US 6,069,156 AGranted

Indole derivatives as cGMP-PDE inhibitors

AssigneeFujisawa Pharmaceutical Co., Ltd.

InventorsTeruo Oku, Kozo Sawada, Akio Kuroda, Kazuhiko Ohne, Atsushi Nomoto, Naomi Hosogai, Yoshimitsu Nakajima, Akira Nagashima, Keizo Sogabe, Kouichi Tamura, Masakazu Kobayashi

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Abstract

Compounds of the formula (I): ##STR1## and their pharmaceutically acceptable compositions are useful in inhibiting the activity of cyclic guanosine 3',5'-monophosphate phosphodiesterase.

Claims9

Dependent claims

A compound of the formula:

##STR14## wherein R.sup.1 is hydrogen, halogen, nitro, acyl, cyano, hydroxyimino(lower)alkyl, lower alkenyl optionally substituted with oxo, or lower alkyl optionally substituted with hydroxy;
R.sup.2 is hydrogen, halogen, lower alkenyl, acyl, or lower alkyl optionally substituted with protected carboxy, carboxy, lower alkoxy or hydroxy;
R.sup.3 is lower alkenyl, or lower alkyl substituted by
(1) aryl optionally substituted with one or more substituents selected from the group consisting of halogen, aryl, lower alkoxy, lower alkylenedioxy, cyano, nitro, carboxy, protected carboxy, acyl, and amino optionally substituted with acyl or protected carboxy, or
(2) a heterocyclic group selected from the group consisting of pyridyl, thienyl, benzothiazolyl, and benzothiophenyl, each of which is optionally substituted with halogen;
and
R.sup.4 is acyl, cyano, halogen, a heterocyclic group, amino optionally substituted with acyl or protected carboxy, or lower alkyl optionally substituted with protected carboxy, carboxy or acyl or as defined above;
or
R.sup.1 and R.sup.2 together with the carbon atoms to which they are attached, represent a 4- to 7-membered carbocyclic ring optionally substituted with oxo;
or a pharmaceutically acceptable salt thereof.

7 more elements

A process for preparing a compound of the formula:

##STR16## wherein R.sup.1 is hydrogen, halogen, nitro, acyl, cyano, hydroxyimino(lower)alkyl, lower alkenyl optionally substituted with oxo, or lower alkyl optionally substituted with hydroxy;
R.sup.2 is hydrogen, halogen, lower alkenyl, acyl, or lower alkyl optionally substituted with protected carboxy, carboxy, lower alkoxy or hydroxy;
R.sup.3 is lower alkenyl;
or lower alkyl substituted by
(1) aryl optionally substituted with one or more substituent(s) selected from the group consisting of halogen, aryl, lower alkoxy, lower alkylenedioxy, cyano, nitro, acyl, and amino optionally substituted with acyl or protected carboxy;
or
(2) a heterocyclic group selected from the group consisting of pyridyl, thienyl, benzothiazolyl, and benzothiophenyl, each of which is optionally substituted with halogen;
and
R.sup.4 is acyl, cyano, halogen, a heterocyclic group, amino optionally substituted with acyl or protected carboxy, or lower alkyl optionally substituted with protected carboxy, carboxy or acyl;
or
R.sup.1 and R.sup.2, together with the carbon atoms to which they are attached, represent a 4- to 7-membered carbocyclic ring optionally substituted with oxo;
or a pharmaceutically acceptable salt thereof, which process comprises,
a) reacting a compound of the formula:
##STR17## wherein R.sup.1, R.sup.2 and R.sup.4 are each as defined above, or a salt thereof, with a compound of the formula:
R.sup.3 --X.sup.1 (III)
wherein R.sup.3 is as defined above, and
X.sup.1 is a leaving group,
to form a compound of the formula:
##STR18## wherein R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are each as defined above, or a salt thereof;
or
b) reacting a compound of the formula ##STR19## wherein R.sup.1, R.sup.2 and R.sup.3 are each as defined above, and R.sup.4 is carboxy or lower alkyl substituted with carboxy, or its reactive derivative at the carboxy group, or a salt thereof;
with a compound of the formula:
##STR20## wherein R.sup.5 is hydrogen or lower alkyl, and R.sup.6 is hydrogen, hydroxy, lower alkoxy, arylsulfonyl, a heterocyclic group, or lower alkyl optionally substituted with lower cycloalkyl or a heterocyclic group;
or
R.sup.5 and R.sup.6, together with the nitrogen atom to which they are attached, represent a heterocyclic group,
or a reactive derivative at the amino group, or a salt thereof, to give a compound of the formula:
##STR21## wherein R.sup.1, R.sup.2, R.sup.3, R.sup.5 and R.sup.6 are each as defined above, and ##STR22## or lower alkyl substituted with ##STR23## or a salt thereof;
c) reacting a compound of the formula (I-5):
##STR24## wherein R.sup.1, R.sup.2 and R.sup.4 are each as defined above, and R.sub.b.sup.3 is lower alkenyl or alkyl, both of which are optionally substituted with oxo and both of which are substituted with aryl which is substituted with carboxy,
or a reactive derivative thereof at the carboxy group, or a salt thereof, with the compound of the formula (IV) as defined above, or a reactive amino compound, or a salt thereof, to form a compound of the formula:
##STR25## wherein R.sup.1, R.sup.2, R.sup.3, R.sup.5 and R.sup.6 are each as defined above, and R.sub.c.sup.3 is lower alkenyl or lower alkyl, both of which are optionally substituted with oxo and both of which are substituted with aryl which is substituted with ##STR26## or a salt thereof;
d) reducing a compound of the formula:
##STR27## wherein R.sup.2, R.sup.3 and R.sup.4 are each as defined above, and R.sub.a.sup.1 is lower alkanoyl optionally substituted with protected carboxy or carboxy, or a salt thereof;
to form a compound of the formula:
##STR28## wherein R.sup.2, R.sup.3 and R.sup.4 are each as defined above, and R.sub.b.sup.1 is lower alkyl optionally substituted with protected carboxy or carboxy, or a salt thereof;
e) reacting a compound of the formula:
##STR29## wherein R.sup.2, R.sup.3 and R.sup.4 are each as defined above, or a salt thereof;
with a compound of the formula:
R.sub.c.sup.1 --X.sup.2 (V)
wherein R.sub.c.sup.1 is lower alkenoyl, aryl, or lower alkanoyl optionally substituted with protected carboxy, carboxy, or aryl;
X.sup.2 is a leaving group, or a salt thereof;
to form a compound of the formula:
##STR30## wherein R.sub.c.sup., R.sup.2, R.sup.3 and R.sup.4 are each as defined above, or a salt thereof;
or
f) dehydrating a compound of the formula:
##STR31## wherein R.sup.1, R.sup.2 and R.sup.3 are each as defined above, or a salt thereof, to form a compound of the formula:
##STR32## wherein R.sup.1, R.sup.2 and R.sup.3 are each as defined above, or a salt thereof;
or
g) reacting a compound of the formula (I-12) defined above, or a salt thereof, with an azide compound, to form a compound of the formula:
##STR33## wherein R.sup.1, R.sup.2 and R.sup.3 are each as defined above, or a salt thereof;
or
h) subjecting a compound of the formula:
##STR34## wherein R.sup.3 and R.sup.4 are each as defined above, and R.sub.a.sup.2 is lower alkyl substituted with protected carboxy, or a salt thereof, to deesterification to form a compound of the formula:
##STR35## wherein R.sup.3 and R.sup.4 are each as defined above, and R.sub.b.sup.2 is lower alkyl substituted with carboxy, or a salt thereof;
or
i) subjecting a compound of the formula (I-15) as defined above, or a salt thereof, to intramolecular acrylation to give a compound of the formula:
##STR36## wherein R.sup.3 and R.sup.4 are each as defined above, and n is 1, 2, 3 or 4, or a salt thereof;
or
j) reacting a compound of the formula:
##STR37## wherein R.sup.2, R.sup.3 and R.sup.4 are each as defined above, and R.sub.d.sup.1 is chloroacetyl, or its salt, with a compound of the formula (IV) defined above, or a salt thereof, to form a compound of the formula:
##STR38## wherein R.sup.2, R.sup.3 and R.sup.4 are each as defined above, and ##STR39## or a salt thereof;
or h) formylating a compound of the formula (I-9) defined above, or a salt thereof, to give a compound of the formula:
##STR40## wherein R.sup.2, R.sup.3 and R.sup.4 are each as defined above, or a salt thereof;
or
l) subjecting a compound of the formula:
##STR41## wherein R.sup.1, R.sup.2 and R.sup.3 are each as defined above, or a salt thereof, to a rearrangement reaction to form a compound of the formula:
##STR42## wherein R.sup.1, R.sup.2, R.sup.3, R.sup.5 and R.sup.6 are each as defined above, and R.sup.7 is hydrogen, protected carboxy, or ##STR43## or a salt thereof;
or m) reacting a compound of the formula:
##STR44## wherein R.sup.1, R.sup.2 and R.sup.3 are each as defined above, or its reactive derivative at the amino group, or a salt thereof, with a compound of the formula:
R.sup.8 --X.sup.3 (VI)
wherein R.sup.8 is acyl, and
X.sup.3 is leaving group, or a salt thereof, or a compound of the formula:
R.sup.9 --N.dbd.C.dbd.O (VII)
wherein R.sup.9 is lower alkyl, to form a compound of the formula:
##STR45## wherein R.sup.1, R.sup.2, R.sup.3 and R.sup.8 are same as defined above, or a salt thereof;
or
n) reducing a compound of the formula:
##STR46## wherein R.sup.1, R.sup.2 and R.sup.4 are each as defined above, and R.sub.d.sup.3 is lower alkyl substituted with aryl which is substituted with nitro, or a salt thereof, to give a compound of the formula:
##STR47## wherein R.sup.1, R.sup.2 and R.sup.4 are each as defined above, and R.sub.e.sup.3 is lower alkyl substituted with aryl which is substituted with amino, or a salt thereof, xviii) subjecting a compound of the formula:
##STR48## wherein R.sup.2, R.sup.3 and R.sup.4 are each as defined above, and R.sub.f.sup.1 is lower alkanoyl substituted with lower alkoxy, or a salt thereof, to dealkylation to give a compound of the formula:
##STR49## wherein R.sup.2, R.sup.3 and R.sup.4 are each as defined above, and R.sub.g.sup.1 is lower alkanoyl substituted with hydroxy, or a salt thereof;
or
o) oxidizing a compound of the formula:
##STR50## wherein R.sup.1, R.sup.3 and R.sup.4 are each as defined above, and R.sub.c.sup.2 is 1-hydroxy(lower)alkyl, or a salt thereof, to form a compound of the formula:
##STR51## wherein R.sup.1, R.sup.3 and R.sup.4 are each as defined above, and R.sub.d.sup.2 is lower alkanoyl, or a salt thereof;
or
p) halogenating a compound of the formula (I-9) defined above, or a salt thereof, to form a compound of the formula:
##STR52## wherein R.sup.2, R.sup.3 and R.sup.4 are each as defined above, and R.sub.h.sup.1 is halogen, or a salt thereof;
or
q) subjecting a compound of the formula (I-9) defined above, or a salt thereof, to nitration to give a compound of the formula:
##STR53## wherein R.sup.2, R.sup.3 and R.sup.4 are each as defined above, or a salt thereof;
or
r) reducing a compound of the formula (I-7) defined above, or a salt thereof, to give a compound of the formula:
##STR54## wherein R.sup.2, R.sup.3 and R.sup.4 are each as defined above, and R.sub.i.sup.1 is lower alkyl optionally substituted with protected carboxy or carboxy, or a salt thereof;
or
s) reacting a compound of the formula:
##STR55## wherein R.sup.2, R.sup.3 and R.sup.4 are each as defined above, and R.sub.j.sup.1 is lower alkanoyl, or its salt, with hydroxylamine or a salt thereof, to form a compound of the formula:
##STR56## wherein R.sup.2, R.sup.3 and R.sup.4 are each as defined above, and R.sub.k.sup.1 is hydroxyimino(lower)alkyl, or a salt thereof, or
t) reacting a compound of the formula:
##STR57## wherein R.sup.1, R.sup.2 and R.sup.4 are each as defined above, R.sub.f.sup.3 is lower alkyl substituted with aryl which is substituted with amino, or its reactive derivative at the amino group, or its salt, with a compound of the formula (VI) as defined above or a salt thereof, or a compound of the formula (VII) defined above, to form a compound of the formula:
##STR58## wherein R.sup.1, R.sup.2 and R.sup.4 are each as defined above, and R.sub.g.sup.3 is lower alkyl substituted with aryl which is substituted with amino substituted with acyl, or its salt.

98 more elements

Dependencies are inferred from the claim text.

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