286] 3-(1-Methyl-1H-indol-3-yl)-1H-quinoxalin-2-one
[0287] FAB-MS: m/z 276 [MH+]
EXAMPLE 59
[0288]
3-[3-(7-Benzyl-3-oxo-3,4-dihydro-quinoxalin-2-yl)-indol-1-yl]propyl-
-ammonium trifluoroacetate
[0289] FAB-MS: m/z 409 [MH+]
EXAMPLE 60
[0290]
3-[3-(1-Methyl-1H-indol-3-yl)-2-oxo-2H-quinoxalin-1-yl]-propyl-ammo-
nium trifluoroacetate
[0291] FAB-MS: m/z 333 [MH+]
EXAMPLE 61
[0292]
4-[3-(3-Oxo-3,4-dihydro-quinoxalin-2-yl)-indol-1-ylmethyl]benzyl-am-
monium acetate
[0293] FAB-MS: m/z 381 [MH+]
EXAMPLE 62
[0294]
2-[3-(3-Oxo-3,4-dihydro-quinoxalin-2-yl)-indol-1-yl]-ethyl-ammonium
acetate
[0295] FAB-MS: m/z 305 [MH+]
EXAMPLE 63
[0296]
3-[3-(3-Oxo-3,4-dihydro-quinoxalin-2-yl)-indol-1-ylmethyl]benzyl-am-
monium acetate
[0297] FAB-MS: m/z 381 [MH+]
EXAMPLE 64
[0298]
4-[3-(4-Methyl-3-oxo-3,4-dihydro-quinoxalin-2-yl)-indol-1-ylmethyl]-
benzyl-ammonium trifluoroacetate
[0299] FAB-MS: m/z 395 [MH+]
EXAMPLE 65
[0300]
3-[3-(4-Methyl-3-oxo-3,4-dihydro-quinoxalin-2-yl)-indol-1-ylmethyl]-
benzyl-ammonium trifluoroacetate
[0301] FAB-MS: m/z 395 [MH+]
EXAMPLE 66
[0302]
3-[2-Methyl-3-(3-oxo-3,4-dihydro-quinoxalin-2-yl)-indol-1-yl]propyl-
-ammonium acetate
[0303] FAB-MS: m/z 333 [MH+]
EXAMPLE 67
[0304]
3-[5-Benzyloxy-3-(3-oxo-3,4-dihydro-quinoxalin-2-yl)-indol-1-yl]-pr-
opyl-ammonium acetate
[0305] FAB-MS: m/z 425 [MH+]
EXAMPLE 68
[0306]
3-[5-Amino-3-(3-oxo-3,4-dihydro-quinoxalin-2-yl)-indol-1-yl]-propyl-
-ammonium acetate
[0307] FAB-MS: m/z 334 [MH+]
EXAMPLE 69
[0308]
3-[6-Nitro-3-(3-oxo-3,4-dihydro-quinoxalin-2-yl)-indol-1-yl]-propyl-
-ammonium acetate
[0309] FAB-MS: m/z 364 [MH+]
EXAMPLE 70
[0310]
3-[2-(4-Chloro-phenyl)-3-(3-oxo-3,4-dihydro-quinoxalin-2-yl)-indol--
1-yl]propyl-ammonium acetate
[0311] FAB-MS: m/z 429 [MH+]
EXAMPLE 71
[0312]
3-[2-Ethyl-3-(3-oxo-3,4-dihydro-quinoxalin-2-yl)-indol-1-yl]propyl--
ammonium acetate
[0313] FAB-MS: ml/z 347 [MH+]
EXAMPLE 72
[0314]
3-[6-Benzyloxy-3-(3-oxo-3,4-dihydro-quinoxalin-2-yl)-indol-1-yl]pro-
pyl-ammonium acetate
[0315] FAB-MS: m/z 425 [MH+]
EXAMPLE 73
[0316]
3-[5-Methoxycarbonyl-3-(3-oxo-3,4-dihydro-quinoxalin-2-yl)-indol-1--
yl]propyl-ammonium acetate
[0317] FAB-MS: m/z 377 [MH+]
EXAMPLE 74
[0318]
3-[6-Hydroxy-3-(3-oxo-3,4-dihydro-quinoxalin-2-yl)-indol-1-yl]propy-
l-ammonium acetate
[0319] FAB-MS: m/z 335 [MH+]
EXAMPLE 75
[0320]
3-[2-Methyl-3-(7-methyl-3-oxo-3,4-dihydro-quinoxalin-2-yl)-indol-1--
yl]propyl-ammonium acetate
[0321] FAB-MS: m/z 347 [MH+]
EXAMPLE 76
[0322]
3-[5-Benzyloxy-3-(7-methyl-3-oxo-3,4-dihydro-quinoxalin-2-yl)-indol-
-1-yl]-propyl-ammonium acetate
[0323] FAB-MS: m/z 439 [MH+]
EXAMPLE 77
[0324]
3-[5-Amino-3-(7-methyl-3-oxo-3,4-dihydro-quinoxalin-2-yl)-indol-1-y-
l]propyl-ammonium acetate
[0325] FAB-MS: m/z 348 [MH+]
EXAMPLE 78
[0326]
3-[3-(7-Methyl-3-oxo-3,4-dihydro-quinoxalin-2-yl)-6-nitro-indol-1-y-
l]propyl-ammonium acetate
[0327] FAB-MS: m/z 378 [MH+]
EXAMPLE 79
[0328]
3-[2-(4-Chloro-phenyl)-3-(7-methyl-3-oxo-3,4-dihydro-quinoxalin-2-y-
l)-indol-1-yl]-propyl-ammonium acetate
[0329] FAB-MS: m/z 444 [MH+]
EXAMPLE 80
[0330]
3-[2-Ethyl-3-(7-methyl-3-oxo-3,4-dihydro-quinoxalin-2-yl)-indol-1-y-
l]propyl-ammonium acetate
[0331] FAB-MS: m/z 361 [MH+]
EXAMPLE 81
[0332]
3-[6-Benzyloxy-3-(7-methyl-3-oxo-3,4-dihydro-quinoxalin-2-yl)-indol-
-1-yl]propyl-ammonium acetate
[0333] FAB-MS: m/z 439 [MH+]
EXAMPLE 82
[0334]
3-[5-Methoxycarbonyl-3-(7-methyl-3-oxo-3,4-dihydro-quinoxalin-2-yl)-
-indol-1-yl]propyl-ammonium acetate
[0335] FAB-MS: m/z 391 [MH+]
EXAMPLE 83
[0336]
3-[6-Hydroxy-3-(7-methyl-3-oxo-3,4-dihydro-quinoxalin-2-yl)-indol-1-
-yl]-propyl-ammonium acetate
[0337] FAB-MS: m/z 349 [MH+]
EXAMPLE 84
[0338]
3-[5-Benzyloxy-3-(6,7-dichloro-3-oxo-3,4-dihydro-quinoxalin-2-yl)-i-
ndol-1-yl]-propyl-ammonium acetate
[0339] FAB-MS: m/z 494 [MH+]
EXAMPLE 85
[0340]
3-[5-Amino-3-(6,7-dichloro-3-oxo-3,4-dihydro-quinoxalin-2-yl)-indol-
-1-yl]-propyl-ammonium acetate
[0341] FAB-MS: m/z 403 [MH+]
EXAMPLE 86
[0342]
3-[3-(6,7-Dichloro-3-oxo-3,4-dihydro-quinoxalin-2-yl)-6-nitro-indol-
-1-yl]-propyl-ammonium acetate
[0343] FAB-MS: m/z 433 [MH+]
EXAMPLE 87
[0344]
3-[2-(4-Chloro-phenyl)-3-(6,7-dichloro-3-oxo-3,4-dihydro-quinoxalin-
-2-yl)-indol-1-yl]-propyl-ammonium acetate
[0345] FAB-MS: m/z 498 [MH+]
EXAMPLE 88
[0346]
3-[3-(6,7-Dichloro-3-oxo-3,4-dihydro-quinoxalin-2-yl)-2-ethyl-indol-
-1-yl]-propyl-ammonium acetate
[0347] FAB-MS: m/z 416 [MH+]
EXAMPLE 89
[0348]
3-[6-Benzyloxy-3-(6,7-dichloro-3-oxo-3,4-dihydro-quinoxalin-2-yl)-i-
ndol-1-yl]-propyl-ammonium acetate
[0349] FAB-MS: m/z 494 [MH+]
EXAMPLE 90
[0350]
3-[3-(6,7-Dichloro-3-oxo-3,4-dihydro-quinoxalin-2-yl)-5-methoxycarb-
onyl-indol-1-yl]-propyl-ammonium acetate
[0351] FAB-MS: m/z 446 [MH+]
EXAMPLE 91
[0352]
3-[3-(6,7-Dichloro-3-oxo-3,4-dihydro-quinoxalin-2-yl)-6-hydroxy-ind-
ol-1-yl]propyl-ammonium acetate
[0353] FAB-MS: m/z 404 [MH+]
EXAMPLE 92
[0354]
3-[2-Methyl-3-(6-nitro-3-oxo-3,4-dihydro-quinoxalin-2-yl)-indol-1-y-
l]propyl-ammonium acetate
[0355] FAB-MS: m/z 378 [MH+]
EXAMPLE 93
[0356]
3-[5-Benzyloxy-3-(6-nitro-3-oxo-3,4-dihydro-quinoxalin-2-yl)-indol--
1-yl]propyl-ammonium acetate
[0357] FAB-MS: m/z 470 [MH+]
EXAMPLE 94
[0358]
3-[5-Amino-3-(6-amino-3-oxo-3,4-dihydro-quinoxalin-2-yl)-indol-1-yl-
]-propyl-ammonium acetate
[0359] FAB-MS: m/z 349 [MH+]
EXAMPLE 95
[0360]
3-[6-Nitro-3-(6-nitro-3-oxo-3,4-dihydro-quinoxalin-2-yl)-indol-1-yl-
]-propyl-ammonium acetate
[0361] FAB-MS: m/z 409 [MH+]
EXAMPLE 96
[0362]
3-[2-Ethyl-3-(6-nitro-3-oxo-3,4-dihydro-quinoxalin-2-yl)-indol-1-yl-
]-propyl-ammonium acetate
[0363] FAB-MS: m/z 392 [MH+]
EXAMPLE 97
[0364]
3-[6-Benzyloxy-3-(6-nitro-3-oxo-3,4-dihydro-quinoxalin-2-yl)-indol--
1-yl]-propyl-ammonium acetate
[0365] FAB-MS: m/z 470 [MH+]
EXAMPLE 98
[0366]
3-[5-Methoxycarbonyl-3-(6-nitro-3-oxo-3,4-dihydro-quinoxalin-2-yl)--
indol-1-yl]propyl-ammonium acetate
[0367] FAB-MS: m/z 422 [MH+]
EXAMPLE 99
[0368]
3-[2-Methyl-3-(5-methyl-3-oxo-3,4-dihydro-quinoxalin-2-yl)-indol-1--
yl]-propyl-ammonium acetate
[0369] FAB-MS: m/z 347 [MH+]
EXAMPLE 100
[0370]
3-[5-Benzyloxy-3-(5-methyl-3-oxo-3,4-dihydro-quinoxalin-2-yl)-indol-
-1-yl]propyl-ammonium acetate
[0371] FAB-MS: m/z 439 [MH+]
EXAMPLE 101
[0372]
3-[5-Amino-3-(5-methyl-3-oxo-3,4-dihydro-quinoxalin-2-yl)-indol-1-y-
l]propyl-ammonium acetate
[0373] FAB-MS: m/z 348 [MH+]
EXAMPLE 102
[0374]
3-[3-(5-Methyl-3-oxo-3,4-dihydro-quinoxalin-2-yl)-6-nitro-indol-1-y-
l]-propyl-ammonium acetate
[0375] FAB-MS: m/z 378 [MH+]
EXAMPLE 103
[0376]
3-[2-(4-Chloro-phenyl)-3-(5-methyl-3-oxo-3,4-dihydro-quinoxalin-2-y-
l)-indol-1-yl]-propyl-ammonium acetate
[0377] FAB-MS: m/z 444 [MH+]
EXAMPLE 104
[0378]
3-[6-Benzyloxy-3-(5-methyl-3-oxo-3,4-dihydro-quinoxalin-2-yl)-indol-
-1-yl]-propyl-ammonium acetate
[0379] FAB-MS: m/z 439 [MH+]
EXAMPLE 105
[0380] 3-[5-Methoxycarbonyl -3-(5-methyl
-3-oxo-3,4-dihydro-quinoxalin-2-y- l)-indol-1-yl]-propyl-ammonium
acetate
[0381] FAB-MS: m/z 391 [MH+]
EXAMPLE 106
[0382]
3-[5-Methoxycarbonyl-3-(5-methyl-3-oxo-3,4-dihydro-quinoxalin-2-yl)-
-indol-1-yl]propyl-ammonium acetate
[0383] FAB-MS: m/z 349 [MH+]
EXAMPLE 107
[0384]
3-[3-(7-Methoxy-3-oxo-3,4-dihydro-quinoxalin-2-yl)-2-methyl-indol-1-
-yl]-propyl-ammonium acetate
[0385] FAB-MS: m/z 363 [MH+]
EXAMPLE 108
[0386]
3-[5-Benzyloxy-3-(7-methoxy-3-oxo-3,4-dihydro-quinoxalin-2-yl)-indo-
l-1-yl]propyl-ammonium acetate
[0387] FAB-MS: m/z 455 [MH+]
EXAMPLE 109
[0388]
3-[5-Amino-3-(7-methoxy-3-oxo-3,4-dihydro-quinoxalin-2-yl)-indol-1--
yl]-propyl-ammonium acetate
[0389] FAB-MS: m/z 364 [MH+]
EXAMPLE 110
[0390]
3-[3-(7-Methoxy-3-oxo-3,4-dihydro-quinoxalin-2-yl)-6-nitro-indol-1--
yl]-propyl-ammonium acetate
[0391] FAB-MS: m/z 394 [MH+]
EXAMPLE 111
[0392]
3-[2-(4-Chloro-phenyl)-3-(7-methoxy-3-oxo-3,4-dihydro-quinoxalin-2--
yl)-indol-1-yl]-propyl-ammonium acetate
[0393] FAB-MS: m/z 460 [MH+]
EXAMPLE 112
[0394]
3-[2-Ethyl-3-(7-methoxy-3-oxo-3,4-dihydro-quinoxalin-2-yl)-indol-1--
yl]-propyl-ammonium acetate
[0395] FAB-MS: m/z 377 [MH+]
EXAMPLE 113
[0396]
3-[6-Benzyloxy-3-(7-methoxy-3-oxo-3,4-dihydro-quinoxalin-2-yl)-indo-
l-1-yl]propyl-ammonium acetate
[0397] FAB-MS: m/z 455 [MH+]
EXAMPLE 114
[0398]
3-[5-Methoxycarbonyl-3-(7-methoxy-3-oxo-3,4-dihydro-quinoxalin-2-yl-
)-indol-1-yl]-propyl-ammonium acetate
[0399] FAB-MS: m/z 407 [MH+]
EXAMPLE 115
[0400]
3-[6-Hydroxy-3-(7-methoxy-3-oxo-3,4-dihydro-quinoxalin-2-yl)-indol--
1-yl]propyl-ammonium acetate
[0401] FAB-MS: m/z 365 [MH+]
EXAMPLE 116
[0402]
3-[1-(3-Hydroxy-propyl)-1H-indol-3-yl]-1H-quinoxalin-2-one
[0403] FAB-MS: m/z 320 [MH+]
EXAMPLE 117
[0404]
Dimethyl-{3-[3-(1-methyl-1H-indol-3-yl)-2-oxo-2H-quinoxalin-1-yl]pr-
opyl}-ammonium trifluoroacetate
[0405] FAB-MS: m/z 361 [MH+]
EXAMPLE 118
[0406]
3-{3-[4-(2-Hydroxy-ethyl)-3-oxo-3,4-dihydro-quinoxalin-2-yl]-indol--
1-yl}propyl-ammonium acetate
[0407] FAB-MS: m/z 363 [MH+]
EXAMPLE 119
[0408]
3-[2-Benzyl-1-(3-hydroxy-propyl)-1H-indol-3-yl]-1H-quinoxalin-2-one
[0409] FAB-MS: m/z 410 [MH+]
EXAMPLE 120
[0410]
3-[2-Benzyl-3-(3-oxo-3,4-dihydro-quinoxalin-2-yl)-indol-1-yl]-propy-
l-ammonium acetate
[0411] FAB-MS: m/z 409 [MH+]
EXAMPLE 121
[0412]
3-[1-(3-Ammonium-propyl)-1H-indol-3-yl]-1,5-dimethyl-2-oxo-1,2-dihy-
dro-pyrido[2,3-b]pyrazin-5-ium bistrifluoroacetate
[0413] FAB-MS: m/z 348 [MH+]
EXAMPLE 122
[0414] [3-(3-Oxo-3,4-dihydro-quinoxalin-2-yl)-indol-1-yl]-acetic
acid tert-butyl ester
[0415] FAB-MS: m/z 376 [MH+]
EXAMPLE 123
[0416] [3-(3-Oxo-3,4-dihydro-quinoxalin-2-yl)-indol-1-yl]-acetic
acid
[0417] FAB-MS: m/z 320 [MH+]
EXAMPLE 124
[0418]
3-[2-Benzyl-1-(3-hydroxy-propyl)-1H-indol-3-yl]-1H-quinoxalin-2-one
[0419] FAB-MS: m/s 410 [MH+]
EXAMPLE 125
[0420]
3-[2-Benzyl-3-(3-oxo-3,4-dihydro-quinoxalin-2-yl)-indol-1-yl]-propy-
l-ammonium acetate
[0421] FAB-MS: m/s 409 [MH+]
EXAMPLE 126
[0422] [3-(3-Oxo-3,4-dihydro-quinoxalin-2-yl)-indol-1-yl]-acetic
acid tert butyl ester
[0423] FAB-MS: in/s 376 [MH+]
EXAMPLE 127
[0424] [3-(3-Oxo-3,4-dihydro-quinoxalin-2-yl)-indol-1-yl]-acetic
acid
[0425] FAB-MS: m/s 320 [MH+]
EXAMPLE 128
[0426]
3-[3-(3-Oxo-3,4-dihydro-benzo[g]quinoxalin-2-yl)-indol-1-yl]-propyl-
-ammonium acetate
[0427] FAB-MS: m/s 369 [MH+]
[0428] The invention also provides the free bases of those of the
above compounds which are exemplified as salts.
* * * * *