Treatment method using a cGMP-Specific PDE inhibitor

Details Treatment method using a cGMP-Specific PDE inhibitor Treatment method using a cGMP-Specific PDE inhibitor

1999-08-24

2001-04-17

Rotman, Alan L. (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C514S249000, C514S250000, C514S092000, C544S247000, C544S343000, C546S087000, C546S085000, C546S064000

Reexamination Certificate

active

06218400

ABSTRACT:

This invention relates to a series of tetracyclic derivatives, to processes for their preparation, pharmaceutical compositions containing them, and their use as therapeutic agents. In particular, the invention relates to tetracyclic derivatives which are potent and selective inhibitors of cyclic guanosine 3′,5′-monophosphate specific phosphodiesterase (cGMP specific PDE) having utility in a variety of therapeutic areas where such inhibition is thought to be beneficial, including the treatment of cardiovascular disorders.
Thus, according to a first aspect, the present invention provides compounds of formula (I)
and salts and solvates (e.g. hydrates) thereof, in which:
R
0
represents hydrogen, halogen or C
1-6
alkyl;
R
1
is selected from the group consisting of:
(a) hydrogen;
(b) C
1-6
alkyl optionally substituted by one or more substituents selected from phenyl, halogen, —CO
2
R
a
and —NR
a
R
b
;
(c) C
3-6
cycloalkyl;
(d) phenyl; and
(e) a 5- or 6-membered heterocyclic ring containing at least one heteroatom selected from oxygen, nitrogen and sulphur, and being optionally substituted by one or more C
1-6
-alkyl, and optionally linked to the nitrogen atom to which R
1
is attached via C
1-6
alkyl;
R
2
is selected from the group consisting of:
(f) C
3-6
cycloalkyl;
(g) phenyl optionally substituted by one or more substituents selected from —OR
a
, —NR
a
R
b
, halogen, hydroxy, trifluoromethyl, cyano and nitro;
(h) a 5- or 6-membered heterocyclic ring containing at least one heteroatom selected from oxygen, nitrogen and sulphur; and
(i) a bicyclic ring
attached to the rest of the molecule via one of the benzene ring carbon atoms and A is a 5- or 6-membered heterocyclic ring as defined in point (h); and
R
a
and R
b
independently represent hydrogen or C
1-6
alkyl.
The term “C
1-6
-alkyl” as used herein denotes any straight or branched alkyl chain containing 1 to 6 carbon atoms, and includes methyl, ethyl, n-propyl, iso-propyl, n-butyl, pentyl, hexyl and the like.
The term “halogen” as used herein denotes fluorine, chlorine, bromine and iodine.
A particular group of compounds according to formula (I) are those wherein R
0
represents any of hydrogen, methyl, bromine and fluorine, although of course the definition of R
0
given in formula (I) includes within its scope other C
1-6
alkyl and halogen groups.
Aptly, R
1
may represent a substituent selected from methyl, ethyl optionally substituted by one or more chlorine atoms, butyl, cyclohexyl and benzyl.
Other suitable R
1
substituents include hydrogen; cycloalkyl groups, such as cyclopropyl; C
1-6
alkyl, typically ethyl or propyl, substituted by an —NR
a
R
b
substituent, such as a dimethylamino substituent; phenyl optionally linked to the nitrogen atom to which R
1
is attached via a C
1-6
-alkyl chain, such as ethyl or the like; and C
1-6
alkyl, e.g. methyl, substituted by —CO
2
R
a
, such as —CH
2
CO
2
Et or the like.
Suitable heterocyclic rings within the definition of R
1
include pyridyl, morpholinyl, piperazinyl, pyrrolidinyl and piperidinyl. Generally such heterocyclic rings are linked to the nitrogen atom to which R
1
is attached via a C
1-6
alkyl chain, more appropriately a C
1-4
alkyl chain.
A particularly apt substituent represented by R
2
is
Other suitable R
2
substituents include thienyl, pyridyl, furyl and phenyl, wherein phenyl can be substituted by one or more substituents selected from —OR
a
(e.g. methoxy), —NR
a
R
b
(e.g. dimethylamino), halogen (in particular chlorine or fluorine), hydroxy, trifluoromethyl, cyano and nitro.
Alternatively, R
2
may represent a suitable C
3-6
cycloalkyl group, such as cyclohexyl or the like.
The pharmaceutically acceptable salts of the compounds of formula (I) which contain a basic centre are acid addition salts formed with pharmaceutically acceptable acids. Examples include the hydrochloride, hydrobromide, sulphate or bisulphate, phosphate or hydrogen phosphate, acetate, benzoate, succinate, fumarate, maleate, lactate, citrate, tartrate, gluconate, methanesulphonate, benzenesulphonate and p-toluenesulphonate salts. Compounds of the formula (I) can also provide pharmaceutically acceptable metal salts, in particular alkali metal salts, with bases. Examples include the sodium and potassium salts.
It is to be understood that the present invention covers all appropriate combinations of particular and preferred groupings hereinabove.
Particular individual compounds of the invention include:
Cis-2-benzyl-5-(3,4-methylenedioxyphenyl)-5,6,11,11a-tetrahydro-1H-imidazo [1′,5′:1,6]pyrido[3,4-b]indole-1,3(2H)-dione;
Trans-2-benzyl-5-(3,4-methylenedioxyphenyl)-5,6,11,11a-tetrahydro-1H-imidazo [1′,5′:1,6]pyrido[3,4-b]indole-1,3(2H)-dione;
Cis-5-(4-methoxyphenyl)-2-methyl-5,6,11,11a-tetrahydro-1H-imidazo [1′,5′:1,6] pyrido[3,4-b]indole-1,3(2H)-dione;
Cis-2-ethyl-5-(4-methoxyphenyl)-5,6,11,11a-tetrahydro-1H-imidazo[1′,5′: 1,6] pyrido[3,4-b]indole-1,3(2H)-dione;
Trans-2-ethyl-5-(4-methoxyphenyl)-5,6,11,11a-tetrahydro-1H-imidazo[1′,5′:1,6] pyrido[3,4-b]indole-1,3(2H)-dione;
Trans-2-ethyl-5-(3,4-methylenedioxyphenyl)-5,6,11,11a-tetrahydro-1H-imidazo [1′,5′:1,6]pyrido[3,4-b]indole-1,3(2H)-dione;
Trans-2-ethyl-5-(2-thienyl)-5,6,11,11a-tetrahydro-1H-imidazo[1′,5′:1,6] pyrido [3,4-b]indole-1,3(2H)-dione;
Trans-5-(4-dimethylaminophenyl)-2-ethyl-5,6,11,11a-tetrahydro-1H-imidazo [1′,5′:1,6] pyrido[3,4-b]indole-1,3(2H)-dione;
Trans-2-butyl-9-methyl-5-phenyl-5,6,11,11a-tetrahydro-1H-imidazo[1′,5′:1,6] pyrido[3,4-b]indole-1,3(2H)-dione;
Trans-9-bromo-2-butyl-5-phenyl-5,6,11,11a-tetrahydro-1H-imidazo[1′,5′:1,6] pyrido[3,4-b]indole-1,3(2H)-dione;
Cis-2-butyl-5-(4-methoxyphenyl)-5,6,11,11a-tetrahydro-1H-imidazo [1′,5′:1,6] pyrido[3,4-b]indole-1,3(2H)-dione;
Trans-2-butyl-5-(4-methoxyphenyl)-5,6,11,11a-tetrahydro-1H-imidazo[1′,5′:1,6] pyrido[3,4-b]indole-1,3(2H)-dione;
Cis-2-butyl-9-fluoro-5-(4-methoxyphenyl)-5,6,11,11a-tetrahydro-1H-imidazo [1′,5′:1,6] pyrido[3,4-b]indole-1,3(2H)-dione;
Trans-2-butyl-9-fluoro-5-(4-methoxyphenyl)-5,6,11,11a-tetrahydro-1H-imidazo [1′,5′:1,6] pyrido[3,4-b]indole-1,3(2H)-dione;
Trans-2-butyl-5-(3,4-methylenedioxyphenyl)-5,6,11,11a-tetrahydro-1H-imidazo [1′,5′:1,6] pyrido[3,4-b]indole-1,3(2H)-dione;
Cis-2-butyl-5-(3-chlorophenyl)-5,6,11,11a-tetrahydro-1H-imidazo[1′,5′:1,6]pyrido [3,4-b]indole-1,3(2H)-dione;
Trans-2-butyl-5-(3-chlorophenyl)-5,6,11,11a-tetrahydro-1H-imidazo[1′,5′:1,6] pyrido [3,4-b]indole-1,3(2H)-dione;
Cis-2-butyl-5-(4-chlorophenyl)-5,6,11,11a-tetrahydro-1H-imidazo [1′,5′:1,6] pyrido [3,4-b]indole-1,3(2H)-dione;
Trans-2-butyl-5-(4-chlorophenyl)-5,6,11,11a-tetrahydro-1H-imidazo [1′,5′:1,6] pyrido[3,4-b]indole-1,3(2H)-dione;
Trans-2-butyl-5-(4-fluorophenyl)-5,6,11,11a-tetrahydro-1H-imidazo[1′,5′:1,6] pyrido [3,4-b]indole-1,3(2H)-dione;
Trans-2-butyl-5-(4-hydroxyphenyl)-5,6,11,11a-tetrahydro-1H-imidazo[1′,5′:1,6] pyrido [3,4-b]indole-1,3(2H)-dione;
Cis-2-butyl-5-(4-trifluoromethylphenyl)-5,6,11,11a-tetrahydro-1H-imidazo [1′,5′:1,6]pyrido[3,4-b]indole-1,3(2H)-dione;
Cis-2-butyl-5-(4-cyanophenyl)-5,6,11,11a-tetrahydro-1H-imidazo[1′,5′:1,6] pyrido [3,4-b]indole-1,3(2H)-dione;
Trans-2-butyl-5-(4-cyanophenyl)-5,6,11,11a-tetrahydro-1H-imidazo[1′,5′:1,6] pyrido[3,4-b]indole-1,3(2H)-dione;
Cis-2-butyl-5-(4-nitrophenyl)-5,6,11,11a-tetrahydro-1H-imidazo[1′,5′:1,6]pyrido [3,4

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