Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-09-29
2003-12-02
Rotman, Alan L. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S332000, C514S235500, C514S253010, C544S124000, C544S360000, C546S194000, C546S256000, C546S193000
Reexamination Certificate
active
06656959
ABSTRACT:
This application is a National Stage application under 35 U.S.C. §371 of PCT/EP99/02045 filed Mar. 24, 1999, which claims priority from EP 98.201.020.9, filed Apr. 1, 1998.
The present invention concerns pyridine derivatives having phosphodiesterase IV (PDE IV) and cytokine inhibiting activity and their preparation; it further relates to compositions comprising them, as well as their use as a medicine.
W095/04045 generically discloses 2-pyridinyl-1-[dialkyloxypiridinyl]-ethanone derivates useful for treating phosphodiesterase IV related disorders. WO 96/31485 describes a number of 1,3-dihydro-1-(phenylalkyl)-2H-imidazol-2-one derivatives having PDE IV and cytokine inhibiting activity.
The compounds of the present invention are structurally different from art-known PDE IV inhibitors. They have therapeutical utility in the treatment of disease states related to an abnormal enzymatic or catalytic activity of PDE IV, and/or disease states related to a physiologically detrimental excess of cytokines, in particular allergic, atopic and inflammatory diseases. The present compounds have an improved pharmacological profile with little or no gastro-intestinal side-effects, which are often associated with art-known PDE IV inhibitors.
The present invention concerns pyridine derivatives having the formula
wherein:
L is hydrogen; C
1-6
alkyl; C
1-6
alkyl substituted with one or two substituents selected from the group consisting of hydroxy, C
1-4
alkyloxy, C
1-4
alkyloxycarbonyl, mono- and di(C
1-4
alkyl)amino, aryl and Het
2
; C
3-6
alkenyl; C
3-6
alkenyl substituted with aryl; C
1-6
alkylcarbonyl; C
1-6
alkyloxycarbonyl; piperidyl; piperidyl substituted with C
1-4
alkyl or arylC
1-4
alkyl; C
1-6
alkylsulfonyl or arylsulfonyl;
—A—B— is a bivalent radical of formula:
—CR
4
═CR
5
—;
(a-1)
or
—CHR
4
—CHR
5
—;
(a-2)
D is O or NR
6
;
Q is a radical of the formula
R
1
is hydrogen or C
1-4
alkyl;
or R
1
and R
2
together may form a bivalent radical of formula —(CH
2
)
m
— wherein m is 1, 2, 3 or 4;
R
2
is hydrogen; halo; C
1-6
alkyl; trifluoromethyl; C
3-6
cycloalkyl; carboxyl; C
1-4
alkyloxycarbonyl; C
3-6
cycloalkylaminocarbonyl; aryl; Het
1
; or C
1-6
alkyl substituted with cyano, amino, hydroxy, C
1-4
alkylcarbonylamino, aryl or Het
1
; or
R
2
is a radical of formula:
—O—R
9
(c−1); or
—NH—R
10
(c−2);
R
3
is hydrogen, halo, hydroxy, C
1-6
alkyl or C
1-6
alkyloxy; or
R
2
and R
3
taken together may form a bivalent radical of formula:
—(CH
2
)
n
—;
(d-1)
—CH
2
—CH
2
—O—CH
2
—CH
2
—;
(d-2)
—CH
2
—CH
2
—N(R
11
)—CH
2
—CH
2
—;
(d-3)
or
—CH
2
—CH═CH—CH
2
—;
(d-4)
wherein n is 2, 3, 4 or 5;
R
4
and R
5
are each independently selected from hydrogen or C
1-4
alkyl;
R
6
is hydrogen, C
1-4
alkyl or cyano;
R
7
and R
8
each independently are hydrogen; C
1-6
alkyl; difluoromethyl; trifluoromethyl; C
3-6
cycloalkyl; a saturated 5-, 6- or 7-membered heterocycle containing one or two heteroatoms each independently selected from oxygen, sulfur or nitrogen; indanyl; 6,7-dihydro-5H-cyclopentapyridyl; bicyclo[2.2.1]-2-heptenyl; bicyclo[2.2.1]heptanyl; C
1-6
alkylsulfonyl; arylsulfonyl; or C
1-6
alkyl substituted with one or two substituents each independently selected from aryl, pyridyl, thienyl, furanyl, indanyl, 6,7-dihydro-5H-cyclopentapyridyl, C
3-7
cycloalkyl and a saturated 5-, 6- or 7-membered heterocycle containing one or two heteroatoms selected from oxygen, sulfur or nitrogen;
R
9
is hydrogen; C
1-6
alkyl; C
1-6
alkyl substituted with hydroxy, carboxyl, C
1-4
alkyloxycarbonyl, amino, mono- or di(C
1-4
alkyl)amino, Het
1
or aryl;
R
10
is hydrogen; C
1-6
alkyl; C
1-4
alkylcarbonyl; C
1-6
alkyl substituted with hydroxy, carboxyl, C
1-4
alkyloxycarbonyl, amino, mono- or di(C
1-4
alkyl)amino, Het
1
or aryl;
R
11
is hydrogen, C
1-6
alkyl, C
1-6
alkylsulfonyl or p-toluenesulfonyl;
aryl is phenyl or phenyl substituted with one, two or three substituents each independently selected from halo, hydroxy, C
1-4
alkyl, C
1-4
alkyloxy, C
3-6
cycloalkyl, trifluoromethyl, amino, nitro, carboxyl, C
1-4
alkyloxycarbonyl and C
1-4
alkylcarbonylamino;
Het
1
is pyridyl; pyridyl substituted with C
1-4
alkyl; furanyl; furanyl substituted with C
1-4
alkyl; thienyl; thienyl substituted with C
1-4
alkylcarbonylamino; hydroxypyridyl, hydroxypyridyl substituted with C
1-4
alkyl or C
1-4
alkoxyC
1-4
alkyl; imidazolyl; imidazolyl substituted with C
1-4
alkyl; thiazolyl; thiazolyl substituted with C
1-4
alkyl; oxazolyl; oxazolyl substituted with C
1-4
alkyl; isoquinolinyl; isoquinolinyl substituted with C
1-4
alkyl; quinolinonyl; quinolinonyl substituted with C
1-4
alkyl; morpholinyl; piperidyl; piperidyl substituted with C
1-4
alkyl, C
1-4
alkyloxycarbonyl or arylC
1-4
alkyl; piperazinyl; piperazinyl substituted with C
1-4
alkyl, C
1-4
alkyloxycarbonyl or arylC
1-4
alkyl; and
Het
2
is morpholinyl; piperidyl; piperidyl substituted with C
1-4
alkyl or arylC
1-4
alkyl; piperazinyl; piperazinyl substituted with C
1-4
alkyl or arylC
1-4
alkyl; pyridyl; pyridyl substituted with C
1-4
alkyl; furanyl; furanyl substituted with C
1-4
alkyl; thienyl or thienyl substituted with C
1-4
alkyl or C
1-4
alkylcarbonylamino;
the N-oxide forms, the pharmaceutically acceptable acid or base addition salts and the stereochemically isomeric forms thereof.
Some of the compounds of formula (I) may also exist in their tautomeric forms. Such forms although not explicitly indicated in the above formula are intended to be included within the scope of the present invention. In particular, compounds of formula (I) wherein L is hydrogen may exist in their corresponding tautomeric form.
In R
7
and R
8
, the saturated 5-, 6- or 7-membered heterocycles containing one or two heteroatoms selected from oxygen, sulfur or nitrogen may suitably be selected from heterocycles such as, for example, tetrahydrofuranyl, dioxolanyl, pyrrolidinyl, morpholinyl, piperidyl, piperazinyl and tetrahydropyranyl. Said heterocyclic radicals are attached to the oxygen atom or the C
1-10
alkyl radical by any carbon atom or, where appropriate, by a nitrogen atom.
Also in R
7
and R
8
, the term 6,7-dihydro-5H-cyclopentapyridyl is meant to represent 6,7hydro-5H-cyclopenta[b]pyridyl or 6,7-dihydro-5H-cyclopenta[c]pyridyl and may be attached to the remainder of the molecule by any of the aliphatic or aromatic carbon atoms.
As used herein the term halo is generic to fluoro, chloro, bromo and iodo; the term C
1-4
alkyl is meant to include straight chained or branched saturated hydrocarbons having from 1 to 4 carbon atoms such as, for example, methyl, ethyl, 1-methylethyl, 1,1dimethylethyl, propyl, 2-methylpropyl and butyl; the term C
1-6
alkyl is meant to include C
1-4
alkyl and the higher homologues thereof having 5 or 6 carbon atoms such as, for example, 2-methylbutyl, pentyl, hexyl and the like; the term C
10
alkyl is meant to include C
1-6
alkyl and the higher homologues thereof having from 7 to 10 carbon atoms such as, for example, heptyl, octyl, nonyl, decyl, I -methylhexyl, 2-methylheptyl and the like; the term C
3-6
alkenyl defines straight and branch chained hydrocarbon radicals containing one double bond and having from 3 to 6 carbon atoms such as, for example, 2-propenyl, 3-butenyl, 2-butenyl, 2-pentenyl, 3-pentenyl, 3-methyl-2-butenyl and the like; and the carbon atom of said C
3-6
alkenyl being connected to a nitrogen atom preferably is saturated; the term C
3-6
cycloalkyl is generic to cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; the term C
3-7
cycloalkyl is meant to include C
3-6
cycloalkyl and cycloheptyl; the term C
1-4
alkanediyl is meant to include straight chained and branched saturated bivalent hydrocarbon radicals having from 1 to 4 carbon atoms, such as, for example, methylene, 1,2-ethanediyl, 1,1-ethanediyl, 1,3-propanediyl, 1,2-propanediyl, 1,4-butanediyl, 2-methyl-1,3-propanediyl and the like.
As used in the foregoing definitions and hereinafter, haloC
1-4
alkanediyl is defined as mono- or polyhalosubstituted C
1-4
alkanediyl, in particular C
1-4
alkanediyl substituted wit
Díaz-Martinez Adolfo
Diels Gaston Stanislas
Freyne Eddy Jean
Matesanz-Ballesteros Maria Encarnacion
Janssen Pharmaceutica N.V.
Robinson Binta
Rotman Alan L.
Woodcock & Washburn LLP
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