Tricyclic compounds, their production and use

Details Tricyclic compounds, their production and use Tricyclic compounds, their production and use

1999-03-09

2001-06-19

Stockton, Laura L. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C548S150000, C548S151000

Reexamination Certificate

active

06248766

ABSTRACT:

This application is the National Phase of International Patent Application PCT/JP97/03384, filed Sep 24, 1997.
TECHNICAL FIELD
The present invention relate to tricyclic compounds having very satisfactory prostaglandin I
2
receptor agonistic activity, their production, intermediates and use.
BACKGROUND ART
It is known that prostaglandin I
2
(PGI
2
) is a substance which is biosynthesized from arachidonic acid through prostaglandin H
2
(PGH
2
) and has potent platelet aggregation inhibitory activity, vasodilative activity, lipid deposition inhibitory activity, and leukocyte activation inhibitory activity. As such, PGI
2
is considered to be effective in the treatment of peripheral vascular diseases (e.g. peripheral embolism, vibration syndrome, Raynaud's disease, etc.), systemic lupus erythematosus, post-PTCA (percutaneous transluminal coronary angioplasty) arterial reobliteration/restenosis, atherosclerosis, thrombosis, diabetic neuropathy, hypertension, ischemic diseases (e.g. cerebral infarction, myocardial infarction, etc.), transient ischemic attack, and glomerulonephritis.
Meanwhile, WO 96/20925, for instance, reports a non-prostanoid PGI
2
receptor agonist compound of the formula:
wherein R
1
represents —X—(CH
2
)
n
COOR
3
wherein X represents —O—, —S— or —CH
2
—; R
3
typically represents hydrogen or C
1-5
lower alkyl; n represents 1-3; R
2
typically represents —CR
4
═CR
5
—O— or —CR
5
═CR
4
—O— wherein R
4
represents —(CH
2
)
m
—Y—R
8
wherein m represents 1-4; Y typically represents —O— or —CH
2
—; R
8
typically represents phenyl; R
5
typically represents hydrogen or C
1-5
lower alkyl.
JP-A-62-252780 discloses an antiulcer tricyclic compound of the formula:
wherein X and Y independently represent hydrogen, halogen, lower alkyl or lower alkoxy; n represents 0-4; R
1
represents hydrogen, lower alkyl, unsubstituted or substituted phenyl; R
2
typically represents lower alkyl, unsubstituted or substituted phenyl, heterocyclic group or cyclic amino; R
3
represents hydrogen, lower alkyl, or acyl; R
2
and R
3
optionally taken together represent cyclic amino.
PGI
2
is by no means chemically and biologically stable enough for use as a medicine. Moreover, it is not clear-cut in the desired action or actions versus other actions, thus unavoidably inducing adverse drug reactions.
Meanwhile, no information is available on the relation of those known tricyclic compounds to the affinity for PGI
2
receptors. Under the circumstances, there is a keen demand for creation of a compound structurally removed from PGI
2
and yet having a high affinity for PGI
2
receptors and acting as a PGI
2
receptor agonist with improved chemical stability and stability against metabolism and greater clinical efficacy than PGI
2
, thus being very satisfactory for use as a medicine.
The inventors of the present invention explored for compounds having PGI
2
receptor agonistic activity and succeeded in the creation of a compound of the formula:
wherein R
1
represents hydrogen or a substituent group;
m represents an integer of 1 to 3;
Ar represents an aromatic group which may be substituted;
X represents a bond or a divalent straight-chain group which have 1 to 6 atoms and may be substituted;
Y represents —S—, —O— or —N(R
2
)— wherein R represents hydrogen or a substituent group;
Z represents —N═ or —C(R
3
)═ wherein R
3
represents hydrogen or a hydrocarbon group;
ring A represents a benzene ring which may be substituted by a substituent in addition to a group of the formula: —O(CH
2
)
m
COR
1
wherein the respective symbols have the same meanings as defined above; and
ring B represents a 5- to 7-membered ring which may be substituted, or a salt thereof,
which compound is structurally characterized in that the benzene ring (ring A) of the tricyclic skeletal system of the formula:
 wherein the respective symbols have the meanings defined above, has a substituent group of the formula —O(CH
2
)
m
COR
1
wherein the respective symbols have the meanings defined above.
The inventors further discovered that because of the above unique chemical structure, the above compound or a salt thereof [hereinafter sometimes referred to briefly as compound (I)], is an excellent PGI
2
receptor agonist having a high affinity for PGI
2
receptors, high chemical stability, and high stability against metabolism and, thus, being fully satisfactory as a medicine. The present invention is predicated on the above findings.
DISCLOSURE OF INVENTION
The present invention to:
(1) compound (I);
(2) a compound of the above (1) wherein R
1
is (i) hydrogen, (ii) a hydroxy which may be substituted by a C
1-6
alkyl, C
1-6
alkenyl, C
2-6
alkynyl, C
3-6
cycloalkyl, C
6-14
aryl or C
7-16
aralkyl group, each of which may be substituted by 1 to 5 substituents selected from the group consisting of halogen, C
1-6
alkyl which may be halogenated, C
2-6
alkenyl which may be halogenated, C
2-6
alkynyl which may be halogenated, C
3-6
cycloalkyl which may be halogenated, C
6-10
aryl, C
7-11
aralkyl, C
1-6
alkoxy which may be halogenated, C
6-10
aryloxy, C
1-6
alkyl-carbonyl, C
6-10
aryl-carbonyl, C
7-11
aralkyl-carbonyl, C
1-6
alkyl-carbonyloxy, C
6-10
aryl-carbonyloxy, carboxy, C
1-6
alkoxy-carbonyl, carbamoyl, mono-C
1-6
alkyl-carbamoyl, di-C
1-6
alkyl-carbamoyl, amidino, imino, amino, mono-C
1-6
alkylamino, di-C
1-6
alkylamino, 3- to 6-membered cyclic amino, C
1-3
alkylenedioxy, hydroxy, nitro, cyano, mercapto, sulfo, sulfino, phosphono, sulfamoyl, mono-C
1-6
alkylsulfamoyl, di-C
1-6
alkylsulfamoyl, C
1-6
alkylthio which may be halogenated, C
6-10
arylthio, C
1-6
alkylsulfinyl, C
6-10
arylsulfinyl, C
1-6
alkylsulfonyl and C
6-10
arylsulfonyl, or (iii) an amino which may be substituted by 1 or 2 substituents selected from the group consisting of C
1-6
alkyl, C
1-6
alkenyl, C
1-6
alkynyl, C
3-6
cycloalkyl, C
6-14
aryl and C
7-16
aralkyl group, each of which may be substituted by 1 to 5 substituents selected from the group consisting of halogen, C
1-6
alkyl which may be halogenated, C
2-6
alkenyl which may be halogenated, C
2-6
alkynyl which may be halogenated, C
3-6
cycloalkyl which may be halogenated, C
6-10
aryl, C
7-11
aralkyl, C
1-6
alkoxy which may be halogenated, C
6-10
aryloxy, C
1-6
alkyl-carbonyl, C
6-10
aryl-carbonyl, C
7-11
aralkyl-carbonyl, C
1-6
alkyl-carbonyloxy, C
6-10
aryl-carbonyloxy, carboxy, C
1-6
alkoxy-carbonyl, carbamoyl, mono-C
1-6
alkyl-carbamoyl, di-C
1-6
alkyl-carbamoyl, amidino, imino, amino, mono-C
1-6
alkylamino, di-C
1-6
alkylamino, 3- to 6-membered cyclic amino, C
1-3
alkylenedioxy, hydroxy, nitro, cyano, mercapto, sulfo, sulfino, phosphono, sulfamoyl, mono-C
1-6
alkylsulfamoyl, di-C
1-6
alkylsulfamoyl, C
1-6
alkylthio which may be halogenated, C
6-10
arylthio, C
1-6
alkylsulfinyl, C
6-10
arylsulfinyl, C
1-6
alkylsulfonyl and C
6-10
arylsulfonyl;
m is an integer of 1 to 3;
Ar is a (i) C
6-14
aryl or (ii) 5- to 10-membered aromatic heterocyclic group containing 1 to 4 hetero atoms selected from among nitrogen, sulfur and oxygen as a ring member other than carbon, each of which may be substituted by 1 to 5 substituents selected from the group consisting of halogen, C
1-3
alkylenedioxy, nitro, cyano, C
1-6
alkyl which may be halogenated, C
3-6
cycloalkyl, C
1-6
alkoxy which may be halogenated, C
3-6
alkylthio which may be halogenated, hydroxy, amino, mono-C
1-6
alkylamino, di-C
1-6
alkylamino, C
1-6
alkyl-carbonyl, carboxy, C
1-6
alkoxy-carbonyl, carbamoyl, mono-C
1-6
alkyl-carbamoyl, di-C
1-6
alkyl-carbamoyl, C
6-10
aryl-carbamoyl, sulfo, C
1-6
alkylsulfonyl, C
6-10
aryl and C
6-10
aryloxy;
X is (i) a bond or (ii) a divalent group of the formula: —Xa—Xb— wherein Xa is a bond, S, SO, SO
2
, O or NR
4
, wherein R
4
is hydrogen, C
1-6
alkyl, C
3-6
cycloalkyl, C
6-14
aryl, C
7-11
aralkyl, formyl, C
1-6
alkyl-carbonyl or C
6-10
aryl-carbonyl; and
Xb is (a) a bond or (b) C
1-5
alkylene, C
2-5
alkenylene, C
2-5
alkynylene or a group of the formula: —(CH
2
)
p
—Xc—(CH
2
)
q
— whe

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