Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-06-26
2003-11-04
Huang, Evelyn Mei (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S405000, C546S082000, C548S359500
Reexamination Certificate
active
06642249
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to immunomodulating compounds, pharmaceutical compositions comprising said compounds, use of said compound as well as a method for treatment of medical conditions which benefit from immunomodulation, wherein said compounds are administered.
BACKGROUND OF THE INVENTION
The immune system possesses the ability to control the homeostasis between the activation and inactivation of lymphocytes through various regulatory mechanisms during and after an immune response. Among these are mechanisms that specifically inhibit and/or turn off an immune response. Thus, when an antigen is presented by MHC molecules to the T-cell receptor, the T-cells become properly activated only in the presence of additional co-stimulatory signals. In the absence of accessory signals there is no lymphocyte activation and either a state of functional inactivation termed anergy or tolerance is induced, or the T-cell is specifically deleted by apoptosis.
One such co-stimulatory signal involves interaction of CD80 on specialised antigen-presenting cells with CD28 on T-cells, which has been demonstrated to be essential for full T-cell activation. (Lenschow et al. (1996) Annu. Rev. Immunol., 14, 233-258).
PRIOR ART
In U.S. Pat. No. 4,312,870 compound A is disclosed as one of several psychoactive compounds but without any biological data. Some related compounds are described by A. Carotti in Bioorganic & Medicinal Chemistry 6 (1998) 389-399, and from data related to these compounds it is obvious that the carboxylic acid substituent greatly diminishes biologic activity measured as affinity for the CNS benzodiazepine receptor.
EP 0354693A1 (Boots) discloses immunomodulatory compounds of general structure B but does not include structures wherein R7 and/or R8 are COOH or contain a COOH group.
Similarly EP 0354694A1 (Boots) discloses immunomodulatory compounds of general structure C but no structures wherein R6 and/or R7 are COOH or contain a COOH group are described.
Also, WO9111448 (Boots) discloses immunomodulatory compounds of general structure D but here are no structures wherein R7 and/or R8 and R8′ are COOH or contain a COOH group.
SUMMARY OF THE INVENTION
The present invention relates in a first aspect to a novel compound having the general formula (I)
wherein X represents a bond or a group selected from substituted or unsubstituted C
1-3
-alkyl, NH—C(O)—C
1-3
-alkyl, NH—C(O)—CH
2
—O—CH
2
or C(O)—NH— (amino acid residue);
Y represents NR4, O or S;
R1 represents H, halo, CF
3
, lower alkyl or lower alkoxy;
R2 and R4 represents independently H or lower alkyl; and
R3 represents H, halo, lower alkyl or lower alkoxy, wherein halo is F, Cl or Br;
wherein lower alkyl represents saturated or unsaturated, straight, branched or cyclic alkyl groups having 1-6 carbon atoms; and
wherein lower alkoxy represents saturated or unsaturated, straight, branched or cyclic alkoxy groups having 1-6 carbon atoms,
with the proviso that R2 is not H, when X is a bond and Y is NH and R3 is H,
or pharmaceutically acceptable salts thereof.
In one preferred embodiment of the invention the compound X is a bond and in another preferred embodiment Y is NH.
In further embodiments the compound is selected from the group comprising
{[3-(3-Oxo-3,5-dihydro-pyrazolo[4,3-c]quinolin-2-yl)-phenylcarbamoyl]-methoxy}-acetic acid,
N-[4-(3-Oxo-3,5-dihydro-pyrazolo[4,3-c]quinolin-2-yl)-phenyl]-succinamic acid,
4-[4-(3-Oxo-3,5-dihydro-pyrazolo[4,3-c]quinolin-2-yl)-phenylcarbamoyl]-butyric acid,
{[4-(3-Oxo-3,5-dihydro-pyrazolo[4,3-c]quinolin-2-yl)-phenylcarbamoyl]-methoxy}-acetic acid,
4-[4-(3-Oxo-3,5-dihydro-pyrazolo[4,3-c]quinolin-2-yl)-phenylcarbamoyl]-2-phenyl-butyric acid,
N-[3-(3-Oxo-3,5-dihydro-pyrazolo[4,3-c]quinolin-2-yl)-phenyl]-succinamic acid,
2-{[4-(3-Oxo-3,5-dihydro-pyrazolo[4,3-c]quinolin-2-yl)-phenylcarbamoyl]-methyl}-benzoic acid,
2-Chloro-4-(3-oxo-3,5-dihydro-pyrazolo[4,3-c]quinolin-2-yl)-benzoic acid,
4-(6,8-Dimethyl-3-oxo-3,5-dihydro-pyrazolo[4,3-c]quinolin-2-yl)-benzoic acid,
4-(8-Methoxy-6-methyl-3-oxo-3,5-dihydro-pyrazolo[4,3-c]quinolin-2-yl)-benzoic acid,
4-(6,8-Dimethoxy-3-oxo-3,5-dihydro-pyrazolo[4,3-c]quinolin-2-yl)-benzoic acid,
4-(7,9-Dimethoxy-3-oxo-3,5-dihydro-pyrazolo[4,3-c]quinolin-2-yl)-benzoic acid,
4-(6-Methyl-3-oxo-8-trifluoromethyl-3,5-dihydro-pyrazolo[4,3-c]quinolin-2-yl)-benzoic acid,
4-(7,9-Dichloro-3-oxo-3,5-dihydro-pyrazolo[4,3-c]quinolin-2-yl)-benzoic acid,
[4-(3-Oxo-3,5-dihydro-pyrazolo[4,3-c]quinolin-2-yl)-phenyl]-propionic acid,
[4-(3-Oxo-3,5-dihydro-pyrazolo[4,3-c]quinolin-2-yl)-phenyl]-acetic acid,
4-(4-Methyl-3-oxo-3H-chromeno[4,3-c]pyrazol-2-yl)-benzoic acid,
4-(3-Oxo-3H-thiochromeno[4,3-c]pyrazol-2-yl)benzoic acid,
4-(5-Methyl-3-oxo-3,5-dihydro-pyrazolo[4,3-c]quinolin-2-yl)-benzoic acid,
2-[4-(3-Oxo-3,5-dihydro-pyrazolo[4,3-c]quinolin-2-yl)-benzoylamino]-3-phenyl-propionic acid, and
2-[4-(3-Oxo-3,5-dihydro-pyrazolo[4,3-c]quinolin-2-yl)-benzoylamino]-2-acetic acid.
In yet another embodiment said compound is a CD80 antagonist, capable of inhibiting the interaction between CD80 and CD28.
The present invention relates in a second aspect to a compound as set forth above for use as a medicament.
In one preferred embodiment said compound is used as a medicament for treatment of medical conditions chosen from the group comprising rheumatoid arthritis, multiple sclerosis, diabetes, asthma, transplantation, systemic lupus erythematosis and psoriasis.
The present invention relates in a third aspect to a compound as set forth above for use as a prodrug, preferably in the form of an ester.
The present invention relates in a fourth aspect to a pharmaceutical composition comprising said compound as active ingredient in association with a pharmaceutically acceptable adjuvant, diluent or carrier.
In one prefered embodiment said pharmaceutical composition is used for treatment of medical conditions chosen from the group comprising rheumatoid arthritis, multiple sclerosis, diabetes, asthma, transplantation, systemic lupus erythematosis and psoriasis.
The present invention relates in a fifth aspect to the use of a compound having the general formula (I)
wherein X represents a bond or a group selected from substituted or unsubstituted C
1-3
-alkyl, NH—C(O)—C
1-3
-alkyl, NH—C(O)—CH
2
—O—CH
2
or C(O)—NH— (amino acid residue);
Y represents NR4, O or S;
R1 represents H, halo, CF
3
, lower alkyl or lower alkoxy;
R2 and R4 represents independently H or lower alkyl; and
R3 represents H, halo, lower alkyl or lower alkoxy,
wherein halo is F, Cl or Br;
wherein lower alkyl represents saturated or unsaturated, straight, branched or cyclic alkyl groups having 1-6 carbon atoms; and
wherein lower alkoxy represents saturated or unsaturated, straight, branched or cyclic alkoxy groups having 1-6 carbon atoms, or pharmaceutically acceptable salts thereof, for the manufacture of a medicament for treatment of medical conditions which benefit from immunomodulation.
In one embodiment said medical conditions are chosen from the group comprising rheumatoid arthritis, multiple sclerosis, diabetes, asthma, transplantation, systemic lupus erythematosis and psoriasis.
The present invention relates in a sixth aspect to a method for treatment of medical conditions which benefit from immunomodulation comprising administration of a therapeutically effective amount of a compound having the general formula (I)
wherein X represents a bond or a group selected from substituted or unsubstituted C
1-3
-alkyl, NH—C(O)—C
1-3
-alkyl, NH—C(O)—CH
2
—O—CH
2
or C(O)—NH— (amino acid residue);
Y represents NR4, O or S;
R1 represents H, halo, CF
3
, lower alkyl or lower alkoxy;
R2 and R4 represents independently H or lower alkyl; and
R3 represents H, halo, lower alk
Björk Per Axel
Fex Tomas
Pettersson Lars Olof Göran
Sørensen Pous
Thrige Dorthe Da Graça
Active Biotech AB
Burns Doane Swecker & Mathis L.L.P.
Huang Evelyn Mei
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