Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-05-01
2002-10-22
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S217000, C514S220000, C514S294000, C514S299000, C514S304000, C514S333000, C514S343000, C514S411000, C514S422000, C514S426000, C540S581000, C540S589000, C540S556000, C546S094000, C546S112000, C546S125000, C546S256000, C546S279100, C548S441000, C548S525000, C548S527000, C548S528000, C548S557000
Reexamination Certificate
active
06468998
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a novel pyrrolidine compound having a potent 5-HT
2
receptor antagonistic action and useful as a therapeutic agent for the diseases such as thrombotic embolism, chronic arterial obstruction, intermittent claudication, coronary artery disease, cerebrovascular disorder, peripheral circulatory disturbance, migraine, diabetic peripheral neuropathy, postherpetic neuralgia, glaucoma, dry eye, xerophthalmia, keratitis sicca and the like.
BACKGROUND ART
Serotonin (5-hydroxytryptamine; hereinafter to be referred to as 5-HT) dramatically enhances platelet aggregation due to collagen, epinephrine and adenosine diphosphate (hereinafter to be referred to as ADP). A serotonin 2 (hereinafter to be referred to as 5-HT
2
) receptor is involved in the promotion of platelet aggregation, erythrocyte deformation, vasoconstriction and blood vessel permeability. Since collateral circulation associated with high 5-HT sensitivity is developed in chronic arterial obstruction, blocking of 5-HT
2
receptor should improve the peripheral circulation because it induces vasodilation at the site of lesion rather than systemic one. In view of the above, a 5-HT
2
receptor antagonist has been searched and, for example, (3-aminopropoxy)bibenzyl derivative having a platelet aggregation inhibitory activity and usable for the treatment and prevention of thrombosis is disclosed in JP-B-63-13427. In addition, reports have documented that sarpogrelate hydrochloride, which is a selective antagonist to a 5-HT
2
receptor, is effective on migraine (J. New Remedies & Clinics, Vol. 45(9), pp. 1833-1836, 1996), on diabetic peripheral neuropathy (Jpn. Pharmacol. Ther., Vol. 24(8), pp. 1853-1857, 1996), and on postherpetic neuralgia (Jpn. Pharmacol. Ther., Vol. 23(7), pp. 1803-1806, 1995). However, the platelet aggregation suppressive action and vasoconstriction suppressive action are not entirely satisfactory and a compound having more superior activity has been demanded.
Moreover, JP-A-8-20531 discloses that 5-HT
2
receptor antagonists, inclusive of sarpogrelate hydrochloride, are effective for the treatment of glaucoma and diminished ocular tension, and JP-A-10-67684 discloses that 5-HT
2
receptor antagonists, inclusive of sarpogrelate hydrochloride, have a lacrimation promoting action and are effective for the treatment of diseases such as dry eye, xerophthalmia, keratitis sicca and the like.
JP-B-49-31985 discloses a compound having a similar structure to the novel pyrrolidine compound of the present invention. It also discloses a 1-substituted-3-amidopyrrolidine derivative having an analgesic and antidepressant action. Journal of Medicinal Chemistry (J. Med. Chem.), Vol. 10(6), pp. 1015-1021, 1967 discloses an N-substituted-3-amidopyrrolidine derivative as a synthetic intermediate for an aminoalkylindole derivative as a centrally acting drug. Japanese Patent Application under PCT laid-open under Kohyo No. 7-506110 discloses a preparation method of (S)-3-amino-1-substituted-pyrrolidine. JP-A-3-95157 discloses a butenoic acid derivative as a therapeutic agent of coronary artery disease. JP-A-1-316349 discloses a preparation method of (S)-3-aminopyrrolidine and a production method of naphthyridine and quinolonecarboxylic acid having (S)-3-aminopyrrolidine as a side chain. Journal of Medicinal Chemistry (J. Med. Chem.), Vol. 11(5), pp. 1034-1037, 1968, U.S. Pat. Nos. 3,424,760, 3,424,761 and 3,424,762 disclose 3-ureidopyrrolidine derivatives having an analgesic and central action. However, these do not take note of the 5-HT
2
receptor antagonistic action or a platelet aggregation inhibitory activity.
DISCLOSURE OF THE INVENTION
The present invention aims at providing a novel compound having a 5-HT
2
receptor antagonistic action, a platelet aggregation suppressive action and a peripheral circulation improving action and/or a novel compound having a lacrimation promoting action.
The present inventors have conducted intensive studies and found that a novel pyrrolidine compound of the following formula (I), an optically active compound thereof and a pharmaceutically acceptable salt thereof have a strong 5-HT
2
receptor antagonistic action along with a platelet aggregation suppressive action, a peripheral circulation improving action and a lacrimation promoting action. As such, the compound of the present invention can be useful for the treatment of diseases such as thrombotic embolism, chronic arterial obstruction, intermittent claudication, coronary artery disease, cerebrovascular disorder, peripheral circulatory disturbance, migraine, diabetic peripheral neuropathy, postherpetic neuralgia, glaucoma, dry eye, xerophthalmia, keratitis sicca and the like.
Accordingly, the present invention provides the following.
[1] A pyrrolidine compound of the formula (I)
wherein
R
1
is a group selected from the groups of the following formulas (1), (2), (3), (4), (5), (6), (7) and (8)
wherein
R
3
and R
4
are the same or different and each is hydrogen, halogen, alkyl, alkoxy, haloalkyl, hydroxy, amino, dialkylamino, nitro, cyano, amido, or R
3
and R
4
in combination form carbonyl,
R
5
, R
6
, R
7
and R
8
are the same or different and each is hydrogen or alkyl, or R
5
—R
6
and R
7
—R
8
are the same or different and each is bonded to form, together with the bond between the carbon atoms they are bonded to, a double bond, optionally substituted cycloalkyl having 3 to 8 carbon atoms, optionally substituted cycloalkenyl having 3 to 8 carbon atoms, optionally substituted cycloalkadienyl having 5 to 8 carbon atoms, optionally substituted aromatic ring or optionally substituted aromatic heterocycle having, as a heteroatom, at least one atom selected from oxygen atom, nitrogen atom and sulfur atom,
ring A and ring B are the same or different and each is optionally substituted cycloalkyl having 3 to 8 carbon atoms, optionally substituted cycloalkenyl having 3 to 8 carbon atoms, optionally substituted cycloalkadienyl having 5 to 8 carbon atoms, optionally substituted aromatic ring or an optionally substituted aromatic heterocycle having at least one atom selected from oxygen atom, nitrogen atom and sulfur atom as a heteroatom,
ring H is optionally substituted cycloalkyl having 3 to 8 carbon atoms,
E is optionally substituted cycloalkyl having 3 to 8 carbon atoms,
Z is carbon atom, nitrogen atom or N-oxide,
Y may not be present to make the ring A and ring B independent, or a single bond, oxygen atom, sulfur atom, SO, SO
2
, CH
2
, CH
2
CH
2
or CH═CH,
p, q, r, s, t and u are the same or different and each is an integer of 1 or 2,
u′ is an integer of 0-2,
r′ and s′ are the same or different and each is an integer of 0-3, and
v, w and x are the same or different and each is an integer of 1-3,
R
9
is hydrogen, alkyl having 1 to 6 carbon atoms, alkoxy having 1 to 6 carbon atoms or hydroxyalkyl having 1 to 6 carbon atoms,
x is C═O, C═S, NH—C═O, SO or SO
2
,
R
2
is hydrogen, alkyl, acyl, optionally substituted arylalkyl, optionally substituted aromatic ring, or an optionally substituted aromatic heterocycle having at least one atom selected from oxygen atom, nitrogen atom and sulfur atom as a heteroatom,
D is optionally substituted linear or branched alkylene having 1 to 8 carbon atoms, and when D is branched alkylene, the carbon atom in the branched chain is optionally bonded further to Ar to form 4- to 8-membered ring, and
Ar is optionally substituted aromatic ring, optionally substituted aromatic heterocycle or fused aromatic heterocycle having at least one atom selected from oxygen atom, nitrogen atom and sulfur atom as a heteroatom,
provided that
when X is NH—C═O, SO or SO
2
, R
2
should be hydrogen, alkyl, optionally substituted arylalkyl, optionally substituted aromatic ring or optionally substituted aromatic heterocycle having at least one atom selected from oxygen atom, nitrogen atom and sulfur atom as a heteroatom,
when R
1
is a group of the formula (5) to formula (7), X should be C═O or C═S and R
2
should be hydrogen
Fujio Masakazu
Kuroita Takanobu
Nakagawa Haruto
McKenzie Thomas C
Mitsubishi Pharma Corporation
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