Quinazoline derivatives and drugs

Details Quinazoline derivatives and drugs Quinazoline derivatives and drugs

2002-09-25

2004-09-21

Rao, Deepak (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S266210, C514S266230, C514S266400, C514S267000, C544S249000, C544S284000, C544S291000, C544S293000

Reexamination Certificate

active

06794389

ABSTRACT:

TECHNICAL FIELD
The present invention relates to a pharmaceutically useful novel heterocyclic derivative or a salt thereof, and a pharmaceutical composition containing the same as an active ingredient.
BACKGROUND ART
As an analgesic, a narcotic analgesic (such as morphine), a non-narcotic analgesic (such as aspirin or indomethacin) or a narco-antagonistic analgesic (such as pentazocine) is employed. A narcotic analgesic exerts its analgesic effect mainly by inhibiting a central algesic excitatory transmission. A non-narcotic analgesic exerts its analgesic effect mainly by inhibiting the production of a peripheral dolorogenic substance. A narco-antagonistic analgesic exerts its analgesic effect in a mechanism similar to that of a narcotic analgesic.
However, there is no analgesic which is effective against a chronic pain which is not suppressed by morphine, an allodynia accompanied with herpes zoster or hyperalgesia, and an excellent analgesic has been desired to be created.
Nociceptin is a neuropeptide related to various nervous activities including an in vivo algesia. Japanese Unexamined Patent Publication No. 10-212290 describes that a nociceptin agonist and/or antagonist may be effective in treating a mental disorder, neuropathy and physiological disorder, and particularly effective in ameliorating anxiety and stress disorder, depression, traumatic disorder, amnesia due to Alzheimer's disease or other dementia, symptoms of epilepsy and spasm, acute and/or chronic pain, drug abuse withdrawal symptoms, water balance control, Na
+
excretion, arterial blood pressure disorder, and eating disorder such as an obesity.
As a non-peptide compound acting on a nociceptin receptor, lofentanil, naloxone benzoylhydrazone and 2-oxoimidazole derivative (International Publication WO9854168) are known. However, these compounds are still at the stage of a basic research, and none of them has been commercially available.
As a compound analogous to a quinazoline derivative in the heterocyclic derivatives of the compound according to the present invention, various compounds were known (International Publication WO9307124, Japanese Examined Patent Publication No. 2923742, International Publication WO9720821, International Publication WO9850370, International Publication WO9909986, Japanese Unexamined Patent Publication No. 47-2927, International Publication WO9817267 and the like). Among these, International Publication WO9720821 describes that a 2-acylaminoquinazoline derivative has an inhibitory effect on a neuropeptide Y (NPY) receptor subtype-Y5 and is effective in ameliorating an algesia or amnesia.
DISCLOSURE OF THE INVENTION
An object of the present invention is to provide a novel compound having an excellent analgesic effect. More particularly, the present invention is intended to provide a novel analgesic having an analgesic effect which is effective widely against a chronic pain or an allodynia accompanied with herpes zoster by acting on a nociceptin receptor.
In order to achieve the above described objects, the present inventors found that compound represented by the following general formula (1) is an agonist and/or antagonist of a nociceptin receptor and has an excellent analgesic effect in processes to synthesize and study various compounds, thereby establishing the present invention.
Accordingly, the present invention relates to a compound represented by the following general formula (1):
or a salt thereof.
In the formula, X and Y are same or different and each represents a nitrogen atom or CH;
R
1
represents a hydrogen atom or alkyl;
A
1
and A
2
are same or different and each represents (1) a single bond or (2) a divalent aliphatic hydrocarbon group which may be substituted and which may include 1 to 3 unsaturated bonds at any positions (such aliphatic hydrocarbon group may contain one heteroatom selected from a group consisting of —NH—, O and S);
Q represents (1) a single bond, (2) an optionally substituted 3- to 8-membered cycloalkylene group, (3) an optionally substituted phenylene group or (4) an optionally substituted 4- to 8-membered divalent heterocyclic group;
R
2A
, R
2C
and R
2D
are same or different and each represents a hydrogen atom, alkyl or phenyl, R
2B
represents a hydrogen atom, alkyl, cyano, nitro or phenyl, or a two nitrogen atoms of a guanidino group are cyclized together with one or two of its substituents R
2B
, R
2C
and R
2D
to form a saturated or unsaturated 5- or 6-membered ring;
or is taken together as —N(R
1
)—A
1
—Q-A
2
—N(R
2A
)— to form a 5- to 7-membered ring;
E represents (1) ethenylene, (2) —NRCO—, (3) —NRCONH—, (4) —CONR—, (5) ethynylene, (6) —NRSO
2
— or (7) aminoalkylene (in which R represents hydrogen or optionally substituted alkyl);
R
3
represents an optionally substituted phenyl group or heterocyclic group;
R
4
and R
5
(1) are same or different and each represents a hydrogen atom, alkyl, alkoxy, aralkyloxy, halogen, nitro, hydroxy, alkoxycarbonyl, —NR
6
R
7
, —NR
6
COR
7
, —NR
6
SO
2
R
7
, —CONR
6
R
7
(in which R
6
and R
7
are same or different and each represents a hydrogen atom or alkyl) or (2) when adjacent to each other are taken together to form —O(CH
2
)
n
O— (wherein n is an integer of 1 or 2) or —CH═CH—CH═CH—.
Preferably, in the formula (1), each of X and Y represents a nitrogen atom or CH;
R
1
represents a hydrogen atom or alkyl;
A
1
and A
2
are same or different and each represents (1) a single bond or (2) alkylene which may be substituted by alkyl, carbamoyl, monoalkylcarbamoyl, dialkylcarbamoyl, hydroxy, alkoxy or trifluoromethyl and which may have 1 to 3 unsaturated bonds at any positions;
Q represents (1) a single bond, (2) a 3- to 8-membered cycloalkylene group which may be substituted by alkyl, alkoxycarbonyl, carbamoyl, monoalkylcarbamoyl, dialkylcarbamoyl or alkoxy, (3) a phenylene group which may be substituted by alkyl, alkoxy, alkoxycarbonyl, carbamoyl, monoalkylcarbamoyl, dialkylcarbamoyl, sulfamoyl, monoalkylsulfamoyl, dialkylsulfamoyl, amino, monoalkylamino, dialkylamino, nitro, halogen, cyano or trifluoromethyl, or (4) a 4- to 8-membered divalent heterocyclic group which may be substituted by alkyl, alkoxy, alkoxycarbonyl, carbamoyl, monoalkylcarbamoyl, dialkylcarbamoyl, amino, monoaklylamino or dialkylamino;
R
2A
, R
2C
and R
2D
are same or different and each represents a hydrogen atom, alkyl or phenyl, R
2B
represents a hydrogen atom, alkyl, cyano group, nitro group or phenyl, or a two nitrogen atoms of a guanidino group are cyclized together with one or two of its substituents R
2B
, R
2C
and R
2D
to form a saturated or unsaturated 5- or 6-membered ring;
or is taken together as —N(R
1
)—A
1
—Q—A
2
—N(R
2A
)— to form a 5- to 7-membered ring;
E represents (1) ethenylene, (2) —NRCO—, (3) —NRCONH—, (4) —CONR—, (5) ethynylene, (6) —NRSO
2
— or (7) aminoalkylene (in which R represents hydrogen or optionally substituted alkyl);
R
3
represents a phenyl group or heterocyclic group which may be substituted by alkyl, alkoxy, alkoxycarbonyl, carbamoyl, monoalkylcarbamoyl, dialkylcarbamoyl, sulfamoyl, monoalkylsulfamoyl, dialkylsulfamoyl, alkylsulfonylamino, N-(alkyl)alkylsulfonylamino, amino, monoalkylamino, dialkylamino, nitro, halogen, cyano, hydroxy or trifluoromethyl; and
R
4
and R
5
(1) are same or different and each represents a hydrogen atom, alkyl, alkoxy, aralkyloxy, halogen, nitro, hydroxy, alkoxycarbonyl, —NR
6
R
7
, —NR
6
COR
7
, —NR
6
SO
2
R
7
, —CONR
6
R
7
(in which R
6
and R
7
are same or different and each represents a hydrogen atom or alkyl) or (2) when adjacent to each other are taken together to form —O(CH
2
)
n
O— (wherein n represents an integer of 1 or 2) or —CH═CH—CH═CH—.
A more preferable compound is represented by the general formula (1), wherein each of X and Y is a nitrogen atom, R
1
is a hydrogen atom or alkyl, A
1
and A
2
are same or different and each is (1) a single bond or (2) optionally substituted alkylene, Q is (1) a single bond, (2) an optionally substituted 4- to 8-membered cycloalkylene group (3) an optionally substituted phen

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