Tetra-substituted phenyl derivatives and processes for their...

Details Tetra-substituted phenyl derivatives and processes for their... Tetra-substituted phenyl derivatives and processes for their...

1998-03-26

2001-03-06

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...

C546S255000, C546S261000, C546S262000

Reexamination Certificate

active

06197792

ABSTRACT:

This invention relates to a novel series of tetra-substituted 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 adenyl 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 adenyl 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 tetra-substituted 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 human recombinant 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 —X
a
R
1
group where X
a
is —O—, —S(O)
m
— [where m is zero or an integer of value 1 or 2], or —N(R
a
)— [where R
a
is a hydrogen atom or an optionally substituted alkyl group] and R
1
is an optionally substituted alkyl group or, (2) ═N—;
X is as described above for X
a
or is a chain —CR═C(R
b
)— or —[—CH(R)]
q
—CH(R
b
)— where R is a hydrogen or a fluorine atom or a methyl group, R
b
is as described below for R
2
and q is zero or the integer 1;
R
2
is (1) an optionally substituted alkyl, alkenyl, cycloalkyl or cycloalkenyl group when X is —O—, —S(O)
m
— or —N(R
a
)—; or when X is —CR═C(R
b
)— or —[—CH(R)]
q
CH(R
b
)— is (2) a hydrogen atom, or an optionally substituted straight or branched alkyl, alkenyl or alkynyl, alkoxy, alkylthio, —CO
2
R
9
(where R
9
is a hydrogen atom or an optionally substituted alkyl, aryl or aralkyl group), —CONR
10
R
11
(where R
10
and R
11
which may be the same or different is as described for R
9
), —CSNR
10
R
11
, —CN or NO
2
group; or R
2
and R
b
, together with the carbon atom to which they are both attached, are linked to form an optionally substituted cycloalkyl or cycloalkenyl group optionally containing one or more X
a
atoms or groups;
R
3
is an atom or group R
13
or —L
1
R
13
where L
1
is a linker group and R
13
is a halogen atom or an Alk
1
[where Alk
1
is an optionally substituted straight or branched C
1-6
alkyl, C
2-6
alkenyl or C
2-6
alkynyl group optionally interrupted by one, two, or three —O—, or —S— atoms or —S(O)p—, [where p is an integer 1 or 2], or —N(R
a
)— groups], or an amino (—NH
2
), substituted amino, nitro, cyano, hydroxyl (—OH), substituted hydroxyl, cycloalkyl, cycloalkoxy, formyl [HC(O)—], carboxyl (—CO
2
H), esterified carboxyl, thiol (—SH), substituted thiol, —C(O)Alk
1
, —SO
3
H, —SO
2
Alk
1
, —SO
2
NH
2
, —SO
2
NHAlk
1
, —SO
2
N[Alk
1
]
2
, —SO
2
NHAr [where Ar is as defined below for R
6
], —SO
2
N(Alk
1
)Ar, —CONH
2
, —CONHAlk
1
, —CON[Alk
1
]
2
, —CONHAr, —CON(Alk
1
)Ar, —NHSO
2
H, —NAlk
1
SO
2
H, —NHSO
2
Alk
1
, —NAlk
1
SO
2
Alk
1
, —N[SO
2
Alk
1
]
2
, —N(Alk
1
)SO
2
N(Alk
1
)Ar, —NHSO
2
NH
2
, —N(Alk
1
)SO
2
NH
2
, —NHSO
2
NHAlk
1
, —N(Alk
1
)SO
2
NHAlk
1
, —NHSO
2
N[Alk
1
]
2
, —NAlk
1
SO
2
N[Alk
1
]
2
, —NHSO
2
NHAr, —N(Alk
1
)SO
2
NHAr, —NHSO
2
N(Alk
1
)Ar, —N(Alk
1
)SO
2
N(Alk
1
)Ar, —NHC(O)Alk
1
, —N(Alk
1
)C(O)Alk
1
, —N[C(O)Alk
1
]
2
, —NHC(O)OAlk
1
, —N(Alk
1
)C(O)OAlk
1
, —Ar, —Het [where Het is a C
5-7
heterocycloalkyl group], —CONHet
1
[where —NHet
1
is a C
5-7
cycloamino group optionally containing one or more —O— or —S— atoms or —N(R
a
)— groups], —SO
2
NHet
1
, —NHSO
2
NHet
1
, —CSAlk
1
, —CSNH
2
, —CSNHAlk
1
, —CSN[Alk
1
]
2
, —CSNHAr, —CSN(Alk
1
)Ar, —NHC(S)Alk
1
, —N(Alk
1
)C(S)Alk
1
, —CSNHet
1
group, —N[C(S)Alk
1
]
2
, —N[C(O)Alk
1
]SO
2
Alk
1
, —N[C(S)Alk
1
]SO
2
Alk
1
, —NHC(O)NH
2
, —NHC(O)NHAlk
1
, —NHC(O)N[Alk
1
]
2
, —N(Alk
1
)CONH
2
, —N(Alk
1
)C(O)NHAlk
1
, —N(Alk
1
)C(O)N[Alk
1
]
2
, —NHC(S)NH
2
, —NHC(S)NHAlk
1
, —NHC(S)N[Alk
1
]
2
, —N(Alk
1
)CSNH
2
, —N(Alk
1
)C(S)NHAlk
1
, or —N(Alk
1
)C(S)N[Alk
1
]
2
, group;
R
4
is a hydrogen atom or is as defined for R
6
;
R
5
is a hydrogen or a fluorine atom, or an OR
c
group where R
c
is a hydrogen atom or an optionally substituted straight or branched alkyl, alkenyl, alkoxyalkyl, alkanoyl, formyl, carboxamido, thiocarboxamido, cycloalkyl, or cycloalkenyl group;
R
6
is a group —(CH
2
)
n
Ar where Ar is an optionally substituted monocyclic or bicyclic aryl ring optionally interrupted by one or more heteroatoms —O—, —S— or —N— and n is zero or the integer 1, 2 or 3;
R
7
and R
8
, which may be the same or different, is a hydrogen or a fluorine atom, or an optionally substituted straight or branched alkyl group; and the salts, solvates, prodrugs, hydrates and N-oxides thereof.
It will be appreciated that compounds of formula (1) may have one or more chiral centres depending on the nature of the groups X, R, R
3
, R
4
, R
5
, R
6
, and R
7
. Where one or more chiral centres is present, enantiomers or diasteromers 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) where X is a chain —CR═C(R
b
)— may exist as geometric isomers depending on the nature of the groups R, R
b
and R
2
, and the invention is to be understood to extend to all such isomers and mixtures thereof.
In the compounds of formula (1), when Y is a halogen atom it may be for example a fluorine, chlorine, bromine or iodine atom.
When ═W— in the compounds of formula (1) is a group ═C(Y)— where Y is a group —X
a
R
1
, R
1
may be, for example, 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 substitutents which may be present on R
1
groups include one or more halogen atoms, e.g. fluorine, or chlorine atoms. Particu

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