The invention relates to compounds of general formula (I) ##STR1## wherein R is selected from ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec.-butyl and allyl; R.sub.4 is selected from hydrogen and pharmaceutically acceptable inorganic and organic cations; R.sub.5 is selected from methyl, ethyl, n-propyl, iso-propyl, methoxy, ethoxy, chloro, bromo, CF.sub.3, and OCH.sub.x F.sub.y ; wherein x=0-2, y=1-3 with the proviso that x+y=3; R.sub.6 is hydrogen; or R.sub.5 and R.sub.6 taken together are methylenedioxy; and any tautomer hereof. The invention also relates to pharmaceutical compositions containing a compound of the general formula (I) together with a pharmaceutically acceptable carrier. Included are also processes for the preparation of the compounds of formula (I), as well as methods of treating mammals suffering from diseases resulting from autoimmunity and pathological inflammation by administering a compound having the formula (I) to said mammal.

FIELD OF THE INVENTION 
The present invention relates to novel quinoline derivatives, to methods 
for their preparation, to compositions containing them, and to methods and 
use for clinical treatment of diseases resulting from autoimmunity such as 
multiple sclerosis, insulin-dependent diabetes mellitus, systemic lupus 
erythematosus, rheumatoid arthritis, inflammatory bowel disease and 
psoriasis and, furthermore, diseases where pathologic inflammation plays a 
major role, such as asthma, atherosclerosis, stroke and Alzheimer's 
disease. More particularly, the present invention relates to novel 
quinoline derivatives suitable for the treatment of, for example, multiple 
sclerosis and its manifestations. 
BACKGROUND OF THE INVENTION 
Autoimmune diseases, e.g., multiple sclerosis (MS), insulin-dependent 
diabetes mellitus (IDDM), systemic lupus erythematosus (SLE), rheumatoid 
arthritis (RA), inflammatory bowel disease (IBD) and psoriasis represent 
assaults by the body's immune system which may be systemic in nature, or 
else directed at individual organs in the body. They appear to be diseases 
in which the immune system makes mistakes and, instead of mediating 
protective functions, becomes the aggressor (1). 
MS is the most common acquired neurologic disease of young adults in 
Western Europe and North America. It accounts for more disability and 
financial loss, both in lost income and in medical care, than any other 
neurologic disease of this age group. There are approximately 250.000 
cases of MS in the United States. 
Although the cause of MS is unknown, advances in brain imaging, immunology, 
and molecular biology have increased researchers' understanding of this 
disease. Several therapies are currently being used to treat MS, but no 
single treatment has demonstrated dramatic treatment efficacy. Current 
treatment of MS falls into three categories: treatment of acute 
exacerbations, modulation of progressive disease, and therapy for specific 
symptoms. MS affects the central nervous system and involves a 
demyelination process, i.e. the myelin sheaths are lost whereas the axons 
are preserved. Myelin provides the isolating material that enables rapid 
nerve impulse conduction. Evidently, in demyelination, this property is 
lost. Although the pathogenic mechanisms responsible for MS are not 
understood, several lines of evidence indicate that demyelination has an 
immunopathologic basis. The pathologic lesions, the plaques, are 
characterised by infiltration of immunologically active cells such as 
macrophages and activated T cells (2). 
In U.S. Pat. No. 4,547,511 and U.S. Pat. No. 4,738,971 and in EP 59,698 
some derivatives of 
N-aryl-1,2-dihydro-4-substituted-1-alkyl-2-oxo-quinoline-3-carboxamide are 
claimed as enhancers of cell-mediated immunity. The compound 
##STR2## 
known as roquinimex (Merck Index 12.sup.th Ed., No. 8418; Linomide.RTM., 
LS2616, 
N-methyl-N-phenyl-1,2-dihydro-4hydroxy-1-methyl-2-oxo-quinoline-3-carboxam 
ide) belongs to this series of compounds. Roquinimex has been reported to 
have multiple immunomodulatory activities not accompanied with general 
immunosuppression (3-12). 
Furthermore, in U.S. Pat. No. 5,580,882 quinoline-3-carboxamide derivatives 
are claimed to be useful in the treatment of conditions associated with 
MS. The particular preferred compound is roquinimex. In U.S. Pat. No. 
5,594,005 quinoline-3-carboxamide derivatives are claimed to be useful in 
the treatment of type I diabetes. The particular preferred compound is 
roquinimex. In WO 95/24195 quinoline-3-carboxamide derivatives are claimed 
to be useful in the treatment of IBD. Particularly preferred compounds are 
roquinimex or a salt thereof. In WO95/24196 quinoline-3-carboxamide 
derivatives are claimed to be useful in the treatment of psoriasis. 
Particularly preferred compounds are roquinimex or a salt thereof. 
In clinical trials comparing roquinimex to placebo, roquinimex was reported 
to hold promise in the treatment of conditions associated with MS (13, 
14). There are, however, some serious drawbacks connected to roquinimex. 
For example, it has been found to be teratogenic in the rat, and to induce 
dose-limiting side effects in man, e.g., a flu-like syndrome, which 
prevents from using the full clinical potential of the compound. 
Further, in WO 92/18483 quinoline derivatives substituted in the 6-position 
with a R.sub.A S (O).sub.n -group (R.sub.A =lower alkyl or aryl; n=0-2) 
are claimed, which possess an immunomodulating, anti-inflammatory and 
anti-cancer effect. 
The substitution, i.e., type and pattern, of the above, specifically 
mentioned, compounds places them outside the scope of the present 
invention. 
DESCRIPTION OF THE INVENTION 
A primary objective of the present invention is to provide structurally 
novel quinoline compounds which by virtue of their pharmacological 
profile, with high potency in experimental models and low level of 
side-effects, are considered to be of value in the treatment of disease 
resulting from autoimmunity and pathologic inflammation. Examples of such 
diseases are multiple sclerosis, insulin-dependent diabetes mellitus, 
systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel 
disease and psoriasis and other diseases where inflammation plays a major 
role, such as asthma, atherosclerosis, stroke and Alzheimer's disease. 
More particularly, the present invention relates to novel quinoline 
derivatives suitable for the treatment of, for example, multiple sclerosis 
and its manifestations. 
It has now surprisingly been found that the novel compounds of general 
formula (I) 
##STR3## 
wherein R is selected from ethyl, n-propyl, iso-propyl, n-butyl, 
iso-butyl, sec.-butyl and allyl; 
R.sub.4 is selected from hydrogen and pharmaceutically acceptable inorganic 
cations, such as sodium, potassium and calcium, and organic cations such 
as monoethanolamine, diethanolamine, dimethylaminoethanol, morpholine and 
the like; 
R.sub.5 is selected from methyl, ethyl, n-propyl, iso-propyl, methoxy, 
ethoxy, chloro, bromo, CF.sub.3, and OCH.sub.x F.sub.y ; 
wherein 
x=0-2, 
y=1-3 with the proviso that 
x+y=3; 
R.sub.6 is hydrogen; or 
R.sub.5 and R.sub.6 taken together are methylenedioxy; 
are unexpectedly effective and specific in the treatment of individuals 
suffering from autoimmune and inflammatory diseases. 
The compounds of general formula (I) may exist in different tautomeric 
forms and all such forms are included herein. 
In a preferred embodiment of the invention R.sub.4 is hydrogen or sodium, 
and R.sub.5 is ethyl, methoxy, chloro or bromo, and R.sub.5 and R.sub.6 
taken together are methylenedioxy, and R is ethyl or n-propyl, especially 
ethyl. 
Several autoimmune diseases in man have experimental models that are 
spontaneously occurring in certain strains of laboratory animals or can be 
induced in laboratory animals by immunisation with specific antigen(s) 
from the target organ. 
Experimental autoimmune encephalomyelitis (EAE) as a model for autoimmune 
inflammatory diseases of the central nervous system (CNS) has been the 
most widely used model for the human disease multiple sclerosis. 
Autoimmunity to type II collagen can experimentally be induced in certain 
strains of mice or rats and may lead to the development of polyarthritis. 
The collagen-induced arthritis has several features in common with the 
human disorder rheumatoid arthritis. 
The hallmark of asthma in humans is an increased reactivity of the airways 
to a range of chemical and physical stimuli. It is now widely accepted 
that products released from inflammatory cells, e.g., activated 
eosinophils, compromise epithelial integrity and promote bronchial 
hyperresponsiveness. The murine model of ovalbumin (OA)-induced lung 
inflammation is dominated by the temporally regulated influx of 
lymphocytes and eosinophils into the bronchial lumen. 
Roquinimex has been found to induce the Beagle Pain Syndrome (BPS) (15, 16) 
in different breeds of beagle dogs. The disease is reflected by clinical 
and laboratory manifestations justifying BPS as a model for the flu-like 
syndrome induced by roquinimex in man. 
The compounds of general formula (I) were assayed for inhibition of EAE in 
mice. Roquinimex was used as treatment control and showed a 70% inhibition 
at 5 mg/kg. Surprising and unexpected results were obtained when 
introducing proper substitution in the 5-position, e.g., 5-chloro, of the 
quinoline ring. In comparison with roquinimex, the potency was increased a 
100-fold. Substitution in the 6-, 7-, and 8-position resulted in less 
active compounds. In general, the EAE activity as seen by the EAE 
inhibition was in the following descending order according to the position 
of the substitution: 5&gt;6&gt;&gt;7=8. The effect of the 5-substitution could 
largely be understood on physiochemical grounds. Moreover, replacement of 
the methyl group on the carboxamide nitrogen with an ethyl group or 
further elongation of the alkyl group to a propyl or butyl group 
extinguished the teratogenic effect of roquinimex in the rat and 
significantly reduced the BPS. On the other hand, changing the R-group 
from alkyl to hydrogen decreased the water-solubility at physiological pH 
more than a 10.sup.5 -fold. Replacement of the alkyl group also affected 
the pharmacokinetic properties. For example, in comparison with roquinimex 
the clearance (Cl) of compound A in dogs was an 800-fold higher. 
##STR4## 
The solubility and pharmacokinetic issues significantly reduce the useful 
order of activity of this class (R.dbd.H) of compounds. Hence, the 
compounds of formula (I) have surprisingly been found to be both 
chemically and pharmacologically different from those drugs hitherto 
suggested for the treatment of MS and its manifestations. 
The compounds of general formula (I) are prepared by the following methods: 
##STR5## 
The compounds of formula (I) may be prepared by known methods, for example, 
by reaction of an ester derivative of the quinoline carboxylic acid (II) 
with an aniline (III) in a suitable solvent such as toluene, xylene and 
the like. Suitable esters are methyl and ethyl esters. 
##STR6## 
The compounds of formula (I) may also be prepared by reaction of an isatoic 
anhydride (IV) with an N-alkyl-N-phenylcarbamoyl acetic acid alkyl ester 
(V) using a strong base, e.g., sodium hydride in a suitable solvent such 
as N,N-dimethylacetamide. Suitable esters are methyl and ethyl esters. 
##STR7## 
The compounds of formula (I) may also be prepared by reaction of a 
quinoline carboxylic acid of formula (VI) with an aniline of formula 
(III). Various coupling reagents known in the art may be used, e.g., 
carbodiimides known from U.S. Pat. No. 4,547,511. One suitable coupling 
method utilises thionyl chloride in the presence of triethylamine and a 
suitable solvent such as dichloromethane. This method may be used in 
instances when direct coupling between ester and aniline does not work. 
The quinoline carboxylic acids of formula (VI) may be obtained from the 
corresponding esters of formula (II) by acidic hydrolysis as described 
below. 
The quinoline carboxylic esters (II) above may be prepared by the methods 
shown in examples 5-8 below. The quinoline carboxylic acids (VI) may be 
prepared by the method shown in example 9 below. 
All embodiments of the invention as disclosed in the claims are herewith 
included in the specification.

The following examples are intended to illustrate the invention without 
restricting the scope thereof. 
EXAMPLE 1 
N-Ethyl-N-phenyl-1,2-dihydro-4-hydroxy-5-methoxy-1-methyl-2-oxo-quinoline-3 
-carboxamide (Method A) 
N-Ethylaniline (3.0 g, 25 mmol) was dissolved in 80 ml of toluene and about 
30 ml of the solvent was distilled off in order to obtain a dry solution. 
To this boiling solution was added 
1,2-dihydro-4hydroxy-5-methoxy-1-methyl-2-oxo-quinoline-3-carboxylic acid 
ethyl ester (2.7 g, 10 mmol). The ethanol formed during the reaction was 
distilled off together with some toluene for about 4 hours. The reaction 
mixture was cooled to room temperature. The precipitate was collected, 
washed with cold toluene and hexane and dried to give the title compound 
(2.8 g), yield 80%. 
.sup.1 H NMR (CDCl.sub.3) .delta. 1.26 (3H, t), 3.50 (3H, s), 3.97 (2H, q), 
4.03 (3H,s), 6.67 (1H, d), (6.87 (1H, d), 7.12-7.25 (3H, m), 7.36-7.44 
(3H, m). 
13C NMR (CDCl.sub.3) .delta. 13.0 (CH.sub.3), 29.6 (CH.sub.3), 43.8 
(CH.sub.2), 56.8 (CH.sub.3), 103.2 (CH), 104.2 (C), 108.3 (CH), 110.5 (C), 
127.3 (2CH), 127.4 (CH), 128.5 (2CH), 131.2 (CH), 141.1 (C), 141.9 (C), 
156.9 (C), 157.1 (C), 160.2 (C), 164.4 (C). ESI MS/MS [M+H].sup.+ 353, 
fragments 232 and 122. 
In essentially the same manner the following compounds were obtained from 
the corresponding starting materials: 
N-ethyl-N-phenyl-1,2-dihydro-1,5-dimethyl-4-hydroxy-2-oxo-quinoline-3-carbo 
xamide. 
.sup.1 H NMR (CDCl.sub.3) .delta. 1.21 (3H, t), 2.83 (3H, s). 3.23 (3H, s), 
3.98 (2H, q), 6.97 (1H, d), 7.02 (1H, d), 7.10-7.25 (5H, m), 7.39 (1H, t), 
13.08 (1H, s). 
13C NMR (CDCl.sub.3) .delta.12.9 (CH.sub.3), 24.4 (CH.sub.3), 29.5 
(CH.sub.3), 45.9 (CH.sub.2), 102.8 (C), 112.2 (CH), 114.3 (C), 125.5 (CH), 
126.4 (2CH), 126.4 (CH), 128.4 (2CH), 131.7 (CH), 139.6 (C), 142.0 (C), 
142.4 (C), 158.1 (C), 169.7 (C), 170.1 (C). ESI MS/MS [M+H].sup.+ 337, 
fragments 216 and 122. 
N-ethyl-N-phenyl-1,2-dihydro-4-bydroxy-5-chloro-1-methyl-2-oxo-quinoline-3- 
carboxamide. 
1H NMR (CDCl.sub.3) .delta. 1.20 (3H, t), 3.28 (3H, s), 3.97 (2H, q), 
7.08-7.25 (7H, m), 7.39 (1H, t), 12.6 (1H, s). 
13C NMR (CDCl.sub.3) .delta. 12.9 (CH.sub.3), 29.8 (CH.sub.3), 45.7 
(CH.sub.2), 105,0 (C), 112.7 (C), 113.3 (CH), 125.4 (CH), 126.7 (2CH), 
126.8 (CH), 128.5 (2CH), 131.6 (CH), 132.7 (C), 142.0 (C), 142.6 (C), 
157.9 (C), 165.6 (C), 168.7 (C). ESI MS/MS [M+H].sup.+ 357, fragments 236 
and 122. 
N-ethyl-N-phenyl-1,2-dihydro-4-hydroxy-5-fluoro-1-methyl-2-oxo-quinoline-3- 
carboxamide. 
1H NMR (CDCl.sub.3 +TFA) .delta. 1.28 (3H, t), 3.66 (3H, s), 3.93-4.05 (2H, 
m), 711 (1H, q), 7.26-7.37 (6H, m), 7.68 (1H, q), 11.42 (1H, s). 
13C NMR (CDCl.sub.3 +TFA) .delta. 12.6 (CH.sub.3), 31.4 (CH.sub.3), 46.4 
(CH.sub.2), 104.4+104.5 (C), 108.7 (C), 110.4+110.5 (CH), 112.7+112.8 
(CH), 126.8 (2CH), 129.7 (CH), 129.8 (2CH), 134.1+134.2 (CH), 139.9 (C), 
141.0 (C), 158.0 (C), 159.3+161.3 (C), 161.4 (C), 166.8 (C); (Some peaks 
are doublets due to F-coupling). ESI MS/MS [M+H].sup.+ 341, fragments 220 
and 122. 
N-ethyl-N-phenyl-1,2-dihydro-4-hydroxy-5-trifluoromethyl-1-methyl-2-oxo-qui 
noline-3 -carboxamide. 
1H NMR (CDCl.sub.3 +TFA) .delta. 1.21 (3H, t), 3.30 (3H, s), 3.99 (2H, q), 
7.10-7.25 (5H, m), 7.42 (1H, d), 7.60 (1H, t), 7.67 (1H, d), 13.05 (1H, 
s). 
13C NMR (CDCl.sub.3 +TFA) .delta. 12.5 (CH.sub.3), 31.1 (CH.sub.3), 46.2 
(CH.sub.2), 106.4 (C), 113.0 (C), 119.5 (CH), 120+122.2+124.4 (CF.sub.3), 
123.4 (CH), 126.6 (2CH), 128.1 (CH), 128.1+128.3 (C), 129.1 (2CH), 132.1 
(CH), 140.5 (C), 141.4 (C), 159.3 (C), 163.7 (C), 167.8 (C). ESI MS/MS 
[M+H].sup.+ 391, fragments 270 and 122. 
N-ethyl-N-phenyl-1,2-dihydro-4-hydroxy-5-trifluoromethoxy-1-methyl-2-oxo-qu 
inoline-3-carboxamide. 
N-allyl-N-phenyl-1,2-dihydro-4-hydroxy-5-chloro-1-methyl-2-oxo-quinoline-3- 
carboxamide. 
1H NMR (CDCl3) .delta. 3.33 (3H, s), 4.57 (2H, m), 5.22 (1H, d), 5.38 (1H, 
d), 6.0 (1H, m), 7.13-730 (7H, m), 7.44 (1H, t), 12.45 (1H, s). 
N-allyl-N-phenyl-1,2-dihydro-4-hydroxy-5-methoxy-1-methyl-2-oxo-quinoline-3 
-carboxamide. 
1H NMR (CDCl.sub.3) .delta. 3.52 (3H, s), 4.04 (3H, s), 4.52 (2H, m), 5.20 
(1H, d), 5.37 (1H, d), 6.02 (1H, m), 6.67 (1H, d), 6.88 (1H, d), 7.10-7.23 
(3H, m), 7.38-7.45 (3H, m), 9.82 (1H, s). 
N-phenyl-N-n-propyl-1,2-dihydro-4-hydroxy-5-methoxy-1-methyl-2-oxo-quinolin 
e-3-carboxamide. 
1H NMR (CDCl.sub.3) .delta. 1.0 (3H, t), 1.65 (2H, m), 3.48 (3H, s), 3.9 
(2H,t), 4.01 (3H, s), 6.65 (1H, d), 6.83 (1H, d), 7.1-7.25 (3H, m), 
7.3-7.45 (3H, m), 9.8 (1H, s). 
EXAMPLE 2 
N-Ethyl-N-phenyl-1,2-dihydro-4-hydroxy-5-chloro-1-methyl-2-oxo-quinoline-3- 
carboxamide (Method B) 
5-Chloro isatoic anhydride (5 g, 25 mmol) was dissolved in 50 ml of 
N,N-dimethylacetamide and cooled to 0.degree. C. Sodium hydride (75%) 
(0.94 g, 1.1 eq.) followed by methyl iodide (1.89 ml, 1.2 eq.) was added 
at a rate to keep the temperature below 5.degree. C. The reaction mixture 
was stirred at 20.degree. C. for 5 hours whereupon the remaining methyl 
iodide was removed under vacuum. Sodium hydride (0.94 g, 1.1 eq.) was 
added together with N-ethyl-N-phenylcarbamoyl acetic acid ethyl ester (6.3 
g, 1.1 eq.). The mixture was heated at 85.degree. C. for 5 hours. After 
cooling to room temperature 50 ml of methanol and 50 ml of 1M hydrochloric 
acid and subsequently 250 ml of water were added. An emulsion was formed 
which crystallised on standing in a refrigerator for 72 hours. The 
crystalline mass was collected by filtration, washed with water, 
water/methanol (1:1) and heptane and dried to afford the title compound 
(6.12 g). The title compound was recrystallised from methanol in &gt;95% 
purity. 
N-Ethyl-phenyl-1,2-dihydro-4-hydroxy-5-chloro-1-methyl-2-oxo-quinoline-3-ca 
rboxamide sodium salt 
A solution of 5 M sodium hydroxide was prepared by dilution of a 50 
weight-% sodium hydroxide solution (10.0 g) with sterile water to the 
total volume of 25 ml. 
N-Ethyl-N-phenyl-1,2-dihydro-4-hydroxy-5-chloro-1-methyl-2-oxo-quinoline-3 
-carboxamide (10.0 g) was suspended in ethanol (150 ml) and the previously 
prepared 5 M sodium hydroxide solution was added to pH 8-12 (5.6 ml). The 
reaction mixture was stirred for another 30 minutes at ambient 
temperature. The resulting precipitation was filtered off and rapidly 
washed twice with ethanol (2.times.150 ml). The precipitate was then dried 
in vacuum over P.sub.2 O.sub.5 to give the title compound (9.5 g), yield 
90%. 
1H NMR (D.sub.2 O). Two isomers in ratio 1:4. .delta. 0.90 (3H, t, minor 
form), 1.10 (3H, t, major form), 3.21 (3H, s, major form), 3.50 (3H, s, 
minor form), 3.50-3.70 (2H, m, minor form), 3.70-3.85 (2H, m, major form), 
6.92-7.51 (8H, m, both forms). 
EXAMPLE 3 
N-Ethyl-N-phenyl-1,2-dihydro-4-hydroxy-5-bromo-1-methyl-2-oxo-quinoline-3-c 
arboxamide (Method C) 
To an ice-cold solution of 
1,2-dihydro-4-hydroxy-5-bromo-1-methyl-2-oxo-quinoline-3-carboxylic acid 
(9.6 g, 0.032 mol), triethylamine (15.5 ml, 0.11 mol) and N-ethylaniline 
(4.2 g, 0.035 mol) in 150 ml of dichloromethane was added dropwise during 
0.5 hours a solution of thionyl chloride (3.0 ml, 0.042 mol) in 10 ml of 
dichloromethane. The stirring was continued at 4.degree. C. for 24 hours. 
The solvents were evaporated. The residue was dissolved in ethyl acetate, 
filtered through celite and extracted with 2 M sodium hydroxide. The 
aqueous phase was washed with ethyl acetate and then acidified with 
hydrochloric acid to pH 5. On standing a crystalline precipitate was 
formed which was filtered off, washed with water and dried to give the 
title compound (8.5 g), yield 69%. 
1H NMR (CDCl.sub.3) .delta. 1.15-1.22 (3H, broad signal), 3.25 (3H, s), 
3.95 (2H, s broad), 7.08-731 (7H, m), 7.43-7.50 (1H, m). 
In essentially the same manner the following compounds were obtained from 
the corresponding starting materials: 
N-ethyl-N-phenyl-1,2-dihydro-4-hydroxy-5,6-methylenedioxy-1-methyl-2-oxo-qu 
inoline-3-carboxamide. 
1H NMR (CDCl.sub.3 +TFA) .delta. 1.27 (3H, t), 3.57 (3H, s), 3.98 (2H, q), 
6.23 (2H, s), 6.86 (1H, d), 7.19 (1H, d), 7.25-7.35 (5H, m), 10.3 (1H, s 
broad). 
13C NMR (CDCl.sub.3 +TFA) .delta. 12.4 (CH.sub.3), 30.9 (CH.sub.3), 46.0 
(CH.sub.2), 101.6 (C), 103.7 (CH.sub.2), 107.4 (C), 108.4 (CH), 113.7 
(CH), 126.7 (2CH), 128.8 (CH), 129.3 (2CH), 134.1 (C), 140.1 (C), 
143.1+143.2 (2C), 157.3 (C), 160.9 (C), 166.3 (C). ESI MS/MS [M+H].sup.+ 
367, fragments 246 and 122. 
N-ethyl-N-phenyl-1,2-dihydro-4-hydroxy-5-ethyl-1-methyl-2-oxo-quinoline-3-c 
arboxamide. 
1H NMR (CDCl.sub.3) .delta. 1.26 (3H, t), 1.31 (3H, t), 3.20-3.34 (5H, m), 
4.0 (2H, q), 7.02-7.07 (2H, m), 7.13-7.28 (5H, m), 7.44 (1H, t) 13.2 (1H, 
s broad). 
13C NMR (CDCl.sub.3) .delta. 13.2 (CH.sub.3), 16.8 (CH.sub.3), 29.8+30.2 
(CH.sub.3 +CH.sub.2), 46.1 (CH.sub.2), 103.3 (C), 112.5 (CH), 113.9 (C), 
124.6 (CH), 126.7+126.7 (3CH), 128.6 (2CH), 132.1 (CH), 142.3 (C), 142.6 
(C), 146.2 (C), 158.3 (C), 169.3 (C), 170.4 (C). ESI MS/MS [M+H].sup.+ 
351, fragments 230 and 122. 
N-phenyl-N-iso-propyl-1,2-dihydro-4-hydroxy-5-chloro-1-methyl-2-oxo-quinoli 
ne-3-carboxamide. 
1H NMR (CDCl.sub.3) .delta. 1.24 (6H, d), 3.38 (3H, s broad), 5.09 (1H, 
broad signal), 7.08 (1H, d), 7.15 (1H, d), 7.15-7.34 (5H, m), 7.34 (1H, 
t), 11.1 (1H, s broad). 
13C NMR (CDCl.sub.3) .delta. 21.0 (2CH.sub.3), 29.9 (CH.sub.3), 48.2 (CH), 
109.4 (C), 112.4 (C), 113.5 (CH), 125.1 (CH), 127.9 (2CH), 127.9 (CH), 
129.6 (2CH), 131.1 (CH), 131.6 (C), 137.9 (C broad), 142.1 (C), 158.6 (C), 
160.6 (C), 167.5 (C). 
N-phenyl-N-(n-propyl)-1,2-dihydro-4-hydroxy-5-chloro-1-methyl-2-oxo-quinoli 
ne-3-carboxamide. 
1H NMR (CDCl.sub.3) .delta. 0.95 (3H, t), 1.58-1.69 (2H, m), 3.29 (3H, s 
broad), 3.88 (2H, broad), 7.08-7.26 (7H, m), 7.41 (1H, t), 12.5 (1H, s 
broad). 
EXAMPLE 4 
N-Ethyl-phenyl-1,2-dihydro-4-hydroxy-5-chloro-1-methyl-2-oxo-quinoline-3-ca 
rboxamide sodium salt 
A solution of 5 M sodium hydroxide was prepared by dilution of a 50 
weight-% sodium hydroxide solution (10.0 g) with sterile water to the 
total volume of 25 ml. 
N-Ethyl-N-phenyl-1,2-dihydro-4-hydroxy-5-chloro-1-methyl-2-oxo-quinoline-3 
-carboxamide (10.0 g) was suspended in ethanol (150 ml) and the previously 
prepared 5 M sodium hydroxide solution was added to pH 8-12 (5.6 ml). The 
reaction mixture was stirred for another 30 minutes at ambient 
temperature, The resulting precipitation was filtered off and rapidly 
washed twice with ethanol (2.times.150 ml). The precipitate was then dried 
in vacuum over P.sub.2 O.sub.5 to give the title compound (9.5 g), yield 
90%. 
1H NMR (D.sub.2 O). Two isomers in ratio 1:4. .delta. 0.90 (3H, t, minor 
form), 1.10 (3H, t, major form), 3.21 (3H, s, major form), 3.50 (3H, s, 
minor form), 3.50-3.70 (2H, m, minor form), 3.70-3.85 (2H, m, major form), 
6.92-7.51 (8H, m, both forms). 
EXAMPLE 5 
1,2-Dihydro-4-hydroxy-5-chloro-1-methyl-2-oxo-quinoline-3-carboxylic acid 
ethyl ester 
Phosgene (51 g, 0.52 mol) dissolved in dioxane (150 ml) was added in 
portions to a mechanically stirred slurry of sodium bicarbonate (44 g, 
0.52 mol) and 2-amino-6chloro-benzoic acid (30 g, 0.175 mol) in dioxane 
(300 ml). Violent reaction with gas evolution occurred and the reaction 
mixture was cooled to keep the temperature below 50.degree. C. After 30 
minutes the reaction mixture was kept at 50.degree. C. for 1 hour. After 
cooling to 15.degree. C. the resulting precipitate was collected, stirred 
with 50 ml of glacial acetic acid in 500 ml of water, collected again and 
dried to give the isatoic anhydride (30.3 g, 0.15 mol). 
The anhydride was added slowly in portions to a mixture of sodium hydride 
(5.5 g, 0.18 mol) in 300 ml of N,N-dimethylformamide. After stirring at 
room temperature for 1 hour, methyl iodide (26 g, 0.18 mol) was added 
dropwise and stirring was continued for 21/2 hours. The mixture was then 
added to 3 l of an ice/water slurry and the precipitate was collected and 
dried to yield the N-methylated isatoic anhydride (24.9 g, 0.118 mol). 
The N-methylated anhydride was heated to 65.degree. C. with sodium 
methoxide (6.3 g, 0.117 mol) in 130 ml of methanol for 1 hour. The 
solvents were evaporated. Water and dichloromethane were added and the 
organic layer was separated, dried and concentrated to yield an oily 
residue (22.7 g, 0.114 mol). 
The residue above was dissolved in 300 ml of dichloromethane together with 
4-aminopyridine (0.2 g) and triethylamine (7.1 ml). The solution was 
cooled and ethyl malonyl chloride (18.9 g, 0.125 mol) was slowly added. 
The mixture was stirred at room temperature for 4 hours and worked up to 
give a syrup. To this syrup was added 450 ml of ethanol and sodium 
methoxide (18.5 g, 0.342 mol) and the mixture was stirred for 3 hours. The 
solvents were evaporated and the residue was dissolved in 750 ml of water, 
washed with ethyl acetate and toluene and subsequently acidified with 5 M 
hydrochloric acid. The resulting precipitate was collected and dried to 
yield the title compound as a white powder (30 g, 0.106 mol) in a total 
yield of 60%. 
1H NMR (CDCl.sub.3) .delta. 1.46 (3H, t), 3.63 (3H, s), 4.49 (2H, q), 7.23 
(1H, d), 7.27 (1H, d), 7.49 (1H, t), 15.0 (1H, s). 
In essentially the same manner the following compounds are obtained from 
the corresponding starting materials: 
1,2-dihydro-4-hydroxy-5-fluoro-1-methyl-2-oxo-quinoline-3-carboxylic acid 
ethyl ester, 
1,2-dihydro-4-hydroxy-1,5-dimethyl-2-oxo-quinoline-3-carboxylic acid ethyl 
ester. 
EXAMPLE 6 
1,2-Dihydro-4-hydroxy-5-trifluoromethyl-1-methyl-2-oxo-quinoline-3-carboxyl 
ic acid ethyl 
2-Fluoro-6-(trifluoromethyl)benzonitrile (10 g, 53 mmol) was warmed at 
40.degree. C. in anhydrous methylamine (200 ml) in an autoclave for 2 
days. The excess methylamine was allowed to evaporate and the resulting 
grey solid was dissolved in dichloromethane (200 ml) together with 
4-aminopyridine (0.1 g) and triethylamine (3.3 ml, 26 mmol). To this 
chilled solution was slowly added ethyl malonyl chloride (8.8 g, 60 mmol). 
The solution was stirred for 4 hours and then worked up to give a 
yellowish syrup. The syrup was dissolved in 100 ml of anhydrous ethanol 
and sodium methoxide (5.4 g, 0.1 mol) was added. After 1 hour, the solvent 
was removed and the residue worked up with dichloromethane and water. The 
quinoline derivative formed was carefully dried and then suspended in 
chilled anhlydrous tetrahydrofuran (250 ml). Sodium hydride (4 g, 0.125 
mol) and then methyl iodide (10 ml, 0.15 mol) was slowly added. The 
mixture was heated under reflux for 6 hours, quenched with water and 
worked up with diethyl ether. The solvents were removed and the residue 
(17.3 g) was dissolved in a mixture of ethanol (50 ml) and conc. 
hydrochloric acid (10 ml). The solution was warmed at 45.degree. C. during 
the night, cooled and the precipitate was collected to give 8 g of the 
title compound. 
1H NMR (CDCl.sub.3) .delta. 1.46 (3H, t), 3.68 (3H, s), 4.50 (2H, q), 7.58 
(1H, m), 7.71 (2H, m), 15.0 (1H, s). 
EXAMPLE 7 
1,2-Dihydro-4-hydroxy-5-methoxy-1-methyl-2-oxo-quinoine-3-carboxylic acid 
ethyl ester 
To a solution of 2,6-difluorobenzonitrile (42 g, 0.3 mol) in 150 ml of 
anhydrous methanol was slowly added sodium methoxide (17.9 g, 0.33 mol) at 
30.degree. C. After being heated under reflux for 1 hour, aqueous 40% 
methylamine (133 ml, 1.2 mol) was added and the solution refluxed for 4 
days. On cooling, a white solid precipitated which was collected by 
filtration. The solid, 2-methoxy-6-(methylamino)benzonitrile, was 
dissolved in an aqueous solution of ethylene glycol (500 ml) and potassium 
hydroxide (14 g). The solution was refluxed at 150.degree. C. overnight, 
cooled to room temperature and the pH adjusted to 4 with conc. 
hydrochloric acid. The precipitate was collected by filtration, washed 
with water (50 ml) and dried under vacuum. The white solid, 
5-methoxy-anthranilic acid (32 g, 0.18 mol), and sodium bicarbonate (38 g, 
0.45 mol) were suspended in 1,4-dioxane (500 ml) and then phosgene (25 ml, 
0.45 mol) was slowly added under cooling in an ice bath. The mixture was 
warmed at 40.degree. C. for 1 hour, cooled to 15.degree. C., water (150 
ml) was added and the white solid collected by filtration. After being 
carefully dried, the solid (20.7 g, 0.1 mol) was added to a solution of 
sodium diethylmalonate (0.17 mol) in anhydrous N,N-dimethylformamide (250 
ml) at room temperature. The solution was heated at 100.degree. C. for 3 
hours, cooled to room temperature, water (250 ml) was added and the pH 
adjusted to 4 with conc. hydrochloric acid. The precipitate was collected 
by filtration and dried under vacuum to give the title compound as pure 
white crystals, 22 g. 
1H NMR (CDCl.sub.3) .delta. 1.43 (t, 3H), 3.62(s, 3H), 3.96(s, 3H), 4.45(q, 
2H), 6.70(d, 1H), 6.92(d, 1H), 7.55(t, 1H), 13.5(s, 1H). 
EXAMPLE 8 
1,2-dihydro 
4-hydroxy-1-methyl-2-oxo-5,6-methylenedioxy-quinoline-3-carboxylic acid 
ethyl ester 
Di-tert-butyl dicarbonate (36 g, 0.17 mol) was added portionwise to a 
solution of 3,4-(methylenedioxy)-aniline (20.6 g, 0.15 mol) in anhydrous 
tetrahydrofuran (150 ml). The solution was reflux heated for 2 hours, then 
concentrated under vacuum to give a black solid residue. The residue was 
dissolved in anhydrous tetrahydrofuran (600 ml) and cooled to -40.degree. 
C. A hexane solution of 1.3 M sec-butyllithium (265 ml, 0.35 mol) was 
added dropwise. 
After stiring the solution for 0.5 hour at -40.degree. C. dry ice (ca 40 g) 
pellets were added. The mixture was allowed to warm to 0.degree. C. and 
water (ca 700 ml) was added. The aqueous solution was acidified with 
hydrochloric acid to pH 3 and extracted with ether. The extracts were 
dried and concentrated to give the N-tBoc protected 
5,6-(methylenedioxy)anthranilic acid as a solid residue (45 g). This acid 
was added to an ice-cooled suspension of sodium hydride (80% in oil, 9.0 
g, 0.30 mol) in N,N-dimethylformamide (200 ml). The mixture was stirred 
for 0.5 hour and methyl iodide (22 ml, 0.35 mol) was added. The mixture 
was stirred at room temperature overnight, was quenched with water (600 
ml) and extracted three times with ether. The organic layer was washed 
with sat. brine, dried and concentrated under vacuum to give a darkbrown 
oil. The oil was dissolved in methanol (400 ml) and conc. hydrochloric 
acid (80 ml) was added. The solution was stirred overnight at room 
temperature, neutralised with 5 M sodium hydroxide and extracted three 
times with ether. The combined extracts were filtered through a column 
with SiO.sub.2 and the eluate concentrated under vacuum to give the 
methylated anthranilic ester (20 g). The ester was dissolved in 
dichloromethane (400 ml) and cooled on an ice-bath. Ethyl malonyl chloride 
(21 g, 0.14 mol) was added and then, after 30 minutes, triethylamine (22 
ml, 0.16 mol). After being stirred for 1 hour at room temperature the 
cloudy mixture was washed with 0.5 M hydrochloric acid and then 
bicarbonate. The organic phase was carefully dried and concentrated under 
vacuum. The residue was then dissolved in dry ethanol (200 ml) and sodium 
methoxide (17 g, 0.32 mol) was added. The mixture was stirred for 1 hour 
and water was added (300 ml). The solution was washed with ethyl acetate 
and then the aqueous solution was acidified with conc. hydrochloric acid. 
The precipitate was collected by filtration and dried under vacuum to give 
the title compound as grey crystals (17 g, overall yield 41%). 
1H NMR (CDCl.sub.3) .delta. 1.45 (3H, t), 3.58 (3H, s), 4.48 (2H, q), 6.17 
(2H, s), 6.71 (1H, d), 7.14 (1H, d). 
EXAMPLE 9 
1,2-Dihydro-4-hydroxy-5-methoxy-1-methyl-2-oxo-quinoline-3-carboxylic acid 
While cooling, 10 ml of conc. hydrochloric acid was added to 30 ml of 
acetic anhydride. To this solution, 
1,2-dihydro-4-hydroxy-5-methoxy-1-methyl-2-oxo-quinoline-3-carboxylic acid 
ethyl ester (10.5 g, 38 mmol) was added and the mixture heated at 
80.degree. C. for 14 hours. The mixture was cooled to room temperature and 
the crystalline product was filtered off, washed with cold methanol and 
dried to give the title compound (7.2 g), yield 77%. 
1H NMR ((CDCl.sub.3) .delta. 3.73 (3H, s) 4.02 (3H, s), 6.82 (1H, d), 7.02 
(1H, d), 7.62 (1H, t). 
EXAMPLE 10 
5-Ethyl isatoic anhydride 
A mixture of chloral hydrate (59.3 g, 0.36 mol), water (700 ml), and sodium 
sulphate (85.8 g, 0.60 mol), was heated to 50.degree. C. When 50.degree. 
C. was reached, sequentially a mixture of 3-ethylaniline (40.8 g, 0.33 
mol), water (700 ml) and conc. hydrochloric acid (33.6 ml) and a mixture 
of hydroxylamine hydrocloride (74.8 g, 1.04 mol) and water (330 ml) were 
added. The resulting mixture was heated to 80.degree. C. during 30 minutes 
and kept for another 10 minutes at this temperature before the reaction 
mixture was cooled on an ice-bath. The resulting precipitate was filtered 
off, washed with water and dried in vacuum over P.sub.2 O.sub.5 to give an 
isonitrosoacetanilide (36.6 g), yield 58% 
The isonitrosoacetanilide (10.0 g, 0.05 mol), was added portionwise to a 
mixture of water (9 ml) and conc. sulphuric acid (60 ml) prewarmed to 
50.degree. C., maintaining the temperature between 50-55.degree. C. When 
the addition was completed, the mixture was heated to 80.degree. C. and 
kept at this temperature for 10 minutes. The reaction mixture was then 
cooled on an ice-bath and poured on 10-12 times the reaction volume of 
crushed ice. The mixture was then left standing for about one hour. The 
water suspension was extracted with dichloromethane which was dried and 
evaporated resulting in an mixture of the two analogues 4-ethyl and 
6-ethyl isatins approximately 0.68:1 (7.6 g), yield 84%. 
The mixture of the two isomers was dissolved in aqueous sodium hydroxide 
and the solution was filtered through celite and then acidified to pH 4. 
The 4-analogue was at this pH extracted into dichloromethane, which was 
dried and evaporated to give the pure 4-ethyl isatin (3.1 g), yield 34%. 
4-Ethyl isatin (3.1 g, 0.018 mol) was added to a mixture of conc. sulphuric 
acid (45 l) in acetic acid (14 ml). The suspension was warmed to 
30.degree. C., hydrogen peroxide 35% (2.2 ml) was added and after the 
addition the temperature was raised to 65.degree. C. After being heated 
for 3 hours, the mixture was cooled and the precipitate filtered off, 
washed with water and dried to give the title compound (1.7 g), yield 48%. 
1H NMR (DMSO-d.sub.6) .delta. 1.12 (3H, t), 3.02 (2H, q), 6.98 (1H, d), 
7.05 (1H, d), 7.58 (1H, t), 11.6 (1H, broad). 
Pharmacological methods 
Acute experimental autoimmune encephalomyelitis (aEAE) 
SJL/N female mice, 8 weeks of age, were used for the experiments. Mouse 
spinal cord homogenate (MSCH) was obtained from 8 to 12 weeks-old C57B1/6 
female mice. The tissue was homogenised on ice and diluted in cold PBS. 
Incomplete Freund's containing 1 mg/ml M. tuberculosis hominis H37Ra was 
emulsified with an equal volume of MSCH to give a final concentration of 
10 mg/ml of MSCH. The inoculum volume of 0.1 ml was injected intradermally 
at the base of the tail. Pertussis toxin was injected i.p. at day 0 and 3 
after immunization. Treatment was given per os daily either at day 3 to 12 
post-immunization or days 3 to 7 and 10 to 12. Control animals received 
saline. The animals, eight per dose group, were scored for clinical signs 
of paralytic disease on a scale from 0 to 5 in the following way; 0, 
normal; 1, limp tail; 2, hind limb paresis; 3 hind limb paralysis and limp 
foreleg; 4, bilateral hind and fore limb paralysis; 5, death. Clinical 
scores were monitored at day 7 and daily from day 9 until the end of the 
experiment at day 14. Treatment effect were calculated as percent 
inhibition of clinical scores compared to saline treated controls. 
Collagen induced arthritis 
DBA/1 male mice between 8 to 10 weeks of age were used for the experiments. 
On day 0 the mice were immunized intradermally at the base of the tail 
with bovine type II collagen (100 .mu.g/mouse) in Freund's complete 
adjuvant. The treatment was given per os daily on days 3 to 7, 10 to 14, 
17 to 21, 24 to 28 and 31 to 35. Fifteen days after immunization mice were 
inspected for signs of arthritis. The animals were inspected three times a 
week. Every second or tbird day individual paws of the arthritic animals 
were scored by a scale from 0-4 (0=no arthritis, 1=arthritis in one of the 
interphalangeal, metatarsophalangeal or intercarpal joints, 2=two 
arthritic joints, 3=three arthritic joints, 4=as in 3 but with more severe 
redness and swelling of the paw). The score for each paw was added to give 
a maximal attainable score of 16 for each mouse. 
Ovalbumin-induced lung inflammation 
C57B1/6 female mice between 10 to 14 weeks of age were used for the 
experiments, 10 mice/group. The mice were sensitized with ovalbumnin (OA) 
in aluminium hydroxide in a volume of 0.2 ml, inoculated ip. Treatment was 
given at day 0 to day 16. Control mice received saline. Fourteen days 
after the OA sensitization mice were exposed for 20 minutes to an aerosol 
of 1.5% w/v, of OA in saline produced by a nebulizer. Vehicle-challenged 
control mice were exposed to saline. Seventy-two hours after OA/vehicle 
challenge, mice were anaesthetised and bronchoalveolar lavage was 
performed by instilling 0.5 ml ice-cold phosphate buffered saline (PBS) 
into the lungs twice. Total cell counts were determined and differential 
counts were made based on identification of eosinophils, 
monocytes/alveolar macrophages, lymphocytes and neutrophils. Eosinophil 
infiltration into the lung tissue was evaluated by histochemical methods 
on frozen lung sections using diaminobenzidine tetrahydrochloride (DAB). 
Teratogenic effects in the rat 
The compounds were administrated subcutaneously to female rats during day 8 
to 14 of pregnancy. The rats were caesarean sectioned and necropsied on 
day 20 after fertlisation. The foetuses were examined for external and 
internal abnormalities. 
Beagle Pain Syndrome (BPS) 
The compounds were administrated intravenously to beagle dogs. The dosage 
was given for five consecutive days. The dogs were evaluated for clinical 
and laboratory signs of the pain syndrome, e.g., fever, increased 
erythrocyte sedimentation rate (ESR), alkaline phosphate (AP), induction 
of acute phase proteins and vasculitis. 
Preferred compounds are 
N-ethyl-N-phenyl-1,2dihydro-4-hydroxy-5-chloro-1-metbyl-2-oxo-quinoline-3- 
carboxamide, 
N-ethyl-N-phenyl-1,2-dihydro-4-hydroxy-5-methoxy-1-methyl-2-oxo-quinoline- 
3-carboxamide, 
N-ethyl-N-phenyl-1,2-dihydro-4-hydroxy-5-bromo-1-methyl-2-oxo-quinoline-3- 
carboxamide and 
N-ethyl-N-phenyl-1,2-dihydro-4-hydroxy-5,6-methylenedioxy-1-methyl-2-oxo-q 
uinoline-3-carboxamide hereinafter called Compound B, C, D and E, 
respectively. Roquinimex and 
N-ethyl-N-phenyl-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-quinoline-3-carboxam 
ide and 
N-methyl-N-phenyl-1,2-dihydro-4-hydroxy-5-chloro-1-methyl-2-oxo-quinoline- 
3-carboxamide hereinafter called Compound F and G, respectively, are 
included as reference compounds: 
______________________________________ 
aEAE inhibition 
% aEAE Inhibition 
Dose, mg/kg 
Compound B 
Compound C 
p.o. (invention) 
(invention) 
Compound F 
Roquinimex 
______________________________________ 
0.04 60 48 not tested 
not tested 
0.2 74 71 not tested 
35 
1 98 73 not tested 
40 
5 96 90 63 69 
______________________________________ 
______________________________________ 
Arthritic score, type II collagen induced arthritis 
Compound Incidence (%) 
Mean score 
(dose 5 mg/kg p.o.) 
day 35 day 35 
______________________________________ 
D (invention) 30 0.4 
E (invention) 10 0.1 
Roquinimex 50 1.7 
______________________________________ 
______________________________________ 
Embryotoxicity - external malformations 
% malformed foetuses 
Dose, mg/kg 
Compound B 
(route) (invention) Compound G Roquinimex 
______________________________________ 
6 0.sup.a) 37.sup.a) 
10 9.sup.b) 
30 1.sup.a) Not tested 30.sup.b) 
______________________________________ 
.sup.a) route s.c. 
.sup.b) route p.o. 
Effective quantities of the compounds of formula (I) are preferably 
administered to a patient in need of such treatment according to usual 
routes of administration and formulated in usual pharmaceutical 
compositions comprising an effective amount of the active ingredient and a 
suitable pharmaceutically acceptable carrier. Such compositions may take a 
variety of forms, e.g. solutions, suspensions, emulsions, tablets, 
capsules, and powders prepared for oral administration, sterile solutions 
for parental administration, suppositories for rectal administration or 
suitable topical formulations. Conventional procedures for the selection 
and preparation of suitable pharmaceutical formulations are described, for 
example, in "Pharmaeuticals--The Science of Dosage Form Design", M. B. 
Aulton, Churchill Livingstone, 1988. 
A suitable daily dose for use in the treatment of MS is contemplated to 
vary between 0.0005 mg/kg to about 10 mg/kg body weight, in particular 
between 0.005 mg/kg to 1 mg/kg body weight, depending upon the specific 
condition to be treated, the age and weight of the specific patient, and 
the specific patient's response to the medication. The exact individual 
dosage, as well as the daily dosage, will be determined according to 
standard medical principles under the direction of a physician. 
Various additives to enhance the stability or ease of administration of the 
drug are contemplated. The pharmaceutical composition may also contain 
additional therapeutically useful substances other than a compound of 
formula (I). 
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