Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-05-03
2002-04-23
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S252050, C514S247000, C544S224000, C544S238000
Reexamination Certificate
active
06376493
ABSTRACT:
This application a 371 of PCT/EP99/08047, filed Oct. 23, 1999.
The invention relates to benzoylpyridazine derivatives of the formula I
in which
R
1
, R
2
in each case independently of one another are —OH, OR
5
, —S—R
5
, —SO—R
5
, —SO
2
—R
5
or Hal,
R
1
and R
2
together are also —O—CH
2
—O—,
R
3
is NH
2
, NHA, NAA′ or a saturated heterocycle having 1 to 4 N, O and/or S atoms which can be unsubstituted or mono-, di- or tri-substituted by Hal, A and/or OA,
Q is absent or is branched or unbranched alkylene having 1-10 C atoms,
R
5
is A, cycloalkyl having 3-7 C atoms, alkylenecycloalkyl having 4-8 C atoms or alkenyl having 2-8 C atoms,
A, A′ in each case independently of one another are alkyl which has 1 to 10 C atoms and which can be substituted by 1 to 5 F and/or Cl atoms and
Hal is F, Cl, Br or I,
and the physiologically acceptable salts and solvates thereof.
1-Benzoyltetrahydropyridazines have been described as progesterone receptor ligands, for example in J. Med. Chem. 38, 4878 (1995). Other arylalkanoylpyridazines are disclosed, for example, in DE 196 32 549.
The invention was based on the object of finding novel compounds which have valuable properties, in particular those which can be used for the reparation of pharmaceuticals.
It has been found that the compounds of the formula I and salts thereof have highly valuable pharmacological properties and are well tolerated.
In particular, they selectively inhibit phosphodiesterase IV combined with an intracellular increase in the cAMP level (N. Sommer et al., Nature Medicine, 1, 244-248 (1995)). The inhibition of PDE IV can be detected, for example, as described by C. W. Davis in Biochim. biophys. Acta 797, 354-362 (1984).
The compounds according to the invention can be employed for treating asthmatic diseases. The antiasthmatic effect of PDE IV inhibitors has been described by, for example, T. J. Torphy et al., in Thorax, 46, 512-523 (1991) and can be determined, for example, by the method of T. Olsson, Acta allergologica 26, 438-447 (1971).
Since cAMP inhibits osteoclastic cells and stimulates osteogenic cells (S. Kasugai et al., M681 and K. Miyamoto, M682, in Abstract of the American Society for Bone and Mineral Research 18
th
annual meeting, 1996, the compounds according to the invention can be used for the treatment of osteoporosis.
Moreover, the compounds have an inhibitory effect on the formation of TNF (tumour necrosis factor) and are therefore suitable for the treatment of allergies and inflammatory diseases, autoimmune diseases and transplant rejection reactions.
They can be used for the treatment of dysmnesia, tumours, cachexia, atherosclerosis, rheumatoid arthritis, multiple sclerosis, morbus Crohn, atopic dermatitis, diabetes mellitus, ulcerative colitis and AIDS.
The effect of PDE IV inhibitors in the treatment of asthma, inflammatory diseases, diabetes mellitus, atopic dermatitis, psoriasis, AIDS, tumour growth or tumour metastases is described, for example, in EP 77 92 91.
The anti-inflammatory effect of the substances according to the invention and their activity for the treatment of, for example, autoimmune diseases, multiple sclerosis or rheumatoid arthritis can be determined following the methods of N. Sommer et al., Nature Medicine, 1, 244-248 (1995) or L. Sekut et al., Clin. Exp. Immunol., 100, 126-132 (1995).
The effect of PDE IV inhibitors in the treatment of tumours is described, for example, in WO 95 35 281, WO 95 17 399 or WO 96 00 215.
The compounds of the formula I can be employed as pharmaceutically active ingredients in human and veterinary medicine. Furthermore, they can be employed as intermediates for the preparation of other pharmaceutically active ingredients.
Accordingly, the invention relates to the compounds of the formula I and to a process for the preparation of compounds of the formula I according to claim 1 and salts thereof, characterized in that a compound of the formula II
in which
R
1
and R
2
have the meanings given in claim 1 is reacted with a compound of the formula III
in which
Q and R
3
have the meanings given in claim 1 and
is Cl, Br, OH or a reactive esterified OH group, or
in that a compound of the formula IV
in which
R
1
and R
2
have the abovementioned meanings is reacted with a compound of the formula V
R
3
—Q—O—CO—L V
in which
R
3
and Q have the abovementioned meanings and L is Cl, Br, OH or a reactive esterified OH group, and/or in that a basic compound of the formula I is converted into a salt thereof by treatment with an acid.
The radicals, R
1
, R
2
, R
3
, Q and L hereinabove and hereinbelow have the meanings given for the formulae I, II, III, IV and V, unless expressly stated otherwise.
The compounds of the formula I can have a chiral centre and can therefore occur in several stereoisomeric forms. The formula I includes all these forms (for example R- and S-forms) and their mixtures (for example the R,S-forms). Solvates are to be understood as meaning, for example, the hydrates or alkoxides of the compounds of the formula I.
A and A′ are by preference alkyl, further preferably alkyl which is substituted by 1 to 5 fluorine and/or chlorine atoms.
In the above formulae, alkyl is by preference unbranched and has 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 C atoms, by preference 1, 2, 3, 4 or 5 C atoms, and is by preference methyl, ethyl, trifluoromethyl, pentafluoro-ethyl or propyl, furthermore preferably isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, but also n-pentyl, neo-pentyl or isopentyl.
Cycloalkyl has by preference 3-7 C atoms and is preferably cyclopropyl and cyclobutyl, furthermore preferably cyclopentyl or cyclohexyl, furthermore also cycloheptyl.
Alkylenecycloalkyl has by preference 4-8 C atoms and is preferably methylenecyclopropyl and methylenecyclobutyl, furthermore preferably methylene-cyclopentyl and methylenecyclohexyl, furthermore also methylenecycloheptyl.
Alkenyl is by preference vinyl, 1- or 2-propenyl, 1-butenyl, isobutenyl, sec-butenyl, and is furthermore preferably 1-pentenyl, isopentenyl or 1-hexenyl.
Alkylene is unbranched or branched and is preferably methylene, ethylene, furthermore preferably propylene, butylene, pentylene, hexylene, furthermore heptylene, octylene, nonylene or decylene.
Hal is by preference F, Cl or Br, but also I.
The radicals R
1
and R
2
can be identical or different and are in the 3- or 4-position of the phenyl ring. For example, they are independently of one another hydroxyl, —S—CH
3
, —SO—CH
3
, —SO
2
CH
3
, F, Cl, Br or I or together methylenedioxy. However, especially preferably they are in each case methoxy, ethoxy, propoxy, isoproproxy, cyclopentoxy, or else fluoro-, difluoro- or trifluoromethoxy, 1-fluoro-, 2-fluoro-, 1,2-difluoro-, 2,2-difluoro-, 1,2,2-trifluoro- or 2,2,2-trifluoro-ethoxy.
R
1
is very especially preferably methyl, ethyl or isopropyl. R
2
is very especially preferably methyl.
Q is by preference for example a bond, methylene, ethylene, propylene, butylene or pentylene.
A heterocycle is by preference for example piperidinyl, tetrahydrofuranyl or pyrrolidinyl.
The radical R
3
is by preference also amino, N-methylamino, N,N-dimethylamino, N-ethylamino, N,N-diethylamino or N-methylpiperidin-4-yl.
The rule that all radicals which occur more than once can be identical or different, that is to say are independent of one another, applies to the entire invention.
Accordingly, the invention relates in particular to those compounds of the formula I in which at least one of the abovementioned radicals has one of the preferred meanings given above. Some preferred groups of compounds can be expressed by the following subformulae Ia to Ie which correspond to the formula I and in which radicals which are not defined in greater detail have the meanings given for the formula I, but where
in Ia,
R
1
and R
2
are in each case independently of
one another OA,
Q
is alkylene having 1-6 C atoms and
R
3
is piperidinyl, pyrazinyl or
pyrrolidinyl, unsubstituted or mono-
or disubstituted by Hal or A;
in Ib,
R
1
and R
2
are in each case independently of
one anot
Jonas Rochus
Kluxen Franz-Werner
Wolf Michael
Merck Patent Gesellschaft mit beschrankter Haftung
Millen White Zelano & Branigan P.C.
Raymond Richard L.
LandOfFree
Benzoylpyridazines does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Benzoylpyridazines, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Benzoylpyridazines will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2888907