N-cinnamoyl derivatives of beta-carboline

Details N-cinnamoyl derivatives of beta-carboline N-cinnamoyl derivatives of beta-carboline

2000-06-12

2001-10-23

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...

C514S277000, C514S290000, C514S291000, C546S080000, C546S084000, C546S087000, C544S106000

Reexamination Certificate

active

06306870

ABSTRACT:

This invention relates to a series of carboline derivatives, to processes for their preparation, pharmaceutical compositions containing them, and their use as therapeutic agents. In particular, the invention relates to carboline 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)
wherein
R
0
represents -hydrogen or -halogen;
R
1
is selected from the group consisting of:
-hydrogen,
—NO
2
,
-trifluoromethyl,
-trifluoromethoxy,
-halogen,
-cyano,
a 5- or 6-membered heterocyclic group containing at least one heteroatom selected from oxygen, nitrogen and sulphur (optionally substituted by —C(═O)OR
a
or C
1-4
alkyl),
—C
1-6
alkyl optionally substituted by —OR
a
,
—C
1-3
alkoxy,
—C(═O)R
a
,
—O—C(═O)R
a
,
—C(═O)OR
a
,
—C
1-4
alkylene C(═O)OR
a
,
—O—C
1-4
alkylene —C(═O)OR
a
,
—C
1-4
alkylene-O—C
1-4
alkylene-C(═O)OR
a
,
—C(═O)NR
a
SO
2
R
c
,
—C(═O)C
1-4
alkylene Het, wherein Het represents 5- or 6-membered heterocyclic group as defined above,
—C
1-4
alkylene NR
a
R
b
,
—C
2-6
alkenyleneNR
a
R
b
,
—C(═O)NR
a
R
b
,
—C(═O)NR
a
R
c
,
—C(═O)NR
a
C
1-4
alkylene OR
b
—C(═O)NR
a
C
1-4
alkylene Het, wherein Het represents a 5- or 6-membered heterocyclic group as defined above,
—OR
a
—OC
2-4
alkylene NR
a
R
b
,
—OC
1-4
alkylene-CH(OR
a
)CH
2
NR
a
R
b
,
—O—C
1-4
alkylene Het, wherein Het represents a 5- or 6-membered heterocyclic group as defined above,
—O—C
2-4
alkylene-OR
a
—O—C
2-4
alkylene-NR
a
—C(═O)—OR
b
,
—NR
a
R
b
,
—NR
a
C
1-4
alkyleneNR
a
R
b
,
—NR
a
C(═O)R
b
,
—NR
a
C(═O)NR
a
R
b
,
—N(SO
2
C
1-4
alkyl)
2
,
—NR
a
(SO
2
C
1-4
alkyl),
—SO
2
NR
a
R
b
, and
—OSO
2
trifluoromethyl;
R
2
is selected from the group consisting of:
-hydrogen,
-halogen,
—OR
a
,
—C
1-6
alkyl,
—NO
2
, and
—NR
a
R
b
,
or R
1
and R
2
, together form a 3- or 4-membered alkylene or alkenylene chain, optionally containing at least one heteratom;
R
3
is selected from the group consisting of:
-hydrogen,
-halogen,
—NO
2
,
-trifluoromethoxy,
—C
1-6
alkyl, and
—C(═O)OR
a
;
R
4
is hydrogen,
or R
3
and R
4
together form a 3- or 4-membered alkylene or alkenylene chain, optionally containing at least one heteratom;
R
a
and R
b
, which may be the same or different, are independently selected from hydrogen and C
1-6
alkyl;
R
c
represents phenyl or C
4-6
cycloalkyl, which phenyl or C
4-6
cycloalkyl can be optionally substituted by one or more halogen atoms, one or more —C(═O)OR
a
or one or more —OR
a
;
n is an integer selected from 1, 2 and 3;
m is an integer selected from 1 and 2;
and pharmaceutically acceptable salts and solvates (e.g. hydrates) thereof.
The terms alkyl or alkylene as used herein respectively contain the appropriate indicated number of carbon atoms and appropriately include straight chained and branched alkyl or alkylene groups, typically methyl, methylene, ethyl and ethylene groups, and straight chained and branched propyl, propylene, butyl and butylene groups. The term C
2-6
alkenylene as used herein contains 2 to 6 carbon atoms and appropriately includes straight chained and branched alkenylene groups, in particular ethenylene or the like.
The terms C
4-6
cycloalkyl denotes cyclic groups containing 4 to 6 carbon atoms, namely cyclobutane, cyclopentane and cyclohexane.
The term halogen as used herein includes fluorine, chlorine, bromine and iodine.
The term 5- or 6-membered heterocyclic group as used herein includes 5- or 6-membered heterocycloalkyl and heteroaryl groups, e.g. tetrahydrofuranyl, piperidyl, piperazinyl pyrrolidinyl, morpholinyl, pyridyl, imidazolyl, furyl, and tetrazolyl.
Appropriately, R
o
represents hydrogen. Alternatively R
o
may represent halogen, in particular fluorine.
R
1
may represent any of the substituents as hereinbefore described, or more particularly may represent any of —OR
a
, —O—C
2-4
alkyleneNR
a
R
b
, —O—C
1-4
alkyleneHet and —O—C
2-4
alkylene-OR
a
. In particular, R
1
represents —O—C
2-4
alkylene NR
a
R
b
, wherein suitably C
2-4
alkylene may represent ethylene and aptly, R
a
and R
b
may independently represent methyl.
Particularly suitably R
2
represents hydrogen. Alternatively, in the case where R
1
and R
2
together form a 3- or 4-membered alkylene or alkenylene chain optionally containing at least one heteratom as hereinbefore described, suitably R
1
and R
2
together form a methylenedioxy chain, an ethyleneoxy chain, an ethylenedioxy chain, an ethenyleneoxy chain, a propylene chain, a butylene chain or —NR
a
ethylene-O—. Aptly, R
1
and R
2
together form methylenedioxy, propylene or —N(CH
3
)—(CH
2
)
2
—O—.
Suitably R
3
and R
4
, together form a 3- or 4-membered alkylene or alkenylene chain, optionally containing at least one heteratom as hereinbefore described. Particularly suitably R
3
and R
4
together form a methylenedioxy chain, an ethyleneoxy chain, an ethylenedioxy chain, an ethenyleneoxy chain, a propylene chain, a butylene chain or —NR
a
ethylene-O—. Aptly R
3
and R
4
together form a methylenedioxy chain, an ethyleneoxy chain, an ethylenedioxy chain, an ethenyleneoxy chain or a propylene chain. In particular, R
3
and R
4
together form methylenedioxy or ethyleneoxy, most particularly ethyleneoxy.
A particular subgroup of compounds according to the present invention can be represented by formula (Ia)
wherein
R
5
is selected from the group consisting of —OH, —OC
2-4
alkylene NR
a
R
b
and O—C
1-4
alkylene Het, wherein Het is as hereinbefore described and
R
6
represents
wherein C represents a 5- or 6-membered rn which may be saturated or partially or fully unsaturated and comprises carbon atoms and optionally one or two heteroatoms selected from oxygen, sulphur and nitrogen, optionally substituted by C
1-4
alkyl;
and pharmaceutically acceptable salts and solvates (e.g. hydrates thereof).
Typically, R
5
represents —OC
2-4
alkylene NR
a
R
b
, in particular —OCH
2
CH
2
N(CH
3
)
2
. Alternatively, R
5
may represent —O—C
1-4
alkylene Het, where Het may suitable be piperidyl, pyrrolidinyl (optionally substituted by C
1-4
alkyl, e.g. methyl) or morpholinyl.
Particularly aptly R
6
represents
The compounds of formula (I) may contain one or more asymmetric centres and thus can exist as enantiomers or diastereoisomers. It is to be understood that the invention includes both mixtures and separate individual isomers of the compounds of formula (I).
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.
Particular individual compounds of the invention include:
(E)-1-(1-Phenyl-1,3,4,9-tetrahydro-&bgr;-carbolin-2-yl)-3-phenylpropene-1-one
(E)-1-(1-Phenyl-1,3,4,9-tetrahydro-&bgr;-carbolin-2-yl)-3-(4-nitrophenyl)propene-1-one
(E)-1-(1-Phenyl-1,3,4,9-tetrahydro-&bgr;-carbolin-2-yl)-3-(4-trifluoromethylphenyl)propene-1-one
(E)-1-(1-Phenyl-1,3,4,9-tetrahydro-&bgr;-carbolin-2-yl)-3-(4-methoxyphenyl)propene-1 one
(E)-1-[1-(4-Methoxyphenyl)-1,3,4,9-tetrahydro-&bgr;-carbolin-2-yl]-3-(4-trifluoromethylphenyl)propene-1-one
(E)-N-[4-[3-Oxo-3-(1-phenyl-1,3,4,9-tetrahydro-&bgr;-carbolin-2-yl)propenyl]phenyl]acetamide
(E)-1-[1-(4-Methoxyphenyl)-1,3,4,9-tetrahydro-&bgr;-carbolin-2-yl)-3-phenylpropene-1-one
(E)-1-[1-(3,4-Methylenedioxyphenyl)

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