Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-03-15
2002-11-12
Criares, Theodore J. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S252010
Reexamination Certificate
active
06479494
ABSTRACT:
The invention relates to arylalkanoylpyridazine rivatives of the formula I
in which
B is A, OA, NH
2
, NHA, NAA′ or an unsaturated heterocycle which has 1 to 4 N, O and/or S atoms and which can be unsubstituted or mono-, di- or trisubstituted by Hal, A and/or OA,
Q is absent or is alkylene having 1-6 C atoms,
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
, Hal, —NO
2
, —NH
2
, —NHR
5
or —NR
5
R
6
,
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 or A,
R
5
, R
6
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,
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 thereof.
1-Benzoyltetrahydropyridazines have been described as progesterone receptor ligands, for example in J. Med. Chem. 38, 4878 (1995).
The invention was based on the object of finding novel compounds which have valuable properties, in particular those which can be used for the preparation 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 inhibit selectively phosphodiesterase IV, which causes an increase of the intracellular cAMP level (N. Sommer et al., Nature Medicine, 1, 244-248 (1995)).
The PDE IV inhibition can be determined analogously to e.g. C. W. Davis in Biochim. biophys. Acta 797, 354-362 (1984).
The compounds of the formula I can be employed for the treatment of asthmatic diseases. The antiasthmatic activity of PDE IV inhibitors is known from 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).
As cAMP inhibits bone decreasing cells and stimulates bone increasing cells (S. Kasugai et al., M681 and K. Miyamoto, M 682, in Abstract of the American Society for Bone and Mineral Research 18
th
annual meeting 1996), the compounds of formula I can be employed for the treatment of osteoporosis.
Moreover, the compounds have an inhibitory effect on the formation of TNF (tumor necrosis factor) and are therefore suitable for the treatment of allergies and inflammatory diseases, autoimmune diseases and transplant rejection reactions. They can furthermore be used for the treatment of dysmnesia, tumors, atherosclerosis, rheumatoid arthritis, multiple sclerosis, Morbus Crohn, atopic dermatitis, diabetes mellitus, ulcerative colitis and AIDS.
PDE IV inhibitors are potent compounds for the treatment of asthmatic and inflammatory diseases, diabetes mellitus, atopic dermatitis, psoriasis, AIDS, tumor growth or tumor metastasis (see e.g. EP 77 92 91).
The antiinflammatory effect of the compounds of the formula I and their potency for the treatment of e.g. autoimmune diseases, 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).
PDE IV inhibitors are effective in the treatment of tumors (see e.g. 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
, R
2
, R
3
and R
4
have the abovementioned meanings
is reacted with a compound of the formula III
in which
B and Q have the abovementioned meanings 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
, R
3
, R
4
and Q have the abovementioned meanings is reacted with a compound of the formula V
B—CO—L V
in which
B has the abovementioned meaning 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
, R
4
, B, Q and L hereinabove and hereinbelow have the meanings given for the formulae I, II, III, IV and V, unless expressly stated otherwise.
Compounds of the formula I can be chiral and can accordingly occur in different isomeric forms. All these forms (e.g. R- and S-forms) and their mixtures (e.g. the R,S-forms) are embraced by 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, pentafluoroethyl 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.
Methylenecycloalkyl has by preference 4-8 C atoms and is preferably methylenecyclopropyl and methylenecyclobutyl, furthermore preferably methylenecyclopentyl 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 by preference unbranched and is preferably methylene or ethylene, furthermore preferably propylene or butylene.
Of the radicals R
3
and R
4
, one is preferably H, while the other is preferably propyl or butyl, but particularly preferably ethyl or methyl. Furthermore, R
1
and R
2
together are also preferably each hydrogen.
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, 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-trifluoroethoxy.
The radical B is by preference 2- or 3-furyl, 2- or 3-thienyl, 1-, 2- or 3-pyrrolyl, 1-, 2-, 4- or 5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 3- or 4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, furthermore preferably 1,2,3-triazol-1-, -4- or -5-yl, 1,2,4-triazol-1-, -3- or -5-yl, 1- or 5-tetrazolyl, 1,2,3-oxadiazol-4- or -5-yl, 1,2,4-oxadiazol-3- or -5-yl, 1,3,4-thiadiazol-2- or -5-yl, 1,2,4-thiadiazol-3- or -5-yl, 1,2,3-thiadiazol-4- or -5-yl, 3- or 4-pyridazinyl, pyrazinyl, 2-, 3-, 4-, 5-, 6- or 7-benzofuryl, 2-, 3-, 4-, 5-, 6- or 7-benzothienyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-indolyl, 1-, 2-, 4- or 5-benzimidazolyl, 1-, 3-, 4-, 5-, 6- or 7-benzopyrazolyl, 2-, 4-, 5-, 6- or 7-benzoxazolyl, 3-, 4-, 5-, 6- or 7-benzoisoxazolyl, 2-, 4-, 5-, 6- or 7-benzothiazolyl, 2-, 4-, 5-, 6- or 7-benzoisothiazolyl, 4-, 5-, 6- or 7-benzo-2,1,3-oxadiazolyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolyl, 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolyl, 3-, 4-, 5-, 6-, 7- or 8-cinnolinyl, 2-, 4-, 5-, 6-, 7- or 8-quinazolinyl.
The radical B is furthermore by preference methyl, ethyl, propyl, n-butyl, methoxy, ethoxy, propoxy, N-methylamino, N,N-dimethylamino, N-ethylamino or N,N-diethylamino.
The rule that all radicals which occur more than once can be identical or different, that
Beier Norbert
Kluxen Franz-Werner
Rochus Jonas
Wolf Michael
Criares Theodore J.
Merck Patent Gesellschaft Mit Beschraenkter Haftung
Millen White Zelano & Branigan P.C.
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