Fluorinated 3,4-dihydroquinoline derivatives used as NOS...

Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...

Reexamination Certificate

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C514S289000, C514S291000, C514S232800, C544S126000, C546S074000, C546S079000, C546S080000, C546S089000, C546S093000, C546S101000

Reexamination Certificate

active

06579883

ABSTRACT:

This application is a 371 of PCT/EP99/08519, filed on Nov. 10, 1999.
The invention relates to fluorinated 3,4-dihydroquinoline derivatives, a process for their production and their use in pharmaceutical agents.
In human cells, there exist at least three forms of nitrogen monoxide synthases, which convert arginine into nitrogen monoxide (NO) and citrulline. Two constitutive NO-synthases (NOS) were identified that are present as calcium/calmodulin-dependent enzymes in the brain (ncNOS or NOS 1) or in the endothelium (ecNOS or NOS 3). Another isoform is the inducible NOS (iNOS or NOS 2), which is a virtually 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.
A number of reviews provide information on the action and inhibitors of NO-synthases. There can be mentioned, for example: Drugs 1998, 1, 321 or Current Pharmac. Design 1997, 3, 447.
As NOS inhibitors, various compounds are known. For example, arginine derivatives, aminopyridines, cyclic amidine derivatives, phenylimidazoles, etc., are described.
It has now been found that the heterocycles that are substituted according to the invention can be used especially advantageously as pharmaceutical agents compared to known compounds.
The invention relates to the compounds of Formula I, their tautomeric and isomeric forms or 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
8
, NR
11
R
12
or C
1-4
alkyl and in which 1 or 2 CH
2
groups can be replaced by O, S(O)
n
, NR
11
, ═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
8
,
d) OR
8
,
e) COOR
8
,
f) COR
8
,
g) CONR
8
R
13
,
h) CSNR
8
R
13
,
i) C(NR
8
)NR
9
R
13
,
j) NR
14
R
15
,
k) C
1-6
alkyl, which optionally is substituted with halogen, OR
8
, SR
8
, NR
14
R
15
, 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
8
or OR
8
,
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
8
, SR
8
, C
1-4
alkyl, CF
3
or NR
8
R
13
,
q) CN,
r) NO
2
,
s) CF
3
,
t) OCF
3
,
R
4
and R
5
, R
5
and R
6
, or R
6
and R
7
together with 2 adjacent carbon atoms form a 5- or 6-membered carbocycle, which can be substituted with NR
14
R
15
,
R
8
, R
9
and R
10
, 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
11
and R
12
, independently of one another, mean
a) Hydrogen,
b) C
1-6
alkyl,
b) COR
16
,
c) CO
2
R
10
,
d) CONR
8
R
9
,
e) CSNR
8
R
9
,
R
13
means:
a) Hydrogen,
b) C
1-6
alkyl, optionally substituted with halogen, amino, hydroxyl or sulfhydryl groups,
c) C
6-10
aryl,
R
14
and R
15
, independently of one another, mean:
a) Hydrogen
b) CO
2
R
10
c) C
1-6
alkyl, optionally substituted with halogen, hydroxy, C
1-4
alkoxy, nitro, amino, C
1-6
alkyl, trifluoromethyl, carboxyl, cyano, carboxamido, C
3-7
cycloalkyl, indanyl, 1,2,3,4-tetrahydronaphthyl, C
6-10
aryl, 5- or 6-membered heteroaryl with 1-4 nitrogen, oxygen or sulfur atoms, whereby the aryl and the heteroaryl radical can be substituted with halogen, hydroxy, C
1-4
alkoxy, C
1-4
alkyl, CF
3
, NO
2
, NH
2
, N(C
1-4
alkyl)
2
or carboxyl,
 or
R
14
and R
15
together with the nitrogen atom form a 5- to 7-membered saturated heterocycle, which can contain another oxygen, nitrogen or sulfur atom and can be substituted with C
1-4
alkyl, phenyl, benzyl or benzoyl or can contain an unsaturated 5-membered heterocycle, which can contain 1-3 N atoms and can be substituted with phenyl, C
1-4
halogen or CH
2
—OH,
R
16
means
a) C
1-6
alkyl,
b) C
6-10
aryl, which optionally is substituted with halogen or C
1-4
alkyl,
 and
n means 0, 1 or 2.
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, or sec-hexyl.
If the alkyl radical is halogenated, the latter can be present in one or more places in halogenated form, whereby trifluoromethyl is preferred.
Alkenyl and alkinyl substituents are respectively straight-chain or branched. For example, the following radicals can be mentioned: vinyl, 2-propenyl, 1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-2-propenyl, 2-pentenyl, 4-hexenyl, ethinyl, 1-propinyl, 2-propinyl, 1-butinyl, 2-butinyl.
Cycloalkyl is defined respectively as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.
As bicyclic compound R
3
, for example, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, or bicyclo[3.2.1]octane is considered.
Halogen means respectively fluorine, chlorine, bromine or iodine.
Aryl is defined respectively as naphthyl or especially phenyl, which can be substituted in one to three places. The phenyl and benzyl radicals can also be substituted by the same or a different component in one to three places.
In each case, the heteroaryl radical 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: 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- and 6-membered heteroaromatic compounds with 1 to 2 nitrogen, oxygen and sulfur atoms and especially thienyl and furanyl, such as 2-furanyl. As substituents of the heteroaryl radicals, especially NO
2
, CN, halogen, C
1-4
alkyl and CF
3
are suitable.
As saturated heterocycles NR
14
R
15
, for example, piperidine, pyrrolidine, morpholine, thiomorpholine, hexahydroazepine and 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. For example, there can be mentioned: N-methyl-piperazine, 2,6-dimethylmorpholine, phenylpiperazine or

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