Pyridine compounds and their pharmaceutical use

Details Pyridine compounds and their pharmaceutical use Pyridine compounds and their pharmaceutical use

2001-08-17

2003-02-18

Seaman, D. Margaret (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C514S340000, C514S342000, C514S343000, C514S345000, C514S354000, C546S268400, C546S276400, C546S279700, C546S281700, C546S290000, C546S304000, C546S314000, C546S339000

Reexamination Certificate

active

06521643

ABSTRACT:

TECHNICAL FIELD
This invention relates to new pyridine compounds. More particularly, this invention relates to new pyridine compounds and pharmaceutically acceptable salts thereof which have pharmacological activities, a process for preparation thereof, a pharmaceutical composition comprising the same and a use of the same.
Accordingly, one object of this invention is to provide the new and useful pyridine compounds and pharmaceutically acceptable salts thereof which possess a strong inhibitory activity on the production of nitric oxide (NO).
Another object of this invention is to provide a process for the preparation of the pyridine compounds and salts thereof.
A further object of this invention is to provide a pharmaceutical composition comprising said pyridine compound or a pharmaceutically acceptable salt thereof.
Still further object of this invention is to provide a use of said pyridine compounds or pharmaceutically acceptable salts thereof as a medicament for prophylactic and therapeutic treatment of nitric oxide synthase (NOS)-mediated diseases such as adult respiratory distress syndrome, myocarditis, synovitis, septic shock, insulin-dependent diabetes mellitus, ulcerative colitis, cerebral infarction, rheumatoid arthritis, osteoarthritis, osteoporosis, systemic lupus erythematosus, rejection by organ transplantation, asthma, pain, ulcer, and the like in human being and animals.
DISCLOSURE OF INVENTION
The object pyridine compounds of the present invention are novel and can be represented by the following general formula (I)
wherein
R
1
and R
2
are the same or different and each is hydrogen, lower alkyl, lower alkoxy, cyano, lower alkoxycarbonyl, carboxy, lower haloalkyl, hydroxy(lower)alkyl, hydroxy, nitro, amino, mono or di(lower)alkylamino, protected hydroxy or lower alkyl substituted by protected hydroxy;
X is a single bond or a group of the formula selected from the group consisting of
wherein R
4
is hydrogen or acyl;
ring A is heterocycle or arylene wherein said heterocycle and arylene may be substituted by suitable substituent(s) selected from the group consisting of lower alkyl, lower alkoxy, halogen and guanidino which may be substituted by suitable substituent(s); and
R
3
is a group of the formula selected from the group consisting of
wherein R
5
is hydrogen, lower alkyl, lower alkylthio, amino which may be substituted by suitable substituent(s) or aromatic heterocyclic group, or when
 may form a bicyclic group selected from the group consisting of
 wherein said bicyclic group may be substituted by suitable substituent(s) selected from the group consisting of lower alkyl and aryl,
R
6
and R
7
are the same or different and each is hydrogen, lower alkyl, cyano, amino, hydroxy, acyl or amidino which may be substituted by suitable substituent(s), and R
8
is thiazolinyl or pyridyl.
Suitable pharmaceutically acceptable salts of the object compound (I) are conventional non-toxic salts and include, for example, a salt with a base or an acid addition salt such as a salt with an inorganic base, for example, an alkaline metal salt (e.g., sodium salt, potassium salt, etc.), an alkaline earth metal salt (e.g., calcium salt, magnesium salt, etc.), an ammonium salt; a salt with an organic base, for example, an organic amine salt (e.g., triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N,N′-dibenzylethylenediamine salt, etc.); an inorganic acid addition salt (e.g., hydrochloride, hydrobromide, sulfate, phosphate, etc.); an organic carboxylic or sulfonic acid addition salt (e.g., formate, acetate, trifluoroacetate, maleate, tartrate, methanesulfonate, benzenesulfonate, toluenesulfonate, etc.); and a salt with a basic or acidic amino acid (e.g., arginine salt, aspartic acid salt, gultamic acid salt, etc.).
In the above and subsequent descriptions of the present specification, suitable examples and illustration of the various definitions which the present invention intends to include within the scope thereof are explained in detail as follows.
The term “lower” is used to intend a group having 1 to 6, preferably 1 to 4, carbon atom(s), unless otherwise provided.
Suitable “lower alkyl” and “lower alkyl moiety” in the terms “hydroxy(lower)alkyl”, “mono or di(lower)alkylamino” and “lower alkylthio” include straight or branched one having 1 to 6 carbon atom(s), such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, neopentyl, tert-pentyl and hexyl, in which more preferred one is C
1
-C
4
alkyl.
Suitable “lower alkoxy” and “lower alkoxy moiety” in the term “lower alkoxycarbonyl” include, straight or branched one having 1 to 6 carbon atom(s), such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentyloxy, neopentyloxy, tert-pentyloxy and hexyloxy, in which more preferred one is C
1
-C
4
alkoxy.
Suitable “lower alkoxycarbonyl” includes, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl and hexyloxycarbonyl.
Suitable “lower haloalkyl” includes, straight or branched one having 1 to 6 carbon atom(s), such as trifluoromethyl, trichloromethyl and tribromomethyl, in which more preferred one is trifluoromethyl.
Suitable “hydroxy(lower)alkyl” includes, for example, hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, 1-hydroxypropyl, 2-hydroxy-1-methylethyl, 4-hydroxybutyl, 3-hydroxybutyl, 2-hydroxybutyl, 1-hydroxybutyl, 1,1-dimethyl-2-hydroxyethyl, 5-hydroxypentyl and 6-hydroxyhexyl.
Suitable “mono or di(lower)alkylamino” includes, for example, methylamino, ethylamino, propylamino, isopropylamino, butylamino, tert-butylamino, N, N-dimethylamino, N, N-diethylamino, N,N-dipropylamino, N,N-dibutylamino, N-ethyl-N-methylamino, N-methyl-N-propylamino and N-butyl-N-methylamino.
Suitable “acyl” includes, for example, carbamoyl, aliphatic acyl group and acyl group containing an aromatic ring, which is referred to as aromatic acyl, or a heterocyclic ring, which is referred to as heterocyclic acyl.
Suitable examples of said acyl are illustrated as follows: carbamoyl; aliphatic acyl such as lower alkanoyl which may be substituted by one to three halogen atoms (e.g., formyl, acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, 2,2-dimethylpropanoyl, hexanoyl, trichloroacetyl, trifluoroacetyl, etc.), lower alkoxycarbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, tert-pentyloxycarbonyl, etc.), lower alkylsulfonyl (e.g., methylsulfonyl, ethylsulfonyl, etc.), lower alkoxysulfonyl (e.g., methoxysulfonyl, ethoxysulfonyl, etc.), cyclo(lower)alkylcarbonyl (e.g., cyclopentylcarbonyl, cyclohexylcarbonyl, etc.), and the like; aromatic acyl such as aroyl (e.g., benzoyl, toluoyl, naphthoyl, etc.), aryl(lower)alkanoyl [e.g., phenyl(lower)alkanoyl (e.g., phenylacetyl, phenylpropanoyl, phenylbutanoyl, etc.), naphthyl(lower)alkanoyl (e.g., naphthylacetyl, naphthylpropanoyl, naphthylbutanoyl, etc.), etc.], aryl(lower)alkoxycarbonyl [e.g., phenyl(lower)alkoxycarbonyl (e.g., benzyloxycarbonyl, etc.), etc.], aryloxycarbonyl (e.g., phenoxycarbonyl, naphthyloxycarbonyl, etc.), aryloxy(lower)alkanoyl (e.g., phenoxyacetyl, phenoxypropionyl, etc.), arylsulfonyl (e.g., phenylsulfonyl, p-tolylsufonyl, etc.), and the like; heterocyclic acyl such as indolylcarbonyl (e.g., indolyl-2-ylcarbonyl, etc.), benzofuranylcarbonyl (e.g., benzofuran-2-ylcarbonyl), quinoxalinylcarbonyl, quinolylcarbonyl, pyrrolylcarbonyl, benzimidazolylcarbonyl, benzothienylcarbonyl, benzothiazolylcarbonyl, imidazolylcarbonyl, pyridylcarbonyl, morpholinylcarbonyl (e.g., morpholinocarbonyl) and the like. More preferred examples of “acyl” include lower alkanoyl having 1 to 6 carbon atoms (e.g., formyl, acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, 2,2-dimethylpropanoyl, hexanoyl, etc.) and lower alkoxycarbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, tert-pentyloxycarbonyl, etc.).
Suitable examples of

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