Benzoxazine and benzothiazine derivatives and their use in...

Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...

Reexamination Certificate

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C544S105000, C546S001000, C549S029000, C549S229000, C549S212000, C514S231500, C514S438000, C514S277000, C514S461000, C514S469000

Reexamination Certificate

active

06365736

ABSTRACT:

The invention relates to benzoxazine and benzothiazine derivatives, the 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 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.
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).
As NOS-inhibitors, different compounds are known. For example, cyclic amidine derivatives are described in WO 96/14844. It is not known from any publication, however, that benzoxazines or benzothiazines inhibit nitrogen monoxide synthases.
The invention relates to the compounds of Formula I, their tautomeric and isomeric forms and salts
in which
X means O, SO
m
or Se,
R
1
means NO
2
, cyano, CF
3, —OCF
3
, —SO
2
NR
7
R
8
, —CONR
7
R
8
, —NR
9
—C(═NR
10
)—R
11
, —NH—CS—NR
7
R
8
, —NH—CO—NR
7
R
8
, NR
12
R
13
, —CO—R
14
, C
6-10
aryl, which optionally is substituted with halogen, cyano C
1-4
alkyl, —S—R
9
, —O—R
9
, —NR
7
R
8
or CONR
7
R
8
,
5- or 6-membered heteroaryl with 1 to 4 heteroatoms, such as oxygen, nitrogen or sulfur, which optionally is substituted with —OR
9
, —SR
9
, halogen, C
1-4
alkyl, NR
7
R
8
or CONR
7
R
8
,
C
1-6
alkyl, which is substituted with halogen, —OR
9
, —SR
9
, —NR
7
R
8
, —NR
7′
R
8′
, ═NR
7
, ═NOC
1-6
alkyl, ═N—NHaryl, phenyl, C
3-7
cycloalkyl or 5- or 6-membered heteroaryl, with 1-3 N, O, or S atoms,
C
2-6
alkenyl, which is substituted with halogen, CONH
2
, C≡N or phenyl,
C
2-6
alkinyl, which is substituted with halogen, CONH
2
, C≡N or phenyl,
C
3-7
cycloalkyl,
R
2
means hydrogen or
R
1
and R
2
together with two adjacent carbon atoms form a 5-, 6-, 7- or 8-membered ring, which can be monocyclic or bicyclic, saturated or unsaturated and in which 1 or 2 CH
2
groups can be replaced by oxygen or carbonyl or its derivative, and which can be substituted with —NR
7
R
8
, —NR
7′
R
8′
or C
1-4
alkyl,
R
3
means hydrogen, halogen, —S—R
9
or —O—R
9
or is the same or different from R
1
,
R
4
means hydrogen or acyl,
R
5
means hydrogen,
R
6
means C
3-7
cycloalkyl, C
6-10
aryl, C
1-6
alkyl, C
2-6
alkenyl or C
2-6
alkynyl radicals, which can be substituted in each case with halogen, OH, O—C
1-6
alkyl, SH, S—C
1-6
alkyl, NR
15
R
16
, 5- or 6-membered heteroaryl with 1-3 N, O or S atoms, phenyl or C
3-7
cycloalkyl,
R
7
and R
8
mean hydrogen, C
1-6
alkyl, phenyl optionally substituted with halogen or C
1-4
alkyl, benzyl optionally substituted with halogen or C
1-4
alkyl or C
3-7
cycloalkyl,
R
7′
means hydrogen, C
1-6
alkyl optionally substituted with OH, phenyl, cyano, COO
1-4
alkyl or carbonyl,
R
8′
means C
1-6
alkyl, which is substituted with C
3-7
cycloalkyl, indanyl, C
6-10
aryl or 5- or 6-membered heteroaryl with 1-3 nitrogen, oxygen or sulfur atoms, whereby the aryl and heteroaryl radicals can be substituted with halogen, C
1-4
alkyl, C
1-4
alkoxy, CF
3
, NO
2
, NH
2
, N(C
1-4
alkyl)
2
, SO
2
CH
3
, —O—CH
2
—O, SO
2
NH
2
, OH or COO—C
1-4
alkyl, or indanyl or 1,2,3,4-tetrahydronaphthyl or
R
7′
and R
8′
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 form an unsaturated 5-membered heterocycle, which can contain 1-3 N atoms and can be substituted with phenyl, C
1-4
alkyl, halogen or CH
2
—OH,
R
9
, R
10
and R
15
, R
16
mean hydrogen or C
1-6
alkyl,
R
11
means C
1-6
alkyl, —NH
2
, —NH—CH
3
, —NH—CN, C
6-10
aryl optionally substituted with halogen, C
1-4
alkyl or CF
3
, or 5- or 6-membered heteroaryl with 1 to 4 nitrogen, sulfur or oxygen atoms that optionally is substituted with halogen, C
1-4
alkyl or CF
3
,
m means 0, 1 or 2,
R
12
, R
13
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, phenyl, benzyl or benzoyl and
R
14
means hydrogen, phenyl, C
1-6
alkyl optionally substituted with CO
2
H, CO
2
C
1-6
alkyl, hydroxy, C
1-4
alkoxy, halogen, NR
7
R
8
, NR
12
R
13
, CONR
7
R
8
or phenyl, or C
2-6
alkenyl optionally substituted with phenyl, cyano, CONR
7
R
8
or CO
2
C
1-4
alkyl.
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, diastereomers, racemates and mixtures thereof, including the tautomeric compounds of Formulas 1a and 1b
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, HCl , HBr, 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, especially C
1-4
alkyl groups.
Alkenyl and alkynyl substituents are in each case straight-chain or branched. 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 phenyl, which can be substituted in one or more places. Phenyl and benzyl radicals R
7
, R
8
and R
8 ′
can also be substituted by the same or a different component in one or more places at any position.
The hetaryl radical can contain a fused benzene ring in each case 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, isooxazole, isothiazole, furan, oxadiazole, oxazole, pyrazine, pyridazine, pyrimidine, pyridine, pyrazole, pyrrole, tetrazole, thiazole, triazole, thiophene, thiadiazole, benzimidazole, benzofuran, benzoxazole, isoquinoline, quinoline. Preferably, pyridine, pyrrole, thiophene, thiazole and imidazole can be mentioned.
As a preferred embodiment for R
11
in the meaning of heteroaryl, thienyl can be considered.
As saturated heterocycles NR
12
R
13
, and NR
7′
R
8′
, 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 optionally is substituted with halogen. For example, there can be mentioned: N-methyl-piperazine, 2,6-dimethylmorpholine, phenylpiperazine or 4-(4-fluorobenzoyl)-piperidine.
If NR
7′

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