Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-03-22
2003-04-29
Fan, Jane (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S261000
Reexamination Certificate
active
06555557
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a novel 2,3-disubstituted pyridine derivative exhibiting a phosphodiesterase IV (hereinafter, referred to as PDE IV) inhibitory activity being useful as a medicament, a process for the preparation thereof, a pharmaceutical composition containing the same, and an intermediate therefor.
BACKGROUND ART
Hitherto, theophylline or various chemical mediator antagonists have been used as an agent for treatment of asthma, but these agents have defects, for example, they cannot exhibit a sufficient inhibitory effect on bronchoconstriction or a sufficient effect on airway inflammatory and they cannot show a sufficient selectivity from their side effects on the cardiovascular system. Steroids also have been used as an agent for treatment of asthma, and their effects on the airway inflammation are potent but their inhibitory effects on bronchoconstriction is weak, and in addition, serious side effects of steroids have also been predicted. Therefore, it has been desired to develop a novel agent exhibiting an inhibitory effect on bronchoconstriction as well as an effect on the airway inflammation.
PDE IV widely distributes onto the bronchial smooth muscle and inflammatory cells including eosinophil, and it is an enzyme catalyzing the destruction of cyclic AMP (hereinafter, occasionally referred to as cAMP). It has widely been known that by inhibiting PDE IV, the constriction of the bronchial smooth muscle is prevented, and the activation of inflammatory cells is prevented (Current Medicinal Chemistry, vol. 2, p. 561-572 (1995)).
The compounds of the following formulae, for example, Rolipram (U.S. Pat. No. 4,193,926), RP-73401 (WO 92 12961), SB-207499 (WO 93 19749), are exemplified as a representative compound having a PDE IV inhibitory activity.
In addition, EP 773024 discloses that an N-substituted nicotinamide compound of the following formula (A) exhibits a PDE IV inhibitory activity.
wherein R
3
is 1-piperidyl, phenyl, benzyl, etc., Y is hydrogen, fluoro or chloro, and X is hydrogen, fluoro, chloro, methoxy, trifluoromethyl, cyano, carboxy, methylcarbamoyl, dimethylcarbamoyl or a carbo(C
1
-C
4
)alkoxy.
In addition, WO 9845268 discloses that a nictoninamide compound of the following formula (B) exhibits a PDE IV inhibitory activity.
wherein m is 0 or 1, n is 0 or 1, o is 0, 1, 2, 3, or 4, p is 0 or 1, q is 0, 1, 2, or 3, r is 0, 1, 2, 3, or 4, t is 0 or 1, A is an oxygen atom, >NH, etc., B is an oxygen atom or NH, D is an oxygen atom or NR
9
, E is CH
2
, an oxygen atom, NH or S(O)
a
, R
1
is a hydrogen atom, a (C
1
-C
6
)alkyl group, a (C
3
-C
7
)heterocyclic group, etc., R
2
, R
3
and R
4
are a hydrogen atom, a hydroxy group, etc., R
5
is a (C
3
-C
7
)heterocycle, R
6
, R
7
and R
8
are a hydrogen atom, a (C
1
-C
6
)alkyl group, etc.
However, conventional PDE IV inhibitors cannot show a sufficient bronchodilating activity, and under such circumstances, it has been desired to develop a novel PDE IV inhibitor exhibiting more potent bronchodilating activity as well as effects on the airway inflammation.
On the other hand, a compound of the above formula (A) or (B) wherein the 3-substituent of the pyridine ring is a pyridylalkyleneoxy group has never been known.
An object of the present invention is to provide a novel 2,3-disubstituted pyridine derivative and a pharmaceutically acceptable salt thereof, which show an excellent PDE IV inhibitory activity.
DISCLOSURE OF INVENTION
The present invention relates to a 2,3-disubstituted pyridine derivative of the following formula (I) or a pharmaceutically acceptable salt thereof, a phosphodiesterase IV inhibitor containing said compound as an active ingredient, and a pharmaceutical composition containing the same.
wherein
A is an oxygen atom, a sulfur atom, CHR
1
or NR
2
, R
1
and R
2
are a hydrogen atom or a lower alkyl group;
X
1
and X
2
are the same or different and each a hydrogen atom, a halogen atom, a nitro group, a cyano group, a hydroxy group, a lower alkyl group, a hydroxy-substituted lower alkyl group, a halogeno-lower alkyl group, a lower alkoxy group, a cyclo-lower alkoxy group, a hydroxy-substituted lower alkoxy group, a halogeno-lower alkoxy group, a lower alkoxy-substituted lower alkoxy group, a carboxy-substituted lower alkoxy group, a lower alkoxycarbonyl-substituted lower alkoxy group, a carboxyl group, a lower alkoxycarbonyl group, a mono- or di-lower alkylaminocarbonyl group, a lower acyl group, a lower acyloxy group, an amino group, a lower acylamino group, a carbamoyl group, a 5-tetrazolyl group, or a group which can be converted into a hydroxy group in vivo;
Y
1
is a hydrogen atom or a lower alkyl group;
Z
1
and Z
2
are the same or different and each a hydrogen atom, a halogen atom, a cyano group, a hydroxy group, a lower alkyl group, a hydroxy-substituted lower alkyl group, a halogeno-lower alkyl group, a lower alkoxy group, a cyclo-lower alkoxy group, a hydroxy-substituted lower alkoxy group, a halogeno-lower alkoxy group, a lower alkoxy-substituted lower alkoxy group, a carboxy-substituted lower alkoxy group, a lower alkoxycarbonyl-substituted lower alkoxy group, a carboxyl group, a lower alkoxycarbonyl group, a mono- or di-lower alkylaminocarbonyl group, a lower acyloxy group, an amino group, a mono- or di-lower alkylamino group, a lower acylamino group, a lower alkoxycarbonylamino group, a lower alkylsulfonylamino group, a carbamoyl group, a 5-tetrazolyl group, or a group which can be convereted into a hydroxy group in vivo; and
n is an integer of 2 to 4.
The pharmaceutically acceptable salt includes a pharmaceutically acceptable acid addition salt, an alkali metal salt, an alkaline earth metal salt or a salt with an organic base. For example, the acid addition salt includes a salt with an inorganic acid such as hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, etc., or a salt with an organic acid such as oxalate, maleate, fumarate, malonate, lactate, malate, citrate, tartrate, benzoate, methanesulfonate, p-toluenesulfonate, gluconate, etc. The alkali metal salt includes, for example, a salt with an inorganic alkali metal such as sodium salt, potassium salt, and the alkaline earth metal salt includes, for example, calcium salt, magnesium salt. The salt with an organic base includes, for example, a salt with ammonia, methylamine, triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, dicyclohexylamine.
The present compound of the formula (I) and a pharmaceutically acceptable salt thereof may exist in the form of a hydrate and/or a solvate, and the present invention also includes these hydrates and solvates as well.
The present compounds of the formula (I) may optionally have one or more asymmetric carbon atoms, and the present invention also includes these stereoisomers and a mixture thereof.
When Z
1
or Z
2
is a hydroxy group and these groups attach to the 2-position or the 4-position of the pyridine ring, the present compounds of the formula (I) may have a keto-enol tautomer, and the present invention also includes these tautomers, and a mixture thereof.
In the compound (I), the group being able to be converted into a hydroxy group in vivo means a group which can be enzymatically or non-enzymatically destructed to a hydroxy group in vivo, for example, one wherein a hydroxy group is acylated, carbonated or carbamated by an acetyl group, a propionyl group, a benzoyl group, an ethoxycarbonyl group, a carbamoyl group, an amino acid residue, etc. Hereinafter, compounds having such groups may occasionally be referred as a prodrug.
The present invention also relates to an intermediate for preparing a 2,3-disubstituted pyridine derivative of the above formula (I), i.e., a pyridine derivative of the following formula (II):
wherein Z
3
is a hydrogen atom, a lower alkyl group, a cyclo-lower alkyl group, a lower alkoxy-substituted lower alkyl group, a lower acyl group, a benzyl group, a benzoyl group, or a mono- or di-lower alkoxy-substituted benzoyl group, Z
4
is a hydrogen atom, a halogen atom, a cyano group, a lower alkox
Itoh Mari
Kawasaki Motoji
Nakamura Shunya
Nigo Tomohiro
Nobata Tadashi
Dainippon Pharmaceutical Company Limited
Fan Jane
Wenderoth , Lind & Ponack, L.L.P.
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