3,6-dihydroxy-24-amidyl steroid derivatives

Details 3,6-dihydroxy-24-amidyl steroid derivatives 3,6-dihydroxy-24-amidyl steroid derivatives

2000-04-28

2003-11-11

Badio, Barbara P. (Department: 1616)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Cyclopentanohydrophenanthrene ring system doai

C552S553000, C552S554000

Reexamination Certificate

active

06645955

ABSTRACT:

BACKGROUND
Nuclear receptors are a family of transcription factors modulated by small hydrophobic signaling molecules, like steroids, thyroid hormone, free fatty acids, vitamin D and retinoids. Nuclear receptors are important pharmacological targets for drug intervention in disease management. For example, Tamoxifen, an estrogen antagonist, interacts with estrogen receptor to deliver its therapeutic effects on breast cancer; RU486, an antagonist of progesterone receptor, is used for termination of pregnancies and menopause-related disorders; and Dexamethasone interacts with glucocorticoid receptor to suppress immune system function and is useful for treating inflammatory diseases such as asthma.
Nuclear receptors have three independent domains I, II and III. Domains I and III modulate transcriptional activities by interacting with other factors of the transcription complex; Domain II involves in DNA-binding; and Domain III is the ligand-binding domain. Domain II is the most conserved region within the nuclear receptor family, with a unique feature of four pairs of cysteine chelated with two zinc atoms which form a “zinc finger” structure. The three domains of nuclear receptors are functionally interchangeable between different members. For example, the androgen receptor DNA-binding domain can be fused to the ligand-binding domain of estrogen receptor and the resulting AR-ER chimeric receptor can modulate androgen-responsive genes by binding to estrogen.
Amino acid sequence homology of the DNA-binding domain between members of nuclear receptor family allows identification of new members of this family through low stringency nucleotide-probe screening. Human genome project also facilitates identification of new genes coding for new nuclear receptors. At present, a few dozens of nuclear receptors have been identified and sequenced, but their ligands have yet to be identified. Recently, a novel nuclear receptor was cloned through degenerate oligonucleotide screening from human and rat cells and was named ubiquitous nuclear receptor (“UR”), because of its ubiquitous expression pattern in the body. UR has been found to form heterodimers with RXR receptors and binds to double-stranded DNA with the sequence motif: AGGTCANNNNAGGTCA (SEQ ID NO: 1) (“DR4”). Promoters containing DR4 can be activated by UR and RXR heterodimer in cultured cells.
LXRa, another new member of the nuclear receptor family has been cloned recently. Amino acid sequence analysis revealed that it shares over 80% homology with UR in the DNA- and ligand-binding domain. The expression of LXRa mRNA is limited to liver and a few other tissues. LXRa has been identified as a transcriptional activator of the cholesterol 7&agr;-hydroxylase gene and plays an important role in cholesterol catabolism.
Recently other nuclear proteins interacting with nuclear receptors have been identified through yeast two-hybrid screening techniques, among which are co-activators and co-repressors of nuclear receptors, e.g., SRC1, 2, 3, and Grip1. These proteins interact with nuclear receptors in a ligand-dependent manner. This property is useful to set up biochemical assays for ligand-receptor interaction.
Steroid derivatives described in this invention are found to modulate the transcriptional activities via binding to UR or LXRa, and thus can be used to treat disorders mediated by such receptors such as atherosclerosis.
SUMMARY
An aspect of this invention relates to steroid derivatives of formula (I):
R
3
is hydrogen, amino, carboxyl, oxo, halo, sulfonic acid, —O-sulfonic acid, or alkyl that is optionally inserted with —NH—, —N(alkyl)-, —O—, —S—, —SO—, —SO
2
—, —O—SO
2
—, —SO
2
—O—, —O—SO
3
—, —SO
3
—O—, —CO—, —CO—O—, —O—CO—, —CO—NH—, —CO—N(alkyl)-, —NH—CO—, or —N(alkyl)-CO—, and further optionally substituted with hydroxy, halo, amino, carboxyl, sulfonic acid, or —O—
0
sulfonic acid. Each of R
1
, R
2
, R
4
, R
4′
, R
6
, R
7
,R
11
, R
12
, R
15
, R
16
and R
17′
, independently, is hydrogen, hydroxy, amino, carboxyl, oxo, halo, sulfonic acid, —O-sulfonic acid, or alkyl that is optionally inserted with —NH—, —N(alkyl)-, —O—, —S—, —SO—, —SO
2
—, —O—SO
2
—, —SO
2
—O—, —O—SO
3
—, —SO
3
—O—, —CO—, —CO—O—, —O—CO—, —CO—NH—, —CO—N(alkyl)-, —NH—CO—, or —N(alkyl)-CO—, and further optionally substituted with hydroxy, halo, amino, carboxyl, sulfonic acid, or —O-sulfonic acid. Each of R
5
, R
8
, R
9
, R
10
, R
13
, and R
14
, independently, is hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxy, hydroxy, or amino. R
17
is —X—Y—Z. X is a bond, or alkyl or alkenyl, optionally inserted with —NH—, —N(alkyl)-, —O—, or —S—, and further optionally forming a cyclic moiety with R
16
and the 2 ring carbon atoms to which R
16
and R
17
are bonded. Y is —CO—, —SO—, —SO
2
—, —O—SO
2
—, —SO
2
—O—, —O—SO
3
—, —SO
3
—O—, —CO—O—, —O—CO—, —CO—NH—, —CO—N(alkyl)-, —NH—CO—, —N(alkyl)-CO—, or a bond. Z is alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, heteroaryl, aralkyl, or heteroaralkyl, and is optionally substituted with hydroxy, alkoxy, amino, halo, sulfonic acid, —O-sulfonic acid, carboxyl, oxo, alkyloxycarbonyl, alkylcarbonyloxy, alkylaminocarbonyl, alkylcarbonylamino, alkylcarbonyl, alkylsulfinyl, alkylsulfonyl, or alkylthio; or is —CH(A)—B. A being a side chain of an amino acid, and B is hydrogen, —NR
a
R
b
, or —COOR
c
wherein each of R
a
, R
b
, and R
c
, independently, is hydrogen or alkyl. n is 0, 1, or 2. Note that when Z is substituted with carboxyl or alkyloxycarbonyl, Y is a bond and either X or Z contains at least one double bond, and that when Y is a bond, either X is —NH-alkyl-, —NH-alkenyl-, —N(alkyl)-alkyl-, —N(alkyl)-alkenyl-, —O-alkyl-, —O-alkenyl-, —S-alkyl-, or —S-alkenyl-; or Z is substituted with halo, sulfonic acid, —O-sulfonic acid, alkylsulfinyl, or alkylsulfonyl, or is alkenyl.
Another aspect of this invention relates to steroid derivatives having the formula (I) as depicted above. Each of R
1
, R
2
, R
3
, R
4
, R
4′
, R
6
, R
7
, R
11
, R
12
, R
15
, R
16
, and R
17′
, independently, is hydrogen, hydroxy, amino, carboxyl, oxo, halo, sulfonic acid, —O-sulfonic acid, or alkyl that is optionally inserted with —NH—, —N(alkyl)-, —O—, —S—, —SO—, —SO
2
—, —O—SO
2
—, —SO
2
—O—, —O—SO
3
—, —SO
3
—O—, —CO—, —CO—O—, —O—CO—, —CO—NH—, —CO—N(alkyl)-, —NH—CO—, or —N(alkyl)-CO—, and further optionally substituted with hydroxy, halo, amino, carboxyl, sulfonic acid, or —O-sulfonic acid. Each of R
5
, R
8
, R
9
, R
10
, R
13
, and R
14
, independently, is hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxy, hydroxy, or amino. R
17
is —X—Y—Z. X is a bond, or alkyl or alkenyl, optionally inserted with —NH—, —N(alkyl)-, —O—, or —S—, and further optionally forming a cyclic moiety with R
16
and the 2 ring carbon atoms to which R
16
and R
17
are bonded. Y is —CO—, —SO—, —SO
2
—, —O—SO
2
—, —SO
2
—O—, —O—SO
3
—, —SO
3
—O—, —CO—O—, —O—CO—, —CO—NH—, —CO—N(alkyl)-, —NH—CO—, —N(alkyl)—CO-, or a bond. Z is alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, heteroaryl, aralkyl, or heteroaralkyl, and is optionally substituted with hydroxy, alkoxy, amino, halo, sulfonic acid, —O-sulfonic acid, carboxyl, oxo, alkyloxycarbonyl, alkylcarbonyloxy, alkylaminocarbonyl, alkylcarbonylamino, alkylcarbonyl, alkylsulfinyl, alkylsulfonyl, or alkylthio; or is —CH(A)—B. A is an amino acid side chain containing an aromatic moiety, and B is hydrogen, —NR
a
R
b
, or —COOR
c
wherein each of R
a
, R
b
, and R
c
, independently, is hydrogen or alkyl. n is 0, 1, or 2. Note that when Z is substituted with carboxyl or alkyloxycarbonyl, Y is a bond and either X or Z contains at least one double bond, and that when Y is a bond, either X is —NH-alkyl-, —NH-alkenyl-, —N(alkyl)-alkyl-, —N(alkyl)-alkenyl-, —O-alkyl-, —O-alkenyl-, —S-alkyl-, or —S-alkenyl-; or Z is substituted with halo, sulfonic acid, —O-sulfonic acid, alkylsulfinyl, or alkylsulfonyl, or is alkenyl.
A further aspect of this invention relates to steroid derivatives of formula (I), supra. Each of R
1
, R
2
, R
3
, R

Affiliated with

Also associated with

Rating

3,6-dihydroxy-24-amidyl steroid derivatives does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with 3,6-dihydroxy-24-amidyl steroid derivatives, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and 3,6-dihydroxy-24-amidyl steroid derivatives will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-3129814