Tetracyclic derivatives, process of preparation and use

Details Tetracyclic derivatives, process of preparation and use Tetracyclic derivatives, process of preparation and use

2002-02-05

2004-08-31

Raymond, Richard L. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S869000, C514S929000

Reexamination Certificate

active

06784179

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
represents hydrogen, C
1-6
alkyl, C
2-6
alkenyl, C
2-6
alkynyl, haloC
1-6
alkyl, C
3-8
cycloalkyl, C
3-8
cycloalkylC
1-3
alkyl, arylC
1-3
alkyl or heteroarylC
1-3
alkyl;
R
2
represents an optionally substituted monocyclic aromatic ring selected from benzene, thiophene, furan and pyridine or an optionally substituted bicyclic ring
attached to the rest of the molecule via one of the benzene ring carbon atoms and wherein the fused ring A is a 5- or 6-membered ring 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; and
R
3
represents hydrogen or C
1-3
alkyl, or R
1
and R
3
together represent a 3- or 4-membered alkyl or alkenyl chain.
There is further provided by the present invention a subgroup of compounds of formula (I), the subgroup comprising compounds of formula (Ia)
and salts and solvates (e.g. hydrates) thereof, in which:
R
0
represents hydrogen, halogen or C
1-6
alkyl;
R
1
represents hydrogen, C
1-6
alkyl, halo C
1-6
alkyl, C
3-8
cycloalkyl, C
3-8
cycloalkylC
1-3
alkyl, arylC
1-3
alkyl or heteroarylC
1-3
alkyl; and
R
2
represents an optionally substituted monocyclic aromatic ring selected from benzene, thiophene, furan and pyridine or an optionally substituted bicyclic ring
attached to the rest of the molecule via one of the benzene ring carbon atoms and wherein the fused ring A is a 5- or 6-membered ring 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.
Within R
1
above, the term “aryl” as part of an arylC
1-3
alkyl group means phenyl or phenyl substituted by one or more (e.g. 1, 2 or 3) substituents selected from halogen, C
1-6
alkyl, C
1-6
alkoxy and methylenedioxy. The term “heteroaryl” as part of a heteroarylC
1-3
alkyl group means thienyl, furyl or pyridyl each optionally substituted by one or more (e.g. 1, 2 or 3) substituents selected from halogen, C
1-6
alkyl and C
1-6
alkoxy. The term “C
3-8
cycloalkyl” as a group or part of a C
3-8
cycloalkylC
1-3
alkyl group means a monocyclic ring comprising three to eight carbon atoms. Examples of suitable cycloalkyl rings include the C
3-6
cycloalkyl rings cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
Within R
2
above, optional benzene ring substituents are selected from one or more (e.g. 1, 2 or 3) atoms or groups comprising halogen, hydroxy, C
1-6
alkyl, C
1-6
alkoxy, —CO
2
R
b
, halo C
1-6
alkyl, halo C
1-6
alkoxy, cyano, nitro and NR
a
R
b
, where R
a
and R
b
are each hydrogen or C
1-6
alkyl, or R
a
may also represent C
2-7
alkanoyl or C
1-6
alkylsulphonyl. Optional substituents for the remaining ring systems are selected from one or more (e.g. 1, 2 or 3) atoms or groups comprising halogen, C
1-6
alkyl, C
1-6
alkoxy and arylC
1-3
alkyl as defined above. The bicyclic ring
may, for example, represent naphthalene, a heterocycle such as benzoxazole, benzothiazole, benzisoxazole, benzimidazole, quinoline, indole, benzothiophene or benzofuran or
(where n is an integer 1 or 2 and X and Y may each represent CH
2
, O, S or NH).
In the above definitions, the term “alkyl” as a group or part of a group means a straight chain or, where available, a branched chain alkyl moiety. For example, it may represent a C
1-4
alkyl function as represented by methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl and t-butyl. The term ‘alkenyl’ as used herein includes straight-chained and branched alkenyl groups, such as vinyl and allyl groups. The term ‘alkynyl’ as used herein includes straight-chained and branched alkynyl groups, suitably acetylene. The term “halogen” herein means a fluorine, chlorine, bromine or iodine atom. The term “haloC
1-6
alkyl” means an alkyl group as defined above comprising one to six carbon atoms substituted at one or more carbon atoms by one or more (e.g. 1, 2 or 3) halogen atoms. Similarly, a halo C
1-6
alkoxy group is a halo C
1-6
alkyl group as defined above linked to the R
2
benzene ring via an oxygen atom. Examples of haloC
1-6
alkyl groups include trifluoromethyl and 2,2,2-trifluoroethyl. An example of a halo C
1-6
alkoxy group is trifluoromethoxy. The term “C
2-7
alkanoyl” means a C
1-6
alkylcarbonyl group where the C
1-6
alkyl portion is as defined above. An example of a suitable C
2-7
alkanoyl group is the C
2
alkanoyl group acetyl.
It will be appreciated that when R
o
is a halogen atom or a C
1-6
alkyl group this substituent may be sited at any available position on the phenyl portion of the tetracyclic ring. However, a particular site of attachment is the ring 10-position.
The compounds of formula (I) may contain two or more asymmetric centres and thus can exist as enantiomers or diastereoisomers. In particular, in formula (I) above two ring chiral centres are denoted with asterisks. It is to be understood that the invention includes both mixtures and separate individual isomers of the compounds of formula (I).
The compounds of formula (I) may also exist in tautomeric forms and the invention includes both mixtures and separate individual tautomers thereof.
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.
A particular group of compounds of the invention are those compounds of formula (I) in which R
0
is hydrogen or halogen (e.g. fluorine), especially hydrogen.
Another particular group of compounds of the invention are those compounds of formula (I) in which R
1
represents hydrogen, C
1-4
alkyl, haloC
1-4
alkyl, C
3-6
cycloalkyl, C
3-6
cycloalkylmethyl, pyridylC
1-3
alkyl, furylC
1-3
alkyl or optionally substituted benzyl. Within this particular group of compounds, examples of C
1-4
alkyl groups are methyl, ethyl, n-propyl, i-propyl and n-butyl. Examples of C
3-6
cycloalkylmethyl groups are cyclopropylmethyl and cyclohexylmethyl. Examples of optionally substituted, benzyl groups include benzyl and halobenzyl (e.g. fluorobenzyl).
A further particular group of compounds of the invention are those compounds of formula (I) in which R
2
represents an optionally substituted benzene, thiophene, furan, pyridine or naphthalene ring or an optionally substituted bicyclic ring
(where n is 1 or 2 and X and Y are each CH
2
or O). Within this particular group of compounds, examples of substituted benzene groups are benzene substituted by one of halogen (e.g. chlorine), hydroxy, C
1-3
alkyl (e.g. methyl, ethyl or i-propyl), C
1-3
alkoxy (e.g. methoxy or ethoxy), —CO
2
R
b
, halomethyl (e.g. trifluoromethyl), halomethoxy (e.g. trifluoromethoxy), cyano, nitro or NR
a
R
b
where R
a
and R
b
are each hydrogen or methyl or R
a
is acetyl; or benzene substituted by dihalo (e.g. dichloro) or by C
1-3
alkoxy (e.g. methoxy) and one of halogen (e.g. chlorine) and hydroxy. An example

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