Thienopyrimidine compounds and salts thereof and process for...

Details Thienopyrimidine compounds and salts thereof and process for... Thienopyrimidine compounds and salts thereof and process for...

2001-08-31

2002-11-19

Ford, John M. (Department: 1624)

Organic compounds -- part of the class 532-570 series

Organic compounds

Four or more ring nitrogens in the bicyclo ring system

C544S115000

Reexamination Certificate

active

06482948

ABSTRACT:

The present invention relates to pyridothienopyrimidine compounds useful as selective cGMP phosphodiesterase (PDE) inhibitors and salts thereof, and processes for the preparation of the same.
BACKGROUND ART
cGMP is a substance playing an important role as a second messenger in the signal transduction system in vivo. Inhibitors of selective cGMP phosphodiesterase (PDE), which is a hydrolase of cGMP, raise cGMP levels in cells and are useful for the prevention and/or therapy of, for example, hypertension, heart failure, cardiac infarction, angina pectoris, arteriosclerosis, restenosis after PTCA (percutaneous transluminal coronary angioplasty), cardiac edema, pulmonary hypertension, renal failure, renal edema, hepatic edema, asthma, bronchitis, dementia, immunodeficiency, glaucoma or impotentia.
Compounds represented by the following formula are reported as cGMP PDE inhibitors having thieno[2,3-d]pyrimidine skeletons in WO 98/06722 and EP 728759.
wherein, X is an optionally substituted cycloalkyl, phenyl or heterocyclic ring.
Furthermore, WO 98/17668, WO 99/28325 and WO 99/55708 have disclosed compounds represented by the following formulae.
wherein, X is a group, such as alkylene or cycloalkyl, substituted with carboxylic acid, carboxylic acid amide or the like.
DISCLOSURE OF THE INVENTION
The present invention is directed to (a) a thienopyrimidine compound represented by Formula (1)
[wherein, Q is a group bound from a to b and represented by Formula (CH
2
)n—N(r
1
)—C(r
2
) (r
3
), CH═CH—CH═CH or (CH
2
)m;
r
1
is hydrogen, C
1-6
alkyl, C
1-6
alkylsulfonyl, benzyl optionally substituted with G
1
, or a group represented by Formula C(═O)r
4
or C(═O)Or
5
;
r
2
and r
3
are, each independently, hydrogen, C
1-6
alkyl or phenyl optionally substituted with G
1
, or r
2
and r
3
join together to form oxo;
r
4
is hydrogen, C
1-6
alkyl, C
2-6
alkenyl, phenyl optionally substituted with G
1
, or a saturated or unsaturated heterocyclic group containing 1 to 4 N, O or S atoms and optionally substituted with G
3
;
r
5
is hydrogen, C
1-6
alkyl, C
2-6
alkenyl or optionally substituted phenyl;
n is 1, 2 or 3; m is 3, 4 or 5;
R
1
is hydrogen or C
1-6
alkyl;
R
2
is C
3-8
cycloalkyl optionally substituted with G
1
, phenyl optionally substituted with G
2
, or a saturated or unsaturated heterocyclic group containing 1 to 4 N, O or S atoms and optionally substituted with G
3
;
R
3
is a saturated or unsaturated heterocyclic group containing 1 to 4 N, O or S atoms and optionally substituted with G
3
, or a group represented by Formula (CH
2
)
k
C(═O)R
4
or CH═CHC(O)R
4
;
R
4
is hydrogen, hydroxy, C
1-6
alkoxy, phenoxy optionally substituted with G
2
, benzyloxy optionally substituted with G
2
, or a group represented by Formula Nr
6
r
7
or NHNr
8
r
9
;
r
6
and re are hydrogen or C
1-6
alkyl;
r
7
and r
9
are hydrogen, C
3-8
cycloalkyl, C
1-6
alkyl optionally substituted with a saturated or unsaturated heterocyclic group containing 1 to 4 N, O or S atoms which may be substituted with C
1-6
alkoxycarbonyl or G
3
, phenyl optionally substituted with G
1
, benzyl optionally substituted with G
1
, or a saturated or unsaturated heterocyclic group containing 1 to 4 N, O or S atoms and optionally substituted with G
3
;
r
6
and r
7
may join, together with N, to form a ring
 (wherein, Y is O, CH
2
or Nr
10
);
r
10
is hydrogen, C
1-6
alkyl, phenyl optionally substituted with G
1
, or benzyl optionally substituted with G
1
;
k is 0, 1 or 2;
G
1
is halogen, C
1-6
alkyl or C
1-6
alkoxy;
G
2
is halogen, C
1-6
alkyl, C
1-6
alkoxy or C
1-2
alkylenedioxy;
G
3
is halogen, C
1-6
alkyl, C
1-6
haloalkyl, C
1-6
alkoxy or C
1-6
alkoxycarbonyl;
Substituents G
1
, G
2
and G
3
on the benzene ring, cycloalkyl or heterocyclic ring may have two or more substituents which may be the same or different;
when R
3
is a saturated or unsaturated heterocyclic group containing 1 to 4 N, O or S atoms and optionally substituted with G
3
, Q is (CH
2
)n—N(r
1
)—C(r
2
) (r
3
) (r
1
, r
2
, r
3
and n are as defined above), and when Q is (CH
2
)m or CH═CH—CH═CH, R
4
is anilino or k=0), and pharmaceutically acceptable salts thereof.
In more detail, the present invention is directed to:
2. a compound represented by Formula (1-1)
(wherein, R
1
, R
2
, R
3
, r
1
, r
2
and r
3
are as defined above); and
3. a compound represented by Formula (1-2)
(wherein, Q′ is a group bound from a to b and represented by Formula CH═CH—CH═CH or (CH
2
)m, and R
1
, R
2
, R
4
and m are as defined above); and furthermore
4. a process for the preparation of a compound of the said Formula (1), characterized by a reaction of a compound of Formula (3)
(wherein, Q and R
3
are as defined above and X is halogen), with a compound of Formula (4)
(wherein, R
1
and R
2
are as defined above).
Forms to Implement the Invention:
In the compounds of the present invention, represented by the said Formula (1)
r
1
is hydrogen; C
1-6
alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl or t-butyl; C
1-6
alkylsulfonyl such as methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl or t-butylsulfonyl; benzyl (optionally substituted at arbitrary positions with halogen such as fluorine, chlorine or bromine; C
1-6
alkyl such as methyl or ethyl; or C
1-6
alkoxy such as methoxy or ethoxy); or a group represented by Formula C(═O)r
4
or C(═O)Or
5
.
r
2
and r
3
are, each independently, hydrogen; C
1-6
alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl or t-butyl; or phenyl (optionally substituted at arbitrary positions with halogen such as fluorine, chlorine or bromine; C
1-6
alkyl such as methyl or ethyl; or C
1-6
alkoxy such as methoxy or ethoxy), or r
2
and r
3
join together to form oxo;
r
4
is hydrogen; C
1-6
alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl or t-butyl; C
2-6
alkenyl such as ethenyl, 1-propenyl or 2-propenyl; phenyl (optionally substituted at arbitrary positions with halogen such as fluorine, chlorine or bromine; C
1-6
alkyl such as methyl or ethyl; or C
1-6
alkoxy such as methoxy or ethoxy); or a saturated or unsaturated heterocyclic group containing 1 to 4 N, O or S atoms (optionally substituted at arbitrary positions with halogen such as fluorine, chlorine or bromine; C
1-6
alkyl such as methyl or ethyl; C
1-6
haloalkyl such as chloromethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl or trifluoromethyl; C
1-6
alkoxy such as methoxy or ethoxy; or C
1-6
alkoxycarbonyl such as methoxycarbonyl or ethoxycarbonyl), such as furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, triazolyl, oxadiazolyl, pyridyl, pyrimidyl or pyridazinyl.
r
5
is hydrogen; C
1-6
alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl or t-butyl; C
2-6
alkenyl such as ethenyl, 1-propenyl or 2-propenyl; or phenyl (optionally substituted at arbitrary positions with halogen such as fluorine, chlorine or bromine; C
1-6
alkyl such as methyl or ethyl; or C
1-6
alkoxy such as methoxy or ethoxy).
n is 1, 2 or 3; m is 3, 4 or 5.
R
1
is hydrogen or C
1-6
alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl or t-butyl.
R
2
is C
3-8
cycloalkyl (optionally substituted at arbitrary positions with halogen such as fluorine, chlorine or bromine; C
1-6
alkyl such as methyl or ethyl; or C
1-6
alkoxy such as methoxy or ethoxy); phenyl (optionally substituted at arbitrary positions with halogen such as fluorine, chlorine or bromine; C
1-6
alkyl such as methyl or ethyl; C
1-6
alkoxy such as methoxy or ethoxy; or C
1-2
alkylenedioxy such as metyhylenedioxy or ethylenedioxy), or a saturated or unsaturated heterocyclic group containing 1 to 4 N, O or S atoms (optionally substituted at arbitrary positions with halogen such as fluorine, chlorine or bromine; C
1-6
alkyl such as methyl or ethyl; C
1-6
haloalkyl such as chloromethyl, dichlorometh

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