3,4-Dihydroquinoline derivatives as nitrogen monoxide...

Details 3,4-Dihydroquinoline derivatives as nitrogen monoxide... 3,4-Dihydroquinoline derivatives as nitrogen monoxide...

2000-08-14

2002-05-21

Huang, Evelyn Mei (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S291000, C514S298000, C514S232800, C544S126000, C546S079000, C546S080000, C546S089000, C546S093000, C546S101000

Reexamination Certificate

active

06391887

ABSTRACT:

The invention relates to 3,4-dihydroquinoline derivatives, a process for their production and their use in pharmaceutical agents.
In human cells, there exist 3 specific forms of nitrogen monoxide synthases, which convert arginine into nitrogen monoxide (NO) and citrulline. Two constitutive NO-synthases (NOS) were thus identified that are present as Ca
++
/calmodulin-dependent enzymes in the brain (ncNOS or NOS 1) or in the endothelium (ecNOS or NOS 3). The third isoform is the inducible NOS (iNOS or NOS 2), which is a Ca
++
-independent enzyme and is induced after activation of different cells by endotoxin or other substances.
NOS-inhibitors and especially specific inhibitors of NOS 1, NOS 2 or NOS 3 are therefore suitable for treatment of different diseases, which are induced or aggravated by pathological concentrations of NO in cells (Clin. Neuropharmac. 18, 1995, page 482).
It has now been found that the heterocycles that are substituted according to the invention can be used especially advantageously as pharmaceutical agents.
The invention relates to the compounds of Formula I, their tautomeric and isomeric forms and their physiologically compatible salts
in which
R
1
and R
2
, independently of one another, mean:
a) Hydrogen,
b) C
1-6
alkyl,
c) OR
8
,
d) NR
8
R
9
,
e) CN,
f) acyl,
g) CO
2
R
10
,
h) CONR
8
R
9
,
i) CSNR
8
R
9
,
R
3
means:
a saturated or unsaturated C
1-5
alkylene radical, which can be substituted in 1 to 4 places with OR
11
, NR
12
R
13
or C
1-4
alkyl and in which 1 or 2 CH
2
groups can be replaced by O, S(O)
n
, NR
14
, ═N— or carbonyl, and which can be bridged with a methano, ethano or propano group,
R
4
, R
5
, R
6
and R
7
, independently of one another, mean:
a) Hydrogen,
b) halogen,
c) S(O)
n
R
16
,
d) OR
16
1
,
e) COOR
16
,
f) COR
16
,
g) CONR
6
R
17
,
h) CSNR
16
R
17
,
i) C(NR
18
)NR
16
R
17
,
j) NR
16
R
19
,
k) C
1-6
alkyl, which optionally is substituted with halogen, OR
16
, SR
16
, COOR
16
, phenyl, 5- to 6-membered heteroaryl with 1-4 N, S or O atoms or C
3-7
cycloalkyl,
l) C
3-7
cycloalkyl,
m) C
2-6
alkenyl, optionally substituted with phenyl or halogen,
n) C
2-6
alkinyl, optionally substituted with phenyl or halogen,
o) C
6-10
aryl, which optionally is substituted with halogen, CN, C
1-4
alkyl, SR
16
or OR
16
,
p) 5- to 6-membered hetaryl with 1 to 4 N, O or S atoms, which contain a slightly condensed benzene ring and can be substituted with halogen, NO
2
, cyano, —OR
16
, SR
16
, C
1-4
alkyl, CF
3
or NR
16
R
17
,
q) CN,
r) NO
2
,
s) CF
3
,
t) OCF
3
,
R
8
, R
9
, R
10
, R
11
, R
16
, R
18
, R
21
and R
22
, independently of one another, mean:
a) Hydrogen,
b) C
1-6
alkyl,
c) C
6-10
aryl, which optionally is substituted with halogen or C
1-4
alkyl,
R
20
means
a) C
1-6
alkyl,
b) C
6-10
aryl, which optionally is substituted with halogen or C
1-4
alkyl,
R
12
, R
13
, R
14
and R
19
, independently of one another, mean:
a) Hydrogen,
b) C
1-6
alkyl,
b) COR
20
,
c) CO
2
R
21
,
d) CONR
21
R
22
,
e) CSNR
21
R
22
,
R
17
means
a) hydrogen,
b) C
1-6
alkyl, optionally substituted with halogens, and amino, hydroxy or sulfhydryl groups,
c) C
6-10
aryl,
n means 0, 1, 2 and
R
16
, R
19
together with the nitrogen atom form a saturated 5-, 6- or 7-membered ring, which can contain another nitrogen, oxygen, or sulfur atom and can be substituted with C
1-4
alkyl or a phenyl, benzyl or benzoyl radical that is optionally substituted with halogen.
The compounds of the formula can be present as tautomers, stereoisomers or geometric isomers. The invention also comprises all possible isomers, such as E- and Z-isomers, S- and R-enantiomers, cis- and trans-diastereomers, racemates and mixtures thereof, including the tautomeric compounds of Formulas Ia and Ib (for R
2
=hydrogen).
The physiologically compatible salts can be formed with inorganic and organic acids, such as, for example, oxalic acid, lactic acid, citric acid, fumaric acid, acetic acid, maleic acid, tartaric acid, phosphoric acid, hydrochloric acid, hydrobromic acid, sulfuric acid, p-toluenesulfonic acid, methanesulfonic acid, i.a.
For salt formation of acid groups, the inorganic or organic bases are also suitable, which are known for the formation of physiologically compatible salts, such as, for example, alkali hydroxides, such as sodium and potassium hydroxide, alkaline-earth hydroxides, such as calcium hydroxide, ammonia, amines such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, tris-(hydroxymethyl)-methylamine, etc.
In each case, alkyl means a straight-chain or branched alkyl group, such as, e.g., methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, sec-pentyl, tert-pentyl, neopentyl, n-hexyl, sec-hexyl, heptyl, octyl, whereby 1 to 4 carbon atoms are preferred.
If the alkyl radical is halogenated, the latter can be present in one or more places, whereby trifluoromethyl is preferred.
Alkenyl and alkinyl radicals are straight-chain or branched in each case and preferably contain up to 4 carbon atoms. For example, the following radicals can be mentioned: vinyl, 2-propenyl, 1-propenyl, 2-butenyl, 1-butenyl, 1-butenyl, 2-butenyl, 1-methyl-1-propenyl, 2-methyl-2-propenyl, 3-methyl-2-propenyl, ethinyl, 1-propinyl, 2-propinyl, 1-butinyl, 2-butinyl.
Cycloalkyl is defined respectively as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.
Halogen means respectively fluorine, chlorine, bromine or iodine.
Aryl is defined respectively as naphthyl or especially phenyl, which can be substituted by the same or a different component in one to three places.
The hetaryl radicals can contain a slightly condensed benzene ring and can be substituted by the same or a different component in one to three places and can be bonded via the heteroatom or a carbon atom. For example, the following 5- and 6-ring heteroaromatic compounds are suitable in each case: Imidazole, indole, isoxazole, isothiazole, furan, oxadiazole, oxazole, pyrazine, pyridazine, pyrimidine, pyridine, pyrazole, pyrrole, tetrazole, thiazole, triazole, thiophene, thiadiazole, benzimidazole, benzofuran, benzoxazole, isoquinoline, quinoline. Preferred are 5- or 6-membered heteroaromatic compounds with 1 to 2 nitrogen, oxygen or sulfur atoms and especially furanyl and thienyl. As substituents of the heteroaryl radicals, especially NO
2
, CN, halogen, C
1-6
alkyl and CF
3
are suitable.
As heterocycle NR
16
R
19
, for example, piperidine, pyrrolidine, morpholine, thiomorpholine, hexahydroazepine or piperazine can be mentioned. The heterocycle can be substituted in 1 to 3 places with C
1-4
alkyl or a phenyl, benzyl or benzoyl radical that is optionally substituted with halogen. Especially suitable are 6-membered saturated heterocycles that can contain another heteroatom and that can be substituted in 1 or 2 places. For example, there can be mentioned: N-methyl-piperazine, 2,6-dimethylmorpholine, phenylpiperazine or 4-(4-fluorobenzoyl)-piperidine.
The acyl radical is derived from straight-chain or branched aliphatic C
1-6
carboxylic acids, such as, for example, formic acid, acetic acid, propionic acid, butyric acid, trimethylacetic acid or caproic acid or from known benzenesulfonic acids, which can be substituted with halogen or C
1-4
alkyl, and C
1-4
alkanesulfonic acids, such as, for example, methanesulfonic acid, and p-toluenesulfonic acid. Preferably alkanoyls can be mentioned.
As preferred meanings of R
1
and R
2
, hydrogen, C
1-6
alkyl and hydroxy can be mentioned.
R
3
preferably means alkylene with 1 to 5 carbon atoms, in which a CH
2
group can be replaced by oxygen or sulfur. For example, —CH
2
—O—CH
2
—, —CH
2
—S—CH
2
—, —(CH
2
)
3
—, —(CH
2
)
4
— and —(CH
2
)
5
— can be mentioned.
Preferred embodiments for R
4
, R
5
, R
6
and R
7
are:
a) Hydrogen,
b) halogen,
c) SR
16
,
d) OR
16
,
e) COOR
16
,
f) COR
16
,
g) CONR
16
R
17
,
h) NR
16
R
19
,
i) C
1-6
alkyl, which optionally is substituted with halogen, COOR
16
or phenyl,
j) C
2-6
alkenyl, optionally substituted with phenyl or halogen,
k) C
2-6
alkinyl, optionally substituted wi

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