Use of maduraohtalazine derivatives as inhibitors of...

Details Use of maduraohtalazine derivatives as inhibitors of... Use of maduraohtalazine derivatives as inhibitors of...

2000-04-13

2002-08-27

Raymond, Richard L. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C544S233000

Reexamination Certificate

active

06440968

ABSTRACT:

FIELD OF THE INVENTION
The invention relates to the derivatives, both known and novel, of maduranic acid and their use as inhibitors of proinflammatory cytokines for producing pharmaceuticals for the treatment of disorders mediated by these cytokines, and process for making.
BACKGROUND
The immune system is a complicated network of interactions of different types of cells and their mediators with one another. The mediators are intercellular signal molecules which regulate, for example, the growth, the differentiation and the function of the cells involved (K. F. Arai et al., Annu. Rev. Biochem. 59 (1990), 783). One important group of mediators are the cytokines, which include the colony-stimulating factors and the interleukins. Cytokines are polypeptides whose diverse molecular characteristics, mechanisms of action, physiological functions and the part played by them in numerous disorders are currently the subjects of intensive research.
Thus, it is known that a number of cytokines are responsible for the control of the immunological defensive responses to pathogens. B lymphocytes and T lymphocytes are of crucial importance for identifying exogenous particles or substances and for initiating the cascade of defensive responses (H. Holtmann, K. Resch, Naturwissensch. 82 (1995), 178). The proliferation, the functional differentiation and the cell activity, but also the rate of release of other cytokines, are controlled for these cells in particular by interleukin-2 (IL-2) and interleukin-4 (IL-4) (W. J. Pichler, Schweiz. Med. Wochenschr. 127 (1997), 341). Both cytokines also act on the enhanced provision of interleukin-5 (IL-5). Thus, IL-2 is able to stimulate the synthesis of IL-5 in T lymphocytes (G. P. Anderson, A. J. Coyle, TiPS 15 (1994), 324).
IL-4 controls T-cell differentiation to increase production of Th2 cells which preferentially produce IL-4 and IL-5 (A. Mori et al., Intern. Immun. 8 (1996), 1889). The action of these 3 cytokines eventually initiates the pathogen-controlling responses which can be manifested as inflammation.
Numerous diseases are thought to be connected with disturbances of this system. Thus, excessive responses to non-hazardous foreign materials can be the cause of allergically induced disorders such as, for example, asthma, rhinitis, conjunctivitis or dermatitis. Immunological protective responses after transplants can lead to unwanted rejection reactions.
Substances able to inhibit the action of interleukin-2,interleukin-4 and interleukin-5 should thus be of great therapeutic benefit for treating disorders mediated by these cytokines.
Glucocorticosteroids such as, for example, beclomethasone or budesonide which have potent antuinflammatory and immunosuppressant activity have been demonstrated to inhibit IL-2,IL-4 and IL-5 (P. J. Barnes, Eur. Respir. J. 9 (1996) Suppl. 22, 154 and J. Schmidt et al., Europ. J. Pharm. 260 (1994), 247). Side effects such as an increase in intraocular pressure, increased susceptibility to infection, impairment of the hormonal control system (osteoporosis, growth retardation in children) can limit the use of glucocorticosteroids. Finally, cyclosporin A (CsA) has also been found to have an inhibitory effect on the three cytokines (B. Ryffel, Pharmacol. Rev. 41 (1989), 407). In this case various side effects have also been found (for example nephrotoxicity) (D. Faulds, K. L. Goa, P. Benfield, Drugs 45 (1993), 953).
The aim of this invention is to provide very active inhibitors of the cytokines interleukin-2, interleukin-4 and interleukin-5 and to produce pharmaceuticals for the treatment of disorders mediated by these cytokines.
Maduranic acid or madurahydroxylactone is a natural product obtained from
Actinomadura rubra
by fermentation (DD 285 614: W. F. Fleck, D. G. Strauss, J. Meyer, Z. Allg. Mikrobiol. 18 (1978) 368-398). The structure of this compound (Formula 1) was elucidated by Paulus and co-workers (E. F. Paulus, K. Dornberger, W. Werner, D. Fenske, Acta Cryst. C50 (1994) 2064-2067):
Antibacterial effects, preferentially on Gram-positive bacteria, have been described for this compound and its alkyl homologues (W. F. Fleck et al., Z. Allg. Mikrobiol. 18 (1978), 389).
In addition, the synthesis of some maduraphthalazine derivatives of Formula
for example with —R: —H, —CH
3
, —(CH
2
)
2
CH
3
, —(CH
2
)
2
OH, -phenyl and of Formula 3
for example with
R
1
═R
2
═R
3
═R
4
═—CH
3
,
R
1
═R
2
═R
3
═R
4
═—COCH
3
,
R
1
═R
2
═—H and R
3
═R
4
═—CH
3
,
R
1
═R
2
═—COCH
3
and R
3
═R
4
═—CH
3
,
R
1
═R
2
═R
4
═—H, and R
3
═—COOCH
3
have been described, and their antimicrobial potential on some Gram-positive bacteria and bacterial gyrase have been investigated (E. Roemer et al., 4
th
Int. Conf. on Chemical Synthesis of Antibiotics and Related Microbial Products, Nashville, USA, 1994).
DESCRIPTION OF THE INVENTION
It has now been surprisingly found that both the previously known and many novel maduraphthalazines are able to inhibit the action of the cytokines interleukin-2, interleukin-4 and interleukin-5. Accordingly, these compounds are of great importance for producing pharmaceuticals for the therapy of disorders mediated by these cytokines. Thus, for example, it has been demonstrated that the compounds according to the present invention can inhibit the migration of eosinophilic granulocytes into the tissue which is characteristic of the asthmatic late phase reaction.
The invention thus relates to a process for inhibiting the action of the cytokines interleukin-2, interleukin4, and interleukin-5, which comprises administering to a patient in need therefore a compound of Formula 4
wherein
R
1
is hydrogen, or branched-chain, or straight-chain C
1-12
alkyl residue optionally substituted one or m —NHC
6-14
aryl, —N(C
6-14
aryl)
2
, —N(C
1-6
alkyl)(C
6-14
aryl), —NHCOR
7
, —NO
2
, —CN, —F, —Cl —Br, —I, —O—C
1-6
alkyl, —O—C
6-14
aryl, —O(CO)R
7
, —S—C
1-6
-alkyl, —S—C
1-14
aryl, —SOR
8
, —SO
2
R
8
, —OSO
2
C
1-6
alkyl, —OSO
2
C
6-14
aryl, —(CS)R
7
, —O(CO)R
7
, —(CO)R
9
, a mono-, bi- or tricyclic saturated or mono- or polyunsaturated carbocycle with 3-14 ring members, mono-, bi- or tricyclic saturated or mono- or polyunsaturated heterocycle with 5-15 ring members and 1-6 heteroatoms, wherein the C
6-14
aryl groups and the included carbocylic and heterocyclic substituents can be optionally substituted one or more times by R
10
,
a mono- or polyunsaturated, straight-chain or branched-chain C
2-12
alkenyl residue optionally substituted one or more times by —OH, —SH, —NH
2
,—NHC
1-6
alkyl, —N(C
1-6
alkyl)
2
, —NHC
6-14
aryl, —N(C
6-14
aryl)
2
, —N(C
1-6
alkyl)(C
6-14
aryl), —NHCOR
7
, —NO
2
, —CN, —F, —Cl, —Br, —I, —O—C
1-6
alkyl, —O—C
6-14
-aryl, —O(CO)R
7
, —S—C
1-6
alkyl, —S—C
6-14
aryl, —SOR
8
, —SO
2
R
8
, —OSO
2
C
1-16
alkyl, —OSO
2
C
6-14
aryl, —(CS)R
7
, —O(CO)R
7
, —(CO)R
9
, mono-, bi- or tricyclic saturated or mono- or polyunsaturated carbocycle with 3-14 ring members, a mono-, bi- or tricyclic saturated or mono- or polyunsaturated heterocycle with 5-15 ring members and 1-6 heteroatoms, the C
6-14
aryl groups and the included carbocyclic and heterocyclic substituents can be optionally substituted one or more times by R
10
,
mono-, bi- or tricyclic saturated or mono- or polyunsaturated carbocycle with 3-14 ring members, optionally substituted one or more times by —OH, —SH, —NH
2
,—NH C
1-6
alkyl, —N(C
1-6
alkyl)
2
, —NHC
6-14
aryl, —N(C
6-14
aryl)
2
, —N(C
1-6
alkyl)(C
6-14
aryl), —NHCOR
7
, —NO
2
, —CN, —F, —Cl, —Br, —I, —O—C
1-6
-alkyl, —O—C
6-14
aryl, —O(CO)R
7
, —S—C
1-6
alkyl, —S—C
6-14
aryl, —SOR
8
, —SO
2
R
8
, —OSO
2
C
1-6
alkyl, —OSO
2
C
6-14
aryl, —(CS)R
7
, —O(CO)R
7
, —(CO)R
9
, the C
6-14
aryl groups can be optionally substituted one or more times by R
10
,
a mono-, bi- or tricyclic saturated or mono- or polyunsaturated heterocycle with 5-15 ring members and 1-6 heteroatoms, optionally substituted one or more times by —OH, —SH, —NH
2
, —NHC
1-6
alkyl, —N(C
1-6
alkyl)
2
, —NHC
6-14
aryl, —N(C
6-14
aryl)
2
, —N

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