Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-01-18
2004-03-30
Berch, Mark L (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C544S060000, C544S120000, C544S355000, C544S295000, C544S405000, C544S408000, C514S227800, C514S235800, C514S252110, C514S255050, C514S252100, C514S218000, C514S217050, C540S544000, C540S575000, C540S598000
Reexamination Certificate
active
06713472
ABSTRACT:
TECHNICAL FIELD
The present invention relates to novel 3-oxo-3,4-dihydro-2H-1,4-thiazine derivatives or 2-oxo-1,2,3,4-tetrahydropyrazine derivatives being useful as pharmaceuticals.
BACKGROUND ART
Compounds having 3-oxo-3,4-dihydro-2H-1,4-thiazine or 2-oxo-1,2,3,4-tetrahydropyrazine as a main skeleton, which are compounds having one double bond in their ring, have scarcely been studied. There were only reports concerning a study of introducing a phenyl group into the 5th-position of 3-oxo-3,4-dihydro-2H-1,4-thiazine derivatives (Japanese Laid-open Patent Publication No. 275869/1990), a study of synthesis of 2-oxo-1,2,3,4-tetrahydropyrazine derivatives as synthetic intermediates of 1,5-imino-3-benzoazocine derivatives aiming at analgesics or antitussives (Japanese Laid-open Patent Publication No. 35176/1983) and the like.
Much less, there has been no report relating to a study wherein various substituents are introduced into a nitrogen atom at the 4th-position of the 3-oxo-3,4-dihydro-2H-1,4-thiazine derivatives or into a nitrogen atom at the 1st-position of the 2-oxo-1,2,3,4-tetrahydropyrazine derivatives and their pharmaceutical utility is examined. In particular, compounds having carboxy-lower alkylene converted into amide, which are subjects of the present invention, have not been studied at all.
It is a very interesting subject to synthesize novel compounds having 3-oxo-3,4-dihydro-2H-1,4-thiazine or 2-oxo-1,2,3,4-tetrahydropyrazine as a main skeleton wherein various substituents are introduced into the nitrogen atom in their ring and to study their pharmaceutical utility.
DISCLOSURE OF THE INVENTION
The present inventors studied preparation of various novel compounds having 3-oxo-3,4-dihydro-2H-1,4-thiazine or 2-oxo-1,2,3,4-tetrahydropyrazine as a main skeleton. Targets of the study are 1) to prepare novel compounds wherein carboxy-lower alkylene converted into amide is introduced into a nitrogen atom at the 4th-position of 3-oxo-3,4-dihydro-2H-1,4-thiazine derivatives or into a nitrogen atom at the 1st-position of 2-oxo-1,2,3,4-tetrahydropyrazine derivatives, and 2) to prepare novel compounds wherein various substituents are introduced into a nitrogen atom at the 4th-position of the 2-oxo-1,2,3,4-tetrahydropyrazine derivatives. As a result, the present inventors succeeded in preparing many novel compounds as mentioned later. Studying their pharmacological actions, these novel compounds were found to exhibit chymase inhibitory effects and to be useful as pharmaceuticals. The present inventors succeeded also in preparing novel compounds which are useful as synthetic intermediates in a process of the preparation of the above-mentioned 3-oxo-3,4-dihydro-2H-1,4-thiazine derivatives or 2-oxo-1,2,3,4-tetrahydropyrazine derivatives.
The present invention relates to compounds represented by the following general formula [I] and salts thereof (hereinafter referred to as “the present compound” as far as there is no proviso), pharmaceutical compositions comprising them as active ingredients, and compounds represented by the general formula [II] being useful as synthetic intermediates of the present compound and salts of the intermediates (hereinafter referred to as “the present synthetic intermediate” as far as there is no proviso),
wherein
X is S or R
6
—(A
2
)
n
—N,
R
1
and R
2
, being the same or different, are hydrogen, lower alkyl, cycloalkyl or aryl,
R
3
and R
4
, being the same or different, are hydrogen, lower alkyl, cycloalkyl, aryl or aromatic heterocycles,
R
5
is hydrogen, lower alkyl, cycloalkyl, aryl or —A
3
—A
4
—R
7
,
R
6
is hydrogen, lower alkyl, cycloalkyl, hydroxy, lower alkoxy, aryl, aryloxy or an aromatic heterocycle,
R
7
is hydrogen, lower alkyl, hydroxy, lower alkoxy, aryl, aryloxy, amino, lower alkylamino, arylamino, an aromatic heterocycle or a nonaromatic heterocycle,
n is 0 or 1,
A
1
is lower alkylene,
A
2
is carbonyl or sulfonyl,
A
3
is lower alkylene, and
A
4
is carbonyl or oxalyl.
Each lower alkyl defined above can be substituted by halogen, hydroxy, lower alkoxy, aryl or aryloxy.
Each lower alkoxy defined above can be substituted by aryl.
Each lower alkylene defined above can be substituted by aryl. The same definitions are applied hereinafter.
[wherein Q is —CH(OH)CO— or —CH(OH)—. The same definition is applied hereinafter.]
The groups defined above have the following meanings through the whole present specification.
The halogen is fluorine, chlorine, bromine or iodine.
The lower alkyl is straight-chain or branched alkyl having one to six carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl or isohexyl. The lower alkyl can be substituted by halogen, cycloalkyl, hydroxy, lower alkoxy, aryl or aryloxy.
The cycloalkyl is cycloalkyl having three to eight carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl. The cycloalkyl can be substituted by halogen, lower alkyl, cycloalkyl, hydroxy, lower alkoxy, aryl or aryloxy.
The lower alkoxy is straight-chain or branched alkoxy having one to six carbon atoms such as methoxy, ethoxy, propoxy, isopropoxy, t-butoxy or hexyloxy. The lower alkoxy can be substituted by halogen, cycloalkyl, hydroxy, lower alkoxy, aryl or aryloxy.
The lower alkylene is straight-chain or branched alkylene having one to six carbon atoms such as methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, methylmethylene, dimethylmethylene, ethylmethylene, propylmethylene, isopropylmethylene, butylmethylene, isobutylmethylene, sec-butylmethylene, tert-butylmethylene, tert-butylethylene, dimethylethylene, ethylethylene, propylethylene, isopropylethylene, methyltrimethylene or propylene. The lower alkylene can be substituted by halogen, cycloalkyl, hydroxy, lower alkoxy, aryl or aryloxy.
The aryl is a monocyclic or condensed aromatic hydrocarbon such as phenyl or naphthyl. The aryl can be substituted by halogen, lower alkyl, cycloalkyl, hydroxy, lower alkoxy, aryl, aryloxy, acyl or nitro.
The aromatic heterocycle is an aromatic heterocycle having one heteroatom in the ring such as pyrrole, furan, thiophene or pyridine; an azole aromatic heterocycle such as imidazole, oxazole, thiazole, pyrazole, isoxazole or isothiazole; an aromatic heterocycle having two nitrogen atoms in the ring such as pyrazine or pyrimidine; or a condensed aromatic heterocycle such as indole, isoindole, benzimidazole, benzoxazole, benzothiazole or quinoline. Each aromatic heterocycle can be substituted by halogen, lower alkyl, cycloalkyl, hydroxy, lower alkoxy, aryl, aryloxy or acyl.
The nonaromatic heterocycle is a saturated nonaromatic heterocycle having one heteroatom in the ring such as pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, tetrahydropyran or homopiperazine; a saturated nonaromatic heterocycle having two heteroatoms in the ring such as imidazolidine, oxazolidine, thiazolidine, pyrazolidine, piperazine, morpholine, thiomorpholine, homopiperidine or homomorpholine; an unsaturated nonaromatic heterocycle having one heteroatom in the ring such as pyrroline, dihydrofuran, dihydrothiophene, tetrahydropiperidine, dihydropiperidine, dihydropyran or pyran; or an unsaturated nonaromatic heterocycle having two heteroatoms such as imidazoline, oxazoline, thiazoline or pyrazoline. Each nonaromatic heterocycle can be substituted by halogen, lower alkyl, cycloalkyl, hydroxy, lower alkoxy, aryl, aryloxy or carbamoyl.
The acyl is lower alkanoyl having two to six carbon atoms such as acetyl, propionyl, butyryl, pivaloyl or pentanecarbonyl, or benzoyl. The phenyl ring of the benzoyl can be substituted by halogen, lower alkyl, cycloalkyl, hydroxy, lower alkoxy, aryl, aryloxy, acyl or nitro.
When the present compound or the present synthetic intermediate has free hydroxy or free amino, —NHR (wherein R is lower alkyl) or imino, they can be protected with a general protecting group.
General protecting groups of hydroxy can be used as the protecting group of hydroxy. Specific examples of the prote
Ban Masakazu
Fujimura Ken-ichi
Hori Masanori
Kobayashi Naoyuki
Matsumoto Eiko
Berch Mark L
Habte Kahsay
Santen Pharmaceutical Co. Ltd.
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