Isoxazole derivatives to be used as phosphodiesterase VII...

Details Isoxazole derivatives to be used as phosphodiesterase VII... Isoxazole derivatives to be used as phosphodiesterase VII...

2002-05-03

2003-03-11

McKane, Joseph K. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C548S247000, C548S248000, C548S249000

Reexamination Certificate

active

06531498

ABSTRACT:

The invention relates to compounds of formula I
in which
R
1
, R
2
, R
3
, R
4
are each, independently of one another, Hal, OA
1
, SA
1
, A, H, COOA
1
, CN or CONA
1
A
2
,
R
5
is COOA
1
, CN or CONA
1
A
2
,
A
1
, A
2
are each, independently of one another, H, A, alkenyl, cycloalkyl or alkylenecycloalkyl,
A is alkyl having 1 to 10 C atoms,
Hal is F, Cl, Br or I,
and their physiologically acceptable salts and/or solvates as phosphodiesterase VII inhibitors.
The invention further relates to the use of the compounds of the formula I for producing a pharmaceutical for controlling allergic disorders, asthma, chronic bronchitis, atopic dermatitis, psoriasis and other skin disorders, inflammatory disorders, autoimmune diseases such as, for example, rheumatoid arthritis, multiple sclerosis, Crohn's disease, diabetes mellitus or ulcerative colitis, osteoporosis, transplant rejection reactions, cachexia, tumour growth or tumour metastases, sepsis, memory disturbances, atherosclerosis and AIDS.
Compounds of the formula I are described by Bionet.
The invention was based on the object of finding novel compounds with valuable properties, in particular those which can be used for producing pharmaceuticals.
It has been found that the compounds of the formula I and their salts have very valuable pharmacological properties while being well tolerated. In particular, they show a specific inhibition of the “rolipram-insensitive” cAMP phosphodiesterase (PDE VII).
The biological activity of the compounds of the formula I can be determined by methods like those described, for example, by M. A. Giembycz et al. in Br. J. Pharmacol. (1996), 118, 1945-1958. The affinity of the compounds for cAMP phosphodiesterase (PDE VII) is determined by measuring their IC
50
values (concentration of the inhibitor required to achieve 50% inhibition of the enzymic activity). The determinations were carried out using homogenized SK-N-SH neuroblastoma cells in place of T lymphocytes, and CI-930 was employed to inhibit PDE III. The latter is a selective PDE III inhibitor (J. A. Bristol et al., J. Med. Chem. 1984, 27(9), 1099-1101).
The compounds of the formula I can be employed for treating asthmatic disorders. The antiasthmatic effect can be determined, for example, in analogy to the method of T. Olsson, Acta allergologica 26, 438-447 (1971).
Since cAMP inhibits osteoclastic cells and stimulates osteoblastic 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 of the formula I can be employed for treating osteoporosis.
The compounds additionally show an antagonistic effect on the production of TNF&agr; (tumour necrosis factor) and are therefore suitable for treating allergic and inflammatory disorders, 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 antiinflammatory effect of the substances of the formula I and their efficacy for the treatment of, for example, autoimmune diseases such as multiple sclerosis or rheumatoid arthritis can be determined in analogy 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 treating cachexia. The anti-cachectic effect 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)).
The PDE VII inhibitors are also able to inhibit the growth of tumour cells and are therefore suitable for tumour therapy (for PDE IV inhibitors, cf. D. Marko et al., Cell Biochem. Biophys. 28, 75ff. (1998)).
They can furthermore be employed for the therapy of sepsis and for treating memory disturbances, atherosclerosis, atopic dermatitis and AIDS, and for treating T-cell-dependent diseases (L. Li et al., Science, 1999, 283, 848-851).
The invention further relates to the use of phosphodiesterase VII inhibitors for producing a pharmaceutical for controlling allergic disorders, asthma, chronic bronchitis, atopic dermatitis, psoriasis and other skin disorders, inflammatory disorders, autoimmune diseases such as, for example, rheumatoid arthritis, multiple sclerosis, Crohn's disease, diabetes mellitus or ulcerative colitis, osteoporosis, transplant rejection reactions, cachexia, tumour growth or tumour metastases, sepsis, memory disturbances, atherosclerosis and AIDS.
The compounds of the formula I can be employed as active pharmaceutical ingredients for inhibiting PDE VII in human and veterinary medicine.
A is alkyl having 1-10 C atoms and has 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 C atoms and is preferably methyl, ethyl or propyl, also preferably isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, but is also n-pentyl, neopentyl, isopentyl or hexyl. It is also possible for 1-7 H atoms in the radicals to be replaced by F and/or Cl. A is therefore also, for example, trifluoromethyl or pentafluoroethyl.
Cycloalkyl has 3-9 C atoms and is preferably, for example, cyclopentyl or cyclohexyl. Alkenyl has 2-10 C atoms, is linear or branched and is preferably vinyl, propenyl or butenyl.
Alkylenecycloalkyl has 4-10 C atoms and is, for example methylenecyclopentyl, ethylenecyclopentyl, methylenecyclohexyl or ethylenecyclohexyl.
Accordingly, the invention relates in particular to those compounds of the formula I as phosphodiesterase VII inhibitors 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 part-formulae Ia to Ig which correspond to formula I and in which the undefined radicals have the meaning stated for formula I, but in which
in Ia
R
1
is H;
in Ib
R
1
and R
2
are H;
in Ic
R
1
is H and
R
2
is F or Cl;
in Id
R
1
, R
2
are each, independently of one another, H or Hal;
in Ie
R
1
, R
2
are each, independently of one another, H or Hal,
A
1
, A
2
are each, independently of one another, H or A;
in If
A
1
, A
2
are each, independently of one another, H or A;
in Ig
R
1
, R
2
are each, independently of one another, H or Hal,
A
1
, A
2
are each, independently of one another, H or A,
A is alkyl having 1, 2, 3 or 4 C atoms,
Hal is F or Cl.
A base of the formula I can be converted with an acid into the relevant acid addition salt, for example by reacting equivalent amounts of the base and the acid in an inert solvent such as ethanol and subsequently evaporating. Acids particularly suitable for this reaction are those which provide physiologically acceptable salts. Thus, it is possible to use inorganic acids, for example sulfuric acid, nitric acid, hydrohalic acids such as hydrochloric acid or hydrobromic acid, phosphoric acids such as orthophosphoric acid, sulfamic acid, also organic acids, in particular aliphatic, alicyclic, araliphatic, aromatic or heterocyclic mono- or polybasic carboxylic, sulfonic or sulfuric acids, for example formic acid, acetic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, maleic acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, methane- or ethanesulfonic acid, ethanedisulfonic acid, 2-hydroxy-ethanesulfonic acid, benzenesulfonic acid, p-toluene-sulfonic acid, naphthalenemono- and -disulfonic acids, lauryl sulfuric acid. Salts with physiologically unacceptable acids, for example picrates, can be used to isolate and/or purify the compounds of the formula I.
The invention furthermore relates to pharmaceutical preparations comprising at least one phosphodiesterase VII inhibitor of the formula I and/or one of its physiologically acceptable salts and/or solvates for controlling allergic disorders, asthma, chronic bronchitis, atopic dermatitis, psoriasis and other skin disorders, inflammatory disorders, autoimmune diseases such as, for example, rheumatoid arthritis, mult

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