US 6,605,639 B1 · Ligands of nuclear receptor

Abstract

It has been newly found out that ascochlorin, which is a publicly known fat-soluble antibiotic, and its homologues serve as a ligand of retinoid X receptor and react in vivo with the amino group of serum protein to form Schiff bases without showing any side effect of retinoid. Ascochlorin and its homologues are usable in treating and/or preventing a disease or condition which can be relieved by the retinoid X receptor ligand-dependent gene transcriptional regulation (for example, diseases caused by the expression of insulin resistance, hypertension, cerebrovascular diseases, rheumatoid arthritis, autoimmune disease, Ca metabolic disorder, complication of diabetes, arteriosclerosis, etc.). Moreover, they can inhibit denaturation and/or necrosis of pancreatic Langerhans islet β-cells and, therefore, are usable in making these cells to sustain the insulin productivity.

Claims13

Dependent claims

A method for treating a disease or condition in a mammal which can be alleviated by the retinoid X receptor ligand (RXRL)-dependent regulation of gene transcription or inhibiting the infiltration of leukocytes into damaged arteries,

wherein said disease or condition in a mammal which can be alleviated by the RXRL-dependent regulation of gene transcription, is arteriosclerosis in a human induced by serum cholesterol;
wherein said method comprises:
administering to said mammal a compound capable of acting as a retinoid X receptor ligand or a pharmaceutically acceptable salt thereof in an amount effective for treating said disease or condition or inhibiting the infiltration of leukocytes into damaged arteries, together with a pharmaceutically acceptable additive, wherein said compound is selected from the group consisting of:
compounds of formula (1)
wherein
# R1 R2 R3 R4 R5 1 —CHO H H Cl H 2 —CHO H H Cl —OAc 3 —CHO H H Br H 4 —CHO H H H H 5 —CHO H CH3CO— Cl H 6 —CHO H —CH3 Cl H 7 —CHO —CH3 —CH3 Cl H 8 —CHO CH3CO— —CH3 Cl H 9 —CHO —CH3 CH3CO— Cl H 10 —CHO —CH3 H Cl H 11 —CHO H CH3CH2— Cl H 12 —CHO H allyl Cl H 13 —CHO H butyl Cl H 14 —CHO H —CH2COOH Cl H 15 —CHO H —(CH2)2COOH Cl H 16 —CHO H —(CH2)3COOH Cl H 17 —CHO H —(CH2)4COOH Cl H 18 —CHO H —CH2COOCH3 Cl H 19 —CHO H nicotinoyl Cl H 20 —CHO H benzoyl Cl H 21 —CHO H isonicotinoyl Cl H
compounds of formula (2)
wherein
# R1 R2 22 Cl H 23 H H 24 Cl —OH 25 Cl —OAc
a compound of formula (3)
a compound of formula (4)
a compound of formula (5)
compounds of formula (6)
wherein
# R1 R2 29 Cl H 30 Cl —CH3 31 Cl CH3CO— 32 H H 33 H —CH3 34 H CH3CO—
and compounds of formula (7)
wherein
# R1 R2 35 Cl H 36 Cl —CH3 37 Cl CH3CO— 38 H H 39 H —CH3 40 H CH3CO—.

15 more elements

wherein said disease or condition in a mammal which can be alleviated by the RXRL-dependent regulation of gene transcription, is arteriosclerosis by hypertension, cerebral angiopathy, arterial restenosis following percutaneous transluminal coronoary angioplasty, or arteriocapillary sclerosis, or arteriosclerosis in transplanted organs;
wherein said method comprises:
administering to said mammal a compound capable of acting as a retinoid X receptor ligand or a pharmaceutically acceptable salt thereof in an amount effective for treating said disease or condition or inhibiting the infiltration of leukocytes into damaged arteries, together with a pharmaceutically acceptable additive, wherein said compound is selected from the group consisting of:
compounds of formula (1)
wherein
# R1 R2 R3 R4 R5 1 —CHO H H Cl H 2 —CHO H H Cl —OAc 3 —CHO H H Br H 4 —CHO H H H H 5 —CHO H CH3CO— Cl H 6 —CHO H —CH3 Cl H 7 —CHO —CH3 —CH3 Cl H 8 —CHO CH3CO— —CH3 Cl H 9 —CHO —CH3 CH3CO— Cl H 10 —CHO —CH3 H Cl H 11 —CHO H CH3CH2— Cl H 12 —CHO H allyl Cl H 13 —CHO H butyl Cl H 14 —CHO H —CH2COOH Cl H 15 —CHO H —(CH2)2COOH Cl H 16 —CHO H —(CH2)3COOH Cl H 17 —CHO H —(CH2)4COOH Cl H 18 —CHO H —CH2COOCH3 Cl H 19 —CHO H nicotinoyl Cl H 20 —CHO H benzoyl Cl H 21 —CHO H isonicotinoyl Cl H
compounds of formula (2)
wherein
# R1 R2 22 Cl H 23 H H 24 Cl —OH 25 Cl —OAc
a compound of formula (3)
a compound of formula (4)
a compound of formula (5)
compounds of formula (6)
wherein
# R1 R2 29 Cl H 30 Cl —CH3 31 Cl CH3CO— 32 H H 33 H —CH3 34 H CH3CO—
and compounds of formula (7)
wherein
# R1 R2 35 Cl H 36 Cl —CH3 37 Cl CH3CO— 38 H H 39 H —CH3 40 H CH3CO—.

15 more elements

A method for treating a disease or condition in a mammal which can be alleviated by the RXRL-dependent regulation of gene transcription,

wherein said disease or condition which can be alleviated by the RXRL-dependent regulation of gene transcription is degeneration and/or necrosis of pancreatic Langerhans' islet β-cells;
wherein said method comprises:
administering to said human a compound capable of acting as a retinoid X receptor ligand or a pharmaceutically acceptable salt thereof in an amount effective for treating said disease or condition, together with a pharmaceutically acceptable additive, wherein said compound selected from the group consisting of:
wherein
# R1 R2 R3 R4 R5 1 —CHO H H Cl H 2 —CHO H H Cl —OAc 3 —CHO H H Br H 4 —CHO H H H H 5 —CHO H CH3CO— Cl H 6 —CHO H —CH3 Cl H 7 —CHO —CH3 —CH3 Cl H 8 —CHO CH3CO— —CH3 Cl H 9 —CHO —CH3 CH3CO— Cl H 10 —CHO —CH3 H Cl H 11 —CHO H CH3CH2— Cl H 12 —CHO H allyl Cl H 13 —CHO H butyl Cl H 14 —CHO H —CH2COOH Cl H 15 —CHO H —(CH2)2COOH Cl H 16 —CHO H —(CH2)3COOH Cl H 17 —CHO H —(CH2)4COOH Cl H 18 —CHO H —CH2COOCH3 Cl H 19 —CHO H nicotinoyl Cl H 20 —CHO H benzoyl Cl H 21 —CHO H isonicotinoyl Cl H
compounds of formula (2)
wherein
# R1 R2 22 Cl H 23 H H 24 Cl —OH 25 Cl —OAc
a compound of formula (3)
a compound of formula (4)
a compound of formula (5)
compounds of formula (6)
wherein
# R1 R2 29 Cl H 30 Cl —CH3 31 Cl CH3CO— 32 H H 33 H —CH3 34 H CH3CO—
and compounds of formula (7)
wherein
# R1 R2 35 Cl H 36 Cl —CH3 37 Cl CH3CO— 38 H H 39 H —CH3 40 H CH3CO—.

14 more elements

Dependencies are inferred from the claim text.

Ligands of nuclear receptor

Life of this patent

Ligands of nuclear receptor

Life of this patent

Abstract

Claims13