Benzoylpyridazines, their preparation and use

Details Benzoylpyridazines, their preparation and use Benzoylpyridazines, their preparation and use

2002-01-09

2004-02-24

Raymond, Richard L. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S252010, C544S224000, C544S238000

Reexamination Certificate

active

06696446

ABSTRACT:

The invention relates to compounds of the formula I
in which
R
1
, R
2
in each case independently of one another are H, OH, OA,
SA, SOA, SO
2
A, F, Cl or A′
2
N—(CH
2
)
n
—O—,
R
1
and R
2
together are also —O—CH
2
—O—,
R
3
, R
4
in each case independently of one another are H, A, Hal,
OH, Office Action, NO
2
, NHA, NA
2
, CN, COOH,
COOA, NHCOA, NHSO
2
A or NHCOOA,
R
5
, R
6
in each case independently of one another are H or alkyl
having 1 to 6 C atoms,
A
is alkyl having 1 to 10 C atoms, which can be substituted
by 1 to 5 F and/or Cl atoms; cycloalkyl having 3-7 C atoms;
alkylenecycloalkyl having 5-10 C atoms; or alkenyl having
2-8 C atoms
A′
is alkyl having 1, 2, 3, 4, 5 or 6 C atoms,
n
is 1, 2, 3 or 4,
Hal
is F, Cl, Br or I,
and their physiologically acceptable salts and solvates.
1-Benzoyltetrahydropyridazines as progesterone receptor ligands are described, for example, in J. Med. Chem. 38, 4878 (1995).
Similar compounds are also disclosed in DE 196 32 549 A1.
The invention was based on the object of finding novel compounds having valuable properties, in particular those which can be used for the production of medicaments.
It has been found that the compounds of the formula I and their salts and solvates have very valuable pharmacological properties together with good tolerability.
In particular, they show a selective inhibition of phosphodiesterase IV, which is associated with an intracellular increase in cAMP (N. Sommer et al., Nature Medicine, 1, 244-248 (1995)).
The inhibition of PDE IV can be demonstrated, for example, analogously to C. W. Davis in Biochim. Biophys. Acta 797, 354-362 (1984).
The compounds according to the invention can be employed for the treatment of asthmatic disorders. The antiasthmatic action of the PDE IV inhibitors is described, for example, by 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 osteogenetic cells (S. Kasugai et al., M 681 and K. Miyamoto, M 682, in Abstracts of the American Society for Bone and Mineral Research 18th Annual Meeting, 1996), the compounds according to the invention can be employed for the treatment of osteoporosis.
The compounds moreover show an antagonistic action on the production of TNF (Tumour Necrosis Factor) and are therefore suitable for the treatment of allergic and inflammatory diseases, autoimmune diseases, such as, for example, rheumatoid arthritis, multiple sclerosis, Crohn's disease, diabetes mellitus or ulcerative colitis, transplant rejection reactions, cachexia and sepsis.
The anti-inflammatory action of the substances according to the invention and their efficacy for the treatment of, for example, autoimmune disorders such as multiple sclerosis or rheumatoid arthritis can be determined analogously to 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 compounds can be employed for the treatment of cachexia. The anti-cachectic action can be tested in TNF-dependent models of cachexia (P. Costelli et al., J. Clin. Invest. 95, 2367ff. (1995); J. M. Argiles et al., Med. Res. Rev. 17, 477ff. (1997)).
PDE IV inhibitors can also inhibit the growth of tumour cells and are therefore suitable for tumour therapy (D. Marko et al., Cell Biochem. Biophys. 28, 75ff. (1998)). The action of PDE IV inhibitors in tumour treatment is described, for example, in WO 95 35 281, WO 95 17 399 or WO 96 00 215.
PDE IV inhibitors can prevent mortality in models of sepsis and are therefore suitable for the therapy of sepsis (W. Fischer et al., Biochem. Pharmacol. 45, 2399ff. (1993)).
They can furthermore be employed for the treatment of memory disorders, atherosclerosis, atopic dermatitis and AIDS.
The action of PDE IV inhibitors in the treatment of asthma, inflammatory disorders, diabetes mellitus, atopic dermatitis, psoriasis, AIDS, cachexia, tumour growth or tumour metastases is described, for example, in EP 77 92 91.
The compounds of the formula I can be employed as pharmaceutical active compounds in human and veterinary medicine. They can furthermore be employed as intermediates for the preparation of further pharmaceutical active compounds.
The invention accordingly 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 of their salts and solvates, characterized in that a compound of the formula II
in which
R
1
and R
2
have the meanings indicated, is reacted with a compound of the formula III
in which
R
3
, R
4
, R
5
, R
6
have the meanings indicated in claim 1, and
L 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
and R
5
have the meanings indicated in claim 1, is reacted with a compound of the formula V
in which
R
3
, R
4
, R
6
have the meanings indicated in claim 1, and
L is Cl, Br, OH or a reactive esterified OH group,
or
in that a compound of the formula VI
in which
R
1
, R
2
, R
5
and R
6
have the meanings indicated in claim 1, is reacted with a compound of the formula VII
in which
R
3
, R
4
have the meanings indicated in claim 1, 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 one of its salts by treatment with an acid.
Solvates of the compounds of the formula I are understood as meaning adducts of inert solvent molecules to the compounds of the formula I, which are formed as a result of their mutual power of attraction. Solvates are, for example, mono- or dihydrates or alcoholates.
Above and below, the radicals R
1
, R
2
, R
3
, R
4
, R
5
, R
6
and L have the meanings indicated in the formulae I, II, III, IV, V, VI and VII, if not expressly stated otherwise.
A is preferably alkyl, furthermore alkyl preferably substituted by 1 to 5 fluorine and/or chlorine atoms, furthermore preferably cycloalkyl.
In the above formulae, alkyl is preferably unbranched and has 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 C atoms, preferably 1, 2, 3, 4, 5 or 6 C atoms, and is preferably methyl, ethyl, trifluoromethyl, pentafluoroethyl or propyl, furthermore preferably isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, but also n-pentyl, neopentyl, isopentyl or n-hexyl. Methyl, ethyl, trifluoromethyl, propyl, isopropyl, butyl, n-pentyl, n-hexyl or n-decyl is particularly preferred.
Cycloalkyl preferably has 3-7 C atoms and is preferably cyclopropyl or cyclobutyl, furthermore preferably cyclopentyl or cyclohexyl, and further also cycloheptyl; cyclopentyl is particularly preferred.
Alkylene is preferably allyl, 2- or 3-butenyl, isobutenyl, sec-butenyl; 4-pentenyl, isopentenyl or 5-hexenyl is further preferred.
Alkylene is preferably unbranched and is preferably methylene or ethylene, and further preferably propylene or butylene.
Alkylenecycloalkyl preferably has 5-10 C atoms and is preferably methylenecyclopropyl, methylenecyclobutyl, furthermore preferably methylenecyclopentyl, methylenecyclohexyl or methylenecycloheptyl, and further also ethylenecyclopropyl, ethylenecyclobutyl, ethylenecyclopentyl, ethylenecyclohexyl or ethylenecycloheptyl, propylenecyclopentyl, propylenecyclohexyl, butylenecyclopentyl or butylenecyclohexyl.
A′ is preferably methyl, ethyl, propyl or butyl.
n is preferably 2 or 3.
Hal is preferably 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. 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. 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.
R
1
is particularly preferably methoxy, ethoxy, cyclopentoxy or isopropoxy.
R
2
is particularly preferably methoxy or ethoxy.
R
3
is preferably A, F, Cl, Br or I, hydro

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