Trisubstituted phenyl derivatives and process for their...

Details Trisubstituted phenyl derivatives and process for their... Trisubstituted phenyl derivatives and process for their...

1998-03-26

2001-10-02

Rotman, Alan L. (Department: 1612)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C546S290000, C546S339000, C546S334000, C514S277000, C514S357000

Reexamination Certificate

active

06297264

ABSTRACT:

This invention relates to a novel series of trisubstituted phenyl derivatives, to processes for their preparation, to pharmaceutical compositions containing them, and to their use in medicine.
Many hormones and neurotransmitters modulate tissue function by elevating intra-cellular levels of adenosine 3′, 5′-cyclic monophosphate (cAMP). The cellular levels of cAMP are regulated by mechanisms which control synthesis and breakdown. The synthesis of cAMP is controlled by adenylyl cyclase which may be directly activated by agents such as forskolin or indirectly activated by the binding of specific agonists to cell surface receptors which are coupled to adenylyl cyclase. The breakdown of cAMP is controlled by a family of phosphodiesterase (PDE) isoenzymes, which also control the breakdown of guanosine 3′,5′-cyclic monophosphate (cGMP). To date, seven members of the family have been described (PDE I-VII) the distribution of which varies from tissue to tissue. This suggests that specific inhibitors of PDE isoenzymes could achieve differential elevation of cAMP in different tissues, [for reviews of PDE distribution, structure, function and regulation, see Beavo & Reifsnyder (1990) TIPS, 11: 150-155 and Nicholson et al (1991) TIPS, 12: 19-27].
There is clear evidence that elevation of cAMP in inflammatory leukocytes leads to inhibition of their activation. Furthermore, elevation of cAMP in airway smooth muscle has a spasmolytic effect. In these tissues, PDE IV plays a major role in the hydrolysis of cAMP. It can be expected, therefore, that selective inhibitors of PDE IV would have therapeutic effects in inflammatory diseases such as asthma, by achieving both anti-inflammatory and bronchodilator effects.
The design of PDE IV inhibitors has met with limited success to date, in that many of the potential PDE IV inhibitors which have been synthesised have lacked potency and/or have been capable of inhibiting more than one type of PDE isoenzyme in a non-selective manner. Lack of a selective action has been a particular problem given the widespread role of cAMP in vivo and what is needed are potent selective PDE IV inhibitors with an inhibitory action against PDE IV and little or no action against other PDE isoenzymes.
We have now found a novel series of trisubstituted phenyl derivatives, members of which are potent inhibitors of PDE IV at concentrations at which they have little or no inhibitory action on other PDE isoenzymes. These compounds inhibit the isolated PDE IV enzyme and also elevate cAMP in isolated leukocytes. The compounds of the invention are therefore of use in medicine, especially in the prophylaxis and treatment of asthma.
Thus according to one aspect of the invention, we provide a compound of formula (1)
wherein
═W— is (1) ═C(Y)— where Y is a halogen atom, or an alkyl or —XR
a
group where X is —O—, —S(O)
m
— [where m is zero or an integer of value 1 or 2], or —N(R
b
)— [where R
b
is a hydrogen atom or an optionally substituted alkyl group] and R
a
is a hydrogen atom or an optionally substituted alkyl group or, (2) ═N—;
L is a —XR, [where R is an optionally substituted alkyl, alkenyl, cycloalkyl or cyloalkenyl group], —C(R
11
)═C(R
1
)(R
2
) or [—CH(R
11
)]
n
CH(R
1
)(R
2
) group where R
11
is a hydrogen or a fluorine atom or a methyl group, and R
1
and R
2
, which may be the same or different, is each a hydrogen or fluorine atom or an optionally substituted alkyl, alkenyl, alkynyl, alkoxy, alkylthio, —CO
2
R
8
, [where R
8
is a hydrogen atom or an optionally substituted alkyl, aralkyl, or aryl group], —CONR
9
R
10
[where R
9
and R
10
, which may be the same or different are as defined for R
8
], —CSNR
9
R
10
, —CN or —NO
2
group, or R
1
and R
2
together with the C atom to which they are attached are linked to form an optionally substituted cycloalkyl or cycloalkenyl group and n is zero or the integer 1;
Z is (1) a group —C(R
3
)(R
4
)C(R
5
)(R
6
)(R
7
) or —C(R
4
)═C(R
5
)(R
6
) where R
3
is a hydrogen or a fluorine atom or an optionally substituted straight or branched alkyl group;
R
4
is a group selected from —X
a
L
1
R
12
[where X
a
is as defined above for X, L
1
is a linker group and R
12
is a hydrogen atom or a cycloaliphatic, heterocycloaliphatic, or monocyclic or bicyclic aryl group optionally containing one or more heteroatoms selected from oxygen, sulphur or nitrogen atoms], —Alk
1
R
12
[where Alk
1
is an optionally substituted straight or branched alkenyl or alkynyl chain optionally containing one or more —O— or —S— atoms or —N(R
b
)—, carbocyclic or heteroatom-containing groups], —CH
2
L
1
R
12a
[where R
12a
is as defined for R
12
but is not a hydrogen atom]; —X
a
R
12a
; or —C(X
b
)R
12a
[where X
b
is an oxygen or sulphur atom];
R
5
is a —(CH
2
)
p
Ar group where p is zero or an integer 1, 2 or 3 and Ar is a monocyclic or bicyclic aryl group optionally containing one or more heteroatoms selected from oxygen, sulphur or nitrogen atoms;
R
6
is a hydrogen or a fluorine atom or an optionally substituted alkyl group;
R
7
is a hydrogen or a fluorine atom or an OR
c
group where R
c
is a hydrogen atom or an optionally substituted alkyl or alkenyl group, or an alkoxyalkyl, alkanoyl, formyl, carboxamido or thiocarboxamido group; or Z is (2) a group —C(R
4
)C(R
5
)(R
6
)(R
7
) where R
4
is a group ═CH
2
, or ═CH(L
1
)
n
—R
12
;
and the salts, solvates, hydrates, prodrugs and N-oxides thereof.
It will be appreciated that certain compounds of formula (1) may have one or more chiral centres, depending on the nature of the groups L
1
, R
1
, R
2
, R
3
, R
4
, R
5
, R
6
and R
7
. Where one or more chiral centres is present, enantiomers or diastereomers may exist, and the invention is to be understood to extend to all such enantiomers, diastereomers and mixtures thereof, including racemates.
Compounds of formula (1) wherein L is a —C(R
11
)═C(R
1
)(R
2
) group and/or Z is the group —C(R
4
)═C(R
5
)(R
6
), may exist as geometric isomers depending on the nature of the groups R
1
, R
2
, R
4
, R
5
, R
6
and R
11
and the invention is to be understood to extend to all such isomers and mixtures thereof.
In the compounds of formula (1), when ═W— is ═C(Y)— and Y is a halogen atom Y may be for example a fluorine, chlorine, bromine or iodine atom.
When W in the compounds of formula (1) is a group ═C(Y)— and Y is —XR
a
, R
a
may be, for example, a hydrogen atom or an optionally substituted straight or branched alkyl group, for example, an optionally substituted C
1-6
alkyl group, such as a methyl, ethyl, n-propyl or i-propyl group. Optional substituents which may be present on R
a
groups include one or more halogen atoms, e.g. fluorine, or chlorine atoms. Particular R
a
groups include for example —CH
2
F, —CH
2
Cl, —CHF
2
, —CHCl
2
, —CF
3
or —CCl
3
groups.
When ═W— in the compounds of formula (1) is a group ═C(Y)— where —Y is —N(R
b
), ═W— may be a ═C(NH
2
)—, ═C(NHCH
3
)— or ═C(NHC
2
H
5
)— group.
In compounds of formula (1), X may be an oxygen or a sulphur atom, or a group —S(O)—, —S(O)
2
—, —NH— or C
1-6
alkylamino, for example a C
1-3
alkylamino, e.g. methylamino [—N(CH
3
)—] or ethylamino [—N(C
2
H
5
)—] group.
Alkyl groups represented by Y, R, R
1
, R
2
, or R
b
in the compounds of formula (1) include optionally substituted straight or branched C
1-6
alkyl groups optionally interrupted by one or more X atoms or groups. Particular examples include C
1-3
alkyl groups such as methyl or ethyl groups. Optional substituents on these groups include one, two or three substituents selected from halogen atoms, e.g. fluorine, chlorine, bromine or iodine atoms, or hydroxyl or C
1-6
alkoxy e.g. C
1-3
alkoxy such as methoxy or ethoxy or —CO
2
R
8
, —CONR
9
R
10
, —CSNR
9
R
10
or —CN groups.
Alkenyl groups represented by R, R
1
or R
2
in the compounds of formula (1) include optionally substituted straight or

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