Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
4-20041/A
2 1 5 q 6 2 q
Azaaliphatically bridqed quinoxaline-2,3-diones
The invention relates to novel azaaliphatically bridged quinoxaline-2,3-diones of formula I
,A2--(CH2)n
O (1),
R3
wherein
A, is lower alkylidene or a group of the formula >CH-A4-R4 (la),
A2 is lower alkylidene or a group of the formula ~CH-A4-R4 (la) or >C=O (Ib) or
>CH(OH)-A5-R4 (Ic),
A3 is a group of the formula ~N-A6-R5 (Id),
A4 is lower alkylene,
As and A6 are each independently of the other lower alkylene or a direct bond,
n is 0 or 1 ,
R~ and R2 are each independently of the other hydrogen, unsubstituted or lower alkyl-
and/or lower alkanoyl-substituted amino, nitro, lower alkanoyl, free or etherified hydroxy,
free or esterified carboxy, carbamoyl, cyano, unsubstituted or halogenated lower alkyl or
halogen,
R3 is hydrogen or hydroxy,
R4 is free or esterified or amidated carboxy, free or esterified phosphono or 5-tetrazolyl, and
R5 is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, aryl, lower alkanoyl, free or
esterified or amidated carboxy, cyano, 5-tetrazolyl, free or etherified or esterified hydroxy or
dihydroxy-lower alkyl,
and their salts, to pharmaceutical compositions coi"prising the novel compounds and to
their use as medicinal active ingredients.
215~62~
- 2 -
Amino that is unsubstituted or substituted by lower alkyl and/or by lower alkanoyl is, for
example, amino, lower alkylamino, lower alkanoylamino, di-lower alkylamino or N-lower
alkyl-N-lower alkanoylamino.
Free or etherified or esterified hydroxy is, for example, free hydroxy or hydroxy etherified by
a lower alkanol or esterified by a lower alkanoic acid, especially hydroxy, lower alkanoyloxy
or lower alkoxy, but may also be lower alkenyloxy or lower alkynyloxy.
Unsubstituted or halogenated lower alkyl is, for example, lower alkyl or poly-halo-lower alkyl,
especially trifluoromethyl.
Free or esterified or amidated carboxy is, for example, carboxy, lower alkoxycarbonyl,
carboxy-lower alkoxycarbonyl, lower alkoxycarbonyl-lower alkoxycarbonyl, lower alkanoyl-
oxy-lower alkoxycarbonyl; phenyl-lower alkoxycarbonyl that is unsubstituted or substituted
by lower alkyl, lower alkoxy, hydroxy, halogen and/or by trifluoromethyl; carbamoyl, lower
alkylcarbamoyl, hydroxy-lower alkylcarbamoyl, di-lower alkylcarbamoyl, di-lower alkylamino-
lower alkylcarbamoyl, amino-lower alkylamino-lower alkylcarbamoyl, 2-oxoimidazolidin-1-yl-
lower alkylcarbamoyl; lower alkyleneamino-lower alkylcarbamoyl that is unsubstituted or
substituted by amino-lower alkylamino or by 2-oxoimidazolidin-1-yl, such as amino-lower
alkylamino-lower alkylenecarbamoyl or 2-oxoimidazolidin-1-yl-lower alkylenecarbamoyl; oxa-
lower alkyleneamino-lower alkylcarbamoyl, unsubstituted or carboxy- or lower alkoxy-
carbonyl-substituted cycloalkylcarbamoyl, cycloalkyl-lower alkylcarbamoyl; phenyl-lower
alkylcarbamoyl that is unsubstituted or substituted by lower alkyl, lower alkoxy, hydroxy,
halogen and/or by trifluoromethyl; N-phenyl- or N-lower alkyl-N-phenyl-carbamoyl that is
unsubstituted or substituted by lower alkyl, lower alkoxy, hydroxy, halogen, nitro, carboxy,
lower alkoxycarbonyl, phenyl, phenyloxy and/or by trifluoromethyl; or free or etherified N-
hydroxycarbamoyl, such as N-hydroxycarbamoyl, N-lower alkoxycarbamoyl, N-lower
alkenyloxycarbamoyl, or N-phenyl-lower alkoxy- or N-phenyl-lower alkenyloxy-carbamoyl
that is unsubstituted or substituted by lower alkyl, lower alkoxy, hydroxy, halogen and/or by
trifluoromethyl .
Free or esterified phosphono may be fully or partially esterified and is, for example,
phosphono, lower alkylphosphono, di-lower alkylphosphono or tri-lower alkylphosphono.
21S~62~
Hereinabove and hereinbelow, lower radicals and compounds are to be understood, for
example, as being those containing up to and including 7, preferably up to and including 4,
carbon atoms (C atoms).
Amino-lower alkylamino-lower alkylcarbamoyl is, for example, N-(amino-C2-C4alkylamino-
C,-C4alkyl)carbamoyl, such as N-[2-(2-aminoethylamino)ethyl]carbamoyl.
Amino-lower alkylamino-lower alkylenecarbamoyl is, for example, amino-C2-C4alkylamino-
piperidinocarbonyl, such as 4-(2-aminoethylamino)piperidinocarbonyl.
Carboxy-lower alkoxycarbonyl is, for example, carboxy-C,-C4alkoxycarbonyl, such as
carboxymethoxycarbonyl, 2-carboxyethoxycarbonyl, 3-carboxypropyloxycarbonyl or 4-
carboxybutyloxycarbonyl .
Cycloalkylcarbamoyl is, for example, N-C3-C6cycloalkylcarbamoyl, such as cyclopropyl-
carbamoyl, cyclobutylcarbamoyl, cyclopentylcarbamoyl or cyclohexylcarbamoyl, but may
also be polycyclic cycloalkylcarbamoyl, such as adamantylcarbamoyl.
Cycloalkyl-lower alkylcarbamoyl is, for example, N-(C3-C6cycloalkyl)-C~-C4alkylcarbamoyl,
such as N-(cyclopropylmethyl)carbamoyl, N-(cyclobutylmethyl)carbamoyl, N-(cyclopentyl-
methyl)carbamoyl or N-(cyclohexylmethyl)carbamoyl.
Dihydroxy-lower alkyl is, for example, ,B,y-dihydroxy-C3-C4alkyl, such as 2,3-dihydroxypropyl.
Di-lower alkylamino is, for example, N,N-di-C,-C7alkylamino, preferably N,N-di-C,-C4alkyl-
amino, such as especially dimethylamino, or secondly diethylamino, dipropylamino, diiso-
propylamino or dibutylamino.
Di-lower alkylamino-lower alkylcarbamoyl is, for example, N,N-di-C~-C4alkylamino-C2-C4-
alkylcarbamoyl, such as N-(2-dimethylaminoethyl)carbamoyl.
21S~62~
Di-lower alkylcarbamoyl is, for example, N,N-di-C1-C7alkylcarbamoyl, preferably N,N-di-
C,-C4alkylcarbamoyl, such as especially dimethylcarbamoyl, or secondly diethylcarbamoyl,
dipropylcarbamoyl, diisopropylcarbamoyl or dibutylcarbamoyl.
Di-lower alkylphosphono is, for example, di-C1-C7alkylphosphono, preferably di-C1-C4alkyl-
phosphono, such as especially dimethylphosphono, or secondly diethylphosphono,
dipropylphosphono, diisopropylphosphono or dibutylphosphono.
Halogen is, for example, halogen having an atomic number of up to and including 35, such
as chlorine or fluorine, and also bromine.
Hydroxy-lower alkylcarbamoyl is, for example, N-(hydroxy-C2-C4alkyl)carbamoyl, such as
hydroxymethylcarbamoyl or 2-hydroxyethylcarbamoyl.
Lower alkanoyl is, for example, N-C1-C~alkanoyl, especially N-C1-C4alkanoyl, such as
formyl, acetyl, propionyl, butyryl or isobutyryl, but may also be C5-C7alkanoyl, such as
pivaloyl.
Lower alkanoylamino is, for example, N-C,-C7alkanoylamino, especially N-C,-C4alkanoyl-
amino, such as formylamino, acetylamino, propionylamino, butyrylamino or isobutyrylamino,
but may also be Cs-C7alkanoylamino, such as pivaloylamino.
N-Lower alkanoyl-N-lower alkylamino is, for example, N-C,-C7alkanoyl-N-C,-C4alkylamino,
especially N-C,-C4alkanoyl-N-C,-C4alkylamino, such as N-formyl-N-methylamino, N-acetyl-
N-methylamino, N-acetyl-N-ethylamino, N-ethyl-N-propionylamino, N-methyl-N-propionyl-
amino, N-butyryl-N-methylamino or N-isobutyryl-N-methylamino.
Lower alkanoyloxy is, for example, N-C~-C7alkanoyloxy, especially N-C,-C4alkanoyloxy,
such as formyloxy, acetoxy, propionyloxy, butyryloxy or isobutyryloxy, but may also be
C5-C7alkanoyloxy, such as pivaloyloxy.
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- 5 -
Lower alkanoyloxy-lower alkoxycarbonyl is, for example, N-C,-C4alkanoyloxy-C,-C4alkoxy-
carbonyl, such as acetoxymethoxycarbonyl, propionyloxymethoxycarbonyl, butyryloxy-
methoxycarbonyl or pivaloyloxymethoxycarbonyl.
Lower alkoxycarbonyl-lower alkoxycarbonyl is, for example, C1-C4alkoxycarbonyl-C,-C4-
alkoxycarbonyl, such as methoxycarbonylmethoxycarbonyl,
ethoxycarbonylmethoxycarbonyl or 2-methoxycarbonylethoxycarbonyl.
Lower alkenyl is, for example, C3-C4alkenyl, such as allyl or methallyl.
Lower alkenyloxy is, for example, C3-C4alkenyloxy, such as allyloxy or methallyloxy.
N-Lower alkenyloxycarbamoyl is, for example, N-C2-C4alkenyloxycarbamoyl, such as N-
vinyloxycarbamoyl, N-allyloxycarbamoyl or N-methallyloxycarbamoyl.
Lower alkynyl is, for example, C3-C4alkynyl, such as propargyl.
Lower alkynyloxy is, for example, C3-C4alkynyloxy, such as propargyloxy.
Lower alkoxy is, for example, C,-C7alkoxy, preferably C,-C4alkoxy, such as methoxy,
ethoxy, propyloxy, isopropyloxy or butyloxy, but may also be isobutyloxy, sec-butyloxy, tert-
butyloxy or a C5-C~alkoxy group, such as a pentyloxy, hexyloxy or heptyloxy group.
N-Lower alkoxycarbamoyl is, for example, N-C,-C4alkoxycarbamoyl, such as methoxy-
carbamoyl, ethoxycarbamoyl, propyloxycarbamoyl, isopropyloxycarbamoyl, butyloxy-carbamoyl or especially tert-butyloxycarbamoyl.
Lower alkoxycarbonyl is, for example, C,-C7alkoxycarbonyl, preferably C1-C4alkoxycarbonyl,
such as methoxycarbonyl, ethoxycarbonyl, propyloxycarbonyl, isopropyloxycarbonyl or
butyloxycarbonyl, but may also be isobutyloxycarbonyl, sec-butyloxycarbonyl, tert-butyloxy-
carbonyl or a pentyloxycarbonyl, hexyloxycarbonyl or heptyloxycarbonyl group.
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- 6 -
Lower alkyl is, for example, C1-C7alkyl, preferably C,-C4alkyl, such as especially methyl or
secondly ethyl, propyl, isopropyl or butyl, but may also be isobutyl, sec-butyl, tert-butyl or a
C5-C7alkyl group, such as a pentyl, hexyl or heptyl group.
Lower alkylamino is, for example, N-C~-C7alkylamino, preferably N-C~-C4alkylamino, such as
especially methylamino or secondly ethylamino, propylamino, isopropylamino or butylamino,
but may also be isobutylamino, seGbutylamino, tert-butylamino or a Cs-C7alkylamino group,
such as a pentylamino, hexylamino or heptylamino group.
Lower alkylcarbamoyl is, for example, N-C,-C7alkylcarbamoyl, preferably N-C,-C4alkyl-
carbamoyl, such as especially methylcarbamoyl or secondly ethylcarbamoyl, propyl-
carbamoyl, isopropylcarbamoyl or butylcarbamoyl, but.may also be isobutylcarbamoyl, sec-
butylcarbamoyl, tert-butylcarbamoyl or a C5-C7alkylcarbamoyl group, such as a pentyl-
carbamoyl, hexylcarbamoyl or heptylcarbamoyl group.
Lower alkylene may be straight-chain or branched and bonded in any desired position and
is, for example, straight-chain or branched C,-C7alkylene, preferably C,-C4alkylene, such as
methylene, 1,2-ethylene, 1,3- or 1,2-propylene, 1,4-, 1,3- or 2,3-butylene or secondly 1,5-,
1,4- or 2,5-pentylene.
Lower alkylidene may be straight-chain or branched and geminally bonded in any desired
position and is, for example, straight-chain or branched C~-C7alkylene, preferably C1-C4-
alkylene, such as methylene, 1,1-ethylidene, 1,1- or 2,2-propylidene, 1,1- or 2,2-butylidene
or secondly 1,1- or 2,2-pentylidene.
N-Lower alkyl-N-phenyl-carbamoyl is, for example, N-C,-C4alkyl-N-phenyl-carbamoyl, such
as especially N-methyl-N-phenyl-carbamoyl or secondly N-ethyl-N-phenyl-carbamoyl, N-
propyl-N-phenyl-carbamoyl, N-isopropyl-N-phenyl-carbamoyl or N-butyl-N-phenyl-
carbamoyl, but may also be N-isobutyl-N-phenyl-carbamoyl, N-sec-butyl-N-phenyl-
carbamoyl or N-tert-butyl-N-phenyl-carbamoyl.
Lower alkylphosphono is, for example, C,-C7alkylphosphono, preferably C,-C4alkyl-
phosphono, such as especially methylphosphono or secondly ethylphosphono, propyl-
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phosphono, isopropylphosphono or butylphosphono, but may also be isobutylphosphono,sec-butylphosphono, tert-butylphosphono or a C5-C7alkylphosphono group, such as a
pentylphosphono, hexylphosphono or heptylphosphono group.
Oxa-lower alkyleneamino-lower alkylcarbamoyl is, for example, N-(morpholino-C2-C4alkyl)-
carbamoyl, such as especially N-(2-morpholinoethyl)ethylcarbamoyl.
2-Oxoimidazolidin-1-yl-lower alkylenecarbamoyl is, for example, N-(2-oxoimidazolidin-1-yl-
C4-C5alkylene)carbamoyl, such as N-[4-(2-oxoimidazolidin-1-yl)piperidinocarbonyl.
2-Oxoimidazolidin-1-yl-lower alkylcarbamoyl is, for example, N-(2-oxoimidazolidin-1-yl-C2-C-
5-alkyl)carbamoyl, such as N-(2-oxoimidazolidin-1-yl)ethylcarbamoyl.
N-Phenyl-lower alkoxycarbamoyl is, for example, phenyl-C1-C4alkoxycarbamoyl, such as
benzyloxycarbamoyl or 1-phenylethoxycarbamoyl, that is unsubstituted or substituted by
C1-C4alkyl, C,-C4alkoxy, hydroxy, halogen and/or by trifluoromethyl.
N-Phenyl-lower alkenyloxycarbamoyl is, for example, N-phenyl-C2-C4alkenyloxycarbamoyl,
such as N-phenylvinyloxycarbamoyl or N-(3-phenylprop-2-enyloxy)carbamoyl.
Phenyl-lower alkoxycarbonyl is, for example, phenyl-C,-C4alkoxycarbonyl, such as benzyl-
oxycarbonyl or 1-phenylethoxycarbonyl, that is unsubstituted or substituted by C,-C4alkyl,
C1-C4alkoxy, hydroxy, halogen and/or by trifluoromethyl.
Phenyl-lower alkylcarbamoyl is, for example, phenyl-C,-C4alkylcarbamoyl, such as benzyl-
carbamoyl or 2-phenylethylcarbamoyl, that is unsubstituted or substituted by C,-C4alkyl,
C1-C4alkoxy, hydroxy, halogen and/or by trifluoromethyl.
Tri-lower alkylphosphono is, for example, tri-C~-C7alkyl phosphono, preferably tri-C~-C4alkyl-
phosphono, such as especially trimethylphosphono, or secondly triethylphosphono, tri-
propylphosphono, triisopropylphosphono or tributylphosphono.
2154621
- 8 -
Compounds of formula I having acidic groups, for examp!e those compounds in which at
least one of the radicals R,, R2, R4 and R5 is or contains carboxy, phosphono or tetrazolyl,
may form salts with bases or internal salts. Compounds of formula I may also form acid
addition salts.
Salts of compounds of formula I with bases are, for example, salts thereof with pharma-
ceutically acceptable bases, such as non-toxic metal salts derived from metals of groups la,
Ib, lla and llb, for example alkali metal salts, especially sodium or potassium salts, alkaline
earth metal salts, especially calcium or magnesium salts, and also ammonium salts with
ammonia or organic amines or quaternary ammonium bases, such as optionally C-hydroxyl-
ated aliphatic amines, especially mono-, di- or tri-lower alkylamines, for example methyl-,
ethyl- or diethyl-amine, mono-, di- or tri-(hydroxy-lower alkyl)amines, such as ethanol-,
diethanol- or triethanol-amine, tris(hydroxymethyl)methylamine or 2-hydroxy-tert-butylamine,
or N-(hydroxy-lower alkyl)-N,N-di-lower alkylamines or N-(polyhydroxy-lower alkyl)-N-lower
alkylamines, such as 2-(dimethylamino)ethanol or D-glucamine or choline, or quaternary
aliphatic ammonium hydroxides, for example tetrabutylammonium hydroxide.
Acid addition salts of compounds of formula I are, for example, the pharmaceutically
acceptable salts thereof with suitable mineral acids, such as hydrohalic acids, sulfuric acid
or phosphoric acid, for example hydrochlorides, hydrobromides, sulfates, hydrogen sulfates
or phosphates, or salts with suitable aliphatic or aromatic sulfonic acids or N-substituted
sulfamic acids, for example methanesulfonates, benzenesulfonates, p-toluenesulfonates or
N-cyclohexylsulfamates (cyclamates).
Also included are both total and partial salts, that is to say salts with 1, 2 or 3, preferably 2,
equivalents of base per mole of acid of formula I or salts with 1, 2 or 3 equivalents, prefer-
ably 1 equivalent, of acid per mole of base of formula 1.
For the purposes of isolation or purification it is also possible to use pharmaceutically
unacceptable salts. Only the pharmaceutically acceptable, non-toxic salts are used thera-
peutically, however, and they are therefore preferred.
21~62~
The compounds of formula I have valuable pharmacological properties. They exhibit a
selective non-competitive antagonistic action with respect to N-methyl-D-aspartic-acid-
sensitive (NMDA-sensitive) excitatory amino acid receptors of warm-blooded animals. In
particular they are capable of binding to strychnine-insensitive glycine binding sites of the
NMDA-receptor. The binding capacity of the compounds prepared according to the
invention and their salts to strychnine-insensitive glycine binding sites of the NMDA-receptor
complex can be determined in vitro, for example in the experimental procedure according to
Baron et al., Eur. J. Pharmacol., Molec. Pharmacol. Section 206, pages 149-154 (1991) and
Canton et al., J. Pharm. Pharmacol. 44, pages 812-816 (1992) on rat cortex membranes
and rat hippocampus membranes. In those experimental procedures it is determined to
what extent l3H]-5,7-dichlorokynurenic acid (3H-DCKA) is displaced, there being determined
the percentage inhibition and optionally, by testing a number of concentrations, the concen-
tration (IC50) required for 50 % displacement. The concentration required for 50 % displace-
ment (IC50) lies in the nanomolar and lower millimolar range, that is to say at concentrations
of approximately from 0.01 to 10 ~mol.
By virtue of those properties the compounds of formula I and the pharmaceutically accept-
able salts thereof are excellently suitable for the prophylactic and therapeutic treatment of
pathological conditions that are responsive to the blocking of glycine binding sites, for
example neurodegenerative disorders, such as those arising from stroke, hypoglycaemia,
anoxia or symptoms of cerebral paralysis; ischaemic disorders, such as cerebral ischaemia,
cerebral ischaemia in cardiosurgery or cardiac arrest, perinatal asphyxia, epileptic fits,
Huntington's chorea, Alzheimer's disease and Parkinson's disease, amyotrophic lateral
sclerosis, spinal and cerebral trauma, and also symptoms of poisoning resulting from
neurotoxins or drug abuse; and ischaemic disorders of the eyes; vascular and muscular
spasms, such as migraine or local or general spasticity; convulsions, such as epilepsy; and
anxiety states and pain, such as trigeminal neuralgias.
The anticonvulsive properties of the compounds according to the invention can be deter-
mined in vivo, for example in mice with reference to their pronounced protective action with
respect to convulsions induced by electric shock or by metrazole, it being possible to use,
for example, the well-established electric shock mouse model or the mouse model for
215~62~
- 10-
metrazole-induced convulsions according to Schmutz et al., Naunyn-Schmiedeberg's Arch.
Pharmacol. 342, 61-66 (1990).
The invention relates, for example, to compounds of formula I wherein
A, is methylene or a group of the formula >CH-A4-R4 (la),
A2 is lower alkylidene or a group of the formula >C=O (Ib),
A3 is a group of the formula >N-A6-Rs (Id),
A4 is lower alkylene,
A6 is lower alkylene or a direct bond,
n isOor1,
R, and R2 are each independently of the other hydrogen, unsubstituted or lower alkyl-
and/or lower alkanoyl-substituted amino, free or etherified hydroxy, unsubstituted or
halogenated lower alkyl or halogen,
R3 is hydrogen or hydroxy,
R4 is free or esterified or amidated carboxy, and
R5 is hydrogen, aryl, lower alkanoyl, free or esterified or amidated carboxy, cyano or free or
etherified hydroxy,
and their salts, pharmaceutical compositions comprising the novel compounds, and their
use as medicinal active ingredients.
The invention relates especially to compounds of formula I wherein
A~ is lower alkylidene or a group of the formula >CH-A4-R4 (la),
A2 is lower alkylidene or a group of the formula >CH-A4-R4 (la) or >C=O (Ib) or
>CH(OH)-A5-R5 (Ic),
A3 is a group of the formula >N-A6-R5 (Id),
A4 is lower alkylene,
A5 and A6 are each independently of the other lower alkylene or a direct bond,
n isOor1,
R, and R2 are each independently of the other hydrogen, nitro, lower alkanoyl, amino, lower
alkylamino, lower alkanoylamino, di-lower alkylamino or N-lower alkyl-N-lower alkanoyl-
amino, carboxy, lower alkoxycarbonyl, carbamoyl, cyano, hydroxy, lower alkoxy, lower
alkenyloxy, lower alkynyloxy, lower alkyl, polyhalo-lower alkyl or halogen,
R3 is hydrogen or hydroxy,
21S~62~
- 11 -
R4 is carboxy, lower alkoxycarbonyl, carboxy-lower alkoxycarbonyl, lower alkoxycarbonyl-
lower alkoxycarbonyl, lower alkanoyloxy-lower alkoxycarbonyl; phenyl-lower alkoxycarbonyl
that is unsubstituted or substituted by lower alkyl, lower alkoxy, hydroxy, halogen and/or by
trifluoromethyl; carbamoyl, lower alkylcarbamoyl, hydroxy-lower alkylcarbamoyl, di-lower
alkylcarbamoyl, di-lower alkylamino-lower alkylcarbamoyl, amino-lower alkylamino-lower
alkylcarbamoyl, 2-oxoimidazolidin-1-yl-lower alkylcarbamoyl, amino-lower alkylamino-lower
alkylenecarbamoyl, 2-oxoimidazolidin-1-yl-lower alkylenecarbamoyl, oxa-lower alkylene-
amino-lower alkylcarbamoyl; unsubstituted or carboxy- or lower alkoxycarbonyl-substituted
cycloalkylcarbamoyl, cycloalkyl-lower alkylcarbamoyl; phenyl-lower alkylcarbamoyl that is
unsubstituted or substituted by lower alkyl, lower alkoxy, hydroxy, halogen and/or by
trifluoromethyl; N-phenyl- or N-lower alkyl-N-phenyl-carbamoyl that is unsubstituted or
substituted by lower alkyl, lower alkoxy, hydroxy, halogen, nitro, carboxy, lower alkoxy-
carbonyl, phenyl, phenyloxy and/or by trifluoromethyl; N-hydroxycarbamoyl, N-lower alkoxy-
carbamoyl, N-lower alkenyloxycarbamoyl; N-phenyl-lower alkoxy- or N-phenyl-lower alkenyl-
oxy-carbamoyl that is unsubstituted or substituted by lower alkyl, lower alkoxy, hydroxy,
halogen and/or by trifluoromethyl; phosphono, lower alkylphosphono, di-lower alkyl-
phosphono, tri-lower alkylphosphono or 5-tetrazolyl, and
Rs is hydrogen, lower alkyl, lower alkenyl, lower alkynyl; phenyl that is unsubstituted or
substituted by lower alkyl, lower alkoxy, hydroxy, halogen and/or by trifluoromethyl; lower
alkanoyl, carboxy, lower alkoxycarbonyl; phenyl-lower alkoxycarbonyl that is unsubstituted
or substituted by lower alkyl, lower alkoxy, hydroxy, halogen and/or by trifluoromethyl;
carbamoyl, lower alkylcarbamoyl, di-lower alkylcarbamoyl; N-phenyl- or N-lower alkyl-N-
phenyl-carbamoyl that is unsubstituted or substituted by lower alkyl, lower alkoxy, hydroxy,
halogen, nitro, carboxy, lower alkoxycarbonyl, phenyl, phenyloxy and/or by trifluoromethyl;
cyano, tetrazolyl, hydroxy, lower alkanoyloxy, lower alkoxy, lower alkenyloxy, lower
alkynyloxy or dihydroxy-lower alkyl,
and their salts.
The invention relates more especially to compounds of formula I whereinA, is C,-C4alkylidene, such as methylene, or a group of the formula ~CH-A4-R4 (la),
A2 is C,-C4alkylidene, such as methylene, or a group of the formula >CH-A4-R4 (la) or
>C=O (Ib),
A3 is a group of the formula >N-A6-R5 (Id),
215462~
- 12-
A4 is C,-C4alkylene,
A5 and A6 are each independently of the other C,-C4alkylene, such as methylene, or a direct
bond,
n is 0,
R, and R2 are each independently of the other hydrogen, nitro, C,-C7alkanoyl, such as
propionyl, amino, C,-C7alkylamino, such as methylamino, C,-C7alkanoylamino, such as
acetamino, di-C,-C4alkylamino, such as dimethylamino, or N-C,-C4alkyl-N-C,-C7alkanoyl-
amino, such as N-acetyl-N-methylamino, hydroxy, carboxy, C,-C4alkoxycarbonyl, such as
methoxy- or ethoxy-carbonyl, carbamoyl, cyano, C,-C4alkoxy, such as methoxy, C2-C4-
alkenyloxy, such as allyloxy, C2-C4alkynyloxy, such as propargyloxy, C1-C4alkyl, such as
methyl or ethyl, trifluoromethyl or halogen, such as fluorine, chlorine or bromine,
R3 is hydrogen or hydroxy,
R4 is carboxy, C,-C4alkoxycarbonyl, such as methoxy- or ethoxy-carbonyl, carboxy-C1-C4-
alkoxycarbonyl, such as carboxymethoxycarbonyl, C1-C4alkoxycarbonyl-C,-C4alkoxy-carbonyl, such as methoxy- or ethoxy-carbonylmethoxycarbonyl, C,-C4alkanoyloxy-C,-C4-
alkoxycarbonyl, such as 2-acetoxyethoxycarbonyl; phenyl-C1-C4alkoxycarbonyl, such as
benzyloxycarbonyl, that is unsubstituted or substituted by C,-C4alkyl, such as methyl,
C,-C4alkoxy, such as methoxy, hydroxy, halogen, such as chlorine, and/or by
trifluoromethyl; carbamoyl, C,-C7alkylcarbamoyl, such as methyl- or butyl-carbamoyl,
hydroxy-C,-C4alkylcarbamoyl, such as 2-hydroxyethylcarbamoyl, di-C,-C4alkylcarbamoyl,
such as dimethyl- or dibutyl-carbamoyl, di-C,-C4alkylamino-C,-C4alkylcarbamoyl, such as 2-
(2-dimethylaminoethyl)ethylcarbamoyl, amino-C,-C4alkylamino-C,-C4alkylcarbamoyl, such
as 2-(2-aminoethyl)ethylcarbamoyl, 2-oxoimidazolidin-1-yl-C,-C4alkylcarbamoyl, such as 2-
(2-oxoimidazolidin-1-yl)-ethylcarbamoyl, amino-C,-C4alkylamino-C,-C4alkylenecarbamoyl,
such as 4-(2-aminoethyl)piperidinocarbonyl, 2-oxoimidazolidin-1-yl-lower
alkylenecarbamoyl, such as 4-(2-oxoimidazolidin-1-yl)piperidinocarbonyl, oxa-C,-C4alkyleneamino-C,-C4alkylcarbamoyl, such as 2-morpholinoethylcarbamoyl, unsubstituted
or carboxy- or C,-C4alkoxycarbonyl- substituted cycloalkylcarbamoyl, such as
cyclopropylcarbamoyl, N-(1-methoxycarbonylcyclopropyl)carbamoyl, adamantylcarbamoyl,
cycloalkyl-C,-C4alkylcarbamoyl, such as cyclopropylmethylcarbamoyl; phenyl-C,-
C4alkylcarbamoyl that is unsubstituted or substituted by C,-C4alkyl, such as methyl, C,-
C4alkoxy, such as methoxy, hydroxy, halogen, such as chlorine, and/or by trifluoromethyl;
N-phenyl- or N-C,-C4alkyl-N-phenyl-carbamoyl, such as N-methyl-N-phenyl-carbamoyl, that
2154624
is unsubstituted or substituted by C1-C4alkyl, such as methyl, C1-C4alkoxy, such as methoxy,
hydroxy, halogen, such as chlorine or fluorine, nitro, carboxy, C1-C4alkoxycarbonyl, such as
methoxycarbonyl, phenyl, phenyloxy and/or by trifluoromethyl; N-hydroxycarbamoyl, N-C1-
C4alkoxycarbamoyl, such as N-tert-butyloxycarbamoyl; N-phenyl-C1-C4alkoxycarbamoyl,
such as N-benzyloxycarbamoyl, that is unsubstituted or substituted by C1-C4alkyl, such as
methyl, C1-C4alkoxy, such as methoxy, hydroxy, halogen, such as chlorine, and/or by
trifluoromethyl; phosphono, C1-C7alkylphosphono, preferably C1-C4alkylphosphono, such as
methylphosphono, ethylphosphono, propylphosphono, isopropylphosphono or
butylphosphono, isobutylphosphono, sec-butylphosphono or tert-butylphosphono, di-C,-
C7alkylphosphono, preferably di-C1-C4alkylphosphono, such as dimethylphosphono, diethyl-
phosphono, dipropylphosphono, diisopropylphosphono or dibutylphosphono, tri-C,-
C7alkylphosphono, preferably tri-C1-C4alkylphosphono, such as trimethylphosphono, triethyl-
phosphono, tripropylphosphono, triisopropylphosphono or tributylphosphono, or 5-tetrazolyl,
and
Rs is hydrogen, C1-C4alkyl, such as methyl, C2-C4alkenyl, such as allyl, C2-C4alkynyl, such
as propargyl; phenyl that is unsubstituted or substituted by C1-C4alkyl, such as methyl,
C1-C4alkoxy, such as methoxy, hydroxy, halogen, such as chlorine, and/or by
trifluoromethyl; C1-C4alkanoyl, such as acetyl, carboxy, C1-C4alkoxycarbonyl, such as
methoxy- or ethoxy-carbonyl, carbamoyl, C,-C4alkylcarbamoyl, such as methylcarbamoyl,
di-C1-C4alkylcarbamoyl, such as dimethylcarbamoyl; N-phenyl- or N-C1-C4alkyl-N-phenyl-
carbamoyl, such as N-methyl-N-phenyl-carbamoyl, that is unsubstituted or substituted by
C,-C4alkyl, such as methyl, C,-C4alkoxy, such as methoxy, hydroxy, halogen, such as
fluorine or chlorine, nitro, carboxy, C,-C4alkoxycarbonyl, such as methoxycarbonyl, phenyl,
phenyloxy and/or by trifluoromethyl; cyano, tet,~olyl or dihydroxy-C2-C4alkyl, such as 2,3-
dihydroxypropyl,
and their salts.
The invention relates especially, for example, to compounds of formula I whereinA, is a group of the formula >CH-A4-R4 (la),
A2 is C1-C4alkylidene, such as methylene, 1,1-ethylidene, 1,1- or 2,2-propylidene or 1,1- or
2,2-butylidene, or carbonyl,
A3 is a group of the formula >N-A5-R5 (Ic),
21$462~
- 14-
A4 is straight-chain or branched C,-C4alkylene, such as methylene, 1,1-ethylidene, 1,1- or
2,2-propylidene or 1,1- or 2,2-butylidene,
A5 is straight-chain or branched C,-C4alkylene, such as methylene, 1,2-ethylene, 1,3- or 1,2-
propylene or 1,4-, 1,3- or 2,3-butylene, or a direct bond,
n is 0,
R, and R2 are each independently of the other hydrogen, C,-C4alkoxy, such as methoxy,
C,-C4alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, tri-
fluoromethyl or halogen having an atomic number of up to and including 35, such as
chlorine or fluorine, and also bromine,
R3 is hydrogen,
R4 is carboxy, C,-C4alkoxycarbonyl, such as methoxycarbonyl, ethoxycarbonyl, propyloxy-
carbonyl, isopropyloxycarbonyl, butyloxycarbonyl, isobutyloxycarbonyl, sec-butyloxy-
carbonyl or tert-butyloxycarbonyl; phenyl-C,-C4alkoxycarbonyl, such as benzyloxycarbonyl
or 1-phenylethoxycarbonyl, that is unsubstituted or substituted by C,-C4alkyl, such as
methyl, C,-C4alkoxy, such as methoxy, hydroxy, halogen having an atomic number of up to
and including 35, such as chlorine, and/or by trifluoromethyl; carbamoyl, N-C1-
C7alkylcarbamoyl, preferably N-C~-C4alkylcarbamoyl, such as methylcarbamoyl,
ethylcarbamoyl, propylcarbamoyl, isopropylcarbamoyl, butylcarbamoyl, isobutylcarbamoyl,
sec-butylcarbamoyl or tert-butylcarbamoyl; phenylcarbamoyl that is unsubstituted or
substituted by C,-C4alkyl, such as methyl, C,-C4alkoxy, such as methoxy, hydroxy, halogen
having an atomic number of up to and including 35, such as chlorine, andlor by tri-
fluoromethyl; N,N-di-C1-C4alkylcarbamoyl, such as dimethylcarbamoyl, diethylcarbamoyl,
dipropylcarbamoyl, diisopropylcarbamoyl or dibutylcarbamoyl, and
R5 is hydrogen, carboxy, C1-C4alkoxycarbonyl, such as methoxycarbonyl, carbamoyl, N-
C,-C4alkylcarbamoyl, such as methylcarbamoyl; phenylcarbamoyl that is unsubstituted or
substituted by C,-C4alkyl, such as methyl, C,-C4alkoxy, such as methoxy, hydroxy, halogen
having an atomic number of up to and including 35, such as chlorine, and/or by trifluoro-
methyl; N,N-di-C,-C4alkylcarbamoyl, such as especially dimethylcarbamoyl, cyano, hydroxy,
C,-C4alkoxy, such as methoxy, ethoxy, propyloxy, isopropyloxy, butyloxy, isobutyloxy, sec-
butyloxy or tert-butyloxy, C3-C4alkenyloxy, such as allyloxy or methallyloxy, or C3-C4alkynyl-
oxy, such as propargyloxy,
and their salts.
215462~
- 15-
The invention relates most especially to compounds of formula I whereinA~ is a group of the formula ~CH-A4-R4 (la),
A2 is methylene,
A3 is a group of the formula >N-A5-R5 (Ic),
A4 is methylene,
n isO,
As is a direct bond,
one of the radicals R1 and R2 is C,-C4alkyl, such as methyl, halogen having an atomic
number of up to and including 35, such as chlorine, fluorine or bromine, or nitro, and the
other is hydrogen or C,-C4alkyl, such as methyl, or halogen having an atomic number of up
to and including 35, such as chlorine, fluorine or bromine,
R3 is hydrogen ist,
R4 is carboxy, phosphono, C,-C4alkoxycarbonyl, such as methoxycarbonyl or ethoxy-
carbonyl, N-hydroxycarbamoyl, N-C,-C4alkylcarbamoyl, such as butyl- or tert-butyl-
carbamoyl, N,N-di-C,-C4alkylcarbamoyl, such as dibutylcarbamoyl, N-(carboxy-C~-C4-
alkyl)carbamoyl, such as carboxymethylcarbamoyl, N-(C,-C4alkoxycarbonyl-C,-C4alkyl)-
carbamoyl, such as N-methoxycarbonylmethylcarbamoyl or N-ethoxycarbonylmethyl-
carbamoyl, N-(hydroxy-C2-C4alkyl)carbamoyl, such as 2-hydroxyethylcarbamoyl, N-C,-C4-
alkoxycarbamoyl, such as N-tert-butyloxycarbamoyl, or an N-phenylcarbamoyl, N-(phenyl-
C,-C4alkyl)carbamoyl, such as benzylcarbamoyl or 2-phenylethylcarbamoyl, or N-(phenyl-
C,-C4alkoxy)carbamoyl, such as N-benzyloxycarbamoyl, group that is unsubstituted or
substituted by C,-C4alkyl, such as methyl, C,-C4alkoxy, such as methoxy, halogen having
an atomic number of up to and including 35, such as chlorine, trifluoromethyl, nitro, carboxy
and/or by C,-C4alkoxycarbonyl, such as methoxycarbonyl or ethoxycarbonyl, and
R5 is hydrogen,
preferably those compounds of formula 1'
P~
H~N~lJ
~j
215162~
- 16-
wherein
one of the radicals R1 and R2 is C1-C4alkyl, such as methyl, halogen having an atomic
number of up to and including 35, such as chlorine, fluorine or bromine, or nitro, and the
other is hydrogen or C,-C4alkyl, such as methyl, or halogen having an atomic number of up
to and including 35, such as chlorine, fluorine or bromine,
R3 is hydrogen, and
R4 is carboxy, C1-C4alkoxycarbonyl, such as methoxycarbonyl or ethoxycarbonyl, N-
hydroxycarbamoyl, N-C1-C4alkylcarbamoyl, such as butyl- or tert-butyl-carbamoyl, N,N-di-C1-
C4-alkylcarbamoyl, such as dibutylcarbamoyl, N-(carboxy-C1-C4alkyl)carbamoyl, such as
carboxymethylcarbamoyl, N-(C1-C4alkoxycarbonyl-C1-C4alkyl)carbamoyl, such as N-
methoxycarbonylmethylcarbamoyl or N-ethoxycarbonylmethylcarbamoyl, N-(hydroxy-C2-C4-
alkyl)carbamoyl, such as 2-hydroxyethylcarbamoyl, N-C1-C4alkoxycarbamoyl, such as N-
tert-butyloxycarbamoyl, or an N-phenylcarbamoyl, N-(phenyl-C,-C4alkyl)carbamoyl, such as
benzylcarbamoyl or 2-phenylethylcarbamoyl, or N-(phenyl-C1-C4alkoxy)carbamoyl, such as
N-benzyloxycarbamoyl, group that is unsubstituted or substituted by C1-C4alkyl, such as
methyl, C1-C4alkoxy, such as methoxy, halogen having an atomic number of up to and
including 35, such as chlorine, trifluoromethyl, nitro, carboxy and/or by C1-C4alkoxycarbonyl,
such as methoxycarbonyl or ethoxycarbonyl,
and their salts.
The invention relates very especially, for example, to compounds of the formulae I and 1'
wherein
A, is a group of the formula ~CH-A4-R4 (la),
A2 is methylene,
A3 is a group of the formula >N-A6-R5 (Ic),
A4 is methylene,
n is 0,
A6 is a direct bond,
R, and R2 are each independently of the other hydrogen or halogen having an atomic
number of up to and including 35, such as chlorine,
R3 is hydrogen,
R4 is carboxy, C,-C4alkoxycarbonyl, such as methoxycarbonyl, ethoxycarbonyl, propyloxy-
carbonyl, isopropyloxycarbonyl, butyloxycarbonyl, isobutyloxycarbonyl, sec-butyloxy-
21~9624
- 17-
carbonyl or tert-butyloxycarbonyl, or an N-phenylcarbamoyl group that is unsubstituted or
substituted by C1-C4alkyl, such as methyl, C,-C4alkoxy, such as methoxy, hydroxy, halogen
having an atomic number of up to and including 35, such as chlorine, and/or by
trifluoromethyl, and
R5 is hydrogen,
and their salts.
The invention relates specifically to the compounds of formula I mentioned in the Examples
and the salts thereof, especially the pharmaceutically acceptable salts thereof.
The process for the preparation of the novel compounds of formula I is based on methods
known perse and is carried out, for example, as follows:
a compound of formula ll
R~
R3
wherein
X1 is a group of the formula -A2- (CH2)n-A1-Y1 (lla) or-A2-(CH2)n-CH=A4-R4 (llb), wherein
Y1 is a nucleofugal leaving group,
is cyclised intramolecularly and, if desired, a resulting compound is converted into a
different compound of formula 1, a mixture of isomers obtainable in accordance with the
process is separated into the components and the preferred isomer is isolated, and/or a
free compound obtainable in accordance with the process is converted into a salt or a salt
obtainable in accordance with the process is converted into the corresponding free
compound.
215~62~
- 18-
ln this connection nucleofugal leaving groups are, for example, reactive esterified hydroxy
groups, such as hydroxy groups esterified by a mineral acid or sulfonic acid, especially
halogen atoms, for example chlorine, bromine or iodine, or hydroxy groups esterified by an
aliphatic or unsubstituted or substituted aromatic sulfonic acid, for example lower alkane-
sulfonyloxy, such as methanesulfonyloxy, or unsubstituted or substituted benzenesulfonyl-
oxy, such as benzenesulfonyloxy, bromobenzenesulfonyloxy or toluenesulfonyloxy.
The intramolecular cyclisation of compounds of formula ll is effected in customary manner,
preferably in an inert organic solvent, such as tetrahydrofuran, dioxane or dimethylform-
amide, if necessary in the presence of a basic condensation agent, such as a tertiary
aliphatic amine, such as triethylamine, or a tertiary aromatic nitrogen base, such as pyridine,
or a metal base, such as an alkali metal hydroxide, alkali metal carbonate or alkali metal
amide, for example sodium or potassium hydroxide, sodium or potassium carbonate or
sodium or potassium amide, advantageously with heating, for example in a temperature
range of approximately from 25 to 120, preferably from 50 to 120.
Starting materials of formula ll are preferably formed in situ and cyclised according to the
invention without being isolated, for example by reacting a compound of formula lll
H~
A3 IH
~N~0 (Ill)
with a compound of formula Y2-A2-(CH2)n-A,-Y~ (IV) or Y2-A2-(CH2)n=A4-R4 (V), wherein
Y, and Y2 are identical or different nucleofugal leaving groups.
Compounds obtainable in accordance with the process can be converted in customary
manner into other compounds of formula 1.
For example, a compound of formula I wherein R4 and optionally R5 are carboxy can be
esterified to the corresponding compound of formula I wherein R4 and optionally Rs are
esterified carboxy. Similarly, a compound of formula I wherein R4 and optionally R5 are free
21S462~
- 19-
or esterified carboxy can be amidated to form the corresponding compound of formula I
wherein R4 and optionally R5 are amidated carboxy. Conversely, a compound of formula I
wherein R4 and optionally R5 are cyano or esterified or amidated carboxy can be hydrolysed
to form the corresponding compound of formula I wherein R4 and optionally R5 are carboxy.
It is also possible to hydrolyse a cyano group R5 to carbamoyl.
In a compound of formula I wherein R, and/or R2 are hydrogen, the hydrogen atom can be
replaced by a radical R, and/or R2 other than hydrogen.
For example, lower alkanoyl can be introduced in customary manner, for example by
reaction with a reactive lower alkanoic acid derivative, such as a lower alkanoic acid
chloride or lower alkanoic acid nitrile, in the presence of aluminium trichloride, and in the
case of reaction with a lower alkanoic acid nitrile if necessary in the presence of boron
trichloride, preferably in a halogenated hydrocarbon, if necessary at boiling temperature.
Furthermore, a lower alkyl, lower alkenyl or lower alkynyl radical R5 can be introduced in
customary manner, for example in the presence of a basic condensation agent, such as in
the presence of tetrabutylammonium iodide in dimethylformamide.
In addition, lower alkenyl R5 can be converted into dihydroxy-lower alkyl in customary
manner, especially by means of osmium tetroxide.
It is also possible in resulting compounds of formula I wherein R5 is hydrogen to introduce a
radical other than hydrogen in customary manner, for example to carry out lower alkylation
or lower alkanoylation or to introduce free or esterified or amidated carboxy or carboxy-
lower alkyl.
Resulting salts can be converted into the free compounds in a manner known per se, for
example by treatment with a base, such as an alkali metal hydroxide, a metal carbonate or
metal hydrogen carbonate, or another of the salt-forming bases mentioned at the beginning,
or with an acid, such as a mineral acid, for example with hydrochloric acid, or another of the
salt-forming acids mentioned at the beginning.
2154624
- 20 -
Resulting salts can be converted into different salts in a manner known perse; acid addition
salts, for example, by treatment with a suitable metal salt, such as a sodium, barium or
silver salt, of a different acid in a suitable solvent in which an inorganic salt being formed is
insoluble and is therefore eliminated from the reaction equilibrium, and basic salts by
freeing of the free acid and conversion into a salt again.
The compounds of formula 1, including their salts, may also be obtained in the form of
hydrates or may include the solvent used for crystallisation.
As a result of the close relationship between the novel compounds in free form and in the
form of their salts, hereinabove and hereinbelow any reference to the free compounds and
their salts is to be understood as including also the corresponding salts and free
compounds, respectively, as appropriate and expedient.
Resulting diastereoisomeric mixtures and mixtures of racemates can be separated into the
pure diastereoisomers or racemates in known manner on the basis of the physico-chemical
differences between the constituents, for example by chromatography and/or fractional
crystallisation.
Resulting racemates can also be resolved into the optical antipodes in accordance with
known methods, for example by recrystallisation from an optically active solvent, with the
aid of microorganisms or by reaction of the resulting diastereoisomeric mixture or racemate
with an optically active auxiliary compound, for example depending on the acidic, basic or
functionally modifiable groups present in compounds of formula 1, with an optically active
acid, base or an optically active alcohol, to form mixtures of diastereoisomeric salts or
functional derivatives, such as esters, and separation thereof into the diastereoisomers from
which the desired enantiomer can be freed in the appropriate customary manner. Bases,
acids and alcohols suitable for that purpose are, for example, optically active alkaloid
bases, such as strychnine, cinchonine or brucine, or D- or L-(1-phenyl)ethylamine, 3-
pipecoline, ephedrine, amphetamine and similar synthetically obtainable bases, optically
active carboxylic or sulfonic acids, such as quinic acid or D- or L-tartaric acid, D- or L-di-o-
toluyltartaric acid, D- or L-malic acid, D- or L-mandelic acid or D- or L-camphorsulfonic acid,
and optically active alcohols, such as borneol or D- or L-(1-phenyl)ethanol.
2I54624
The invention relates also to those forms of the process according to which a compound
obtainable as intermediate at any stage of the process is used as starting material and the
remaining steps are carried out or a starting material is used in the form of a salt or, espe-
cially, is formed under the reaction conditions.
The invention relates also to novel starting materials, which have been developed
specifically for the preparation of the compounds according to the invention, especially the
group of starting materials that result in the compounds of formula I described at the
beginning as being preferred, to the processes for their preparation and to their use as
intermediates.
The invention relates also to pharmaceutical compositions comprising the compounds
according to the invention or pharmaceutically acceptable salts thereof as active ingre-
dients, and to processes for the preparation thereof.
The pharmaceutical compositions according to the invention, which comprise the compound
according to the invention or pharmaceutically acceptable salts thereof, are for enteral, such
as oral and also rectal, and parenteral administration to (a) warm-blooded animal(s), the
compositions comprising the pharmacological active ingredient alone or together with a
pharmaceutically acceptable carrier. The daily dose of the active ingredient depends upon
age and individual condition and upon the mode of administration.
The novel pharmaceutical compositions comprise, for example, from approximately 10 % to
approximately 80 %, preferably from approximately 20 % to approximately 60 %, active
ingredient. Pharmaceutical compositions according to the invention for enteral or parenteral
administration are, for example, those in unit dose forms, such as dragées, tablets,
capsules or suppositories, and also ampoules. They are prepared in a manner known per
se, for example by means of conventional mixing, granulating, confectioning, dissolving or
Iyophilising processes. For example, pharmaceutical compositions for oral administration
can be obtained by combining the active ingredient with solid carriers, optionally granulating
-22- 215462~
a resulting mixture, and processing the mixture or granules, if desired or necessary, after
the addition of suitable excipients, to form tablets or dragée cores.
Suitable carriers are especially fillers, such as sugars, for example lactose, saccharose,
mannitol or sorbitol, cellulose preparations and/or calcium phosphates, for example tri-
calcium phosphate or calcium hydrogen phosphate, and also binders, such as starch pastes
using, for example, corn, wheat, rice or potato starch, gelatin, tragacanth, methylcellulose
and/or polyvinylpyrrolidone, if desired disintegrators, such as the above-mentioned
starches, and also carboxymethyl starch, cross-linked polyvinylpyrrolidone, agar, alginic
acid or a salt thereof, such as sodium alginate. Excipients are especially flow agents, flow-
conditioners and lubricants, for example silicic acid, talc, stearic acid or salts thereof, such
as magnesium or calcium stearate, and/or polyethylene glycol. Dragée cores are provided
with suitable, optionally enteric, coatings, there being used interalia concentrated sugar
solutions which may contain gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol
and/or titanium dioxide, or coating solutions in suitable organic solvents or solvent mixtures
or, for the preparation of enteric coatings, solutions of suitable cellulose preparations, such
as acetylcellulose phthalate or hydroxypropylmethylcellulose phthalate. Dyes or pigments
may be added to the tablets or dragée coatings, for example for identification purposes or
to indicate different doses of active ingredient.
Other orally administrable pharmaceutical compositions are hard gelatin capsules and also
soft, sealed capsules consisting of gelatin and a plasticiser, such as glycerol or sorbitol. The
hard gelatin capsules may comprise the active ingredient in the form of granules, for
example in admixture with fillers, such as lactose, binders, such as starches, and/or
glidants, such as talc or magnesium stearate, and if desired stabilisers. In soft capsules the
active ingredient is preferably dissolved or suspended in suitable liquids, such as fatty oils,
paraffin oil or liquid polyethylene glycols, it likewise being possible to add stabilisers.
Suitable rectally administrable pharmaceutical compositions are, for example, suppositories
that consist of a combination of the active ingredient with a suppository base material.
Suitable suppository base materials are, for example, natural or synthetic triglycerides,
paraffin hydrocarbons, polyethylene glycols or higher alkanols. It is also possible to use
gelatin rectal capsules which comprise a combination of the active ingredient with a base
215~62~
material. Suitable base materials are, for example, liquid triglycerides, polyethylene glycols
or paraffin hydrocarbons.
For parenteral ad",inisL,ation there are suitable, especially, aqueous solutions of an active
ingredient in water-soluble form, for example in the form of a water-soluble salt, and also
suspensions of the active ingredient, such as corresponding oily injection suspensions,
there being used suitable lipophilic solvents or vehicles, such as fatty oils, for example
sesame oil, or synthetic fatty acid esters, for example ethyl oleate or triglycerides, or
aqueous injection suspensions which comprise viscosity-increasing substances, for
example sodium carboxymethylcellulose, sorbitol and/or dextran, and optionally also
stabilisers.
The dosage of the active ingredient depends upon the species of warm-blooded animal,
age and individual condition and also upon the mode of adl"inisl,dlion. In a normal case the
approximate daily dose for oral administration to a patient weighing about 75 kg is
estimated to be from approximately 10 mg to approximately 500 mg.
The following Examples serve to illustrate the invention; temperatures are given in degrees
Celsius, pressures in mbar.
Example 1: 2.0 9 (4.07 mmol) of 5-amino-6,7-dichloro-quinoxaline-2,3-dione and 1.98 9
(6.1 mmol) of fumaric acid monoethyl ester chloride are suspended in 80 ml of anhydrous
dioxane and the suspension is heated at reflux overnight under argon. The reaction mixture
is allowed to cool to room temperature and the reaction product is filtered off and washed in
succession with dioxane and diethyl ether. After drying, 2.56 9 (6.88 mmol; 85 % of theory)
of 8,9-dichloro-2,4,5-trioxo-2,3,5,6-tetrahydro-1 H,4H-1,3a,6-triaza-phenalen-3-ylacetic acid
ethyl ester having a melting point of ~ 300 are obtained.
Example 2: 492 mg (2 mmol) of 5-amino-6,7-dichloro-quinoxaline-2,3-dione and 2.07 g
(10 mmol) of fumaric acid monobenzyl ester chloride are dissolved in 20 ml of anhydrous
dioxane and heated at reflux under argon overnight. The reaction mixture is allowed to cool
to room temperature; 80 ml of diethyl ether are added and the reaction product is filtered off
and washed with diethyl ether. The crude product is taken up in ethyl acetate and heated at
215962~
- 24 -
reflux again for 10 minutes. The mixture is filtered while hot, followed by washing with ethyl
acetate and diethyl ether and allowing to dry. 490 mg (1.13 mmol; 56 % of theory) of 8,9-
dichloro-2,4,5-trioxo-2,3,5,6-tetrahydro-1 H,4H-1,3a,6-triaza-phenalen-3-ylacetic acid benzyl
ester are obtained in the form of a light-brown solid having a melting point of 295-298
(decomp.).
Example 3: 1.12 9 (3 mmol) of 8,9-dichloro-2,4,5-trioxo-2,3,5,6-tetrahydro-1H,4H-1,3a,6-
triaza-phenalen-3-ylacetic acid ethyl ester are suspended in 30 ml of a mixture of 2 parts
tetrahydrofuran and 1 part water, and 630 mg (15 mmol) of lithium hydroxide monohydrate
are added. The resulting solution is stirred at room temperature for 60 hours. The tetra-
hydrofuran is removed under reduced pressure. A very small amount of precipitate forms
which is removed by filtration and discarded. 30 ml of 1 N hydrochloric acid are added, with
stirring, and the resulting white precipitate is filtered off, washed in succession with water,
acetone and diethyl ether and allowed to dry. 970 mg (2.82 mmol; 94% of theory) of 8,9-
dichloro-2,4,5-trioxo-2,3,5,6-tetrahydro-1 H74H-1,3a,6-triaza-phenalen-3-ylacetic acid are
obtained in the form of a white solid having a melting point of ~ 300.
Example 4: 688 mg (2 mmol) of 8,9-dichloro-2,4,5-trioxo-2,3,5,6-tetrahydro-1H,4H-1,3a,6-
triaza-phenalen-3-ylacetic acid, 279 mg (3 mmol) of aniline, 767 mg (4 mmol) of N-(3-di-
methylamino)propyl-N`-ethyl-carbodiimide hydrochloride and 541 mg (4 mmol) of N-hydroxybenzotriazole are dissolved in 20 ml of dimethylformamide and stirred at room
temperature under argon overnight. The reaction mixture is then stirred into 600 ml of water.
The mixture is then stirred for 10 minutes, followed by filtration, washing with water and
drying over phosphorus pentoxide under a high vacuum. 770 mg (1.84 mmol; 92% of
theory) of 8,9-dichloro-2,4,5-trioxo-2,3,5,6-tetrahydro-1 H,4H-1,3a,6-triaza-phenalen-3-yl-N-
phenyl-acetamide are obtained in the form of a light-brown solid having a melting point of >
300.
Example 5: In a manner analogous to that described in Example 1, 8,9-dimethyl-2,4,5-
trioxo-2,3,5,6-tetrahydro-1 H,4H-1,3a,6-triaza-phenalen-3-ylacetic acid ethyl ester having a
melting point of > 300 is obtained.
215~62~
- 25 -
Example 6: In a manner analogous to that described in Example 3, 8,9-dimethyl-2,4,5-
trioxo-2,3,5,6-tetrahydro-1 H,4H-1 ,3a,6-triaza-phenalen-3-ylacetic acid having a melting
point of > 300 is obtained from the ester according to Example 5.
Example 7: In a manner analogous to that described in Example 4, 8,9-dimethyl-2,4,5-
trioxo-2,3,5,6-tetrahydro-1 H,4H-1 ,3a,6-triaza-phenalen-3-ylacetic acid-N-phenyl-acetamide
having a melting point of > 300 is obtained from the acid according to Example 6.
Example 8: With stirring, 30 g (122 mmol) of 5-amino-6,7-dichloro-quinoxaline-2,3-dione are
heated at 100 with 32.7 g (183 mmol) of 4-bromocrotonic acid methyl ester in 100 ml of
dimethylformamide for 20 hours. The mixture is allowed to cool to room temperature,
poured into 2 litres of ice-water, stirred for 15 minutes,. followed by filtration, washing with
water and drying. 40.61 9 (118 mmol; 97% of theory) of 8,9-dichloro-4,5-dioxo-2,3,5,6-
tetrahydro-1 H,4H-1 ,3a,6-triaza-phenalen-3-ylacetic acid methyl ester having a melting point
of 264-268 are obtained.
Example 9: The following compounds are obtained in a manner analogous to that described
in Example 8:
8,9-dimethyl-4,5-dioxo-2,3,5,6-tetrahydro-1 H,4H-1 ,3a,6-triaza-phenalen-3-ylacetic acid
methyl ester, m.p. 303-306;
8,9-difluoro-4,5-dioxo-2,3,5,6-tetrahydro-1 H,4H-1 ,3a,6-triaza-phenalen-3-ylacetic acid -
methyl ester, m.p. > 250;
4,5-dioxo-2,3,5,6-tetrahydro-1 H,4H-1 ,3a,6-triaza-phenalen-3-ylacetic acid methyl ester,
m.p. 244-247;
8-bromo-4,5-dioxo-2,3,5,6-tetrahydro-1 H ,4H-1 ,3a,6-triaza-phenalen-3-ylacetic acid methyl
ester and
8-trifluoromethyl-4,5-dioxo-2,3,5,6-tetrahydro-1 H,4H-1 ,3a,6-triaza-phenalen-3-ylacetic acid
methyl ester, m.p. 150-154.
Example 10: 14.15 g (41.1 mmol) of 8,9-dichloro-4,5-dioxo-2,3,5,6-tetrahydro-1H,4H-1,3a,6-
triaza-phenalen-3-ylacetic acid methyl ester are made into a suspension in 200 ml of
methanol; 100 ml of aqueous sodium hydroxide solution are added and the mixture is
stirred at room temperature for 1 hour. The methanol is removed under reduced pressure.
2154~?~
- 26 -
The aqueous phase is washed twice using 60 ml of diethyl ether each time and acidified to
pH = 1 by the slow addition of 2N hydrochloric acid with stirring. The solid precipitate is
filtered off with suction, washed with water and dried.11.5 9 (34.8 mmol, 85% of theory) of
8,9-dichloro-4,5-dioxo-2,3,5,6-tetrahydro-1 H,4H-1,3a,6-triaza-phenalen-3-ylacetic acid
having a melting point of 268-272 are obtained.
Example 11: The following compounds are obtained in a manner analogous to that
described in Example 10:
8,9-dimethyl-4,5-dioxo-2,3,5,6-tetrahydro-1 H,4H-1,3a,6-triaza-phenalen-3-ylacetic acid,
m.p. 285-287;
8,9-difluoro-4,5-dioxo-2,3,5,6-tetrahydro-1 H,4H-1,3a,6-triaza-phenalen-3-ylacetic acid,
m.p. 239-245;
4,5-dioxo-2,3,5,6-tetrahydro-1 H,4H-1,3a,6-triaza-phenalen-3-ylacetic acid, m.p. ~ 260;
8-bromo-4,5-dioxo-2,3,5,6-tetrahydro-1H,4H-1,3a,6-triaza-phenalen-3-ylacetic acid,
m.p. > 260 and
8-trifluoromethyl-4,5-dioxo-2,3,5,6-tetrahydro-1 H,4H-1,3a,6-triaza-phenalen-3-ylacetic acid,
m.p. ~200.
Example 12: 300 mg (0.91 mmol) of 8,9-dichloro-4,5-dioxo-2,3,5,6-tetrahydro-1H,4H-1,3a,6-
triaza-phenalen-3-ylacetic acid, 0.12 ml (1.36 mmol) of aniline, 384 mg (1.82 mmol) of N-(3-
dimethylamino)propyl-N`-ethyl-carbodiimide hydrochloride and 246 mg (1.82 mmol) of N-
hydroxybenzotriazole are stirred in 10 ml of anhydrous dimethylformamide at room tempera-
ture for 48 hours. The reaction mixture is then stirred into 250 ml of ice-water. The mixture is
filtered, followed by washing with water and allowing to dry. 310 mg (1.84 mmol; 84% of
theory) of 8,9-dichloro-4,5-dioxo-2,3,5,6-tetrahydro-1H,4H-1,3a,6-triaza-phenalen-3-yl-N-
phenyl-acetamide are obtained in the form of a light-brown solid having a melting point of
00.
Example 13: The following compounds are obtained in a manner analogous to that
described in Example 12:
8,9-dimethyl-4,5-dioxo-2,3,5,6-tetrahydro-1 H,4H-1,3a,6-triaza-phenalene-3-N-phenyl-
acetamide, m.p. > 300;
-27- 215~62.~1
8,9-difluoro-4,5-dioxo-2,3,5,6-tetrahydro-1 H,4H-1,3a,6-triaza-phenalene-3-N-phenyl-
acetamide, m.p. > 260;
4,5-dioxo-2,3,5,6-tetrahydro-1 H,4H-1,3a,6-triaza-phenalene-3-N-phenyl-acetamide,
m.p. 284-290;
8-bromo-4,5-dioxo-2,3,5,6-tetrahydro-1 H,4H-1,3a,6-triaza-phenalene-3-phenyl-acetamide,
m.p. > 250 and
8-trifluoromethyl-4,5-dioxo-2,3,5,6-tetrahydro-1 H,4H-1,3a,6-triaza-phenalene-3-phenyl-
acetamide, m.p. > 250.
Example 14: In a manner analogous to that described in Example 12, starting from 8,9-di-
chloro-4,5-dioxo-2,3,5,6-tetrahydro-1 H,4H-1,3a,6-triaza-phenalen-3-ylacetic acid, it is also
possible to obtain the amides thereof listed below:
.
8,9-dichloro-4,5-dioxo-2,3,5,6-tetrahydro-1 H,4H-1,3a,6-triaza-phenalen-3-yl-N-benzyl-
acetamide, m.p. 255-260;
8,9-dichloro-4,5-dioxo-2,3,5,6-tetrahydro-1 H,4H-1,3a,6-triaza-phenalen-3-yl-N-(2-phenyl-
ethyl)-acetamide, m.p. 170-175;
8,9-dichloro-4,5-dioxo-2,3,5,6-tetrahydro-1 H,4H-1,3a,6-triaza-phenalen-3-yl-N-(2-hydroxy-
ethyl)-acetamide, m.p. >250;
8,9-dichloro-4,5-dioxo-2,3,5,6-tetrahydro-1 H,4H-1,3a,6-triaza-phenalen-3-yl-N-(ethoxy-
carbonylmethyl)-acetamide, m.p. > 250;
8,9-dichloro-4,5-dioxo-2,3,5,6-tetrahydro-1 H,4H-1,3a,6-triaza-phenalen-3-yl-N-(carboxy-
methyl)-acetamide, m.p. > 250;
8,9-dichloro-4,5-dioxo-2,3,5,6-tetrahydro-1 H,4H-1,3a,6-triaza-phenalen-3-yl-N-(3-trifluoro-
methylphenyl)-acetamide, m.p. > 300;
8,9-dichloro-4,5-dioxo-2,3,5,6-tetrahydro-1 H,4H-1,3a,6-triaza-phenalen-3-yl-N-(4-chloro-
phenyl)-acetamide, m.p. > 300;
8,9-dichloro-4,5-dioxo-2,3,5,6-tetrahydro-1 H,4H-1,3a,6-triaza-phenalen-3-yl-N-(4-methyl-
phenyl)-acetamide, m.p. > 300;
8,9-dichloro-4,5-dioxo-2,3,5,6-tetrahydro-1 H,4H-1,3a,6-triaza-phenalen-3-yl-N-(4-methoxy-
phenyl)-acetamide, m.p. > 300;
8,9-dichloro-4,5-dioxo-2,3,5,6-tetrahydro-1 H,4H-1,3a,6-triaza-phenalen-3-yl-N-(4-phenoxy-
phenyl)-acetamide, m.p. > 300;
2ls96~
- 28 -
8,9-dichloro-4,5-dioxo-2,3,5,6-tetrahydro-1 H,4H-1,3a,6-triaza-phenalen-3-yl-N-(3-nitro-
phenyl)-acetamide, m.p. > 300;
8,9-dichloro-4,5-dioxo-2,3,5,6-tetrahydro-1 H,4H-1,3a,6-triaza-phenalen-3-yl-N-(4-ethoxy-
carbonylphenyl)acetamide, m.p. ~ 300;
8,9-dichloro-4,5-dioxo-2,3,5,6-tetrahydro-1 H,4H-1,3a,6-triaza-phenalen-3-yl-N-(4-trifluoro-
methylphenyl)-acetamide, m.p. > 300;
8,9-dichloro-4,5-dioxo-2,3,5,6-tetrahydro-1 H,4H-1,3a,6-triaza-phenalen-3-yl-N-benzyloxy-
acetamide, m.p. 186-189;
8,9-dichloro-4,5-dioxo-2,3,5,6-tetrahydro-1 H,4H-1,3a,6-triaza-phenalen-3-yl-N-tert-butyloxy-
acetamide, m.p. > 300;
8,9-dichloro-4,5-dioxo-2,3,5,6-tetrahydro-1 H,4H-1,3a,6-triaza-phenalen-3-yl-N-(3-biphenyl)-
acetamide, m.p. ~ 300;
8,9-dichloro-4,5-dioxo-2,3,5,6-tetrahydro-1 H,4H-1,3a,6-triaza-phenalen-3-yl-N-(3-phenoxy-
phenyl)-acetamide, m.p. 262-266;
8,9-dichloro-4,5-dioxo-2,3,5,6-tetrahydro-1 H ,4H-1,3a,6-triaza-phenalen-3-yl-N, N-dimethyl-
acetamide, m.p. > 300;
8,9-dichloro-4,5-dioxo-2,3,5,6-tetrahydro-1 H,4H-1,3a,6-triaza-phenalen-3-yl-N-butyl-acet-
amide;
8,9-dichloro-4,5-dioxo-2,3,5,6-tetrahydro-1 H,4H-1,3a,6-triaza-phenalen-3-yl-N-tert-butyl-
acetamide, m.p. > 260;
8,9-dichloro-4,5-dioxo-2,3,5,6-tetrahydro-1 H,4H-1,3a,6-triaza-phenalen-3-yl-N,N-dibutyl-
acetamide;
8,9-dichloro-4,5-dioxo-2,3,5,6-tetrahydro-1 H,4H-1,3a,6-triaza-phenalen-3-yl-N-(adamantan-
1-yl)-acetamide, m.p. ~ 260;
8,9-dichloro-4,5-dioxo-2,3,5,6-tetrahydro-1 H,4H-1,3a,6-triaza-phenalen-3-yl-N-methyl-acet-
amide, m.p. > 280;
7,8-dichloro-4-{2-oxo-2-[4-(2-oxo-imidazolidin-1-yl)piperidin-1-yl~ethyl~5,6-dihydro-1 H,4H-
1,3a,6-triaza-phenalene-2,3-dione, m.p. > 260;
8,9-dichloro-4,5-dioxo-2,3,5,6-tetrahydro-1 H,4H-1,3a,6-triaza-phenalen-3-yl-N-methyl-N-
phenyl-acetamide, m.p. ~ 280,
8,9-dichloro-4,5-dioxo-2,3,5,6-tetrahydro-1 H,4H-1,3a,6-triaza-phenalen-3-yl-N-[2-(2-
oxoimidazolidin-1-yl]ethyl]-acetamide, m.p. > 260 and
2154624
- 29 -
8,9-dichloro-4,5-dioxo-2,3,5,6-tetrahydro-1 H,4H-1,3a,6-triaza-phenalen-3-yl-N-(2-morpho-
linoethyl)-acetamide, m.p. > 280.
Example 15: 20.5 ml of a 1-molar solution of boron trichloride in heptane are added at 0
under argon to a solution of 2.57 9 (9.33 mmol) of 4,5-dioxo-2,3,5,6-tetrahydro-1 H,4H-
1,3a,6-triaza-phenalen-3-ylacetic acid methyl ester in 40 ml of 1,2-dichloroethane. After
10 minutes there are added first 2.74 g (20.5 mmol) of aluminium trichloride and then 2.75 9
(50 mmol) of propionitrile. The mixture is allowed to rise to room temperature and then
heated at reflux for 3 hours. The mixture is allowed to cool to room temperature; 50 ml of
2N hydrochloric acid are added and the mixture is heated at reflux again for 1 hour. After
again cooling to room temperature,100 ml of water are added and the mixture is extracted
by shaking twice using 100 ml of trichloromethane each time, washed with saturated
sodium chloride solution and dried over sodium sulfate. The mixture is concentrated to
dryness by evaporation and taken up in 15 ml of tetrahydrofuran; 30 ml of 1N sodium
hydroxide solution are added and the mixture is stirred overnight. Then 20 ml of water are
added and the mixture is washed twice using 50 ml of diethyl ether each time, acidified to
pH = 2 with dilute hydrochloric acid and extracted by shaking twice using 100 ml of ethyl
acetate each time. The combined extracts are dried over sodium sulfate and concentrated
by evaporation. The evaporation residue is taken up in 5 ml of anhydrous
dimethylformamide; 211 mg (2.27 mmol) of aniline, 435 mg (2.27 mmol) of N-(3-dimethyl-
amino)propyl-N`-ethyl-carbodiimide hydrochloride and 348 mg (2.27 mmol) of N-hydroxy-
benzotriazole are added and the mixture is stirred at room temperature for 48 hours, then
poured into 400 ml of water, filtered with suction, washed with water and dried. 9-Propionyl-
4,5-dioxo-2,3,5,6-tetrahydro-1H,4H-1,3a,6-triaza-phenalen-3-yl-N-phenyl-acetamide is
obtained, m.p. ~ 300.
Example 16: 16.8 9 (80 mmol) of trifluoroacetic acid anhydride are added dropwise at
boiling temperature under nitrogen to a mixture of 0.88 9 (11 mmol) of ammonium nitrate,
2.75 9 (10 mmol) of 4,5-dioxo-2,3,5,6-tetrahydro-1H,4H-1,3a,6-triaza-phenalen-3-ylacetic
acid methyl ester and 60 ml of trichloromethane. The mixture is heated at reflux for a further
2 hours, then allowed to cool to room temperature, poured into ice-water, extracted by
shaking with ethyl acetate, washed with water and saturated sodium chloride solution, dried
over magnesium sulfate and concentrated by evaporation. The evaporation residue is
21 ~; 46%~
- 30 -
chromatographed on silica gel with ethyl acetate as eluant. 1.07 9 of 9-nitro-4,5-dioxo-
2,3,5,6-tetrahydro-1 H,4H-1 ,3a,6-triaza-phenalen-3-ylacetic acid methyl ester and 0.43 9 of
7-nitro-4,5-dioxo-2,3,5,6-tetrahydro-1 H,4H-1 ,3a,6-triaza-phenalen-3-ylacetic acid methyl
ester are obtained.
Example 17: In a manner analogous to that described in Example 10, from 9-nitro-4,5-
dioxo-2,3,5,6-tetrahydro-1 H,4H-1 ,3a,6-triaza-phenalen-3-ylacetic acid methyl ester and 7-
nitro-4,5-dioxo-2,3,5,6-tetrahydro-1 H ,4H-1 ,3a,6-triaza-phenalen-3-ylacetic acid methyl ester
there are obtained 9-nitro-4,5-dioxo-2,3,5,6-tetrahydro-1H,4H-1,3a,6-triaza-phenalen-3-
ylacetic acid, m.p. > 250, and 7-nitro-4,5-dioxo-2,3,5,6-tetrahydro-1 H,4H-1 ,3a,6-triaza-
phenalen-3-ylacetic acid, m.p. ~250.
Example 18: In a manner analogous to that described in Example 12, from 9-nitro-4,5-
dioxo-2,3,5,6-tetrahydro-1 H,4H-1 ,3a,6-triaza-phenalen-3-ylacetic acid, m.p. ~ 250, and 7-
nitro-4,5-dioxo-2,3,5,6-tetrahydro-1 H,4H-1 ,3a,6-triaza-phenalen-3-ylacetic acid there are
obtained 9-nitro-4,5-dioxo-2,3,5,6-tetrahydro-1H,4H-1,3a,6-triaza-phenalen-3-yl-N-phenyl-
acetamide, m.p. ~ 250, and 7-nitro-4,5-dioxo-2,3,5,6-tetrahydro-1 H,4H-1 ,3a,6-triaza-
phenalen-3-yl-N-phenyl-acelamide, m.p. 220-240 (decomp.).
Example 19: 2.31 9 (6.52 mmol) of 8-bromo-4,5-dioxo-2,3,5,6-tetrahydro-1H,4H-1,3a,6-
triaza-phenalen-3-ylacetic acid methyl ester, 13.04 mmol of allyl bromide and 6.52 mmol of
tetrabutylammonium iodide are heated at 100 in 20 ml of anhydrous dimethylformamide for
5 days. The dimethylformamide is removed under reduced pressure and the residue is
chromatographed on silica gel using ethyl acetate as eluant. 1.81 9 of 1-allyl-8-bromo-4,5-
dioxo-2,3,5,6-tetrahydro-1 H,4H-1 ,3a,6-triaza-phenalen-3-ylacetic acid methyl ester are
obtained.
Example 20: In a manner analogous to that described in Example 10, 1-allyl-8-bromo-4,5-
dioxo-2,3,5,6-tetrahydro-1 H,4H-1 ,3a,6-triaza-phenalen-3-ylacetic acid, m.p. 243-245, is
obtained from 1-allyl-8-bromo-4,5-dioxo-2,3,5,6-tetrahydro-1H,4H-1,3a,6-triaza-phenalen-3-
ylacetic acid methyl ester.
215462~ -
- 31 -
Example 21: In a manner analogous to that described in Example 12, 1-allyl-8-bromo-4,5-
dioxo-2,3,5,6-tetrahydro-1H,4H-1,3a,6-triaza-phenalen-3-yl-N-phenyl-acetamide, m.p.
> 250, is obtained from 1-allyl-8-bromo-4,5-dioxo-2,3,5,6-tetrahydro-1H,4H-1,3a,6-triaza-
phenalen-3-ylacetic acid.
Example 22: 219 mg (0.48 mmol) of 1-allyl-8-bromo-4,5-dioxo-2,3,5,6-tetrahydro-1H,4H-
1,3a,6-triaza-phenalen-3-yl-N-phenyl-acetamide, 75 mg (0.55 mmol) of N-
methylmorpholine-N-oxide and 0.4 ml of a 4 % aqueous solution of osmium tetroxide are
stirred in a mixture of 7 ml of water, 7 ml of dioxane and 1 ml of tert-butanol for 16 hours.
The organic solvents are removed. Cold water is added to the residue, followed by filtration
with suction, washing with water and drying. 85 mg of 8-bromo-1-(2,3-dihydroxypropyl)-4,5-
dioxo-2,3,5,6-tetrahydro-1H,4H-1,3a,6-triaza-phenalen-3-yl-N-phenyl-acetamide, m.p. >
250, are obtained.
Example 23: 2.49 9 (10.1 mmol) of 5-amino-6,7-dichloro-quinoxaline-2,3-dione and 2.70 g
(12.62 mmol) of E-1,4-dibromo-2-butene are heated at 100 in 60 ml of anhydrous dimethyl-
formamide under argon for 48 hours. The mixture is allowed to cool to room temperature,
poured into 700 ml of ice-water, stirred for 15 minutes, filtered, washed with water, dried
and taken up in 50 ml of acetone, followed by boiling at reflux for 20 minutes, cooling to
room temperature, filtration, washing with acetone and drying.1.50 9 (5.03 mmol, 50% of
theory) of 7,8-dichloro-4-vinyl-5,6-dihydro-1H,4H-1,3a,6-triaza-phenalene-2,3-dione, m.p. >
260, are obtained.
Example 24: 570 mg (2.32 mmol) of 5-amino-6,7-dichloro-quinoxaline-2,3-dione and 523
mg (4.63 mmol) of chloroacetyl chloride are heated at reflux in 25 ml of dioxane, with
stirring, for 16 hours. The mixture is allowed to cool to room temperature, followed by
filtration, washing with diethyl ether and drying. The resulting solid is made into a
suspension with 490 mg (3.54 mmol) of potassium carbonate in 40 ml of anhydrous
dimethylformamide and stirred at room temperature for 16 hours, then poured into a mixture
of 600 ml of water and 15 ml of concentrated hydrochloric acid, filtered, washed with water
and acetone and made into a suspension in 50 ml of ethanol. The suspension is heated at
reflux for 30 minutes, filtered while hot, washed with ethanol and diethyl ether and dried.
2154624
310 mg (1.08 mmol, 47% of theory) of 7,8-dichloro-1H,6H-1,3a,6-triaza-phenalene-2,3,5-
trione are obtained.
Example 25: 2.45 9 (10 mmol) of 5-amino-6,7-dichloro-quinoxaline-2,3-dione and 7.7 9 of 3-
bromoprop-1-enephosphonic acid diethyl ester are dissolved in 40 ml of anhydrousdimethylformamide and heated at 90 for 4 days. The mixture is allowed to cool to room
temperature and then poured into 500 ml of ice-water; 100 ml of 1N sodium hydroxide
solution are added and the mixture is washed twice using 500 ml of dichloromethane each
time. The aqueous phase is acidified to pH 1 with dilute hydrochloric acid, and the resulting
precipitate is filtered off, washed with water and dried. The resulting solid is suspended at
0 in 20 ml of dichloromethane, and 580 mg (5.7 mmol) of trimethylbromosilane are added.
The mixture is stirred ovemight at room temperature and concentrated by evaporation
under reduced pressure. The evaporation residue is made into a suspension with 10 ml of
methanol and poured into 100 ml of 0.1 N hydrochloric acid. The mixture is filtered and after
washing with water and drying 250 mg of 8,9-dichloro-4,5-dioxo-2,3,5,6-tetrahydro-1 H,4H-
1,3a,6-triaza-phenalen-3-ylmethanephosphonic acid having a melting point of ~ 250 are
obtained.
Example 26: Tablets, each comprising 50 mg of 8,9-dichloro-2,4,5-trioxo-2,3,5,6-tetrahydro-
1 H,4H-1,3a,6-triaza-phenalen-3-ylacetic acid or a salt, for example the sodium salt, thereof
can be prepared as follows:
Composition (10 000 tablets)
active ingredient 500.0 9
lactose 500.0 9
potato starch
gelatin 8.0 9
talc 60.0 9
magnesium stearate 10.0 9
silicon dioxide (highly dispersed) 20.0 9
ethanol q.s.
215462~
- 33 -
The active ingredient is mixed with the lactose and 292 9 of the potato starch, and the
mixture is moistened with an ethanolic solution of the gelatin and granulated through a
sieve. After drying, the remainder of the potato starch, the magnesium stearate, the talc and
the silicon dioxide are mixed in and the mixture is compressed to form tablets each
weighing 145.0 mg and comprising 50 mg of active ingredient; if desired, the tablets may be
provided with dividing notches for finer adaptation of the dose.
Example 27: A sterile-filtered aqueous gelatin solution, containing 20 % cyclodextrins as
solubiliser, comprising 3 mg of 8,9-dichloro-2,4,5-trioxo-2,3,5,6-tetrahydro-1 H,4H-1,3a,6-
triaza-phenalen-3-ylacetic acid or a salt, for example the sodium salt, thereof as active
ingredient, is so mixed, with heating and under aseptic conditions, with a sterile gelatin
solution containing phenol as preservative, that 1.0 ml of solution has the following
composition:
active ingredient 3 mg
gelatin 150.0 mg
phenol 4.7 mg
dist. water with 20 % cyclodextrins as solubiliser 1.0 ml
Example 28: For the preparation of a sterile dry substance for injection, comprising 5 mg of
8,9-dichloro-2,4,5-trioxo-2,3,5,6-tetrahydro-1 H,4H-1,3a,6-triaza-phenalen-3-ylacetic acid or
a salt, for example the sodium salt, thereof, 5 mg of one of the compounds of formula I
mentioned in the preceding Examples as active ingredient are dissolved in 1 ml of an
aqueous solution containing 20 mg of mannitol and 20 % cyclodextrins as solubiliser. The
solution is sterile-filtered and, under aseptic conditions, introduced into a 2 ml ampoule,
frozen and Iyophilised. Before use, the Iyophilisate is dissolved in 1 ml of distilled water or
1 ml of physiological saline. The solution is administered intramuscularly or intravenously.
This formulation can also be introduced into double-chamber disposable syringes.
Example 29: For the preparation of 10 000 film-coated tablets, each comprising 100 mg of
8,9-dichloro-2,4,5-trioxo-2,3,5,6-tetrahydro-1 H,4H-1,3a,6-triaza-phenalen-3-ylacetic acid or
a salt, for example the sodium salt, thereof, the method of preparation is as follows:
215~62~
- 34-
active ingredient 1000 9
corn starch 680 9
colloidal silicic acid 200 9
magnesium stearate 20 g
stearic acid 50 9
sodium carboxymethyl starch 250 9
water q. s.
A mixture of one of the compounds of formula I mentioned in the preceding Examples, as
active ingredient, 50 9 of corn starch and the colloidal silicic acid is processed to form a
moist mass with a starch paste consisting of 250 9 of com starch and 2.2 kg of demineral-
ised water. The mass is forced through a sieve of 3 mm mesh size and dried in a fluidised-
bed drier at 45 for 30 minutes. The dried granules are then pressed through a sieve of
1 mm mesh size, mixed with a previously sieved mixture (1 mm sieve) of 330 9 of com
starch, the magnesium stearate, the stearic acid and the sodium carboxymethyl starch and
compressed to form slightly biconvex tablets.
Example 30: In a manner analogous to that described in Examples 26 to 29 it is also
possible to prepare pharmaceutical compositions comprising a different compound
according to any one of Examples 1 to 25.
