The invention encompasses the novel compound of Formula I useful in the treatment of diseases, including asthma, by raising the level of cyclic adenosine-3',5'-monophosphate (cAMP) through the inhibition of phosphodiesterase IV (PDE 4). ##STR1## or a pharmaceutically acceptable salt or hydrate thereof. The invention also encompasses pharmaceutical compositions and methods for treatment.

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:
 ##STR2##
 or a pharmaceutically acceptable salt or hydrate thereof wherein:
 Y represents N or N-oxide;
 R.sup.1 and R.sup.2 are independently selected from: H, C.sub.1-6 alkyl and
 haloC.sub.1-6 alkyl,
 R.sup.3 and R.sup.4 are independently selected from H and C.sub.1-6 alkyl,
 or R.sup.3 and R.sup.4 attached to the same carbon atom are taken together
 and represent a carbonyl oxygen atom, or
 R.sup.3 and R.sup.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.sup.5 is present or absent;
 when present, R.sup.5 represents a member selected from the group
 consisting of: H, C.sub.1-6 alkyl, C(O)C.sub.1-6 alkyl, C(O)Ar.sup.1,
 CO.sub.2 C.sub.1-6 alkyl, CO.sub.2 Ar.sup.1, or an oxide oxygen atom, the
 alkyl portions of which are optionally substituted with 1-3 halo, hydroxy,
 C.sub.1-4 alkyl or with one aryl group selected from phenyl, thienyl,
 thiazolyl, pyridyl and naphthyl;
 or R.sup.5 is taken in combination with one R.sup.3 group that is present,
 and represents along with the R.sup.3 group and any intervening atoms a
 5-6 membered heterocyclic ring,
 or R.sup.5 is taken with a substituent on Ar.sup.1 and represents a 5-6
 membered heterocyclic ring fused to Ar.sup.1 ;
 when R.sup.5 is absent, the dotted line represents a bond and the carbon
 atom to which it is attached does not contain an R.sup.3 group;
 R.sup.6 and R.sup.7 are independently selected from the group consisting
 of: H, halo, C.sub.1-6 alkyl, haloC.sub.1-6 alkyl and CN;
 n represents an integer of from 0-6;
 each Ar.sup.1 is independently selected from the group consisting of:
 (a) thienyl
 (b) thiazolyl,
 (c) pyridyl
 (d) phenyl and
 (e) naphthyl,
 each Ar.sup.1 being optionally substituted with 1-3 members selected from
 the group consisting of:
 (1) halo,
 (2) C.sub.1-6 alkoxy,
 (3) C.sub.1-7 alkylthio,
 (4) CN,
 (5) C.sub.1-6 alkyl,
 (6) C.sub.1-6 hydroxyalkyl,
 (7) --CO.sub.2 H, --CO.sub.2 C.sub.1-6 alkyl,
 (8) NH(SO.sub.2 Me), N(SO.sub.2 Me).sub.2,
 (9) SO.sub.2 Me,
 (10) NO.sub.2,
 (11) C.sub.1-6 alkenyl,
 (12) haloC.sub.1-6 alkyl, and
 (13) NH.sub.2,
 and when Ar.sup.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:
 ##STR3##
 as well as pharmaceutically acceptable salts and hydrates thereof wherein:
 Y represents N or N-oxide;
 R.sup.1 and R.sup.2 are independently selected from: H, C.sub.1-6 alkyl and
 haloC.sub.1-6 alkyl,
 R.sup.3 and R.sup.4 are independently selected from H and C.sub.1-6 alkyl,
 or R.sup.3 and R.sup.4 attached to the same carbon atom are taken together
 and represent a carbonyl oxygen atom, or
 R.sup.3 and R.sup.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.sup.5 is present or absent;
 when present, R.sup.5 represents a member selected from the group
 consisting of: H, C.sub.1-6 alkyl, C(O)C.sub.1-6 alkyl, C(O)Ar.sup.1,
 CO.sub.2 C.sub.1-6 alkyl, CO.sub.2 Ar.sup.1, or an oxide oxygen atom, the
 alkyl portions of which are optionally substituted with 1-3 halo, hydroxy,
 C.sub.1-4 alkyl or with one aryl group selected from phenyl, thienyl,
 thiazolyl, pyridyl and naphthyl;
 or R.sup.5 is taken in combination with one R.sup.3 group that is present,
 and represents along with the R.sup.3 group and any intervening atoms a
 5-6 membered heterocyclic ring,
 or R.sup.5 is taken with a substituent on Ar.sup.1 and represents a 5-6
 membered heterocyclic ring fused to Ar.sup.1 ;
 when R.sup.5 is absent, the dotted line represents a bond and the carbon
 atom to which it is attached does not contain an R.sup.3 group;
 R.sup.6 and R.sup.7 are independently selected from the group consisting
 of: H, halo, C.sub.1-6 alkyl, haloC.sub.1-6 alkyl and CN;
 n represents an integer of from 0-6;
 each Ar.sup.1 is independently selected from the group consisting of:
 (a) thienyl
 (b) thiazolyl,
 (c) pyridyl
 (d) phenyl and
 (e) naphthyl,
 each Ar.sup.1 being optionally substituted with 1-3 members selected from
 the group consisting of:
 (1) halo,
 (2) C.sub.1-6 alkoxy,
 (3) C.sub.1-7 alkylthio,
 (4) CN,
 (5) C.sub.1-6 alkyl,
 (6) C.sub.1-6 hydroxyalkyl,
 (7) --CO.sub.2 H, --CO.sub.2 C.sub.1-6 alkyl,
 (8) NH(SO.sub.2 Me), N(SO.sub.2 Me).sub.2,
 (9) SO.sub.2 Me,
 (10) NO.sub.2,
 (11) C.sub.1-6 alkenyl,
 (12) haloC.sub.1-6 alkyl, and
 (13) NH.sub.2,
 and when Ar.sup.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.
 The following definitions pertain to the terms used herein unless otherwise
 indicated.
 Halo is intended to include F, Cl, Br and I. HaloC.sub.1-6 alkyl refers to
 an alkyl group having 1-9 halo groups attached. Examples include
 --CH.sub.2 F, --CHF.sub.2, --CF.sub.3, --CH.sub.2 CH.sub.2 F,
 --CHFCH.sub.2 F, --CF.sub.2 CH.sub.2 F, --CF.sub.2 CHF.sub.2 and
 --CF.sub.2 CF.sub.3.
 Alkyl groups include straight or branched alkyl groups having 1-7 carbon
 atoms, and cyclic alkyl groups having from 3-7 carbon atoms. Cycloalkyl
 groups with alkyl substituent groups attached are also included. Examples
 of C.sub.1-6 alkyl groups include methyl, ethyl, propyl, 2-propyl, s- and
 t-butyl, butyl, pentyl, hexyl, 1,1-dimethylethyl, cyclopropyl, cyclobutyl,
 cyclopentyl and cyclohexyl. Examples of C.sub.1-6 alkoxy groups include
 methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclohexyloxy, and
 the like.
 Likewise, C.sub.1-7 alkylthio is intended to include alkylthio groups of
 from 1 to 7 carbon atoms of a straight, branched or cyclic configuration.
 Examples of alkylthio groups include methylthio, propylthio,
 isopropylthio, cycloheptylthio, etc. By way of illustration, the
 propylthio group signifies --SCH.sub.2 CH.sub.2 CH.sub.3.
 Preferred values of R.sup.1 and R.sup.2 are C.sub.1-6 alkyl and
 haloC.sub.1-6 alkyl. More preferred values are selected from the group
 consisting of CH.sub.3, CH.sub.2 F, CHF.sub.2, CF.sub.3 and most
 preferably CHF.sub.2. Within this subset, all other variables are as
 originally defined.
 Preferred values of n are 0, 1, 2 and 3. More preferred values are 0 and 1.
 Within these subsets, all other variables are as originally defined.
 Preferred values of Ar.sup.1 are phenyl and naphthyl. More preferred is
 phenyl. Within these subsets, all other variables are as originally
 defined.
 Preferred values of R.sup.3 and R.sup.4 are H and methyl. Within this
 subset, all other variables are as originally defined.
 When present, R.sup.5 may represent a member selected from the group
 consisting of: H, C.sub.1-6 alkyl, C(O)C.sub.1-6 alkyl, C(O)Ar.sup.1,
 CO.sub.2 H, CO.sub.2 H, CO.sub.2 C.sub.1-6 alkyl, CO.sub.2 Ar.sup.1, or an
 oxide oxygen atom, the alkyl portions of which are optionally substituted
 with 1-3 halo, hydroxy, C.sub.1-4 alkyl or aryl groups.
 Alternatively, R.sup.5 is taken in combination with one of the R.sup.3
 groups that is present, and represents along with the R.sup.3 group and
 any intervening atoms a 5-6 membered ring, or R.sup.5 is taken with a
 substituent on Ar.sup.1 and represents a 5-6 membered ring fused to
 Ar.sup.1. An example of R.sup.5 taken in combination with one R.sup.3
 group is shown below:
 ##STR4##
 An example of R.sup.5 taken in combination with a substituent on Ar.sup.1
 is shown below:
 ##STR5##
 As shown above, the ring represented by R.sup.5 in combination with one
 R.sup.3 group or a substituent on Ar.sup.1 is heterocyclic, containing 1
 nitrogen atom, and can be 5-7 membered.
 An example of a compound wherein R.sup.5 is absent and the dotted line
 represents a bond, and the carbon atom to which it is attached does not
 contain an R.sup.3 group is shown below:
 ##STR6##
 Preferably R.sup.5 is present and represents a member selected from the
 group consisting of: H, C.sub.1-6 alkyl, C(O)C.sub.1-6 alkyl or CO.sub.2
 C.sub.1-6 alkyl, the alkyl portions of which are optionally substituted
 with 1-3 halo, hydroxy, C.sub.1-4 alkyl groups or with one phenyl,
 thienyl, thiazolyl, pyridyl or naphthyl group. Within this subset, all
 other variables are as originally defined.
 Preferably R.sup.6 and R.sup.7 represent H or C.sub.1-6 alkyl. More
 preferably R.sup.6 and R.sup.7 represent H. Within these subsets, all
 other variables are as originally defined.
 Preferably Y is in the 4 position relative to the point of attachment to
 the ethylene moiety.
 Preferably the N shown in the pyridyl ring is in the 3 position relative to
 the point of attachment to the ethylene moiety.
 A subset of compounds that is of particular interest is defined with
 respect to formula I wherein:
 R.sup.1 and R.sup.2 are C.sub.1-6 alkyl or haloC.sub.1-6 alkyl;
 n is 0, 1, 2 or 3;
 Ar.sup.1 is phenyl or naphthyl,
 R.sup.3 and R.sup.4 are H and methyl;
 R.sup.5 is present and represents a member selected from the group
 consisting of: H, C.sub.1-6 alkyl, C(O)C.sub.1-6 alkyl or CO.sub.2
 C.sub.1-6 alkyl, the alkyl portions of which are optionally substituted
 with 1-3 halo, hydroxy, C.sub.1-4 alkyl groups or with one phenyl,
 thienyl, thiazolyl, pyridyl or naphthyl group;
 R.sup.6 and R.sup.7 represent H or C.sub.1-6 alkyl;
 Y is in the 4 position relative to the point of attachment to the ethylene
 moiety; and the N shown in the pyridyl ring is in the 3 position relative
 to the point of attachment to the ethylene moiety.
 More particularly, the subset is defined as above wherein R.sup.6 and
 R.sup.7 represent H.
 Further, the subset is as defined above, wherein R.sup.1 and R.sup.2 are
 CHF.sub.2, and n is 0, 1 or 2.
 Even more particularly, the subset is as defined above wherein R.sup.1 and
 R.sup.2 are CHF.sub.2 ;
 n is 0 or 1;
 R.sup.3 and R.sup.4 are H and
 Ar.sup.1 is phenyl.
 Examples of compounds of the invention are disclosed below:
 1.
 4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-[6-(benzylamino)3-pyridyl]ethyl}py
 ridine,
 2.
 4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-[6-(S)-(1-phenylethylamino)3-pyrid
 yl]ethyl}pyridine,
 3.
 4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-[6-(R)-(1-phenylethylamino)3-pyrid
 yl]ethyl}pyridine,
 4.
 4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-{6-[1-(4-fluorophenyl)ethylamino]3
 -pyridyl}ethyl}pyridine,
 5.
 4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-{6-[1-(4-fluorophenyl)ethylamino]3
 -pyridyl}ethyl}pyridine-N-oxide,
 6.
 4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-[6-(benzylamino)3-pyridyl]ethyl}py
 ridine-N-oxide,
 7.
 4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-[6-(S)-(1-phenylethylamino)3-pyrid
 yl]ethyl}pyridine-N-oxide,
 8.
 4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-[6-(R)-(1-phenylethylamino)3-pyrid
 yl]ethyl}pyridine-N-oxide,
 9.
 4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-[6-(2-phenylethylamino)3-pyridyl]e
 thyl}pyridine-N-oxide,
 10.
 4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-[6-[2-(2-phenylethylamino)3-pyridy
 l]ethyl}pyridine-N-oxide,
 11.
 4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-[6-(1-methyl-1-phenylethylamino)3-
 pyridyl]ethyl}pyridine-N-oxide,
 12.
 (Enantiomer-1)-4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-[6-(1-methyl-1-phen
 ylethylamino)3-pyridyl]ethyl}pyridine-N-oxide,
 13.
 (Enantiomer-2)-4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-[6-(1-methyl-1-phen
 ylethylamino)3-pyridyl]ethyl}pyridine-N-oxide,
 14.
 (Enantiomer-2)-4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-[6-(1-methyl-1-phen
 ylethylamino)3-pyridyl-N-oxide]ethyl}pyridine-N-oxide,
 15.
 4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-}6-[(2-pyridyl)methylamino]3-pyrid
 yl}ethyl}pyridine-N-oxide,
 16.
 4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-}6-[(2-pyridyl-N-oxide))methylamin
 o]3-pyridyl}ethyl}pyridine-N-oxide,
 17.
 4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-[6-(R)-(1-phenylpropylamino)3-pyri
 dyl]ethyl}pyridine-N-oxide,
 18.
 (Enantiomer-1)-4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-[6-(1-methyl-1-phen
 ylethylamino)3-pyridyl]ethyl}pyridine,
 19.
 (Enantiomer-2)-4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-[6-(1-methyl-1-phen
 ylethylamino)3-pyridyl]ethyl}pyridine,
 20.
 (Enantiomer-2)-4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-[6-(1-methyl-1-phen
 ylethylamino)3-pyridyl-N-oxide]ethyl}pyridine,
 21.
 (Enantiomer-1)-4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-{6-[1-methyl-1-phen
 ylethylamino)3-pyridyl}ethyl}pyridine-N-oxide,
 22.
 (Enantiomer-1)-4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-{6-[1-methyl-1-phen
 ylethylamino)3-pyridyl}ethyl}pyridine-N-oxide,
 23.
 4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-{6-[1-methyl-1-(4-benzyloxyphenyl)
 ethylamino]3-pyridyl}ethyl}pyridine-N-oxide,
 24.
 4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-{6-[1-methyl-1-(4-hydroxyphenyl)et
 hylamino]3-pyridyl}ethyl}pyridine-N-oxide,
 25.
 (Enantiomer-1)-4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-{6-[1-methyl-1-(3-t
 olyl)ethylamino]3-pyridyl}ethyl}pyridine-N-oxide,
 26.
 (Enantiomer-1)-4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-{6-[1-methyl-1-(3-f
 luorophenyl)ethylamino]3-pyridyl}ethyl}pyridine-N-oxide,
 27.
 (Enantiomer-1)-4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-{6-[1-methyl-1-(3-b
 romophenyl)ethylamino]3-pyridyl}ethyl}pyridine-N-oxide,
 28.
 4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-{6-[1-methyl-1-(2-pyridyl)ethylami
 no]3-pyridyl}ethyl}pyridine-N-oxide,
 29.
 4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-{6-[1-methyl-1-(2-pyridyl)-N-oxide
 ))ethylamino]3-pyridyl}ethyl}pyridine-N-oxide,
 30.
 (Enantiomer-1)-4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-{6-[1-methyl-1-(4-c
 hlorophenyl)ethylamino]3-pyridyl}ethyl}pyridine-N-oxide,
 31.
 (Enantiomer-2)-4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-{6-[1-methyl-1-(4-c
 hlorophenyl)ethylamino]3-pyridyl}ethyl}pyridine-N-oxide,
 32.
 4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-{6-[1-methyl-1-(2-tolyl)ethylamino
 ]3-pyridyl}ethyl}pyridine-N-oxide,
 33.
 (Enantiomer-1)-4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-{6-[1-methyl-1-(4-m
 ethylsulfonylphenyl)ethylamino]3-pyridyl}ethyl}pyridine-N-oxide,
 34.
 4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-{6-[1-methyl-1-(4-trifluoromethylp
 henyl)ethylamino]3-pyridyl}ethyl}pyridine-N-oxide,
 35.
 4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-{6-[1-methyl-1-(4-difluorophenyl)e
 thylamino]3-pyridyl}ethyl}pyridine-N-oxide,
 36.
 4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-{6-[1,1-dimethyl-2-(4-fluorophenyl
 )ethylamino]3-pyridyl}ethyl}pyridine-N-oxide,
 37.
 4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-{6-[2-(4-fluorophenylethylamino]3-
 pyridyl}ethyl}pyridine-N-oxide,
 38.
 4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-{6-[1-methyl-1-(3,5-difluorophenyl
 )ethylamino]3-pyridyl}ethyl}pyridine-N-oxide,
 39.
 4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-{6-[1-methyl-1-(2,4-difluorophenyl
 )ethylamino]3-pyridyl}ethyl}pyridine-N-oxide,
 40.
 (Enantiomer-1)-4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-[6-(4-fluorobenzyla
 mine)3-pyridyl]ethyl}pyridine-N-oxide,
 41.
 (Enantiomer-2)-4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-[6-(4-fluorobenzyla
 mine)3-pyridyl]ethyl}pyridine-N-oxide,
 42.
 (Enantiomer-1)-4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-{6-[1-methyl-1-(4-e
 thylphenyl)ethylamino]3-pyridyl}ethyl}pyridine-N-oxide,
 43.
 4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-[6-(2,4-difluorobenzylamine)3-pyri
 dyl]ethyl}pyridine-N-oxide,
 44.
 4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-{6-[4-fluorophenylamido]3-pyridyl}
 ethyl}pyridine-N-oxide,
 45.
 4-[2-[3,4-Bis(difluoromethoxy)phenyl]-2-{6-[4-fluorophenylamido]3-pyridyl}
 ethyl}pyridine-N-oxide,
 46. (Enantiomer-1)-4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-{6-
 [4-fluorophenylamido]3-pyridyl}ethyl}pyridine-N-oxide,
 47. (Enantiomer-1)-4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-[6-
 (1-methyl-1-thiazolylethylamino)3-pyridyl]ethyl}pyridine-N-oxide,
 48.
 4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-{6-[1-methyl-1-(4-difluoromethoxyp
 henyl)ethylamino]3-pyridyl}ethyl}pyridine-N-oxide,
 49. (Enantiomer-2)-4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-[6-
 (1-methyl-1-phenylethylamino)3-pyridyl]ethyl}pyridine-N-oxide
 hydromethanesulfonate,
 50.
 4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-{6-[1-ethyl-1-(4-fluorophenyl)prop
 ylamino]3-pyridyl}ethyl}pyridine-N-oxide,
 51. (Enantiomer-1)-4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-{6-
 [4-methylphenylamido]3-pyridyl}pyridine-N-oxide,
 52.
 4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-{6-[2-methyl-2-(4-fluorophenyl)pro
 pylamino]3-pyridyl}ethyl}pyridine-N-oxide,
 53. (Enantiomer-1)-4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-{6-
 [1,1-dimethyl2-(4-fluorophenyl)ethylamino]3-pyridyl]pyridine-N-oxide,
 54.
 4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-[6-(N-methyl-N-benzylamino)3-pyrid
 yl]ethyl}pyridine-N-oxide,
 55.
 4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-[6-(N,N-dibenzylamino)3-pyridyl]et
 hyl}pyridine-N-oxide,
 56.
 4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-[6-(N-methyl-N-benzylamino)3-pyrid
 yl]ethyl}pyridine-N-oxide,
 57.
 4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-[6-(N-methyl-N-benzylamino)3-pyrid
 yl]ethyl}pyridine-N-oxide,
 58.
 4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-[6-(N-methyl-N-2-phenylethylamino)
 3-pyridyl]ethyl}pyridine-N-oxide,
 59.
 4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-[6-(N-ethyl-N-benzylamino)3-pyridy
 l]ethyl}pyridine-N-oxide,
 60.
 4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-[6-(N-i-propyl-N-benzylamino)3-pyr
 idyl]ethyl}pyridine-N-oxide,
 61.
 4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-[6-(N-tert-butyl-N-benzylamino)3-p
 yridyl]ethyl}pyridine-N-oxide,
 62.
 4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-[6-(N-methyl-N-4-chlorobenzylamino
 )3-pyridyl]ethyl}pyridine-N-oxide,
 63.
 4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-[6-(N-methyl-N-3-methoxybenzylamin
 o)3-pyridyl]ethyl}pyridine-N-oxide,
 64.
 4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-{6-(N-methyl-N-(3-pyridyl)methylam
 ino]3-pyridyl}ethyl}pyridine-N-oxide,
 65.
 4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-[6-(N-methyl-N-2-methylbenzylamino
 )3-pyridyl]ethyl}pyridine-N-oxide,
 66.
 4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-{6-(N-methyl-N-(2-naphthyl)methyla
 mino]3-pyridyl}ethyl}pyridine-N-oxide,
 67.
 4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-[6-(N-2-hydroxyethyl-N-benzylamino
 )3-pyridyl]ethyl}pyridine-N-oxide,
 68.
 4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-[6-(N-methyl-N-4-methoxyphenylamin
 o)3-pyridyl]ethyl}pyridine-N-oxide,
 69.
 4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-[6-(N-methyl-N-4-methoxyphenylamin
 o)3-pyridyl]ethyl}pyridine-N-oxide,
 70.
 4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-[6-(N-methyl-N-(S)-1-phenylethylam
 ino)3-pyridyl]ethyl}pyridine,
 71.
 4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-[6-(N-methyl-N-(S)-1-phenylethylam
 ino)3-pyridyl]ethyl}pyridine-N-oxide,
 72.
 4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-[6-(N-methyl-N-(R)-1-phenylethylam
 ino)3-pyridyl]ethyl}pyridine-N-oxide,
 73.
 4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-[6-(N-methyl-N-phenylamino)3-pyrid
 yl]ethyl}pyridine-N-oxide,
 74.
 4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-[6-(N-hydroxyl-N-benzylamino)3-pyr
 idyl]ethyl}pyridine-N-oxide,
 75.
 4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-[6-(N-ethyl-N-(R)-1-phenylethylami
 no)3-pyridyl]ethyl}pyridine-N-oxide,
 76.
 4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-[6-(N-ethyl-N-(S)-1-phenylethylami
 no)3-pyridyl]ethyl}pyridine-N-oxide,
 77.
 4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-[6-(N-methyl-N-(3-pyridyl-N-oxide)
 methylamino]3-pyridyl]ethyl}pyridine-N-oxide,
 78.
 (Enantiomer-2)-4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-{6-[methoxy(4-fluor
 ophenyl)methanimine]3-pyridyl}ethyl}pyridine-N-oxide,
 79.
 (Enantiomer-1)-4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-[6-(N-methyl-4-fluo
 rophenylamido)3-pyridyl]ethyl}pyridine-N-oxide,
 80. 4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-[6-(N-benzyl
 trifluoroacetamido)3-pyridyl]ethyl}pyridine,
 81. 4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-[6-(N-benzyl
 acetamide)3-pyridyl]ethyl}pyridine-N-oxide,
 82.
 4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-[6-(N-1-methyl-1-phenyl)ethyl-N-(t
 ert-butyloxycarbonyl)amino]3-pyridyl}ethyl}pyridine-N-oxide,
 83.
 (Enantiomer-2)-4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-}6-[N-(1-methyl-1-p
 henyl)ethyl-N-(tert-butyloxycarbonyl)amino]3-pyridyl}ethyl}pyridine-N-oxide
 ,
 84.
 (Enantiomer-1)-4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-}6-[N-(1-methyl-1-p
 henyl)ethyl-N-(benzyloxycarbonyl)amino]3-pyridyl}ethyl}pyridine,
 85.
 (Enantiomer-2)-4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-}6-[N-(1-methyl-1-p
 henyl)ethyl-N-(benzyloxycarbonyl)amino]3-pyridyl}ethyl}pyridine,
 86.
 (Enantiomer-1)-4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-}6-[N-(1-methyl-1-(
 4-methylphenyl))ethyl-N-(benzyloxycarbonyl)amino]3-pyridyl}ethyl}pyridine,
 87.
 (Enantiomer-2)-4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-}6-[N-(1-methyl-1-(
 4-methylphenyl))ethyl-N-(benzyloxycarbonyl)amino]3-pyridyl}ethyl}pyridine,
 88.
 (Enantiomer-1)-4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-}6-[N-(1-methyl-1-(
 4-fluorophenyl))ethyl-N-(benzyloxycarbonyl)amino]3-pyridyl}ethyl}pyridine,
 89.
 (Enantiomer-2)-4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-}6-[N-(1-methyl-1-(
 4-fluorophenyl))ethyl-N-(benzyloxycarbonyl)amino]3-pyridyl}ethyl}pyridine,
 90.
 (Enantiomer-1)-4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-}6-[N-(1-methyl-1-(
 3-methylphenyl))ethyl-N-(benzyloxycarbonyl)amino]3-pyridyl}ethyl}pyridine,
 91.
 (Enantiomer-2)-4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-}6-[N-(1-methyl-1-(
 3-methylphenyl))ethyl-N-(benzyloxycarbonyl)amino]3-pyridyl}ethyl}pyridine,
 92.
 (Enantiomer-1)-4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-}6-[N-(1-methyl-1-(
 3-bromophenyl))ethyl-N-(benzyloxycarbonyl)amino]3-pyridyl}ethyl}pyridine,
 93.
 (Enantiomer-2)-4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-}6-[N-(1-methyl-1-(
 3-bromophenyl))ethyl-N-(benzyloxycarbonyl)amino]3-pyridyl}ethyl}pyridine,
 94.
 (Enantiomer-1)-4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-}6-[N-(1-methyl-1-(
 3-fluorophenyl))ethyl-N-(benzyloxycarbonyl)amino]3-pyridyl}ethyl}pyridine,
 95.
 (Enantiomer-2)-4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-}6-[N-(1-methyl-1-(
 3-fluorophenyl))ethyl-N-(benzyloxycarbonyl)amino]3-pyridyl}ethyl}pyridine,
 96.
 (Enantiomer-1)-4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-}6-[N-(1,1-dimethyl
 -2-(4-fluorophenyl))ethyl-N-(benzyloxycarbonyl)amino]3-pyridyl}ethyl}pyridi
 ne-N-oxide,
 97.
 (Enantiomer-2)-4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-}6-[N-(1,1-dimethyl
 -2-(4-fluorophenyl))ethyl-N-(benzyloxycarbonyl)amino]3-pyridyl}ethyl}pyridi
 ne-N-oxide,
 98.
 4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-{6-[N-(1,1-dimethyl-2-(4-fluorophe
 nyl))ethyl-N-(benzyloxycarbonyl)amino]3-pyridyl-N-oxide}ethyl}pyridine-N-ox
 ide,
 99.
 (Enantiomer-2)-4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-}6-[N,N-di(4-fluoro
 benzamide)]3-pyridyl}ethyl}pyridine-N-oxide,
 100.
 4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-[6-[1,2,3,4-tetrahydroisoquinoline
 ]3-pyridyl}ethyl}pyridine-N-oxide,
 101.
 4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-[6-(1-aminoindane)3-pyridyl]ethyl}
 pyridine-N-oxide,
 102.
 (Diastereomer-1)-4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-{6-[(R)-1-aminoin
 dane]3-pyridyl}ethyl}pyridine-N-oxide,
 103.
 (Diastereomer-2)-4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-{6-[(R)-1-aminoin
 dane]3-pyridyl}ethyl}pyridine-N-oxide,
 104.
 (Diastereomer-3)-4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-{6-[(S)-1-aminoin
 dane]3-pyridyl}ethyl}pyridine-N-oxide,
 105.
 (Diastereomer-4)-4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-{6-[(S)-1-aminoin
 dane]3-pyridyl}ethyl}pyridine-N-oxide,
 106.
 4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-[6-(2-phenylpyrolidine)3-pyridyl]e
 thyl}pyridine-N-oxide,
 107.
 4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-{6-[1-(4-fluorophenyl)cyclopenylam
 ino]3-pyridyl}ethyl}pyridine-N-oxide, and
 108.
 4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-[6-(2-aminoindane)3-pyridyl]ethyl}
 pyridine-N-oxide.
 As used herein, the terms "Enantiomer-1", "Enantiomer-2", "Diastereomer-1"
 and "Diastereomer-2" refer to the order of separation when purified using
 HPLC.
 The compounds described herein contain one or more asymmetric centers and
 may thus give rise to diastereomers and optical isomers. The present
 invention is meant to include all such possible isomers and diastereomers
 as well as their racemic and resolved, enantiomerically pure forms and
 pharmaceutically acceptable salts thereof.
 The invention also encompasses a pharmaceutical composition that is
 comprised of a compound of formula I in combination with a
 pharmaceutically acceptable carrier.
 Preferably the composition is comprised of a pharmaceutically acceptable
 carrier and a non-toxic therapeutically effective amount of compound of
 formula I as described above.
 Moreover, within this preferred embodiment, the invention encompasses a
 pharmaceutical composition for the treatment or prevention of disease by
 inhibition of PDE 4, resulting in an elevation of cAMP, comprising a
 pharmaceutically acceptable carrier and a non-toxic therapeutically
 effective amount of compound of formula I as described above.
 The term "pharmaceutically acceptable salts" refers to salts prepared from
 pharmaceutically acceptable non-toxic bases including inorganic bases and
 organic bases. Salts derived from inorganic bases include aluminum,
 ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic
 salts, manganous, potassium, sodium, zinc, and the like. Particularly
 preferred are the ammonium, calcium, magnesium, potassium, and sodium
 salts. Salts derived from pharmaceutically acceptable organic non-toxic
 bases include salts of primary, secondary, and tertiary amines,
 substituted amines including naturally occurring substituted amines,
 cyclic amines, and basic ion exchange resins, such as arginine, betaine,
 caffeine, choline, N,N-dibenzylethylenediamine, diethylamine,
 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine,
 ethylenediamine, N-ethylmorphonine, N-ethylpiperidine, glucamine,
 glucosamine, histidine, hydrabamine, isopropylamine, lysine,
 methylglucamine, morpholine, piperazine, piperidine, polyamine resins,
 procaine, purines, theobromine, triethylamine, trimethylamine,
 tripropylamine, tromethamine, and the like.
 It will be understood that references to the compounds of Formula I are
 meant to also include the pharmaceutically acceptable salts.
 The compounds of formula I are selective and potent inhibitors of PDE 4.
 the biological activity and utility of the compounds may be demonstrated
 as described herein.
 The compounds according to the invention are thus of particular use in the
 prophylaxis and treatment of human diseases where an unwanted inflammatory
 response or muscular spasm (for example bladder or alimentary smooth
 muscle spasm) is present and where elevation of cAMP levels may be
 expected to prevent or alleviate the disease or condition.
 Particular uses to which the compounds of the invention may be put include
 the prophylaxis and treatment of asthma, especially inflammed lung
 associated with asthma, cystic fibrosis, in the treatment of inflammatory
 airway disease, chronic bronchitis, eosinophilic granuloma, psoriasis and
 other benign and malignant proliferative skin diseases, endotoxic shock,
 septic shock, ulcerative colitis, Crohn's disease, reperfusion injury of
 the myocardium and brain, inflammatory arthritis, chronic
 glomerulonephritis, atopic dermatitis, urticaria, adult respiratory
 distress syndrome, diabetes insipidus, allergic rhinitis, allergic
 conjunctivitis, vernal conjunctivitis, arterial restenosis and
 atherosclerosis.
 The compounds of the invention also suppress neurogenic inflammation. They
 are, therefore, analgesic, antitussive and antihyperalgesic in
 inflammatory diseases associated with irritation and pain.
 The compounds also elevate cAMP in lymphocytes and thereby suppress
 unwanted lymphocyte activation in immune-based diseases such as rheumatoid
 arthritis, ankylosing spondylitis, transplant rejection and graft versus
 host disease.
 The compounds also reduce gastric acid secretion and therefore can be used
 to treat conditions associated with hypersecretion of gastric acid.
 The compounds also supress cytokine synthesis by inflammatory cells in
 response to immune or infectious stimulation. They are, therefore, useful
 in the treatment of bacterial, fungal or viral induced sepsis and septic
 shock in which cytokines such as tumour necrosis factor (TNF) are key
 mediators.
 The compounds of the invention also suppress inflammation and pyrexia due
 to cytokines and are, therefore, useful in the treatment of inflammation
 and cytokine-mediated chronic tissue degeneration which occurs in diseases
 such as rheumatoid or osteo-arthritis.
 The over-production of cytokines such as TNF in bacterial, fungal or viral
 infections or in diseases such as cancer, leads to cachexia and muscle
 wasting. Compounds of the invention ameliorate these symptoms as well.
 The compounds of the invention elevate cAMP in certain areas of the brain
 and thereby counteract depression and memory impairment.
 Compounds of the invention suppress cell proliferation in certain tumour
 cells and can be used, therefore, to prevent tumour growth and invasion of
 normal tissues.
 For the prophylaxis or treatment of disease the compounds may be
 administered as pharmaceutical compositions, and according to a further
 aspect of the invention we provide a pharmaceutical composition which
 comprises a compound of formula (1) together with one or more
 pharmaceutically acceptable carriers, excipients or diluents.
 For the treatment or prevention of any of the diseases or conditions
 described herein, the compounds of formula I may be administered orally,
 topically, parenterally, by inhalation spray or rectally in formulations
 containing conventional non-toxic pharmaceutically acceptable carriers,
 adjuvants and vehicles.
 The term parenteral as used herein includes subcutaneous, intradermal,
 intravenous, intramuscular and intrasternal injection or infusion
 techniques. In addition to the treatment of warm-blood animals such as
 mice, rats, horses, cattle sheep, dogs, cats, etc., the compounds of the
 invention are useful for the treatment of humans.
 Oral pharmaceutical compositions containing the active ingredient are
 typically in the form of tablets, troches, lozenges, aqueous or oily
 suspensions, dispersible powders or granules, emulsions, hard or soft
 capsules, syrups or elixirs. Compositions intended for oral use may be
 prepared according to any method known to the art for the manufacture of
 pharmaceutical compositions and such compositions may contain one or more
 agents selected from the group consisting of sweetening agents, flavoring
 agents, coloring agents and preserving agents in order to provide
 pharmaceutically elegant and palatable preparations.
 Tablets contain the active ingredient in admixture with non-toxic
 pharmaceutically acceptable excipients which are suitable for the
 manufacture of tablets. These excipients may be for example, inert
 diluents, such as calcium carbonate, sodium carbonate, lactose, calcium
 phosphate or sodium phosphate; granulating and disintegrating agents, for
 example, corn starch, or alginic acid; binding agents, for example starch,
 gelatin or acacia, and lubricating agents, for example, magnesium
 stearate, stearic acid or talc. The tablets may be uncoated or they may be
 coated by known techniques to delay disintegration and absorption in the
 gastrointestinal tract and thereby provide a sustained action over a
 longer period. For example, a time delay material such as glyceryl
 monostearate or glyceryl distearate may be employed. They may also be
 coated by the technique described in the U.S. Pat. Nos. 4,256,108;
 4,166,452; and 4,265,874 to form osmotic therapeutic tablets for control
 release.
 In hard gelatin capsules, the active ingredient is typically mixed with an
 inert solid diluent, for example, calcium carbonate, calcium phosphate or
 kaolin. In soft gelatin capsules, the active ingredient is typically mixed
 with water or an oil medium, for example peanut oil, liquid paraffin or
 olive oil.
 Aqueous suspensions contain the active material in admixture with
 excipients suitable for the manufacture of aqueous suspensions. Such
 excipients are suspending agents, for example sodium
 carboxymethyl-cellulose, methylcellulose, hydroxy-propylmethycellulose,
 sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia;
 dispersing or wetting agents may be a naturally-occurring phosphatide, for
 example lecithin, or condensation products of an alkylene oxide with fatty
 acids, for example polyoxyethylene stearate, or condensation products of
 ethylene oxide with long chain aliphatic alcohols, for example
 heptadecaethylene-oxycetanol, or condensation products of ethylene oxide
 with partial esters derived from fatty acids and a hexitol such as
 polyoxyethylene sorbitol monooleate, or condensation products of ethylene
 oxide with partial esters derived from fatty acids and hexitol anhydrides,
 for example polyethylene sorbitan monooleate. The aqueous suspensions may
 also contain one or more preservatives, for example ethyl, or n-propyl,
 p-hydroxybenzoate, one or more coloring agents, one or more flavoring
 agents, and one or more sweetening agents, such as sucrose, saccharin or
 aspartame.
 Oily suspensions may be formulated by suspending the active ingredient in a
 vegetable oil, for example arachis oil, olive oil, sesame oil or coconut
 oil, or in mineral oil such as liquid paraffin. The oily suspensions may
 contain a thickening agent, for example beeswax, hard paraffin or cetyl
 alcohol. Sweetening agents such as those set forth above, and flavoring
 agents may be added to provide a palatable oral preparation. These
 compositions may be preserved by the addition of an anti-oxidant such as
 ascorbic acid.
 Dispersible powders and granules suitable for preparation of an aqueous
 suspension by the addition of water provide the active ingredient in
 admixture with a dispersing or wetting agent, suspending agent and one or
 more preservatives. Suitable dispersing or wetting agents and suspending
 agents are exemplified by those already mentioned above. Additional
 excipients, for example sweetening, flavoring and coloring agents, may
 also be present.
 The pharmaceutical compositions of the invention may also be in the form of
 an oil-in-water emulsion. The oil phase may be a vegetable oil, for
 example olive oil or arachis oil, or a mineral oil, for example liquid
 paraffin or mixtures of these. Suitable emulsifying agents may be
 naturally-occurring phosphatides, for example soy bean, lecithin, and
 esters or partial esters derived from fatty acids and hexitol anhydrides,
 for example sorbitan monooleate, and condensation products of the said
 partial esters with ethylene oxide, for example polyoxyethylene sorbitan
 monooleate. The emulsions may also contain sweetening and flavoring
 agents.
 Syrups and elixirs may be formulated with sweetening agents, for example
 glycerol, propylene glycol, sorbitol or sucrose. Such formulations may
 also contain a demulcent, a preservative and flavoring and coloring
 agents.
 The pharmaceutical compositions may be in the form of a sterile injectable
 aqueous or oleagenous suspension. This suspension may be formulated
 according to the known art using those suitable dispersing or wetting
 agents and suspending agents which have been mentioned above.
 The sterile injectable preparation may also be a sterile injectable
 solution or suspension in a non-toxic parenterally-acceptable diluent or
 solvent, for example as a solution in 1,3-butane diol. Among the
 acceptable vehicles and solvents that may be employed are water, Ringer's
 solution and isotonic sodium chloride solution.
 In addition, sterile, fixed oils may be employed as a solvent or suspending
 medium. For this purpose any bland fixed oil may be employed including
 synthetic mono- or diglycerides.
 In addition, fatty acids such as oleic acid find use in the preparation of
 injectables.
 Compounds of formula I may also be administered in the form of
 suppositories for rectal administration of the drug. These compositions
 can be prepared by mixing the drug with a suitable non-irritating
 excipient which is solid at ordinary temperatures but liquid at normal
 body temperature and will therefore melt to release the drug. Examples of
 such materials include cocoa butter and polyethylene glycols.
 For topical use, creams, ointments, jellies, solutions or suspensions,
 containing the compound of Formula I are employed. (For purposes of this
 applicator, topical application also includes mouth washes and gargles.)
 Dosage levels of the order of from about 0.01 mg to about 140 mg/kg of body
 weight per day are useful in the treatment of the above-indicated
 conditions, or alternatively about 0.5 mg to about 7 g per patient per
 day. For example, inflammation may be effectively treated by the
 administration of from about 0.01 to 50 mg to about 3.5 g per patient per
 day.
 The amount of active ingredient that may be combined with the carrier
 materials to produce a single dosage form will vary depending upon the
 host treated and the particular mode of administration. For example, a
 formulation intended for the oral administration to humans may contain
 from about 0.5 mg to about 5 g of active agent, compounded with an
 appropriate and convenient amount of carrier material which may vary from
 about 5 to about 95 percent of the total composition. Unit dosage forms
 will generally contain between from about 1 mg to about 500 mg of the
 active ingredient, typically 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg,
 500 mg, 600 mg, 800 mg or 1000 mg.
 It is understood, however, that the specific dose level for any particular
 patient will depend upon a variety of factors including the age, body
 weight, general health, sex, diet, time of administration, route of
 administration, rate of excretion, drug combination and the severity of
 the particular disease undergoing therapy.
 The compounds of the invention can be synthesized using the general
 synthesis schemes provided below. It will be apparent to one skilled in
 the art that similar methodology could be used to prepare the enantiomers
 or the racemates of the illustrated compounds.
 The following abbreviations have the indicated meanings:

ALKYL GROUP ABBREVIATIONS
 Me = methyl
 Et = ethyl
 n-Pr = normal propyl
 i-Pr = isopropyl
 n-Bu = normal butyl
 i-Bu = isobutyl
 s-Bu = secondary butyl
 t-Bu = tertiary butyl
 c-Pr = cyclopropyl
 c-Bu = cyclobutyl
 c-Pen = cyclopentyl
 c-Hex = cyclohexyl
 SCHEME 1
 The preparation of bromopyridine intermediate 1 is shown in Scheme 1.
 Monolithiation of 2,5-dibromopyridine followed by the addition
 3,4-bis(difluoromethoxy)benzaldehyde as found in U.S. Pat. No. 5,710,170
 gave the secondary alcohol which was subsequently oxidized to the
 corresponding ketone with an oxidizing agent such as MnO.sub.2.
 ##STR7##
 SCHEME 2
 The preparation of bromopyridine intermediate 2 and 3 is shown in Scheme 2.
 The secondary alcohol II was converted to the corresponding chloride III
 using a chlorinating agent such as thionyl chloride in the presence of a
 base. This chloride was condensed with the a-anion of ethyl 4-pyridyl
 acetate, affording the ester IV which upon hydrolysis with a base such as
 lithium hydroxide, followed by acidification with an acid such as
 hydrochloric acid afforded the decarboxylated intermediate 2. Oxidation of
 the pyridine to the pyridine-N-oxide 3 was done with an oxidizing agent
 such as MMPP.
 ##STR8##
 SCHEME 3
 The general method for the preparation of substituted alcohols is presented
 in Scheme 3. Esterification of a suitable carboxylic acid V under Fisher's
 conditions followed by dialkylation of the methyl ester VI with a base
 such as LHMDS and a suitable alkylating agent, afforded the corresponding
 gem-.alpha.,.alpha.-disubstituted ester VII. This intermediate is
 converted to the alcohol VIII by reduction with a reducing agent such as
 lithium aluminum hydride.
 ##STR9##
 R.sup.a represents a substituent group attached to Ar.sup.1, wherein
 Ar.sup.1 represents phenyl. Up to 3 R.sup.a groups may be present. The
 alkyl iodide provides the source for R.sup.3 and R.sup.4, which can be the
 same or different.
 SCHEME 4
 Scheme 4 is presenting the preparation of the substituted amine XIX.
 Nitrile XVI was dialkylated with a base such as NaHMDS and an alkylating
 agent such as methyl iodide followed by hydrolysis of the cyanide XVII to
 the corresponding amide XVIII. Finally, reduction of the amine with a
 reducing agent such as borane dimethyl sulfide gave access to the amine
 XIX.
 ##STR10##
 SCHEME 5
 The general transformation for the preparation of gem-disubstituted
 benzylamine XX is shown in Scheme 5. A suitable benzonitrile was treated
 with an excess of methyl organocerium reagent to produce the desired
 substituted amine XIa.
 ##STR11##
 SCHEME 6
 Substituted amine XIb was prepared according to the sequence presented in
 Scheme 6. Phenol XXa was first converted to a difluoromethoxy group with
 an alkylating agent such as methyl 2-chloro-2,2-difluoroacetate and a base
 such as potassium carbonate. This intermediate XXb was then treated with
 an excess of methyl organocerium reagent to afford the amine XIb.
 ##STR12##
 SCHEME 7
 Scheme 7 is presenting the general method of preparation of
 6-amino-3-pyridyl derivatives of formula Ik and Ij. Bromopyridines 2 or 3
 were coupled with a suitable secondary amine in the presence of copper (I)
 iodide. In the case of more hindered or non-reactive amines, the
 intermediate 2 was preferred as starting material in order to avoid
 extensive reduction of the N-oxide. The pyridine Ij was then oxidized to
 the pyridine-N-oxide Ik with an oxidizing agent such as MMPP.
 ##STR13##
 SCHEME 8
 The synthesis of 6-amino-3-pyridyl derivatives of formula Il to Io is shown
 in Scheme 8. Bromopyridine 2 was coupled with a suitable primary amine in
 the presence of copper (I) iodide. Protection by acylation afforded Im.
 R.sup.b represents alkyl, haloalkyl, aralkyl or aryl. Oxidation of this
 amide Im with an oxidizing agent such as MMPP followed by the hydrolysis
 of the protecting group with a base such as lithium hydroxide, gave access
 to the desired free amine pyridine-N-oxide In. In the case where the amine
 was protected as a trifluoroacetamide, the MMPP oxidation lead to the
 direct formation of hydroxylamine pyridine-N-oxide Io.
 ##STR14##
 SCHEME 9
 Scheme 9 is presenting an alternative route for the preparation of
 6-amino-3-pyridyl derivatives of formula In and Ip. The coupling of a
 suitable amine with the bromopyridine intermediate 1 was performed with
 CuI. The resulting amino ketone XXIX was then protected as a suitable
 carbamate, the ketone XXX was reduced to the secondary alcohol XXXI with a
 reducing agent such as sodium borohydride and then converted to the
 corresponding chloride XXXII with a chlorinating agent such as thionyl
 chloride and a base. This chloride was condensed with the .alpha.-anion of
 ethyl 4-pyridyl acetate, affording the ester XXXIII which upon hydrolysis
 with a base such as lithium hydroxide, followed by acidification with an
 acid such as hydrochloric acid afforded the decarboxylated intermediate
 Ip. Oxidation of the pyridine to the pyridine-N-oxide was done with an
 oxidizing agent such as MMPP and finally the carbamate protecting group
 was removed under hydrogenolysis condition (for CBZ protecting agent) or
 in the presence of a Lewis acid such as trimethylsilyl iodide and a base
 such as di-tert-butylpyridine.
 ##STR15##
 ##STR16##
 SCHEME 10
 In Scheme 10 another approach is presented for the synthesis of
 6-amino-3-pyridyl derivatives of formula Iq to Is. The amine functionality
 was introduced by a copper (I) coupling of intermediate 2 with a benzylic
 amine such as .alpha.-methyl benzylamino followed by the deprotection of
 the benzylic residue with an acid such as trifluoroacetic acid to access
 the aminopyridine XXXIV. This amine was heated in a suitable dimethyl
 acetal and the resulting imine XXXV was then treated with a nucleophile
 such as methyl Grignard to access the gem-dimethyl derivative Iq. The
 4-pyridyl-N-oxide Is was obtained by a sequence of protection of the amine
 with trifluoroacetic anhydride, oxidation with an oxidizing agent such as
 MMPP and deprotection of the amine with a base such as lithium hydroxide.
 ##STR17##
 ##STR18##
 SCHEME 11
 Scheme 11 is presenting the preparation of different amide derivatives of
 formula It and Iu to Iw starting with the aminopyridine XXXIV. In the
 presence of a suitable acylating agent the mono and bis-amide were
 obtained. The corresponding N-oxide derivatives Iv and Iw were prepared by
 oxidation with an oxidizing agent such as MMPP followed by the mono
 hydrolysis of the bis-amide Iv to give the mono-amide pyridine-N-oxide Iw.
 ##STR19##
 SCHEME 12
 In Scheme 12 the synthesis of 6-amino-3-pyridyl derivatives of formula Ij
 and Ik, starting from hindered secondary amines, is shown. The coupling of
 a suitable amine with the bromopyridine intermediate 1 was performed with
 CuI. The resulting amino ketone XXXVI was reduced to the secondary alcohol
 XXXVII with a reducing agent such as sodium borohydride and then converted
 to the corresponding chloride XXXVIII with a chlorinating agent such as
 thionyl chloride and a suitable base. The chloride was condensed with the
 .alpha.-anion of ethyl 4-pyridyl acetate, affording the ester XXXIX which
 upon hydrolysis with a base such as lithium hydroxide, followed by
 acidification with an acid such as hydrochloric acid afforded the
 decarboxylated intermediate Ij. Oxidation of the pyridine to the
 pyridine-N-oxide Ik was done with an oxidizing agent such as MMPP.
 ##STR20##
 ##STR21##
 SCHEME 13
 In Scheme 13 the treatment of a suitable amide Iw with a base such as
 sodium hydride and an alkylating agent such as methyl iodide afforded the
 N-methyl amide Iy and the Imide Ix from O-alkylation.
 ##STR22##
 SCHEME 14
 In Scheme 14 a suitable amine Il was protected as a carbamate in the
 presence of a suitable chloroformate or a dicarbonate.
 ##STR23##
 SCHEME 15
 In Scheme 15 several derivatives of formula Il and Iz were obtained
 starting from the same intermediate Ip.sub.1. Oxidation of this compounded
 lead to the formation of the monopyridine-N-oxide XL which were both
 deprotected with a reducing agent such as Pd/C under an hydrogen
 atmosphere to afford respectively the free pyridine Il.sub.1 and a mixture
 of mono and the bis-N-oxide XLII and XLI. Simple deprotection of carbamate
 Ip.sub.1 produced the free amine Il.sub.1.
 ##STR24##
 ##STR25##
 SCHEME 16
 In scheme 16 the amine Il was alkylated by reductive amination of acetic
 acid in the presence of an excess of a reducing agent such as sodium
 borohydride. Oxidation of the pyridine Ij with an oxidizing agent such as
 MMPP lead to the pyridine-N-oxide Ik.
 ##STR26##
 Representative compounds are shown in the tables below.
 TABLE 1
 ##STR27##
 Ex.sup.a Y' R.sup.3a R.sup.4a n' R.sup.3b R.sup.4b Ar.sup.1 -Ra
 1 -- H H 0 -- -- phenyl
 2 -- Me.sup.b H 0 -- -- phenyl
 3 -- H Me.sup.c 0 -- -- phcnyl
 4 -- Me.sup.f H 0 -- -- 4-fluorophenyl
 5 O Me.sup.f H 0 -- -- 4-fluorophenyl
 6 O H H 0 -- -- phenyl
 7 O Me.sup.b H 0 -- -- phenyl
 8 O H Me.sup.c 0 -- -- phenyl
 9 O H H 1 H H phenyl
 10 O H H 1 H H 2-pyridyl
 11 O Me Me 0 -- -- phenyl
 12.sup.d O Me Me 0 -- -- phenyl
 13.sup.d O Me Me 0 -- -- phenyl
 14.sup.e O Me Me 0 -- -- phenyl
 15 O H H 0 -- -- 2-pyridyl
 16 O H H 0 -- -- 2-pyridyl-
 N-oxide
 17 O Et.sup.c H 0 -- -- phenyl
 18.sup.d -- Me Me 0 -- -- phenyl
 19.sup.d -- Me Me 0 -- -- phenyl
 20.sup.e -- Me Me 0 -- -- phenyl
 21.sup.d O Me Me 0 -- -- 4-fluorophenyl
 22.sup.d O Me Me 0 -- -- 4-tolyl
 23 O Me Me 0 -- -- 4-benzyloxyphenyl
 24 O Me Me 0 -- -- 4-hydroxyphenyl
 25.sup.d O Me Me 0 -- -- 3-tolyl
 26.sup.d O Me Me 0 -- -- 3-fluorophenyl
 27.sup.d O Me Me 0 -- -- 3-bromophenyl
 28 O Me Me 0 -- -- 2-pyridyl
 29 O Me Me 0 -- -- 2-pyridyl-
 N-oxide
 30.sup.d O Me Me 0 -- -- 4-chlorophenyl
 31.sup.d O Me Me 0 -- -- 4-chlorophenyl
 32 O Me Me 0 -- -- 2-tolyl
 33.sup.d O Me Me 0 -- -- 4-(methyl
 sulfonyl)phenyl
 34 O Me Me 0 -- -- 4-(trifluoro
 methyl)phenyl
 35 O Me Me 0 -- -- 3,4-difluoro
 phenyl
 36 O Me Me 1 H H 4-fluorophenyl
 37 O H H 1 H H 4-fluorophenyl
 38 O Me Me 0 -- -- 3,5-difluoro
 phenyl
 39 O Me Me 0 -- -- 2,4-difluoro
 phenyl
 40.sup.d O H H 0 -- -- 4-fluorophenyl
 41.sup.d O H H 0 -- -- 4-fluorophenyl
 42.sup.d O Me Me 0 -- -- 4-ethylphenyl
 43 O H H 0 -- -- 2,4-difluoro
 phenyl
 44 -- O O 0 -- -- 4-fluorophenyl
 45 O O O 0 -- -- 4-fluorophenyl
 46.sup.d O O O 0 -- -- 4-fluorophenyl
 47.sup.d O Me Me 0 -- -- thiazolyl
 48 O Me Me 0 -- -- 4-(difluoro
 methoxy)phenyl
 49.sup.g O Me Me 0 -- -- phenyl
 50 O Et Et 0 -- -- 4-fluorophenyl
 51.sup.d O O O 0 -- -- 4-tolyl
 52 O H H 1 Me Me 4-fluorophenyl
 53.sup.d O Me Me 1 H H 4-fluorophenyl
 .sup.a Unless specified, all the compounds are racemic mixture.
 .sup.b (S) stereoisomer.
 .sup.c (R) stereoisomer.
 .sup.d Optically pure.
 .sup.e (N)-oxide of the 2,5-disubstituted pyridine.
 .sup.f (R, S) mixture.
 .sup.g MeSO.sub.3 H salt.
 TABLE 2
 ##STR28##
 Ex.sup.a Y' m R.sup.3a R.sup.4a n' R.sup.3b R.sup.4b R.sup.5
 Ar.sup.1 -R.sup.a
 54 -- 1 H H 0 -- -- Me phenyl
 55 -- 1 H H 0 -- -- Bn phenyl
 56 O 1 H H 0 -- -- Me phenyl
 57.sup.b O 1 H H 0 -- -- Me phenyl
 58 O 1 H H 1 H H Me phenyl
 59 O 1 H H 0 -- -- Et phenyl
 60 O 1 H H 0 -- -- i-Pr phenyl
 61 O 1 H H 0 -- -- t-Bu phenyl
 62 O 1 H H 0 -- -- Me 4-chloro
 phenyl
 63 O 1 H H 0 -- -- Me 3-methoxy
 phenyl
 64 O 1 H H 0 -- -- Me 3-pyridyl
 65 O 1 H H 0 -- -- Me 2-methyl
 phenyl
 66 O 1 H H 0 -- -- Me 2-naphthyl
 67 O 1 H H 0 -- -- 2-hydroxy phenyl
 ethyl
 68 -- 0 -- -- 0 -- -- Me 4-methoxy
 phenyl
 69 O 0 -- -- 0 -- -- Me 4-methoxy
 phenyl
 70 -- 1 Me.sup.c H 0 -- -- Me phenyl
 71 O 1 Me.sup.c H 0 -- -- Me phenyl
 72 O 1 H Me.sup.d 0 -- -- Me phenyl
 73 O 0 -- -- 0 -- -- Me phenyl
 74 O 1 H H 0 -- -- OH phenyl
 75 O 1 H Me.sup.d 0 -- -- Et phenyl
 76 O 1 Me.sup.c H 0 -- -- Et phenyl
 77 O 1 H H 0 -- -- Me 3-pyridyl-
 N-oxide
 78.sup.e O 1 OMe -- 0 -- -- -- 4-fluoro
 phenyl
 79.sup.e O 1 O O 0 -- -- Me 4-fluoro
 phenyl
 80 -- 1 H H 0 -- -- CF.sub.3 CO phenyl
 81 O 1 H H 0 -- -- CH.sub.3 CO phenyl
 82 O 1 Me Me 0 -- -- BOC phenyi
 83.sup.e O 1 Me Me 0 -- -- BOC phenyl
 84.sup.e -- 1 Me Me 0 -- -- CBZ phenyl
 85.sup.e -- 1 Me Me 0 -- -- CBZ phenyl
 86.sup.e -- 1 Me Me 0 -- -- CBZ 4-methyl
 phenyl
 87.sup.e -- 1 Me Me 0 -- -- CBZ 4-methyl
 phenyl
 88.sup.e -- 1 Me Me 0 -- -- CBZ 4-fluoro
 phenyl
 89.sup.e -- 1 Me Me 0 -- -- CBZ 4-fluoro
 phenyl
 90.sup.e -- 1 Me Me 0 -- -- CBZ 3-methyl
 phenyl
 91.sup.e -- 1 Me Me 0 -- -- CBZ 3-methyl
 phenyl
 92.sup.e -- 1 Me Me 0 -- -- CBZ 3-bromo
 phenyl
 93.sup.e -- 1 Me Me 0 -- -- CBZ 3-bromo
 phenyl
 94.sup.e -- 1 Me Me 0 -- -- CBZ 3-fluoro
 phenyl
 95.sup.e -- 1 Me Me 0 -- -- CBZ 3-fluoro
 phenyl
 96.sup.e O 1 Me Me 1 H H CBZ 4-fluoro
 phenyl
 97.sup.e O 1 Me Me 1 H H CBZ 4-fluoro
 phenyl
 98.sup.f O 1 Me Me 1 H H CBZ 4-fluoro
 phenyl
 99.sup.f O 1 O O 0 -- -- p-F-Bz 4-fluoro
 phenyl
 .sup.a Unless specified, all the compounds are racemic mixture.
 .sup.b Hydrochloride salt (2HCl).
 .sup.c (S) stereoisomer.
 .sup.d (R) stereoisomer.
 .sup.e Optically pure.
 .sup.f (N)-oxide of the 2,5-disubstituted pyridine.
 TABLE 3
 ##STR29##
 TABLE 4
 ##STR30##
 Ex Isomer
 101 Racemic
 102 Diastereomer 1
 103 Diastereomer 2
 104 Diastereomer 3
 105 Diastereomer 4
 TABLE 5
 ##STR31##
 TABLE 6
 ##STR32##
 TABLE 7
 ##STR33##
 TABLE 8
 ##STR34##
 Y' m R.sup.3a R.sup.4a n' R.sup.3b R.sup.4b Ar.sup.1 -Ra
 O 0 -- -- 0 -- -- 4-(trifluoromethoxy)
 phenyl
 -- 0 -- -- 0 -- -- 4-(methoxycarbonyl)
 phenyl
 O 0 -- -- 0 -- -- 4-(methoxycarbonyl)
 phenyl
 -- 0 -- -- 0 -- -- 4-(2-hydroxypropan-2-yl)
 phenyl
 O 0 -- -- 0 -- -- 4-(2-hydroxypropan-2-yl)
 phenyl
 O 0 -- -- 0 -- -- 4-nitrophenyl
 O 0 -- -- 0 -- -- 4-(methylsulphonyl
 amino)phenyl
 O 0 -- -- 0 -- -- 4-(trifluoromethyl)
 phenyl
 O 0 -- -- 0 -- -- 3-(methylsulphonyl
 amino)phenyl
 O 0 -- -- 0 -- -- 4-(2-propenyl)phenyl
 O 0 -- -- 0 -- -- 4-(2-propyl)phenyl
 O 0 -- -- 0 -- -- 4-(dimethylsulphonyl
 amino)phenyl
 O 0 -- -- 0 -- -- 3-(hydroxymethyl)-4-
 (carboxyl)phenyl
 O 1 H H 0 -- -- 3,4-difluorophenyl
 O 1 H H 0 -- -- 4-(methylsulfonyl)phenyl
 -- 1 H H 0 -- -- 3,5-difluorophenyl
 O 1 H H 0 -- -- 3,5-difluorophenyl
 -- 1 H H 1 Me Me 4-fluorophenyl
 -- 1 H H 1 H H 4-fluorophenyl
 O 1 H H 0 -- -- 4-(trifluoromethyl)phenyl
 O 1 H H 0 -- -- 4-(trifluoromethoxy)
 phenyl
 O 1 Me Me 1 H H phenyl
 O 1 H H 0 -- -- 2-thienyl
 -- 1 Me Me 0 -- -- 4-fluorophenyl
 O 1 H H 0 -- -- 4-fluorophenyl
 O 1 H H 0 -- -- 4-chlorophenyl
 TABLE 9
 ##STR35##
 Y' m R.sup.3a R.sup.4a n' R.sup.3b R.sup.4b R.sup.a
 O 0 -- -- 0 -- -- 4-(trifluoromethoxy)
 -- 0 -- -- 0 -- -- 4-(methoxycarbonyl)
 O 0 -- -- 0 -- -- 4-(methoxycarbonyl)
 -- 0 -- -- 0 -- -- 4-(2-hydroxypropan-
 2-yl)
 O 0 -- -- 0 -- -- 4-(2-hydroxypropan-
 2-yl)
 O 0 -- -- 0 -- -- 4-nitro
 O 0 -- -- 0 -- -- 4-(methylsulphonyl
 amino)
 O 0 -- -- 0 -- -- 4-(trifluoromethyl)
 O 0 -- -- 0 -- -- 5-(methylsulphonyl
 amino)
 O 0 -- -- 0 -- -- 4-(2-propenyl)
 O 0 -- -- 0 -- -- 4-(2-propyl)
 O 0 -- -- 0 -- -- 4-(dimethylsulphonyl
 amino)
 O 0 -- -- 0 -- -- 4-(hydroxymethyl)-5-
 (carboxyl)
 O 1 H H 0 -- -- --
 O 1 Me H 0 -- -- --
 O 1 H H 0 -- -- 4,5-difluoro
 O 1 H H 0 -- -- 4-(methylsulfonyl)
 -- 1 H H 0 -- -- 3-fluoro
 -- 1 H H 0 -- -- 4,5-difluoro
 O 1 H H 0 -- -- 4,5-dichloro
 O 1 H H 0 -- -- 5-fluoro
 -- 1 H H 1 Me Me 4-fluoro
 O 1 H H 1 Me Me 4-fluoro
 -- 1 H H 1 H H 5-fluoro
 O 1 H H 1 H H 4-fluoro
 O 1 H H 0 -- -- 4-(trifluoromethyl)
 O 1 H H 0 -- -- 4-(trifluoromethoxy)
 O 1 Me Me 1 H H --
 O 1 H H 0 -- -- --
 -- 1 Me Me 0 -- -- 4-fluoro
 O 1 Me Me 0 -- -- 4-fluoro
 O 1 H H 0 -- -- 4-fluoro
 O 1 H H 0 -- -- 4-chloro
 TABLE 10
 ##STR36##
 Y' m R.sup.3a R.sup.4a n' R.sup.3b R.sup.4b R.sup.a
 O 0 -- -- 0 -- -- 4-(trifluoromethoxy)
 -- 0 -- -- 0 -- -- 4-(methoxycarbonyl)
 O 0 -- -- 0 -- -- 4-(methoxycarbonyl)
 -- 0 -- -- 0 -- -- 4-(2-hydroxypropan-
 2-yl)
 O 0 -- -- 0 -- -- 4-(2-hydroxypropan-
 2-yl)
 O 0 -- -- 0 -- -- 4-nitro
 O 0 -- -- 0 -- -- 4-(methylsulphonyl
 amino)
 O 0 -- -- 0 -- -- 4-(trifluoromethyl)
 O 0 -- -- 0 -- -- 5-(methylsulphonyl
 amino)
 O 0 -- -- 0 -- -- 4-(2-propenyl)
 O 0 -- -- 0 -- -- 4-(2-propyl)
 O 0 -- -- 0 -- -- 4-(dimethylsulphonyl
 amino)
 O 0 -- -- 0 -- -- 4-(hydroxymethyl)-5-
 (carboxyl)
 O 1 H H 0 -- -- --
 O 1 Me H 0 -- -- --
 O 1 H H 0 -- -- 4,5-difluoro
 O 1 H H 0 -- -- 4-(methylsulfonyl)
 -- 1 H H 0 -- -- 4,5-dichloro
 -- 1 H H 0 -- -- 5-fluoro
 O 1 H H 0 -- -- 4,5-dichloro
 O 1 H H 0 -- -- 5 -fluoro
 -- 1 H H 1 Me Me 4-fluoro
 O 1 H H 1 Me Me 4-fluoro
 -- 1 H H 1 H H 4-fluoro
 O 1 H H 1 H H 4-fluoro
 O 1 H H 0 -- -- 4-(trifluoromethyl)
 O 1 H H 0 -- -- 4-(trifluoromethoxy)
 O 1 Me Me 1 H H --
 O 1 H H 0 -- -- --
 -- 1 Me Me 0 -- -- 4-fluoro
 O 1 Me Me 0 -- -- 4-fluoro
 O 1 H H 0 -- -- 4-fluoro
 O 1 H H 0 -- -- 4-chloro
 TABLE 11
 ##STR37##
 Y' m R.sup.3a R.sup.4a n' R.sup.3b R.sup.4b R.sup.a
 O 0 -- -- 0 -- -- 6-(trifluoromethoxy)
 -- 0 -- -- 0 -- -- 6-(methoxycarbonyl)
 O 0 -- -- 0 -- -- 6-(methoxycarbonyl)
 -- 0 -- -- 0 -- -- 6-(2-hydroxypropan-
 2-yl)
 O 0 -- -- 0 -- -- 6-(2-hydroxypropan-
 2-yl)
 O 0 -- -- 0 -- -- 6-nitro
 O 0 -- -- 0 -- -- 6-(methylsulphonyl
 amino)
 O 0 -- -- 0 -- -- 6-(trifluoromethyl)
 O 0 -- -- 0 -- -- 5-(methylsulphonyl
 amino)
 O 0 -- -- 0 -- -- 6-(2-propenyl)
 O 0 -- -- 0 -- -- 6-(2-propyl)
 O 0 -- -- 0 -- -- 6-(dimethylsulphonyl
 amino)
 O 0 -- -- 0 -- -- 5-(hydroxymethyl)-6-
 (carboxyl)
 O 1 H H 0 -- -- --
 O 1 Me H 0 -- -- --
 O 1 H H 0 -- -- 5,6-difluoro
 O 1 H H 0 -- -- 6-(methylsulfonyl)
 -- 1 H H 0 -- -- 4,6-difluoro
 -- 1 H H 0 -- -- 5,6-dichloro
 O 1 H H 0 -- -- 4,6-difluoro
 O 1 H H 0 -- -- 5,6-dimethyl
 -- 1 H H 1 Me Me 6-fluoro
 O 1 H H 1 Me Me 6-fluoro
 -- 1 H H 1 H H 6-fluoro
 O 1 H H 1 H H 6-fluoro
 O 1 H H 0 -- -- 6-(trifluoromethyl)
 O 1 H H 0 -- -- 6-(trifluoromethoxy)
 O 1 Me Me 1 H H --
 O 1 H H 0 -- -- --
 -- 1 Me Me 0 -- -- 6-fluoro
 O 1 Me Me 0 -- -- 6-fluoro
 O 1 H H 0 -- -- 6-fluoro
 O 1 H H 0 -- -- 6-fluoro
 TABLE 12
 ##STR38##
 Y' m R.sup.3a R.sup.4a n' R.sup.3b R.sup.4b R.sup.a
 O 0 -- -- 0 -- -- 7-(trifluoro
 methoxy)
 -- 0 -- -- 0 -- -- 7-(methoxy
 carbonyl)
 O 0 -- -- 0 -- -- 7-(methoxy
 carbonyl)
 -- 0 -- -- 0 -- -- 7-(2-hydroxy
 propan-2-yl)
 O 0 -- -- 0 -- -- 7-(2-hydroxy
 propan-2-yl)
 O 0 -- -- 0 -- -- 7-nitro
 O 0 -- -- 0 -- -- 7-(methylsulphonyl
 amino)
 O 0 -- -- 0 -- -- 7-(trifluoromethyl)
 O 0 -- -- 0 -- -- 6-(methylsulphonyl
 amino)
 O 0 -- -- 0 -- -- 7-(2-propenyl)
 O 0 -- -- 0 -- -- 7-(2-propyl)
 O 0 -- -- 0 -- -- 7-(dimethyl
 sulphonylamino)
 O 0 -- -- 0 -- -- 6-(hydroxymethyl)-7-
 (carboxyl)
 O 1 H H 0 -- -- --
 O 1 Me H 0 -- -- --
 O 1 H H 0 -- -- 6,7-difluoro
 O 1 H H 0 -- -- 7-(methylsulfonyl)
 -- 1 H H 0 -- -- 6,7-difluoro
 -- 1 H H 0 -- -- 5,7-difluoro
 O 1 H H 0 -- -- 5-fluoro
 O 1 H H 0 -- -- 6-fluoro
 -- 1 H H 1 Me Me 7-fluoro
 O 1 H H 1 Me Me 7-fluoro
 -- 1 H H 1 H H 7-fluoro
 O 1 H H 1 H H 7-fluoro
 O 1 H H 0 -- -- 7-(trifluoro
 methyl)
 O 1 H H 0 -- -- 7-(trifluoro
 methoxy)
 O 1 Me Me 1 H H --
 O 1 H H 0 -- -- --
 -- 1 Me Me 0 -- -- 7-fluoro
 O 1 Me Me 0 -- -- 7-fluoro
 O 1 H H 0 -- -- 7-fluoro
 O 1 H H 0 -- -- 7-chloro
 TABLE 13
 ##STR39##
 ASSAYS DEMONSTRATING BIOLOGICAL-ACTIVITY
 LPS and FMLP-Induced TNF-.alpha. and LTB.sub.4 Assays in Human Whole Blood
 Whole blood provides a protein and cell-rich milieu appropriate for the
 study of biochemical efficacy of anti-inflammatory compounds such as PDE
 4-selective inhibitors. Normal non-stimulated human blood does not contain
 detectable levels of TNF-.alpha. and LTB4. Upon stimulation with LPS,
 activated monocytes express and secrete TNF-a up to 8 hours and plasma
 levels remain stable for 24 hours. Published studies have shown that
 inhibition of TNF-.alpha. by increasing intracellular cAMP via PDE 4
 inhibition and/or enhanced adenylyl cyclase activity occurs at the
 transcriptional level. LTB4 synthesis is also sensitive to levels of
 intracellular cAMP and can be completely inhibited by PDE 4-selective
 inhibitors. As there is little LTB.sub.4 produced during a 24 hour LPS
 stimulation of whole blood, an additional LPS stimulation followed by fMLP
 challenge of human whole blood is necessary for LTB.sub.4 synthesis by
 activated neutrophils. Thus, using the same blood sample it is possible to
 evaluate the potency of a compound on two surrogate markers of PDE 4
 activity in the whole blood.
 Fresh blood was collected in heparinized tubes by venipuncture from healthy
 human volunteers (male and female). These subjects had no apparent
 inflammatory conditions and had not taken any NSAIDs for at least 4 days
 prior to blood collection. Five hundred .mu.L aliquots of blood were
 pre-incubated with either 2 .mu.L of vehicle (DMSO) or 2 .mu.L test
 compound at varying concentrations for 15 minutes at 37.degree. C. This
 was followed by the addition of either 10 .mu.L vehicle (PBS) as blanks or
 0 .mu.L LPS (1 .mu.g/ml final concentration, Sigma Chem. #L-2630 for E.
 coli, serotype 0111:B4; diluted in 0.1% w/v BSA (in PBS)). After 24 hours
 of incubation at 37.degree. C., another 10 .mu.L of PBS (blank) or 10
 .mu.L of LPS (1 .mu.g/ml final concentration) was added to blood and
 incubated for 30 minutes at 37.degree. C. The blood was then challenged
 with either 10 .mu.L of PBS (blank) or 10 .mu.L of fMLP (1 .mu.M final
 concentration, Sigma Chem #F-3506; diluted in 1% w/v BSA (in PBS)) for 15
 minutes at 37.degree. C. The blood samples were centrifuged at
 1500.times.g for 10 minutes at 4.degree. C. to obtain plasma. A 50 .mu.L
 aliquot of plasma was mixed with 200 .mu.L methanol for protein
 precipitation and centrifuged as above. The supernatant was assayed for
 LTB.sub.4 using an enzyme immunoassay kit (Cayman Chemicals #520111)
 according to the manufacturer's procedure. TNF-.alpha. was assayed in
 diluted plasma (in PBS) using an ELISA kit (Cistron Biotechnology)
 according to manufacturer's procedure.
 Anti-allergic Activity in vivo
 Compounds of the invention have been tested for effects on an IgE-mediated
 allergic pulmonary inflammation induced by inhalation of antigen by
 sensitised guinea pigs. Guinea pigs were initially sensitised to ovalbumin
 under mild cyclophosphamide-induced immunosuppression, by intraperitoneal
 injection of antigen in combinations with aluminium hydroxide and
 pertussis vaccine. Booster doses of antigen were given two and four weeks
 later and at six weeks, animals were challenged with aerosolised ovalbumin
 whilst under cover of an intraperitoneally administered anti-histamine
 agent (mepyramine). After a further 48 h, bronchial alveolar lavages (BAL)
 were performed and the numbers of eosinophils and other leukocytes in the
 BAL fluids were counted. The lungs were also removed for histological
 examination for inflammatory damage. Administration of compounds of the
 Examples (0.001-10 mg/kg i.p. or p.o.), up to three times during the 48 h
 following antigen challenge, lead to a significant reduction in the
 eosinophilia and the accumulation of other inflammatory leukocytes. There
 was also less inflammatory damage in the lungs of animals treated with
 compounds of the Examples.
 SPA Based PDE Activity Assay Protocol
 Compounds which inhibit the hydrolysis of cAMP to AMP by the type-IV
 cAMP-specific phosphodiesterases were screened in 96-well plate format as
 follows:
 In a 96 well-plate at 30.degree. C. was added the test compound (dissolved
 in 2 .mu.l DMSO), 188 ml of substrate buffer containing [2,8-.sup.3 H]
 adenosine 3',5'-cyclic phosphate (cAMP, 100 nM to 50 .mu.M), 10 mM
 MgCl.sub.2, 1 mM EDTA, 50 mM Tris, pH 7.5. The reaction was initiated by
 the addition of 10 ml of human recombinant PDE-IV (the amount was
 controlled so that .about.10% product was formed in 10 min.). The reaction
 was stopped after 10 min. by the addition of 1 mg of PDE-SPA beads
 (Amersham). The product AMP generated was quantified on a Microbeta
 96-well plate counter. The signal in the absence of enzyme was defined as
 the background. 100% activity was defined as the signal detected in the
 presence of enzyme and DMSO with the background subtracted. Percentage of
 inhibition was calculated accordingly. IC.sub.50 value was approximated
 with a non-linear regression fit using the standard 4-parameter/multiple
 binding sites equation from a ten point titration.
 IC.sub.50 values shown in Table 7 were determined with 100 nM cAMP using
 the purified GST fusion protein of the human recombinant phosphodiesterase
 IVa (met-248) produced from a baculovirus/Sf-9 expression system.
 TABLE 14
 In Vitro Potency of some representative PDE 4 Inhibitors.
 IC.sub.50 (nM)
 Ex. GST-Met 248 PDE 4a
 1 0.75
 11 1.63
 54 2.84
 69 3.1
 99 0.84
 The invention will now be illustrated by the following non-limiting
 examples in which, unless stated otherwise:
 (i) all operations were carried out at room or ambient temperature, that
 is, at a temperature in the range 18-25.degree. C.; evaporation of solvent
 was carried out using a rotary evaporator under reduced pressure (600-4000
 pascals: 4.5-30 mm. Hg) with a bath temperature of up to 60.degree. C.;
 the course of reactions was followed by thin layer chromatography (TLC)
 and reaction times are given for illustration only; melting points are
 uncorrected and `d` indicates decomposition; the melting points given are
 those obtained for the materials prepared as described; polymorphism may
 result in isolation of materials with different melting points in some
 preparations; the structure and purity of all final products were assured
 by at least one of the following techniques: TLC, mass spectrometry,
 nuclear magnetic resonance (NMR) spectrometry or microanalytical data;
 yields are given for illustration only; when given, NMR data is in the
 form of delta (.delta.) values for major diagnostic protons, given in
 parts per million (ppm) relative to tetramethylsilane (TMS) as internal
 standard, determined at 300 MHz, 400 MHz or 500 MHz using the indicated
 solvent; conventional abbreviations used for signal shape are: s. singlet;
 d. doublet; t. triplet; m. multiplet; br. broad; etc.: in addition "Ar"
 signifies an aromatic signal; chemical symbols have their usual meanings;
 the following abbreviations have also been used v (volume), w (weight),
 b.p. (boiling point), m.p. (melting point), L (liter(s)), mL
 (milliliters), g (gram(s)), mg (milligrams(s)), mol (moles), mmol
 (millimoles), eq (equivalent(s)).