1,3-dihydro-1-(phenylalkyl)-2H-imidazol-2-one derivatves

Details 1,3-dihydro-1-(phenylalkyl)-2H-imidazol-2-one derivatves 1,3-dihydro-1-(phenylalkyl)-2H-imidazol-2-one derivatves

1999-07-27

2002-06-11

Higel, Floyd D. (Department: 1626)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C514S391000, C514S399000, C514S400000, C514S397000, C548S323500, C548S325100, C548S325500

Reexamination Certificate

active

06403805

ABSTRACT:

The present invention concerns the use of 1,3-dihydro-1-(phenylalkyl)-2H-imidazol-2-one derivatives for the manufacture of a medicament for treating warm-blooded animals suffering from disease states related to an abnormal enzymatic or catalytic activity of phosphodiesterase IV (PDE IV), and/or disease states related to a physiologically detrimental excess of cytokines, in particular allergic, atopic and inflammatory diseases. The present invention also relates to new compounds having PDE IV and cytokine inhibiting activity, processes for their preparation and compositions comprising said new compounds.
1-[2-(3,4-diethoxyphenyl)ethyl]-1,2-dihydro-2H-imidazol-2-one and a number of (1,3-dihydro- and 1,3,4,5-tetrahydro-)(1-[2-(3,4-dimethoxyphenyl)propyl]- and 1-[2-(3,4-dimethoxyphenyl)ethyl])-2H-imidazol-2-one derivatives are specifically disclosed in U.S. Pat. No. 3,184,460 as therapeutic agents acting on the central nervous system, in particular, as tranquilizers. Synthetic Communications (1985) 15(10), 883-889, discloses a synthetic pathway for the preparation of 1,3,4,5-tetrahydro-1-[2-(3,4-dimethoxy-phenyl)ethyl]-3-phenylmethyl-2H-imidazol-2-one. In the Chemical and Pharmaceutical Bulletin (1980), 28(6), 1810-1813, 1,3,4,5-tetrahydro-1,3-bis[2-(3,4-dimethoxyphenyl)ethyl]-2H-imidazol-2-one and 1,3,4,5-tetrahydro-1-[2-(3,4-dimethoxyphenyl)ethyl]-2H-imidazol-2-one are disclosed as intermediates in the synthesis of a diazasteroid system. WO 94/12461, WO 94/14742 and WO 94/20446 generically describe a number of 1-(phenylalkyl)-2-hydroxy-imidazole derivatives as selective PDE IV inhibitors.
Unexpectedly, particular 1,3-dihydro-1-(phenylalkyl)-2H-imidazol-2-one derivatives show improved PDE IV inhibiting activity over the art compounds. In addition, the compounds of the present invention were found to display cytokine inhibiting activity. In view of these pharmacological properties, the present compounds have therapeutical utility in the treatment of disease states related to an abnormal enzymatic or catalytic activity of PDE IV, or disease related to a physiologically detrimental excess of cytokines, in particular allergic, atopic and inflammatory diseases.
The present invention concerns the use of compounds of formula (I) for the manufacture of a medicament for treating warm-blooded animals suffering from disease states related to an abnormal enzymatic or catalytic activity of phosphodiesterase IV (PDE IV), and/or disease states related to a physiologically detrimental excess of cytokines, in particular allergic, atopic and inflammatory diseases, and compounds having the formula
the N-oxide forms the pharmaceutically acceptable acid or base addition salts and the stereochemically isomeric forms thereof, wherein:
R
1
and R
2
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 selected from oxygen, sulfur or nitrogen; indanyl; bicyclo[2.2.1]-2-heptenyl; bicyclo[2.2.1]heptanyl; C
1-6
alkylsulfonyl; arylsulfonyl; or C
1-10
alkyl substituted with one or two substituents each independently selected from aryl, pyridinyl, thienyl, furanyl, 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
4
is hydrogen, halo or C
1-6
alkyloxy;
R
3
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
4
is a radical of formula:
—O—R
6
(a−1); or
—NH—R
7
(a−2);
wherein
R
6
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
7
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
5
is hydrogen, halo, hydroxy or C
1-6
alkyl; or
R
4
and R
5
taken together may form a bivalent radical of formula:
—(CH
2
)
n
—(b−1);
—CH
2
—CH
2
—O—CH
2
—CH
2
—(b−2);
—CH
2
—CH
2
—N(R
8
)—CH
2
—CH
2
—(b−3); or
—CH
2
—CH═CH—CH
2
—(b−4);
wherein
n is 2, 3, 4 or 5;
R
8
is hydrogen, C
1-6
alkyl, C
1-6
alkylsulfonyl or p-toluenesulfonyl;
Y is a direct bond, haloC
1-4
alkanediyl or C
1-4
alkanediyl;
—A—B— is a bivalent radical of formula:
—CR
9
═CR
10
—(c−1); or
—CHR
9
—CHR
10
—(c−2);
wherein each R
9
and R
10
independently is hydrogen or C
1-4
alkyl; and
L is hydrogen; C
1-6
alkyl; C
1-6
alkylcarbonyl; C
1-6
alkyloxycarbonyl; 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; piperidinyl; piperidinyl substituted with C
1-4
alkyl or arylC
1-4
alkyl; C
1-6
alkylsulfonyl or arylsulfonyl;
aryl is phenyl or phenyl substituted with one, two or three substituents 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 pyridinyl; pyridinyl substituted with C
1-4
alkyl; furanyl; furanyl substituted with C
1-4
alkyl; thienyl; thienyl substituted with C
1-4
alkylcarbonylamino; hydroxypyridinyl, hydroxypyridinyl substituted with C
1-4
alkyl or C
1-4
alkoxy-C
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; piperidinyl; piperidinyl 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; piperidinyl; piperidinyl substituted with C
1-4
alkyl or arylC
1-4
alkyl; piperazinyl; piperazinyl substituted with C
1-4
alkyl or arylC
1-4
alkyl; pyridinyl; pyridinyl 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 present invention also relates to a method of treating warm-blooded animals suffering from 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, more in particular asthmatic and atopic diseases, most particular atopic dermatitis. Said method comprises the administration of a therapeutically effective amount of a compound of formula (I) or a N-oxide form, a pharmaceutically acceptable acid or base addition salt or a stereochemically isomeric form thereof in admixture with a pharmaceutical carrier.
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 R
1
and R
2
, the saturated 5-, 6- and 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, piperidinyl, piperazinyl and tetrahydropyranyl. Said heterocyclic radicals are attached to the C
1-10
alkyl radical by any carbon atom or, where appropriate, by a nitrogen atom.
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, 1,1-di-methylethyl, pr

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