Pharmaceutically active compounds

Details Pharmaceutically active compounds Pharmaceutically active compounds

2000-10-06

2003-01-07

Shah, Mukund J. (Department: 1614)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C544S184000

Reexamination Certificate

active

06503908

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to pharmaceutically useful compounds, in particular compounds which are useful in the inhibition of cyclic guanosine 3′,5′-monophosphate phosphodiesterases (cGMP PDEs), such as type 5 cyclic guanosine 3′,5′-monophosphate phosphodiesterases (cGMP PDE5). The compounds therefore have utility in a variety of therapeutic areas, including male erectile dysfunction (MED).
PRIOR ART
Certain cGMP PDE-inhibiting 2-phenyl substituted imidazotriazinone derivatives are disclosed in international patent application WO 99/24433.
DISCLOSURE OF THE INVENTION
According to a first aspect of the invention there is provided compounds of formula I,
wherein
R
1
and R
2
independently represent phenyl (optionally substituted by one or more substituents selected from halo, —CN, —CF
3
, —OCF
3
, C
1-4
alkoxy or C
1-4
alkyl (which latter two groups are optionally substituted by C
1-4
haloalkyl or C
1-4
haloalkoxy)) or C
1-6
alkyl optionally interrupted by —O—, —S— and/or —N(R
4
)— and/or optionally substituted and/or terminated by Het
2
, a N-linked heterocyclic group (selected from piperidinyl and morpholinyl) or phenyl (which latter group is optionally substituted by one or more substituents selected from halo, —CN, —CF
3
, —OCF
3
, C
1-4
alkoxy or C
1-4
alkyl (which latter two groups are optionally substituted by C
1-4
haloalkyl or C
1-4
haloalkoxy));
R
4
represents H or C
1-4
alkyl;
R
3
represents OR
5
or N(R
6
)R
7
;
R
5
represents C
3-6
cycloalkyl, —(C
1-4
alkylene)-1-piperidinyl, tetrahydrofuranyl, tetrahydropyranyl or C
1-6
alkyl, which latter group is optionally substituted and/or terminated by one or two substituents selected from C
3-5
cycloalkyl, —OR
8
, —N(R
6
)R
7
, phenyl, furanyl and pyridinyl, and which C
1-6
alkyl group is optionally terminated by a C
1-4
haloalkyl group;
R
6
and R
7
independently represent, at each occurrence when used herein, H, C
1-4
alkyl (optionally substituted by C
3-5
cycloalkyl or C
1-4
alkoxy), or R
6
and R
7
, together with the nitrogen atom to which they are attached, form an azetidinyl, pyrrolidinyl, piperidinyl or morpholinyl group;
R
8
represents H, C
1-4
alkyl (which C
1-4
alkyl group is optionally terminated by a C
1-4
haloalkyl group) or benzyl;
Het
1
represents a 4-R
9
-1-piperazinyl group optionally substituted with one or two C
1-4
alkyl groups and optionally in the form of its 4-N-oxide;
R
9
represents H, pyridinyl, pyrimidinyl, C
3-6
alkenyl or C
1-4
alkyl optionally substituted by one or two substituents selected from —OH, —N(R
6
)R
7
, —C(O)N(R
6
)R
7
, benzodioxolyl, benzodioxanyl or phenyl (which latter group is optionally substituted by C
1-4
alkoxy);
Het
2
represents a C-linked 6-membered heterocyclic group containing one or two nitrogen atoms, optionally in the form of its mono-N-oxide, or a C-linked 5-membered heterocyclic group containing two or three nitrogen atoms, wherein either of said heterocyclic groups is optionally substituted with C
1-4
alkyl, C
1-4
alkoxy or N(H)R
10
; and
R
10
represents H, C
1-4
alkyl or C
1-4
alkanoyl;
or a pharmaceutically, or a veterinarily, acceptable derivative thereof;
which compounds are referred to together hereinafter as “the compounds of the invention”.
Unless otherwise indicated, each alkyl, alkoxy and alkenyl group identified herein may, when there is a sufficient number of carbon atoms (i.e. three) be linear or branched chain. Alkanoyl groups identified herein may also, when there is a sufficient number of carbon atoms (i.e. four) be linear or branched chain. The term “halo”, when used herein, includes fluoro, chloro, bromo and iodo. As used herein, haloalkyl and haloalkoxy groups are preferably —CF
3
and —OCF
3
respectively.
For the avoidance of doubt, each R
6
and R
7
group identified herein is independent of other R
6
and R
7
groups, respectively. For example, when R
5
and R
9
both represent alkyl substituted by —N(R
6
)R
7
, the two individual —N(R
6
)R
7
substituents are independent of one another, and are not necessarily identical (though this possibility is not excluded).
The term “pharmaceutically, or a veterinarily, acceptable derivative” includes salts and solvates. The pharmaceutically or veterinarily acceptable salts of the compounds of the invention which contain a basic centre are, for example, non-toxic acid addition salts formed with inorganic acids such as hydrochloric, hydrobromic, hydroiodic, sulphuric and phosphoric acid, with carboxylic acids or with organo-sulphonic acids.
Examples include the HCl, HBr, HI, sulphate or bisulphate, nitrate, phosphate or hydrogen phosphate, acetate, benzoate, succinate, saccarate, fumarate, maleate, lactate, citrate, tartrate, gluconate, camsylate, methanesulphonate, ethanesulphonate, benzenesulphonate, p-toluenesulphonate and pamoate salts. Compounds of the invention can also provide pharmaceutically or veterinarily acceptable metal salts, in particular non-toxic alkali and alkaline earth metal salts, with bases. Examples include the sodium, potassium, aluminium, calcium, magnesium, zinc and diethanolamine salts. Pharmaceutically acceptable derivatives also include C
1-4
alkyl ammonium salts. For a review on suitable pharmaceutical salts see Berge et al,
J. Pharm, Sci.,
66, 1-19, 1977.
The pharmaceutically acceptable solvates of the compounds of the invention include the hydrates thereof.
Also included within the scope of the compound and various salts of the invention are polymorphs thereof.
Abbreviations are listed at the end of this specification.
Preferred compounds of the invention include those wherein:
R
1
and R
2
independently represent optionally substituted phenyl or C
1-4
alkyl optionally substituted and/or terminated by Het
2
or optionally substituted phenyl;
R
3
represents OR
5
;
R
5
represents C
1-5
alkyl optionally substituted and/or terminated by C
1-2
alkoxy;
Het
1
represents a 4-R
9
-1-piperazinyl group;
R
9
represents C
1-4
alkyl;
Het
2
represents an optionally substituted C-linked 6-membered heterocyclic group containing two, or preferably one, nitrogen atoms.
More preferred compounds of the invention include those wherein:
R
1
and R
2
independently represent phenyl, methyl, ethyl, propyl, benzyl or pyridylmethyl;
R
3
represents ethoxy (optionally substituted or terminated by a methoxy group), propoxy or butoxy;
Het
1
represents 4-ethyl-1-piperazinyl.
The compounds of the invention may exhibit tautomerism. All tautomeric forms of the compounds of formula I and mixtures thereof, are included within the scope of the invention.
A compound of the formula (I) contains one or more asymmetric carbon atoms and therefore exists in two or more stereoisomeric forms. Where a compound of the formula (I) contains an alkenyl or alkenylene group, cis (E) and trans (Z) isomerism may also occur. The present invention includes the individual stereoisomers of the compounds of the formula (I) and, where appropriate, the individual tautomeric forms thereof, together with mixtures thereof. Separation of diastereoisomers or cis and trans isomers may be achieved by conventional techniques, e.g. by fractional crystallisation, chromatography or H.P.L.C. of a stereoisomeric mixture of a compound of the formula (I) or a suitable salt or derivative thereof. An individual enantiomer of a compound of the formula (I) may also be prepared from a corresponding optically pure intermediate or by resolution, such as by H.P.L.C. of the corresponding racemate using a suitable chiral support or by fractional crystallisation of the diastereoisomeric salts formed by reaction of the corresponding racemate with a suitable optically active acid or base, as appropriate.
All stereoisomers are included within the scope of the invention.
Also included within the scope of the invention are radiolabelled derivatives of compounds of formula I which are suitable for biological studies.
Preparation
According to a further aspect of the invention there is provided processes for the preparation of compounds of the invention, as illustrated

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