Heterosubstituted pyridine derivatives as PDE4 inhibitors

Details Heterosubstituted pyridine derivatives as PDE4 inhibitors Heterosubstituted pyridine derivatives as PDE4 inhibitors

2000-04-17

2001-03-13

Davis, Zinna Northington (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C546S256000, C546S264000, C514S332000

Reexamination Certificate

active

06200993

ABSTRACT:

BACKGROUND OF THE INVENTION
This invention relates to compounds and pharmaceutical compositions containing such compounds useful for treating diseases by raising the level of cyclic adenosine 3′,5′-monophosphate (cAMP) through the inhibition of phosphodiesterase IV (PDE 4).
Many hormones and neurotransmitters modulate tissue function by elevating intra-cellular levels of 3′,5′-cyclic adenosine 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, nine members of the family have been described (PDE 1-9) 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, Nicholson et al (1991) TIPS, 12: 19-27 and Houslay et al (1998) Adv. Pharmacol. 44: 225-342].
The availability of PDE isotype selective inhibitors has enabled the role of PDEs in a variety of cell types to be investigated. In particular it has been established that PDE 4 controls the breakdown of cAMP in many inflammatory cells, for example, basophils (Peachell P. T. et al., (1992) J. Immunol. 148 2503-2510) and eosinophils (Dent G. et al., (1991) Br. J. Pharmacol. 103 1339-1346) and that inhibition of this isotype is associated with the inhibition of cell activation. Furthermore, elevation of cAMP in airway smooth muscle has a spasmolytic effect. Consequently PDE 4 inhibitors are currently being developed as potential anti-inflammatory drugs particularly for the prophylaxis and treatment of asthma, by achieving both anti-inflammatory and bronchodilator effects.
The application of molecular cloning to the study of PDEs has revealed that for each isotype there may be one or more isoforms. For PDE 4, it is has been shown that there are four isoforms (A, B, C and D) each coded for by a separate gene in both rodents (Swinnen J. V. et al., (1989) Proc. Natl. Acad. Sci. USA 86 5325-5329) and man (Bolger G. et al., (1993) Mol. Cell Biol. 13 6558-6571).
The existence of multiple PDE 4s raises the prospect of obtaining inhibitors that are selective for individual isoforms thus increasing the specificity of action of such inhibitors. This assumes that the different PDE 4 isoforms are functionally distinct. Indirect evidence in support of this comes from the selective distribution of these isoforms in different tissues (Swinnen et al., 1989; Bolger et al., 1993; Obernolte R. et at., (1993) Gene 129 239-247, ibid) and the high degree of sequence conservation amongst isoforms of different species.
To date full length cDNAs for human PDE 4A, B, C and D (Bolger et al., 1993 ibid; Obernolte et al., 1993 ibid; Mclaughlin M. et al., (1993) J. Biol. Chem. 268 6470-6476, Owens et al (1997) Cell. Signal., 9: 575-585) and rat PDE 4A, B and D (Davis R. et al., (1989) Proc. Natl. Acad. Sci. USA 86 3604-3608; Swinnen J. V. et al., (1991) J. Biol. Chem. 266 18370-18377), have been reported, enabling functional recombinant enzymes to be produced by expression of the cDNAs in an appropriate host cell. These cDNAs have been isolated by conventional hybridisation methods.
The design of PDE 4 inhibitors for the treatment of inflammatory diseases such as asthma, has met with limited success to date. Many of the PDE 4 inhibitors which have been synthesised have lacked potency and/or inhibit more than one type of PDE isoenzyme in a non-selective manner. PDE 4 inhibitors that are relatively potent and selective for PDE 4, are reported to be emetic as well. Indeed this side effect has been so universal that experts have expressed their belief that the emesis experienced upon administration of a PDE 4 inhibitor, may be mechanism based.
One object of the present invention is to provide heterosubstituted pyridines derivatives that are inhibitors of PDE 4 at concentrations at which they have little or no inhibitory action on other PDE isoenzymes. These compounds inhibit the human recombinant PDE 4 enzyme and also elevate cAMP in isolated leukocytes. The compounds thus prevent, alleviate or reduce inflammation in the lungs, such as that induced by carrageenan, platelet-activating factor (PAF), interleukin-5 (IL-5) or antigen challenge. The compounds also suppress the hyperresponsiveness of airway smooth muscle seen in inflammed lungs.
Another object of the present invention is to provide compounds that have good oral activity and that at orally effective doses, exhibit a reduced incidence of the side-effects associated with known PDE 4 inhibitors, such as rolipram. The compounds of the invention are therefore of use in medicine, especially in the prophylaxis and treatment of asthma and other inflammatory conditions.
SUMMARY OF THE INVENTION
A compound represented by formula I:
or a pharmaceutically acceptable salt or hydrate thereof wherein:
Y represents N or N-oxide;
R
1
and R
2
are independently selected from: H, C
1-6
alkyl and haloC
1-6
alkyl,
R
3
and R
4
are independently selected from H and C
1-6
alkyl, or R
3
and R
4
attached to the same carbon atom are taken together and represent a carbonyl oxygen atom, or
R
3
and R
4
attached to different carbon atoms considered in combination with the carbon atoms to which they are attached along with any intervening atoms and represent a saturated 5, 6 or 7 membered carbocyclic ring,
R
5
is present or absent;
when present, R
5
represents a member selected from the group consisting of: H, C
1-6
alkyl, C(O)C
1-6
alkyl, C(O)Ar
1
, CO
2
C
1-6
alkyl, CO
2
Ar
1
, or an oxide oxygen atom, the alkyl portions of which are optionally substituted with 1-3 halo, hydroxy, C
1-4
alkyl or with one aryl group selected from phenyl, thienyl, thiazolyl, pyridyl and naphthyl;
or R
5
is taken in combination with one R
3
group that is present, and represents along with the R
3
group and any intervening atoms a 5-6 membered heterocyclic ring,
or R
5
is taken with a substituent on Ar
1
and represents a 5-6 membered heterocyclic ring fused to Ar
1
;
when R
5
is absent, the dotted line represents a bond and the carbon atom to which it is attached does not contain an R
3
group;
R
6
and R
7
are independently selected from the group consisting of: H, halo, C
1-6
alkyl, haloC
1-6
alkyl and CN;
n represents an integer of from 0-6;
each Ar
1
is independently selected from the group consisting of:
(a) thienyl
(b) thiazolyl,
(c) pyridyl
(d) phenyl and
(e) naphthyl,
each Ar
1
being optionally substituted with 1-3 members selected from the group consisting of:
(1) halo,
(2) C
1-6
alkoxy,
(3) C
1-7
alkylthio,
(4) CN,
(5) C
1-6
alkyl,
(6) C
1-6
hydroxyalkyl,
(7) —CO
2
H, —CO
2
C
1-6
alkyl,
(8) NH(SO
2
Me), N(SO
2
Me)
2
,
(9) SO
2
Me,
(10) NO
2
,
(11) C
1-6
alkenyl,
(12) haloC
1-6
alkyl, and
(13) NH
2
,
and when Ar
1
represents a phenyl or naphthyl group with two or three substituents, two such substituents may be considered in combination and represent a 5 or 6 membered fused lacone ring.
Pharmaceutical compositions and methods of treatment are also included.
DETAILED DESCRIPTION OF THE INVENTION
The present invention includes compounds represented by formula I:
as well as pharmaceutically acceptable salts and hydrates thereof wherein:
Y represents N or N-oxide;
R
1
and R
2
are independently selected from: H, C
1-6
alkyl and haloC
1-6
alkyl,
R
3
and R
4
are independently selected from H and C
1-6
alkyl, or R
3
and R
4
attached to the same carbon atom are taken together and represent a carbonyl oxygen atom, or
R
3
and R
4
attached to different carbon atoms considered in com

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