Arylalkylpyridazinones

Details Arylalkylpyridazinones Arylalkylpyridazinones

1996-04-19

2002-06-04

Ford, John M. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C544S239000

Reexamination Certificate

active

06399611

ABSTRACT:

The invention relates to compounds of the formula I
in which
R
1
and R
2
in each case independently of one another are H or A,
R
3
and R
4
in each case independently of one another are —OH, —OR
10
, —S—R
10
, —SOR
10
, —SO
2
R
10
, —SO
2
R
10
, Hal, —NO
2
, —NH
2
, —NHR
10
or —NR
10
R
11
, or together are methylenedioxy,
R
5
is a phenyl radical which is unsubstituted or mono- or disubstituted by R
6
and/or R
7
,
Q is absent or is alkylene having 1-6 C atoms,
R
6
and R
7
in each case independently of one another are —NH
2
, —NR
8
R
9
, —NHR
10
, —NR
10
R
11
, —NO
2
, Hal, —CN, —OA, —COOH or —COOA,
R
8
and R
9
in each case independently of one another are H, —COOA, —SO—A, —SO
2
A, —CONH
2
, —CONHA, —CONA
2
, —CO—COOH, —CO—COOA, —CO—CONH
2
, —CO—CONHA, —CO—CONA
2
, or acyl, i.e., carboxylic acyl, having 1-8 C atoms which is optionally substituted by 1-5 F and/or Cl atoms,
A is alkyl preferably having 1 to 6 C atoms which can be substituted by 1-5 F and/or Cl atoms,
R
10
and R
11
in each case independently of one another are A, cycloalkyl having 3-7 C atoms, methylenecycloalkyl having 4-8 C atoms or alkenyl having 2-8 C atoms and
Hal is F, Cl, Br or I, and their physiologically acceptable salts.
Similar compounds are disclosed in DE 195 02 699.3.
The invention is based on the object of finding novel compounds having useful properties, in particular those which can be used for the production of medicaments.
Upon further study of the specification and appended claims, further objects and advantages of this invention will become apparent to those skilled in the art.
It has been found that the compounds of the formula I and their salts have useful pharmacological properties together with good tolerability. In particular, they show inhibition of phosphodiesterase IV and can be employed for the treatment of asthmatic disorders. The anti-asthmatic action can be determined, for example, by the method of T.Olsson, Acta allergologica 26, 438-447 (1971).
The compounds additionally show an inhibitory action on the formation of TNF (Tumour Necrosis Factor) and are therefore suitable for the treatment of allergic and inflammatory diseases, autoimmune diseases and transplant rejection reactions. They can also be employed for the treatment of memory disorders.
The compounds of the formula I can therefore be used as pharmaceutically active compounds in human and veterinary medicine. They can further be employed as intermediates for the production of other pharmaceutically active compounds.
The invention accordingly relates to the compounds of the formula I and their salts and to a process for the preparation of these compounds and their salts, characterized in that a compound of the formula II
in which
R
1
, R
2
R
3
and R
4
have the meanings indicated above, is reacted with a compound of the formula III
R
5
—Q—X  III
in which
R
5
and Q have the meanings indicated, and
X is Cl, Br, OH or a reactive esterified OH group,
or in that a compound of the formula IV
in which
R
1
, R
2
, R
3
and R
4
have the meanings indicated, and
E is H or alkyl having 1-4 C atoms, is reacted with a compound of the formula V
H
2
N—NH—Q—R
5
  V
in which
Q and R
5
have the meanings indicated, or in that in a compound of the formula I a radical R
5
is converted into another radical R
5
by reducing a nitro group, alkylating or acylating a primary or a secondary amino group or hydrolyzing a cyano group,
and/or in that a compound which corresponds to the formula I, but instead of R
3
and/or R
4
contains one or two free OH groups, is optionally reacted with a compound of the formula R
3
—X or R
4
—X in which R
3
, R
4
and X have the meanings indicated, and/or a base of the formula I is converted into one of its salts by treating with an acid.
Above and below, the radicals R
1
, R
2
, R
3
, R
4
, R
5
, Q and X have the meanings indicated in the formulae I, II and III, unless expressly stated otherwise.
A is alkyl.
In the above formulae, alkyl is preferably unbranched and has 1 to 6 C atoms, preferably 1, 2, 3 or 4 C atoms, and is preferably methyl, further preferably ethyl or propyl, furthermore preferably isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, but also n-pentyl or isopentyl.
Cycloalkyl preferably has 3-7 C atoms and is preferably cyclopropyl or cyclobutyl, furthermore preferably cyclopentyl or cyclohexyl, and further also cycloheptyl.
Methylenecycloalkyl preferably has 4-8 C atoms and is preferably methylenecyclopropyl or methylenecyclobutyl, furthermore preferably methylenecyclopentyl or methylenecyclohexyl, and further also methylene-cycloheptyl.
Alkenyl is preferably vinyl, 1- or 2-propenyl, 1-butenyl, isobutenyl, sec-butenyl, and is further preferably 1-pentenyl, isopentenyl or 1-hexenyl.
Alkylene is preferably unbranched and is preferably methylene or ethylene, and further preferably propylene or butylene.
Of the radicals R
1
and R
2
, one is preferably H, while the other is preferably propyl or butyl, but particularly preferably ethyl or methyl. R1 and R2 are further preferably together also each hydrogen.
Hal is preferably F, Cl or Br, but also I.
The radicals R
3
and R
4
can be identical or different and are preferably in the 3- or 4-position of the phenyl ring. They are, for example, independently of one another hydroxyl, —S—CH
3
, —SO—CH
3
, —SO
2
CH
3
, F, Cl, Br or I or together methylenedioxy. Particularly preferably, however, they are each methoxy, ethoxy, propoxy, cyclopentoxy, or else fluoro-, difluoro- or trifluoromethoxy, or 1-fluoro-, 2-fluoro-, 1,2-difluoro-, 2,2-difluoro-, 1,2,2-trifluoro- or 2,2,2-trifluoroethoxy.
The radical R
5
is preferably phenyl. The phenyl radical is preferably mono- or disubstituted. Preferred substituents are cyano, nitro, amino, acetamido, trifluoroacetamido, methoxy and/or chlorine, also preferred are methylsulfonamido, propionylamino, 2-methylpropionylamino, isobutyrylamino and/or pivalylamino, and further preferred are methoxycarbonylamino, methoxalylamino, ureido and/or carboxyl.
Q—R
5
is preferably benzyl, 2-, 3- or 4-nitrobenzyl, 2-, 3- or 4-cyanobenzyl, 2-, 3- or 4-aminobenzyl, 2-, 3- or 4-acetamidobenzyl, 2-, 3- or 4-trifluoroacetamidobenzyl, 2-, 3- or 4-methoxybenzyl, 2-, 3- or 4-chlorobenzyl, is further preferably 2-, 3- or 4-methylsulfonamidobenzyl, 2-, 3- or 4-propionylaminobenzyl, 2-, 3- or 4-(2-methylpropionylamino)-benzyl, 2, 3- or 4-isobutyrylaminobenzyl, 2-, 3- or 4-pivalylaminobenzyl, 2-, 3- or 4-methoxycarbonyl-aminobenzyl, 2-, 3- or 4-ureidobenzyl, 2-, 3- or 4-carboxybenzyl, 2-, 3- or 4-methoxalylaminobenzyl, and is also preferably 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dinitrobenzyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-diaminobenzyl, 2,3-, 2,4-, 2,5-, 2,6-3,4- or 3,5-diacetamidobenzyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-bis(trifluoroacetamido)benzyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dimethoxybenzyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dichlorobenzyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dimethylsulfonamidobenzyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dipropionylaminobenzyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-bis(2-methylpropionylamino)benzyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-diisobutyrylaminobenzyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dimethoxycarbonylaminobenzyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dimethoxalylaminobenzyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-diureidobenzyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dicarboxybenzyl.
Accordingly, the invention in particular relates to those compounds of the formula I in which at least one of the said radicals has one of the preferred meanings indicated above. Some preferred groups of compounds can be expressed by the following sub-formulae Ia to Ie which correspond to the formula I and in which the radicals which are not described in greater detail have the meaning indicated in the formula I, but in which
in Ia R
1
is H,
R
2
is H or A,
R
3
is OA;
in Ib R1 is H,
R
2
is methyl or ethyl,
R
3
and R
4
are each independently of one another
in Ic R
1
is H,
R
2
is methyl or ethyl,
R
3
is OA
R
4
is OA where A is mono-, di- or trifluoro-substituted al

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