Heterobicyclic derivatives

Details Heterobicyclic derivatives Heterobicyclic derivatives

2002-01-18

2004-04-27

Raymond, Richard L. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S249000

Reexamination Certificate

active

06727245

ABSTRACT:

TECHNICAL FIELD
This invention relates to new heterobicyclic derivatives and pharmaceutically acceptable salts thereof which are useful as a medicament.
BACKGROUND ART
Some heterobicyclic derivatives have been known as described, for example, in EP 0 008 864 A2.
DISCLOSURE OF INVENTION
This invention relates to new heterobicyclic derivatives.
One object of this invention is to provide the new and useful pyridopyrazine derivatives and pharmaceutically acceptable salts thereof which possess a strong phosphodiesterase IV (PDE IV)-inhibitory activity and a strong inhibitory activity on the production of tumor necrosis factor (TNF).
Another object of this invention is to provide processes for preparation of the pyridopyrazine derivatives and salts thereof.
A further object of this invention is to provide a pharmaceutical composition comprising said pyridopyrazine derivatives or a pharmaceutically acceptable salt thereof.
Still further object of this invention is to provide a use of said pyridopyrazine derivatives or a pharmaceutically acceptable salt thereof as a medicament for prophylactic and therapeutic treatment of PDE-IV and TNF mediated diseases such as chronic inflammatory diseases, specific autoimmune diseases, sepsis-induced organ injury, and the like in human being and animals.
The object pyridopyrazine derivatives of the present invention are novel and can be represented by the following general formula (I):
wherein
R
1
is aryl which may have suitable substituent(s), ar(lower)alkyl which may have suitable substituent(s), halo(lower)alkyl, protected carboxy(lower)alkyl, acyl(lower)alkyl, heterocyclic group or heterocyclic(lower)alkyl which may have suitable substituent(s),
R
2
is aryl which may have suitable substituent(s) or heterocyclic group, and
R
3
is hydrogen, lower alkoxy or arylthio.
The object compound (I) of the present invention can be prepared by the following processes.
wherein
R
1
, R
2
and R
3
are each as defined above,
R
a
1
is halo(lower)alkyl,
R
a
2
is aryl having amino or aryl having aminoaryl,
R
b
2
is aryl having acylamino or aryl having acylaminoaryl,
R
4
is lower alkyl,
R
5
is N-protective group,
Y is halogen,
Y
⊖
is halide, and
A is lower alkylene.
The starting compound (II) of the present invention can be prepared by the following processes.
wherein
R
2
, R
3
and R
4
are each as defined above,
R
6
is heterocyclic group which may have 1 to 3 halogen,
R
7
is aryl,
R
8
is aryl having acylamino,
R
9
is lower alkyl, and
X
1
, X
2
, X
3
, X
4
and X
5
are each a leaving group.
Suitable pharmaceutically acceptable salts of the object compound (I) are conventional non-toxic salts and may include a salt with a base or an acid addition salt such as a salt with an inorganic base, for example, an alkali 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, fumarate, methanesulfonate, benzenesulfonate, toluenesulfonate, etc.); a salt with a basic or acidic amino acid (e.g., arginine, aspartic acid, glutamic acid, 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.
The term “higher” is used to intend a group having 7 to 20 carbon atoms, unless otherwise provided.
Suitable “lower alkyl” and “lower alkyl moiety” in the terms “ar(lower)alkyl”, halo(lower)alkyl, “protected carboxy(lower)alkyl”, “acyl(lower)alkyl”, “heterocyclic(lower)alkyl” and “heterocyclicoxycarbonyl(lower)alkyl” may 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, tert-pentyl, hexyl, and the like, and in which more preferable example may be C
1
-C
4
alkyl.
Suitable “lower alkenyl” may include vinyl, 1-(or 2-)propenyl, 1-(or 2- or 3-)butenyl, 1-(or 2- or 3- or 4-)pentenyl, 1-(or 2- or 3- or 4- or 5-)hexenyl, methylvinyl, ethylvinyl, 1-(or 2- or 3-)methyl-1-(or 2-)propenyl, 1-(or 2- or 3-)ethyl-1-(or 2-)propenyl, 1-(or 2- or 3- or 4-)methyl-1-(or 2- or 3-)butenyl, and the like, in which more preferable example may be C
2
-C
4
alkenyl.
Suitable “lower alkynyl” may include ethynyl, 1-propynyl, propargyl, 1-methylpropargyl, 1 or 2 or 3-butynyl, 1 or 2 or 3 or 4-pentynyl, 1 or 2 or 3 or 4 or 5-hexynyl, and the like.
Suitable “lower alkoxy” may include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, t-butoxy, pentyloxy, t-pentyloxy, hexyloxy and the like.
Suitable “lower alkylene” may include straight or branched one such as methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, methylmethylene, ethylethylene, propylene, and the like, in which more preferable example may be C
1
-C
4
alkylene and the most preferable one may be methylene.
Suitable “cyclo(lower)alkyl” may include cyclopentyl, cyclohexyl and the like.
Suitable “cyclo(lower)alkenyl” may include cyclohexenyl, cyclohexadienyl and the like.
Suitable “aryl” and “aryl moiety” in the terms “ar(lower)alkyl”, “arylthio”, “aminoaryl” and “acylaminoaryl” may include phenyl, naphthyl and the like.
Suitable “halogen” and “halogen moiety” in the term “halo(lower)alkyl” may include fluorine, bromine, chlorine and iodine.
Suitable “leaving group” may include acid residue, lower alkoxy as exemplified above, and the like.
Suitable “acid residue” may include halogen as exemplified above, acyloxy and the like.
Suitable “halide” may include fluoride, bromide, chloride and the like.
Suitable “protected carboxy” and “protected carboxy moiety” in the term “protected carboxy(lower)alkyl” may include esterified carboxy and the like. And suitable example of said ester may be the ones such as lower alkyl ester (e.g., methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, t-butyl ester, pentyl ester, t-pentyl ester, hexyl ester, etc.); lower alkenyl ester (e.g., vinyl ester, allyl ester, etc.); lower alkynyl ester (e.g. ethynyl ester, propynyl ester, etc.); lower alkoxy(lower)alkyl ester (e.g., methoxymethyl ester, ethoxymethyl ester, isopropoxymethyl ester, 1-methoxyethyl ester, 1-ethoxyethyl ester, etc.); lower alkylthio(lower)alkyl ester (e.g., methylthiomethyl ester, ethylthiomethyl ester, ethylthioethyl ester, isopropoxythiomethyl ester, etc.); mono(or di or tri)halo(lower)alkyl ester (e.g., 2-iodoethyl ester, 2,2,2-trichloroethyl ester, etc.); lower alkanoyloxy(lower)alkyl ester (e.g., acetoxymethyl ester, propionyloxymethyl ester, butyryloxymethyl ester, valeryloxymethyl ester, pivaloyloxymethyl ester, hexanoyloxymethyl ester, 1-acetoxyethyl ester, 2-acetoxyethyl ester, 2-propionyloxyethyl ester, etc.); lower alkoxycarbonyloxy(lower)alkyl ester (e.g., methoxycarbonyloxymethyl ester, ethoxycarbonyloxymethyl ester, propoxycarbonyloxymethyl ester, 1-(or 2-)[methoxycarbonyloxy]ethyl ester, 1-(or 2-)[ethoxycarbonyloxy]ethyl ester, 1-(or 2-)[propoxycarbonyloxy]ethyl ester, 1-(or 2-)[isopropoxycarbonyloxy]ethyl ester, etc.); lower alkanesulfonyl(lower)alkyl ester (e.g., mesylmethyl ester, 2-mesylethyl ester, etc.); lower alkoxycarbonyloxy(lower)alkyl ester (e.g., methoxycarbonyloxymethyl ester, ethoxycarbonyloxymethyl ester, propoxycarbonyloxymethyl ester, t-butoxycarbonyloxymethyl ester, 1-(or 2-)methoxycarbonyloxyethyl ester, 1-(or 2-)ethoxycarbonyloxyethyl ester, 1-(or 2-)isopropoxycarbonylo

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